HomeCirculationVol. 122, No. 5ACCF/AHA Clopidogrel Clinical Alert: Approaches to the FDA “Boxed Warning” Free AccessReview ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessReview ArticlePDF/EPUBACCF/AHA Clopidogrel Clinical Alert: Approaches to the FDA “Boxed Warning”A Report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents and the American Heart Association Writing Committee Members David R. HolmesJr, MD, FACC, FSCAI, Chair, Gregory J. Dehmer, MD, FACC, FAHA, FSCAI, FACP, Sanjay Kaul, MBBS, FACC, FAHA, Dana Leifer, MD, FAHA, Patrick T. O'Gara, MD, FACC, FAHA and C. Michael Stein, MD Writing Committee Members Search for more papers by this author , David R. HolmesJrDavid R. HolmesJr Search for more papers by this author , Gregory J. DehmerGregory J. Dehmer Search for more papers by this author , Sanjay KaulSanjay Kaul Search for more papers by this author , Dana LeiferDana Leifer Search for more papers by this author , Patrick T. O'GaraPatrick T. O'Gara Search for more papers by this author and C. Michael SteinC. Michael Stein Search for more papers by this author Originally published28 Jun 2010https://doi.org/10.1161/CIR.0b013e3181ee08edCirculation. 2010;122:537–557Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: June 28, 2010: Previous Version 1 Preamble…5371. Review of FDA Boxed Warning—What Did the FDA Say?…538 1.1. Background and Significance of Boxed Warnings and How These Relate to the Clopidogrel Warning…5392. Evidence on Variability to Clopidogrel Response…539 2.1. Genetic Variability and Clopidogrel Response…539 2.1.1. CYP2C19 Variants…539 2.1.2. Other Genetic Polymorphisms…540 2.1.2.1. ABCB1…540 2.1.2.2. Other CYP Isoenzymes…542 2.1.2.3. P2Y12 Receptor…5423. Current Status of CYP2C19 Genotyping Assays…5434. Alternative Dosing Regimens for Clopidogrel…5435. Review of Ongoing Trials…5446. Conclusions…548 6.1. Issues for Consideration…548 6.2. Recommendations for Practice…549References…550Appendix 1. Author Disclosures…553Appendix 2. Peer Reviewer Disclosures…553Appendix 3. FDA Drug Safety Communication…556PreambleThe recent US Food and Drug Administration (FDA) “boxed warning” on clopidogrel raises important questions for practitioners and patients. The warning addresses the need for pharmacogenomic testing to identify patients’ altered clopidogrel metabolism and thus their risk for a suboptimal clinical response to clopidogrel. Although there is an expanding database on genetic polymorphisms that may affect clopidogrel metabolism and thus clinical outcomes, there are no evidence-based data upon which todevelop specific recommendations on the role of genetic testing in routine care nor strategies proven to improve the safety/efficacy of specific pharmacologic approaches.To provide guidance on this issue, the American College of Cardiology Foundation (ACCF) and the American Heart Association (AHA) convened a writing committee. The ACCF and AHA adhere to a rigorous policy regarding relationships with industry and other entities (RWI) of authors and peer reviewers for clinical document development (see http://www.cardiosource.org/Science-And-Quality/Practice-Guidelines-and-Quality-Standards/Relationships-With-Industry-Policy.aspx). This policy requires that a majority of writing committee members have no relevant relationships with industry to this topic, a standard that has been achieved for this document as indicated in Appendix 1. In the spirit of full disclosure, comprehensive RWI (RWI not relevant to this document) for all authors is available online for public view. RWI restrictions are not applicable for participation in the external peer review process for clinical documents in order to ensure that a variety of constituencies/views inform the final document; however, all relevant reviewer RWI is published in Appendix 2 for the purpose of full transparency. In addition, reviewer affiliation for this document is recorded in Appendix 2, indicating participation of the following societies in the review process: the American Academy of Family Physicians, the American College of Physicians, the Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons. The ACCF and AHA believe this document will be helpful during a time when