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/Title (Genetic Testing for CYP450 Polymorphisms to Predict Response to Clopidogrel: current evidence and test availability � PLOS Currents Evidence on Genomic Tests)
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BT 15.000 718.042 Td /F2 21.0 Tf  [(Genetic Testing for CYP450 Polymorphisms to Predict )] TJ ET
BT 15.000 693.094 Td /F2 21.0 Tf  [(Response to Clopidogrel: current evidence and test availability)] TJ ET
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BT 15.000 671.524 Td /F2 13.5 Tf  [(Application: Pharmacogenomics)] TJ ET
Q
BT 15.000 653.050 Td /F3 9.8 Tf  [(September 20, 2010)] TJ ET
BT 26.250 641.209 Td /F1 9.8 Tf  [(, )] TJ ET
BT 31.671 641.209 Td /F1 9.8 Tf  [(, )] TJ ET
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BT 37.092 641.209 Td /F1 9.8 Tf  [(Ren�e M. Ned)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 629.304 Td /F1 9.8 Tf  [(Ned RM. Genetic Testing for CYP450 Polymorphisms to Predict Response to Clopidogrel: current evidence and test )] TJ ET
BT 529.116 629.304 Td /F1 9.8 Tf  [(availability: )] TJ ET
BT 26.250 617.400 Td /F1 9.8 Tf  [(Application: Pharmacogenomics. PLOS Currents Evidence on Genomic Tests. 2010 Sep 20 . Edition 1. doi: )] TJ ET
BT 26.250 605.495 Td /F1 9.8 Tf  [(10.1371/currents.RRN1180.)] TJ ET
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BT 26.250 576.392 Td /F4 12.0 Tf  [(Abstract)] TJ ET
BT 26.250 556.438 Td /F1 9.8 Tf  [(The anti-platelet agent clopidogrel bisulfate \(sold under the trade name Plavix in the United States\) is a widely prescribed )] TJ ET
BT 26.250 544.533 Td /F1 9.8 Tf  [(medication for the prevention of blood clots in patients with acute coronary syndrome, in those who have suffered other )] TJ ET
BT 26.250 532.629 Td /F1 9.8 Tf  [(cardiovascular disease-related events such as ischemic stroke, and in patients who are undergoing percutaneous coronary )] TJ ET
BT 26.250 520.724 Td /F1 9.8 Tf  [(intervention. Response to clopidogrel varies substantially due to genetic and acquired factors. Patients who experience )] TJ ET
BT 26.250 508.819 Td /F1 9.8 Tf  [(recurrent cardiovascular ischemic or thrombotic events while taking clopidogrel are typically described as non-responsive or )] TJ ET
BT 26.250 496.914 Td /F1 9.8 Tf  [(resistant.)] TJ ET
BT 26.250 477.510 Td /F1 9.8 Tf  [(The drug�s oxidation is mainly dependent on the cytochrome P450 enzyme 2C19 \(CYP2C19\). Patients with certain genetic )] TJ ET
BT 26.250 465.605 Td /F1 9.8 Tf  [(variants in CYP2C19 have been found to have lower levels of the active metabolite, less platelet inhibition, and greater risk of )] TJ ET
BT 26.250 453.700 Td /F1 9.8 Tf  [(major adverse cardiovascular events such as heart attack, stroke, and death. Testing for CYP2C19 polymorphisms may identify )] TJ ET
BT 26.250 441.795 Td /F1 9.8 Tf  [(patients who will not respond adequately to the standard clopidogrel regimen and who should, consequently, be given an )] TJ ET
BT 26.250 429.891 Td /F1 9.8 Tf  [(alternate treatment strategy. This article outlines the evidence concerning pharmacogenetic testing for clopidogrel response, )] TJ ET
BT 26.250 417.986 Td /F1 9.8 Tf  [(including data on clinical validity and clinical utility, and summarizes the currently available tests marketed for this purpose.)] TJ ET
BT 26.250 381.383 Td /F4 12.0 Tf  [(Clinical Scenario)] TJ ET
BT 26.250 361.429 Td /F1 9.8 Tf  [(Pharmacogenetic testing to identify patients at risk of an inadequate response to the standard clopidogrel regimen so that )] TJ ET
BT 26.250 349.524 Td /F1 9.8 Tf  [(alternate treatment strategies can be initiated, with the goal of preventing adverse cardiovascular events such as stent )] TJ ET
BT 26.250 337.620 Td /F1 9.8 Tf  [(thromboses, recurrent ischemic events, and death.)] TJ ET
BT 26.250 318.215 Td /F4 9.8 Tf  [(Test Description)] TJ ET
BT 26.250 298.810 Td /F1 9.8 Tf  [(Genetic polymorphisms in several genes \(e.g., )] TJ ET
BT 229.450 298.810 Td /F5 9.8 Tf  [(CYP1A2)] TJ ET
BT 266.841 298.810 Td /F1 9.8 Tf  [( , )] TJ ET
BT 274.972 298.810 Td /F5 9.8 Tf  [(CYP3A4)] TJ ET
BT 312.364 298.810 Td /F1 9.8 Tf  [( , and )] TJ ET
BT 339.469 298.810 Td /F5 9.8 Tf  [(CYP3A5)] TJ ET
BT 376.860 298.810 Td /F1 9.8 Tf  [( \) have been studied for an association with )] TJ ET
BT 26.250 286.905 Td /F1 9.8 Tf  [(antiplatelet response and clinical outcomes in those taking clopidogrel. However, despite the many enzymes known to be )] TJ ET
BT 26.250 275.001 Td /F1 9.8 Tf  [(involved in the metabolism of clopidogrel, only genetic variation in )] TJ ET
BT 311.827 275.001 Td /F5 9.8 Tf  [(CYP2C19)] TJ ET
BT 355.176 275.001 Td /F1 9.8 Tf  [( has been consistently and significantly associated )] TJ ET
BT 26.250 263.096 Td /F1 9.8 Tf  [(with clopidogrel response in multiple populations )] TJ ET
0.267 0.267 0.267 rg
BT 238.127 263.096 Td /F1 9.8 Tf  [([1])] TJ ET
BT 248.969 263.096 Td /F1 9.8 Tf  [([2])] TJ ET
BT 259.811 263.096 Td /F1 9.8 Tf  [([3])] TJ ET
0.271 0.267 0.267 rg
BT 270.653 263.096 Td /F1 9.8 Tf  [( .)] TJ ET
BT 26.250 243.691 Td /F1 9.8 Tf  [(The numerous commercial pharmacogenetic tests that are available genotype variants in )] TJ ET
BT 412.077 243.691 Td /F5 9.8 Tf  [(CYP2C19)] TJ ET
BT 455.425 243.691 Td /F1 9.8 Tf  [( for the purpose of )] TJ ET
BT 26.250 231.786 Td /F1 9.8 Tf  [(predicting response to clopidogrel \(see Table 1\). These tests differ in genotyping methodology, sample type required, and )] TJ ET
BT 26.250 219.882 Td /F1 9.8 Tf  [(availability \(direct-to-consumer or physician-ordered\). However, all tests include, at a minimum, the most common alleles \(*1, )] TJ ET
BT 26.250 207.977 Td /F1 9.8 Tf  [(and loss-of-function alleles *2 and *3\), which have been shown to account for most of the variability in response to clopidogrel )] TJ ET
0.267 0.267 0.267 rg
BT 569.793 207.977 Td /F1 9.8 Tf  [([1])] TJ ET
BT 26.250 196.072 Td /F1 9.8 Tf  [([2])] TJ ET
0.271 0.267 0.267 rg
BT 37.092 196.072 Td /F1 9.8 Tf  [( . Some tests also include other identified reduced-function variants \(named *4, *5, *6, *7, *8, *9, and *10\). A newer allele, )] TJ ET
BT 26.250 184.167 Td /F5 9.8 Tf  [(CYP2C19*17)] TJ ET
BT 84.233 184.167 Td /F1 9.8 Tf  [( , has been described that is associated with increased enzymatic activity and ultra-rapid drug metabolism )] TJ ET
0.267 0.267 0.267 rg
BT 542.668 184.167 Td /F1 9.8 Tf  [([4])] TJ ET
BT 553.510 184.167 Td /F1 9.8 Tf  [([5])] TJ ET
0.271 0.267 0.267 rg
BT 564.352 184.167 Td /F1 9.8 Tf  [( , )] TJ ET
BT 26.250 172.263 Td /F1 9.8 Tf  [(which in turn is predicted to result in higher levels of the active metabolite of clopidogrel.)] TJ ET
BT 26.250 152.858 Td /F1 9.8 Tf  [(Each test includes:)] TJ ET
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39.522 137.943 39.078 138.127 38.631 138.127 c
38.185 138.127 37.741 137.943 37.425 137.627 c
37.109 137.311 36.925 136.867 36.925 136.421 c
36.925 135.974 37.109 135.530 37.425 135.214 c
37.741 134.898 38.185 134.715 38.631 134.715 c
39.078 134.715 39.522 134.898 39.838 135.214 c
40.154 135.530 40.337 135.974 40.337 136.421 c f
BT 45.750 133.453 Td /F1 9.8 Tf  [(Analysis of multiple single nucleotide polymorphisms in CYP2C19.)] TJ ET
40.337 120.766 m 
40.337 121.213 40.154 121.657 39.838 121.973 c
39.522 122.288 39.078 122.472 38.631 122.472 c
38.185 122.472 37.741 122.288 37.425 121.973 c
37.109 121.657 36.925 121.213 36.925 120.766 c
36.925 120.319 37.109 119.875 37.425 119.559 c
37.741 119.244 38.185 119.060 38.631 119.060 c
39.078 119.060 39.522 119.244 39.838 119.559 c
40.154 119.875 40.337 120.319 40.337 120.766 c f
BT 45.750 117.798 Td /F1 9.8 Tf  [(Genotype-based prediction of CYP2C19 enzymatic activity to categorize patients as: )] TJ ET
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59.022 106.634 58.578 106.818 58.131 106.818 c
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56.609 106.002 56.425 105.558 56.425 105.111 c
56.425 104.665 56.609 104.221 56.925 103.905 c
57.241 103.589 57.685 103.405 58.131 103.405 c
58.578 103.405 59.022 103.589 59.338 103.905 c
59.654 104.221 59.837 104.665 59.837 105.111 c s
BT 65.250 102.144 Td /F1 9.8 Tf  [(Extensive metabolizers [carrying two �normal� alleles \(i.e., *1/*1\)].)] TJ ET
0.39 w 1 J 1 j
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59.837 89.903 59.654 90.347 59.338 90.663 c
59.022 90.979 58.578 91.163 58.131 91.163 c
57.685 91.163 57.241 90.979 56.925 90.663 c
56.609 90.347 56.425 89.903 56.425 89.457 c
56.425 89.010 56.609 88.566 56.925 88.250 c
57.241 87.934 57.685 87.750 58.131 87.750 c
58.578 87.750 59.022 87.934 59.338 88.250 c
59.654 88.566 59.837 89.010 59.837 89.457 c s
BT 65.250 86.489 Td /F1 9.8 Tf  [(Intermediate metabolizers [carrying one reduced-function allele \(e.g., *1/*2\)].)] TJ ET
0.39 w 1 J 1 j
59.837 73.802 m 
59.837 74.248 59.654 74.692 59.338 75.008 c
59.022 75.324 58.578 75.508 58.131 75.508 c
57.685 75.508 57.241 75.324 56.925 75.008 c
56.609 74.692 56.425 74.248 56.425 73.802 c
56.425 73.355 56.609 72.911 56.925 72.595 c
57.241 72.279 57.685 72.095 58.131 72.095 c
58.578 72.095 59.022 72.279 59.338 72.595 c
59.654 72.911 59.837 73.355 59.837 73.802 c s
BT 65.250 70.834 Td /F1 9.8 Tf  [(Poor metabolizers [carrying two reduced-function alleles \(e.g., *2/*2 or *2/*3\)].)] TJ ET
0.39 w 1 J 1 j
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59.837 58.594 59.654 59.038 59.338 59.354 c
59.022 59.669 58.578 59.853 58.131 59.853 c
57.685 59.853 57.241 59.669 56.925 59.354 c
56.609 59.038 56.425 58.594 56.425 58.147 c
56.425 57.700 56.609 57.256 56.925 56.940 c
57.241 56.625 57.685 56.441 58.131 56.441 c
58.578 56.441 59.022 56.625 59.338 56.940 c
59.654 57.256 59.837 57.700 59.837 58.147 c s
BT 65.250 55.179 Td /F1 9.8 Tf  [(Ultra-rapid metabolizers [carrying one or two increased-function alleles \(i.e., *1/*17 or *17/*17\), though it is not clear )] TJ ET
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15.000 662.316 577.500 75.684 re W n
0.267 0.267 0.267 rg
BT 15.000 718.042 Td /F2 21.0 Tf  [(Genetic Testing for CYP450 Polymorphisms to Predict )] TJ ET
BT 15.000 693.094 Td /F2 21.0 Tf  [(Response to Clopidogrel: current evidence and test availability)] TJ ET
0.271 0.267 0.267 rg
BT 15.000 671.524 Td /F2 13.5 Tf  [(Application: Pharmacogenomics)] TJ ET
Q
BT 15.000 653.050 Td /F3 9.8 Tf  [(September 20, 2010)] TJ ET
BT 26.250 641.209 Td /F1 9.8 Tf  [(, )] TJ ET
BT 31.671 641.209 Td /F1 9.8 Tf  [(, )] TJ ET
0.267 0.267 0.267 rg
BT 37.092 641.209 Td /F1 9.8 Tf  [(Ren�e M. Ned)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 629.304 Td /F1 9.8 Tf  [(Ned RM. Genetic Testing for CYP450 Polymorphisms to Predict Response to Clopidogrel: current evidence and test )] TJ ET
BT 529.116 629.304 Td /F1 9.8 Tf  [(availability: )] TJ ET
BT 26.250 617.400 Td /F1 9.8 Tf  [(Application: Pharmacogenomics. PLOS Currents Evidence on Genomic Tests. 2010 Sep 20 . Edition 1. doi: )] TJ ET
BT 26.250 605.495 Td /F1 9.8 Tf  [(10.1371/currents.RRN1180.)] TJ ET
q
15.000 40.894 577.500 562.220 re W n
0.271 0.267 0.267 rg
BT 26.250 576.392 Td /F4 12.0 Tf  [(Abstract)] TJ ET
BT 26.250 556.438 Td /F1 9.8 Tf  [(The anti-platelet agent clopidogrel bisulfate \(sold under the trade name Plavix in the United States\) is a widely prescribed )] TJ ET
BT 26.250 544.533 Td /F1 9.8 Tf  [(medication for the prevention of blood clots in patients with acute coronary syndrome, in those who have suffered other )] TJ ET
BT 26.250 532.629 Td /F1 9.8 Tf  [(cardiovascular disease-related events such as ischemic stroke, and in patients who are undergoing percutaneous coronary )] TJ ET
BT 26.250 520.724 Td /F1 9.8 Tf  [(intervention. Response to clopidogrel varies substantially due to genetic and acquired factors. Patients who experience )] TJ ET
BT 26.250 508.819 Td /F1 9.8 Tf  [(recurrent cardiovascular ischemic or thrombotic events while taking clopidogrel are typically described as non-responsive or )] TJ ET
BT 26.250 496.914 Td /F1 9.8 Tf  [(resistant.)] TJ ET
BT 26.250 477.510 Td /F1 9.8 Tf  [(The drug�s oxidation is mainly dependent on the cytochrome P450 enzyme 2C19 \(CYP2C19\). Patients with certain genetic )] TJ ET
BT 26.250 465.605 Td /F1 9.8 Tf  [(variants in CYP2C19 have been found to have lower levels of the active metabolite, less platelet inhibition, and greater risk of )] TJ ET
BT 26.250 453.700 Td /F1 9.8 Tf  [(major adverse cardiovascular events such as heart attack, stroke, and death. Testing for CYP2C19 polymorphisms may identify )] TJ ET
BT 26.250 441.795 Td /F1 9.8 Tf  [(patients who will not respond adequately to the standard clopidogrel regimen and who should, consequently, be given an )] TJ ET
BT 26.250 429.891 Td /F1 9.8 Tf  [(alternate treatment strategy. This article outlines the evidence concerning pharmacogenetic testing for clopidogrel response, )] TJ ET
BT 26.250 417.986 Td /F1 9.8 Tf  [(including data on clinical validity and clinical utility, and summarizes the currently available tests marketed for this purpose.)] TJ ET
BT 26.250 381.383 Td /F4 12.0 Tf  [(Clinical Scenario)] TJ ET
BT 26.250 361.429 Td /F1 9.8 Tf  [(Pharmacogenetic testing to identify patients at risk of an inadequate response to the standard clopidogrel regimen so that )] TJ ET
BT 26.250 349.524 Td /F1 9.8 Tf  [(alternate treatment strategies can be initiated, with the goal of preventing adverse cardiovascular events such as stent )] TJ ET
BT 26.250 337.620 Td /F1 9.8 Tf  [(thromboses, recurrent ischemic events, and death.)] TJ ET
BT 26.250 318.215 Td /F4 9.8 Tf  [(Test Description)] TJ ET
BT 26.250 298.810 Td /F1 9.8 Tf  [(Genetic polymorphisms in several genes \(e.g., )] TJ ET
BT 229.450 298.810 Td /F5 9.8 Tf  [(CYP1A2)] TJ ET
BT 266.841 298.810 Td /F1 9.8 Tf  [( , )] TJ ET
BT 274.972 298.810 Td /F5 9.8 Tf  [(CYP3A4)] TJ ET
BT 312.364 298.810 Td /F1 9.8 Tf  [( , and )] TJ ET
BT 339.469 298.810 Td /F5 9.8 Tf  [(CYP3A5)] TJ ET
BT 376.860 298.810 Td /F1 9.8 Tf  [( \) have been studied for an association with )] TJ ET
BT 26.250 286.905 Td /F1 9.8 Tf  [(antiplatelet response and clinical outcomes in those taking clopidogrel. However, despite the many enzymes known to be )] TJ ET
BT 26.250 275.001 Td /F1 9.8 Tf  [(involved in the metabolism of clopidogrel, only genetic variation in )] TJ ET
BT 311.827 275.001 Td /F5 9.8 Tf  [(CYP2C19)] TJ ET
BT 355.176 275.001 Td /F1 9.8 Tf  [( has been consistently and significantly associated )] TJ ET
BT 26.250 263.096 Td /F1 9.8 Tf  [(with clopidogrel response in multiple populations )] TJ ET
0.267 0.267 0.267 rg
BT 238.127 263.096 Td /F1 9.8 Tf  [([1])] TJ ET
BT 248.969 263.096 Td /F1 9.8 Tf  [([2])] TJ ET
BT 259.811 263.096 Td /F1 9.8 Tf  [([3])] TJ ET
0.271 0.267 0.267 rg
BT 270.653 263.096 Td /F1 9.8 Tf  [( .)] TJ ET
BT 26.250 243.691 Td /F1 9.8 Tf  [(The numerous commercial pharmacogenetic tests that are available genotype variants in )] TJ ET
BT 412.077 243.691 Td /F5 9.8 Tf  [(CYP2C19)] TJ ET
BT 455.425 243.691 Td /F1 9.8 Tf  [( for the purpose of )] TJ ET
BT 26.250 231.786 Td /F1 9.8 Tf  [(predicting response to clopidogrel \(see Table 1\). These tests differ in genotyping methodology, sample type required, and )] TJ ET
BT 26.250 219.882 Td /F1 9.8 Tf  [(availability \(direct-to-consumer or physician-ordered\). However, all tests include, at a minimum, the most common alleles \(*1, )] TJ ET
BT 26.250 207.977 Td /F1 9.8 Tf  [(and loss-of-function alleles *2 and *3\), which have been shown to account for most of the variability in response to clopidogrel )] TJ ET
0.267 0.267 0.267 rg
BT 569.793 207.977 Td /F1 9.8 Tf  [([1])] TJ ET
BT 26.250 196.072 Td /F1 9.8 Tf  [([2])] TJ ET
0.271 0.267 0.267 rg
BT 37.092 196.072 Td /F1 9.8 Tf  [( . Some tests also include other identified reduced-function variants \(named *4, *5, *6, *7, *8, *9, and *10\). A newer allele, )] TJ ET
BT 26.250 184.167 Td /F5 9.8 Tf  [(CYP2C19*17)] TJ ET
BT 84.233 184.167 Td /F1 9.8 Tf  [( , has been described that is associated with increased enzymatic activity and ultra-rapid drug metabolism )] TJ ET
0.267 0.267 0.267 rg
BT 542.668 184.167 Td /F1 9.8 Tf  [([4])] TJ ET
BT 553.510 184.167 Td /F1 9.8 Tf  [([5])] TJ ET
0.271 0.267 0.267 rg
BT 564.352 184.167 Td /F1 9.8 Tf  [( , )] TJ ET
BT 26.250 172.263 Td /F1 9.8 Tf  [(which in turn is predicted to result in higher levels of the active metabolite of clopidogrel.)] TJ ET
BT 26.250 152.858 Td /F1 9.8 Tf  [(Each test includes:)] TJ ET
0.271 0.267 0.267 RG
40.337 136.421 m 
40.337 136.867 40.154 137.311 39.838 137.627 c
39.522 137.943 39.078 138.127 38.631 138.127 c
38.185 138.127 37.741 137.943 37.425 137.627 c
37.109 137.311 36.925 136.867 36.925 136.421 c
36.925 135.974 37.109 135.530 37.425 135.214 c
37.741 134.898 38.185 134.715 38.631 134.715 c
39.078 134.715 39.522 134.898 39.838 135.214 c
40.154 135.530 40.337 135.974 40.337 136.421 c f
BT 45.750 133.453 Td /F1 9.8 Tf  [(Analysis of multiple single nucleotide polymorphisms in CYP2C19.)] TJ ET
40.337 120.766 m 
40.337 121.213 40.154 121.657 39.838 121.973 c
39.522 122.288 39.078 122.472 38.631 122.472 c
38.185 122.472 37.741 122.288 37.425 121.973 c
37.109 121.657 36.925 121.213 36.925 120.766 c
36.925 120.319 37.109 119.875 37.425 119.559 c
37.741 119.244 38.185 119.060 38.631 119.060 c
39.078 119.060 39.522 119.244 39.838 119.559 c
40.154 119.875 40.337 120.319 40.337 120.766 c f
BT 45.750 117.798 Td /F1 9.8 Tf  [(Genotype-based prediction of CYP2C19 enzymatic activity to categorize patients as: )] TJ ET
0.39 w 1 J 1 j
59.837 105.111 m 
59.837 105.558 59.654 106.002 59.338 106.318 c
59.022 106.634 58.578 106.818 58.131 106.818 c
57.685 106.818 57.241 106.634 56.925 106.318 c
56.609 106.002 56.425 105.558 56.425 105.111 c
56.425 104.665 56.609 104.221 56.925 103.905 c
57.241 103.589 57.685 103.405 58.131 103.405 c
58.578 103.405 59.022 103.589 59.338 103.905 c
59.654 104.221 59.837 104.665 59.837 105.111 c s
BT 65.250 102.144 Td /F1 9.8 Tf  [(Extensive metabolizers [carrying two �normal� alleles \(i.e., *1/*1\)].)] TJ ET
0.39 w 1 J 1 j
59.837 89.457 m 
59.837 89.903 59.654 90.347 59.338 90.663 c
59.022 90.979 58.578 91.163 58.131 91.163 c
57.685 91.163 57.241 90.979 56.925 90.663 c
56.609 90.347 56.425 89.903 56.425 89.457 c
56.425 89.010 56.609 88.566 56.925 88.250 c
57.241 87.934 57.685 87.750 58.131 87.750 c
58.578 87.750 59.022 87.934 59.338 88.250 c
59.654 88.566 59.837 89.010 59.837 89.457 c s
BT 65.250 86.489 Td /F1 9.8 Tf  [(Intermediate metabolizers [carrying one reduced-function allele \(e.g., *1/*2\)].)] TJ ET
0.39 w 1 J 1 j
59.837 73.802 m 
59.837 74.248 59.654 74.692 59.338 75.008 c
59.022 75.324 58.578 75.508 58.131 75.508 c
57.685 75.508 57.241 75.324 56.925 75.008 c
56.609 74.692 56.425 74.248 56.425 73.802 c
56.425 73.355 56.609 72.911 56.925 72.595 c
57.241 72.279 57.685 72.095 58.131 72.095 c
58.578 72.095 59.022 72.279 59.338 72.595 c
59.654 72.911 59.837 73.355 59.837 73.802 c s
BT 65.250 70.834 Td /F1 9.8 Tf  [(Poor metabolizers [carrying two reduced-function alleles \(e.g., *2/*2 or *2/*3\)].)] TJ ET
0.39 w 1 J 1 j
59.837 58.147 m 
59.837 58.594 59.654 59.038 59.338 59.354 c
59.022 59.669 58.578 59.853 58.131 59.853 c
57.685 59.853 57.241 59.669 56.925 59.354 c
56.609 59.038 56.425 58.594 56.425 58.147 c
56.425 57.700 56.609 57.256 56.925 56.940 c
57.241 56.625 57.685 56.441 58.131 56.441 c
58.578 56.441 59.022 56.625 59.338 56.940 c
59.654 57.256 59.837 57.700 59.837 58.147 c s
BT 65.250 55.179 Td /F1 9.8 Tf  [(Ultra-rapid metabolizers [carrying one or two increased-function alleles \(i.e., *1/*17 or *17/*17\), though it is not clear )] TJ ET
Q
q
15.000 662.316 577.500 75.684 re W n
0.267 0.267 0.267 rg
BT 15.000 718.042 Td /F2 21.0 Tf  [(Genetic Testing for CYP450 Polymorphisms to Predict )] TJ ET
BT 15.000 693.094 Td /F2 21.0 Tf  [(Response to Clopidogrel: current evidence and test availability)] TJ ET
0.271 0.267 0.267 rg
BT 15.000 671.524 Td /F2 13.5 Tf  [(Application: Pharmacogenomics)] TJ ET
Q
BT 15.000 653.050 Td /F3 9.8 Tf  [(September 20, 2010)] TJ ET
BT 26.250 641.209 Td /F1 9.8 Tf  [(, )] TJ ET
BT 31.671 641.209 Td /F1 9.8 Tf  [(, )] TJ ET
0.267 0.267 0.267 rg
BT 37.092 641.209 Td /F1 9.8 Tf  [(Ren�e M. Ned)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 629.304 Td /F1 9.8 Tf  [(Ned RM. Genetic Testing for CYP450 Polymorphisms to Predict Response to Clopidogrel: current evidence and test )] TJ ET
BT 529.116 629.304 Td /F1 9.8 Tf  [(availability: )] TJ ET
BT 26.250 617.400 Td /F1 9.8 Tf  [(Application: Pharmacogenomics. PLOS Currents Evidence on Genomic Tests. 2010 Sep 20 . Edition 1. doi: )] TJ ET
BT 26.250 605.495 Td /F1 9.8 Tf  [(10.1371/currents.RRN1180.)] TJ ET
q
15.000 40.894 577.500 562.220 re W n
0.271 0.267 0.267 rg
BT 26.250 576.392 Td /F4 12.0 Tf  [(Abstract)] TJ ET
BT 26.250 556.438 Td /F1 9.8 Tf  [(The anti-platelet agent clopidogrel bisulfate \(sold under the trade name Plavix in the United States\) is a widely prescribed )] TJ ET
BT 26.250 544.533 Td /F1 9.8 Tf  [(medication for the prevention of blood clots in patients with acute coronary syndrome, in those who have suffered other )] TJ ET
BT 26.250 532.629 Td /F1 9.8 Tf  [(cardiovascular disease-related events such as ischemic stroke, and in patients who are undergoing percutaneous coronary )] TJ ET
BT 26.250 520.724 Td /F1 9.8 Tf  [(intervention. Response to clopidogrel varies substantially due to genetic and acquired factors. Patients who experience )] TJ ET
BT 26.250 508.819 Td /F1 9.8 Tf  [(recurrent cardiovascular ischemic or thrombotic events while taking clopidogrel are typically described as non-responsive or )] TJ ET
BT 26.250 496.914 Td /F1 9.8 Tf  [(resistant.)] TJ ET
BT 26.250 477.510 Td /F1 9.8 Tf  [(The drug�s oxidation is mainly dependent on the cytochrome P450 enzyme 2C19 \(CYP2C19\). Patients with certain genetic )] TJ ET
BT 26.250 465.605 Td /F1 9.8 Tf  [(variants in CYP2C19 have been found to have lower levels of the active metabolite, less platelet inhibition, and greater risk of )] TJ ET
BT 26.250 453.700 Td /F1 9.8 Tf  [(major adverse cardiovascular events such as heart attack, stroke, and death. Testing for CYP2C19 polymorphisms may identify )] TJ ET
BT 26.250 441.795 Td /F1 9.8 Tf  [(patients who will not respond adequately to the standard clopidogrel regimen and who should, consequently, be given an )] TJ ET
BT 26.250 429.891 Td /F1 9.8 Tf  [(alternate treatment strategy. This article outlines the evidence concerning pharmacogenetic testing for clopidogrel response, )] TJ ET
BT 26.250 417.986 Td /F1 9.8 Tf  [(including data on clinical validity and clinical utility, and summarizes the currently available tests marketed for this purpose.)] TJ ET
BT 26.250 381.383 Td /F4 12.0 Tf  [(Clinical Scenario)] TJ ET
BT 26.250 361.429 Td /F1 9.8 Tf  [(Pharmacogenetic testing to identify patients at risk of an inadequate response to the standard clopidogrel regimen so that )] TJ ET
BT 26.250 349.524 Td /F1 9.8 Tf  [(alternate treatment strategies can be initiated, with the goal of preventing adverse cardiovascular events such as stent )] TJ ET
BT 26.250 337.620 Td /F1 9.8 Tf  [(thromboses, recurrent ischemic events, and death.)] TJ ET
BT 26.250 318.215 Td /F4 9.8 Tf  [(Test Description)] TJ ET
BT 26.250 298.810 Td /F1 9.8 Tf  [(Genetic polymorphisms in several genes \(e.g., )] TJ ET
BT 229.450 298.810 Td /F5 9.8 Tf  [(CYP1A2)] TJ ET
BT 266.841 298.810 Td /F1 9.8 Tf  [( , )] TJ ET
BT 274.972 298.810 Td /F5 9.8 Tf  [(CYP3A4)] TJ ET
BT 312.364 298.810 Td /F1 9.8 Tf  [( , and )] TJ ET
BT 339.469 298.810 Td /F5 9.8 Tf  [(CYP3A5)] TJ ET
BT 376.860 298.810 Td /F1 9.8 Tf  [( \) have been studied for an association with )] TJ ET
BT 26.250 286.905 Td /F1 9.8 Tf  [(antiplatelet response and clinical outcomes in those taking clopidogrel. However, despite the many enzymes known to be )] TJ ET
BT 26.250 275.001 Td /F1 9.8 Tf  [(involved in the metabolism of clopidogrel, only genetic variation in )] TJ ET
BT 311.827 275.001 Td /F5 9.8 Tf  [(CYP2C19)] TJ ET
BT 355.176 275.001 Td /F1 9.8 Tf  [( has been consistently and significantly associated )] TJ ET
BT 26.250 263.096 Td /F1 9.8 Tf  [(with clopidogrel response in multiple populations )] TJ ET
0.267 0.267 0.267 rg
BT 238.127 263.096 Td /F1 9.8 Tf  [([1])] TJ ET
BT 248.969 263.096 Td /F1 9.8 Tf  [([2])] TJ ET
BT 259.811 263.096 Td /F1 9.8 Tf  [([3])] TJ ET
0.271 0.267 0.267 rg
BT 270.653 263.096 Td /F1 9.8 Tf  [( .)] TJ ET
BT 26.250 243.691 Td /F1 9.8 Tf  [(The numerous commercial pharmacogenetic tests that are available genotype variants in )] TJ ET
BT 412.077 243.691 Td /F5 9.8 Tf  [(CYP2C19)] TJ ET
BT 455.425 243.691 Td /F1 9.8 Tf  [( for the purpose of )] TJ ET
BT 26.250 231.786 Td /F1 9.8 Tf  [(predicting response to clopidogrel \(see Table 1\). These tests differ in genotyping methodology, sample type required, and )] TJ ET
BT 26.250 219.882 Td /F1 9.8 Tf  [(availability \(direct-to-consumer or physician-ordered\). However, all tests include, at a minimum, the most common alleles \(*1, )] TJ ET
BT 26.250 207.977 Td /F1 9.8 Tf  [(and loss-of-function alleles *2 and *3\), which have been shown to account for most of the variability in response to clopidogrel )] TJ ET
0.267 0.267 0.267 rg
BT 569.793 207.977 Td /F1 9.8 Tf  [([1])] TJ ET
BT 26.250 196.072 Td /F1 9.8 Tf  [([2])] TJ ET
0.271 0.267 0.267 rg
BT 37.092 196.072 Td /F1 9.8 Tf  [( . Some tests also include other identified reduced-function variants \(named *4, *5, *6, *7, *8, *9, and *10\). A newer allele, )] TJ ET
BT 26.250 184.167 Td /F5 9.8 Tf  [(CYP2C19*17)] TJ ET
BT 84.233 184.167 Td /F1 9.8 Tf  [( , has been described that is associated with increased enzymatic activity and ultra-rapid drug metabolism )] TJ ET
0.267 0.267 0.267 rg
BT 542.668 184.167 Td /F1 9.8 Tf  [([4])] TJ ET
BT 553.510 184.167 Td /F1 9.8 Tf  [([5])] TJ ET
0.271 0.267 0.267 rg
BT 564.352 184.167 Td /F1 9.8 Tf  [( , )] TJ ET
BT 26.250 172.263 Td /F1 9.8 Tf  [(which in turn is predicted to result in higher levels of the active metabolite of clopidogrel.)] TJ ET
BT 26.250 152.858 Td /F1 9.8 Tf  [(Each test includes:)] TJ ET
0.271 0.267 0.267 RG
40.337 136.421 m 
40.337 136.867 40.154 137.311 39.838 137.627 c
39.522 137.943 39.078 138.127 38.631 138.127 c
38.185 138.127 37.741 137.943 37.425 137.627 c
37.109 137.311 36.925 136.867 36.925 136.421 c
36.925 135.974 37.109 135.530 37.425 135.214 c
37.741 134.898 38.185 134.715 38.631 134.715 c
39.078 134.715 39.522 134.898 39.838 135.214 c
40.154 135.530 40.337 135.974 40.337 136.421 c f
BT 45.750 133.453 Td /F1 9.8 Tf  [(Analysis of multiple single nucleotide polymorphisms in CYP2C19.)] TJ ET
40.337 120.766 m 
40.337 121.213 40.154 121.657 39.838 121.973 c
39.522 122.288 39.078 122.472 38.631 122.472 c
38.185 122.472 37.741 122.288 37.425 121.973 c
37.109 121.657 36.925 121.213 36.925 120.766 c
36.925 120.319 37.109 119.875 37.425 119.559 c
37.741 119.244 38.185 119.060 38.631 119.060 c
39.078 119.060 39.522 119.244 39.838 119.559 c
40.154 119.875 40.337 120.319 40.337 120.766 c f
BT 45.750 117.798 Td /F1 9.8 Tf  [(Genotype-based prediction of CYP2C19 enzymatic activity to categorize patients as: )] TJ ET
0.39 w 1 J 1 j
59.837 105.111 m 
59.837 105.558 59.654 106.002 59.338 106.318 c
59.022 106.634 58.578 106.818 58.131 106.818 c
57.685 106.818 57.241 106.634 56.925 106.318 c
56.609 106.002 56.425 105.558 56.425 105.111 c
56.425 104.665 56.609 104.221 56.925 103.905 c
57.241 103.589 57.685 103.405 58.131 103.405 c
58.578 103.405 59.022 103.589 59.338 103.905 c
59.654 104.221 59.837 104.665 59.837 105.111 c s
BT 65.250 102.144 Td /F1 9.8 Tf  [(Extensive metabolizers [carrying two �normal� alleles \(i.e., *1/*1\)].)] TJ ET
0.39 w 1 J 1 j
59.837 89.457 m 
59.837 89.903 59.654 90.347 59.338 90.663 c
59.022 90.979 58.578 91.163 58.131 91.163 c
57.685 91.163 57.241 90.979 56.925 90.663 c
56.609 90.347 56.425 89.903 56.425 89.457 c
56.425 89.010 56.609 88.566 56.925 88.250 c
57.241 87.934 57.685 87.750 58.131 87.750 c
58.578 87.750 59.022 87.934 59.338 88.250 c
59.654 88.566 59.837 89.010 59.837 89.457 c s
BT 65.250 86.489 Td /F1 9.8 Tf  [(Intermediate metabolizers [carrying one reduced-function allele \(e.g., *1/*2\)].)] TJ ET
0.39 w 1 J 1 j
59.837 73.802 m 
59.837 74.248 59.654 74.692 59.338 75.008 c
59.022 75.324 58.578 75.508 58.131 75.508 c
57.685 75.508 57.241 75.324 56.925 75.008 c
56.609 74.692 56.425 74.248 56.425 73.802 c
56.425 73.355 56.609 72.911 56.925 72.595 c
57.241 72.279 57.685 72.095 58.131 72.095 c
58.578 72.095 59.022 72.279 59.338 72.595 c
59.654 72.911 59.837 73.355 59.837 73.802 c s
