By Paul A. Gurbel, MD; Udaya S. Tantry, PhD

From concerns about the safety and efficacy of generic clopidogrel formulations to questions about the usefulness of antiplatelet therapy monitoring, 2013 certainly brought a slew of controversies to the world of antiplatelet therapy. In this edition of Platelet Focus, we’re reviewing the major developments of the last year—as well as the debates they incited.

Is Generic Clopidogrel as Good as Plavix?

The use of inexpensive generic clopidogrel has increased significantly; however, in the absence of rigorous studies demonstrating pharmacodynamic and clinical efficacy and safety, some important concerns have been raised regarding generic clopidogrel’s widespread adoption. Per the US Food and Drug Administration’s (FDA’s) Abbreviated New Drug Application process, generic formulations are not required to prove their efficacy and safety through clinical trials. Instead, they are approved based on small studies—for example, one formulation of clopidogrel bisulfate was approved based only on pharmacokinetic measurements in a group of only 24 healthy volunteers who received a single 150 mg clopidogrel dose periodically over 32 hours.¹

Concerns regarding the FDA’s approval process for generic forms of clopidogrel have been raised.² In a recent study involving more than 1,500 ACS patients in Italy, a generic formulation was associated with greater adenosine diphosphate (ADP)–induced platelet aggregation (average difference = 2–11%) and a higher prevalence of high on-treatment platelet reactivity (HPR; 42.4% vs. 25.4%; p < 0.0001), compared to Plavix^®.¹ Most recently, generic clopidogrel resulted in a 3.2-fold increase in 30-day stent thrombosis rate compared to 3-year historic data of Plavix^® (0.38% [4 of 105] vs. 0.12% [17 of 14,432]; p = 0.050).³ Some generic clopidogrel formulations also have been reported to contain methyl chloride, which is known to exhibit genotoxic properties.⁴

However, other studies have demonstrated no significant differences between various generic formulations and Plavix^®, though there are significant limitations with these: only the difference in mean platelet aggregation was reported; measurements of active metabolite generation were lacking; and, in most cases, only one laboratory method was used to assess pharmacodynamic response.^5-8 These observations highlight the concerns associated with widespread transition to the generic clopidogrel and call for more precaution and close monitoring of clopidogrel response while adopting generic clopidogrel.

Is Antiplatelet Therapy Monitoring Still Useful?

Evidence of a strong association between ADP-related HPR (determined by platelet function assays) and post-PCI ischemic events recently prompted American and European guidelines associations to issue a Class IIb recommendation for platelet function testing (PFT) to facilitate the choice of P2Y₁₂ inhibitor in high-risk patients undergoing PCI.⁹ Prospective randomized trials (GRAVITAS, TRIGGER-PCI, and ARCTIC) that evaluated the utility of personalized antiplatelet therapy; however, failed to demonstrate any clinical benefit of PFT, questioning whether treatment modification based on the results of PFT actually influences outcomes.^10,11 It should be noted that these randomized trials were had several limitations—such as enrollment of low-risk patients (resulting in low event rates and underpowering) and the use of high-dose clopidogrel (a suboptimal strategy to overcome HPR). Therefore, the results of these randomized trials were not sufficient to refute the utility of personalized antiplatelet therapy in PCI patients.¹²

The recently published multinational prospective registry, ADAPT-DES, platelet reactivity was assessed with the VerifyNow^® P2Y₁₂ Test (Accumetrics; San Diego, California) in 8,583 patients (52% ACS patients) who underwent successful PCI. Results from the analysis reinforced the independent association between HPR (>208 PRU) and definite/probable stent thrombosis (ST) at 30 days (HR = 3.0; p = 0.005), 1 year (HR = 2.49; p = 0.001), and 2 years (HR = 1.84; p = 0.009). In addition, >208 PRU was independently associated with a lesser incidence of bleeding at 1 year (HR = 0.73; p = 0.002) and 2 years (HR = 0.82; p = 0.02).13

TABLE 1: Platelet Reactivity Cutoff Associated with Ischemic and Bleeding Events (Therapeutic Window)   Cutoff for Ischemic Event Occurrences Cutoff for Bleeding Event Occurrences VerifyNow PRU Assay >208 PRU <85 PRU Multiplate Analyzer (ADP-induced aggregation) >46 <19 Thrombelastpgraphy Platelet Mapping Assay (ADP-induced platelet-fibrin clot strength [mm]) >47 <31 Platelet Reactivity Index (VASP-PRI) >47 <16%

Similarly, an association between low on-treatment platelet reactivity to ADP and greater bleeding risk has been demonstrated in recent studies.¹² A consensus document highlighting the above observations, along with a concept for therapeutic window with updated cutoffs for HPR and low platelet reactivity for P2Y₁₂ inhibitor therapy, has recently been published (TABLE 1).

In the future, studies will likely demonstrate noninferiority, rather than superiority, from the selective use of generic clopidogrel and the new P2Y₁₂ inhibitors, given the concerns of continuing a patient on clopidogrel therapy who has HPR. However, the low event rates observed in current practice would require enrollment of a very large number of patients for adequate power. Moreover, the prospect of finding funding for this type of endeavor is not promising.