information on this topic is incomplete and continually changing. For some of the clinical issues in this document, final published data may not be available, in which case we have clearly identified this concern in the text. In addition to this document, an expert consensus document on the interaction of clopidogrel and proton pump inhibitors is in progress by the ACCF, American College of Gastroenterology, and AHA. Our organizations remain committed to providing guidance on key clinical issues to promote optimal patient care.Ralph G. Brindis, MD, MPH, FACC, FSCAIPresident, American College of Cardiology FoundationClyde W. Yancy, Jr, MD, FACC, FAHAPresident, American Heart Association1. Review of FDA Boxed Warning—What Did the FDA Say?On March 12, 2010, the FDA approved a new label for clopidogrel with a “boxed warning” (Appendix 3) about the diminished effectiveness of the drug in patients with impaired ability to convert the drug into its active form.1 This warning was the third FDA label change related to this issue in the last year. The boxed warning is based on the concern that the antiplatelet effect of clopidogrel depends primarily on its activation by the cytochrome P450 (CYP) system. Patients with decreased CYP2C19 function because of genetic polymorphisms metabolize clopidogrel poorly and have higher rates of cardiovascular events after acute coronary syndrome (ACS) and percutaneous coronary interventions (PCIs) than patients with normal CYP2C19 function. The warning also notes that tests are available to identify patients with genetic polymorphisms, and that alternative treatment strategies should be considered in poor metabolizers of the drug.The new label emphasizes a single study of 40 healthy subjects (10 each with different degrees of CYP2C19 function—poor, intermediate, extensive, and ultrarapid) in a crossover design. Each group was randomized to a 300-mg loading dose (LD) followed by a 75-mg per day maintenance dose (MD), or a 600-mg LD followed by 150-mg per day MD, each for a total of 5 days (Appendix 3). After a washout period, subjects were crossed over to the alternate treatment. The chief findings were decreased active metabolite exposure and increased platelet aggregation in the poor metabolizers compared with the other groups. When poor metabolizers received the 600-mg LD followed by 150 mg daily MD, active metabolite exposure and antiplatelet response were greater than with the 300-mg LD and 75 mg per day MD regimen, but remained quantitatively less than the response in the extensive metabolizers when they received the 300 mg and 75 mg regimen. Two different assays for platelet function were used—platelet aggregation stimulated by 5 micromolar adenosine diphosphate (ADP) and the vasodilator-stimulated phosphoprotein phopsphorylation assay. Improvement in platelet inhibitory responses with higher-dose clopidogrel in poor metabolizers was apparent only with the former assay. There was no comment about statistical significance in the labeling material. Analysis of the final as yet unpublished data set of this study, which played a prominent role in the boxed warning, will be essential to a more complete understanding of the issues.To fully understand the new label, it is necessary to consider the other background information upon which the label was developed. There are 3 major CYP2C19 genetic polymorphisms. CYP2C19*1 corresponds to normal function. CYP2C19*2 and CYP2C19*3 are loss-of-function alleles and explain most of the reduced function in those who are “poor metabolizers.” CYP2C19*2 and *3 account for 85% and 99% of the nonfunctional alleles in whites and Asians, respectively (Appendix 3). Poor metabolizers have 2 loss-of-function alleles. Intermediate metabolizers have 1 copy of a loss-of-function allele and may also have decreased active metabolite levels and reduced antiplatelet effects when treated with clopidogrel, but the boxed warning only refers to poor metabolizers. Thenew label alludes to multiple retrospective, prospective randomized, and cohort clopidogrel studies that document increased major adverse cardiac event (MACE) rates in populations with genetic polymorphisms. Several cohort studies cited in