BT 65.250 70.834 Td /F1 9.8 Tf  [(Poor metabolizers [carrying two reduced-function alleles \(e.g., *2/*2 or *2/*3\)].)] TJ ET
0.39 w 1 J 1 j
59.837 58.147 m 
59.837 58.594 59.654 59.038 59.338 59.354 c
59.022 59.669 58.578 59.853 58.131 59.853 c
57.685 59.853 57.241 59.669 56.925 59.354 c
56.609 59.038 56.425 58.594 56.425 58.147 c
56.425 57.700 56.609 57.256 56.925 56.940 c
57.241 56.625 57.685 56.441 58.131 56.441 c
58.578 56.441 59.022 56.625 59.338 56.940 c
59.654 57.256 59.837 57.700 59.837 58.147 c s
BT 65.250 55.179 Td /F1 9.8 Tf  [(Ultra-rapid metabolizers [carrying one or two increased-function alleles \(i.e., *1/*17 or *17/*17\), though it is not clear )] TJ ET
Q
q
0.000 0.000 0.000 rg
BT 291.710 19.825 Td /F1 11.0 Tf  [(1)] TJ ET
BT 25.000 19.825 Td /F1 11.0 Tf  [(PLOS Currents Evidence on Genomic Tests)] TJ ET
0.39 w 1 J 1 j
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BT 296.800 334.304 Td /F1 9.8 Tf  [(*8, *9, *10, *17)] TJ ET
0.000 0.000 0.000 rg
417.400 351.290 118.000 1.000 re f
417.400 314.340 1.000 37.950 re f
0.271 0.267 0.267 rg
BT 423.300 341.935 Td /F1 9.8 Tf  [(Buccal \(cheek\) swab)] TJ ET
0.000 0.000 0.000 rg
534.400 351.290 110.500 1.000 re f
534.400 314.340 1.000 37.950 re f
643.900 314.340 1.000 37.950 re f
0.271 0.267 0.267 rg
BT 540.300 341.935 Td /F1 9.8 Tf  [(Yes)] TJ ET
0.000 0.000 0.000 rg
32.500 314.340 131.800 1.000 re f
32.500 273.840 1.000 41.500 re f
0.271 0.267 0.267 rg
BT 38.900 304.985 Td /F1 9.8 Tf  [(Cytochrome P450 2C19 )] TJ ET
BT 38.900 297.354 Td /F5 9.8 Tf  [(\(CYP2C19\))] TJ ET
BT 88.742 297.354 Td /F1 9.8 Tf  [( 7 Mutations)] TJ ET
0.000 0.000 0.000 rg
163.300 314.340 128.600 1.000 re f
163.300 273.840 1.000 41.500 re f
0.271 0.267 0.267 rg
BT 169.200 304.985 Td /F1 9.8 Tf  [(ARUP Laboratories)] TJ ET
0.000 0.000 0.000 rg
290.900 314.340 127.500 1.000 re f
290.900 273.840 1.000 41.500 re f
0.271 0.267 0.267 rg
BT 296.800 304.985 Td /F1 9.8 Tf  [(*1, *2, *3, *4, *5, *6, *7, *8)] TJ ET
0.000 0.000 0.000 rg
417.400 314.340 118.000 1.000 re f
417.400 273.840 1.000 41.500 re f
0.271 0.267 0.267 rg
BT 423.300 304.985 Td /F1 9.8 Tf  [(Whole blood)] TJ ET
0.000 0.000 0.000 rg
534.400 314.340 110.500 1.000 re f
534.400 273.840 1.000 41.500 re f
643.900 273.840 1.000 41.500 re f
0.271 0.267 0.267 rg
BT 540.300 304.985 Td /F1 9.8 Tf  [(No)] TJ ET
0.000 0.000 0.000 rg
32.500 273.841 131.800 1.000 re f
32.500 235.316 1.000 39.525 re f
0.271 0.267 0.267 rg
BT 38.900 264.486 Td /F1 9.8 Tf  [(CYP450 2C19 Gene Test / )] TJ ET
BT 38.900 256.854 Td /F1 9.8 Tf  [(Genetic Physician Consult)] TJ ET
0.000 0.000 0.000 rg
163.300 273.841 128.600 1.000 re f
163.300 235.316 1.000 39.525 re f
0.271 0.267 0.267 rg
BT 169.200 264.486 Td /F1 9.8 Tf  [(MyMedLab, Inc.)] TJ ET
0.000 0.000 0.000 rg
290.900 273.841 127.500 1.000 re f
290.900 235.316 1.000 39.525 re f
0.271 0.267 0.267 rg
BT 296.800 264.486 Td /F1 9.8 Tf  [(Unspecified)] TJ ET
0.000 0.000 0.000 rg
417.400 273.841 118.000 1.000 re f
417.400 235.316 1.000 39.525 re f
0.271 0.267 0.267 rg
BT 423.300 264.486 Td /F1 9.8 Tf  [(Buccal \(cheek\) swab)] TJ ET
0.000 0.000 0.000 rg
534.400 273.841 110.500 1.000 re f
534.400 235.316 1.000 39.525 re f
643.900 235.316 1.000 39.525 re f
0.271 0.267 0.267 rg
BT 540.300 264.486 Td /F1 9.8 Tf  [(Yes, though orders )] TJ ET
BT 540.300 256.854 Td /F1 9.8 Tf  [(must be approved by )] TJ ET
BT 540.300 249.223 Td /F1 9.8 Tf  [(a MyMedLab )] TJ ET
BT 540.300 241.592 Td /F1 9.8 Tf  [(physician)] TJ ET
0.000 0.000 0.000 rg
32.500 235.316 131.800 1.000 re f
32.500 194.365 131.800 1.000 re f
32.500 194.366 1.000 41.950 re f
0.271 0.267 0.267 rg
BT 38.900 225.961 Td /F1 9.8 Tf  [(Clopidogrel Genetic Test)] TJ ET
0.000 0.000 0.000 rg
163.300 235.316 128.600 1.000 re f
163.300 194.365 128.600 1.000 re f
163.300 194.366 1.000 41.950 re f
0.271 0.267 0.267 rg
BT 169.200 225.961 Td /F1 9.8 Tf  [(TheranostiCs Lab)] TJ ET
0.000 0.000 0.000 rg
290.900 235.316 127.500 1.000 re f
290.900 194.365 127.500 1.000 re f
290.900 194.366 1.000 41.950 re f
0.271 0.267 0.267 rg
BT 296.800 225.961 Td /F1 9.8 Tf  [(Unspecified)] TJ ET
0.000 0.000 0.000 rg
417.400 235.316 118.000 1.000 re f
417.400 194.365 118.000 1.000 re f
417.400 194.366 1.000 41.950 re f
0.271 0.267 0.267 rg
BT 423.300 225.961 Td /F1 9.8 Tf  [(Buccal \(cheek\) swab)] TJ ET
0.000 0.000 0.000 rg
534.400 235.316 110.500 1.000 re f
534.400 194.365 110.500 1.000 re f
534.400 194.366 1.000 41.950 re f
643.900 194.366 1.000 41.950 re f
0.271 0.267 0.267 rg
BT 540.300 225.961 Td /F1 9.8 Tf  [(Yes)] TJ ET
BT 26.250 147.842 Td /F1 9.8 Tf  [(Note: These tests were found through Google searches combining terms such as �clopidogrel�, �genetic test� and �CYP2C19� )] TJ ET
BT 26.250 135.937 Td /F1 9.8 Tf  [(and by searching individual websites of known commercial genetics companies \(such as Pathway Genomics\). Attempts were )] TJ ET
BT 26.250 124.032 Td /F1 9.8 Tf  [(made to make this table comprehensive. However, there are tests that genotype variants in )] TJ ET
BT 421.846 124.032 Td /F5 9.8 Tf  [(CYP2C19)] TJ ET
BT 465.195 124.032 Td /F1 9.8 Tf  [( that either do not specify )] TJ ET
BT 26.250 112.127 Td /F1 9.8 Tf  [(that the test is for pharmacogenetic purposes, or do not specifically mention that the test can be used in determining response )] TJ ET
BT 26.250 100.223 Td /F1 9.8 Tf  [(to clopidogrel. Such tests have not been included in this table.)] TJ ET
BT 26.250 80.818 Td /F4 9.8 Tf  [(Disclaimer:)] TJ ET
Q
q
15.000 27.723 577.500 749.277 re W n
0.271 0.267 0.267 rg
BT 65.250 767.476 Td /F1 9.8 Tf  [(whether *1/*17 carriers have a different phenotype than *1/*1 carriers].)] TJ ET
BT 26.250 740.571 Td /F4 9.8 Tf  [(Table 1. Pharmacogenetic Tests for Clopidogrel Response)] TJ ET
1.000 1.000 1.000 rg
33.000 194.865 611.400 535.825 re f
0.000 0.000 0.000 rg
32.500 730.191 131.800 1.000 re f
32.500 693.641 1.000 37.550 re f
0.271 0.267 0.267 rg
BT 38.900 720.336 Td /F4 9.8 Tf  [(Test)] TJ ET
0.000 0.000 0.000 rg
163.300 730.191 128.600 1.000 re f
163.300 693.641 1.000 37.550 re f
0.271 0.267 0.267 rg
BT 169.200 720.336 Td /F4 9.8 Tf  [(Company)] TJ ET
0.000 0.000 0.000 rg
290.900 730.191 127.500 1.000 re f
290.900 693.641 1.000 37.550 re f
0.271 0.267 0.267 rg
BT 296.800 720.336 Td /F6 9.8 Tf  [(CYP2C19)] TJ ET
BT 340.148 720.336 Td /F4 9.8 Tf  [(Variants )] TJ ET
BT 296.800 712.704 Td /F4 9.8 Tf  [(Included)] TJ ET
0.000 0.000 0.000 rg
417.400 730.191 118.000 1.000 re f
417.400 693.641 1.000 37.550 re f
0.271 0.267 0.267 rg
BT 423.300 720.336 Td /F4 9.8 Tf  [(Sample Type)] TJ ET
0.000 0.000 0.000 rg
534.400 730.191 110.500 1.000 re f
534.400 693.641 1.000 37.550 re f
643.900 693.641 1.000 37.550 re f
0.271 0.267 0.267 rg
BT 540.300 720.336 Td /F4 9.8 Tf  [(Available Direct-to-)] TJ ET
BT 540.300 712.704 Td /F4 9.8 Tf  [(consumer \(DTC\))] TJ ET
0.000 0.000 0.000 rg
32.500 693.640 131.800 1.000 re f
32.500 635.091 1.000 59.550 re f
0.271 0.267 0.267 rg
BT 38.900 684.286 Td /F1 9.8 Tf  [(AccuType� CP testing for )] TJ ET
BT 38.900 676.654 Td /F1 9.8 Tf  [(Clopidogrel CYP2C19 )] TJ ET
BT 38.900 669.023 Td /F1 9.8 Tf  [(Genotype \(*1, *2, *3, *4, )] TJ ET
BT 38.900 661.392 Td /F1 9.8 Tf  [(*5\))] TJ ET
0.000 0.000 0.000 rg
163.300 693.640 128.600 1.000 re f
163.300 635.091 1.000 59.550 re f
0.271 0.267 0.267 rg
BT 169.200 684.286 Td /F1 9.8 Tf  [(Quest Diagnostics)] TJ ET
0.000 0.000 0.000 rg
290.900 693.640 127.500 1.000 re f
290.900 635.091 1.000 59.550 re f
0.271 0.267 0.267 rg
BT 296.800 684.286 Td /F1 9.8 Tf  [(*1, *2, *3, *4, *5)] TJ ET
0.000 0.000 0.000 rg
417.400 693.640 118.000 1.000 re f
417.400 635.091 1.000 59.550 re f
0.271 0.267 0.267 rg
BT 423.300 684.286 Td /F1 9.8 Tf  [(Whole blood or saliva)] TJ ET
0.000 0.000 0.000 rg
534.400 693.640 110.500 1.000 re f
534.400 635.091 1.000 59.550 re f
643.900 635.091 1.000 59.550 re f
0.271 0.267 0.267 rg
BT 540.300 684.286 Td /F1 9.8 Tf  [(No)] TJ ET
0.000 0.000 0.000 rg
32.500 635.091 131.800 1.000 re f
32.500 590.041 1.000 46.050 re f
0.271 0.267 0.267 rg
BT 38.900 625.736 Td /F1 9.8 Tf  [(Clopidogrel P450 )] TJ ET
BT 38.900 618.104 Td /F1 9.8 Tf  [(Genotype)] TJ ET
0.000 0.000 0.000 rg
163.300 635.091 128.600 1.000 re f
163.300 590.041 1.000 46.050 re f
0.271 0.267 0.267 rg
BT 169.200 625.736 Td /F1 9.8 Tf  [(Quest Diagnostics)] TJ ET
0.000 0.000 0.000 rg
290.900 635.091 127.500 1.000 re f
290.900 590.041 1.000 46.050 re f
0.271 0.267 0.267 rg
BT 296.800 625.736 Td /F1 9.8 Tf  [(*1, *2, *3 \(also includes )] TJ ET
BT 296.800 618.104 Td /F1 9.8 Tf  [(26 variants in )] TJ ET
BT 357.494 618.104 Td /F5 9.8 Tf  [(CYP2D6)] TJ ET
BT 395.421 618.104 Td /F1 9.8 Tf  [( \))] TJ ET
0.000 0.000 0.000 rg
417.400 635.091 118.000 1.000 re f
417.400 590.041 1.000 46.050 re f
0.271 0.267 0.267 rg
BT 423.300 625.736 Td /F1 9.8 Tf  [(Whole blood)] TJ ET
0.000 0.000 0.000 rg
534.400 635.091 110.500 1.000 re f
534.400 590.041 1.000 46.050 re f
643.900 590.041 1.000 46.050 re f
0.271 0.267 0.267 rg
BT 540.300 625.736 Td /F1 9.8 Tf  [(No)] TJ ET
0.000 0.000 0.000 rg
32.500 590.041 131.800 1.000 re f
32.500 544.991 1.000 46.050 re f
0.271 0.267 0.267 rg
BT 38.900 580.686 Td /F1 9.8 Tf  [(Plavitest for Clopidogrel )] TJ ET
BT 38.900 573.054 Td /F1 9.8 Tf  [(Resistance \(CYP 2C19\))] TJ ET
0.000 0.000 0.000 rg
163.300 590.041 128.600 1.000 re f
163.300 544.991 1.000 46.050 re f
0.271 0.267 0.267 rg
BT 169.200 580.686 Td /F1 9.8 Tf  [(Genelex Corporation)] TJ ET
0.000 0.000 0.000 rg
290.900 590.041 127.500 1.000 re f
290.900 544.991 1.000 46.050 re f
0.271 0.267 0.267 rg
BT 296.800 580.686 Td /F1 9.8 Tf  [(*1, *2, *3, *4, *5, *6, *7, *8)] TJ ET
0.000 0.000 0.000 rg
417.400 590.041 118.000 1.000 re f
417.400 544.991 1.000 46.050 re f
0.271 0.267 0.267 rg
BT 423.300 580.686 Td /F1 9.8 Tf  [(Whole blood or buccal )] TJ ET
BT 423.300 573.054 Td /F1 9.8 Tf  [(\(cheek\) swab)] TJ ET
0.000 0.000 0.000 rg
534.400 590.041 110.500 1.000 re f
534.400 544.991 1.000 46.050 re f
643.900 544.991 1.000 46.050 re f
0.271 0.267 0.267 rg
BT 540.300 580.686 Td /F1 9.8 Tf  [(No)] TJ ET
0.000 0.000 0.000 rg
32.500 544.990 131.800 1.000 re f
32.500 508.940 1.000 37.050 re f
0.271 0.267 0.267 rg
BT 38.900 535.636 Td /F1 9.8 Tf  [(Comprehensive DNA Drug )] TJ ET
BT 38.900 528.004 Td /F1 9.8 Tf  [(Sensitivity Test)] TJ ET
0.000 0.000 0.000 rg
163.300 544.990 128.600 1.000 re f
163.300 508.940 1.000 37.050 re f
0.271 0.267 0.267 rg
BT 169.200 535.636 Td /F1 9.8 Tf  [(Genelex Corporation)] TJ ET
0.000 0.000 0.000 rg
290.900 544.990 127.500 1.000 re f
290.900 508.940 1.000 37.050 re f
0.271 0.267 0.267 rg
BT 296.800 535.636 Td /F1 9.8 Tf  [(Unspecified)] TJ ET
0.000 0.000 0.000 rg
417.400 544.990 118.000 1.000 re f
417.400 508.940 1.000 37.050 re f
0.271 0.267 0.267 rg
BT 423.300 535.636 Td /F1 9.8 Tf  [(Whole blood or buccal )] TJ ET
BT 423.300 528.004 Td /F1 9.8 Tf  [(\(cheek\) swab)] TJ ET
0.000 0.000 0.000 rg
534.400 544.990 110.500 1.000 re f
534.400 508.940 1.000 37.050 re f
643.900 508.940 1.000 37.050 re f
0.271 0.267 0.267 rg
BT 540.300 535.636 Td /F1 9.8 Tf  [(No)] TJ ET
0.000 0.000 0.000 rg
32.500 508.940 131.800 1.000 re f
32.500 459.390 1.000 50.550 re f
0.271 0.267 0.267 rg
BT 38.900 499.585 Td /F1 9.8 Tf  [(Medications Panel [part of )] TJ ET
BT 38.900 491.954 Td /F1 9.8 Tf  [(the �Health Compass�])] TJ ET
0.000 0.000 0.000 rg
163.300 508.940 128.600 1.000 re f
163.300 459.390 1.000 50.550 re f
0.271 0.267 0.267 rg
BT 169.200 499.585 Td /F1 9.8 Tf  [(Navigenics, Inc.)] TJ ET
0.000 0.000 0.000 rg
290.900 508.940 127.500 1.000 re f
290.900 459.390 1.000 50.550 re f
0.271 0.267 0.267 rg
BT 296.800 499.585 Td /F1 9.8 Tf  [(�Two of the most )] TJ ET
BT 296.800 491.954 Td /F1 9.8 Tf  [(common genetic variants )] TJ ET
BT 296.800 484.323 Td /F1 9.8 Tf  [(in )] TJ ET
BT 307.096 484.323 Td /F5 9.8 Tf  [(CYP2C19)] TJ ET
BT 350.444 484.323 Td /F1 9.8 Tf  [( �)] TJ ET
0.000 0.000 0.000 rg
417.400 508.940 118.000 1.000 re f
417.400 459.390 1.000 50.550 re f
0.271 0.267 0.267 rg
BT 423.300 499.585 Td /F1 9.8 Tf  [(Saliva)] TJ ET
0.000 0.000 0.000 rg
534.400 508.940 110.500 1.000 re f
534.400 459.390 1.000 50.550 re f
643.900 459.390 1.000 50.550 re f
0.271 0.267 0.267 rg
BT 540.300 499.585 Td /F1 9.8 Tf  [(No)] TJ ET
0.000 0.000 0.000 rg
32.500 459.390 131.800 1.000 re f
32.500 409.390 1.000 51.000 re f
0.271 0.267 0.267 rg
BT 38.900 450.035 Td /F1 9.8 Tf  [(Clopidogrel Efficacy [part )] TJ ET
BT 38.900 442.404 Td /F1 9.8 Tf  [(of the �Health Edition� test])] TJ ET
0.000 0.000 0.000 rg
163.300 459.390 128.600 1.000 re f
163.300 409.390 1.000 51.000 re f
0.271 0.267 0.267 rg
BT 169.200 450.035 Td /F1 9.8 Tf  [(23andMe)] TJ ET
0.000 0.000 0.000 rg
290.900 459.390 127.500 1.000 re f
290.900 409.390 1.000 51.000 re f
0.271 0.267 0.267 rg
BT 296.800 450.035 Td /F1 9.8 Tf  [(*1, *2, *3, *4, *8, and *17)] TJ ET
0.000 0.000 0.000 rg
417.400 459.390 118.000 1.000 re f
417.400 409.390 1.000 51.000 re f
0.271 0.267 0.267 rg
BT 423.300 450.035 Td /F1 9.8 Tf  [(Saliva)] TJ ET
0.000 0.000 0.000 rg
534.400 459.390 110.500 1.000 re f
534.400 409.390 1.000 51.000 re f
643.900 409.390 1.000 51.000 re f
0.271 0.267 0.267 rg
BT 540.300 450.035 Td /F1 9.8 Tf  [(Yes)] TJ ET
0.000 0.000 0.000 rg
32.500 409.390 131.800 1.000 re f
32.500 351.290 1.000 59.100 re f
0.271 0.267 0.267 rg
BT 38.900 400.035 Td /F1 9.8 Tf  [(Drug Response )] TJ ET
BT 38.900 392.404 Td /F1 9.8 Tf  [(\(Medication\) [part of the )] TJ ET
BT 38.900 384.773 Td /F1 9.8 Tf  [(�Total Health Insight� test])] TJ ET
0.000 0.000 0.000 rg
163.300 409.390 128.600 1.000 re f
163.300 351.290 1.000 59.100 re f
0.271 0.267 0.267 rg
BT 169.200 400.035 Td /F1 9.8 Tf  [(Pathway Genomics)] TJ ET
0.000 0.000 0.000 rg
290.900 409.390 127.500 1.000 re f
290.900 351.290 1.000 59.100 re f
0.271 0.267 0.267 rg
BT 296.800 400.035 Td /F1 9.8 Tf  [(Unspecified)] TJ ET
0.000 0.000 0.000 rg
417.400 409.390 118.000 1.000 re f
417.400 351.290 1.000 59.100 re f
0.271 0.267 0.267 rg
BT 423.300 400.035 Td /F1 9.8 Tf  [(Saliva)] TJ ET
0.000 0.000 0.000 rg
534.400 409.390 110.500 1.000 re f
534.400 351.290 1.000 59.100 re f
643.900 351.290 1.000 59.100 re f
0.271 0.267 0.267 rg
BT 540.300 400.035 Td /F1 9.8 Tf  [(Yes, except in New )] TJ ET
BT 540.300 392.404 Td /F1 9.8 Tf  [(York state)] TJ ET
0.000 0.000 0.000 rg
32.500 351.290 131.800 1.000 re f
32.500 314.340 1.000 37.950 re f
0.271 0.267 0.267 rg
BT 38.900 341.935 Td /F1 9.8 Tf  [(Clopidogrel Activation)] TJ ET
0.000 0.000 0.000 rg
163.300 351.290 128.600 1.000 re f
163.300 314.340 1.000 37.950 re f
0.271 0.267 0.267 rg
BT 169.200 341.935 Td /F1 9.8 Tf  [(Matrix Genomics)] TJ ET
0.000 0.000 0.000 rg
290.900 351.290 127.500 1.000 re f
290.900 314.340 1.000 37.950 re f
0.271 0.267 0.267 rg
BT 296.800 341.935 Td /F1 9.8 Tf  [(*1, *2, *3, *4, *5, *6, *7, )] TJ ET
BT 296.800 334.304 Td /F1 9.8 Tf  [(*8, *9, *10, *17)] TJ ET
0.000 0.000 0.000 rg
417.400 351.290 118.000 1.000 re f
417.400 314.340 1.000 37.950 re f
0.271 0.267 0.267 rg
BT 423.300 341.935 Td /F1 9.8 Tf  [(Buccal \(cheek\) swab)] TJ ET
0.000 0.000 0.000 rg
534.400 351.290 110.500 1.000 re f
534.400 314.340 1.000 37.950 re f
643.900 314.340 1.000 37.950 re f
0.271 0.267 0.267 rg
BT 540.300 341.935 Td /F1 9.8 Tf  [(Yes)] TJ ET
0.000 0.000 0.000 rg
32.500 314.340 131.800 1.000 re f
32.500 273.840 1.000 41.500 re f
0.271 0.267 0.267 rg
BT 38.900 304.985 Td /F1 9.8 Tf  [(Cytochrome P450 2C19 )] TJ ET
BT 38.900 297.354 Td /F5 9.8 Tf  [(\(CYP2C19\))] TJ ET
BT 88.742 297.354 Td /F1 9.8 Tf  [( 7 Mutations)] TJ ET
0.000 0.000 0.000 rg
163.300 314.340 128.600 1.000 re f
163.300 273.840 1.000 41.500 re f
0.271 0.267 0.267 rg
BT 169.200 304.985 Td /F1 9.8 Tf  [(ARUP Laboratories)] TJ ET
0.000 0.000 0.000 rg
290.900 314.340 127.500 1.000 re f
290.900 273.840 1.000 41.500 re f
0.271 0.267 0.267 rg
BT 296.800 304.985 Td /F1 9.8 Tf  [(*1, *2, *3, *4, *5, *6, *7, *8)] TJ ET
0.000 0.000 0.000 rg
417.400 314.340 118.000 1.000 re f
417.400 273.840 1.000 41.500 re f
0.271 0.267 0.267 rg
BT 423.300 304.985 Td /F1 9.8 Tf  [(Whole blood)] TJ ET
0.000 0.000 0.000 rg
534.400 314.340 110.500 1.000 re f
534.400 273.840 1.000 41.500 re f
643.900 273.840 1.000 41.500 re f
0.271 0.267 0.267 rg
BT 540.300 304.985 Td /F1 9.8 Tf  [(No)] TJ ET
0.000 0.000 0.000 rg
32.500 273.841 131.800 1.000 re f
32.500 235.316 1.000 39.525 re f
0.271 0.267 0.267 rg
BT 38.900 264.486 Td /F1 9.8 Tf  [(CYP450 2C19 Gene Test / )] TJ ET
BT 38.900 256.854 Td /F1 9.8 Tf  [(Genetic Physician Consult)] TJ ET
0.000 0.000 0.000 rg
163.300 273.841 128.600 1.000 re f
163.300 235.316 1.000 39.525 re f
0.271 0.267 0.267 rg
BT 169.200 264.486 Td /F1 9.8 Tf  [(MyMedLab, Inc.)] TJ ET
0.000 0.000 0.000 rg
290.900 273.841 127.500 1.000 re f
290.900 235.316 1.000 39.525 re f
0.271 0.267 0.267 rg
BT 296.800 264.486 Td /F1 9.8 Tf  [(Unspecified)] TJ ET
0.000 0.000 0.000 rg
417.400 273.841 118.000 1.000 re f
417.400 235.316 1.000 39.525 re f
0.271 0.267 0.267 rg
BT 423.300 264.486 Td /F1 9.8 Tf  [(Buccal \(cheek\) swab)] TJ ET
0.000 0.000 0.000 rg
534.400 273.841 110.500 1.000 re f
534.400 235.316 1.000 39.525 re f
643.900 235.316 1.000 39.525 re f
0.271 0.267 0.267 rg
BT 540.300 264.486 Td /F1 9.8 Tf  [(Yes, though orders )] TJ ET
BT 540.300 256.854 Td /F1 9.8 Tf  [(must be approved by )] TJ ET
BT 540.300 249.223 Td /F1 9.8 Tf  [(a MyMedLab )] TJ ET
BT 540.300 241.592 Td /F1 9.8 Tf  [(physician)] TJ ET
0.000 0.000 0.000 rg
32.500 235.316 131.800 1.000 re f
32.500 194.365 131.800 1.000 re f
32.500 194.366 1.000 41.950 re f
0.271 0.267 0.267 rg
BT 38.900 225.961 Td /F1 9.8 Tf  [(Clopidogrel Genetic Test)] TJ ET
0.000 0.000 0.000 rg
163.300 235.316 128.600 1.000 re f
163.300 194.365 128.600 1.000 re f
163.300 194.366 1.000 41.950 re f
0.271 0.267 0.267 rg
BT 169.200 225.961 Td /F1 9.8 Tf  [(TheranostiCs Lab)] TJ ET
0.000 0.000 0.000 rg
290.900 235.316 127.500 1.000 re f
290.900 194.365 127.500 1.000 re f
290.900 194.366 1.000 41.950 re f
0.271 0.267 0.267 rg
BT 296.800 225.961 Td /F1 9.8 Tf  [(Unspecified)] TJ ET
0.000 0.000 0.000 rg
417.400 235.316 118.000 1.000 re f
417.400 194.365 118.000 1.000 re f
417.400 194.366 1.000 41.950 re f
0.271 0.267 0.267 rg
BT 423.300 225.961 Td /F1 9.8 Tf  [(Buccal \(cheek\) swab)] TJ ET
0.000 0.000 0.000 rg
534.400 235.316 110.500 1.000 re f
534.400 194.365 110.500 1.000 re f
534.400 194.366 1.000 41.950 re f
643.900 194.366 1.000 41.950 re f
0.271 0.267 0.267 rg
BT 540.300 225.961 Td /F1 9.8 Tf  [(Yes)] TJ ET
BT 26.250 147.842 Td /F1 9.8 Tf  [(Note: These tests were found through Google searches combining terms such as �clopidogrel�, �genetic test� and �CYP2C19� )] TJ ET
BT 26.250 135.937 Td /F1 9.8 Tf  [(and by searching individual websites of known commercial genetics companies \(such as Pathway Genomics\). Attempts were )] TJ ET
BT 26.250 124.032 Td /F1 9.8 Tf  [(made to make this table comprehensive. However, there are tests that genotype variants in )] TJ ET
BT 421.846 124.032 Td /F5 9.8 Tf  [(CYP2C19)] TJ ET
BT 465.195 124.032 Td /F1 9.8 Tf  [( that either do not specify )] TJ ET
BT 26.250 112.127 Td /F1 9.8 Tf  [(that the test is for pharmacogenetic purposes, or do not specifically mention that the test can be used in determining response )] TJ ET
BT 26.250 100.223 Td /F1 9.8 Tf  [(to clopidogrel. Such tests have not been included in this table.)] TJ ET
BT 26.250 80.818 Td /F4 9.8 Tf  [(Disclaimer:)] TJ ET
Q
q
15.000 27.723 577.500 749.277 re W n
0.271 0.267 0.267 rg
BT 65.250 767.476 Td /F1 9.8 Tf  [(whether *1/*17 carriers have a different phenotype than *1/*1 carriers].)] TJ ET
BT 26.250 740.571 Td /F4 9.8 Tf  [(Table 1. Pharmacogenetic Tests for Clopidogrel Response)] TJ ET
1.000 1.000 1.000 rg
33.000 194.865 611.400 535.825 re f
0.000 0.000 0.000 rg
32.500 730.191 131.800 1.000 re f
32.500 693.641 1.000 37.550 re f
0.271 0.267 0.267 rg
BT 38.900 720.336 Td /F4 9.8 Tf  [(Test)] TJ ET
0.000 0.000 0.000 rg
163.300 730.191 128.600 1.000 re f
163.300 693.641 1.000 37.550 re f
0.271 0.267 0.267 rg
BT 169.200 720.336 Td /F4 9.8 Tf  [(Company)] TJ ET
0.000 0.000 0.000 rg
290.900 730.191 127.500 1.000 re f
290.900 693.641 1.000 37.550 re f
0.271 0.267 0.267 rg
BT 296.800 720.336 Td /F6 9.8 Tf  [(CYP2C19)] TJ ET
BT 340.148 720.336 Td /F4 9.8 Tf  [(Variants )] TJ ET
BT 296.800 712.704 Td /F4 9.8 Tf  [(Included)] TJ ET
0.000 0.000 0.000 rg
417.400 730.191 118.000 1.000 re f
417.400 693.641 1.000 37.550 re f
0.271 0.267 0.267 rg
BT 423.300 720.336 Td /F4 9.8 Tf  [(Sample Type)] TJ ET
0.000 0.000 0.000 rg
534.400 730.191 110.500 1.000 re f
534.400 693.641 1.000 37.550 re f
643.900 693.641 1.000 37.550 re f
0.271 0.267 0.267 rg
BT 540.300 720.336 Td /F4 9.8 Tf  [(Available Direct-to-)] TJ ET
BT 540.300 712.704 Td /F4 9.8 Tf  [(consumer \(DTC\))] TJ ET
0.000 0.000 0.000 rg
32.500 693.640 131.800 1.000 re f
32.500 635.091 1.000 59.550 re f
0.271 0.267 0.267 rg
BT 38.900 684.286 Td /F1 9.8 Tf  [(AccuType� CP testing for )] TJ ET
BT 38.900 676.654 Td /F1 9.8 Tf  [(Clopidogrel CYP2C19 )] TJ ET
BT 38.900 669.023 Td /F1 9.8 Tf  [(Genotype \(*1, *2, *3, *4, )] TJ ET
BT 38.900 661.392 Td /F1 9.8 Tf  [(*5\))] TJ ET
0.000 0.000 0.000 rg
163.300 693.640 128.600 1.000 re f
163.300 635.091 1.000 59.550 re f
0.271 0.267 0.267 rg
BT 169.200 684.286 Td /F1 9.8 Tf  [(Quest Diagnostics)] TJ ET
0.000 0.000 0.000 rg
290.900 693.640 127.500 1.000 re f
290.900 635.091 1.000 59.550 re f
0.271 0.267 0.267 rg
BT 296.800 684.286 Td /F1 9.8 Tf  [(*1, *2, *3, *4, *5)] TJ ET
0.000 0.000 0.000 rg
417.400 693.640 118.000 1.000 re f
417.400 635.091 1.000 59.550 re f
0.271 0.267 0.267 rg
BT 423.300 684.286 Td /F1 9.8 Tf  [(Whole blood or saliva)] TJ ET
0.000 0.000 0.000 rg
534.400 693.640 110.500 1.000 re f
534.400 635.091 1.000 59.550 re f
643.900 635.091 1.000 59.550 re f
0.271 0.267 0.267 rg
BT 540.300 684.286 Td /F1 9.8 Tf  [(No)] TJ ET
0.000 0.000 0.000 rg
32.500 635.091 131.800 1.000 re f
32.500 590.041 1.000 46.050 re f
0.271 0.267 0.267 rg
BT 38.900 625.736 Td /F1 9.8 Tf  [(Clopidogrel P450 )] TJ ET
BT 38.900 618.104 Td /F1 9.8 Tf  [(Genotype)] TJ ET
0.000 0.000 0.000 rg
163.300 635.091 128.600 1.000 re f
163.300 590.041 1.000 46.050 re f
0.271 0.267 0.267 rg
BT 169.200 625.736 Td /F1 9.8 Tf  [(Quest Diagnostics)] TJ ET
0.000 0.000 0.000 rg
290.900 635.091 127.500 1.000 re f
290.900 590.041 1.000 46.050 re f
0.271 0.267 0.267 rg
BT 296.800 625.736 Td /F1 9.8 Tf  [(*1, *2, *3 \(also includes )] TJ ET
BT 296.800 618.104 Td /F1 9.8 Tf  [(26 variants in )] TJ ET
BT 357.494 618.104 Td /F5 9.8 Tf  [(CYP2D6)] TJ ET
BT 395.421 618.104 Td /F1 9.8 Tf  [( \))] TJ ET
0.000 0.000 0.000 rg
417.400 635.091 118.000 1.000 re f
417.400 590.041 1.000 46.050 re f
0.271 0.267 0.267 rg
BT 423.300 625.736 Td /F1 9.8 Tf  [(Whole blood)] TJ ET
0.000 0.000 0.000 rg
534.400 635.091 110.500 1.000 re f
534.400 590.041 1.000 46.050 re f
643.900 590.041 1.000 46.050 re f
0.271 0.267 0.267 rg
BT 540.300 625.736 Td /F1 9.8 Tf  [(No)] TJ ET
0.000 0.000 0.000 rg
32.500 590.041 131.800 1.000 re f
32.500 544.991 1.000 46.050 re f
0.271 0.267 0.267 rg
BT 38.900 580.686 Td /F1 9.8 Tf  [(Plavitest for Clopidogrel )] TJ ET
BT 38.900 573.054 Td /F1 9.8 Tf  [(Resistance \(CYP 2C19\))] TJ ET
0.000 0.000 0.000 rg
163.300 590.041 128.600 1.000 re f
163.300 544.991 1.000 46.050 re f
0.271 0.267 0.267 rg
BT 169.200 580.686 Td /F1 9.8 Tf  [(Genelex Corporation)] TJ ET
0.000 0.000 0.000 rg
290.900 590.041 127.500 1.000 re f
290.900 544.991 1.000 46.050 re f
0.271 0.267 0.267 rg
BT 296.800 580.686 Td /F1 9.8 Tf  [(*1, *2, *3, *4, *5, *6, *7, *8)] TJ ET
0.000 0.000 0.000 rg
417.400 590.041 118.000 1.000 re f
417.400 544.991 1.000 46.050 re f
0.271 0.267 0.267 rg
BT 423.300 580.686 Td /F1 9.8 Tf  [(Whole blood or buccal )] TJ ET
BT 423.300 573.054 Td /F1 9.8 Tf  [(\(cheek\) swab)] TJ ET
0.000 0.000 0.000 rg
534.400 590.041 110.500 1.000 re f
534.400 544.991 1.000 46.050 re f
643.900 544.991 1.000 46.050 re f
0.271 0.267 0.267 rg
BT 540.300 580.686 Td /F1 9.8 Tf  [(No)] TJ ET
0.000 0.000 0.000 rg
32.500 544.990 131.800 1.000 re f
32.500 508.940 1.000 37.050 re f
0.271 0.267 0.267 rg
BT 38.900 535.636 Td /F1 9.8 Tf  [(Comprehensive DNA Drug )] TJ ET
BT 38.900 528.004 Td /F1 9.8 Tf  [(Sensitivity Test)] TJ ET
0.000 0.000 0.000 rg
163.300 544.990 128.600 1.000 re f
163.300 508.940 1.000 37.050 re f
0.271 0.267 0.267 rg
BT 169.200 535.636 Td /F1 9.8 Tf  [(Genelex Corporation)] TJ ET
0.000 0.000 0.000 rg
290.900 544.990 127.500 1.000 re f
290.900 508.940 1.000 37.050 re f
0.271 0.267 0.267 rg
BT 296.800 535.636 Td /F1 9.8 Tf  [(Unspecified)] TJ ET
0.000 0.000 0.000 rg
417.400 544.990 118.000 1.000 re f
417.400 508.940 1.000 37.050 re f
0.271 0.267 0.267 rg
BT 423.300 535.636 Td /F1 9.8 Tf  [(Whole blood or buccal )] TJ ET
BT 423.300 528.004 Td /F1 9.8 Tf  [(\(cheek\) swab)] TJ ET
0.000 0.000 0.000 rg
534.400 544.990 110.500 1.000 re f
534.400 508.940 1.000 37.050 re f
643.900 508.940 1.000 37.050 re f
0.271 0.267 0.267 rg
BT 540.300 535.636 Td /F1 9.8 Tf  [(No)] TJ ET
0.000 0.000 0.000 rg
32.500 508.940 131.800 1.000 re f
32.500 459.390 1.000 50.550 re f
0.271 0.267 0.267 rg
BT 38.900 499.585 Td /F1 9.8 Tf  [(Medications Panel [part of )] TJ ET
BT 38.900 491.954 Td /F1 9.8 Tf  [(the �Health Compass�])] TJ ET
0.000 0.000 0.000 rg
163.300 508.940 128.600 1.000 re f
163.300 459.390 1.000 50.550 re f
0.271 0.267 0.267 rg
BT 169.200 499.585 Td /F1 9.8 Tf  [(Navigenics, Inc.)] TJ ET
0.000 0.000 0.000 rg
290.900 508.940 127.500 1.000 re f
290.900 459.390 1.000 50.550 re f
0.271 0.267 0.267 rg
BT 296.800 499.585 Td /F1 9.8 Tf  [(�Two of the most )] TJ ET
BT 296.800 491.954 Td /F1 9.8 Tf  [(common genetic variants )] TJ ET
BT 296.800 484.323 Td /F1 9.8 Tf  [(in )] TJ ET
BT 307.096 484.323 Td /F5 9.8 Tf  [(CYP2C19)] TJ ET
BT 350.444 484.323 Td /F1 9.8 Tf  [( �)] TJ ET
0.000 0.000 0.000 rg
417.400 508.940 118.000 1.000 re f
417.400 459.390 1.000 50.550 re f
0.271 0.267 0.267 rg
BT 423.300 499.585 Td /F1 9.8 Tf  [(Saliva)] TJ ET
0.000 0.000 0.000 rg
534.400 508.940 110.500 1.000 re f
534.400 459.390 1.000 50.550 re f
643.900 459.390 1.000 50.550 re f
0.271 0.267 0.267 rg
BT 540.300 499.585 Td /F1 9.8 Tf  [(No)] TJ ET
0.000 0.000 0.000 rg
32.500 459.390 131.800 1.000 re f
32.500 409.390 1.000 51.000 re f
0.271 0.267 0.267 rg
BT 38.900 450.035 Td /F1 9.8 Tf  [(Clopidogrel Efficacy [part )] TJ ET
BT 38.900 442.404 Td /F1 9.8 Tf  [(of the �Health Edition� test])] TJ ET
0.000 0.000 0.000 rg
163.300 459.390 128.600 1.000 re f
163.300 409.390 1.000 51.000 re f
0.271 0.267 0.267 rg
BT 169.200 450.035 Td /F1 9.8 Tf  [(23andMe)] TJ ET
0.000 0.000 0.000 rg
290.900 459.390 127.500 1.000 re f
290.900 409.390 1.000 51.000 re f
0.271 0.267 0.267 rg
BT 296.800 450.035 Td /F1 9.8 Tf  [(*1, *2, *3, *4, *8, and *17)] TJ ET
0.000 0.000 0.000 rg
417.400 459.390 118.000 1.000 re f
417.400 409.390 1.000 51.000 re f
0.271 0.267 0.267 rg
BT 423.300 450.035 Td /F1 9.8 Tf  [(Saliva)] TJ ET
0.000 0.000 0.000 rg
534.400 459.390 110.500 1.000 re f
534.400 409.390 1.000 51.000 re f
643.900 409.390 1.000 51.000 re f
0.271 0.267 0.267 rg
BT 540.300 450.035 Td /F1 9.8 Tf  [(Yes)] TJ ET
0.000 0.000 0.000 rg
32.500 409.390 131.800 1.000 re f
32.500 351.290 1.000 59.100 re f
0.271 0.267 0.267 rg
BT 38.900 400.035 Td /F1 9.8 Tf  [(Drug Response )] TJ ET
BT 38.900 392.404 Td /F1 9.8 Tf  [(\(Medication\) [part of the )] TJ ET
BT 38.900 384.773 Td /F1 9.8 Tf  [(�Total Health Insight� test])] TJ ET
0.000 0.000 0.000 rg
163.300 409.390 128.600 1.000 re f
163.300 351.290 1.000 59.100 re f
0.271 0.267 0.267 rg
BT 169.200 400.035 Td /F1 9.8 Tf  [(Pathway Genomics)] TJ ET
0.000 0.000 0.000 rg
290.900 409.390 127.500 1.000 re f
290.900 351.290 1.000 59.100 re f
0.271 0.267 0.267 rg
BT 296.800 400.035 Td /F1 9.8 Tf  [(Unspecified)] TJ ET
0.000 0.000 0.000 rg
417.400 409.390 118.000 1.000 re f
417.400 351.290 1.000 59.100 re f
0.271 0.267 0.267 rg
BT 423.300 400.035 Td /F1 9.8 Tf  [(Saliva)] TJ ET
0.000 0.000 0.000 rg
534.400 409.390 110.500 1.000 re f
534.400 351.290 1.000 59.100 re f
643.900 351.290 1.000 59.100 re f
0.271 0.267 0.267 rg
BT 540.300 400.035 Td /F1 9.8 Tf  [(Yes, except in New )] TJ ET
BT 540.300 392.404 Td /F1 9.8 Tf  [(York state)] TJ ET
0.000 0.000 0.000 rg
32.500 351.290 131.800 1.000 re f
32.500 314.340 1.000 37.950 re f
0.271 0.267 0.267 rg
BT 38.900 341.935 Td /F1 9.8 Tf  [(Clopidogrel Activation)] TJ ET
0.000 0.000 0.000 rg
163.300 351.290 128.600 1.000 re f
163.300 314.340 1.000 37.950 re f
0.271 0.267 0.267 rg
BT 169.200 341.935 Td /F1 9.8 Tf  [(Matrix Genomics)] TJ ET
0.000 0.000 0.000 rg
290.900 351.290 127.500 1.000 re f
290.900 314.340 1.000 37.950 re f
0.271 0.267 0.267 rg
BT 296.800 341.935 Td /F1 9.8 Tf  [(*1, *2, *3, *4, *5, *6, *7, )] TJ ET