P2Y₁₂ Receptor Blocker Therapy in Patients with STEMI An accumulating body of data suggests that drug absorption in ACS patients is impaired, particularly in patients with STEMI. This is likely due to an impaired bioavailability of clopidogrel in STEMI patients, resulting in suboptimal platelet inhibition.¹⁴ In a recent prospective, single-blind study, 55 STEMI patients undergoing PCI were randomized to either ticagrelor or prasugrel and serial PFT was performed.¹⁵ Although platelet reactivity measured by VerifyNow was as high as that from previous studies conducted in stable, non-PCI patients at 1 hour, it did not differ significantly between ticagrelor and prasugrel therapy.

However, HPR at 2 hours persisted in a significant percentage of patients in both groups; again, this differs from the findings in stable, non-PCI patients where the frequency of high on-treatment platelet reactivity was negligible.¹⁵ In another study of 50 patients with STEMI undergoing primary PCI on bivalirudin monotherapy, patients were randomly treated with 60 mg prasugrel loading dose or 180 mg ticagrelor loading dose. Both prasugrel and ticagrelor therapy were only effective in inhibiting platelet reactivity in ~50% of patients at 2 hours, and at least 4 hours were required to achieve effective platelet inhibition in ~80% of patients. Interestingly, morphine use was associated with a delayed activity of both agents.¹⁶ In a subsequent study, 24 healthy volunteers were randomly treated with placebo or 5 mg intravenous morphine in addition to 600 mg clopidogrel; here, morphine use was associated with delayed clopidogrel absorption and reduced clopidogrel active metabolite levels and maximum platelet inhibition (up to 4 hours).¹⁷ While these findings are very provocative for STEMI patients, future larger studies are needed to confirm these results and their clinical relevance.

Smoker’s Paradox: Fact or Fiction?

Numerous large-scale randomized trials have unequivocally demonstrated significant risk reduction in ischemic event occurrence with clopidogrel therapy in patients with coronary artery disease (CAD).¹⁸ However, a recent analysis of the same trials demonstrated a comparative lack or absence of clinical benefit of clopidogrel therapy in nonsmoking patients—the so-called “smokers’ paradox.”¹⁸

In support of the latter observation, smokers with stable CAD in the PARADOX study had significantly lower on-treatment, ADP-related platelet reactivity, which was associated with a significantly higher exposure to clopidogrel active metabolite, than nonsmokers.¹⁹ Recent analyses of three large-scale trials evaluating the efficacy of newer, more potent oral P2Y₁₂ inhibitors (prasugrel and ticagrelor) in patients with ACS have also suggested another potential explanation for the smokers’ paradox, beyond enhanced clopidogrel pharmacokinetic and pharmacoynamic efficacy in smokers (TABLE 2).^20-22

The greater treatment effect associated with more potent platelet inhibitors in smokers than nonsmokers does not appear to be readily explained by an enhanced overall thrombotic risk in smokers. Perhaps, as some research has suggested, smoking may create a vascular disease state that is more responsive to P2Y₁₂ inhibition,²³ but the explanation is still unclear. Identifying differences in the pathophysiology of thrombotic event occurrence in smokers versus nonsmokers may facilitate future strategies to personalize antithrombotic therapy.

TABLE 2: Influence of Smoking Status on Clinical Outcome in Patients Treated with Clopidogrel or New Oral P2Y12 Inhibitors.   Treatment Primary Endpoint Nonsmokers Smokers p Value TRITON- TIMI 38 Clopidogrel vs. prasugrel in ACS patients undergoing PCI CV death, MI, or stroke 0.84 (0.74-0.96) 0.76 (0.64-0.91) 0.39   Ex- or non-smokers Habitual smokers PLATO Clopidogrel vs. ticagrelor in ACS patients Vascular death, MI, or stroke 0.89 (0.79-1.00) 0.83 (0.68-1.00) 0.50   Not current smokers Current smokers TRILOGY ACS Clopidogrel vs. prasugrel in ACS patients managed medically CV death, MI, or stroke 1.06 (0.90-1.25) 0.54 (0.39-0.74) 0.0002

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References

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9. Trenk D, et al. J Am Coll Cardiol. 2012;59:2159–64.
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14. Alexopoulos D, et al. Circ Cardiovasc Interv. 2012;5:797-804.
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16. Hobl EL, et al. J Am Coll Cardiol. 2013 November 21. [Epub ahead of print]
17. Gurbel PA, et al. JAMA. 2012;307:2495-6.
18. Gurbel PA, et al. J Am Coll Cardiol. 2013; 62:505-12.
19. Hochholzer W, et al. Am Heart J. 2011;162:518-26.e5.
20. Cornel JH, et al. Am Heart J. 2012;164:334-342.e1.
21. Cornel JH, et al. J Am Coll Cardiol. 2013;61(Suppl_10):A39.
22. Gurbel PA, et al. Thromb Haemost. 2013 (in press).

Keywords: Coronary Artery Disease, Platelet Aggregation Inhibitors, Platelet Function Tests, Methyl Chloride, Risk Reduction Behavior, Ticlopidine, Piperazines, Single-Blind Method, Morphine, Hirudins, Smoking, Stents, Registries, United States Food and Drug Administration, Thrombosis, Platelet Aggregation, Peptide Fragments

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