|Year : 2009 | Volume
| Issue : 3 | Page : 110-120
Awad Alqahtani, Abdulrahman Alnabti
M.D, Department of Cardiology and Cardiothoracic Surgery, Hamad Medical Corporation, Doha, Qatar
|Date of Web Publication||17-Jun-2010|
M.D., Department of Cardiology and Cardiothoracic Surgery, Hamad Medical Corporation, P.O. Box 3050, Doha
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Antiplatelet therapy is a cornerstone in cardiovascular medicine. Aspirin and clopidogrel have emerged as critical therapies in the treatment of cardiovascular disease. Despite their efficacy, patients on these medications continue to suffer complications. Millions of patients are currently on low-dose antiplatelet therapy but it is unknown how many of these patients are under-treated or on the wrong medication.
Clopidogrel hypo responsiveness or "resistance" is an emerging clinical entity with potentially severe consequences such as recurrent myocardial infarction, stroke, or death. The mechanism of resistance remains ill-defined, but there are specific clinical, cellular, and genetic factors that influence therapeutic failure. These factors range from physicians who fail to prescribe these medications despite appropriate indications to polymorphisms of platelet membrane glycoproteins. Rapid and accurate diagnosis of antiplatelet resistance also remains an issue as new bedside tests are developed. By understanding the mechanism of therapeutic failure and by improving the diagnosis of this clinical entity, a new era of individualized antiplatelet therapy may arise with routine measurements of platelet activity in the same way that cholesterol, blood pressure, and blood sugar are followed, thus improving the care for millions of people.
This review article focuses on the mechanism of clopidogrel actions, available tools and mechanisms to assess and explain its responsiveness in addition to future management options.
Keywords: clopidogrel, clopidogrel resistance,clopidogrel hyporesponsiveness
|How to cite this article:|
Alqahtani A, Alnabti A. Clopidogrel hyporesponsiveness. Heart Views 2009;10:110-20
| Introduction|| |
Platelets normally circulate in a resting form. In response to a vascular injury, e.g, rupture of an atherosclerotic plaque in a coronary artery, platelet activation and aggregation play an important role in the pathogenesis of arterial thrombosis leading to acute coronary syndromes (ACS) and in thrombotic complications during and after percutaneous coronary interventions (PCI) , . The goal of antiplatelet therapy is to prevent or treat this platelet-dependent thrombus. This article reviews a clinically important category of antiplatelet drugs: the P2Y 12 antagonists [Table 1].
| ADP Receptors and Mechanism of Action of Clopidogrel|| |
Adenosine diphosphate (ADP), an important platelet agonist in vivo, has 2 types of receptors in the platelet plasma membrane: P2Y 1 and P2Y 12  . P2Y1 is a 7-transmembrane receptor linked to a Gq protein [Figure 1]A. The end result of ADP signalling through its P2Y 1 receptor is calcium mobilization, platelet shape change, and rapidly reversible platelet aggregation. P2Y 12 is also a 7-transmembrane domain receptor, but it is linked to a G-inhibitory protein [Figure 1]. The end result of ADP signalling through its P2Y 12 receptor is amplification of stable platelet aggregation and secretion.
| Currently-Approved P2Y 12 Antagonists|| |
Currently, the FDA has approved two P2Y 12 antagonists: ticlopidine and clopidogrel, which are thienopyridines [Table 1]. They are metabolized through cytochrome P450 in the liver. The thienopyridine metabolites [Figure 2], not the parent ticlopidine or clopidogrel molecules, irreversibly antagonize the P2Y 12 receptor [Figure 1],[Table 1]. Ticlopidine, the first FDA-approved P2Y 12 antagonist, is given orally twice a day. However, in Canada and most other countries, ticlopidine has been largely replaced in clinical practice by clopidogrel, which can be given orally in a more convenient daily dose. Clopidgrel has a better side-effect profile. For example, neutropenia is less and the incidence of thrombotic thrombocytopenic purpura is lower  .
Clopidogrel selectively and irreversibly inhibits the P2Y 12 receptor  . Clopidogrel is an inactive pro-drug that requires oxidation by the hepatic cytochrome P450 (CYP) system to generate an active metabolite. However, > 85% of the prodrug is hydrolyzed by esterases in the blood to an inactive carboxylic acid derivative, and only 15% of the pro-drug is metabolized by the CYP system in the liver to generate an active metabolite. In particular, the thiophene ring of clopidogrel is oxidized to form an intermediate metabolite (2-oxo-clopidogrel), which is further oxidized, resulting in the opening of the thiophene ring and the formation of a carboxyl and thiol group. The reactive thiol group of the active metabolite of clopidogrel forms a disulfide bridge between one or more cysteine residues of the P2Y 12 receptor, resulting in its irreversible blockade for the life span of the platelet. Thus, P2Y 12 receptor blockade acts early in the cascade of events leading to the formation of the platelet thrombus and effectively inhibits platelet aggregation. In fact, platelet P2Y 12 blockade prevents platelet degranulation and the release reaction, which elaborates prothrombotic and inflammatory mediators from the platelet, and also inhibits the transformation of the GP IIb/IIIa receptor to the form that binds fibrinogen and links platelets [Figure 1].