BT 296.800 334.304 Td /F1 9.8 Tf  [(*8, *9, *10, *17)] TJ ET
0.000 0.000 0.000 rg
417.400 351.290 118.000 1.000 re f
417.400 314.340 1.000 37.950 re f
0.271 0.267 0.267 rg
BT 423.300 341.935 Td /F1 9.8 Tf  [(Buccal \(cheek\) swab)] TJ ET
0.000 0.000 0.000 rg
534.400 351.290 110.500 1.000 re f
534.400 314.340 1.000 37.950 re f
643.900 314.340 1.000 37.950 re f
0.271 0.267 0.267 rg
BT 540.300 341.935 Td /F1 9.8 Tf  [(Yes)] TJ ET
0.000 0.000 0.000 rg
32.500 314.340 131.800 1.000 re f
32.500 273.840 1.000 41.500 re f
0.271 0.267 0.267 rg
BT 38.900 304.985 Td /F1 9.8 Tf  [(Cytochrome P450 2C19 )] TJ ET
BT 38.900 297.354 Td /F5 9.8 Tf  [(\(CYP2C19\))] TJ ET
BT 88.742 297.354 Td /F1 9.8 Tf  [( 7 Mutations)] TJ ET
0.000 0.000 0.000 rg
163.300 314.340 128.600 1.000 re f
163.300 273.840 1.000 41.500 re f
0.271 0.267 0.267 rg
BT 169.200 304.985 Td /F1 9.8 Tf  [(ARUP Laboratories)] TJ ET
0.000 0.000 0.000 rg
290.900 314.340 127.500 1.000 re f
290.900 273.840 1.000 41.500 re f
0.271 0.267 0.267 rg
BT 296.800 304.985 Td /F1 9.8 Tf  [(*1, *2, *3, *4, *5, *6, *7, *8)] TJ ET
0.000 0.000 0.000 rg
417.400 314.340 118.000 1.000 re f
417.400 273.840 1.000 41.500 re f
0.271 0.267 0.267 rg
BT 423.300 304.985 Td /F1 9.8 Tf  [(Whole blood)] TJ ET
0.000 0.000 0.000 rg
534.400 314.340 110.500 1.000 re f
534.400 273.840 1.000 41.500 re f
643.900 273.840 1.000 41.500 re f
0.271 0.267 0.267 rg
BT 540.300 304.985 Td /F1 9.8 Tf  [(No)] TJ ET
0.000 0.000 0.000 rg
32.500 273.841 131.800 1.000 re f
32.500 235.316 1.000 39.525 re f
0.271 0.267 0.267 rg
BT 38.900 264.486 Td /F1 9.8 Tf  [(CYP450 2C19 Gene Test / )] TJ ET
BT 38.900 256.854 Td /F1 9.8 Tf  [(Genetic Physician Consult)] TJ ET
0.000 0.000 0.000 rg
163.300 273.841 128.600 1.000 re f
163.300 235.316 1.000 39.525 re f
0.271 0.267 0.267 rg
BT 169.200 264.486 Td /F1 9.8 Tf  [(MyMedLab, Inc.)] TJ ET
0.000 0.000 0.000 rg
290.900 273.841 127.500 1.000 re f
290.900 235.316 1.000 39.525 re f
0.271 0.267 0.267 rg
BT 296.800 264.486 Td /F1 9.8 Tf  [(Unspecified)] TJ ET
0.000 0.000 0.000 rg
417.400 273.841 118.000 1.000 re f
417.400 235.316 1.000 39.525 re f
0.271 0.267 0.267 rg
BT 423.300 264.486 Td /F1 9.8 Tf  [(Buccal \(cheek\) swab)] TJ ET
0.000 0.000 0.000 rg
534.400 273.841 110.500 1.000 re f
534.400 235.316 1.000 39.525 re f
643.900 235.316 1.000 39.525 re f
0.271 0.267 0.267 rg
BT 540.300 264.486 Td /F1 9.8 Tf  [(Yes, though orders )] TJ ET
BT 540.300 256.854 Td /F1 9.8 Tf  [(must be approved by )] TJ ET
BT 540.300 249.223 Td /F1 9.8 Tf  [(a MyMedLab )] TJ ET
BT 540.300 241.592 Td /F1 9.8 Tf  [(physician)] TJ ET
0.000 0.000 0.000 rg
32.500 235.316 131.800 1.000 re f
32.500 194.365 131.800 1.000 re f
32.500 194.366 1.000 41.950 re f
0.271 0.267 0.267 rg
BT 38.900 225.961 Td /F1 9.8 Tf  [(Clopidogrel Genetic Test)] TJ ET
0.000 0.000 0.000 rg
163.300 235.316 128.600 1.000 re f
163.300 194.365 128.600 1.000 re f
163.300 194.366 1.000 41.950 re f
0.271 0.267 0.267 rg
BT 169.200 225.961 Td /F1 9.8 Tf  [(TheranostiCs Lab)] TJ ET
0.000 0.000 0.000 rg
290.900 235.316 127.500 1.000 re f
290.900 194.365 127.500 1.000 re f
290.900 194.366 1.000 41.950 re f
0.271 0.267 0.267 rg
BT 296.800 225.961 Td /F1 9.8 Tf  [(Unspecified)] TJ ET
0.000 0.000 0.000 rg
417.400 235.316 118.000 1.000 re f
417.400 194.365 118.000 1.000 re f
417.400 194.366 1.000 41.950 re f
0.271 0.267 0.267 rg
BT 423.300 225.961 Td /F1 9.8 Tf  [(Buccal \(cheek\) swab)] TJ ET
0.000 0.000 0.000 rg
534.400 235.316 110.500 1.000 re f
534.400 194.365 110.500 1.000 re f
534.400 194.366 1.000 41.950 re f
643.900 194.366 1.000 41.950 re f
0.271 0.267 0.267 rg
BT 540.300 225.961 Td /F1 9.8 Tf  [(Yes)] TJ ET
BT 26.250 147.842 Td /F1 9.8 Tf  [(Note: These tests were found through Google searches combining terms such as �clopidogrel�, �genetic test� and �CYP2C19� )] TJ ET
BT 26.250 135.937 Td /F1 9.8 Tf  [(and by searching individual websites of known commercial genetics companies \(such as Pathway Genomics\). Attempts were )] TJ ET
BT 26.250 124.032 Td /F1 9.8 Tf  [(made to make this table comprehensive. However, there are tests that genotype variants in )] TJ ET
BT 421.846 124.032 Td /F5 9.8 Tf  [(CYP2C19)] TJ ET
BT 465.195 124.032 Td /F1 9.8 Tf  [( that either do not specify )] TJ ET
BT 26.250 112.127 Td /F1 9.8 Tf  [(that the test is for pharmacogenetic purposes, or do not specifically mention that the test can be used in determining response )] TJ ET
BT 26.250 100.223 Td /F1 9.8 Tf  [(to clopidogrel. Such tests have not been included in this table.)] TJ ET
BT 26.250 80.818 Td /F4 9.8 Tf  [(Disclaimer:)] TJ ET
Q
q
0.000 0.000 0.000 rg
BT 291.710 19.825 Td /F1 11.0 Tf  [(2)] TJ ET
BT 25.000 19.825 Td /F1 11.0 Tf  [(PLOS Currents Evidence on Genomic Tests)] TJ ET
0.39 w 1 J 1 j
Q
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/Length 33688 >>
stream

0.271 0.267 0.267 rg
0.39 w 1 J 1 j
q
15.000 21.735 577.500 755.265 re W n
0.271 0.267 0.267 rg
BT 26.250 767.476 Td /F4 9.8 Tf  [(Inclusion of tests in this table does not constitute an endorsement of any test by the Centers for Disease Control and )] TJ ET
BT 26.250 755.571 Td /F4 9.8 Tf  [(Prevention \(CDC\) nor the Department of Health and Human Services \(DHHS\) of the U.S. government. No endorsement )] TJ ET
BT 26.250 743.667 Td /F4 9.8 Tf  [(should be inferred.)] TJ ET
BT 26.250 707.064 Td /F4 12.0 Tf  [(Public Health Importance)] TJ ET
BT 26.250 687.110 Td /F1 9.8 Tf  [(Clopidogrel is the second highest top-selling drug in the world )] TJ ET
0.267 0.267 0.267 rg
BT 294.492 687.110 Td /F1 9.8 Tf  [([6])] TJ ET
0.271 0.267 0.267 rg
BT 305.334 687.110 Td /F1 9.8 Tf  [( ; approximately 29 million prescriptions were dispensed in )] TJ ET
BT 26.250 675.205 Td /F1 9.8 Tf  [(2008 in the United States alone )] TJ ET
0.267 0.267 0.267 rg
BT 165.002 675.205 Td /F1 9.8 Tf  [([7])] TJ ET
0.271 0.267 0.267 rg
BT 175.844 675.205 Td /F1 9.8 Tf  [( .)] TJ ET
BT 26.250 655.800 Td /F1 9.8 Tf  [(Estimates of the prevalence of laboratory-defined clopidogrel non-responsiveness vary widely, but have been estimated at 21-)] TJ ET
BT 26.250 643.896 Td /F1 9.8 Tf  [(26% overall )] TJ ET
0.267 0.267 0.267 rg
BT 79.894 643.896 Td /F1 9.8 Tf  [([8])] TJ ET
BT 90.737 643.896 Td /F1 9.8 Tf  [([9])] TJ ET
BT 101.579 643.896 Td /F1 9.8 Tf  [([10])] TJ ET
0.271 0.267 0.267 rg
BT 117.842 643.896 Td /F1 9.8 Tf  [( .)] TJ ET
BT 26.250 624.491 Td /F1 9.8 Tf  [(An inadequate response to clopidogrel can cause stent thromboses, recurrent ischemic events, and death )] TJ ET
0.267 0.267 0.267 rg
BT 485.270 624.491 Td /F1 9.8 Tf  [([8])] TJ ET
BT 496.112 624.491 Td /F1 9.8 Tf  [([9])] TJ ET
BT 506.954 624.491 Td /F1 9.8 Tf  [([10])] TJ ET
0.271 0.267 0.267 rg
BT 523.217 624.491 Td /F1 9.8 Tf  [( . )] TJ ET
BT 26.250 612.586 Td /F1 9.8 Tf  [(Approximately 9% of patients taking clopidogrel have a major adverse cardiovascular event such as myocardial infarction, )] TJ ET
BT 26.250 600.681 Td /F1 9.8 Tf  [(stroke, or cardiovascular death )] TJ ET
0.267 0.267 0.267 rg
BT 162.262 600.681 Td /F1 9.8 Tf  [([11])] TJ ET
BT 178.525 600.681 Td /F1 9.8 Tf  [([12])] TJ ET
0.271 0.267 0.267 rg
BT 194.788 600.681 Td /F1 9.8 Tf  [( . Alternately, an enhanced response to clopidogrel may cause major bleeding )] TJ ET
0.267 0.267 0.267 rg
BT 533.494 600.681 Td /F1 9.8 Tf  [([13])] TJ ET
0.271 0.267 0.267 rg
BT 549.757 600.681 Td /F1 9.8 Tf  [( , )] TJ ET
BT 26.250 588.777 Td /F1 9.8 Tf  [(which typically occurs in �1.5% of patients \(though much higher rates have been reported\) )] TJ ET
0.267 0.267 0.267 rg
BT 415.880 588.777 Td /F1 9.8 Tf  [([11])] TJ ET
BT 432.142 588.777 Td /F1 9.8 Tf  [([12])] TJ ET
BT 448.405 588.777 Td /F1 9.8 Tf  [([13])] TJ ET
BT 464.668 588.777 Td /F1 9.8 Tf  [([14])] TJ ET
0.271 0.267 0.267 rg
BT 480.931 588.777 Td /F1 9.8 Tf  [( .)] TJ ET
BT 26.250 569.372 Td /F1 9.8 Tf  [(Sizeable proportions of some populations possess at least one loss-of-function )] TJ ET
BT 368.202 569.372 Td /F5 9.8 Tf  [(CYP2C19)] TJ ET
BT 411.550 569.372 Td /F1 9.8 Tf  [( allele \(typically *2 or *3\) that could )] TJ ET
BT 26.250 557.467 Td /F1 9.8 Tf  [(affect clopidogrel response: � 30-50% of Asians, 11-16% of Caucasians, and 14-25% of African-Americans )] TJ ET
0.267 0.267 0.267 rg
BT 487.952 557.467 Td /F1 9.8 Tf  [([1])] TJ ET
BT 498.793 557.467 Td /F1 9.8 Tf  [([15])] TJ ET
BT 515.056 557.467 Td /F1 9.8 Tf  [([16])] TJ ET
0.271 0.267 0.267 rg
BT 531.319 557.467 Td /F1 9.8 Tf  [( . It is )] TJ ET
BT 26.250 545.562 Td /F1 9.8 Tf  [(estimated that the )] TJ ET
BT 106.463 545.562 Td /F5 9.8 Tf  [(CYP2C19)] TJ ET
BT 149.812 545.562 Td /F1 9.8 Tf  [( �poor metabolizer� phenotype is exhibited by 10-25% of Asians, 2-3% of Caucasians, and 4% of )] TJ ET
BT 26.250 533.658 Td /F1 9.8 Tf  [(African-Americans )] TJ ET
0.267 0.267 0.267 rg
BT 108.599 533.658 Td /F1 9.8 Tf  [([1])] TJ ET
BT 119.441 533.658 Td /F1 9.8 Tf  [([15])] TJ ET
BT 135.704 533.658 Td /F1 9.8 Tf  [([16])] TJ ET
0.271 0.267 0.267 rg
BT 151.966 533.658 Td /F1 9.8 Tf  [( . )] TJ ET
BT 160.098 533.658 Td /F5 9.8 Tf  [(CYP2C19*2)] TJ ET
BT 212.660 533.658 Td /F1 9.8 Tf  [( and )] TJ ET
BT 234.344 533.658 Td /F5 9.8 Tf  [(*3)] TJ ET
BT 243.558 533.658 Td /F1 9.8 Tf  [( account for more than 95% of cases of the �poor metabolizer� phenotype )] TJ ET
0.267 0.267 0.267 rg
BT 562.217 533.658 Td /F1 9.8 Tf  [([1])] TJ ET
0.271 0.267 0.267 rg
BT 573.059 533.658 Td /F1 9.8 Tf  [( . )] TJ ET
BT 26.250 521.753 Td /F1 9.8 Tf  [(The allele frequency of )] TJ ET
BT 127.591 521.753 Td /F5 9.8 Tf  [(CYP2C19*17)] TJ ET
BT 185.575 521.753 Td /F1 9.8 Tf  [( is estimated as 18-27% among Caucasians, 17-18% among Africans/African-Americans, )] TJ ET
BT 26.250 509.848 Td /F1 9.8 Tf  [(and 0.5 � 4% among Asians )] TJ ET
0.267 0.267 0.267 rg
BT 150.904 509.848 Td /F1 9.8 Tf  [([4])] TJ ET
0.271 0.267 0.267 rg
BT 26.250 490.443 Td /F1 9.8 Tf  [(Recently, the U.S. Food and Drug Administration \(FDA\) issued a black box warning for clopidogrel due to the reduced )] TJ ET
BT 26.250 478.539 Td /F1 9.8 Tf  [(effectiveness of the drug in poor metabolizers )] TJ ET
0.267 0.267 0.267 rg
BT 225.677 478.539 Td /F1 9.8 Tf  [([17])] TJ ET
BT 241.940 478.539 Td /F1 9.8 Tf  [([18])] TJ ET
0.271 0.267 0.267 rg
BT 258.202 478.539 Td /F1 9.8 Tf  [( .)] TJ ET
BT 26.250 441.936 Td /F4 12.0 Tf  [(Published Reviews, Recommendations and Guidelines)] TJ ET
BT 26.250 421.982 Td /F4 9.8 Tf  [(Systematic evidence reviews)] TJ ET
BT 26.250 402.577 Td /F1 9.8 Tf  [(None.)] TJ ET
BT 26.250 383.172 Td /F4 9.8 Tf  [(Recommendations by independent group)] TJ ET
BT 26.250 363.768 Td /F1 9.8 Tf  [(None.)] TJ ET
BT 26.250 344.363 Td /F4 9.8 Tf  [(Guidelines by professional groups)] TJ ET
BT 26.250 324.958 Td /F1 9.8 Tf  [(In July 2010, the American College of Cardiology Foundation \(ACCF\) and the American Heart Association \(AHA\) published a )] TJ ET
BT 26.250 313.053 Td /F1 9.8 Tf  [(Clinical Alert in response to the FDA�s black box warning on clopidogrel )] TJ ET
0.267 0.267 0.267 rg
BT 336.739 313.053 Td /F1 9.8 Tf  [([19])] TJ ET
0.271 0.267 0.267 rg
BT 353.002 313.053 Td /F1 9.8 Tf  [( . The report stated that:)] TJ ET
0.271 0.267 0.267 RG
40.337 296.616 m 
40.337 297.063 40.154 297.507 39.838 297.823 c
39.522 298.139 39.078 298.322 38.631 298.322 c
38.185 298.322 37.741 298.139 37.425 297.823 c
37.109 297.507 36.925 297.063 36.925 296.616 c
36.925 296.170 37.109 295.726 37.425 295.410 c
37.741 295.094 38.185 294.910 38.631 294.910 c
39.078 294.910 39.522 295.094 39.838 295.410 c
40.154 295.726 40.337 296.170 40.337 296.616 c f
BT 45.750 293.649 Td /F1 9.8 Tf  [(The evidence base is insufficient to recommend routine genetic testing at the present time.)] TJ ET
40.337 280.962 m 
40.337 281.408 40.154 281.852 39.838 282.168 c
39.522 282.484 39.078 282.668 38.631 282.668 c
38.185 282.668 37.741 282.484 37.425 282.168 c
37.109 281.852 36.925 281.408 36.925 280.962 c
36.925 280.515 37.109 280.071 37.425 279.755 c
37.741 279.439 38.185 279.255 38.631 279.255 c
39.078 279.255 39.522 279.439 39.838 279.755 c
40.154 280.071 40.337 280.515 40.337 280.962 c f
BT 45.750 277.994 Td /F1 9.8 Tf  [(�Clinical judgment is required to assess clinical risk and variability in patients considered to be at increased risk. Genetic )] TJ ET
BT 45.750 266.089 Td /F1 9.8 Tf  [(testing to determine if a patient is predisposed to poor clopidogrel metabolism \(�poor metabolizers�\) may be considered )] TJ ET
BT 45.750 254.184 Td /F1 9.8 Tf  [(before starting clopidogrel therapy in patients believed to be at moderate or high risk for poor outcomes. This might include, )] TJ ET
BT 45.750 242.280 Td /F1 9.8 Tf  [(among others, patients undergoing elective high-risk PCI procedures \(e.g., treatment of extensive and/or very complex )] TJ ET
BT 45.750 230.375 Td /F1 9.8 Tf  [(disease\).�)] TJ ET
BT 26.250 207.220 Td /F4 9.8 Tf  [(Other guidelines)] TJ ET
BT 26.250 187.815 Td /F1 9.8 Tf  [(The U.S. Food and Drug Administration \(FDA\) determined in 2009 that the available data have �provided compelling evidence )] TJ ET
BT 26.250 175.911 Td /F1 9.8 Tf  [(that genetic variation in )] TJ ET
BT 129.220 175.911 Td /F5 9.8 Tf  [(CYP2C19)] TJ ET
BT 172.568 175.911 Td /F1 9.8 Tf  [( is a significant and independent predictor of clopidogrel pharmacokinetics, )] TJ ET
BT 26.250 164.006 Td /F1 9.8 Tf  [(pharmacodynamics and clinical response�, which prompted the FDA to change clopidogrel�s prescribing information )] TJ ET
0.267 0.267 0.267 rg
BT 526.932 164.006 Td /F1 9.8 Tf  [([3])] TJ ET
BT 537.774 164.006 Td /F1 9.8 Tf  [([20])] TJ ET
BT 554.037 164.006 Td /F1 9.8 Tf  [([21])] TJ ET
0.271 0.267 0.267 rg
BT 570.300 164.006 Td /F1 9.8 Tf  [( . )] TJ ET
BT 26.250 152.101 Td /F1 9.8 Tf  [(More recently \(March 12, 2010\), the FDA issued a black box warning for clopidogrel )] TJ ET
0.267 0.267 0.267 rg
BT 389.847 152.101 Td /F1 9.8 Tf  [([17])] TJ ET
BT 406.110 152.101 Td /F1 9.8 Tf  [([18])] TJ ET
0.271 0.267 0.267 rg
BT 422.373 152.101 Td /F1 9.8 Tf  [( due to the reduced effectiveness of )] TJ ET
BT 26.250 140.196 Td /F1 9.8 Tf  [(the drug in poor metabolizers. The FDA recommended that health professionals be aware that some patients may be poor )] TJ ET
BT 26.250 128.292 Td /F1 9.8 Tf  [(metabolizers of clopidogrel because of low CYP2C19 activity and to also �be aware that tests are available to determine )] TJ ET
BT 26.250 116.387 Td /F1 9.8 Tf  [(patients� CYP2C19 status� )] TJ ET
0.267 0.267 0.267 rg
BT 143.299 116.387 Td /F1 9.8 Tf  [([17])] TJ ET
0.271 0.267 0.267 rg
BT 159.562 116.387 Td /F1 9.8 Tf  [( . )] TJ ET
BT 167.693 116.387 Td /F4 9.8 Tf  [( The FDA neither mandated nor explicitly recommended )] TJ ET
BT 429.383 116.387 Td /F6 9.8 Tf  [(CYP2C19)] TJ ET
BT 472.732 116.387 Td /F4 9.8 Tf  [( genetic testing in )] TJ ET
BT 26.250 104.482 Td /F4 9.8 Tf  [(patients prescribed clopidogrel )] TJ ET
BT 174.167 104.482 Td /F1 9.8 Tf  [( , and the agency did not offer any specific guidance on drug dosing in )] TJ ET
BT 479.303 104.482 Td /F5 9.8 Tf  [(CYP2C19)] TJ ET
BT 522.652 104.482 Td /F1 9.8 Tf  [( variant )] TJ ET
BT 26.250 92.577 Td /F1 9.8 Tf  [(allele carriers )] TJ ET
0.267 0.267 0.267 rg
BT 86.924 92.577 Td /F1 9.8 Tf  [([17])] TJ ET
0.271 0.267 0.267 rg
BT 103.187 92.577 Td /F1 9.8 Tf  [( . The November 2009 label update did recommend that doctors avoid use of clopidogrel �in patients with )] TJ ET
BT 26.250 80.673 Td /F1 9.8 Tf  [(impaired CYP2C19 function due to known genetic variation or due to drugs that inhibit CYP2C19 activity� )] TJ ET
0.267 0.267 0.267 rg
BT 480.912 80.673 Td /F1 9.8 Tf  [([21])] TJ ET
0.271 0.267 0.267 rg
BT 497.175 80.673 Td /F1 9.8 Tf  [( , while the more )] TJ ET
BT 26.250 68.768 Td /F1 9.8 Tf  [(recent warning no longer specifically advises against use of clopidogrel in )] TJ ET
BT 345.426 68.768 Td /F5 9.8 Tf  [(CYP2C19)] TJ ET
BT 388.774 68.768 Td /F1 9.8 Tf  [( poor metabolizers )] TJ ET
0.267 0.267 0.267 rg
BT 471.679 68.768 Td /F1 9.8 Tf  [([17])] TJ ET
0.271 0.267 0.267 rg
BT 487.942 68.768 Td /F1 9.8 Tf  [( .)] TJ ET
Q
q
15.000 21.735 577.500 755.265 re W n
0.271 0.267 0.267 rg
BT 26.250 767.476 Td /F4 9.8 Tf  [(Inclusion of tests in this table does not constitute an endorsement of any test by the Centers for Disease Control and )] TJ ET
BT 26.250 755.571 Td /F4 9.8 Tf  [(Prevention \(CDC\) nor the Department of Health and Human Services \(DHHS\) of the U.S. government. No endorsement )] TJ ET
BT 26.250 743.667 Td /F4 9.8 Tf  [(should be inferred.)] TJ ET
BT 26.250 707.064 Td /F4 12.0 Tf  [(Public Health Importance)] TJ ET
BT 26.250 687.110 Td /F1 9.8 Tf  [(Clopidogrel is the second highest top-selling drug in the world )] TJ ET
0.267 0.267 0.267 rg
BT 294.492 687.110 Td /F1 9.8 Tf  [([6])] TJ ET
0.271 0.267 0.267 rg
BT 305.334 687.110 Td /F1 9.8 Tf  [( ; approximately 29 million prescriptions were dispensed in )] TJ ET
BT 26.250 675.205 Td /F1 9.8 Tf  [(2008 in the United States alone )] TJ ET
0.267 0.267 0.267 rg
BT 165.002 675.205 Td /F1 9.8 Tf  [([7])] TJ ET
0.271 0.267 0.267 rg
BT 175.844 675.205 Td /F1 9.8 Tf  [( .)] TJ ET
BT 26.250 655.800 Td /F1 9.8 Tf  [(Estimates of the prevalence of laboratory-defined clopidogrel non-responsiveness vary widely, but have been estimated at 21-)] TJ ET
BT 26.250 643.896 Td /F1 9.8 Tf  [(26% overall )] TJ ET
0.267 0.267 0.267 rg
BT 79.894 643.896 Td /F1 9.8 Tf  [([8])] TJ ET
BT 90.737 643.896 Td /F1 9.8 Tf  [([9])] TJ ET
BT 101.579 643.896 Td /F1 9.8 Tf  [([10])] TJ ET
0.271 0.267 0.267 rg
BT 117.842 643.896 Td /F1 9.8 Tf  [( .)] TJ ET
BT 26.250 624.491 Td /F1 9.8 Tf  [(An inadequate response to clopidogrel can cause stent thromboses, recurrent ischemic events, and death )] TJ ET
0.267 0.267 0.267 rg
BT 485.270 624.491 Td /F1 9.8 Tf  [([8])] TJ ET
BT 496.112 624.491 Td /F1 9.8 Tf  [([9])] TJ ET
BT 506.954 624.491 Td /F1 9.8 Tf  [([10])] TJ ET
0.271 0.267 0.267 rg
BT 523.217 624.491 Td /F1 9.8 Tf  [( . )] TJ ET
BT 26.250 612.586 Td /F1 9.8 Tf  [(Approximately 9% of patients taking clopidogrel have a major adverse cardiovascular event such as myocardial infarction, )] TJ ET
BT 26.250 600.681 Td /F1 9.8 Tf  [(stroke, or cardiovascular death )] TJ ET
0.267 0.267 0.267 rg
BT 162.262 600.681 Td /F1 9.8 Tf  [([11])] TJ ET
BT 178.525 600.681 Td /F1 9.8 Tf  [([12])] TJ ET
0.271 0.267 0.267 rg
BT 194.788 600.681 Td /F1 9.8 Tf  [( . Alternately, an enhanced response to clopidogrel may cause major bleeding )] TJ ET
0.267 0.267 0.267 rg
BT 533.494 600.681 Td /F1 9.8 Tf  [([13])] TJ ET
0.271 0.267 0.267 rg
BT 549.757 600.681 Td /F1 9.8 Tf  [( , )] TJ ET
BT 26.250 588.777 Td /F1 9.8 Tf  [(which typically occurs in �1.5% of patients \(though much higher rates have been reported\) )] TJ ET
0.267 0.267 0.267 rg
BT 415.880 588.777 Td /F1 9.8 Tf  [([11])] TJ ET
BT 432.142 588.777 Td /F1 9.8 Tf  [([12])] TJ ET
BT 448.405 588.777 Td /F1 9.8 Tf  [([13])] TJ ET
BT 464.668 588.777 Td /F1 9.8 Tf  [([14])] TJ ET
0.271 0.267 0.267 rg
BT 480.931 588.777 Td /F1 9.8 Tf  [( .)] TJ ET
BT 26.250 569.372 Td /F1 9.8 Tf  [(Sizeable proportions of some populations possess at least one loss-of-function )] TJ ET
BT 368.202 569.372 Td /F5 9.8 Tf  [(CYP2C19)] TJ ET
BT 411.550 569.372 Td /F1 9.8 Tf  [( allele \(typically *2 or *3\) that could )] TJ ET
BT 26.250 557.467 Td /F1 9.8 Tf  [(affect clopidogrel response: � 30-50% of Asians, 11-16% of Caucasians, and 14-25% of African-Americans )] TJ ET
0.267 0.267 0.267 rg
BT 487.952 557.467 Td /F1 9.8 Tf  [([1])] TJ ET
BT 498.793 557.467 Td /F1 9.8 Tf  [([15])] TJ ET
BT 515.056 557.467 Td /F1 9.8 Tf  [([16])] TJ ET
0.271 0.267 0.267 rg
BT 531.319 557.467 Td /F1 9.8 Tf  [( . It is )] TJ ET
BT 26.250 545.562 Td /F1 9.8 Tf  [(estimated that the )] TJ ET
BT 106.463 545.562 Td /F5 9.8 Tf  [(CYP2C19)] TJ ET
BT 149.812 545.562 Td /F1 9.8 Tf  [( �poor metabolizer� phenotype is exhibited by 10-25% of Asians, 2-3% of Caucasians, and 4% of )] TJ ET
BT 26.250 533.658 Td /F1 9.8 Tf  [(African-Americans )] TJ ET
0.267 0.267 0.267 rg
BT 108.599 533.658 Td /F1 9.8 Tf  [([1])] TJ ET
BT 119.441 533.658 Td /F1 9.8 Tf  [([15])] TJ ET
BT 135.704 533.658 Td /F1 9.8 Tf  [([16])] TJ ET
0.271 0.267 0.267 rg
BT 151.966 533.658 Td /F1 9.8 Tf  [( . )] TJ ET
BT 160.098 533.658 Td /F5 9.8 Tf  [(CYP2C19*2)] TJ ET
BT 212.660 533.658 Td /F1 9.8 Tf  [( and )] TJ ET
BT 234.344 533.658 Td /F5 9.8 Tf  [(*3)] TJ ET
BT 243.558 533.658 Td /F1 9.8 Tf  [( account for more than 95% of cases of the �poor metabolizer� phenotype )] TJ ET
0.267 0.267 0.267 rg
BT 562.217 533.658 Td /F1 9.8 Tf  [([1])] TJ ET
0.271 0.267 0.267 rg
BT 573.059 533.658 Td /F1 9.8 Tf  [( . )] TJ ET
BT 26.250 521.753 Td /F1 9.8 Tf  [(The allele frequency of )] TJ ET
BT 127.591 521.753 Td /F5 9.8 Tf  [(CYP2C19*17)] TJ ET
BT 185.575 521.753 Td /F1 9.8 Tf  [( is estimated as 18-27% among Caucasians, 17-18% among Africans/African-Americans, )] TJ ET
BT 26.250 509.848 Td /F1 9.8 Tf  [(and 0.5 � 4% among Asians )] TJ ET
0.267 0.267 0.267 rg
BT 150.904 509.848 Td /F1 9.8 Tf  [([4])] TJ ET
0.271 0.267 0.267 rg
BT 26.250 490.443 Td /F1 9.8 Tf  [(Recently, the U.S. Food and Drug Administration \(FDA\) issued a black box warning for clopidogrel due to the reduced )] TJ ET
BT 26.250 478.539 Td /F1 9.8 Tf  [(effectiveness of the drug in poor metabolizers )] TJ ET
0.267 0.267 0.267 rg
BT 225.677 478.539 Td /F1 9.8 Tf  [([17])] TJ ET
BT 241.940 478.539 Td /F1 9.8 Tf  [([18])] TJ ET
0.271 0.267 0.267 rg
BT 258.202 478.539 Td /F1 9.8 Tf  [( .)] TJ ET
BT 26.250 441.936 Td /F4 12.0 Tf  [(Published Reviews, Recommendations and Guidelines)] TJ ET
BT 26.250 421.982 Td /F4 9.8 Tf  [(Systematic evidence reviews)] TJ ET
BT 26.250 402.577 Td /F1 9.8 Tf  [(None.)] TJ ET
BT 26.250 383.172 Td /F4 9.8 Tf  [(Recommendations by independent group)] TJ ET
BT 26.250 363.768 Td /F1 9.8 Tf  [(None.)] TJ ET
BT 26.250 344.363 Td /F4 9.8 Tf  [(Guidelines by professional groups)] TJ ET
BT 26.250 324.958 Td /F1 9.8 Tf  [(In July 2010, the American College of Cardiology Foundation \(ACCF\) and the American Heart Association \(AHA\) published a )] TJ ET
BT 26.250 313.053 Td /F1 9.8 Tf  [(Clinical Alert in response to the FDA�s black box warning on clopidogrel )] TJ ET
0.267 0.267 0.267 rg
BT 336.739 313.053 Td /F1 9.8 Tf  [([19])] TJ ET
0.271 0.267 0.267 rg
BT 353.002 313.053 Td /F1 9.8 Tf  [( . The report stated that:)] TJ ET
0.271 0.267 0.267 RG
40.337 296.616 m 
40.337 297.063 40.154 297.507 39.838 297.823 c
39.522 298.139 39.078 298.322 38.631 298.322 c
38.185 298.322 37.741 298.139 37.425 297.823 c
37.109 297.507 36.925 297.063 36.925 296.616 c
36.925 296.170 37.109 295.726 37.425 295.410 c
37.741 295.094 38.185 294.910 38.631 294.910 c
39.078 294.910 39.522 295.094 39.838 295.410 c
40.154 295.726 40.337 296.170 40.337 296.616 c f
BT 45.750 293.649 Td /F1 9.8 Tf  [(The evidence base is insufficient to recommend routine genetic testing at the present time.)] TJ ET
40.337 280.962 m 
40.337 281.408 40.154 281.852 39.838 282.168 c
39.522 282.484 39.078 282.668 38.631 282.668 c
38.185 282.668 37.741 282.484 37.425 282.168 c
37.109 281.852 36.925 281.408 36.925 280.962 c
36.925 280.515 37.109 280.071 37.425 279.755 c
37.741 279.439 38.185 279.255 38.631 279.255 c
39.078 279.255 39.522 279.439 39.838 279.755 c
40.154 280.071 40.337 280.515 40.337 280.962 c f
BT 45.750 277.994 Td /F1 9.8 Tf  [(�Clinical judgment is required to assess clinical risk and variability in patients considered to be at increased risk. Genetic )] TJ ET
BT 45.750 266.089 Td /F1 9.8 Tf  [(testing to determine if a patient is predisposed to poor clopidogrel metabolism \(�poor metabolizers�\) may be considered )] TJ ET
BT 45.750 254.184 Td /F1 9.8 Tf  [(before starting clopidogrel therapy in patients believed to be at moderate or high risk for poor outcomes. This might include, )] TJ ET
BT 45.750 242.280 Td /F1 9.8 Tf  [(among others, patients undergoing elective high-risk PCI procedures \(e.g., treatment of extensive and/or very complex )] TJ ET
BT 45.750 230.375 Td /F1 9.8 Tf  [(disease\).�)] TJ ET
BT 26.250 207.220 Td /F4 9.8 Tf  [(Other guidelines)] TJ ET
BT 26.250 187.815 Td /F1 9.8 Tf  [(The U.S. Food and Drug Administration \(FDA\) determined in 2009 that the available data have �provided compelling evidence )] TJ ET
BT 26.250 175.911 Td /F1 9.8 Tf  [(that genetic variation in )] TJ ET
BT 129.220 175.911 Td /F5 9.8 Tf  [(CYP2C19)] TJ ET
BT 172.568 175.911 Td /F1 9.8 Tf  [( is a significant and independent predictor of clopidogrel pharmacokinetics, )] TJ ET
BT 26.250 164.006 Td /F1 9.8 Tf  [(pharmacodynamics and clinical response�, which prompted the FDA to change clopidogrel�s prescribing information )] TJ ET
0.267 0.267 0.267 rg
BT 526.932 164.006 Td /F1 9.8 Tf  [([3])] TJ ET
BT 537.774 164.006 Td /F1 9.8 Tf  [([20])] TJ ET
BT 554.037 164.006 Td /F1 9.8 Tf  [([21])] TJ ET
0.271 0.267 0.267 rg
BT 570.300 164.006 Td /F1 9.8 Tf  [( . )] TJ ET
BT 26.250 152.101 Td /F1 9.8 Tf  [(More recently \(March 12, 2010\), the FDA issued a black box warning for clopidogrel )] TJ ET
0.267 0.267 0.267 rg
BT 389.847 152.101 Td /F1 9.8 Tf  [([17])] TJ ET
BT 406.110 152.101 Td /F1 9.8 Tf  [([18])] TJ ET
0.271 0.267 0.267 rg
BT 422.373 152.101 Td /F1 9.8 Tf  [( due to the reduced effectiveness of )] TJ ET
BT 26.250 140.196 Td /F1 9.8 Tf  [(the drug in poor metabolizers. The FDA recommended that health professionals be aware that some patients may be poor )] TJ ET
BT 26.250 128.292 Td /F1 9.8 Tf  [(metabolizers of clopidogrel because of low CYP2C19 activity and to also �be aware that tests are available to determine )] TJ ET
BT 26.250 116.387 Td /F1 9.8 Tf  [(patients� CYP2C19 status� )] TJ ET
0.267 0.267 0.267 rg
BT 143.299 116.387 Td /F1 9.8 Tf  [([17])] TJ ET
0.271 0.267 0.267 rg
BT 159.562 116.387 Td /F1 9.8 Tf  [( . )] TJ ET
BT 167.693 116.387 Td /F4 9.8 Tf  [( The FDA neither mandated nor explicitly recommended )] TJ ET
BT 429.383 116.387 Td /F6 9.8 Tf  [(CYP2C19)] TJ ET
BT 472.732 116.387 Td /F4 9.8 Tf  [( genetic testing in )] TJ ET
BT 26.250 104.482 Td /F4 9.8 Tf  [(patients prescribed clopidogrel )] TJ ET
BT 174.167 104.482 Td /F1 9.8 Tf  [( , and the agency did not offer any specific guidance on drug dosing in )] TJ ET
BT 479.303 104.482 Td /F5 9.8 Tf  [(CYP2C19)] TJ ET
BT 522.652 104.482 Td /F1 9.8 Tf  [( variant )] TJ ET
BT 26.250 92.577 Td /F1 9.8 Tf  [(allele carriers )] TJ ET
0.267 0.267 0.267 rg
BT 86.924 92.577 Td /F1 9.8 Tf  [([17])] TJ ET
0.271 0.267 0.267 rg
BT 103.187 92.577 Td /F1 9.8 Tf  [( . The November 2009 label update did recommend that doctors avoid use of clopidogrel �in patients with )] TJ ET
BT 26.250 80.673 Td /F1 9.8 Tf  [(impaired CYP2C19 function due to known genetic variation or due to drugs that inhibit CYP2C19 activity� )] TJ ET
0.267 0.267 0.267 rg
BT 480.912 80.673 Td /F1 9.8 Tf  [([21])] TJ ET
0.271 0.267 0.267 rg
BT 497.175 80.673 Td /F1 9.8 Tf  [( , while the more )] TJ ET
BT 26.250 68.768 Td /F1 9.8 Tf  [(recent warning no longer specifically advises against use of clopidogrel in )] TJ ET
BT 345.426 68.768 Td /F5 9.8 Tf  [(CYP2C19)] TJ ET
BT 388.774 68.768 Td /F1 9.8 Tf  [( poor metabolizers )] TJ ET
0.267 0.267 0.267 rg
BT 471.679 68.768 Td /F1 9.8 Tf  [([17])] TJ ET
0.271 0.267 0.267 rg
BT 487.942 68.768 Td /F1 9.8 Tf  [( .)] TJ ET
Q
q
15.000 21.735 577.500 755.265 re W n
0.271 0.267 0.267 rg
BT 26.250 767.476 Td /F4 9.8 Tf  [(Inclusion of tests in this table does not constitute an endorsement of any test by the Centers for Disease Control and )] TJ ET
BT 26.250 755.571 Td /F4 9.8 Tf  [(Prevention \(CDC\) nor the Department of Health and Human Services \(DHHS\) of the U.S. government. No endorsement )] TJ ET
BT 26.250 743.667 Td /F4 9.8 Tf  [(should be inferred.)] TJ ET
BT 26.250 707.064 Td /F4 12.0 Tf  [(Public Health Importance)] TJ ET
BT 26.250 687.110 Td /F1 9.8 Tf  [(Clopidogrel is the second highest top-selling drug in the world )] TJ ET
0.267 0.267 0.267 rg
BT 294.492 687.110 Td /F1 9.8 Tf  [([6])] TJ ET
0.271 0.267 0.267 rg
BT 305.334 687.110 Td /F1 9.8 Tf  [( ; approximately 29 million prescriptions were dispensed in )] TJ ET
BT 26.250 675.205 Td /F1 9.8 Tf  [(2008 in the United States alone )] TJ ET
0.267 0.267 0.267 rg
BT 165.002 675.205 Td /F1 9.8 Tf  [([7])] TJ ET
0.271 0.267 0.267 rg
BT 175.844 675.205 Td /F1 9.8 Tf  [( .)] TJ ET
BT 26.250 655.800 Td /F1 9.8 Tf  [(Estimates of the prevalence of laboratory-defined clopidogrel non-responsiveness vary widely, but have been estimated at 21-)] TJ ET
BT 26.250 643.896 Td /F1 9.8 Tf  [(26% overall )] TJ ET
0.267 0.267 0.267 rg
BT 79.894 643.896 Td /F1 9.8 Tf  [([8])] TJ ET
BT 90.737 643.896 Td /F1 9.8 Tf  [([9])] TJ ET