prior FDA versions of the label and referred to in the most recent label have also shown variations in event rates that depend on CYP2C19 genotype.2–4 As the new label notes, tests are now available to determine CYP2C19 genotypes for clinical purposes.Conversely, it is also important to note what the label does not say. When the first of the label revisions was being developed in early 2009, the FDA proposed a recommendation for genotyping to identify patients with impaired CYP2C19 function and a comment stating that higher doses may be considered in these patients. After discussion with the manufacturer, however, no recommendation for genotyping was included in the label at that time. Instead, the initial 2009 revision (dated May 5, 2009) simply noted that “poor metabolizer status is associated with diminished response to clopidogrel” and that “the optimal dose for poor metabolizers has yet to be determined”.5 The second revision in 2009 advised avoiding the use of clopidogrel “in patients with impaired CYP2C19 function due to known genetic polymorphisms or due to drugs that inhibit CYP2C19 activity” and added additional information about the interaction of clopidogrel and omeprazole.6 The most recent revision, in March 2010, no longer specifically advises avoidance of clopidogrel in patients with known genetic polymorphisms of CYP2C19 but rather states that physicians should “consider alternative treatment or treatment strategies in patients identified as CYP2C19 poor metabolizers”.1 In addition, it should be noted that although it is assumed that it is the influence of the genotype on the phenotype of platelet reactivity that causes the increased rate of adverse clinical events, it remains possible that there may be other independent adverse effects of the genotype.In the current warning, the moderate position of the FDA does not appear merely to be a reluctance to make strong recommendations about genetic testing, but rather to reflect an attempt to weigh the evidence and to give the prescriber more information. The FDA has made recommendations of different strengths related to genetic variations on multiple occasions7 in recent years with some boxed warnings like those for carbamazepine and abacavir that explicitly recommend genetic testing and advise against generally treating patients with certain genotypes with these drugs.8,9 In contrast, the FDA-approved label for warfarin mentions information about allelic variants that alter patient responsiveness to it, but does not include a “boxed warning” about this.101.1. Background and Significance of Boxed Warnings and How These Relate to the Clopidogrel WarningIt is important to understand when the FDA requires such a warning. The Code of Federal Regulations10a requires that “labeling shall be revised to include a warning as soon as there is reasonable evidence of an association of a serious hazard with a drug; a causal relationship need not have been proved. Special problems, particularly those that may lead to death or serious injury, may be required by the [FDA] to be placed in a prominently displayed box. The ‘boxed warning’ ordinarily shall be based on clinical data”.11The FDA leaves decisions about what to do with the information in boxed warnings up to individual clinicians.11 It does not necessarily recommend a particular plan for how to deal with the information. It has been emphasized that the intent of information that the FDA puts into such a warning is to share the data with prescribers so they can be informed and make decisions based on patient-specific factors. The decision to perform CYP2C19 genetic testing is best made by the prescriber of the medication and the informed patient.In brief, the clopidogrel boxed warning leaves the issue of whether to perform CYP2C19 testing up to the individual physician. It does not specifically require genetic testing or other changes in evaluation or treatment and does not imply that there are solid evidence-based reasons for such actions. Rather, it serves to make clinicians aware of the imperfect, but significant, knowledge that we have about genetic variations in response to clopidogrel and to emphasize that clinicians should use this knowledge