BT 101.579 643.896 Td /F1 9.8 Tf  [([10])] TJ ET
0.271 0.267 0.267 rg
BT 117.842 643.896 Td /F1 9.8 Tf  [( .)] TJ ET
BT 26.250 624.491 Td /F1 9.8 Tf  [(An inadequate response to clopidogrel can cause stent thromboses, recurrent ischemic events, and death )] TJ ET
0.267 0.267 0.267 rg
BT 485.270 624.491 Td /F1 9.8 Tf  [([8])] TJ ET
BT 496.112 624.491 Td /F1 9.8 Tf  [([9])] TJ ET
BT 506.954 624.491 Td /F1 9.8 Tf  [([10])] TJ ET
0.271 0.267 0.267 rg
BT 523.217 624.491 Td /F1 9.8 Tf  [( . )] TJ ET
BT 26.250 612.586 Td /F1 9.8 Tf  [(Approximately 9% of patients taking clopidogrel have a major adverse cardiovascular event such as myocardial infarction, )] TJ ET
BT 26.250 600.681 Td /F1 9.8 Tf  [(stroke, or cardiovascular death )] TJ ET
0.267 0.267 0.267 rg
BT 162.262 600.681 Td /F1 9.8 Tf  [([11])] TJ ET
BT 178.525 600.681 Td /F1 9.8 Tf  [([12])] TJ ET
0.271 0.267 0.267 rg
BT 194.788 600.681 Td /F1 9.8 Tf  [( . Alternately, an enhanced response to clopidogrel may cause major bleeding )] TJ ET
0.267 0.267 0.267 rg
BT 533.494 600.681 Td /F1 9.8 Tf  [([13])] TJ ET
0.271 0.267 0.267 rg
BT 549.757 600.681 Td /F1 9.8 Tf  [( , )] TJ ET
BT 26.250 588.777 Td /F1 9.8 Tf  [(which typically occurs in �1.5% of patients \(though much higher rates have been reported\) )] TJ ET
0.267 0.267 0.267 rg
BT 415.880 588.777 Td /F1 9.8 Tf  [([11])] TJ ET
BT 432.142 588.777 Td /F1 9.8 Tf  [([12])] TJ ET
BT 448.405 588.777 Td /F1 9.8 Tf  [([13])] TJ ET
BT 464.668 588.777 Td /F1 9.8 Tf  [([14])] TJ ET
0.271 0.267 0.267 rg
BT 480.931 588.777 Td /F1 9.8 Tf  [( .)] TJ ET
BT 26.250 569.372 Td /F1 9.8 Tf  [(Sizeable proportions of some populations possess at least one loss-of-function )] TJ ET
BT 368.202 569.372 Td /F5 9.8 Tf  [(CYP2C19)] TJ ET
BT 411.550 569.372 Td /F1 9.8 Tf  [( allele \(typically *2 or *3\) that could )] TJ ET
BT 26.250 557.467 Td /F1 9.8 Tf  [(affect clopidogrel response: � 30-50% of Asians, 11-16% of Caucasians, and 14-25% of African-Americans )] TJ ET
0.267 0.267 0.267 rg
BT 487.952 557.467 Td /F1 9.8 Tf  [([1])] TJ ET
BT 498.793 557.467 Td /F1 9.8 Tf  [([15])] TJ ET
BT 515.056 557.467 Td /F1 9.8 Tf  [([16])] TJ ET
0.271 0.267 0.267 rg
BT 531.319 557.467 Td /F1 9.8 Tf  [( . It is )] TJ ET
BT 26.250 545.562 Td /F1 9.8 Tf  [(estimated that the )] TJ ET
BT 106.463 545.562 Td /F5 9.8 Tf  [(CYP2C19)] TJ ET
BT 149.812 545.562 Td /F1 9.8 Tf  [( �poor metabolizer� phenotype is exhibited by 10-25% of Asians, 2-3% of Caucasians, and 4% of )] TJ ET
BT 26.250 533.658 Td /F1 9.8 Tf  [(African-Americans )] TJ ET
0.267 0.267 0.267 rg
BT 108.599 533.658 Td /F1 9.8 Tf  [([1])] TJ ET
BT 119.441 533.658 Td /F1 9.8 Tf  [([15])] TJ ET
BT 135.704 533.658 Td /F1 9.8 Tf  [([16])] TJ ET
0.271 0.267 0.267 rg
BT 151.966 533.658 Td /F1 9.8 Tf  [( . )] TJ ET
BT 160.098 533.658 Td /F5 9.8 Tf  [(CYP2C19*2)] TJ ET
BT 212.660 533.658 Td /F1 9.8 Tf  [( and )] TJ ET
BT 234.344 533.658 Td /F5 9.8 Tf  [(*3)] TJ ET
BT 243.558 533.658 Td /F1 9.8 Tf  [( account for more than 95% of cases of the �poor metabolizer� phenotype )] TJ ET
0.267 0.267 0.267 rg
BT 562.217 533.658 Td /F1 9.8 Tf  [([1])] TJ ET
0.271 0.267 0.267 rg
BT 573.059 533.658 Td /F1 9.8 Tf  [( . )] TJ ET
BT 26.250 521.753 Td /F1 9.8 Tf  [(The allele frequency of )] TJ ET
BT 127.591 521.753 Td /F5 9.8 Tf  [(CYP2C19*17)] TJ ET
BT 185.575 521.753 Td /F1 9.8 Tf  [( is estimated as 18-27% among Caucasians, 17-18% among Africans/African-Americans, )] TJ ET
BT 26.250 509.848 Td /F1 9.8 Tf  [(and 0.5 � 4% among Asians )] TJ ET
0.267 0.267 0.267 rg
BT 150.904 509.848 Td /F1 9.8 Tf  [([4])] TJ ET
0.271 0.267 0.267 rg
BT 26.250 490.443 Td /F1 9.8 Tf  [(Recently, the U.S. Food and Drug Administration \(FDA\) issued a black box warning for clopidogrel due to the reduced )] TJ ET
BT 26.250 478.539 Td /F1 9.8 Tf  [(effectiveness of the drug in poor metabolizers )] TJ ET
0.267 0.267 0.267 rg
BT 225.677 478.539 Td /F1 9.8 Tf  [([17])] TJ ET
BT 241.940 478.539 Td /F1 9.8 Tf  [([18])] TJ ET
0.271 0.267 0.267 rg
BT 258.202 478.539 Td /F1 9.8 Tf  [( .)] TJ ET
BT 26.250 441.936 Td /F4 12.0 Tf  [(Published Reviews, Recommendations and Guidelines)] TJ ET
BT 26.250 421.982 Td /F4 9.8 Tf  [(Systematic evidence reviews)] TJ ET
BT 26.250 402.577 Td /F1 9.8 Tf  [(None.)] TJ ET
BT 26.250 383.172 Td /F4 9.8 Tf  [(Recommendations by independent group)] TJ ET
BT 26.250 363.768 Td /F1 9.8 Tf  [(None.)] TJ ET
BT 26.250 344.363 Td /F4 9.8 Tf  [(Guidelines by professional groups)] TJ ET
BT 26.250 324.958 Td /F1 9.8 Tf  [(In July 2010, the American College of Cardiology Foundation \(ACCF\) and the American Heart Association \(AHA\) published a )] TJ ET
BT 26.250 313.053 Td /F1 9.8 Tf  [(Clinical Alert in response to the FDA�s black box warning on clopidogrel )] TJ ET
0.267 0.267 0.267 rg
BT 336.739 313.053 Td /F1 9.8 Tf  [([19])] TJ ET
0.271 0.267 0.267 rg
BT 353.002 313.053 Td /F1 9.8 Tf  [( . The report stated that:)] TJ ET
0.271 0.267 0.267 RG
40.337 296.616 m 
40.337 297.063 40.154 297.507 39.838 297.823 c
39.522 298.139 39.078 298.322 38.631 298.322 c
38.185 298.322 37.741 298.139 37.425 297.823 c
37.109 297.507 36.925 297.063 36.925 296.616 c
36.925 296.170 37.109 295.726 37.425 295.410 c
37.741 295.094 38.185 294.910 38.631 294.910 c
39.078 294.910 39.522 295.094 39.838 295.410 c
40.154 295.726 40.337 296.170 40.337 296.616 c f
BT 45.750 293.649 Td /F1 9.8 Tf  [(The evidence base is insufficient to recommend routine genetic testing at the present time.)] TJ ET
40.337 280.962 m 
40.337 281.408 40.154 281.852 39.838 282.168 c
39.522 282.484 39.078 282.668 38.631 282.668 c
38.185 282.668 37.741 282.484 37.425 282.168 c
37.109 281.852 36.925 281.408 36.925 280.962 c
36.925 280.515 37.109 280.071 37.425 279.755 c
37.741 279.439 38.185 279.255 38.631 279.255 c
39.078 279.255 39.522 279.439 39.838 279.755 c
40.154 280.071 40.337 280.515 40.337 280.962 c f
BT 45.750 277.994 Td /F1 9.8 Tf  [(�Clinical judgment is required to assess clinical risk and variability in patients considered to be at increased risk. Genetic )] TJ ET
BT 45.750 266.089 Td /F1 9.8 Tf  [(testing to determine if a patient is predisposed to poor clopidogrel metabolism \(�poor metabolizers�\) may be considered )] TJ ET
BT 45.750 254.184 Td /F1 9.8 Tf  [(before starting clopidogrel therapy in patients believed to be at moderate or high risk for poor outcomes. This might include, )] TJ ET
BT 45.750 242.280 Td /F1 9.8 Tf  [(among others, patients undergoing elective high-risk PCI procedures \(e.g., treatment of extensive and/or very complex )] TJ ET
BT 45.750 230.375 Td /F1 9.8 Tf  [(disease\).�)] TJ ET
BT 26.250 207.220 Td /F4 9.8 Tf  [(Other guidelines)] TJ ET
BT 26.250 187.815 Td /F1 9.8 Tf  [(The U.S. Food and Drug Administration \(FDA\) determined in 2009 that the available data have �provided compelling evidence )] TJ ET
BT 26.250 175.911 Td /F1 9.8 Tf  [(that genetic variation in )] TJ ET
BT 129.220 175.911 Td /F5 9.8 Tf  [(CYP2C19)] TJ ET
BT 172.568 175.911 Td /F1 9.8 Tf  [( is a significant and independent predictor of clopidogrel pharmacokinetics, )] TJ ET
BT 26.250 164.006 Td /F1 9.8 Tf  [(pharmacodynamics and clinical response�, which prompted the FDA to change clopidogrel�s prescribing information )] TJ ET
0.267 0.267 0.267 rg
BT 526.932 164.006 Td /F1 9.8 Tf  [([3])] TJ ET
BT 537.774 164.006 Td /F1 9.8 Tf  [([20])] TJ ET
BT 554.037 164.006 Td /F1 9.8 Tf  [([21])] TJ ET
0.271 0.267 0.267 rg
BT 570.300 164.006 Td /F1 9.8 Tf  [( . )] TJ ET
BT 26.250 152.101 Td /F1 9.8 Tf  [(More recently \(March 12, 2010\), the FDA issued a black box warning for clopidogrel )] TJ ET
0.267 0.267 0.267 rg
BT 389.847 152.101 Td /F1 9.8 Tf  [([17])] TJ ET
BT 406.110 152.101 Td /F1 9.8 Tf  [([18])] TJ ET
0.271 0.267 0.267 rg
BT 422.373 152.101 Td /F1 9.8 Tf  [( due to the reduced effectiveness of )] TJ ET
BT 26.250 140.196 Td /F1 9.8 Tf  [(the drug in poor metabolizers. The FDA recommended that health professionals be aware that some patients may be poor )] TJ ET
BT 26.250 128.292 Td /F1 9.8 Tf  [(metabolizers of clopidogrel because of low CYP2C19 activity and to also �be aware that tests are available to determine )] TJ ET
BT 26.250 116.387 Td /F1 9.8 Tf  [(patients� CYP2C19 status� )] TJ ET
0.267 0.267 0.267 rg
BT 143.299 116.387 Td /F1 9.8 Tf  [([17])] TJ ET
0.271 0.267 0.267 rg
BT 159.562 116.387 Td /F1 9.8 Tf  [( . )] TJ ET
BT 167.693 116.387 Td /F4 9.8 Tf  [( The FDA neither mandated nor explicitly recommended )] TJ ET
BT 429.383 116.387 Td /F6 9.8 Tf  [(CYP2C19)] TJ ET
BT 472.732 116.387 Td /F4 9.8 Tf  [( genetic testing in )] TJ ET
BT 26.250 104.482 Td /F4 9.8 Tf  [(patients prescribed clopidogrel )] TJ ET
BT 174.167 104.482 Td /F1 9.8 Tf  [( , and the agency did not offer any specific guidance on drug dosing in )] TJ ET
BT 479.303 104.482 Td /F5 9.8 Tf  [(CYP2C19)] TJ ET
BT 522.652 104.482 Td /F1 9.8 Tf  [( variant )] TJ ET
BT 26.250 92.577 Td /F1 9.8 Tf  [(allele carriers )] TJ ET
0.267 0.267 0.267 rg
BT 86.924 92.577 Td /F1 9.8 Tf  [([17])] TJ ET
0.271 0.267 0.267 rg
BT 103.187 92.577 Td /F1 9.8 Tf  [( . The November 2009 label update did recommend that doctors avoid use of clopidogrel �in patients with )] TJ ET
BT 26.250 80.673 Td /F1 9.8 Tf  [(impaired CYP2C19 function due to known genetic variation or due to drugs that inhibit CYP2C19 activity� )] TJ ET
0.267 0.267 0.267 rg
BT 480.912 80.673 Td /F1 9.8 Tf  [([21])] TJ ET
0.271 0.267 0.267 rg
BT 497.175 80.673 Td /F1 9.8 Tf  [( , while the more )] TJ ET
BT 26.250 68.768 Td /F1 9.8 Tf  [(recent warning no longer specifically advises against use of clopidogrel in )] TJ ET
BT 345.426 68.768 Td /F5 9.8 Tf  [(CYP2C19)] TJ ET
BT 388.774 68.768 Td /F1 9.8 Tf  [( poor metabolizers )] TJ ET
0.267 0.267 0.267 rg
BT 471.679 68.768 Td /F1 9.8 Tf  [([17])] TJ ET
0.271 0.267 0.267 rg
BT 487.942 68.768 Td /F1 9.8 Tf  [( .)] TJ ET
Q
q
0.000 0.000 0.000 rg
BT 291.710 19.825 Td /F1 11.0 Tf  [(3)] TJ ET
BT 25.000 19.825 Td /F1 11.0 Tf  [(PLOS Currents Evidence on Genomic Tests)] TJ ET
0.39 w 1 J 1 j
Q
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0.271 0.267 0.267 RG
0.39 w 1 J 1 j
q
15.000 27.051 577.500 749.949 re W n
0.271 0.267 0.267 rg
BT 26.250 750.278 Td /F4 12.0 Tf  [(Evidence Overview)] TJ ET
BT 26.250 730.324 Td /F6 9.8 Tf  [(Analytic Validity)] TJ ET
BT 101.569 730.324 Td /F4 9.8 Tf  [( : )] TJ ET
BT 110.236 730.324 Td /F1 9.8 Tf  [( Test accuracy and reliability in identifying )] TJ ET
BT 292.844 730.324 Td /F5 9.8 Tf  [(CYP2C19)] TJ ET
BT 336.193 730.324 Td /F1 9.8 Tf  [( genotypes \(analytic sensitivity and specificity\).)] TJ ET
0.271 0.267 0.267 RG
40.337 713.887 m 
40.337 714.334 40.154 714.778 39.838 715.094 c
39.522 715.409 39.078 715.593 38.631 715.593 c
38.185 715.593 37.741 715.409 37.425 715.094 c
37.109 714.778 36.925 714.334 36.925 713.887 c
36.925 713.440 37.109 712.996 37.425 712.680 c
37.741 712.365 38.185 712.181 38.631 712.181 c
39.078 712.181 39.522 712.365 39.838 712.680 c
40.154 712.996 40.337 713.440 40.337 713.887 c f
BT 45.750 710.919 Td /F1 9.8 Tf  [(When reported, accuracy of the various genotyping methods/platforms used in commercial tests is noted as = 99% )] TJ ET
0.267 0.267 0.267 rg
BT 542.405 710.919 Td /F1 9.8 Tf  [([22])] TJ ET
BT 558.668 710.919 Td /F1 9.8 Tf  [([23])] TJ ET
BT 45.750 699.015 Td /F1 9.8 Tf  [([24])] TJ ET
BT 62.013 699.015 Td /F1 9.8 Tf  [([25])] TJ ET
BT 78.276 699.015 Td /F1 9.8 Tf  [([26])] TJ ET
BT 94.539 699.015 Td /F1 9.8 Tf  [([27])] TJ ET
0.271 0.267 0.267 rg
BT 110.802 699.015 Td /F1 9.8 Tf  [( . However, no information on analytic sensitivity or specificity can be found for the tests offered by Pathway )] TJ ET
BT 45.750 687.110 Td /F1 9.8 Tf  [(Genomics )] TJ ET
0.267 0.267 0.267 rg
BT 92.345 687.110 Td /F1 9.8 Tf  [([28])] TJ ET
0.271 0.267 0.267 rg
BT 108.608 687.110 Td /F1 9.8 Tf  [( , Matrix Genomics )] TJ ET
0.267 0.267 0.267 rg
BT 192.585 687.110 Td /F1 9.8 Tf  [([29])] TJ ET
0.271 0.267 0.267 rg
BT 208.848 687.110 Td /F1 9.8 Tf  [( , or MyMedLab )] TJ ET
0.267 0.267 0.267 rg
BT 279.292 687.110 Td /F1 9.8 Tf  [([30])] TJ ET
0.271 0.267 0.267 rg
BT 295.555 687.110 Td /F1 9.8 Tf  [( , or for some tests offered by Quest Diagnostics )] TJ ET
0.267 0.267 0.267 rg
BT 506.896 687.110 Td /F1 9.8 Tf  [([31])] TJ ET
0.271 0.267 0.267 rg
BT 523.159 687.110 Td /F1 9.8 Tf  [( or Genelex )] TJ ET
BT 45.750 675.205 Td /F1 9.8 Tf  [(Corporation )] TJ ET
0.267 0.267 0.267 rg
BT 99.394 675.205 Td /F1 9.8 Tf  [([32])] TJ ET
0.271 0.267 0.267 rg
BT 115.657 675.205 Td /F1 9.8 Tf  [( .)] TJ ET
40.337 662.518 m 
40.337 662.965 40.154 663.409 39.838 663.725 c
39.522 664.040 39.078 664.224 38.631 664.224 c
38.185 664.224 37.741 664.040 37.425 663.725 c
37.109 663.409 36.925 662.965 36.925 662.518 c
36.925 662.071 37.109 661.627 37.425 661.311 c
37.741 660.996 38.185 660.812 38.631 660.812 c
39.078 660.812 39.522 660.996 39.838 661.311 c
40.154 661.627 40.337 662.071 40.337 662.518 c f
BT 45.750 659.550 Td /F1 9.8 Tf  [(Cross validation of the techniques used inCYP2C19genotyping assays, along with their reliability, specificity, and )] TJ ET
BT 45.750 647.646 Td /F1 9.8 Tf  [(reproducibility, is extremely limited )] TJ ET
0.267 0.267 0.267 rg
BT 196.904 647.646 Td /F1 9.8 Tf  [([19])] TJ ET
0.271 0.267 0.267 rg
BT 213.167 647.646 Td /F1 9.8 Tf  [( .)] TJ ET
BT 26.250 624.491 Td /F6 9.8 Tf  [(Clinical Validity)] TJ ET
BT 98.322 624.491 Td /F4 9.8 Tf  [( : )] TJ ET
BT 106.990 624.491 Td /F1 9.8 Tf  [( Test accuracy and reliability in predicting response to clopidogrel \(predictive value\).)] TJ ET
40.337 608.054 m 
40.337 608.500 40.154 608.944 39.838 609.260 c
39.522 609.576 39.078 609.760 38.631 609.760 c
38.185 609.760 37.741 609.576 37.425 609.260 c
37.109 608.944 36.925 608.500 36.925 608.054 c
36.925 607.607 37.109 607.163 37.425 606.847 c
37.741 606.531 38.185 606.347 38.631 606.347 c
39.078 606.347 39.522 606.531 39.838 606.847 c
40.154 607.163 40.337 607.607 40.337 608.054 c f
BT 45.750 605.086 Td /F1 9.8 Tf  [(Numerous published studies have examined the relationship of CYP2C19alleles to clopidogrel response )] TJ ET
0.267 0.267 0.267 rg
BT 497.156 605.086 Td /F1 9.8 Tf  [([33])] TJ ET
0.271 0.267 0.267 rg
BT 513.418 605.086 Td /F1 9.8 Tf  [(. )] TJ ET
0.39 w 1 J 1 j
59.837 592.399 m 
59.837 592.846 59.654 593.290 59.338 593.606 c
59.022 593.921 58.578 594.105 58.131 594.105 c
57.685 594.105 57.241 593.921 56.925 593.606 c
56.609 593.290 56.425 592.846 56.425 592.399 c
56.425 591.952 56.609 591.508 56.925 591.192 c
57.241 590.877 57.685 590.693 58.131 590.693 c
58.578 590.693 59.022 590.877 59.338 591.192 c
59.654 591.508 59.837 591.952 59.837 592.399 c s
0.267 0.267 0.267 rg
BT 65.250 589.431 Td /F1 9.8 Tf  [(HuGE Navigator)] TJ ET
0.271 0.267 0.267 rg
BT 136.230 589.431 Td /F1 9.8 Tf  [( : query �clopidogrel and CYP2C19�)] TJ ET
40.337 572.994 m 
40.337 573.441 40.154 573.885 39.838 574.201 c
39.522 574.517 39.078 574.700 38.631 574.700 c
38.185 574.700 37.741 574.517 37.425 574.201 c
37.109 573.885 36.925 573.441 36.925 572.994 c
36.925 572.548 37.109 572.104 37.425 571.788 c
37.741 571.472 38.185 571.288 38.631 571.288 c
39.078 571.288 39.522 571.472 39.838 571.788 c
40.154 572.104 40.337 572.548 40.337 572.994 c f
BT 45.750 570.027 Td /F1 9.8 Tf  [(At least 22 studies have examined pharmacokinetic and/or pharmacodynamic responses byCYP2C19genotype; these )] TJ ET
BT 45.750 558.122 Td /F1 9.8 Tf  [(studies differed in the populations tested and the specific pharmacokinetic or pharmacodynamic measure\(s\) that were )] TJ ET
BT 45.750 546.217 Td /F1 9.8 Tf  [(employed \(most studies reviewed in )] TJ ET
0.267 0.267 0.267 rg
BT 203.427 546.217 Td /F1 9.8 Tf  [([1])] TJ ET
BT 214.269 546.217 Td /F1 9.8 Tf  [([34])] TJ ET
0.271 0.267 0.267 rg
BT 230.532 546.217 Td /F1 9.8 Tf  [( \). Twenty studies examined reduced-function variants \(mostly *2 alone or in )] TJ ET
BT 45.750 534.312 Td /F1 9.8 Tf  [(combination with other variants\) )] TJ ET
0.267 0.267 0.267 rg
BT 186.091 534.312 Td /F1 9.8 Tf  [([2])] TJ ET
BT 196.934 534.312 Td /F1 9.8 Tf  [([35])] TJ ET
BT 213.197 534.312 Td /F1 9.8 Tf  [([36])] TJ ET
BT 229.460 534.312 Td /F1 9.8 Tf  [([37])] TJ ET
BT 245.723 534.312 Td /F1 9.8 Tf  [([38])] TJ ET
BT 261.986 534.312 Td /F1 9.8 Tf  [([39])] TJ ET
BT 278.249 534.312 Td /F1 9.8 Tf  [([40])] TJ ET
BT 294.512 534.312 Td /F1 9.8 Tf  [([41])] TJ ET
BT 310.775 534.312 Td /F1 9.8 Tf  [([42])] TJ ET
BT 327.038 534.312 Td /F1 9.8 Tf  [([43])] TJ ET
BT 343.300 534.312 Td /F1 9.8 Tf  [([44])] TJ ET
BT 359.563 534.312 Td /F1 9.8 Tf  [([45])] TJ ET
BT 375.826 534.312 Td /F1 9.8 Tf  [([46])] TJ ET
BT 392.089 534.312 Td /F1 9.8 Tf  [([47])] TJ ET
BT 408.352 534.312 Td /F1 9.8 Tf  [([48])] TJ ET
BT 424.615 534.312 Td /F1 9.8 Tf  [([49])] TJ ET
BT 440.878 534.312 Td /F1 9.8 Tf  [([50])] TJ ET
BT 457.141 534.312 Td /F1 9.8 Tf  [([51])] TJ ET
BT 473.404 534.312 Td /F1 9.8 Tf  [([52])] TJ ET
BT 489.667 534.312 Td /F1 9.8 Tf  [([53])] TJ ET
0.271 0.267 0.267 rg
BT 505.930 534.312 Td /F1 9.8 Tf  [( . All studies )] TJ ET
BT 45.750 522.408 Td /F1 9.8 Tf  [(except one )] TJ ET
0.267 0.267 0.267 rg
BT 96.157 522.408 Td /F1 9.8 Tf  [([37])] TJ ET
0.271 0.267 0.267 rg
BT 112.421 522.408 Td /F1 9.8 Tf  [( reported statistically significant differences in clopidogrel response in reduced-function allele carriers. In )] TJ ET
BT 45.750 510.503 Td /F1 9.8 Tf  [(these 19 studies, p values ranged from 4.3�10)] TJ ET
BT 246.551 514.391 Td /F1 8.7 Tf  [(-11)] TJ ET
BT 259.075 510.503 Td /F1 9.8 Tf  [(to <0.05.)] TJ ET
40.337 497.816 m 
40.337 498.262 40.154 498.706 39.838 499.022 c
39.522 499.338 39.078 499.522 38.631 499.522 c
38.185 499.522 37.741 499.338 37.425 499.022 c
37.109 498.706 36.925 498.262 36.925 497.816 c
36.925 497.369 37.109 496.925 37.425 496.609 c
37.741 496.293 38.185 496.109 38.631 496.109 c
39.078 496.109 39.522 496.293 39.838 496.609 c
40.154 496.925 40.337 497.369 40.337 497.816 c f
BT 45.750 494.848 Td /F1 9.8 Tf  [(Seven studies have examined the association of the *17 variant with pharmacokinetic or pharmacodynamic responses )] TJ ET
BT 45.750 482.943 Td /F1 9.8 Tf  [(specifically to clopidogrel, with inconsistent results )] TJ ET
0.267 0.267 0.267 rg
BT 264.657 482.943 Td /F1 9.8 Tf  [([2])] TJ ET
BT 275.499 482.943 Td /F1 9.8 Tf  [([39])] TJ ET
BT 291.762 482.943 Td /F1 9.8 Tf  [([44])] TJ ET
BT 308.025 482.943 Td /F1 9.8 Tf  [([48])] TJ ET
BT 324.288 482.943 Td /F1 9.8 Tf  [([53])] TJ ET
BT 340.551 482.943 Td /F1 9.8 Tf  [([54])] TJ ET
BT 356.814 482.943 Td /F1 9.8 Tf  [([55])] TJ ET
0.271 0.267 0.267 rg
BT 373.077 482.943 Td /F1 9.8 Tf  [( . Only one of these studies measured plasma )] TJ ET
BT 45.750 471.039 Td /F1 9.8 Tf  [(levels of the clopidogrel active metabolite. However, *17 allele carriers were grouped with *1/*1 extensive metabolizers; and )] TJ ET
BT 45.750 459.134 Td /F1 9.8 Tf  [(so individual effects of the *17 allele on clopidogrel metabolism cannot be determined )] TJ ET
0.267 0.267 0.267 rg
BT 416.425 459.134 Td /F1 9.8 Tf  [([44])] TJ ET
0.271 0.267 0.267 rg
BT 432.688 459.134 Td /F1 9.8 Tf  [( .)] TJ ET
40.337 446.447 m 
40.337 446.893 40.154 447.337 39.838 447.653 c
39.522 447.969 39.078 448.153 38.631 448.153 c
38.185 448.153 37.741 447.969 37.425 447.653 c
37.109 447.337 36.925 446.893 36.925 446.447 c
36.925 446.000 37.109 445.556 37.425 445.240 c
37.741 444.924 38.185 444.740 38.631 444.740 c
39.078 444.740 39.522 444.924 39.838 445.240 c
40.154 445.556 40.337 446.000 40.337 446.447 c f
BT 45.750 443.479 Td /F1 9.8 Tf  [(Only one clinical trial explicitly reported measures of clinical validity. In the EXCELSIOR \(Impact of Extent of Clopidogrel-)] TJ ET
BT 45.750 431.574 Td /F1 9.8 Tf  [(Induced Platelet Inhibition During Elective Stent Implantation on Clinical Event Rate\) trial, the sensitivity and specificity )] TJ ET
BT 45.750 419.670 Td /F1 9.8 Tf  [(ofCYP2C19*2carrier status for detecting high on-clopidogrel residual platelet aggregation \(RPA\) was 45.1% and 75.0%, )] TJ ET
BT 45.750 407.765 Td /F1 9.8 Tf  [(respectively )] TJ ET
0.267 0.267 0.267 rg
BT 99.931 407.765 Td /F1 9.8 Tf  [([35])] TJ ET
0.271 0.267 0.267 rg
BT 116.194 407.765 Td /F1 9.8 Tf  [( . Measures of sensitivity and specificity can be calculated from data reported in some of the other )] TJ ET
BT 45.750 395.860 Td /F1 9.8 Tf  [(published studies.)] TJ ET
40.337 383.173 m 
40.337 383.620 40.154 384.064 39.838 384.380 c
39.522 384.695 39.078 384.879 38.631 384.879 c
38.185 384.879 37.741 384.695 37.425 384.380 c
37.109 384.064 36.925 383.620 36.925 383.173 c
36.925 382.726 37.109 382.282 37.425 381.966 c
37.741 381.651 38.185 381.467 38.631 381.467 c
39.078 381.467 39.522 381.651 39.838 381.966 c
40.154 382.282 40.337 382.726 40.337 383.173 c f
BT 45.750 380.205 Td /F1 9.8 Tf  [(No investigators explicitly included estimates of positive predictive value \(PPV\) or negative predictive value \(NPV\) for )] TJ ET
BT 45.750 368.301 Td /F1 9.8 Tf  [(clopidogrel response in their original published reports. Using data from the EXCELSIOR report )] TJ ET
0.267 0.267 0.267 rg
BT 459.209 368.301 Td /F1 9.8 Tf  [([35])] TJ ET
0.271 0.267 0.267 rg
BT 475.471 368.301 Td /F1 9.8 Tf  [( , estimates of PPV and )] TJ ET
BT 45.750 356.396 Td /F1 9.8 Tf  [(NPV are 41.6% and 77.6%, respectively.)] TJ ET
BT 26.250 333.241 Td /F6 9.8 Tf  [(Clinical Utility)] TJ ET
BT 90.727 333.241 Td /F4 9.8 Tf  [( : )] TJ ET
BT 99.394 333.241 Td /F1 9.8 Tf  [( Net benefit of test in improving health outcomes.)] TJ ET
40.337 316.804 m 
40.337 317.251 40.154 317.695 39.838 318.011 c
39.522 318.326 39.078 318.510 38.631 318.510 c
38.185 318.510 37.741 318.326 37.425 318.011 c
37.109 317.695 36.925 317.251 36.925 316.804 c
36.925 316.357 37.109 315.913 37.425 315.597 c
37.741 315.282 38.185 315.098 38.631 315.098 c
39.078 315.098 39.522 315.282 39.838 315.597 c
40.154 315.913 40.337 316.357 40.337 316.804 c f
BT 45.750 313.836 Td /F1 9.8 Tf  [(A recent meta-analysis of seven prospective cohort studies was published that examined the CYP2C19*2 variant and )] TJ ET
BT 45.750 301.932 Td /F1 9.8 Tf  [(cardiovascular recurrences in 8,043 coronary artery disease patients taking clopidogrel. The authors found a statistically )] TJ ET
BT 45.750 290.027 Td /F1 9.8 Tf  [(significant increased risk of major adverse cardiovascular events in CYP2C19*2 carriers \(RR = 1.96\) and an even greater )] TJ ET
BT 45.750 278.122 Td /F1 9.8 Tf  [(risk when stent thrombosis was analyzed separately using four studies that included 4,975 patients \(RR = 3.82\) )] TJ ET
0.267 0.267 0.267 rg
BT 527.780 278.122 Td /F1 9.8 Tf  [([56])] TJ ET
0.271 0.267 0.267 rg
BT 544.043 278.122 Td /F1 9.8 Tf  [( .)] TJ ET
40.337 265.435 m 
40.337 265.882 40.154 266.326 39.838 266.642 c
39.522 266.957 39.078 267.141 38.631 267.141 c
38.185 267.141 37.741 266.957 37.425 266.642 c
37.109 266.326 36.925 265.882 36.925 265.435 c
36.925 264.988 37.109 264.544 37.425 264.228 c
37.741 263.913 38.185 263.729 38.631 263.729 c
39.078 263.729 39.522 263.913 39.838 264.228 c
40.154 264.544 40.337 264.988 40.337 265.435 c f
BT 45.750 262.467 Td /F1 9.8 Tf  [(A more recent meta-analysis that was not restricted to prospective cohort studies examined the CYP2C19*2 variant and the )] TJ ET
BT 45.750 250.563 Td /F1 9.8 Tf  [(incidence of major adverse cardiovascular events \(MACE\) and mortality in patients taking clopidogrel )] TJ ET
0.267 0.267 0.267 rg
BT 483.574 250.563 Td /F1 9.8 Tf  [([57])] TJ ET
0.271 0.267 0.267 rg
BT 499.837 250.563 Td /F1 9.8 Tf  [( . The pooled data )] TJ ET
BT 45.750 238.658 Td /F1 9.8 Tf  [(showed that CYP2C19*2 carriers had a statistically significant increased risk of MACE \(OR = 1.29\) using data from ten )] TJ ET
BT 45.750 226.753 Td /F1 9.8 Tf  [(studies \(11,959 patients\). Carriers of *2 also had statistically significant increases in risk for stent thrombosis \(OR = 3.45 )] TJ ET
BT 45.750 214.848 Td /F1 9.8 Tf  [(using data from 4 studies including 4,905 patients\) and death \(OR = 1.79 using data from 5 studies including 6,225 )] TJ ET
BT 45.750 202.944 Td /F1 9.8 Tf  [(patients\). Four studies including 5,694 patients allowed the separate assessment of heterozygotes and homozygotes of the )] TJ ET
BT 45.750 191.039 Td /F1 9.8 Tf  [(*2 allele. Increased risks for MACE and stent thrombosis were noted for both groups, though the odds ratio for MACE was )] TJ ET
BT 45.750 179.134 Td /F1 9.8 Tf  [(significant only for homozygotes )] TJ ET
0.267 0.267 0.267 rg
BT 187.184 179.134 Td /F1 9.8 Tf  [([57])] TJ ET
0.271 0.267 0.267 rg
BT 203.447 179.134 Td /F1 9.8 Tf  [( .)] TJ ET
40.337 166.447 m 
40.337 166.894 40.154 167.338 39.838 167.654 c
39.522 167.969 39.078 168.153 38.631 168.153 c
38.185 168.153 37.741 167.969 37.425 167.654 c
37.109 167.338 36.925 166.894 36.925 166.447 c
36.925 166.000 37.109 165.556 37.425 165.240 c
37.741 164.925 38.185 164.741 38.631 164.741 c
39.078 164.741 39.522 164.925 39.838 165.240 c
40.154 165.556 40.337 166.000 40.337 166.447 c f
BT 45.750 163.479 Td /F1 9.8 Tf  [(Hulot and Fuster )] TJ ET
0.267 0.267 0.267 rg
BT 120.532 163.479 Td /F1 9.8 Tf  [([58])] TJ ET
0.271 0.267 0.267 rg
BT 136.796 163.479 Td /F1 9.8 Tf  [( calculated the PPV for clinical outcomes ofCYP2C19loss-of-function variants using data from two )] TJ ET
BT 45.750 151.575 Td /F1 9.8 Tf  [(studies. They estimate the PPV for a cardiovascular event is between 12% )] TJ ET
0.267 0.267 0.267 rg
BT 370.357 151.575 Td /F1 9.8 Tf  [([36])] TJ ET
0.271 0.267 0.267 rg
BT 386.620 151.575 Td /F1 9.8 Tf  [( and 20% )] TJ ET
0.267 0.267 0.267 rg
BT 430.524 151.575 Td /F1 9.8 Tf  [([59])] TJ ET
0.271 0.267 0.267 rg
BT 446.787 151.575 Td /F1 9.8 Tf  [( .)] TJ ET
40.337 138.887 m 
40.337 139.334 40.154 139.778 39.838 140.094 c
39.522 140.410 39.078 140.594 38.631 140.594 c
38.185 140.594 37.741 140.410 37.425 140.094 c
37.109 139.778 36.925 139.334 36.925 138.887 c
36.925 138.441 37.109 137.997 37.425 137.681 c
37.741 137.365 38.185 137.181 38.631 137.181 c
39.078 137.181 39.522 137.365 39.838 137.681 c
40.154 137.997 40.337 138.441 40.337 138.887 c f
BT 45.750 135.920 Td /F1 9.8 Tf  [(Most studies have examined CYP2C19 genotypes only among patients taking clopidogrel. In the only published study to )] TJ ET
BT 45.750 124.015 Td /F1 9.8 Tf  [(date that included a placebo-controlled group, neither CYP2C19* 2or *3 allele carriage nor metabolizer phenotype )] TJ ET
BT 45.750 112.110 Td /F1 9.8 Tf  [(influenced the effect of clopidogrel on cardiovascular disease-related outcomes compared to the placebo group )] TJ ET
0.267 0.267 0.267 rg
BT 527.527 112.110 Td /F1 9.8 Tf  [([60])] TJ ET
0.271 0.267 0.267 rg
BT 543.790 112.110 Td /F1 9.8 Tf  [( .)] TJ ET
40.337 99.423 m 
40.337 99.870 40.154 100.314 39.838 100.630 c
39.522 100.946 39.078 101.129 38.631 101.129 c
38.185 101.129 37.741 100.946 37.425 100.630 c
37.109 100.314 36.925 99.870 36.925 99.423 c
36.925 98.977 37.109 98.533 37.425 98.217 c
37.741 97.901 38.185 97.717 38.631 97.717 c
39.078 97.717 39.522 97.901 39.838 98.217 c
40.154 98.533 40.337 98.977 40.337 99.423 c f
BT 45.750 96.456 Td /F1 9.8 Tf  [(Tests that assay CYP2C19*17 may also identify individuals at increased risk for bleeding events )] TJ ET
0.267 0.267 0.267 rg
BT 462.465 96.456 Td /F1 9.8 Tf  [([13])] TJ ET
BT 478.728 96.456 Td /F1 9.8 Tf  [([14])] TJ ET
0.271 0.267 0.267 rg
BT 494.991 96.456 Td /F1 9.8 Tf  [( or those who may )] TJ ET
BT 45.750 84.551 Td /F1 9.8 Tf  [(derive a larger benefit \(reduction in cardiovascular events\) with clopidogrel treatment compared to placebo )] TJ ET
0.267 0.267 0.267 rg
BT 506.896 84.551 Td /F1 9.8 Tf  [([60])] TJ ET
0.271 0.267 0.267 rg
BT 523.159 84.551 Td /F1 9.8 Tf  [( .)] TJ ET
40.337 71.864 m 
40.337 72.310 40.154 72.754 39.838 73.070 c
39.522 73.386 39.078 73.570 38.631 73.570 c
38.185 73.570 37.741 73.386 37.425 73.070 c
37.109 72.754 36.925 72.310 36.925 71.864 c
36.925 71.417 37.109 70.973 37.425 70.657 c
37.741 70.341 38.185 70.157 38.631 70.157 c
39.078 70.157 39.522 70.341 39.838 70.657 c
40.154 70.973 40.337 71.417 40.337 71.864 c f
BT 45.750 68.896 Td /F1 9.8 Tf  [(There are no published clinical trial data evaluating the net benefit of CYP2C19 testing prior to administration of clopidogrel )] TJ ET
BT 45.750 56.991 Td /F1 9.8 Tf  [(in improving health outcomes.)] TJ ET
40.337 44.304 m 
40.337 44.751 40.154 45.195 39.838 45.511 c
39.522 45.827 39.078 46.010 38.631 46.010 c
38.185 46.010 37.741 45.827 37.425 45.511 c
37.109 45.195 36.925 44.751 36.925 44.304 c
36.925 43.858 37.109 43.414 37.425 43.098 c
37.741 42.782 38.185 42.598 38.631 42.598 c
39.078 42.598 39.522 42.782 39.838 43.098 c
40.154 43.414 40.337 43.858 40.337 44.304 c f
BT 45.750 41.337 Td /F1 9.8 Tf  [(It is unknown if the risk from a given individual�s genomic profile changes over time, depending on the specific clinical )] TJ ET
Q
q
15.000 27.051 577.500 749.949 re W n
0.271 0.267 0.267 rg
BT 26.250 750.278 Td /F4 12.0 Tf  [(Evidence Overview)] TJ ET
BT 26.250 730.324 Td /F6 9.8 Tf  [(Analytic Validity)] TJ ET
BT 101.569 730.324 Td /F4 9.8 Tf  [( : )] TJ ET
BT 110.236 730.324 Td /F1 9.8 Tf  [( Test accuracy and reliability in identifying )] TJ ET
BT 292.844 730.324 Td /F5 9.8 Tf  [(CYP2C19)] TJ ET
BT 336.193 730.324 Td /F1 9.8 Tf  [( genotypes \(analytic sensitivity and specificity\).)] TJ ET
0.271 0.267 0.267 RG
40.337 713.887 m 
40.337 714.334 40.154 714.778 39.838 715.094 c
39.522 715.409 39.078 715.593 38.631 715.593 c
38.185 715.593 37.741 715.409 37.425 715.094 c
37.109 714.778 36.925 714.334 36.925 713.887 c
36.925 713.440 37.109 712.996 37.425 712.680 c
37.741 712.365 38.185 712.181 38.631 712.181 c
39.078 712.181 39.522 712.365 39.838 712.680 c
40.154 712.996 40.337 713.440 40.337 713.887 c f
BT 45.750 710.919 Td /F1 9.8 Tf  [(When reported, accuracy of the various genotyping methods/platforms used in commercial tests is noted as = 99% )] TJ ET
0.267 0.267 0.267 rg
BT 542.405 710.919 Td /F1 9.8 Tf  [([22])] TJ ET
BT 558.668 710.919 Td /F1 9.8 Tf  [([23])] TJ ET
BT 45.750 699.015 Td /F1 9.8 Tf  [([24])] TJ ET
BT 62.013 699.015 Td /F1 9.8 Tf  [([25])] TJ ET
BT 78.276 699.015 Td /F1 9.8 Tf  [([26])] TJ ET
BT 94.539 699.015 Td /F1 9.8 Tf  [([27])] TJ ET
0.271 0.267 0.267 rg
BT 110.802 699.015 Td /F1 9.8 Tf  [( . However, no information on analytic sensitivity or specificity can be found for the tests offered by Pathway )] TJ ET
BT 45.750 687.110 Td /F1 9.8 Tf  [(Genomics )] TJ ET
0.267 0.267 0.267 rg
BT 92.345 687.110 Td /F1 9.8 Tf  [([28])] TJ ET
0.271 0.267 0.267 rg
BT 108.608 687.110 Td /F1 9.8 Tf  [( , Matrix Genomics )] TJ ET
0.267 0.267 0.267 rg
BT 192.585 687.110 Td /F1 9.8 Tf  [([29])] TJ ET
0.271 0.267 0.267 rg
BT 208.848 687.110 Td /F1 9.8 Tf  [( , or MyMedLab )] TJ ET
0.267 0.267 0.267 rg
BT 279.292 687.110 Td /F1 9.8 Tf  [([30])] TJ ET
0.271 0.267 0.267 rg
BT 295.555 687.110 Td /F1 9.8 Tf  [( , or for some tests offered by Quest Diagnostics )] TJ ET
0.267 0.267 0.267 rg
BT 506.896 687.110 Td /F1 9.8 Tf  [([31])] TJ ET
0.271 0.267 0.267 rg
BT 523.159 687.110 Td /F1 9.8 Tf  [( or Genelex )] TJ ET
BT 45.750 675.205 Td /F1 9.8 Tf  [(Corporation )] TJ ET
0.267 0.267 0.267 rg
BT 99.394 675.205 Td /F1 9.8 Tf  [([32])] TJ ET
0.271 0.267 0.267 rg
BT 115.657 675.205 Td /F1 9.8 Tf  [( .)] TJ ET
40.337 662.518 m 
40.337 662.965 40.154 663.409 39.838 663.725 c
39.522 664.040 39.078 664.224 38.631 664.224 c
38.185 664.224 37.741 664.040 37.425 663.725 c
37.109 663.409 36.925 662.965 36.925 662.518 c
36.925 662.071 37.109 661.627 37.425 661.311 c
37.741 660.996 38.185 660.812 38.631 660.812 c
39.078 660.812 39.522 660.996 39.838 661.311 c
40.154 661.627 40.337 662.071 40.337 662.518 c f
BT 45.750 659.550 Td /F1 9.8 Tf  [(Cross validation of the techniques used inCYP2C19genotyping assays, along with their reliability, specificity, and )] TJ ET
BT 45.750 647.646 Td /F1 9.8 Tf  [(reproducibility, is extremely limited )] TJ ET
0.267 0.267 0.267 rg
BT 196.904 647.646 Td /F1 9.8 Tf  [([19])] TJ ET
0.271 0.267 0.267 rg
BT 213.167 647.646 Td /F1 9.8 Tf  [( .)] TJ ET
BT 26.250 624.491 Td /F6 9.8 Tf  [(Clinical Validity)] TJ ET
BT 98.322 624.491 Td /F4 9.8 Tf  [( : )] TJ ET
BT 106.990 624.491 Td /F1 9.8 Tf  [( Test accuracy and reliability in predicting response to clopidogrel \(predictive value\).)] TJ ET
40.337 608.054 m 
40.337 608.500 40.154 608.944 39.838 609.260 c
39.522 609.576 39.078 609.760 38.631 609.760 c
38.185 609.760 37.741 609.576 37.425 609.260 c
37.109 608.944 36.925 608.500 36.925 608.054 c
36.925 607.607 37.109 607.163 37.425 606.847 c
37.741 606.531 38.185 606.347 38.631 606.347 c
39.078 606.347 39.522 606.531 39.838 606.847 c
40.154 607.163 40.337 607.607 40.337 608.054 c f
BT 45.750 605.086 Td /F1 9.8 Tf  [(Numerous published studies have examined the relationship of CYP2C19alleles to clopidogrel response )] TJ ET
0.267 0.267 0.267 rg
BT 497.156 605.086 Td /F1 9.8 Tf  [([33])] TJ ET
0.271 0.267 0.267 rg
BT 513.418 605.086 Td /F1 9.8 Tf  [(. )] TJ ET
0.39 w 1 J 1 j
59.837 592.399 m 
59.837 592.846 59.654 593.290 59.338 593.606 c
59.022 593.921 58.578 594.105 58.131 594.105 c
57.685 594.105 57.241 593.921 56.925 593.606 c
56.609 593.290 56.425 592.846 56.425 592.399 c
56.425 591.952 56.609 591.508 56.925 591.192 c
57.241 590.877 57.685 590.693 58.131 590.693 c
58.578 590.693 59.022 590.877 59.338 591.192 c
59.654 591.508 59.837 591.952 59.837 592.399 c s
0.267 0.267 0.267 rg
BT 65.250 589.431 Td /F1 9.8 Tf  [(HuGE Navigator)] TJ ET
0.271 0.267 0.267 rg
BT 136.230 589.431 Td /F1 9.8 Tf  [( : query �clopidogrel and CYP2C19�)] TJ ET
40.337 572.994 m 
40.337 573.441 40.154 573.885 39.838 574.201 c
39.522 574.517 39.078 574.700 38.631 574.700 c
38.185 574.700 37.741 574.517 37.425 574.201 c
37.109 573.885 36.925 573.441 36.925 572.994 c
36.925 572.548 37.109 572.104 37.425 571.788 c
37.741 571.472 38.185 571.288 38.631 571.288 c
39.078 571.288 39.522 571.472 39.838 571.788 c
40.154 572.104 40.337 572.548 40.337 572.994 c f
BT 45.750 570.027 Td /F1 9.8 Tf  [(At least 22 studies have examined pharmacokinetic and/or pharmacodynamic responses byCYP2C19genotype; these )] TJ ET
BT 45.750 558.122 Td /F1 9.8 Tf  [(studies differed in the populations tested and the specific pharmacokinetic or pharmacodynamic measure\(s\) that were )] TJ ET
BT 45.750 546.217 Td /F1 9.8 Tf  [(employed \(most studies reviewed in )] TJ ET
0.267 0.267 0.267 rg
BT 203.427 546.217 Td /F1 9.8 Tf  [([1])] TJ ET
BT 214.269 546.217 Td /F1 9.8 Tf  [([34])] TJ ET
0.271 0.267 0.267 rg
BT 230.532 546.217 Td /F1 9.8 Tf  [( \). Twenty studies examined reduced-function variants \(mostly *2 alone or in )] TJ ET
BT 45.750 534.312 Td /F1 9.8 Tf  [(combination with other variants\) )] TJ ET
0.267 0.267 0.267 rg
BT 186.091 534.312 Td /F1 9.8 Tf  [([2])] TJ ET
BT 196.934 534.312 Td /F1 9.8 Tf  [([35])] TJ ET
BT 213.197 534.312 Td /F1 9.8 Tf  [([36])] TJ ET
BT 229.460 534.312 Td /F1 9.8 Tf  [([37])] TJ ET
BT 245.723 534.312 Td /F1 9.8 Tf  [([38])] TJ ET
BT 261.986 534.312 Td /F1 9.8 Tf  [([39])] TJ ET
BT 278.249 534.312 Td /F1 9.8 Tf  [([40])] TJ ET
BT 294.512 534.312 Td /F1 9.8 Tf  [([41])] TJ ET
BT 310.775 534.312 Td /F1 9.8 Tf  [([42])] TJ ET
BT 327.038 534.312 Td /F1 9.8 Tf  [([43])] TJ ET
BT 343.300 534.312 Td /F1 9.8 Tf  [([44])] TJ ET
BT 359.563 534.312 Td /F1 9.8 Tf  [([45])] TJ ET
BT 375.826 534.312 Td /F1 9.8 Tf  [([46])] TJ ET
BT 392.089 534.312 Td /F1 9.8 Tf  [([47])] TJ ET
BT 408.352 534.312 Td /F1 9.8 Tf  [([48])] TJ ET
BT 424.615 534.312 Td /F1 9.8 Tf  [([49])] TJ ET
BT 440.878 534.312 Td /F1 9.8 Tf  [([50])] TJ ET
BT 457.141 534.312 Td /F1 9.8 Tf  [([51])] TJ ET
BT 473.404 534.312 Td /F1 9.8 Tf  [([52])] TJ ET
BT 489.667 534.312 Td /F1 9.8 Tf  [([53])] TJ ET
0.271 0.267 0.267 rg
BT 505.930 534.312 Td /F1 9.8 Tf  [( . All studies )] TJ ET
BT 45.750 522.408 Td /F1 9.8 Tf  [(except one )] TJ ET
0.267 0.267 0.267 rg
BT 96.157 522.408 Td /F1 9.8 Tf  [([37])] TJ ET
0.271 0.267 0.267 rg
BT 112.421 522.408 Td /F1 9.8 Tf  [( reported statistically significant differences in clopidogrel response in reduced-function allele carriers. In )] TJ ET
BT 45.750 510.503 Td /F1 9.8 Tf  [(these 19 studies, p values ranged from 4.3�10)] TJ ET
BT 246.551 514.391 Td /F1 8.7 Tf  [(-11)] TJ ET
BT 259.075 510.503 Td /F1 9.8 Tf  [(to <0.05.)] TJ ET
40.337 497.816 m 
40.337 498.262 40.154 498.706 39.838 499.022 c
39.522 499.338 39.078 499.522 38.631 499.522 c
38.185 499.522 37.741 499.338 37.425 499.022 c
37.109 498.706 36.925 498.262 36.925 497.816 c
36.925 497.369 37.109 496.925 37.425 496.609 c
37.741 496.293 38.185 496.109 38.631 496.109 c
39.078 496.109 39.522 496.293 39.838 496.609 c
40.154 496.925 40.337 497.369 40.337 497.816 c f
BT 45.750 494.848 Td /F1 9.8 Tf  [(Seven studies have examined the association of the *17 variant with pharmacokinetic or pharmacodynamic responses )] TJ ET
BT 45.750 482.943 Td /F1 9.8 Tf  [(specifically to clopidogrel, with inconsistent results )] TJ ET
0.267 0.267 0.267 rg
BT 264.657 482.943 Td /F1 9.8 Tf  [([2])] TJ ET
BT 275.499 482.943 Td /F1 9.8 Tf  [([39])] TJ ET
BT 291.762 482.943 Td /F1 9.8 Tf  [([44])] TJ ET
BT 308.025 482.943 Td /F1 9.8 Tf  [([48])] TJ ET
BT 324.288 482.943 Td /F1 9.8 Tf  [([53])] TJ ET
BT 340.551 482.943 Td /F1 9.8 Tf  [([54])] TJ ET
BT 356.814 482.943 Td /F1 9.8 Tf  [([55])] TJ ET
0.271 0.267 0.267 rg
BT 373.077 482.943 Td /F1 9.8 Tf  [( . Only one of these studies measured plasma )] TJ ET
BT 45.750 471.039 Td /F1 9.8 Tf  [(levels of the clopidogrel active metabolite. However, *17 allele carriers were grouped with *1/*1 extensive metabolizers; and )] TJ ET
BT 45.750 459.134 Td /F1 9.8 Tf  [(so individual effects of the *17 allele on clopidogrel metabolism cannot be determined )] TJ ET
0.267 0.267 0.267 rg
BT 416.425 459.134 Td /F1 9.8 Tf  [([44])] TJ ET
0.271 0.267 0.267 rg
BT 432.688 459.134 Td /F1 9.8 Tf  [( .)] TJ ET
40.337 446.447 m 
40.337 446.893 40.154 447.337 39.838 447.653 c
39.522 447.969 39.078 448.153 38.631 448.153 c
38.185 448.153 37.741 447.969 37.425 447.653 c
37.109 447.337 36.925 446.893 36.925 446.447 c
36.925 446.000 37.109 445.556 37.425 445.240 c
37.741 444.924 38.185 444.740 38.631 444.740 c
39.078 444.740 39.522 444.924 39.838 445.240 c
40.154 445.556 40.337 446.000 40.337 446.447 c f
BT 45.750 443.479 Td /F1 9.8 Tf  [(Only one clinical trial explicitly reported measures of clinical validity. In the EXCELSIOR \(Impact of Extent of Clopidogrel-)] TJ ET
BT 45.750 431.574 Td /F1 9.8 Tf  [(Induced Platelet Inhibition During Elective Stent Implantation on Clinical Event Rate\) trial, the sensitivity and specificity )] TJ ET
BT 45.750 419.670 Td /F1 9.8 Tf  [(ofCYP2C19*2carrier status for detecting high on-clopidogrel residual platelet aggregation \(RPA\) was 45.1% and 75.0%, )] TJ ET
BT 45.750 407.765 Td /F1 9.8 Tf  [(respectively )] TJ ET
0.267 0.267 0.267 rg
BT 99.931 407.765 Td /F1 9.8 Tf  [([35])] TJ ET
0.271 0.267 0.267 rg
BT 116.194 407.765 Td /F1 9.8 Tf  [( . Measures of sensitivity and specificity can be calculated from data reported in some of the other )] TJ ET
BT 45.750 395.860 Td /F1 9.8 Tf  [(published studies.)] TJ ET
40.337 383.173 m 
40.337 383.620 40.154 384.064 39.838 384.380 c
39.522 384.695 39.078 384.879 38.631 384.879 c
38.185 384.879 37.741 384.695 37.425 384.380 c
37.109 384.064 36.925 383.620 36.925 383.173 c
36.925 382.726 37.109 382.282 37.425 381.966 c
37.741 381.651 38.185 381.467 38.631 381.467 c
39.078 381.467 39.522 381.651 39.838 381.966 c
40.154 382.282 40.337 382.726 40.337 383.173 c f
BT 45.750 380.205 Td /F1 9.8 Tf  [(No investigators explicitly included estimates of positive predictive value \(PPV\) or negative predictive value \(NPV\) for )] TJ ET
BT 45.750 368.301 Td /F1 9.8 Tf  [(clopidogrel response in their original published reports. Using data from the EXCELSIOR report )] TJ ET
0.267 0.267 0.267 rg
BT 459.209 368.301 Td /F1 9.8 Tf  [([35])] TJ ET
0.271 0.267 0.267 rg
BT 475.471 368.301 Td /F1 9.8 Tf  [( , estimates of PPV and )] TJ ET
BT 45.750 356.396 Td /F1 9.8 Tf  [(NPV are 41.6% and 77.6%, respectively.)] TJ ET
BT 26.250 333.241 Td /F6 9.8 Tf  [(Clinical Utility)] TJ ET
BT 90.727 333.241 Td /F4 9.8 Tf  [( : )] TJ ET
BT 99.394 333.241 Td /F1 9.8 Tf  [( Net benefit of test in improving health outcomes.)] TJ ET
40.337 316.804 m 
40.337 317.251 40.154 317.695 39.838 318.011 c
39.522 318.326 39.078 318.510 38.631 318.510 c
38.185 318.510 37.741 318.326 37.425 318.011 c
37.109 317.695 36.925 317.251 36.925 316.804 c
36.925 316.357 37.109 315.913 37.425 315.597 c
37.741 315.282 38.185 315.098 38.631 315.098 c
39.078 315.098 39.522 315.282 39.838 315.597 c
40.154 315.913 40.337 316.357 40.337 316.804 c f
BT 45.750 313.836 Td /F1 9.8 Tf  [(A recent meta-analysis of seven prospective cohort studies was published that examined the CYP2C19*2 variant and )] TJ ET
BT 45.750 301.932 Td /F1 9.8 Tf  [(cardiovascular recurrences in 8,043 coronary artery disease patients taking clopidogrel. The authors found a statistically )] TJ ET
BT 45.750 290.027 Td /F1 9.8 Tf  [(significant increased risk of major adverse cardiovascular events in CYP2C19*2 carriers \(RR = 1.96\) and an even greater )] TJ ET
BT 45.750 278.122 Td /F1 9.8 Tf  [(risk when stent thrombosis was analyzed separately using four studies that included 4,975 patients \(RR = 3.82\) )] TJ ET
0.267 0.267 0.267 rg
BT 527.780 278.122 Td /F1 9.8 Tf  [([56])] TJ ET
0.271 0.267 0.267 rg
BT 544.043 278.122 Td /F1 9.8 Tf  [( .)] TJ ET
40.337 265.435 m 
40.337 265.882 40.154 266.326 39.838 266.642 c
39.522 266.957 39.078 267.141 38.631 267.141 c
38.185 267.141 37.741 266.957 37.425 266.642 c
37.109 266.326 36.925 265.882 36.925 265.435 c
36.925 264.988 37.109 264.544 37.425 264.228 c
37.741 263.913 38.185 263.729 38.631 263.729 c
39.078 263.729 39.522 263.913 39.838 264.228 c
40.154 264.544 40.337 264.988 40.337 265.435 c f
BT 45.750 262.467 Td /F1 9.8 Tf  [(A more recent meta-analysis that was not restricted to prospective cohort studies examined the CYP2C19*2 variant and the )] TJ ET
BT 45.750 250.563 Td /F1 9.8 Tf  [(incidence of major adverse cardiovascular events \(MACE\) and mortality in patients taking clopidogrel )] TJ ET
0.267 0.267 0.267 rg
BT 483.574 250.563 Td /F1 9.8 Tf  [([57])] TJ ET
0.271 0.267 0.267 rg
BT 499.837 250.563 Td /F1 9.8 Tf  [( . The pooled data )] TJ ET
BT 45.750 238.658 Td /F1 9.8 Tf  [(showed that CYP2C19*2 carriers had a statistically significant increased risk of MACE \(OR = 1.29\) using data from ten )] TJ ET
BT 45.750 226.753 Td /F1 9.8 Tf  [(studies \(11,959 patients\). Carriers of *2 also had statistically significant increases in risk for stent thrombosis \(OR = 3.45 )] TJ ET
BT 45.750 214.848 Td /F1 9.8 Tf  [(using data from 4 studies including 4,905 patients\) and death \(OR = 1.79 using data from 5 studies including 6,225 )] TJ ET
BT 45.750 202.944 Td /F1 9.8 Tf  [(patients\). Four studies including 5,694 patients allowed the separate assessment of heterozygotes and homozygotes of the )] TJ ET
BT 45.750 191.039 Td /F1 9.8 Tf  [(*2 allele. Increased risks for MACE and stent thrombosis were noted for both groups, though the odds ratio for MACE was )] TJ ET
BT 45.750 179.134 Td /F1 9.8 Tf  [(significant only for homozygotes )] TJ ET
0.267 0.267 0.267 rg
BT 187.184 179.134 Td /F1 9.8 Tf  [([57])] TJ ET
0.271 0.267 0.267 rg
BT 203.447 179.134 Td /F1 9.8 Tf  [( .)] TJ ET
40.337 166.447 m 
40.337 166.894 40.154 167.338 39.838 167.654 c
39.522 167.969 39.078 168.153 38.631 168.153 c
38.185 168.153 37.741 167.969 37.425 167.654 c
37.109 167.338 36.925 166.894 36.925 166.447 c
36.925 166.000 37.109 165.556 37.425 165.240 c
37.741 164.925 38.185 164.741 38.631 164.741 c
39.078 164.741 39.522 164.925 39.838 165.240 c
40.154 165.556 40.337 166.000 40.337 166.447 c f
BT 45.750 163.479 Td /F1 9.8 Tf  [(Hulot and Fuster )] TJ ET
0.267 0.267 0.267 rg
BT 120.532 163.479 Td /F1 9.8 Tf  [([58])] TJ ET
0.271 0.267 0.267 rg
BT 136.796 163.479 Td /F1 9.8 Tf  [( calculated the PPV for clinical outcomes ofCYP2C19loss-of-function variants using data from two )] TJ ET
BT 45.750 151.575 Td /F1 9.8 Tf  [(studies. They estimate the PPV for a cardiovascular event is between 12% )] TJ ET
0.267 0.267 0.267 rg
BT 370.357 151.575 Td /F1 9.8 Tf  [([36])] TJ ET
0.271 0.267 0.267 rg
BT 386.620 151.575 Td /F1 9.8 Tf  [( and 20% )] TJ ET
0.267 0.267 0.267 rg
BT 430.524 151.575 Td /F1 9.8 Tf  [([59])] TJ ET
0.271 0.267 0.267 rg
BT 446.787 151.575 Td /F1 9.8 Tf  [( .)] TJ ET
40.337 138.887 m 
40.337 139.334 40.154 139.778 39.838 140.094 c
39.522 140.410 39.078 140.594 38.631 140.594 c
38.185 140.594 37.741 140.410 37.425 140.094 c
37.109 139.778 36.925 139.334 36.925 138.887 c
36.925 138.441 37.109 137.997 37.425 137.681 c
37.741 137.365 38.185 137.181 38.631 137.181 c
39.078 137.181 39.522 137.365 39.838 137.681 c
40.154 137.997 40.337 138.441 40.337 138.887 c f
BT 45.750 135.920 Td /F1 9.8 Tf  [(Most studies have examined CYP2C19 genotypes only among patients taking clopidogrel. In the only published study to )] TJ ET
BT 45.750 124.015 Td /F1 9.8 Tf  [(date that included a placebo-controlled group, neither CYP2C19* 2or *3 allele carriage nor metabolizer phenotype )] TJ ET
BT 45.750 112.110 Td /F1 9.8 Tf  [(influenced the effect of clopidogrel on cardiovascular disease-related outcomes compared to the placebo group )] TJ ET
0.267 0.267 0.267 rg
BT 527.527 112.110 Td /F1 9.8 Tf  [([60])] TJ ET
0.271 0.267 0.267 rg
BT 543.790 112.110 Td /F1 9.8 Tf  [( .)] TJ ET
40.337 99.423 m 
40.337 99.870 40.154 100.314 39.838 100.630 c
39.522 100.946 39.078 101.129 38.631 101.129 c
38.185 101.129 37.741 100.946 37.425 100.630 c
37.109 100.314 36.925 99.870 36.925 99.423 c
36.925 98.977 37.109 98.533 37.425 98.217 c
37.741 97.901 38.185 97.717 38.631 97.717 c
39.078 97.717 39.522 97.901 39.838 98.217 c
40.154 98.533 40.337 98.977 40.337 99.423 c f
BT 45.750 96.456 Td /F1 9.8 Tf  [(Tests that assay CYP2C19*17 may also identify individuals at increased risk for bleeding events )] TJ ET
0.267 0.267 0.267 rg
BT 462.465 96.456 Td /F1 9.8 Tf  [([13])] TJ ET
BT 478.728 96.456 Td /F1 9.8 Tf  [([14])] TJ ET
0.271 0.267 0.267 rg
BT 494.991 96.456 Td /F1 9.8 Tf  [( or those who may )] TJ ET
BT 45.750 84.551 Td /F1 9.8 Tf  [(derive a larger benefit \(reduction in cardiovascular events\) with clopidogrel treatment compared to placebo )] TJ ET
0.267 0.267 0.267 rg
BT 506.896 84.551 Td /F1 9.8 Tf  [([60])] TJ ET
0.271 0.267 0.267 rg
BT 523.159 84.551 Td /F1 9.8 Tf  [( .)] TJ ET
40.337 71.864 m 
40.337 72.310 40.154 72.754 39.838 73.070 c
39.522 73.386 39.078 73.570 38.631 73.570 c
38.185 73.570 37.741 73.386 37.425 73.070 c
37.109 72.754 36.925 72.310 36.925 71.864 c
36.925 71.417 37.109 70.973 37.425 70.657 c
37.741 70.341 38.185 70.157 38.631 70.157 c
39.078 70.157 39.522 70.341 39.838 70.657 c
40.154 70.973 40.337 71.417 40.337 71.864 c f
BT 45.750 68.896 Td /F1 9.8 Tf  [(There are no published clinical trial data evaluating the net benefit of CYP2C19 testing prior to administration of clopidogrel )] TJ ET
BT 45.750 56.991 Td /F1 9.8 Tf  [(in improving health outcomes.)] TJ ET
40.337 44.304 m 
40.337 44.751 40.154 45.195 39.838 45.511 c
39.522 45.827 39.078 46.010 38.631 46.010 c
38.185 46.010 37.741 45.827 37.425 45.511 c
37.109 45.195 36.925 44.751 36.925 44.304 c
36.925 43.858 37.109 43.414 37.425 43.098 c
37.741 42.782 38.185 42.598 38.631 42.598 c
39.078 42.598 39.522 42.782 39.838 43.098 c
40.154 43.414 40.337 43.858 40.337 44.304 c f
BT 45.750 41.337 Td /F1 9.8 Tf  [(It is unknown if the risk from a given individual�s genomic profile changes over time, depending on the specific clinical )] TJ ET
Q
q
15.000 27.051 577.500 749.949 re W n
0.271 0.267 0.267 rg
BT 26.250 750.278 Td /F4 12.0 Tf  [(Evidence Overview)] TJ ET
BT 26.250 730.324 Td /F6 9.8 Tf  [(Analytic Validity)] TJ ET
BT 101.569 730.324 Td /F4 9.8 Tf  [( : )] TJ ET
BT 110.236 730.324 Td /F1 9.8 Tf  [( Test accuracy and reliability in identifying )] TJ ET
BT 292.844 730.324 Td /F5 9.8 Tf  [(CYP2C19)] TJ ET
BT 336.193 730.324 Td /F1 9.8 Tf  [( genotypes \(analytic sensitivity and specificity\).)] TJ ET
0.271 0.267 0.267 RG
40.337 713.887 m 
40.337 714.334 40.154 714.778 39.838 715.094 c
39.522 715.409 39.078 715.593 38.631 715.593 c
38.185 715.593 37.741 715.409 37.425 715.094 c
37.109 714.778 36.925 714.334 36.925 713.887 c
36.925 713.440 37.109 712.996 37.425 712.680 c
37.741 712.365 38.185 712.181 38.631 712.181 c
39.078 712.181 39.522 712.365 39.838 712.680 c
40.154 712.996 40.337 713.440 40.337 713.887 c f
BT 45.750 710.919 Td /F1 9.8 Tf  [(When reported, accuracy of the various genotyping methods/platforms used in commercial tests is noted as = 99% )] TJ ET
0.267 0.267 0.267 rg
BT 542.405 710.919 Td /F1 9.8 Tf  [([22])] TJ ET
BT 558.668 710.919 Td /F1 9.8 Tf  [([23])] TJ ET
BT 45.750 699.015 Td /F1 9.8 Tf  [([24])] TJ ET
BT 62.013 699.015 Td /F1 9.8 Tf  [([25])] TJ ET
BT 78.276 699.015 Td /F1 9.8 Tf  [([26])] TJ ET
BT 94.539 699.015 Td /F1 9.8 Tf  [([27])] TJ ET
0.271 0.267 0.267 rg
BT 110.802 699.015 Td /F1 9.8 Tf  [( . However, no information on analytic sensitivity or specificity can be found for the tests offered by Pathway )] TJ ET
BT 45.750 687.110 Td /F1 9.8 Tf  [(Genomics )] TJ ET
0.267 0.267 0.267 rg
BT 92.345 687.110 Td /F1 9.8 Tf  [([28])] TJ ET
0.271 0.267 0.267 rg
BT 108.608 687.110 Td /F1 9.8 Tf  [( , Matrix Genomics )] TJ ET
0.267 0.267 0.267 rg
BT 192.585 687.110 Td /F1 9.8 Tf  [([29])] TJ ET
0.271 0.267 0.267 rg
BT 208.848 687.110 Td /F1 9.8 Tf  [( , or MyMedLab )] TJ ET
0.267 0.267 0.267 rg
BT 279.292 687.110 Td /F1 9.8 Tf  [([30])] TJ ET
0.271 0.267 0.267 rg
BT 295.555 687.110 Td /F1 9.8 Tf  [( , or for some tests offered by Quest Diagnostics )] TJ ET
0.267 0.267 0.267 rg
BT 506.896 687.110 Td /F1 9.8 Tf  [([31])] TJ ET
0.271 0.267 0.267 rg
BT 523.159 687.110 Td /F1 9.8 Tf  [( or Genelex )] TJ ET
BT 45.750 675.205 Td /F1 9.8 Tf  [(Corporation )] TJ ET
0.267 0.267 0.267 rg
BT 99.394 675.205 Td /F1 9.8 Tf  [([32])] TJ ET
0.271 0.267 0.267 rg
BT 115.657 675.205 Td /F1 9.8 Tf  [( .)] TJ ET
40.337 662.518 m 
40.337 662.965 40.154 663.409 39.838 663.725 c
39.522 664.040 39.078 664.224 38.631 664.224 c
38.185 664.224 37.741 664.040 37.425 663.725 c
37.109 663.409 36.925 662.965 36.925 662.518 c
36.925 662.071 37.109 661.627 37.425 661.311 c
37.741 660.996 38.185 660.812 38.631 660.812 c
39.078 660.812 39.522 660.996 39.838 661.311 c
40.154 661.627 40.337 662.071 40.337 662.518 c f
BT 45.750 659.550 Td /F1 9.8 Tf  [(Cross validation of the techniques used inCYP2C19genotyping assays, along with their reliability, specificity, and )] TJ ET
BT 45.750 647.646 Td /F1 9.8 Tf  [(reproducibility, is extremely limited )] TJ ET
0.267 0.267 0.267 rg
BT 196.904 647.646 Td /F1 9.8 Tf  [([19])] TJ ET
0.271 0.267 0.267 rg
BT 213.167 647.646 Td /F1 9.8 Tf  [( .)] TJ ET
BT 26.250 624.491 Td /F6 9.8 Tf  [(Clinical Validity)] TJ ET
BT 98.322 624.491 Td /F4 9.8 Tf  [( : )] TJ ET
BT 106.990 624.491 Td /F1 9.8 Tf  [( Test accuracy and reliability in predicting response to clopidogrel \(predictive value\).)] TJ ET
40.337 608.054 m 
40.337 608.500 40.154 608.944 39.838 609.260 c
39.522 609.576 39.078 609.760 38.631 609.760 c
38.185 609.760 37.741 609.576 37.425 609.260 c
37.109 608.944 36.925 608.500 36.925 608.054 c
36.925 607.607 37.109 607.163 37.425 606.847 c
37.741 606.531 38.185 606.347 38.631 606.347 c
39.078 606.347 39.522 606.531 39.838 606.847 c
40.154 607.163 40.337 607.607 40.337 608.054 c f
BT 45.750 605.086 Td /F1 9.8 Tf  [(Numerous published studies have examined the relationship of CYP2C19alleles to clopidogrel response )] TJ ET
0.267 0.267 0.267 rg
BT 497.156 605.086 Td /F1 9.8 Tf  [([33])] TJ ET
0.271 0.267 0.267 rg
BT 513.418 605.086 Td /F1 9.8 Tf  [(. )] TJ ET
0.39 w 1 J 1 j
59.837 592.399 m 
59.837 592.846 59.654 593.290 59.338 593.606 c
59.022 593.921 58.578 594.105 58.131 594.105 c
57.685 594.105 57.241 593.921 56.925 593.606 c
56.609 593.290 56.425 592.846 56.425 592.399 c
56.425 591.952 56.609 591.508 56.925 591.192 c
57.241 590.877 57.685 590.693 58.131 590.693 c
58.578 590.693 59.022 590.877 59.338 591.192 c
59.654 591.508 59.837 591.952 59.837 592.399 c s
0.267 0.267 0.267 rg
BT 65.250 589.431 Td /F1 9.8 Tf  [(HuGE Navigator)] TJ ET
0.271 0.267 0.267 rg
BT 136.230 589.431 Td /F1 9.8 Tf  [( : query �clopidogrel and CYP2C19�)] TJ ET
40.337 572.994 m 
40.337 573.441 40.154 573.885 39.838 574.201 c
39.522 574.517 39.078 574.700 38.631 574.700 c
38.185 574.700 37.741 574.517 37.425 574.201 c
37.109 573.885 36.925 573.441 36.925 572.994 c
36.925 572.548 37.109 572.104 37.425 571.788 c
37.741 571.472 38.185 571.288 38.631 571.288 c
39.078 571.288 39.522 571.472 39.838 571.788 c
40.154 572.104 40.337 572.548 40.337 572.994 c f
BT 45.750 570.027 Td /F1 9.8 Tf  [(At least 22 studies have examined pharmacokinetic and/or pharmacodynamic responses byCYP2C19genotype; these )] TJ ET
BT 45.750 558.122 Td /F1 9.8 Tf  [(studies differed in the populations tested and the specific pharmacokinetic or pharmacodynamic measure\(s\) that were )] TJ ET
BT 45.750 546.217 Td /F1 9.8 Tf  [(employed \(most studies reviewed in )] TJ ET
0.267 0.267 0.267 rg
BT 203.427 546.217 Td /F1 9.8 Tf  [([1])] TJ ET
BT 214.269 546.217 Td /F1 9.8 Tf  [([34])] TJ ET
0.271 0.267 0.267 rg
BT 230.532 546.217 Td /F1 9.8 Tf  [( \). Twenty studies examined reduced-function variants \(mostly *2 alone or in )] TJ ET
BT 45.750 534.312 Td /F1 9.8 Tf  [(combination with other variants\) )] TJ ET
0.267 0.267 0.267 rg
BT 186.091 534.312 Td /F1 9.8 Tf  [([2])] TJ ET
BT 196.934 534.312 Td /F1 9.8 Tf  [([35])] TJ ET
BT 213.197 534.312 Td /F1 9.8 Tf  [([36])] TJ ET
BT 229.460 534.312 Td /F1 9.8 Tf  [([37])] TJ ET
BT 245.723 534.312 Td /F1 9.8 Tf  [([38])] TJ ET
BT 261.986 534.312 Td /F1 9.8 Tf  [([39])] TJ ET
BT 278.249 534.312 Td /F1 9.8 Tf  [([40])] TJ ET
BT 294.512 534.312 Td /F1 9.8 Tf  [([41])] TJ ET
BT 310.775 534.312 Td /F1 9.8 Tf  [([42])] TJ ET
BT 327.038 534.312 Td /F1 9.8 Tf  [([43])] TJ ET
BT 343.300 534.312 Td /F1 9.8 Tf  [([44])] TJ ET
BT 359.563 534.312 Td /F1 9.8 Tf  [([45])] TJ ET
BT 375.826 534.312 Td /F1 9.8 Tf  [([46])] TJ ET
BT 392.089 534.312 Td /F1 9.8 Tf  [([47])] TJ ET
BT 408.352 534.312 Td /F1 9.8 Tf  [([48])] TJ ET
BT 424.615 534.312 Td /F1 9.8 Tf  [([49])] TJ ET
BT 440.878 534.312 Td /F1 9.8 Tf  [([50])] TJ ET
BT 457.141 534.312 Td /F1 9.8 Tf  [([51])] TJ ET
BT 473.404 534.312 Td /F1 9.8 Tf  [([52])] TJ ET
BT 489.667 534.312 Td /F1 9.8 Tf  [([53])] TJ ET
0.271 0.267 0.267 rg
BT 505.930 534.312 Td /F1 9.8 Tf  [( . All studies )] TJ ET
BT 45.750 522.408 Td /F1 9.8 Tf  [(except one )] TJ ET
0.267 0.267 0.267 rg
BT 96.157 522.408 Td /F1 9.8 Tf  [([37])] TJ ET
0.271 0.267 0.267 rg
BT 112.421 522.408 Td /F1 9.8 Tf  [( reported statistically significant differences in clopidogrel response in reduced-function allele carriers. In )] TJ ET
BT 45.750 510.503 Td /F1 9.8 Tf  [(these 19 studies, p values ranged from 4.3�10)] TJ ET
BT 246.551 514.391 Td /F1 8.7 Tf  [(-11)] TJ ET
BT 259.075 510.503 Td /F1 9.8 Tf  [(to <0.05.)] TJ ET
40.337 497.816 m 
40.337 498.262 40.154 498.706 39.838 499.022 c
39.522 499.338 39.078 499.522 38.631 499.522 c
38.185 499.522 37.741 499.338 37.425 499.022 c
37.109 498.706 36.925 498.262 36.925 497.816 c
36.925 497.369 37.109 496.925 37.425 496.609 c
37.741 496.293 38.185 496.109 38.631 496.109 c
39.078 496.109 39.522 496.293 39.838 496.609 c
40.154 496.925 40.337 497.369 40.337 497.816 c f
BT 45.750 494.848 Td /F1 9.8 Tf  [(Seven studies have examined the association of the *17 variant with pharmacokinetic or pharmacodynamic responses )] TJ ET
BT 45.750 482.943 Td /F1 9.8 Tf  [(specifically to clopidogrel, with inconsistent results )] TJ ET
0.267 0.267 0.267 rg
BT 264.657 482.943 Td /F1 9.8 Tf  [([2])] TJ ET
BT 275.499 482.943 Td /F1 9.8 Tf  [([39])] TJ ET
BT 291.762 482.943 Td /F1 9.8 Tf  [([44])] TJ ET
BT 308.025 482.943 Td /F1 9.8 Tf  [([48])] TJ ET
BT 324.288 482.943 Td /F1 9.8 Tf  [([53])] TJ ET
BT 340.551 482.943 Td /F1 9.8 Tf  [([54])] TJ ET
BT 356.814 482.943 Td /F1 9.8 Tf  [([55])] TJ ET
0.271 0.267 0.267 rg
BT 373.077 482.943 Td /F1 9.8 Tf  [( . Only one of these studies measured plasma )] TJ ET
BT 45.750 471.039 Td /F1 9.8 Tf  [(levels of the clopidogrel active metabolite. However, *17 allele carriers were grouped with *1/*1 extensive metabolizers; and )] TJ ET
BT 45.750 459.134 Td /F1 9.8 Tf  [(so individual effects of the *17 allele on clopidogrel metabolism cannot be determined )] TJ ET
0.267 0.267 0.267 rg
BT 416.425 459.134 Td /F1 9.8 Tf  [([44])] TJ ET
0.271 0.267 0.267 rg
BT 432.688 459.134 Td /F1 9.8 Tf  [( .)] TJ ET
40.337 446.447 m 
40.337 446.893 40.154 447.337 39.838 447.653 c
39.522 447.969 39.078 448.153 38.631 448.153 c
38.185 448.153 37.741 447.969 37.425 447.653 c
37.109 447.337 36.925 446.893 36.925 446.447 c
36.925 446.000 37.109 445.556 37.425 445.240 c
37.741 444.924 38.185 444.740 38.631 444.740 c
39.078 444.740 39.522 444.924 39.838 445.240 c
40.154 445.556 40.337 446.000 40.337 446.447 c f
BT 45.750 443.479 Td /F1 9.8 Tf  [(Only one clinical trial explicitly reported measures of clinical validity. In the EXCELSIOR \(Impact of Extent of Clopidogrel-)] TJ ET