to make decisions about how to treat individual patients.2. Evidence on Variability to Clopidogrel ResponseClopidogrel, a thienopyridine P2Y12 ADP receptor antagonist, requires bioactivation to its active metabolite (R130964) to inhibit platelet aggregation. There is substantial individual variability in response to clopidogrel, with inhibition of ADP-induced platelet aggregation ranging from less than 10% to almost complete inhibition of platelet aggregation with a wide distribution across this range, such that there is no dichotomous separation into “responders” and “nonresponders”.12 Nevertheless, a meta-analysis and other data suggest that residual platelet reactivity in patients receiving clopidogrel is associated with an increased risk of cardiac, cerebrovascular, and peripheral arterial events.12–14 This variability may be due to pharmacokinetic (PK) or pharmacodynamic (PD) factors (ie, differences respectively in either kinetics/concentration of the active metabolite or in the response of platelets). The variability in clopidogrel PK and PD is due to several factors: demographic variables such as increased age and body mass index, comorbidities such as diabetes and dyslipidemia, and other factors that remain to be identified.15 Although genetic variability also plays an important role in ADP-stimulated platelet aggregation in response to clopidogrel, known genetic and nongenetic factors explain only a portion of the majority of variation.152.1. Genetic Variability and Clopidogrel Response2.1.1. CYP2C19 VariantsCYP2C19 plays an important role in the bioactivation of clopidogrel, a prodrug. Once absorbed, only approximately 15% of clopidogrel is bioactivated in the liver in a 2-step process that is mediated by several CYP450 isoenzymes (Figure 1).16 Of these, CYP2C19 is responsible for approximately 45% of the first step (the formation of 2-oxo-clopidogrel) and approximately 20% of the final step—the generation of the pharmacologically active thiol metabolite. There are genetic polymorphisms in several CYP450 enzymes involved in the metabolism of clopidogrel, but variants in CYP2C19, particularly CYP2C19*2, are reproducibly associated with variability in clopidogrel active metabolite bioavailability, antiplatelet effects, and clinical outcomes.2,15,17 The CYP2C19*2 variant encodes a nonfunctional protein. There are ethnic differences in its distribution; approximately 50% of Chinese, 34% of African Americans, 25% of Whites, and 19% of Mexican Americans carry at least 1 copy of the reduced function CYP2C19*2 allele.18,19 Other genetic polymorphisms associated with impaired CYP2C19 activity and possibly adverse clinical events (CYP2C19*3, *4, *5, *8) are much less common in Whites, African Americans, and Hispanics.18 In the randomized control TRITON–TIMI 38 (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel–Thrombolysis In Myocardial Infarction 38), comparing clopidogrel with prasugrel in patients with ACS, CYP2C19*2 accounted for 95% of the subjects classified as carriers of a reduced CYP2C19 function allele.17 The number of reduced function alleles is important: individuals with 1 variant allele (intermediate metabolizers) had 26% to 31% lower exposure to the active metabolite of clopidogrel, and those with 2 genetic polymorphisms (poor metabolizers) had 46% to 55% lower exposure compared with those with no CYP2C19 polymorphisms.17Download figureDownload PowerPointFigure 1. Schematic representation of the metabolism of clopidogrel and prasugrel. Reprinted with permission from Mega et al.16The effect of variant CYP2C19 alleles on clinical outcome in response to clopidogrel has been reported in multiple studies (Table 1).20,21 All of these were cohort studies, with 1 being a genetic substudy derived from TRITON–TIMI 38. A significant association between the CYP2C19*2 polymorphism and an increased risk of major adverse cardiovascular events was reported in 5 of 7 studies. The risk ranged from a 53% relative increase in TRITON–TIMI 3817 to an approximately 5-fold increase in a cohort study of young patients treated with clopidogrel after acute myocardial infarction (MI).2 In the latter study, after multivariable analysis, CYP2C19*2 was the