BT 45.750 431.574 Td /F1 9.8 Tf  [(Induced Platelet Inhibition During Elective Stent Implantation on Clinical Event Rate\) trial, the sensitivity and specificity )] TJ ET
BT 45.750 419.670 Td /F1 9.8 Tf  [(ofCYP2C19*2carrier status for detecting high on-clopidogrel residual platelet aggregation \(RPA\) was 45.1% and 75.0%, )] TJ ET
BT 45.750 407.765 Td /F1 9.8 Tf  [(respectively )] TJ ET
0.267 0.267 0.267 rg
BT 99.931 407.765 Td /F1 9.8 Tf  [([35])] TJ ET
0.271 0.267 0.267 rg
BT 116.194 407.765 Td /F1 9.8 Tf  [( . Measures of sensitivity and specificity can be calculated from data reported in some of the other )] TJ ET
BT 45.750 395.860 Td /F1 9.8 Tf  [(published studies.)] TJ ET
40.337 383.173 m 
40.337 383.620 40.154 384.064 39.838 384.380 c
39.522 384.695 39.078 384.879 38.631 384.879 c
38.185 384.879 37.741 384.695 37.425 384.380 c
37.109 384.064 36.925 383.620 36.925 383.173 c
36.925 382.726 37.109 382.282 37.425 381.966 c
37.741 381.651 38.185 381.467 38.631 381.467 c
39.078 381.467 39.522 381.651 39.838 381.966 c
40.154 382.282 40.337 382.726 40.337 383.173 c f
BT 45.750 380.205 Td /F1 9.8 Tf  [(No investigators explicitly included estimates of positive predictive value \(PPV\) or negative predictive value \(NPV\) for )] TJ ET
BT 45.750 368.301 Td /F1 9.8 Tf  [(clopidogrel response in their original published reports. Using data from the EXCELSIOR report )] TJ ET
0.267 0.267 0.267 rg
BT 459.209 368.301 Td /F1 9.8 Tf  [([35])] TJ ET
0.271 0.267 0.267 rg
BT 475.471 368.301 Td /F1 9.8 Tf  [( , estimates of PPV and )] TJ ET
BT 45.750 356.396 Td /F1 9.8 Tf  [(NPV are 41.6% and 77.6%, respectively.)] TJ ET
BT 26.250 333.241 Td /F6 9.8 Tf  [(Clinical Utility)] TJ ET
BT 90.727 333.241 Td /F4 9.8 Tf  [( : )] TJ ET
BT 99.394 333.241 Td /F1 9.8 Tf  [( Net benefit of test in improving health outcomes.)] TJ ET
40.337 316.804 m 
40.337 317.251 40.154 317.695 39.838 318.011 c
39.522 318.326 39.078 318.510 38.631 318.510 c
38.185 318.510 37.741 318.326 37.425 318.011 c
37.109 317.695 36.925 317.251 36.925 316.804 c
36.925 316.357 37.109 315.913 37.425 315.597 c
37.741 315.282 38.185 315.098 38.631 315.098 c
39.078 315.098 39.522 315.282 39.838 315.597 c
40.154 315.913 40.337 316.357 40.337 316.804 c f
BT 45.750 313.836 Td /F1 9.8 Tf  [(A recent meta-analysis of seven prospective cohort studies was published that examined the CYP2C19*2 variant and )] TJ ET
BT 45.750 301.932 Td /F1 9.8 Tf  [(cardiovascular recurrences in 8,043 coronary artery disease patients taking clopidogrel. The authors found a statistically )] TJ ET
BT 45.750 290.027 Td /F1 9.8 Tf  [(significant increased risk of major adverse cardiovascular events in CYP2C19*2 carriers \(RR = 1.96\) and an even greater )] TJ ET
BT 45.750 278.122 Td /F1 9.8 Tf  [(risk when stent thrombosis was analyzed separately using four studies that included 4,975 patients \(RR = 3.82\) )] TJ ET
0.267 0.267 0.267 rg
BT 527.780 278.122 Td /F1 9.8 Tf  [([56])] TJ ET
0.271 0.267 0.267 rg
BT 544.043 278.122 Td /F1 9.8 Tf  [( .)] TJ ET
40.337 265.435 m 
40.337 265.882 40.154 266.326 39.838 266.642 c
39.522 266.957 39.078 267.141 38.631 267.141 c
38.185 267.141 37.741 266.957 37.425 266.642 c
37.109 266.326 36.925 265.882 36.925 265.435 c
36.925 264.988 37.109 264.544 37.425 264.228 c
37.741 263.913 38.185 263.729 38.631 263.729 c
39.078 263.729 39.522 263.913 39.838 264.228 c
40.154 264.544 40.337 264.988 40.337 265.435 c f
BT 45.750 262.467 Td /F1 9.8 Tf  [(A more recent meta-analysis that was not restricted to prospective cohort studies examined the CYP2C19*2 variant and the )] TJ ET
BT 45.750 250.563 Td /F1 9.8 Tf  [(incidence of major adverse cardiovascular events \(MACE\) and mortality in patients taking clopidogrel )] TJ ET
0.267 0.267 0.267 rg
BT 483.574 250.563 Td /F1 9.8 Tf  [([57])] TJ ET
0.271 0.267 0.267 rg
BT 499.837 250.563 Td /F1 9.8 Tf  [( . The pooled data )] TJ ET
BT 45.750 238.658 Td /F1 9.8 Tf  [(showed that CYP2C19*2 carriers had a statistically significant increased risk of MACE \(OR = 1.29\) using data from ten )] TJ ET
BT 45.750 226.753 Td /F1 9.8 Tf  [(studies \(11,959 patients\). Carriers of *2 also had statistically significant increases in risk for stent thrombosis \(OR = 3.45 )] TJ ET
BT 45.750 214.848 Td /F1 9.8 Tf  [(using data from 4 studies including 4,905 patients\) and death \(OR = 1.79 using data from 5 studies including 6,225 )] TJ ET
BT 45.750 202.944 Td /F1 9.8 Tf  [(patients\). Four studies including 5,694 patients allowed the separate assessment of heterozygotes and homozygotes of the )] TJ ET
BT 45.750 191.039 Td /F1 9.8 Tf  [(*2 allele. Increased risks for MACE and stent thrombosis were noted for both groups, though the odds ratio for MACE was )] TJ ET
BT 45.750 179.134 Td /F1 9.8 Tf  [(significant only for homozygotes )] TJ ET
0.267 0.267 0.267 rg
BT 187.184 179.134 Td /F1 9.8 Tf  [([57])] TJ ET
0.271 0.267 0.267 rg
BT 203.447 179.134 Td /F1 9.8 Tf  [( .)] TJ ET
40.337 166.447 m 
40.337 166.894 40.154 167.338 39.838 167.654 c
39.522 167.969 39.078 168.153 38.631 168.153 c
38.185 168.153 37.741 167.969 37.425 167.654 c
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BT 26.250 387.472 Td /F4 12.0 Tf  [(Acknowledgments)] TJ ET
BT 26.250 367.518 Td /F1 9.8 Tf  [(I would like to thank Shelley Reyes, Nicole F. Dowling, and Cecelia Bellcross in the Office of Public Health Genomics for )] TJ ET
BT 26.250 355.613 Td /F1 9.8 Tf  [(comments and guidance.)] TJ ET
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BT 26.250 287.151 Td /F1 9.8 Tf  [(Services, Centers for Disease Control and Prevention.)] TJ ET
BT 26.250 250.549 Td /F4 12.0 Tf  [(Competing interests)] TJ ET
BT 26.250 230.595 Td /F1 9.8 Tf  [(The author declares that no competing interests exist.)] TJ ET
BT 26.250 193.992 Td /F4 12.0 Tf  [(Disclaimer)] TJ ET
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BT 26.250 162.133 Td /F1 9.8 Tf  [(suggest that you discuss them with your health care provider.)] TJ ET
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BT 38.132 98.076 Td /F1 9.8 Tf  [(Verstuyft C, Simon T, Kim RB. Personalized medicine and antiplatelet therapy: ready for prime time? Eur Heart J. 2009 )] TJ ET
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59.837 675.861 m 
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BT 65.250 633.429 Td /F1 9.8 Tf  [(Currently, there are no standardized clinical guidelines to manage patients with an inadequate response to clopidogrel. )] TJ ET
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0.271 0.267 0.267 rg
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40.337 548.530 m 
40.337 548.977 40.154 549.421 39.838 549.737 c
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38.185 550.236 37.741 550.052 37.425 549.737 c
37.109 549.421 36.925 548.977 36.925 548.530 c
36.925 548.083 37.109 547.639 37.425 547.323 c
37.741 547.008 38.185 546.824 38.631 546.824 c
39.078 546.824 39.522 547.008 39.838 547.323 c
40.154 547.639 40.337 548.083 40.337 548.530 c f
BT 45.750 545.562 Td /F1 9.8 Tf  [(Human Cytochrome P450 \(CYP\) Allele Nomenclature Committee, CYP2C19 allele nomenclature \( )] TJ ET
0.267 0.267 0.267 rg
BT 45.750 533.658 Td /F1 9.8 Tf  [(https://www.cypalleles.ki.se/cyp2c19.htm)] TJ ET
0.271 0.267 0.267 rg
BT 217.516 533.658 Td /F1 9.8 Tf  [( \), last accessed: March 17, 2010.)] TJ ET
40.337 520.970 m 
40.337 521.417 40.154 521.861 39.838 522.177 c
39.522 522.493 39.078 522.677 38.631 522.677 c
38.185 522.677 37.741 522.493 37.425 522.177 c
37.109 521.861 36.925 521.417 36.925 520.970 c
36.925 520.524 37.109 520.080 37.425 519.764 c
37.741 519.448 38.185 519.264 38.631 519.264 c
39.078 519.264 39.522 519.448 39.838 519.764 c
40.154 520.080 40.337 520.524 40.337 520.970 c f
0.267 0.267 0.267 rg
BT 45.750 518.003 Td /F1 9.8 Tf  [(HuGE Navigator)] TJ ET
0.271 0.267 0.267 rg
BT 116.730 518.003 Td /F1 9.8 Tf  [(: query �clopidogrel and CYP2C19�)] TJ ET
40.337 505.316 m 
40.337 505.762 40.154 506.206 39.838 506.522 c
39.522 506.838 39.078 507.022 38.631 507.022 c
38.185 507.022 37.741 506.838 37.425 506.522 c
37.109 506.206 36.925 505.762 36.925 505.316 c
36.925 504.869 37.109 504.425 37.425 504.109 c
37.741 503.793 38.185 503.609 38.631 503.609 c
39.078 503.609 39.522 503.793 39.838 504.109 c
40.154 504.425 40.337 504.869 40.337 505.316 c f
0.267 0.267 0.267 rg
BT 45.750 502.348 Td /F1 9.8 Tf  [(U.S. Food and Drug Administration:)] TJ ET
BT 199.644 502.348 Td /F1 9.8 Tf  [(Table of Valid Genomic Biomarkers in the Context of Approved Drug Labels)] TJ ET
0.271 0.267 0.267 rg
40.337 489.661 m 
40.337 490.108 40.154 490.552 39.838 490.868 c
39.522 491.183 39.078 491.367 38.631 491.367 c
38.185 491.367 37.741 491.183 37.425 490.868 c
37.109 490.552 36.925 490.108 36.925 489.661 c
36.925 489.214 37.109 488.770 37.425 488.454 c
37.741 488.139 38.185 487.955 38.631 487.955 c
39.078 487.955 39.522 488.139 39.838 488.454 c
40.154 488.770 40.337 489.214 40.337 489.661 c f
0.267 0.267 0.267 rg
BT 45.750 486.693 Td /F1 9.8 Tf  [(ClinicalTrials.gov:)] TJ ET
BT 122.132 486.693 Td /F1 9.8 Tf  [(Clopidogrel and CYP2C19)] TJ ET
0.271 0.267 0.267 rg
BT 236.470 486.693 Td /F1 9.8 Tf  [( . Note: not all clinical trials list a pharmacogenetic component to their study, )] TJ ET
BT 45.750 474.789 Td /F1 9.8 Tf  [(even if one exists. For instance, some studies have been found to include genetic analyses only after publication of those )] TJ ET
BT 45.750 462.884 Td /F1 9.8 Tf  [(data. Consequently, searching for �clopidogrel and CYP2C19� or a similar search will not return all relevant studies.)] TJ ET
40.337 450.197 m 
40.337 450.643 40.154 451.087 39.838 451.403 c
39.522 451.719 39.078 451.903 38.631 451.903 c
38.185 451.903 37.741 451.719 37.425 451.403 c
37.109 451.087 36.925 450.643 36.925 450.197 c
36.925 449.750 37.109 449.306 37.425 448.990 c
37.741 448.674 38.185 448.490 38.631 448.490 c
39.078 448.490 39.522 448.674 39.838 448.990 c
40.154 449.306 40.337 449.750 40.337 450.197 c f
0.267 0.267 0.267 rg
BT 45.750 447.229 Td /F1 9.8 Tf  [(PharmGKB:)] TJ ET
BT 97.766 447.229 Td /F1 9.8 Tf  [(clopidogrel)] TJ ET
0.271 0.267 0.267 rg
BT 144.907 447.229 Td /F1 9.8 Tf  [( , )] TJ ET
0.267 0.267 0.267 rg
BT 153.039 447.229 Td /F1 9.8 Tf  [(clinical PGx for clopidogrel)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 424.074 Td /F1 9.8 Tf  [(Last updated: )] TJ ET
BT 88.046 424.074 Td /F5 9.8 Tf  [(September 16, 2010)] TJ ET
BT 26.250 387.472 Td /F4 12.0 Tf  [(Acknowledgments)] TJ ET
BT 26.250 367.518 Td /F1 9.8 Tf  [(I would like to thank Shelley Reyes, Nicole F. Dowling, and Cecelia Bellcross in the Office of Public Health Genomics for )] TJ ET
BT 26.250 355.613 Td /F1 9.8 Tf  [(comments and guidance.)] TJ ET
BT 26.250 319.010 Td /F4 12.0 Tf  [(Funding information)] TJ ET
BT 26.250 299.056 Td /F1 9.8 Tf  [(This work was supported by the Office of Public Health Genomics, Office of Surveillance, Epidemiology, and Laboratory )] TJ ET
BT 26.250 287.151 Td /F1 9.8 Tf  [(Services, Centers for Disease Control and Prevention.)] TJ ET
BT 26.250 250.549 Td /F4 12.0 Tf  [(Competing interests)] TJ ET
BT 26.250 230.595 Td /F1 9.8 Tf  [(The author declares that no competing interests exist.)] TJ ET
BT 26.250 193.992 Td /F4 12.0 Tf  [(Disclaimer)] TJ ET
BT 26.250 174.038 Td /F1 9.8 Tf  [(The CDC does not offer medical advice to individuals. If you have specific concerns about your health or genetic testing, we )] TJ ET
BT 26.250 162.133 Td /F1 9.8 Tf  [(suggest that you discuss them with your health care provider.)] TJ ET
BT 26.250 125.531 Td /F4 12.0 Tf  [(References)] TJ ET
BT 26.250 98.076 Td /F1 9.8 Tf  [(1.)] TJ ET
BT 38.132 98.076 Td /F1 9.8 Tf  [(Verstuyft C, Simon T, Kim RB. Personalized medicine and antiplatelet therapy: ready for prime time? Eur Heart J. 2009 )] TJ ET
BT 26.250 86.172 Td /F1 9.8 Tf  [(Aug;30\(16\):1943-63. Epub 2009 Jul 28. PubMed PMID: 19638479.)] TJ ET
BT 26.250 66.767 Td /F1 9.8 Tf  [(2.)] TJ ET
BT 38.132 66.767 Td /F1 9.8 Tf  [(Shuldiner AR, O'Connell JR, Bliden KP, Gandhi A, Ryan K, Horenstein RB, Damcott CM, Pakyz R, Tantry US, Gibson Q, )] TJ ET
BT 26.250 54.862 Td /F1 9.8 Tf  [(Pollin TI, Post W, Parsa A, Mitchell BD, Faraday N, Herzog W, Gurbel PA. Association of cytochrome P450 2C19 genotype with )] TJ ET
Q
q
15.000 40.577 577.500 736.423 re W n
0.271 0.267 0.267 rg
BT 45.750 767.476 Td /F1 9.8 Tf  [(scenario \(for example, acute coronary syndrome versus stable angina pectoris\) )] TJ ET
0.267 0.267 0.267 rg
BT 389.837 767.476 Td /F1 9.8 Tf  [([19])] TJ ET
0.271 0.267 0.267 rg
BT 406.100 767.476 Td /F1 9.8 Tf  [( . However, a meta-analysis )] TJ ET
BT 45.750 755.571 Td /F1 9.8 Tf  [(demonstrated that the increased occurrence of major adverse cardiovascular events and of mortality in CYP2C19*2 )] TJ ET
BT 45.750 743.667 Td /F1 9.8 Tf  [(carriers was independent of patients� baseline cardiovascular risk )] TJ ET
0.267 0.267 0.267 rg
BT 329.690 743.667 Td /F1 9.8 Tf  [([57])] TJ ET
0.271 0.267 0.267 rg
BT 345.952 743.667 Td /F1 9.8 Tf  [( .)] TJ ET
0.271 0.267 0.267 RG
40.337 730.980 m 
40.337 731.426 40.154 731.870 39.838 732.186 c
39.522 732.502 39.078 732.686 38.631 732.686 c
38.185 732.686 37.741 732.502 37.425 732.186 c
37.109 731.870 36.925 731.426 36.925 730.980 c
36.925 730.533 37.109 730.089 37.425 729.773 c
37.741 729.457 38.185 729.273 38.631 729.273 c
39.078 729.273 39.522 729.457 39.838 729.773 c
40.154 730.089 40.337 730.533 40.337 730.980 c f
BT 45.750 728.012 Td /F1 9.8 Tf  [(Any benefits of DNA testing may be hampered by the following considerations: )] TJ ET
0.39 w 1 J 1 j
59.837 715.325 m 
59.837 715.771 59.654 716.215 59.338 716.531 c
59.022 716.847 58.578 717.031 58.131 717.031 c
57.685 717.031 57.241 716.847 56.925 716.531 c
56.609 716.215 56.425 715.771 56.425 715.325 c
56.425 714.878 56.609 714.434 56.925 714.118 c
57.241 713.802 57.685 713.619 58.131 713.619 c
58.578 713.619 59.022 713.802 59.338 714.118 c
59.654 714.434 59.837 714.878 59.837 715.325 c s
BT 65.250 712.357 Td /F1 9.8 Tf  [(The response to clopidogrel is unclear for some CYP2C19 genotypes, such as reduced-function alleles in the presence )] TJ ET
BT 65.250 700.452 Td /F1 9.8 Tf  [(of *17. The only study to directly assess the combined effect of *17 and reduced-function alleles \(in this case, *2\) found )] TJ ET
BT 65.250 688.548 Td /F1 9.8 Tf  [(a gradient of effect on pharmacodynamic response to clopidogrel )] TJ ET
0.267 0.267 0.267 rg
BT 348.137 688.548 Td /F1 9.8 Tf  [([53])] TJ ET
0.271 0.267 0.267 rg
BT 364.399 688.548 Td /F1 9.8 Tf  [( .)] TJ ET
0.39 w 1 J 1 j
59.837 675.861 m 
59.837 676.307 59.654 676.751 59.338 677.067 c
59.022 677.383 58.578 677.567 58.131 677.567 c
57.685 677.567 57.241 677.383 56.925 677.067 c
56.609 676.751 56.425 676.307 56.425 675.861 c
56.425 675.414 56.609 674.970 56.925 674.654 c
57.241 674.338 57.685 674.154 58.131 674.154 c
58.578 674.154 59.022 674.338 59.338 674.654 c
59.654 674.970 59.837 675.414 59.837 675.861 c s
BT 65.250 672.893 Td /F1 9.8 Tf  [(Genotyping only for CYP2C19 alleles does not capture all of the genetic variability in pharmacodynamic, )] TJ ET
BT 65.250 660.988 Td /F1 9.8 Tf  [(pharmacokinetic, or clinical responses to clopidogrel. Variants in the ABCB1 gene also seem to be potentially )] TJ ET
BT 65.250 649.083 Td /F1 9.8 Tf  [(important to the interindividual variability in these phenotypes )] TJ ET
0.267 0.267 0.267 rg
BT 331.327 649.083 Td /F1 9.8 Tf  [([3])] TJ ET
BT 342.169 649.083 Td /F1 9.8 Tf  [([14])] TJ ET
BT 358.432 649.083 Td /F1 9.8 Tf  [([61])] TJ ET
BT 374.695 649.083 Td /F1 9.8 Tf  [([62])] TJ ET
0.271 0.267 0.267 rg
BT 390.958 649.083 Td /F1 9.8 Tf  [( .)] TJ ET
0.39 w 1 J 1 j
59.837 636.396 m 
59.837 636.843 59.654 637.287 59.338 637.603 c
59.022 637.919 58.578 638.102 58.131 638.102 c
57.685 638.102 57.241 637.919 56.925 637.603 c
56.609 637.287 56.425 636.843 56.425 636.396 c
56.425 635.950 56.609 635.506 56.925 635.190 c
57.241 634.874 57.685 634.690 58.131 634.690 c
58.578 634.690 59.022 634.874 59.338 635.190 c
59.654 635.506 59.837 635.950 59.837 636.396 c s
BT 65.250 633.429 Td /F1 9.8 Tf  [(Currently, there are no standardized clinical guidelines to manage patients with an inadequate response to clopidogrel. )] TJ ET
BT 65.250 621.524 Td /F1 9.8 Tf  [(Typically, one or more alternatives are tried: higher loading or maintenance doses of clopidogrel, dual therapy with )] TJ ET
BT 65.250 609.619 Td /F1 9.8 Tf  [(aspirin if this has not already been initiated, or treatment with another antiplatelet medication )] TJ ET
0.267 0.267 0.267 rg
BT 465.731 609.619 Td /F1 9.8 Tf  [([19])] TJ ET
0.271 0.267 0.267 rg
BT 481.994 609.619 Td /F1 9.8 Tf  [( .)] TJ ET
BT 26.250 565.517 Td /F4 12.0 Tf  [(Links)] TJ ET
40.337 548.530 m 
40.337 548.977 40.154 549.421 39.838 549.737 c
39.522 550.052 39.078 550.236 38.631 550.236 c
38.185 550.236 37.741 550.052 37.425 549.737 c
37.109 549.421 36.925 548.977 36.925 548.530 c
36.925 548.083 37.109 547.639 37.425 547.323 c
37.741 547.008 38.185 546.824 38.631 546.824 c
39.078 546.824 39.522 547.008 39.838 547.323 c
40.154 547.639 40.337 548.083 40.337 548.530 c f
BT 45.750 545.562 Td /F1 9.8 Tf  [(Human Cytochrome P450 \(CYP\) Allele Nomenclature Committee, CYP2C19 allele nomenclature \( )] TJ ET
0.267 0.267 0.267 rg
BT 45.750 533.658 Td /F1 9.8 Tf  [(https://www.cypalleles.ki.se/cyp2c19.htm)] TJ ET
0.271 0.267 0.267 rg
BT 217.516 533.658 Td /F1 9.8 Tf  [( \), last accessed: March 17, 2010.)] TJ ET
40.337 520.970 m 
40.337 521.417 40.154 521.861 39.838 522.177 c
39.522 522.493 39.078 522.677 38.631 522.677 c
38.185 522.677 37.741 522.493 37.425 522.177 c
37.109 521.861 36.925 521.417 36.925 520.970 c
36.925 520.524 37.109 520.080 37.425 519.764 c
37.741 519.448 38.185 519.264 38.631 519.264 c
39.078 519.264 39.522 519.448 39.838 519.764 c
40.154 520.080 40.337 520.524 40.337 520.970 c f
0.267 0.267 0.267 rg
BT 45.750 518.003 Td /F1 9.8 Tf  [(HuGE Navigator)] TJ ET
0.271 0.267 0.267 rg
BT 116.730 518.003 Td /F1 9.8 Tf  [(: query �clopidogrel and CYP2C19�)] TJ ET
40.337 505.316 m 
40.337 505.762 40.154 506.206 39.838 506.522 c
39.522 506.838 39.078 507.022 38.631 507.022 c
38.185 507.022 37.741 506.838 37.425 506.522 c
37.109 506.206 36.925 505.762 36.925 505.316 c
36.925 504.869 37.109 504.425 37.425 504.109 c
37.741 503.793 38.185 503.609 38.631 503.609 c
39.078 503.609 39.522 503.793 39.838 504.109 c
40.154 504.425 40.337 504.869 40.337 505.316 c f
0.267 0.267 0.267 rg
BT 45.750 502.348 Td /F1 9.8 Tf  [(U.S. Food and Drug Administration:)] TJ ET
BT 199.644 502.348 Td /F1 9.8 Tf  [(Table of Valid Genomic Biomarkers in the Context of Approved Drug Labels)] TJ ET
0.271 0.267 0.267 rg
40.337 489.661 m 
40.337 490.108 40.154 490.552 39.838 490.868 c
39.522 491.183 39.078 491.367 38.631 491.367 c
38.185 491.367 37.741 491.183 37.425 490.868 c
37.109 490.552 36.925 490.108 36.925 489.661 c
36.925 489.214 37.109 488.770 37.425 488.454 c
37.741 488.139 38.185 487.955 38.631 487.955 c
39.078 487.955 39.522 488.139 39.838 488.454 c
40.154 488.770 40.337 489.214 40.337 489.661 c f
0.267 0.267 0.267 rg
BT 45.750 486.693 Td /F1 9.8 Tf  [(ClinicalTrials.gov:)] TJ ET
BT 122.132 486.693 Td /F1 9.8 Tf  [(Clopidogrel and CYP2C19)] TJ ET
0.271 0.267 0.267 rg
BT 236.470 486.693 Td /F1 9.8 Tf  [( . Note: not all clinical trials list a pharmacogenetic component to their study, )] TJ ET
BT 45.750 474.789 Td /F1 9.8 Tf  [(even if one exists. For instance, some studies have been found to include genetic analyses only after publication of those )] TJ ET
BT 45.750 462.884 Td /F1 9.8 Tf  [(data. Consequently, searching for �clopidogrel and CYP2C19� or a similar search will not return all relevant studies.)] TJ ET
40.337 450.197 m 
40.337 450.643 40.154 451.087 39.838 451.403 c
39.522 451.719 39.078 451.903 38.631 451.903 c
38.185 451.903 37.741 451.719 37.425 451.403 c
37.109 451.087 36.925 450.643 36.925 450.197 c
36.925 449.750 37.109 449.306 37.425 448.990 c
37.741 448.674 38.185 448.490 38.631 448.490 c
39.078 448.490 39.522 448.674 39.838 448.990 c
40.154 449.306 40.337 449.750 40.337 450.197 c f
0.267 0.267 0.267 rg
BT 45.750 447.229 Td /F1 9.8 Tf  [(PharmGKB:)] TJ ET
BT 97.766 447.229 Td /F1 9.8 Tf  [(clopidogrel)] TJ ET
0.271 0.267 0.267 rg
BT 144.907 447.229 Td /F1 9.8 Tf  [( , )] TJ ET
0.267 0.267 0.267 rg
BT 153.039 447.229 Td /F1 9.8 Tf  [(clinical PGx for clopidogrel)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 424.074 Td /F1 9.8 Tf  [(Last updated: )] TJ ET
BT 88.046 424.074 Td /F5 9.8 Tf  [(September 16, 2010)] TJ ET
BT 26.250 387.472 Td /F4 12.0 Tf  [(Acknowledgments)] TJ ET
BT 26.250 367.518 Td /F1 9.8 Tf  [(I would like to thank Shelley Reyes, Nicole F. Dowling, and Cecelia Bellcross in the Office of Public Health Genomics for )] TJ ET
BT 26.250 355.613 Td /F1 9.8 Tf  [(comments and guidance.)] TJ ET
BT 26.250 319.010 Td /F4 12.0 Tf  [(Funding information)] TJ ET
BT 26.250 299.056 Td /F1 9.8 Tf  [(This work was supported by the Office of Public Health Genomics, Office of Surveillance, Epidemiology, and Laboratory )] TJ ET
BT 26.250 287.151 Td /F1 9.8 Tf  [(Services, Centers for Disease Control and Prevention.)] TJ ET
BT 26.250 250.549 Td /F4 12.0 Tf  [(Competing interests)] TJ ET
BT 26.250 230.595 Td /F1 9.8 Tf  [(The author declares that no competing interests exist.)] TJ ET
BT 26.250 193.992 Td /F4 12.0 Tf  [(Disclaimer)] TJ ET
BT 26.250 174.038 Td /F1 9.8 Tf  [(The CDC does not offer medical advice to individuals. If you have specific concerns about your health or genetic testing, we )] TJ ET
BT 26.250 162.133 Td /F1 9.8 Tf  [(suggest that you discuss them with your health care provider.)] TJ ET
BT 26.250 125.531 Td /F4 12.0 Tf  [(References)] TJ ET
BT 26.250 98.076 Td /F1 9.8 Tf  [(1.)] TJ ET
BT 38.132 98.076 Td /F1 9.8 Tf  [(Verstuyft C, Simon T, Kim RB. Personalized medicine and antiplatelet therapy: ready for prime time? Eur Heart J. 2009 )] TJ ET
BT 26.250 86.172 Td /F1 9.8 Tf  [(Aug;30\(16\):1943-63. Epub 2009 Jul 28. PubMed PMID: 19638479.)] TJ ET
BT 26.250 66.767 Td /F1 9.8 Tf  [(2.)] TJ ET
BT 38.132 66.767 Td /F1 9.8 Tf  [(Shuldiner AR, O'Connell JR, Bliden KP, Gandhi A, Ryan K, Horenstein RB, Damcott CM, Pakyz R, Tantry US, Gibson Q, )] TJ ET
BT 26.250 54.862 Td /F1 9.8 Tf  [(Pollin TI, Post W, Parsa A, Mitchell BD, Faraday N, Herzog W, Gurbel PA. Association of cytochrome P450 2C19 genotype with )] TJ ET
Q
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0.000 0.000 0.000 rg
BT 291.710 19.825 Td /F1 11.0 Tf  [(5)] TJ ET
BT 25.000 19.825 Td /F1 11.0 Tf  [(PLOS Currents Evidence on Genomic Tests)] TJ ET
0.39 w 1 J 1 j
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BT 26.250 692.952 Td /F1 9.8 Tf  [(PMCID: PMC2829691.)] TJ ET
BT 26.250 673.548 Td /F1 9.8 Tf  [(5.)] TJ ET
BT 38.132 673.548 Td /F1 9.8 Tf  [(Sim SC, Risinger C, Dahl ML, Aklillu E, Christensen M, Bertilsson L, Ingelman-Sundberg M. A common novel CYP2C19 )] TJ ET
BT 26.250 661.643 Td /F1 9.8 Tf  [(gene variant causes ultrarapid drug metabolism relevant for the drug response to proton pump inhibitors and antidepressants. )] TJ ET
BT 26.250 649.738 Td /F1 9.8 Tf  [(Clin Pharmacol Ther. 2006 Jan;79\(1\):103-13. PubMed PMID: 16413245.)] TJ ET
BT 26.250 630.333 Td /F1 9.8 Tf  [(6.)] TJ ET
BT 38.132 630.333 Td /F1 9.8 Tf  [(IMS Health. Top-line Industry Data: 2009 Global Prescription Sales Information. IMS Health Web site. Accessed July 2, 2010.)] TJ ET
0.267 0.267 0.267 rg
BT 26.250 621.847 Td /F1 7.5 Tf  [(REFERENCE LINK)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 603.297 Td /F1 9.8 Tf  [(7.)] TJ ET
BT 38.132 603.297 Td /F1 9.8 Tf  [(Top 200 Drugs of 2008. Accessed March 15, 2010.)] TJ ET
0.267 0.267 0.267 rg
BT 26.250 594.812 Td /F1 7.5 Tf  [(REFERENCE LINK)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 576.261 Td /F1 9.8 Tf  [(8.)] TJ ET
BT 38.132 576.261 Td /F1 9.8 Tf  [(Snoep JD, Hovens MM, Eikenboom JC, van der Bom JG, Jukema JW, Huisman MV. Clopidogrel nonresponsiveness in )] TJ ET
BT 26.250 564.357 Td /F1 9.8 Tf  [(patients undergoing percutaneous coronary intervention with stenting: a systematic review and meta-analysis. Am Heart J. 2007 )] TJ ET
BT 26.250 552.452 Td /F1 9.8 Tf  [(Aug;154\(2\):221-31. Review. PubMed PMID: 17643570.)] TJ ET
BT 26.250 533.047 Td /F1 9.8 Tf  [(9.)] TJ ET
BT 38.132 533.047 Td /F1 9.8 Tf  [(Combescure C, Fontana P, Mallouk N, Berdague P, Labruyere C, Barazer I, Gris JC, Laporte S, Fabbro-Peray P, Reny JL; )] TJ ET
BT 26.250 521.142 Td /F1 9.8 Tf  [(CLOpidogrel and Vascular ISchemic Events Meta-analysis Study Group. Clinical implications of clopidogrel non-response in )] TJ ET
BT 26.250 509.238 Td /F1 9.8 Tf  [(cardiovascular patients: a systematic review and meta-analysis. J Thromb Haemost. 2010 May;8\(5\):923-33. Epub 2010 Feb 12. )] TJ ET
BT 26.250 497.333 Td /F1 9.8 Tf  [(PubMed PMID: 20156305.)] TJ ET
BT 26.250 477.928 Td /F1 9.8 Tf  [(10.)] TJ ET
BT 43.553 477.928 Td /F1 9.8 Tf  [(Sofi F, Marcucci R, Gori AM, Giusti B, Abbate R, Gensini GF. Clopidogrel non-responsiveness and risk of cardiovascular )] TJ ET
BT 26.250 466.023 Td /F1 9.8 Tf  [(morbidity. An updated meta-analysis. Thromb Haemost. 2010 Mar 31;103\(4\):841-8. Epub 2010 Feb 2. PubMed PMID: )] TJ ET
BT 26.250 454.119 Td /F1 9.8 Tf  [(20135063.)] TJ ET
BT 26.250 434.714 Td /F1 9.8 Tf  [(11.)] TJ ET
BT 43.553 434.714 Td /F1 9.8 Tf  [(Helton TJ, Bavry AA, Kumbhani DJ, Duggal S, Roukoz H, Bhatt DL. Incremental effect of clopidogrel on important outcomes )] TJ ET
BT 26.250 422.809 Td /F1 9.8 Tf  [(in patients with cardiovascular disease: a meta-analysis of randomized trials. Am J Cardiovasc Drugs. 2007;7\(4\):289-97. )] TJ ET
BT 26.250 410.904 Td /F1 9.8 Tf  [(PubMed PMID: 17696569.)] TJ ET
BT 26.250 391.500 Td /F1 9.8 Tf  [(12.)] TJ ET
BT 43.553 391.500 Td /F1 9.8 Tf  [(Berger JS, Bhatt DL, Cannon CP, Chen Z, Jiang L, Jones JB, Mehta SR, Sabatine MS, Steinhubl SR, Topol EJ, Berger PB. )] TJ ET
BT 26.250 379.595 Td /F1 9.8 Tf  [(The relative efficacy and safety of clopidogrel in women and men a sex-specific collaborative meta-analysis. J Am Coll Cardiol. )] TJ ET
BT 26.250 367.690 Td /F1 9.8 Tf  [(2009 Nov 17;54\(21\):1935-45. Review. PubMed PMID: 19909874.)] TJ ET
BT 26.250 348.285 Td /F1 9.8 Tf  [(13.)] TJ ET
BT 43.553 348.285 Td /F1 9.8 Tf  [(Sibbing D, Schulz S, Braun S, Morath T, Stegherr J, Mehilli J, Sch�mig A, von Beckerath N, Kastrati A. Antiplatelet effects )] TJ ET
BT 26.250 336.381 Td /F1 9.8 Tf  [(of clopidogrel and bleeding in patients undergoing coronary stent placement. J Thromb Haemost. 2010 Feb;8\(2\):250-6. Epub )] TJ ET
BT 26.250 324.476 Td /F1 9.8 Tf  [(2009 Nov 28. PubMed PMID: 19943882.)] TJ ET
BT 26.250 305.071 Td /F1 9.8 Tf  [(14.)] TJ ET
BT 43.553 305.071 Td /F1 9.8 Tf  [(Wallentin L, James S, Storey RF, Armstrong M, Barratt BJ, Horrow J, Husted S, Katus H, Steg PG, Shah SH, Becker RC; )] TJ ET
BT 26.250 293.166 Td /F1 9.8 Tf  [(for the PLATO investigators. Effect of CYP2C19 and ABCB1 single nucleotide polymorphisms on outcomes of treatment with )] TJ ET
BT 26.250 281.262 Td /F1 9.8 Tf  [(ticagrelor versus clopidogrel for acute coronary syndromes: a genetic substudy of the PLATO trial. Lancet. 2010 Aug 27. [Epub )] TJ ET
BT 26.250 269.357 Td /F1 9.8 Tf  [(ahead of print] PubMed PMID: 20801498.)] TJ ET
BT 26.250 249.952 Td /F1 9.8 Tf  [(15.)] TJ ET
BT 43.553 249.952 Td /F1 9.8 Tf  [(Rosemary J, Adithan C. The pharmacogenetics of CYP2C9 and CYP2C19: ethnic variation and clinical significance. Curr )] TJ ET
BT 26.250 238.047 Td /F1 9.8 Tf  [(Clin Pharmacol. 2007 Jan;2\(1\):93-109. Review. PubMed PMID: 18690857.)] TJ ET
BT 26.250 218.643 Td /F1 9.8 Tf  [(16.)] TJ ET
BT 43.553 218.643 Td /F1 9.8 Tf  [(Myrand SP, Sekiguchi K, Man MZ, Lin X, Tzeng RY, Teng CH, Hee B, Garrett M, Kikkawa H, Lin CY, Eddy SM, Dostalik J, )] TJ ET
BT 26.250 206.738 Td /F1 9.8 Tf  [(Mount J, Azuma J, Fujio Y, Jang IJ, Shin SG, Bleavins MR, Williams JA, Paulauskis JD, Wilner KD. Pharmacokinetics/genotype )] TJ ET
BT 26.250 194.833 Td /F1 9.8 Tf  [(associations for major cytochrome P450 enzymes in native and first- and third-generation Japanese populations: comparison )] TJ ET
BT 26.250 182.928 Td /F1 9.8 Tf  [(with Korean, Chinese, and Caucasian populations. Clin Pharmacol Ther. 2008 Sep;84\(3\):347-61. Epub 2008 Mar 19. PubMed )] TJ ET
BT 26.250 171.024 Td /F1 9.8 Tf  [(PMID: 18231117.)] TJ ET
BT 26.250 151.619 Td /F1 9.8 Tf  [(17.)] TJ ET
BT 43.553 151.619 Td /F1 9.8 Tf  [(FDA Drug Safety Communication: Reduced effectiveness of Plavix \(clopidogrel\) in patients who are poor metabolizers of )] TJ ET
BT 26.250 139.714 Td /F1 9.8 Tf  [(the drug. Accessed March 12, 2010)] TJ ET
0.267 0.267 0.267 rg
BT 26.250 131.228 Td /F1 7.5 Tf  [(REFERENCE LINK)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 112.678 Td /F1 9.8 Tf  [(18.)] TJ ET
BT 43.553 112.678 Td /F1 9.8 Tf  [(Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership. Plavix \(clopidogrel bisulfate\). Prescribing Information. )] TJ ET
BT 26.250 100.773 Td /F1 9.8 Tf  [(Bridgewater, NJ; Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership; revised March 2010. Accessed on March 18, 2010.)] TJ ET
0.267 0.267 0.267 rg
BT 26.250 92.287 Td /F1 7.5 Tf  [(REFERENCE LINK)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 73.737 Td /F1 9.8 Tf  [(19.)] TJ ET
BT 43.553 73.737 Td /F1 9.8 Tf  [(Holmes DR Jr, Dehmer GJ, Kaul S, Leifer D, O'Gara PT, Stein CM. ACCF/AHA Clopidogrel Clinical Alert: Approaches to )] TJ ET
BT 26.250 61.833 Td /F1 9.8 Tf  [(the FDA "Boxed Warning" A Report of the American College of Cardiology Foundation Task Force on Clinical Expert )] TJ ET
BT 26.250 49.928 Td /F1 9.8 Tf  [(Consensus Documents and the American Heart Association. J Am Coll Cardiol. 2010 Jul 20;56\(4\):321-41. PubMed PMID: )] TJ ET
Q
q
15.000 35.642 577.500 741.358 re W n
0.271 0.267 0.267 rg
BT 26.250 767.476 Td /F1 9.8 Tf  [(the antiplatelet effect and clinical efficacy of clopidogrel therapy. JAMA. 2009 Aug 26;302\(8\):849-57. PubMed PMID: 19706858.)] TJ ET
BT 26.250 748.071 Td /F1 9.8 Tf  [(3.)] TJ ET
BT 38.132 748.071 Td /F1 9.8 Tf  [(Ellis KJ, Stouffer GA, McLeod HL, Lee CR. Clopidogrel pharmacogenomics and risk of inadequate platelet inhibition: US FDA )] TJ ET
BT 26.250 736.167 Td /F1 9.8 Tf  [(recommendations. Pharmacogenomics. 2009 Nov;10\(11\):1799-817. Review. PubMed PMID: 19891556.)] TJ ET
BT 26.250 716.762 Td /F1 9.8 Tf  [(4.)] TJ ET
BT 38.132 716.762 Td /F1 9.8 Tf  [(Li-Wan-Po A, Girard T, Farndon P, Cooley C, Lithgow J. Pharmacogenetics of CYP2C19: functional and clinical implications )] TJ ET
BT 26.250 704.857 Td /F1 9.8 Tf  [(of a new variant CYP2C19*17. Br J Clin Pharmacol. 2010 Mar;69\(3\):222-30. PubMed PMID: 20233192; PubMed Central )] TJ ET
BT 26.250 692.952 Td /F1 9.8 Tf  [(PMCID: PMC2829691.)] TJ ET
BT 26.250 673.548 Td /F1 9.8 Tf  [(5.)] TJ ET
BT 38.132 673.548 Td /F1 9.8 Tf  [(Sim SC, Risinger C, Dahl ML, Aklillu E, Christensen M, Bertilsson L, Ingelman-Sundberg M. A common novel CYP2C19 )] TJ ET
BT 26.250 661.643 Td /F1 9.8 Tf  [(gene variant causes ultrarapid drug metabolism relevant for the drug response to proton pump inhibitors and antidepressants. )] TJ ET
BT 26.250 649.738 Td /F1 9.8 Tf  [(Clin Pharmacol Ther. 2006 Jan;79\(1\):103-13. PubMed PMID: 16413245.)] TJ ET
BT 26.250 630.333 Td /F1 9.8 Tf  [(6.)] TJ ET
BT 38.132 630.333 Td /F1 9.8 Tf  [(IMS Health. Top-line Industry Data: 2009 Global Prescription Sales Information. IMS Health Web site. Accessed July 2, 2010.)] TJ ET
0.267 0.267 0.267 rg
BT 26.250 621.847 Td /F1 7.5 Tf  [(REFERENCE LINK)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 603.297 Td /F1 9.8 Tf  [(7.)] TJ ET
BT 38.132 603.297 Td /F1 9.8 Tf  [(Top 200 Drugs of 2008. Accessed March 15, 2010.)] TJ ET
0.267 0.267 0.267 rg
BT 26.250 594.812 Td /F1 7.5 Tf  [(REFERENCE LINK)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 576.261 Td /F1 9.8 Tf  [(8.)] TJ ET
BT 38.132 576.261 Td /F1 9.8 Tf  [(Snoep JD, Hovens MM, Eikenboom JC, van der Bom JG, Jukema JW, Huisman MV. Clopidogrel nonresponsiveness in )] TJ ET
BT 26.250 564.357 Td /F1 9.8 Tf  [(patients undergoing percutaneous coronary intervention with stenting: a systematic review and meta-analysis. Am Heart J. 2007 )] TJ ET
BT 26.250 552.452 Td /F1 9.8 Tf  [(Aug;154\(2\):221-31. Review. PubMed PMID: 17643570.)] TJ ET
BT 26.250 533.047 Td /F1 9.8 Tf  [(9.)] TJ ET
BT 38.132 533.047 Td /F1 9.8 Tf  [(Combescure C, Fontana P, Mallouk N, Berdague P, Labruyere C, Barazer I, Gris JC, Laporte S, Fabbro-Peray P, Reny JL; )] TJ ET
BT 26.250 521.142 Td /F1 9.8 Tf  [(CLOpidogrel and Vascular ISchemic Events Meta-analysis Study Group. Clinical implications of clopidogrel non-response in )] TJ ET
BT 26.250 509.238 Td /F1 9.8 Tf  [(cardiovascular patients: a systematic review and meta-analysis. J Thromb Haemost. 2010 May;8\(5\):923-33. Epub 2010 Feb 12. )] TJ ET
BT 26.250 497.333 Td /F1 9.8 Tf  [(PubMed PMID: 20156305.)] TJ ET
BT 26.250 477.928 Td /F1 9.8 Tf  [(10.)] TJ ET
BT 43.553 477.928 Td /F1 9.8 Tf  [(Sofi F, Marcucci R, Gori AM, Giusti B, Abbate R, Gensini GF. Clopidogrel non-responsiveness and risk of cardiovascular )] TJ ET
BT 26.250 466.023 Td /F1 9.8 Tf  [(morbidity. An updated meta-analysis. Thromb Haemost. 2010 Mar 31;103\(4\):841-8. Epub 2010 Feb 2. PubMed PMID: )] TJ ET
BT 26.250 454.119 Td /F1 9.8 Tf  [(20135063.)] TJ ET
BT 26.250 434.714 Td /F1 9.8 Tf  [(11.)] TJ ET
BT 43.553 434.714 Td /F1 9.8 Tf  [(Helton TJ, Bavry AA, Kumbhani DJ, Duggal S, Roukoz H, Bhatt DL. Incremental effect of clopidogrel on important outcomes )] TJ ET
BT 26.250 422.809 Td /F1 9.8 Tf  [(in patients with cardiovascular disease: a meta-analysis of randomized trials. Am J Cardiovasc Drugs. 2007;7\(4\):289-97. )] TJ ET
BT 26.250 410.904 Td /F1 9.8 Tf  [(PubMed PMID: 17696569.)] TJ ET
BT 26.250 391.500 Td /F1 9.8 Tf  [(12.)] TJ ET
BT 43.553 391.500 Td /F1 9.8 Tf  [(Berger JS, Bhatt DL, Cannon CP, Chen Z, Jiang L, Jones JB, Mehta SR, Sabatine MS, Steinhubl SR, Topol EJ, Berger PB. )] TJ ET
BT 26.250 379.595 Td /F1 9.8 Tf  [(The relative efficacy and safety of clopidogrel in women and men a sex-specific collaborative meta-analysis. J Am Coll Cardiol. )] TJ ET
BT 26.250 367.690 Td /F1 9.8 Tf  [(2009 Nov 17;54\(21\):1935-45. Review. PubMed PMID: 19909874.)] TJ ET
BT 26.250 348.285 Td /F1 9.8 Tf  [(13.)] TJ ET
BT 43.553 348.285 Td /F1 9.8 Tf  [(Sibbing D, Schulz S, Braun S, Morath T, Stegherr J, Mehilli J, Sch�mig A, von Beckerath N, Kastrati A. Antiplatelet effects )] TJ ET
BT 26.250 336.381 Td /F1 9.8 Tf  [(of clopidogrel and bleeding in patients undergoing coronary stent placement. J Thromb Haemost. 2010 Feb;8\(2\):250-6. Epub )] TJ ET
BT 26.250 324.476 Td /F1 9.8 Tf  [(2009 Nov 28. PubMed PMID: 19943882.)] TJ ET
BT 26.250 305.071 Td /F1 9.8 Tf  [(14.)] TJ ET
BT 43.553 305.071 Td /F1 9.8 Tf  [(Wallentin L, James S, Storey RF, Armstrong M, Barratt BJ, Horrow J, Husted S, Katus H, Steg PG, Shah SH, Becker RC; )] TJ ET
BT 26.250 293.166 Td /F1 9.8 Tf  [(for the PLATO investigators. Effect of CYP2C19 and ABCB1 single nucleotide polymorphisms on outcomes of treatment with )] TJ ET
BT 26.250 281.262 Td /F1 9.8 Tf  [(ticagrelor versus clopidogrel for acute coronary syndromes: a genetic substudy of the PLATO trial. Lancet. 2010 Aug 27. [Epub )] TJ ET
BT 26.250 269.357 Td /F1 9.8 Tf  [(ahead of print] PubMed PMID: 20801498.)] TJ ET
BT 26.250 249.952 Td /F1 9.8 Tf  [(15.)] TJ ET
BT 43.553 249.952 Td /F1 9.8 Tf  [(Rosemary J, Adithan C. The pharmacogenetics of CYP2C9 and CYP2C19: ethnic variation and clinical significance. Curr )] TJ ET
BT 26.250 238.047 Td /F1 9.8 Tf  [(Clin Pharmacol. 2007 Jan;2\(1\):93-109. Review. PubMed PMID: 18690857.)] TJ ET
BT 26.250 218.643 Td /F1 9.8 Tf  [(16.)] TJ ET
BT 43.553 218.643 Td /F1 9.8 Tf  [(Myrand SP, Sekiguchi K, Man MZ, Lin X, Tzeng RY, Teng CH, Hee B, Garrett M, Kikkawa H, Lin CY, Eddy SM, Dostalik J, )] TJ ET
BT 26.250 206.738 Td /F1 9.8 Tf  [(Mount J, Azuma J, Fujio Y, Jang IJ, Shin SG, Bleavins MR, Williams JA, Paulauskis JD, Wilner KD. Pharmacokinetics/genotype )] TJ ET
BT 26.250 194.833 Td /F1 9.8 Tf  [(associations for major cytochrome P450 enzymes in native and first- and third-generation Japanese populations: comparison )] TJ ET
BT 26.250 182.928 Td /F1 9.8 Tf  [(with Korean, Chinese, and Caucasian populations. Clin Pharmacol Ther. 2008 Sep;84\(3\):347-61. Epub 2008 Mar 19. PubMed )] TJ ET
BT 26.250 171.024 Td /F1 9.8 Tf  [(PMID: 18231117.)] TJ ET
BT 26.250 151.619 Td /F1 9.8 Tf  [(17.)] TJ ET
BT 43.553 151.619 Td /F1 9.8 Tf  [(FDA Drug Safety Communication: Reduced effectiveness of Plavix \(clopidogrel\) in patients who are poor metabolizers of )] TJ ET
BT 26.250 139.714 Td /F1 9.8 Tf  [(the drug. Accessed March 12, 2010)] TJ ET
0.267 0.267 0.267 rg
BT 26.250 131.228 Td /F1 7.5 Tf  [(REFERENCE LINK)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 112.678 Td /F1 9.8 Tf  [(18.)] TJ ET
BT 43.553 112.678 Td /F1 9.8 Tf  [(Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership. Plavix \(clopidogrel bisulfate\). Prescribing Information. )] TJ ET
BT 26.250 100.773 Td /F1 9.8 Tf  [(Bridgewater, NJ; Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership; revised March 2010. Accessed on March 18, 2010.)] TJ ET
0.267 0.267 0.267 rg
BT 26.250 92.287 Td /F1 7.5 Tf  [(REFERENCE LINK)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 73.737 Td /F1 9.8 Tf  [(19.)] TJ ET
BT 43.553 73.737 Td /F1 9.8 Tf  [(Holmes DR Jr, Dehmer GJ, Kaul S, Leifer D, O'Gara PT, Stein CM. ACCF/AHA Clopidogrel Clinical Alert: Approaches to )] TJ ET
BT 26.250 61.833 Td /F1 9.8 Tf  [(the FDA "Boxed Warning" A Report of the American College of Cardiology Foundation Task Force on Clinical Expert )] TJ ET
BT 26.250 49.928 Td /F1 9.8 Tf  [(Consensus Documents and the American Heart Association. J Am Coll Cardiol. 2010 Jul 20;56\(4\):321-41. PubMed PMID: )] TJ ET
Q
q
0.000 0.000 0.000 rg
BT 291.710 19.825 Td /F1 11.0 Tf  [(6)] TJ ET
BT 25.000 19.825 Td /F1 11.0 Tf  [(PLOS Currents Evidence on Genomic Tests)] TJ ET
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0.271 0.267 0.267 rg
BT 26.250 767.476 Td /F1 9.8 Tf  [(20633831.)] TJ ET
BT 26.250 748.071 Td /F1 9.8 Tf  [(20.)] TJ ET
BT 43.553 748.071 Td /F1 9.8 Tf  [(U.S. Food and Drug Administration \(FDA\). Plavix \(clopidogrel bisulfate\) 75 mg tablets: Safety Labeling Changes Approved )] TJ ET
BT 26.250 736.167 Td /F1 9.8 Tf  [(By FDA Center for Drug Evaluation and Research \(CDER\) -- May 2009. Accessed March 19, 2010.)] TJ ET
BT 26.250 716.762 Td /F1 9.8 Tf  [(21.)] TJ ET
BT 43.553 716.762 Td /F1 9.8 Tf  [(U.S. Food and Drug Administration \(FDA\). Plavix \(clopidogrel bisulfate\) 75 mg tablet: Safety Labeling Changes Approved )] TJ ET
BT 26.250 704.857 Td /F1 9.8 Tf  [(By FDA Center for Drug Evaluation and Research \(CDER\) - November 2009. Accessed March 19, 2010.)] TJ ET
0.267 0.267 0.267 rg
BT 26.250 696.371 Td /F1 7.5 Tf  [(REFERENCE LINK)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 677.821 Td /F1 9.8 Tf  [(22.)] TJ ET
BT 43.553 677.821 Td /F1 9.8 Tf  [(Roche Diagnostics. About the AmpliChip CYP450 Test. Accessed May 11, 2010.)] TJ ET
0.267 0.267 0.267 rg
BT 26.250 669.335 Td /F1 7.5 Tf  [(REFERENCE LINK)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 650.785 Td /F1 9.8 Tf  [(23.)] TJ ET
BT 43.553 650.785 Td /F1 9.8 Tf  [(Genelex: Plavitest Technical Information. Accessed March 22, 2010.)] TJ ET
0.267 0.267 0.267 rg
BT 26.250 642.299 Td /F1 7.5 Tf  [(REFERENCE LINK)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 623.749 Td /F1 9.8 Tf  [(24.)] TJ ET
BT 43.553 623.749 Td /F1 9.8 Tf  [(Navigenics, Inc. Applying Preventive Genomic Medicine in Clinical Practice. Available at )] TJ ET
BT 26.250 611.844 Td /F1 9.8 Tf  [(https://www.navigenics.com/visitor/for_physicians/.)] TJ ET
BT 26.250 592.440 Td /F1 9.8 Tf  [(25.)] TJ ET
BT 43.553 592.440 Td /F1 9.8 Tf  [(ARUP Laboratories. Technical Bulletin-- Cytochrome P450 2C19 \(CYP2C19\) 7 Mutations: for detection of CYP2C19 )] TJ ET
BT 26.250 580.535 Td /F1 9.8 Tf  [(mutations affecting drug metabolism. Last updated February 2009. Available at https://www.aruplab.com/Testing-)] TJ ET
BT 26.250 568.630 Td /F1 9.8 Tf  [(Information/technicalbulletins.jsp.)] TJ ET
BT 26.250 549.225 Td /F1 9.8 Tf  [(26.)] TJ ET
BT 43.553 549.225 Td /F1 9.8 Tf  [(23andMe, Inc. How accurate is the genetic data you provide? Accessed April 8, 2010.)] TJ ET
0.267 0.267 0.267 rg
BT 26.250 540.739 Td /F1 7.5 Tf  [(REFERENCE LINK)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 522.189 Td /F1 9.8 Tf  [(27.)] TJ ET
BT 43.553 522.189 Td /F1 9.8 Tf  [(TheranostiCs Lab. FAQs. Accessed April 8, 2010.)] TJ ET
0.267 0.267 0.267 rg
BT 26.250 513.703 Td /F1 7.5 Tf  [(REFERENCE LINK)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 495.153 Td /F1 9.8 Tf  [(28.)] TJ ET
BT 43.553 495.153 Td /F1 9.8 Tf  [(Pathway Genomics. Drug Response \(Medication\). Accessed June 14, 2010.)] TJ ET
0.267 0.267 0.267 rg
BT 26.250 486.667 Td /F1 7.5 Tf  [(REFERENCE LINK)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 468.117 Td /F1 9.8 Tf  [(29.)] TJ ET
BT 43.553 468.117 Td /F1 9.8 Tf  [(Matrix Genomics. Drug Metabolism- Clopidogrel \(Plavix\) Activation. Accessed April 6, 2010)] TJ ET
0.267 0.267 0.267 rg
BT 26.250 459.631 Td /F1 7.5 Tf  [(REFERENCE LINK)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 441.081 Td /F1 9.8 Tf  [(30.)] TJ ET
BT 43.553 441.081 Td /F1 9.8 Tf  [(MyMedLab, Inc. CYP450 2C19 \(PlavixTM\) Gene Test / Genetic Physician Consult. Accessed June 30, 2010.)] TJ ET
0.267 0.267 0.267 rg
BT 26.250 432.595 Td /F1 7.5 Tf  [(REFERENCE LINK)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 414.045 Td /F1 9.8 Tf  [(31.)] TJ ET
BT 43.553 414.045 Td /F1 9.8 Tf  [(Quest Diagnostics. AccuType� CP testing for Clopidogrel CYP2C19 Genotype \(*1, *2, *3, *4, *5\). Accessed May 11, 2010.)] TJ ET
0.267 0.267 0.267 rg
BT 26.250 405.559 Td /F1 7.5 Tf  [(REFERENCE LINK)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 387.009 Td /F1 9.8 Tf  [(32.)] TJ ET
BT 43.553 387.009 Td /F1 9.8 Tf  [(Genelex Corporation. DNA Drug Sensitivity Testing. Accessed March 22, 2010)] TJ ET
0.267 0.267 0.267 rg
BT 26.250 378.523 Td /F1 7.5 Tf  [(REFERENCE LINK)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 359.973 Td /F1 9.8 Tf  [(33.)] TJ ET
BT 43.553 359.973 Td /F1 9.8 Tf  [(HuGE Navigator)] TJ ET
0.267 0.267 0.267 rg
BT 26.250 351.487 Td /F1 7.5 Tf  [(REFERENCE LINK)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 332.937 Td /F1 9.8 Tf  [(34.)] TJ ET
BT 43.553 332.937 Td /F1 9.8 Tf  [(Ma TK, Lam YY, Tan VP, Kiernan TJ, Yan BP. Impact of genetic and acquired alteration in cytochrome P450 system on )] TJ ET
BT 26.250 321.033 Td /F1 9.8 Tf  [(pharmacologic and clinical response to clopidogrel. Pharmacol Ther. 2010 Feb;125\(2\):249-59. Epub 2009 Nov 14. Review. )] TJ ET
BT 26.250 309.128 Td /F1 9.8 Tf  [(PubMed PMID: 19919843.)] TJ ET
BT 26.250 289.723 Td /F1 9.8 Tf  [(35.)] TJ ET
BT 43.553 289.723 Td /F1 9.8 Tf  [(Hochholzer W, Trenk D, Fromm MF, Valina CM, Stratz C, Bestehorn HP, B�ttner HJ, Neumann FJ. Impact of cytochrome )] TJ ET
BT 26.250 277.818 Td /F1 9.8 Tf  [(P450 2C19 loss-of-function polymorphism and of major demographic characteristics on residual platelet function after loading )] TJ ET
BT 26.250 265.914 Td /F1 9.8 Tf  [(and maintenance treatment with clopidogrel in patients undergoing elective coronary stent placement. J Am Coll Cardiol. 2010 )] TJ ET
BT 26.250 254.009 Td /F1 9.8 Tf  [(Jun 1;55\(22\):2427-34. PubMed PMID: 20510210.)] TJ ET
BT 26.250 234.604 Td /F1 9.8 Tf  [(36.)] TJ ET
BT 43.553 234.604 Td /F1 9.8 Tf  [(Mega JL, Close SL, Wiviott SD, Shen L, Hockett RD, Brandt JT, Walker JR, Antman EM, Macias W, Braunwald E, Sabatine )] TJ ET
BT 26.250 222.699 Td /F1 9.8 Tf  [(MS. Cytochrome p-450 polymorphisms and response to clopidogrel. N Engl J Med. 2009 Jan 22;360\(4\):354-62. Epub 2008 Dec )] TJ ET
BT 26.250 210.795 Td /F1 9.8 Tf  [(22. PubMed PMID: 19106084.)] TJ ET
BT 26.250 191.390 Td /F1 9.8 Tf  [(37.)] TJ ET
BT 43.553 191.390 Td /F1 9.8 Tf  [(Fontana P, Senouf D, Mach F. Biological effect of increased maintenance dose of clopidogrel in cardiovascular outpatients )] TJ ET
BT 26.250 179.485 Td /F1 9.8 Tf  [(and influence of the cytochrome P450 2C19*2 allele on clopidogrel responsiveness. Thromb Res. 2008;121\(4\):463-8. Epub )] TJ ET
BT 26.250 167.580 Td /F1 9.8 Tf  [(2007 Aug 2. PubMed PMID: 17681590.)] TJ ET
BT 26.250 148.176 Td /F1 9.8 Tf  [(38.)] TJ ET
BT 43.553 148.176 Td /F1 9.8 Tf  [(Brandt JT, Close SL, Iturria SJ, Payne CD, Farid NA, Ernest CS 2nd, Lachno DR, Salazar D, Winters KJ. Common )] TJ ET
BT 26.250 136.271 Td /F1 9.8 Tf  [(polymorphisms of CYP2C19 and CYP2C9 affect the pharmacokinetic and pharmacodynamic response to clopidogrel but not )] TJ ET
BT 26.250 124.366 Td /F1 9.8 Tf  [(prasugrel. J Thromb Haemost. 2007 Dec;5\(12\):2429-36. Epub 2007 Sep 26. PubMed PMID: 17900275.)] TJ ET
BT 26.250 104.961 Td /F1 9.8 Tf  [(39.)] TJ ET
BT 43.553 104.961 Td /F1 9.8 Tf  [(Gladding P, Webster M, Zeng I, Farrell H, Stewart J, Ruygrok P, Ormiston J, El-Jack S, Armstrong G, Kay P, Scott D, )] TJ ET
BT 26.250 93.057 Td /F1 9.8 Tf  [(Gunes A, Dahl ML. The pharmacogenetics and pharmacodynamics of clopidogrel response: an analysis from the PRINC \(Plavix )] TJ ET
BT 26.250 81.152 Td /F1 9.8 Tf  [(Response in Coronary Intervention\) trial. JACC Cardiovasc Interv. 2008 Dec;1\(6\):620-7. PubMed PMID: 19463375.)] TJ ET
BT 26.250 61.747 Td /F1 9.8 Tf  [(40.)] TJ ET
BT 43.553 61.747 Td /F1 9.8 Tf  [(Hulot JS, Bura A, Villard E, Azizi M, Remones V, Goyenvalle C, Aiach M, Lechat P, Gaussem P. Cytochrome P450 2C19 )] TJ ET
BT 26.250 49.842 Td /F1 9.8 Tf  [(loss-of-function polymorphism is a major determinant of clopidogrel responsiveness in healthy subjects. Blood. 2006 Oct )] TJ ET
Q
q
15.000 35.557 577.500 741.443 re W n
0.271 0.267 0.267 rg
BT 26.250 767.476 Td /F1 9.8 Tf  [(20633831.)] TJ ET
BT 26.250 748.071 Td /F1 9.8 Tf  [(20.)] TJ ET
BT 43.553 748.071 Td /F1 9.8 Tf  [(U.S. Food and Drug Administration \(FDA\). Plavix \(clopidogrel bisulfate\) 75 mg tablets: Safety Labeling Changes Approved )] TJ ET
BT 26.250 736.167 Td /F1 9.8 Tf  [(By FDA Center for Drug Evaluation and Research \(CDER\) -- May 2009. Accessed March 19, 2010.)] TJ ET
BT 26.250 716.762 Td /F1 9.8 Tf  [(21.)] TJ ET
BT 43.553 716.762 Td /F1 9.8 Tf  [(U.S. Food and Drug Administration \(FDA\). Plavix \(clopidogrel bisulfate\) 75 mg tablet: Safety Labeling Changes Approved )] TJ ET
BT 26.250 704.857 Td /F1 9.8 Tf  [(By FDA Center for Drug Evaluation and Research \(CDER\) - November 2009. Accessed March 19, 2010.)] TJ ET
0.267 0.267 0.267 rg
BT 26.250 696.371 Td /F1 7.5 Tf  [(REFERENCE LINK)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 677.821 Td /F1 9.8 Tf  [(22.)] TJ ET
BT 43.553 677.821 Td /F1 9.8 Tf  [(Roche Diagnostics. About the AmpliChip CYP450 Test. Accessed May 11, 2010.)] TJ ET
0.267 0.267 0.267 rg
BT 26.250 669.335 Td /F1 7.5 Tf  [(REFERENCE LINK)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 650.785 Td /F1 9.8 Tf  [(23.)] TJ ET
BT 43.553 650.785 Td /F1 9.8 Tf  [(Genelex: Plavitest Technical Information. Accessed March 22, 2010.)] TJ ET
0.267 0.267 0.267 rg
BT 26.250 642.299 Td /F1 7.5 Tf  [(REFERENCE LINK)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 623.749 Td /F1 9.8 Tf  [(24.)] TJ ET
BT 43.553 623.749 Td /F1 9.8 Tf  [(Navigenics, Inc. Applying Preventive Genomic Medicine in Clinical Practice. Available at )] TJ ET
BT 26.250 611.844 Td /F1 9.8 Tf  [(https://www.navigenics.com/visitor/for_physicians/.)] TJ ET
BT 26.250 592.440 Td /F1 9.8 Tf  [(25.)] TJ ET
BT 43.553 592.440 Td /F1 9.8 Tf  [(ARUP Laboratories. Technical Bulletin-- Cytochrome P450 2C19 \(CYP2C19\) 7 Mutations: for detection of CYP2C19 )] TJ ET
BT 26.250 580.535 Td /F1 9.8 Tf  [(mutations affecting drug metabolism. Last updated February 2009. Available at https://www.aruplab.com/Testing-)] TJ ET
BT 26.250 568.630 Td /F1 9.8 Tf  [(Information/technicalbulletins.jsp.)] TJ ET
BT 26.250 549.225 Td /F1 9.8 Tf  [(26.)] TJ ET
BT 43.553 549.225 Td /F1 9.8 Tf  [(23andMe, Inc. How accurate is the genetic data you provide? Accessed April 8, 2010.)] TJ ET
0.267 0.267 0.267 rg
BT 26.250 540.739 Td /F1 7.5 Tf  [(REFERENCE LINK)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 522.189 Td /F1 9.8 Tf  [(27.)] TJ ET
BT 43.553 522.189 Td /F1 9.8 Tf  [(TheranostiCs Lab. FAQs. Accessed April 8, 2010.)] TJ ET
0.267 0.267 0.267 rg
BT 26.250 513.703 Td /F1 7.5 Tf  [(REFERENCE LINK)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 495.153 Td /F1 9.8 Tf  [(28.)] TJ ET
BT 43.553 495.153 Td /F1 9.8 Tf  [(Pathway Genomics. Drug Response \(Medication\). Accessed June 14, 2010.)] TJ ET
0.267 0.267 0.267 rg
BT 26.250 486.667 Td /F1 7.5 Tf  [(REFERENCE LINK)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 468.117 Td /F1 9.8 Tf  [(29.)] TJ ET
BT 43.553 468.117 Td /F1 9.8 Tf  [(Matrix Genomics. Drug Metabolism- Clopidogrel \(Plavix\) Activation. Accessed April 6, 2010)] TJ ET
0.267 0.267 0.267 rg
BT 26.250 459.631 Td /F1 7.5 Tf  [(REFERENCE LINK)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 441.081 Td /F1 9.8 Tf  [(30.)] TJ ET
BT 43.553 441.081 Td /F1 9.8 Tf  [(MyMedLab, Inc. CYP450 2C19 \(PlavixTM\) Gene Test / Genetic Physician Consult. Accessed June 30, 2010.)] TJ ET
0.267 0.267 0.267 rg
BT 26.250 432.595 Td /F1 7.5 Tf  [(REFERENCE LINK)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 414.045 Td /F1 9.8 Tf  [(31.)] TJ ET
BT 43.553 414.045 Td /F1 9.8 Tf  [(Quest Diagnostics. AccuType� CP testing for Clopidogrel CYP2C19 Genotype \(*1, *2, *3, *4, *5\). Accessed May 11, 2010.)] TJ ET
0.267 0.267 0.267 rg
BT 26.250 405.559 Td /F1 7.5 Tf  [(REFERENCE LINK)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 387.009 Td /F1 9.8 Tf  [(32.)] TJ ET
BT 43.553 387.009 Td /F1 9.8 Tf  [(Genelex Corporation. DNA Drug Sensitivity Testing. Accessed March 22, 2010)] TJ ET
0.267 0.267 0.267 rg
BT 26.250 378.523 Td /F1 7.5 Tf  [(REFERENCE LINK)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 359.973 Td /F1 9.8 Tf  [(33.)] TJ ET
BT 43.553 359.973 Td /F1 9.8 Tf  [(HuGE Navigator)] TJ ET
0.267 0.267 0.267 rg
BT 26.250 351.487 Td /F1 7.5 Tf  [(REFERENCE LINK)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 332.937 Td /F1 9.8 Tf  [(34.)] TJ ET
BT 43.553 332.937 Td /F1 9.8 Tf  [(Ma TK, Lam YY, Tan VP, Kiernan TJ, Yan BP. Impact of genetic and acquired alteration in cytochrome P450 system on )] TJ ET
BT 26.250 321.033 Td /F1 9.8 Tf  [(pharmacologic and clinical response to clopidogrel. Pharmacol Ther. 2010 Feb;125\(2\):249-59. Epub 2009 Nov 14. Review. )] TJ ET
BT 26.250 309.128 Td /F1 9.8 Tf  [(PubMed PMID: 19919843.)] TJ ET
BT 26.250 289.723 Td /F1 9.8 Tf  [(35.)] TJ ET
BT 43.553 289.723 Td /F1 9.8 Tf  [(Hochholzer W, Trenk D, Fromm MF, Valina CM, Stratz C, Bestehorn HP, B�ttner HJ, Neumann FJ. Impact of cytochrome )] TJ ET
BT 26.250 277.818 Td /F1 9.8 Tf  [(P450 2C19 loss-of-function polymorphism and of major demographic characteristics on residual platelet function after loading )] TJ ET
BT 26.250 265.914 Td /F1 9.8 Tf  [(and maintenance treatment with clopidogrel in patients undergoing elective coronary stent placement. J Am Coll Cardiol. 2010 )] TJ ET
BT 26.250 254.009 Td /F1 9.8 Tf  [(Jun 1;55\(22\):2427-34. PubMed PMID: 20510210.)] TJ ET
BT 26.250 234.604 Td /F1 9.8 Tf  [(36.)] TJ ET
BT 43.553 234.604 Td /F1 9.8 Tf  [(Mega JL, Close SL, Wiviott SD, Shen L, Hockett RD, Brandt JT, Walker JR, Antman EM, Macias W, Braunwald E, Sabatine )] TJ ET
BT 26.250 222.699 Td /F1 9.8 Tf  [(MS. Cytochrome p-450 polymorphisms and response to clopidogrel. N Engl J Med. 2009 Jan 22;360\(4\):354-62. Epub 2008 Dec )] TJ ET
BT 26.250 210.795 Td /F1 9.8 Tf  [(22. PubMed PMID: 19106084.)] TJ ET
BT 26.250 191.390 Td /F1 9.8 Tf  [(37.)] TJ ET
BT 43.553 191.390 Td /F1 9.8 Tf  [(Fontana P, Senouf D, Mach F. Biological effect of increased maintenance dose of clopidogrel in cardiovascular outpatients )] TJ ET
BT 26.250 179.485 Td /F1 9.8 Tf  [(and influence of the cytochrome P450 2C19*2 allele on clopidogrel responsiveness. Thromb Res. 2008;121\(4\):463-8. Epub )] TJ ET
BT 26.250 167.580 Td /F1 9.8 Tf  [(2007 Aug 2. PubMed PMID: 17681590.)] TJ ET
BT 26.250 148.176 Td /F1 9.8 Tf  [(38.)] TJ ET
BT 43.553 148.176 Td /F1 9.8 Tf  [(Brandt JT, Close SL, Iturria SJ, Payne CD, Farid NA, Ernest CS 2nd, Lachno DR, Salazar D, Winters KJ. Common )] TJ ET
BT 26.250 136.271 Td /F1 9.8 Tf  [(polymorphisms of CYP2C19 and CYP2C9 affect the pharmacokinetic and pharmacodynamic response to clopidogrel but not )] TJ ET
BT 26.250 124.366 Td /F1 9.8 Tf  [(prasugrel. J Thromb Haemost. 2007 Dec;5\(12\):2429-36. Epub 2007 Sep 26. PubMed PMID: 17900275.)] TJ ET
BT 26.250 104.961 Td /F1 9.8 Tf  [(39.)] TJ ET
BT 43.553 104.961 Td /F1 9.8 Tf  [(Gladding P, Webster M, Zeng I, Farrell H, Stewart J, Ruygrok P, Ormiston J, El-Jack S, Armstrong G, Kay P, Scott D, )] TJ ET
BT 26.250 93.057 Td /F1 9.8 Tf  [(Gunes A, Dahl ML. The pharmacogenetics and pharmacodynamics of clopidogrel response: an analysis from the PRINC \(Plavix )] TJ ET
BT 26.250 81.152 Td /F1 9.8 Tf  [(Response in Coronary Intervention\) trial. JACC Cardiovasc Interv. 2008 Dec;1\(6\):620-7. PubMed PMID: 19463375.)] TJ ET
BT 26.250 61.747 Td /F1 9.8 Tf  [(40.)] TJ ET
BT 43.553 61.747 Td /F1 9.8 Tf  [(Hulot JS, Bura A, Villard E, Azizi M, Remones V, Goyenvalle C, Aiach M, Lechat P, Gaussem P. Cytochrome P450 2C19 )] TJ ET
BT 26.250 49.842 Td /F1 9.8 Tf  [(loss-of-function polymorphism is a major determinant of clopidogrel responsiveness in healthy subjects. Blood. 2006 Oct )] TJ ET
Q
q
15.000 35.557 577.500 741.443 re W n
0.271 0.267 0.267 rg
BT 26.250 767.476 Td /F1 9.8 Tf  [(20633831.)] TJ ET
BT 26.250 748.071 Td /F1 9.8 Tf  [(20.)] TJ ET
BT 43.553 748.071 Td /F1 9.8 Tf  [(U.S. Food and Drug Administration \(FDA\). Plavix \(clopidogrel bisulfate\) 75 mg tablets: Safety Labeling Changes Approved )] TJ ET
BT 26.250 736.167 Td /F1 9.8 Tf  [(By FDA Center for Drug Evaluation and Research \(CDER\) -- May 2009. Accessed March 19, 2010.)] TJ ET
BT 26.250 716.762 Td /F1 9.8 Tf  [(21.)] TJ ET
BT 43.553 716.762 Td /F1 9.8 Tf  [(U.S. Food and Drug Administration \(FDA\). Plavix \(clopidogrel bisulfate\) 75 mg tablet: Safety Labeling Changes Approved )] TJ ET
BT 26.250 704.857 Td /F1 9.8 Tf  [(By FDA Center for Drug Evaluation and Research \(CDER\) - November 2009. Accessed March 19, 2010.)] TJ ET
0.267 0.267 0.267 rg
BT 26.250 696.371 Td /F1 7.5 Tf  [(REFERENCE LINK)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 677.821 Td /F1 9.8 Tf  [(22.)] TJ ET
BT 43.553 677.821 Td /F1 9.8 Tf  [(Roche Diagnostics. About the AmpliChip CYP450 Test. Accessed May 11, 2010.)] TJ ET
0.267 0.267 0.267 rg
BT 26.250 669.335 Td /F1 7.5 Tf  [(REFERENCE LINK)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 650.785 Td /F1 9.8 Tf  [(23.)] TJ ET
BT 43.553 650.785 Td /F1 9.8 Tf  [(Genelex: Plavitest Technical Information. Accessed March 22, 2010.)] TJ ET
0.267 0.267 0.267 rg
BT 26.250 642.299 Td /F1 7.5 Tf  [(REFERENCE LINK)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 623.749 Td /F1 9.8 Tf  [(24.)] TJ ET
BT 43.553 623.749 Td /F1 9.8 Tf  [(Navigenics, Inc. Applying Preventive Genomic Medicine in Clinical Practice. Available at )] TJ ET
BT 26.250 611.844 Td /F1 9.8 Tf  [(https://www.navigenics.com/visitor/for_physicians/.)] TJ ET
BT 26.250 592.440 Td /F1 9.8 Tf  [(25.)] TJ ET
BT 43.553 592.440 Td /F1 9.8 Tf  [(ARUP Laboratories. Technical Bulletin-- Cytochrome P450 2C19 \(CYP2C19\) 7 Mutations: for detection of CYP2C19 )] TJ ET
BT 26.250 580.535 Td /F1 9.8 Tf  [(mutations affecting drug metabolism. Last updated February 2009. Available at https://www.aruplab.com/Testing-)] TJ ET
BT 26.250 568.630 Td /F1 9.8 Tf  [(Information/technicalbulletins.jsp.)] TJ ET
BT 26.250 549.225 Td /F1 9.8 Tf  [(26.)] TJ ET
BT 43.553 549.225 Td /F1 9.8 Tf  [(23andMe, Inc. How accurate is the genetic data you provide? Accessed April 8, 2010.)] TJ ET
0.267 0.267 0.267 rg
BT 26.250 540.739 Td /F1 7.5 Tf  [(REFERENCE LINK)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 522.189 Td /F1 9.8 Tf  [(27.)] TJ ET
BT 43.553 522.189 Td /F1 9.8 Tf  [(TheranostiCs Lab. FAQs. Accessed April 8, 2010.)] TJ ET
0.267 0.267 0.267 rg
BT 26.250 513.703 Td /F1 7.5 Tf  [(REFERENCE LINK)] TJ ET
0.271 0.267 0.267 rg
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BT 26.250 421.762 Td /F1 9.8 Tf  [(48.)] TJ ET
BT 43.553 421.762 Td /F1 9.8 Tf  [(Geisler T, Schaeffeler E, Dippon J, Winter S, Buse V, Bischofs C, Zuern C, Moerike K, Gawaz M, Schwab M. CYP2C19 and )] TJ ET
BT 26.250 409.857 Td /F1 9.8 Tf  [(nongenetic factors predict poor responsiveness to clopidogrel loading dose after coronary stent implantation. )] TJ ET
BT 26.250 397.953 Td /F1 9.8 Tf  [(Pharmacogenomics. 2008 Sep;9\(9\):1251-9. PubMed PMID: 18781853.)] TJ ET
BT 26.250 378.548 Td /F1 9.8 Tf  [(49.)] TJ ET
BT 43.553 378.548 Td /F1 9.8 Tf  [(Kim IS, Choi BR, Jeong YH, Kwak CH, Kim S. The CYP2C19*2 and CYP2C19*3 polymorphisms are associated with high )] TJ ET
BT 26.250 366.643 Td /F1 9.8 Tf  [(post-treatment platelet reactivity in Asian patients with acute coronary syndrome. J Thromb Haemost. 2009 May;7\(5\):897-9. )] TJ ET