only factor independently associated with new cardiovascular events (hazard ratio [HR] 4.04 [95% confidence interval (CI) 1.81 to 9.02]; P=0.0006).2 However, because none of the studies were randomized, the possibility of bias and confounding variables cannot be excluded. For example, patients who had an event were more likely to be receiving clopidogrel at baseline in some studies. Thus, a group of clopidogrel nonresponders may have been preselected and overrepresented in some studies. In addition, the scope of the genetic problem is not isolated to patients with 2 deficient alleles (homozygotes). This has important implications because of the higher prevalence of heterozygotes in the population. The data on positive and predictive risk in specific patient populations are incomplete.22 Thus, caution must be observed in drawing definitive conclusions from these observational studies. Table 1. CYP2C19*2 Polymorphisms and Cardiovascular OutcomesSource, Year (Region)Patients, n (Age, Years)DiseaseClopidogrel DosageDuration of Follow-Up (Months)Outcome (n)Frequency of Genotype, n (%)RR (95% CI)Adjustment*1/*1*1/*2*2/*2Reprinted with permission from Sofi et al.20†Calculated from data taken from the original text.‡Only patients who were still taking clopidogrel after 1 year.ACS indicates acute coronary syndromes; AMI, acute myocardial infarction; BMI, body mass index; CAD, coronary artery disease; CI, confidence interval; CV, cardiovascular; LD, loading dose; MD, maintenance dose; MI, myocardial infarction; n.d., no date; RR, risk ratio; and STEMI, ST-segment–elevation myocardial infarction.Trenk et al, 2008 (Germany)21797 (mean: 66.4)CADLD 600 mg12Death and MI (24)552 (69.3)228 (28.6)17 (2.1)0.67 (0.25–1.78)†NoneMD 75 mg day−1Simon et al, 2009 (France)222178 (mean: 70.1)AMILD 300 mg12Death from any cause (225)1561 (71.7)564 (25.9)53 (2.4)0.89 (0.68–1.18)†NoneMD 75 mg day−1Collet et al, 2009 (France)2259 (18–45)MILD n.d.100Death, MI, urgent coronary revascularization (26) Stent thrombosis (12)186 (71.8)73 (28.2)5.38 (2.32–12.47)BMI smoking, diabetes, stent implantation, STEMI, use of proton-pump inhibitorsMD 75 mg day−16.04 (1.75–20.80)Mega et al, 2009 (United States)171459 (mean: 60.1)ACSLD 300 mg15Death from CV causes, MI, stroke (129) Stent thrombosis (18)1064 (72.9)395 (27.1)1.53 (1.07–2.19)NoneMD 75 mg day−13.09 (1.19–8.00)Sibbing et al, 2009 (Germany)42485 (mean: 66.5)CADLD 600 mg1Stent thrombosis (17)1805 (73)633 (25)47 (2)3.81 (1.45–10.02)Age, diabetes, ACS, type of stentMD 75 mg day−1Giusti et al, 2009 (Italy)3772 (mean: 68.3)ACSLD 600 mg6Stent thrombosis + cardiac mortality (29) Stent thrombosis (24)525 (68)221 (28.6)26 (3.4)2.70 (1.00–8.42)Residual platelet reactivity, traditional CV risk factors, clinical and procedural risk factorsMD 75 mg day−13.43 (1.01–12.78)Shuldiner et al, 2009 (United States)1593‡(mean: 65)CADLD 300/600 mg day−112MI, unplanned target and nontarget lesion revascularization, hospitalization, death from CV causes (n not reported)66 (70.9)27 (29.1)3.40 (1.36–8.46)Age, gender, raceMD 75 mg day−1These clinical efficacy datamirror the effect of genetic polymorphisms on platelet function in both heterozygotes as well as homozygotes. Carriers of a CYP2C19*2 allele have been found to have an absolute reduction in platelet aggregation in response to clopidogrel that was 9 percentage points less than that of noncarriers.17 Other studies23 have noted that carriers of at least 1 reduced function CYP2C19 allele have less response to clopidogrel reflected as a higher residual platelet reactivity index. In a genome-wide association study performed in a homogenous population of healthy Amish—PAPI (Pharmacogenomics of Antiplatelet Intervention)—clopidogrel reduced ADP-induced platelet aggregation to 41%, 47%, and 65% of baseline in subjects with 0, 1, and 2 CYP2C19*2 alleles, respectively,15 thereby exhibiting a gene-dose effect. However, even in this relatively homogenous population, CYP2C19*2 genotype accounted for only 12% of the variability in clopidogrel response.15In contrast to clopidogrel, the FDA-approved drug, prasugrel, is oxidized to its active form in a single CYP-dependent step (Figure 1). In 238 healthy subjects tested, there