BT 26.250 354.738 Td /F1 9.8 Tf  [(Epub 2009 Feb 12. PubMed PMID: 19220726.)] TJ ET
BT 26.250 335.334 Td /F1 9.8 Tf  [(50.)] TJ ET
BT 43.553 335.334 Td /F1 9.8 Tf  [(Aleil B, L�on C, Cazenave JP, Gachet C. CYP2C19*2 polymorphism is not the sole determinant of the response to )] TJ ET
BT 26.250 323.429 Td /F1 9.8 Tf  [(clopidogrel: implications for its monitoring. J Thromb Haemost. 2009 Oct;7\(10\):1747-9. Epub 2009 Jul 17. PubMed PMID: )] TJ ET
BT 26.250 311.524 Td /F1 9.8 Tf  [(19624462.)] TJ ET
BT 26.250 292.119 Td /F1 9.8 Tf  [(51.)] TJ ET
BT 43.553 292.119 Td /F1 9.8 Tf  [(Trenk D, Hochholzer W, Fromm MF, Chialda LE, Pahl A, Valina CM, Stratz C, Schmiebusch P, Bestehorn HP, B�ttner HJ, )] TJ ET
BT 26.250 280.215 Td /F1 9.8 Tf  [(Neumann FJ. Cytochrome P450 2C19 681G>A polymorphism and high on-clopidogrel platelet reactivity associated with )] TJ ET
BT 26.250 268.310 Td /F1 9.8 Tf  [(adverse 1-year clinical outcome of elective percutaneous coronary intervention with drug-eluting or bare-metal stents. J Am Coll )] TJ ET
BT 26.250 256.405 Td /F1 9.8 Tf  [(Cardiol. 2008 May 20;51\(20\):1925-34. PubMed PMID: 18482659.)] TJ ET
BT 26.250 237.000 Td /F1 9.8 Tf  [(52.)] TJ ET
BT 43.553 237.000 Td /F1 9.8 Tf  [(Jeong YH, Kim IS, Park Y, Kang MK, Koh JS, Hwang SJ, Kwak CH, Hwang JY. Carriage of cytochrome 2C19 )] TJ ET
BT 26.250 225.096 Td /F1 9.8 Tf  [(polymorphism is associated with risk of high post-treatment platelet reactivity on high maintenance-dose clopidogrel of 150 )] TJ ET
BT 26.250 213.191 Td /F1 9.8 Tf  [(mg/day: results of the ACCEL-DOUBLE \(Accelerated Platelet Inhibition by a Double Dose of Clopidogrel According to Gene )] TJ ET
BT 26.250 201.286 Td /F1 9.8 Tf  [(Polymorphism\) study. JACC Cardiovasc Interv. 2010 Jul;3\(7\):731-41. PubMed PMID: 20650435.)] TJ ET
BT 26.250 181.881 Td /F1 9.8 Tf  [(53.)] TJ ET
BT 43.553 181.881 Td /F1 9.8 Tf  [(Sibbing D, Gebhard D, Koch W, Braun S, Stegherr J, Morath T, von Beckerath N, Mehilli J, Sch�mig A, Schuster T, Kastrati )] TJ ET
BT 26.250 169.977 Td /F1 9.8 Tf  [(A. Isolated and interactive impact of common CYP2C19 genetic variants on the antiplatelet effect of chronic clopidogrel therapy. )] TJ ET
BT 26.250 158.072 Td /F1 9.8 Tf  [(J Thromb Haemost. 2010 May 21. [Epub ahead of print] PubMed PMID: 20492469.)] TJ ET
BT 26.250 138.667 Td /F1 9.8 Tf  [(54.)] TJ ET
BT 43.553 138.667 Td /F1 9.8 Tf  [(Fr�re C, Cuisset T, Gaborit B, Alessi MC, Hulot JS. The CYP2C19*17 allele is associated with better platelet response to )] TJ ET
BT 26.250 126.762 Td /F1 9.8 Tf  [(clopidogrel in patients admitted for non-ST acute coronary syndrome. J Thromb Haemost. 2009 Aug;7\(8\):1409-11. Epub 2009 )] TJ ET
BT 26.250 114.858 Td /F1 9.8 Tf  [(May 30. PubMed PMID: 19496924.)] TJ ET
BT 26.250 95.453 Td /F1 9.8 Tf  [(55.)] TJ ET
BT 43.553 95.453 Td /F1 9.8 Tf  [(Sibbing D, Koch W, Gebhard D, Schuster T, Braun S, Stegherr J, Morath T, Sch�mig A, von Beckerath N, Kastrati A. )] TJ ET
BT 26.250 83.548 Td /F1 9.8 Tf  [(Cytochrome 2C19*17 allelic variant, platelet aggregation, bleeding events, and stent thrombosis in clopidogrel-treated patients )] TJ ET
BT 26.250 71.643 Td /F1 9.8 Tf  [(with coronary stent placement. Circulation. 2010 Feb 2;121\(4\):512-8. Epub 2010 Jan 18. PubMed PMID: 20083681.)] TJ ET
BT 26.250 52.239 Td /F1 9.8 Tf  [(56.)] TJ ET
BT 43.553 52.239 Td /F1 9.8 Tf  [(Sofi F, Giusti B, Marcucci R, Gori AM, Abbate R, Gensini GF. Cytochrome P450 2C19\(*\)2 polymorphism and cardiovascular )] TJ ET
Q
q
15.000 37.953 577.500 739.047 re W n
0.271 0.267 0.267 rg
BT 26.250 767.476 Td /F1 9.8 Tf  [(1;108\(7\):2244-7. Epub 2006 Jun 13. PubMed PMID: 16772608.)] TJ ET
BT 26.250 748.071 Td /F1 9.8 Tf  [(41.)] TJ ET
BT 43.553 748.071 Td /F1 9.8 Tf  [(Hulot JS, Wuerzner G, Bachelot-Loza C, Azizi M, Blanchard A, Peyrard S, Funck-Brentano C, Gaussem P. Effect of an )] TJ ET
BT 26.250 736.167 Td /F1 9.8 Tf  [(increased clopidogrel maintenance dose or lansoprazole co-administration on the antiplatelet response to clopidogrel in )] TJ ET
BT 26.250 724.262 Td /F1 9.8 Tf  [(CYP2C19-genotyped healthy subjects. J Thromb Haemost. 2010 Mar;8\(3\):610-3. Epub 2009 Dec 21. PubMed PMID: 20040040.)] TJ ET
BT 26.250 704.857 Td /F1 9.8 Tf  [(42.)] TJ ET
BT 43.553 704.857 Td /F1 9.8 Tf  [(Kim KA, Park PW, Hong SJ, Park JY. The effect of CYP2C19 polymorphism on the pharmacokinetics and )] TJ ET
BT 26.250 692.952 Td /F1 9.8 Tf  [(pharmacodynamics of clopidogrel: a possible mechanism for clopidogrel resistance. Clin Pharmacol Ther. 2008 Aug;84\(2\):236-)] TJ ET
BT 26.250 681.048 Td /F1 9.8 Tf  [(42. Epub 2008 Mar 5. PubMed PMID: 18323861.)] TJ ET
BT 26.250 661.643 Td /F1 9.8 Tf  [(43.)] TJ ET
BT 43.553 661.643 Td /F1 9.8 Tf  [(Umemura K, Furuta T, Kondo K. The common gene variants of CYP2C19 affect pharmacokinetics and pharmacodynamics )] TJ ET
BT 26.250 649.738 Td /F1 9.8 Tf  [(in an active metabolite of clopidogrel in healthy subjects. J Thromb Haemost. 2008 Aug;6\(8\):1439-41. Epub 2008 Jun 4. )] TJ ET
BT 26.250 637.833 Td /F1 9.8 Tf  [(PubMed PMID: 18532997.)] TJ ET
BT 26.250 618.429 Td /F1 9.8 Tf  [(44.)] TJ ET
BT 43.553 618.429 Td /F1 9.8 Tf  [(Varenhorst C, James S, Erlinge D, Brandt JT, Braun OO, Man M, Siegbahn A, Walker J, Wallentin L, Winters KJ, Close SL. )] TJ ET
BT 26.250 606.524 Td /F1 9.8 Tf  [(Genetic variation of CYP2C19 affects both pharmacokinetic and pharmacodynamic responses to clopidogrel but not prasugrel )] TJ ET
BT 26.250 594.619 Td /F1 9.8 Tf  [(in aspirin-treated patients with coronary artery disease. Eur Heart J. 2009 Jul;30\(14\):1744-52. Epub 2009 May 9. PubMed )] TJ ET
BT 26.250 582.714 Td /F1 9.8 Tf  [(PMID: 19429918; PubMed Central PMCID: PMC2709885.)] TJ ET
BT 26.250 563.310 Td /F1 9.8 Tf  [(45.)] TJ ET
BT 43.553 563.310 Td /F1 9.8 Tf  [(Frere C, Cuisset T, Morange PE, Quilici J, Camoin-Jau L, Saut N, Faille D, Lambert M, Juhan-Vague I, Bonnet JL, Alessi )] TJ ET
BT 26.250 551.405 Td /F1 9.8 Tf  [(MC. Effect of cytochrome p450 polymorphisms on platelet reactivity after treatment with clopidogrel in acute coronary )] TJ ET
BT 26.250 539.500 Td /F1 9.8 Tf  [(syndrome. Am J Cardiol. 2008 Apr 15;101\(8\):1088-93. Epub 2008 Feb 6. PubMed PMID: 18394438.)] TJ ET
BT 26.250 520.095 Td /F1 9.8 Tf  [(46.)] TJ ET
BT 43.553 520.095 Td /F1 9.8 Tf  [(Giusti B, Gori AM, Marcucci R, Saracini C, Sestini I, Paniccia R, Valente S, Antoniucci D, Abbate R, Gensini GF. )] TJ ET
BT 26.250 508.191 Td /F1 9.8 Tf  [(Cytochrome P450 2C19 loss-of-function polymorphism, but not CYP3A4 IVS10 + 12G/A and P2Y12 T744C polymorphisms, is )] TJ ET
BT 26.250 496.286 Td /F1 9.8 Tf  [(associated with response variability to dual antiplatelet treatment in high-risk vascular patients. Pharmacogenet Genomics. 2007 )] TJ ET
BT 26.250 484.381 Td /F1 9.8 Tf  [(Dec;17\(12\):1057-64. PubMed PMID: 18004210.)] TJ ET
BT 26.250 464.976 Td /F1 9.8 Tf  [(47.)] TJ ET
BT 43.553 464.976 Td /F1 9.8 Tf  [(Fontana P, Hulot JS, De Moerloose P, Gaussem P. Influence of CYP2C19 and CYP3A4 gene polymorphisms on )] TJ ET
BT 26.250 453.072 Td /F1 9.8 Tf  [(clopidogrel responsiveness in healthy subjects. J Thromb Haemost. 2007 Oct;5\(10\):2153-5. Epub 2007 Aug 3. PubMed PMID: )] TJ ET
BT 26.250 441.167 Td /F1 9.8 Tf  [(17697139.)] TJ ET
BT 26.250 421.762 Td /F1 9.8 Tf  [(48.)] TJ ET
BT 43.553 421.762 Td /F1 9.8 Tf  [(Geisler T, Schaeffeler E, Dippon J, Winter S, Buse V, Bischofs C, Zuern C, Moerike K, Gawaz M, Schwab M. CYP2C19 and )] TJ ET
BT 26.250 409.857 Td /F1 9.8 Tf  [(nongenetic factors predict poor responsiveness to clopidogrel loading dose after coronary stent implantation. )] TJ ET
BT 26.250 397.953 Td /F1 9.8 Tf  [(Pharmacogenomics. 2008 Sep;9\(9\):1251-9. PubMed PMID: 18781853.)] TJ ET
BT 26.250 378.548 Td /F1 9.8 Tf  [(49.)] TJ ET
BT 43.553 378.548 Td /F1 9.8 Tf  [(Kim IS, Choi BR, Jeong YH, Kwak CH, Kim S. The CYP2C19*2 and CYP2C19*3 polymorphisms are associated with high )] TJ ET
BT 26.250 366.643 Td /F1 9.8 Tf  [(post-treatment platelet reactivity in Asian patients with acute coronary syndrome. J Thromb Haemost. 2009 May;7\(5\):897-9. )] TJ ET
BT 26.250 354.738 Td /F1 9.8 Tf  [(Epub 2009 Feb 12. PubMed PMID: 19220726.)] TJ ET
BT 26.250 335.334 Td /F1 9.8 Tf  [(50.)] TJ ET
BT 43.553 335.334 Td /F1 9.8 Tf  [(Aleil B, L�on C, Cazenave JP, Gachet C. CYP2C19*2 polymorphism is not the sole determinant of the response to )] TJ ET
BT 26.250 323.429 Td /F1 9.8 Tf  [(clopidogrel: implications for its monitoring. J Thromb Haemost. 2009 Oct;7\(10\):1747-9. Epub 2009 Jul 17. PubMed PMID: )] TJ ET
BT 26.250 311.524 Td /F1 9.8 Tf  [(19624462.)] TJ ET
BT 26.250 292.119 Td /F1 9.8 Tf  [(51.)] TJ ET
BT 43.553 292.119 Td /F1 9.8 Tf  [(Trenk D, Hochholzer W, Fromm MF, Chialda LE, Pahl A, Valina CM, Stratz C, Schmiebusch P, Bestehorn HP, B�ttner HJ, )] TJ ET
BT 26.250 280.215 Td /F1 9.8 Tf  [(Neumann FJ. Cytochrome P450 2C19 681G>A polymorphism and high on-clopidogrel platelet reactivity associated with )] TJ ET
BT 26.250 268.310 Td /F1 9.8 Tf  [(adverse 1-year clinical outcome of elective percutaneous coronary intervention with drug-eluting or bare-metal stents. J Am Coll )] TJ ET
BT 26.250 256.405 Td /F1 9.8 Tf  [(Cardiol. 2008 May 20;51\(20\):1925-34. PubMed PMID: 18482659.)] TJ ET
BT 26.250 237.000 Td /F1 9.8 Tf  [(52.)] TJ ET
BT 43.553 237.000 Td /F1 9.8 Tf  [(Jeong YH, Kim IS, Park Y, Kang MK, Koh JS, Hwang SJ, Kwak CH, Hwang JY. Carriage of cytochrome 2C19 )] TJ ET
BT 26.250 225.096 Td /F1 9.8 Tf  [(polymorphism is associated with risk of high post-treatment platelet reactivity on high maintenance-dose clopidogrel of 150 )] TJ ET
BT 26.250 213.191 Td /F1 9.8 Tf  [(mg/day: results of the ACCEL-DOUBLE \(Accelerated Platelet Inhibition by a Double Dose of Clopidogrel According to Gene )] TJ ET
BT 26.250 201.286 Td /F1 9.8 Tf  [(Polymorphism\) study. JACC Cardiovasc Interv. 2010 Jul;3\(7\):731-41. PubMed PMID: 20650435.)] TJ ET
BT 26.250 181.881 Td /F1 9.8 Tf  [(53.)] TJ ET
BT 43.553 181.881 Td /F1 9.8 Tf  [(Sibbing D, Gebhard D, Koch W, Braun S, Stegherr J, Morath T, von Beckerath N, Mehilli J, Sch�mig A, Schuster T, Kastrati )] TJ ET
BT 26.250 169.977 Td /F1 9.8 Tf  [(A. Isolated and interactive impact of common CYP2C19 genetic variants on the antiplatelet effect of chronic clopidogrel therapy. )] TJ ET
BT 26.250 158.072 Td /F1 9.8 Tf  [(J Thromb Haemost. 2010 May 21. [Epub ahead of print] PubMed PMID: 20492469.)] TJ ET
BT 26.250 138.667 Td /F1 9.8 Tf  [(54.)] TJ ET
BT 43.553 138.667 Td /F1 9.8 Tf  [(Fr�re C, Cuisset T, Gaborit B, Alessi MC, Hulot JS. The CYP2C19*17 allele is associated with better platelet response to )] TJ ET
BT 26.250 126.762 Td /F1 9.8 Tf  [(clopidogrel in patients admitted for non-ST acute coronary syndrome. J Thromb Haemost. 2009 Aug;7\(8\):1409-11. Epub 2009 )] TJ ET
BT 26.250 114.858 Td /F1 9.8 Tf  [(May 30. PubMed PMID: 19496924.)] TJ ET
BT 26.250 95.453 Td /F1 9.8 Tf  [(55.)] TJ ET
BT 43.553 95.453 Td /F1 9.8 Tf  [(Sibbing D, Koch W, Gebhard D, Schuster T, Braun S, Stegherr J, Morath T, Sch�mig A, von Beckerath N, Kastrati A. )] TJ ET
BT 26.250 83.548 Td /F1 9.8 Tf  [(Cytochrome 2C19*17 allelic variant, platelet aggregation, bleeding events, and stent thrombosis in clopidogrel-treated patients )] TJ ET
BT 26.250 71.643 Td /F1 9.8 Tf  [(with coronary stent placement. Circulation. 2010 Feb 2;121\(4\):512-8. Epub 2010 Jan 18. PubMed PMID: 20083681.)] TJ ET
BT 26.250 52.239 Td /F1 9.8 Tf  [(56.)] TJ ET
BT 43.553 52.239 Td /F1 9.8 Tf  [(Sofi F, Giusti B, Marcucci R, Gori AM, Abbate R, Gensini GF. Cytochrome P450 2C19\(*\)2 polymorphism and cardiovascular )] TJ ET
Q
q
15.000 37.953 577.500 739.047 re W n
0.271 0.267 0.267 rg
BT 26.250 767.476 Td /F1 9.8 Tf  [(1;108\(7\):2244-7. Epub 2006 Jun 13. PubMed PMID: 16772608.)] TJ ET
BT 26.250 748.071 Td /F1 9.8 Tf  [(41.)] TJ ET
BT 43.553 748.071 Td /F1 9.8 Tf  [(Hulot JS, Wuerzner G, Bachelot-Loza C, Azizi M, Blanchard A, Peyrard S, Funck-Brentano C, Gaussem P. Effect of an )] TJ ET
BT 26.250 736.167 Td /F1 9.8 Tf  [(increased clopidogrel maintenance dose or lansoprazole co-administration on the antiplatelet response to clopidogrel in )] TJ ET
BT 26.250 724.262 Td /F1 9.8 Tf  [(CYP2C19-genotyped healthy subjects. J Thromb Haemost. 2010 Mar;8\(3\):610-3. Epub 2009 Dec 21. PubMed PMID: 20040040.)] TJ ET
BT 26.250 704.857 Td /F1 9.8 Tf  [(42.)] TJ ET
BT 43.553 704.857 Td /F1 9.8 Tf  [(Kim KA, Park PW, Hong SJ, Park JY. The effect of CYP2C19 polymorphism on the pharmacokinetics and )] TJ ET
BT 26.250 692.952 Td /F1 9.8 Tf  [(pharmacodynamics of clopidogrel: a possible mechanism for clopidogrel resistance. Clin Pharmacol Ther. 2008 Aug;84\(2\):236-)] TJ ET
BT 26.250 681.048 Td /F1 9.8 Tf  [(42. Epub 2008 Mar 5. PubMed PMID: 18323861.)] TJ ET
BT 26.250 661.643 Td /F1 9.8 Tf  [(43.)] TJ ET
BT 43.553 661.643 Td /F1 9.8 Tf  [(Umemura K, Furuta T, Kondo K. The common gene variants of CYP2C19 affect pharmacokinetics and pharmacodynamics )] TJ ET
BT 26.250 649.738 Td /F1 9.8 Tf  [(in an active metabolite of clopidogrel in healthy subjects. J Thromb Haemost. 2008 Aug;6\(8\):1439-41. Epub 2008 Jun 4. )] TJ ET
BT 26.250 637.833 Td /F1 9.8 Tf  [(PubMed PMID: 18532997.)] TJ ET
BT 26.250 618.429 Td /F1 9.8 Tf  [(44.)] TJ ET
BT 43.553 618.429 Td /F1 9.8 Tf  [(Varenhorst C, James S, Erlinge D, Brandt JT, Braun OO, Man M, Siegbahn A, Walker J, Wallentin L, Winters KJ, Close SL. )] TJ ET
BT 26.250 606.524 Td /F1 9.8 Tf  [(Genetic variation of CYP2C19 affects both pharmacokinetic and pharmacodynamic responses to clopidogrel but not prasugrel )] TJ ET
BT 26.250 594.619 Td /F1 9.8 Tf  [(in aspirin-treated patients with coronary artery disease. Eur Heart J. 2009 Jul;30\(14\):1744-52. Epub 2009 May 9. PubMed )] TJ ET
BT 26.250 582.714 Td /F1 9.8 Tf  [(PMID: 19429918; PubMed Central PMCID: PMC2709885.)] TJ ET
BT 26.250 563.310 Td /F1 9.8 Tf  [(45.)] TJ ET
BT 43.553 563.310 Td /F1 9.8 Tf  [(Frere C, Cuisset T, Morange PE, Quilici J, Camoin-Jau L, Saut N, Faille D, Lambert M, Juhan-Vague I, Bonnet JL, Alessi )] TJ ET
BT 26.250 551.405 Td /F1 9.8 Tf  [(MC. Effect of cytochrome p450 polymorphisms on platelet reactivity after treatment with clopidogrel in acute coronary )] TJ ET
BT 26.250 539.500 Td /F1 9.8 Tf  [(syndrome. Am J Cardiol. 2008 Apr 15;101\(8\):1088-93. Epub 2008 Feb 6. PubMed PMID: 18394438.)] TJ ET
BT 26.250 520.095 Td /F1 9.8 Tf  [(46.)] TJ ET
BT 43.553 520.095 Td /F1 9.8 Tf  [(Giusti B, Gori AM, Marcucci R, Saracini C, Sestini I, Paniccia R, Valente S, Antoniucci D, Abbate R, Gensini GF. )] TJ ET
BT 26.250 508.191 Td /F1 9.8 Tf  [(Cytochrome P450 2C19 loss-of-function polymorphism, but not CYP3A4 IVS10 + 12G/A and P2Y12 T744C polymorphisms, is )] TJ ET
BT 26.250 496.286 Td /F1 9.8 Tf  [(associated with response variability to dual antiplatelet treatment in high-risk vascular patients. Pharmacogenet Genomics. 2007 )] TJ ET
BT 26.250 484.381 Td /F1 9.8 Tf  [(Dec;17\(12\):1057-64. PubMed PMID: 18004210.)] TJ ET
BT 26.250 464.976 Td /F1 9.8 Tf  [(47.)] TJ ET
BT 43.553 464.976 Td /F1 9.8 Tf  [(Fontana P, Hulot JS, De Moerloose P, Gaussem P. Influence of CYP2C19 and CYP3A4 gene polymorphisms on )] TJ ET
BT 26.250 453.072 Td /F1 9.8 Tf  [(clopidogrel responsiveness in healthy subjects. J Thromb Haemost. 2007 Oct;5\(10\):2153-5. Epub 2007 Aug 3. PubMed PMID: )] TJ ET
BT 26.250 441.167 Td /F1 9.8 Tf  [(17697139.)] TJ ET
BT 26.250 421.762 Td /F1 9.8 Tf  [(48.)] TJ ET
BT 43.553 421.762 Td /F1 9.8 Tf  [(Geisler T, Schaeffeler E, Dippon J, Winter S, Buse V, Bischofs C, Zuern C, Moerike K, Gawaz M, Schwab M. CYP2C19 and )] TJ ET
BT 26.250 409.857 Td /F1 9.8 Tf  [(nongenetic factors predict poor responsiveness to clopidogrel loading dose after coronary stent implantation. )] TJ ET
BT 26.250 397.953 Td /F1 9.8 Tf  [(Pharmacogenomics. 2008 Sep;9\(9\):1251-9. PubMed PMID: 18781853.)] TJ ET
BT 26.250 378.548 Td /F1 9.8 Tf  [(49.)] TJ ET
BT 43.553 378.548 Td /F1 9.8 Tf  [(Kim IS, Choi BR, Jeong YH, Kwak CH, Kim S. The CYP2C19*2 and CYP2C19*3 polymorphisms are associated with high )] TJ ET
BT 26.250 366.643 Td /F1 9.8 Tf  [(post-treatment platelet reactivity in Asian patients with acute coronary syndrome. J Thromb Haemost. 2009 May;7\(5\):897-9. )] TJ ET
BT 26.250 354.738 Td /F1 9.8 Tf  [(Epub 2009 Feb 12. PubMed PMID: 19220726.)] TJ ET
BT 26.250 335.334 Td /F1 9.8 Tf  [(50.)] TJ ET
BT 43.553 335.334 Td /F1 9.8 Tf  [(Aleil B, L�on C, Cazenave JP, Gachet C. CYP2C19*2 polymorphism is not the sole determinant of the response to )] TJ ET
BT 26.250 323.429 Td /F1 9.8 Tf  [(clopidogrel: implications for its monitoring. J Thromb Haemost. 2009 Oct;7\(10\):1747-9. Epub 2009 Jul 17. PubMed PMID: )] TJ ET
BT 26.250 311.524 Td /F1 9.8 Tf  [(19624462.)] TJ ET
BT 26.250 292.119 Td /F1 9.8 Tf  [(51.)] TJ ET
BT 43.553 292.119 Td /F1 9.8 Tf  [(Trenk D, Hochholzer W, Fromm MF, Chialda LE, Pahl A, Valina CM, Stratz C, Schmiebusch P, Bestehorn HP, B�ttner HJ, )] TJ ET
BT 26.250 280.215 Td /F1 9.8 Tf  [(Neumann FJ. Cytochrome P450 2C19 681G>A polymorphism and high on-clopidogrel platelet reactivity associated with )] TJ ET
BT 26.250 268.310 Td /F1 9.8 Tf  [(adverse 1-year clinical outcome of elective percutaneous coronary intervention with drug-eluting or bare-metal stents. J Am Coll )] TJ ET
BT 26.250 256.405 Td /F1 9.8 Tf  [(Cardiol. 2008 May 20;51\(20\):1925-34. PubMed PMID: 18482659.)] TJ ET
BT 26.250 237.000 Td /F1 9.8 Tf  [(52.)] TJ ET
BT 43.553 237.000 Td /F1 9.8 Tf  [(Jeong YH, Kim IS, Park Y, Kang MK, Koh JS, Hwang SJ, Kwak CH, Hwang JY. Carriage of cytochrome 2C19 )] TJ ET
BT 26.250 225.096 Td /F1 9.8 Tf  [(polymorphism is associated with risk of high post-treatment platelet reactivity on high maintenance-dose clopidogrel of 150 )] TJ ET
BT 26.250 213.191 Td /F1 9.8 Tf  [(mg/day: results of the ACCEL-DOUBLE \(Accelerated Platelet Inhibition by a Double Dose of Clopidogrel According to Gene )] TJ ET
BT 26.250 201.286 Td /F1 9.8 Tf  [(Polymorphism\) study. JACC Cardiovasc Interv. 2010 Jul;3\(7\):731-41. PubMed PMID: 20650435.)] TJ ET
BT 26.250 181.881 Td /F1 9.8 Tf  [(53.)] TJ ET
BT 43.553 181.881 Td /F1 9.8 Tf  [(Sibbing D, Gebhard D, Koch W, Braun S, Stegherr J, Morath T, von Beckerath N, Mehilli J, Sch�mig A, Schuster T, Kastrati )] TJ ET
BT 26.250 169.977 Td /F1 9.8 Tf  [(A. Isolated and interactive impact of common CYP2C19 genetic variants on the antiplatelet effect of chronic clopidogrel therapy. )] TJ ET
BT 26.250 158.072 Td /F1 9.8 Tf  [(J Thromb Haemost. 2010 May 21. [Epub ahead of print] PubMed PMID: 20492469.)] TJ ET
BT 26.250 138.667 Td /F1 9.8 Tf  [(54.)] TJ ET
BT 43.553 138.667 Td /F1 9.8 Tf  [(Fr�re C, Cuisset T, Gaborit B, Alessi MC, Hulot JS. The CYP2C19*17 allele is associated with better platelet response to )] TJ ET
BT 26.250 126.762 Td /F1 9.8 Tf  [(clopidogrel in patients admitted for non-ST acute coronary syndrome. J Thromb Haemost. 2009 Aug;7\(8\):1409-11. Epub 2009 )] TJ ET
BT 26.250 114.858 Td /F1 9.8 Tf  [(May 30. PubMed PMID: 19496924.)] TJ ET
BT 26.250 95.453 Td /F1 9.8 Tf  [(55.)] TJ ET
BT 43.553 95.453 Td /F1 9.8 Tf  [(Sibbing D, Koch W, Gebhard D, Schuster T, Braun S, Stegherr J, Morath T, Sch�mig A, von Beckerath N, Kastrati A. )] TJ ET
BT 26.250 83.548 Td /F1 9.8 Tf  [(Cytochrome 2C19*17 allelic variant, platelet aggregation, bleeding events, and stent thrombosis in clopidogrel-treated patients )] TJ ET
BT 26.250 71.643 Td /F1 9.8 Tf  [(with coronary stent placement. Circulation. 2010 Feb 2;121\(4\):512-8. Epub 2010 Jan 18. PubMed PMID: 20083681.)] TJ ET
BT 26.250 52.239 Td /F1 9.8 Tf  [(56.)] TJ ET
BT 43.553 52.239 Td /F1 9.8 Tf  [(Sofi F, Giusti B, Marcucci R, Gori AM, Abbate R, Gensini GF. Cytochrome P450 2C19\(*\)2 polymorphism and cardiovascular )] TJ ET
Q
q
0.000 0.000 0.000 rg
BT 291.710 19.825 Td /F1 11.0 Tf  [(8)] TJ ET
BT 25.000 19.825 Td /F1 11.0 Tf  [(PLOS Currents Evidence on Genomic Tests)] TJ ET
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BT 26.250 767.476 Td /F1 9.8 Tf  [(recurrences in patients taking clopidogrel: a meta-analysis. Pharmacogenomics J. 2010 Mar 30. [Epub ahead of print] PubMed )] TJ ET
BT 26.250 755.571 Td /F1 9.8 Tf  [(PMID: 20351750.)] TJ ET
BT 26.250 736.167 Td /F1 9.8 Tf  [(57.)] TJ ET
BT 43.553 736.167 Td /F1 9.8 Tf  [(Hulot JS, Collet JP, Silvain J, Pena A, Bellemain-Appaix A, Barth�l�my O, Cayla G, Beygui F, Montalescot G. )] TJ ET
BT 26.250 724.262 Td /F1 9.8 Tf  [(Cardiovascular risk in clopidogrel-treated patients according to cytochrome P450 2C19*2 loss-of-function allele or proton pump )] TJ ET
BT 26.250 712.357 Td /F1 9.8 Tf  [(inhibitor coadministration: a systematic meta-analysis. J Am Coll Cardiol. 2010 Jul 6;56\(2\):134-43. PubMed PMID: 20620727.)] TJ ET
BT 26.250 692.952 Td /F1 9.8 Tf  [(58.)] TJ ET
BT 43.553 692.952 Td /F1 9.8 Tf  [(Hulot JS, Fuster V. Antiplatelet therapy: Personalized medicine for clopidogrel resistance? Nat Rev Cardiol. 2009 )] TJ ET
BT 26.250 681.048 Td /F1 9.8 Tf  [(May;6\(5\):334-6. PubMed PMID: 19377495.)] TJ ET
BT 26.250 661.643 Td /F1 9.8 Tf  [(59.)] TJ ET
BT 43.553 661.643 Td /F1 9.8 Tf  [(Collet JP, Hulot JS, Pena A, Villard E, Esteve JB, Silvain J, Payot L, Brugier D, Cayla G, Beygui F, Bensimon G, Funck-)] TJ ET
BT 26.250 649.738 Td /F1 9.8 Tf  [(Brentano C, Montalescot G. Cytochrome P450 2C19 polymorphism in young patients treated with clopidogrel after myocardial )] TJ ET
BT 26.250 637.833 Td /F1 9.8 Tf  [(infarction: a cohort study. Lancet. 2009 Jan 24;373\(9660\):309-17. Epub 2008 Dec 26. PubMed PMID: 19108880.)] TJ ET
BT 26.250 618.429 Td /F1 9.8 Tf  [(60.)] TJ ET
BT 43.553 618.429 Td /F1 9.8 Tf  [(Par� G, M.D. SRM, Yusuf S, Anand SS, Connolly SJ, Hirsh J, Simonsen K, Bhatt DL, Fox KAA, Eikelboom JW: Effects of )] TJ ET
BT 26.250 606.524 Td /F1 9.8 Tf  [(CYP2C19 Genotype on Outcomes of Clopidogrel Treatment. NEJM. 2010 Aug 29; online. PMID: pending.)] TJ ET
BT 26.250 587.119 Td /F1 9.8 Tf  [(61.)] TJ ET
BT 43.553 587.119 Td /F1 9.8 Tf  [(Mega JL, Close SL, Wiviott SD, Shen L, Walker JR, Simon T, Antman EM, Braunwald E, Sabatine MS. Genetic variants in )] TJ ET
BT 26.250 575.214 Td /F1 9.8 Tf  [(ABCB1 and CYP2C19 and cardiovascular outcomes after treatment with clopidogrel and prasugrel in the TRITON-TIMI 38 trial: )] TJ ET
BT 26.250 563.310 Td /F1 9.8 Tf  [(a pharmacogenetic analysis. Lancet. 2010 Aug 27. [Epub ahead of print] PubMed PMID: 20801494.)] TJ ET
BT 26.250 543.905 Td /F1 9.8 Tf  [(62.)] TJ ET
BT 43.553 543.905 Td /F1 9.8 Tf  [(Simon T, Verstuyft C, Mary-Krause M, Quteineh L, Drouet E, M�neveau N, Steg PG, Ferri�res J, Danchin N, Becquemont )] TJ ET
BT 26.250 532.000 Td /F1 9.8 Tf  [(L; French Registry of Acute ST-Elevation and Non-ST-Elevation Myocardial Infarction \(FAST-MI\) Investigators. Genetic )] TJ ET
BT 26.250 520.095 Td /F1 9.8 Tf  [(determinants of response to clopidogrel and cardiovascular events. N Engl J Med. 2009 Jan 22;360\(4\):363-75. Epub 2008 Dec )] TJ ET
BT 26.250 508.191 Td /F1 9.8 Tf  [(22. PubMed PMID: 19106083.)] TJ ET
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BT 26.250 767.476 Td /F1 9.8 Tf  [(recurrences in patients taking clopidogrel: a meta-analysis. Pharmacogenomics J. 2010 Mar 30. [Epub ahead of print] PubMed )] TJ ET
BT 26.250 755.571 Td /F1 9.8 Tf  [(PMID: 20351750.)] TJ ET
BT 26.250 736.167 Td /F1 9.8 Tf  [(57.)] TJ ET
BT 43.553 736.167 Td /F1 9.8 Tf  [(Hulot JS, Collet JP, Silvain J, Pena A, Bellemain-Appaix A, Barth�l�my O, Cayla G, Beygui F, Montalescot G. )] TJ ET
BT 26.250 724.262 Td /F1 9.8 Tf  [(Cardiovascular risk in clopidogrel-treated patients according to cytochrome P450 2C19*2 loss-of-function allele or proton pump )] TJ ET
BT 26.250 712.357 Td /F1 9.8 Tf  [(inhibitor coadministration: a systematic meta-analysis. J Am Coll Cardiol. 2010 Jul 6;56\(2\):134-43. PubMed PMID: 20620727.)] TJ ET
BT 26.250 692.952 Td /F1 9.8 Tf  [(58.)] TJ ET
BT 43.553 692.952 Td /F1 9.8 Tf  [(Hulot JS, Fuster V. Antiplatelet therapy: Personalized medicine for clopidogrel resistance? Nat Rev Cardiol. 2009 )] TJ ET
BT 26.250 681.048 Td /F1 9.8 Tf  [(May;6\(5\):334-6. PubMed PMID: 19377495.)] TJ ET
BT 26.250 661.643 Td /F1 9.8 Tf  [(59.)] TJ ET
BT 43.553 661.643 Td /F1 9.8 Tf  [(Collet JP, Hulot JS, Pena A, Villard E, Esteve JB, Silvain J, Payot L, Brugier D, Cayla G, Beygui F, Bensimon G, Funck-)] TJ ET
BT 26.250 649.738 Td /F1 9.8 Tf  [(Brentano C, Montalescot G. Cytochrome P450 2C19 polymorphism in young patients treated with clopidogrel after myocardial )] TJ ET
BT 26.250 637.833 Td /F1 9.8 Tf  [(infarction: a cohort study. Lancet. 2009 Jan 24;373\(9660\):309-17. Epub 2008 Dec 26. PubMed PMID: 19108880.)] TJ ET
BT 26.250 618.429 Td /F1 9.8 Tf  [(60.)] TJ ET
BT 43.553 618.429 Td /F1 9.8 Tf  [(Par� G, M.D. SRM, Yusuf S, Anand SS, Connolly SJ, Hirsh J, Simonsen K, Bhatt DL, Fox KAA, Eikelboom JW: Effects of )] TJ ET
BT 26.250 606.524 Td /F1 9.8 Tf  [(CYP2C19 Genotype on Outcomes of Clopidogrel Treatment. NEJM. 2010 Aug 29; online. PMID: pending.)] TJ ET
BT 26.250 587.119 Td /F1 9.8 Tf  [(61.)] TJ ET
BT 43.553 587.119 Td /F1 9.8 Tf  [(Mega JL, Close SL, Wiviott SD, Shen L, Walker JR, Simon T, Antman EM, Braunwald E, Sabatine MS. Genetic variants in )] TJ ET
BT 26.250 575.214 Td /F1 9.8 Tf  [(ABCB1 and CYP2C19 and cardiovascular outcomes after treatment with clopidogrel and prasugrel in the TRITON-TIMI 38 trial: )] TJ ET
BT 26.250 563.310 Td /F1 9.8 Tf  [(a pharmacogenetic analysis. Lancet. 2010 Aug 27. [Epub ahead of print] PubMed PMID: 20801494.)] TJ ET
BT 26.250 543.905 Td /F1 9.8 Tf  [(62.)] TJ ET
BT 43.553 543.905 Td /F1 9.8 Tf  [(Simon T, Verstuyft C, Mary-Krause M, Quteineh L, Drouet E, M�neveau N, Steg PG, Ferri�res J, Danchin N, Becquemont )] TJ ET
BT 26.250 532.000 Td /F1 9.8 Tf  [(L; French Registry of Acute ST-Elevation and Non-ST-Elevation Myocardial Infarction \(FAST-MI\) Investigators. Genetic )] TJ ET
BT 26.250 520.095 Td /F1 9.8 Tf  [(determinants of response to clopidogrel and cardiovascular events. N Engl J Med. 2009 Jan 22;360\(4\):363-75. Epub 2008 Dec )] TJ ET
BT 26.250 508.191 Td /F1 9.8 Tf  [(22. PubMed PMID: 19106083.)] TJ ET
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BT 26.250 767.476 Td /F1 9.8 Tf  [(recurrences in patients taking clopidogrel: a meta-analysis. Pharmacogenomics J. 2010 Mar 30. [Epub ahead of print] PubMed )] TJ ET
BT 26.250 755.571 Td /F1 9.8 Tf  [(PMID: 20351750.)] TJ ET
BT 26.250 736.167 Td /F1 9.8 Tf  [(57.)] TJ ET
BT 43.553 736.167 Td /F1 9.8 Tf  [(Hulot JS, Collet JP, Silvain J, Pena A, Bellemain-Appaix A, Barth�l�my O, Cayla G, Beygui F, Montalescot G. )] TJ ET
BT 26.250 724.262 Td /F1 9.8 Tf  [(Cardiovascular risk in clopidogrel-treated patients according to cytochrome P450 2C19*2 loss-of-function allele or proton pump )] TJ ET
BT 26.250 712.357 Td /F1 9.8 Tf  [(inhibitor coadministration: a systematic meta-analysis. J Am Coll Cardiol. 2010 Jul 6;56\(2\):134-43. PubMed PMID: 20620727.)] TJ ET
BT 26.250 692.952 Td /F1 9.8 Tf  [(58.)] TJ ET
BT 43.553 692.952 Td /F1 9.8 Tf  [(Hulot JS, Fuster V. Antiplatelet therapy: Personalized medicine for clopidogrel resistance? Nat Rev Cardiol. 2009 )] TJ ET
BT 26.250 681.048 Td /F1 9.8 Tf  [(May;6\(5\):334-6. PubMed PMID: 19377495.)] TJ ET
BT 26.250 661.643 Td /F1 9.8 Tf  [(59.)] TJ ET
BT 43.553 661.643 Td /F1 9.8 Tf  [(Collet JP, Hulot JS, Pena A, Villard E, Esteve JB, Silvain J, Payot L, Brugier D, Cayla G, Beygui F, Bensimon G, Funck-)] TJ ET
BT 26.250 649.738 Td /F1 9.8 Tf  [(Brentano C, Montalescot G. Cytochrome P450 2C19 polymorphism in young patients treated with clopidogrel after myocardial )] TJ ET
BT 26.250 637.833 Td /F1 9.8 Tf  [(infarction: a cohort study. Lancet. 2009 Jan 24;373\(9660\):309-17. Epub 2008 Dec 26. PubMed PMID: 19108880.)] TJ ET
BT 26.250 618.429 Td /F1 9.8 Tf  [(60.)] TJ ET
BT 43.553 618.429 Td /F1 9.8 Tf  [(Par� G, M.D. SRM, Yusuf S, Anand SS, Connolly SJ, Hirsh J, Simonsen K, Bhatt DL, Fox KAA, Eikelboom JW: Effects of )] TJ ET
BT 26.250 606.524 Td /F1 9.8 Tf  [(CYP2C19 Genotype on Outcomes of Clopidogrel Treatment. NEJM. 2010 Aug 29; online. PMID: pending.)] TJ ET
BT 26.250 587.119 Td /F1 9.8 Tf  [(61.)] TJ ET
BT 43.553 587.119 Td /F1 9.8 Tf  [(Mega JL, Close SL, Wiviott SD, Shen L, Walker JR, Simon T, Antman EM, Braunwald E, Sabatine MS. Genetic variants in )] TJ ET
BT 26.250 575.214 Td /F1 9.8 Tf  [(ABCB1 and CYP2C19 and cardiovascular outcomes after treatment with clopidogrel and prasugrel in the TRITON-TIMI 38 trial: )] TJ ET
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BT 26.250 543.905 Td /F1 9.8 Tf  [(62.)] TJ ET
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