was no significant decrease in the plasma concentrations of active metabolite or platelet inhibition in response to prasugrel in carriers versus noncarriers of at least 1 reduced function allele for the CYP genes tested (2C19, 2C9, 2B6, 3A5, 1A2).16 Similar observations were reported in patients with stable coronary artery disease.23 The association of these genetic variants with cardiovascular outcomes was examined in 1466 patients with ACS allocated prasugrel in TRITON-TIMI 38. No significant associations were found between any of the CYP genes tested and risk of cardiovascular death, MI, or stroke.16 Ticagrelor, which is not yet approved, is a reversible, nonthienopyridine P2Y12 receptor antagonist; it is not a prodrug, and does not require biotransformation.24,25 The effect of genetic polymorphisms in CYP isoenzyme function or number for this drug remains incompletely defined. Other drugs, such as elinogrel (not yet approved), have also been studied.262.1.2. Other Genetic PolymorphismsOther genetic variations may also affect the PK, PD, and clinical efficacy of clopidogrel.272.1.2.1. ABCB1Intestinal absorption is limited by the P-glycoprotein efflux-transporter encoded by the adenosine triphosphate-binding cassette containing gene ABCB1, also known as the multidrug resistant (MDR1) gene. Compared with noncarriers (wild-type or CC genotype), the bioavailability of clopidogrel is significantly reduced among patients receiving a 300- or 600-mg LD before elective PCI who have either 1 (CT genotype) or 2 (TT genotype) copies of the ABCB1 C3435T single nucleotide polymorphism.28 In acute MI patients, the frequency of the variant TT genotype (TT 26%, CC 26%, CT 48%) was significantly higher among the 294 patients with an outcome event (death, nonfatal MI, or stroke at 1 year) compared with the 1914 patients without an event (29% versus 26%, P=0.04). In addition, patients with the TT genotype had significantly higher event rates at 1 year than those with the ABCB1 wild-type (CC) genotype (15.5% versus 10.7%; adjusted HR 1.72; 95% CI 1.20 to 2.47).22 Patients who possessed 2 CYP2C19 loss-of-function alleles and at least 1 ABCB1 variant allele were at the highest risk for a primary outcome event (HR 5.31; 95% CI 2.13 to 13.20) compared with patients who had both CYP2C19 and ABCB1.22 In another study of 2934 ACS patients, TT homozygotes had a 72% increased risk of the composite primary end point (cardiovascular death, MI, or stroke at 15 months) compared with either CC or CT patients (HR 1.72, P=0.002).29 Additional information on the frequency and consequences of combined, functionally important genetic polymorphisms is required.2.1.2.2. Other CYP IsoenzymesThe CYP3A4 and CYP3A5 enzymes also play a role in the conversion of clopidogrel to its active metabolite. In a substudy of healthy volunteers analyzed along with TRITON–TIMI 38, carrier status for a reduced function allele of CYP2C9, 3A5, and 1A2 was not associated with a consistent reduction of the PK or PD responses to clopidogrel. Carriers of a reduced function CYP2B6 allele, however, tended to have a lower plasma exposure to the active metabolite of clopidogrel and tended to have less reduction of platelet aggregation in response to clopidogrel.16,17 One other study reported that subjects with the CYP3A5*3 allele had significantly decreased response to clopidogrel when it was combined with itraconazole, a CYP3A inhibitor, compared with CYP3A5*1 homozygotes.302.1.2.3. P2Y12 ReceptorStudies have also assessed genetic variation in the gene encoding the P2Y12 receptor (the binding site for clopidogrel metabolite). In the FAST-MI (Registry on Acute ST–Elevation Myocardial Infarction) study, no association was found with clopidogrel responsiveness and the genetic polymorphism encoding the P2Y12 receptor.22 Other studies have also yielded similar results.313. Current Status of CYP2C19 Genotyping AssaysGiven the increasing importance of genetic variations, there has been increasing interest in genetic testing to identify optimal strategies of care. This feature is a central component of the new clopidogrel boxed warning. Commercial assays are available from both research and clinical laboratories. Cross validation of the techniques used and their reliability, specificity, and reproducibility are extremely limited. While results of commercial assays can be applied, they are not available in the acute phases of patient care. Point-of-care assays for the common CYP2C19 polymorphisms are not available at this time. In addition, genetic polymorphisms with gain-of-function (CYP2C19*17), and uncommon alleles with reduced function (eg, CYP2C19*3, *4, *5) may affect clinical outcomes. An important patient care issue relates to the cost for these tests (approximately $500), which are typically not reimbursed by major payers. Alternatives to genetic testing focus on the phenotype—specifically, platelet function. Platelet function assays can measure the effect of ADP or P2Y12 activation on platelet aggregation, receptor expression, or the level of intracellular molecules (eg, vasodilator-stimulated phosphoprotein phopsphorylation), thereby directly or indirectly measuring the platelet inhibitory effect of clopidogrel (ie, clopidogrel responsiveness or on-treatment reactivity). Additional clinical studies are underway to test whether altering therapy in response to residual high platelet reactivity after clopidogrel administration is associated with improved clinical outcomes.4. Alternative Dosing Regimens for ClopidogrelEvaluation of the different strategies developed and tested to overcome clopidogrel nonresponsiveness must consider the type of study, patient population, metrics of evaluation, and duration of follow-up. Each of these variables may affect interpretation of these data and the application of a specific therapeutic approach to an individual patient. There are few data on the inhibitory effect of alternative dosing regimens in CYP2C19 intermediate and/or poor metabolizers.Several studies have evaluated the effect of different combinations of clopidogrel LDs and MDs on platelet aggregation, metabolites of clopidogrel, and other measures of platelet function32–41 (Table 2). Some studies were performed specifically in patients with a documented suboptimal response to the usual dosing protocols for clopidogrel.35,36,38 However, there are less data on the effect of alternative dosing regimens in intermediate and/or poor metabolizers and a lack of data supporting a change in therapy based on genotyping alone. In general, a 600-mg LD or double LD (second 600-mg dose 2 hours later) improves the degree of acute platelet inhibition.33,37 Moreover, an MD of 150 mg daily results in a greater degree of platelet inhibition in many studies in patients with a reduced response to the usual 75-mg MD.36–38 However, even at the higher dose, some patients do not reach an optimal level of platelet inhibition ex vivo.35Table 2. Pharmacodynamic Studies of Platelet Responsiveness to Different Clopidogrel Dosing ProtocolsStudyRegimenMetricResultsADP indicates adenosine diphosphate; ALBION, Assessment of the Best Loading Dose of Clopidogrel to Blunt Platelet Activation, Inflammation and Ongoing Necrosis; C, clopidogrel; DM, diabetes mellitus; IPA, inhibition of platelet aggregation; ISAR-CHOICE, Intracoronary Stenting and Antithrombotic Regimen: Choose Between 3 Higher Oral Doses for Immediate Clopidogrel Effect; LD, loading dose; MD, maintenance dose; NSTEMI, non–ST-segment elevation myocardial infarction; OPTIMUS, Optimizing Antiplatelet Therapy in Diabetes Mellitus; PCI, percutaneous coronary intervention; PRINC, Plavix Response in Coronary Intervention; and VASP-02, Vasodilator-Stimulated Phosphoprotein-02 Randomized Study.ISAR-CHOICE33 60 elective PCI patients; C-naïveC, 300, 600, 900 mg LDPlatelet aggregometry, active thiol metabolite of C600 mg dose had highest active drug metabolite level and platelet suppression compared with the 300 mg dose.von Beckerath et al.34 60 patients after successful PCI; 600 mg C loadC, 150 mg daily vs. 75 mg daily (MD)30-d platelet functionC, 150 mg daily had more intense platelet inhibition.OPTIMUS study35 40 patients with type 2 DM and documented suboptimal response to CC, 150 mg daily vs. 75 mg daily (MD)Repeat platelet function testing after 30 d150 mg dose improved rates of platelet inhibition, but 60% of patients still had suboptimal