Large multicenter randomized controlled trials have demonstrated the benefits of clopidogrel. The CURE (Clopidogrel in Unstable angina to prevent Recurrent Events) trial was performed in 12,562 patients with acute coronary syndrome, unstable angina, or non-ST elevation myocardial infarction  . These patients were randomized to either a clopidogrel loading dose of 300mg or placebo followed by clopidogrel 75mg daily plus aspirin 75 to 325mg daily or placebo plus aspirin 75 to 325mg daily. Patients were followed for twelve months, with a primary end point of myocardial infarction, stroke, and cardiovascular death. The study found a relative risk reduction (RRR) of 20% in the clopidogrel-treated group (P < 0.001). The PCI-CURE (Percutaneous Coronary Intervention CURE) study was a continuation of the CURE study  . 2658 patients who went on to PCI received open-label thienopyridine and were randomized to either clopidogrel plus aspirin or placebo plus aspirin thirty days post-PCI and then followed for twelve months. Based on a composite end point of cardiovascular death or myocardial infarction from randomization to the end of follow-up in PCI-CURE, patients treated with clopidogrel had a 31% RRR compared with patients treated with placebo (P < 0.002).
The CREDO (Clopidogrel for the Reduction of Events During Observation) trial confirmed the beneficial effect of clopidogrel in post-PCI patients  . Subsequently, the COMMIT (ClOpidogrel and Metoprolol in Myocardial Infarction Trial) and CLARITY-TIMI 28 (CLopidogrel as Adjunctive ReperfusIon TherapY-Thrombolysis In Myocardial Infarction 28) trials demonstrated the benefit of clopidogrel and aspirin in patients with ST-elevation myocardial infarction , . However, in patients with stable cardiovascular disease or asymptomatic patients with multiple cardiovascular risk factors, the CHARISMA (Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance) trial reported that the combination of clopidogrel plus aspirin was not significantly more effective than aspirin alone in reducing the rate of myocardial infarction, stroke, or death from cardiovascular causes  . Furthermore, the risk of moderate-to severe bleeding was increased  . In a retrospective analysis of the CHARISMA trial, dual antiplatelet therapy with clopidogrel and aspirin in the primary prevention subgroup of patients was associated with an increase in cardiovascular death  . The cause of this apparent harm has not been elucidated".The trials are summarized in [Table 2].
| Definition of Clopidogrel Responsiveness|| |
Standardized definitions to define characterize individual responsiveness to clopidogrel are still lacking. This is due not only to the numerous assays currently available to assess clopidogrel induced antiplatelet effects but also to the methodological variability within each technique. Light transmittance aggregometry (LTA) has been most extensively evaluated to define clopidogrel responsiveness, and several definitions of clopidogrel responsiveness have been used. Earlier studies have defined clopidogrel responsiveness according to the absolute differences between pre- and posttreatment platelet reactivity  .
Other studies have defined clopidogrel responsiveness according to the degree of inhibition of platelet aggregation or IPA, defined as the percent decrease in aggregation values obtained at baseline and after treatment  . These studies have shown clopidogrel induced antiplatelet effect to be highly variable and that a considerable number of patients may have poor or no antiplatelet effects. Using an arbitrary cut off value of < 10% with the respective definitions, these ex-vivo platelet function studies have thus led to the identification of individuals with poor antiplatelet effects as "clopidogrel resistant" or "nonresponders." Subsequent investigations, however, have empirically used different doses of agonists, different cut off values, and different assays to describe clopidogrel induced antiplatelet effects resulting in a highly variable reported prevalence of poor clopidogrel responders , .
Use of different nomenclature to describe individuals with ineffective clopidogrel platelet inhibition such as "low responder," "hyporesponder," "semi-responder," "suboptimal responder" among others and in addition to the ones described in the preceding text, has also further compounded the confusion on this topic. Increasing knowledge on the clinical impact of inter-individual variability of clopidogrel-induced antiplatelet effects has allowed progress in our current understanding of clopidogrel responsiveness. In fact, previous descriptions of clopidogrel response, which imply knowledge of baseline platelet function for its assessment, overestimate ischemic risk compared with post-treatment values of platelet reactivity  .
Given the better prognostic implications of posttreatment platelet reactivity, current investigations now aim to establish therapeutic thresholds to characterize optimal P2Y 12 inhibition in clopidogrel treated patients. Use of post-treatment platelet reactivity values as a measure of effectiveness of clopidogrel effects is in line with how other biological variables and their response to treatment are quantified. Accordingly, as per other biological processes, clopidogrel responsiveness should not be considered in a dichotomous way  , but as a continuous and variable parameter.
| Mechanisms leading to Clopidogrel response variability|| |
The possible mechanisms of clopidogrel response variability or "resistance" are shown in [Figure 2]. Noncompliance is an important issue. If a patient is not taking clopidogrel or only taking it intermittently, the patient will appear by platelet function testing to be hyporesponsive or "resistant" to clopidogrel. In addition to clopidogrel, many other drugs are metabolized through cytochrome P450 in the liverand therefore may interfere with the effectiveness of clopidogrel. One reported example of this phenomenon is atorvastatin  but large clinical studies have not confirmed that this is a clinically-relevant interaction , . Single nucleotide polymorphisms (SNPs), e.g., the IVS10+12G>A SNP of the CYP3A4 gene, may modulate platelet activation in patients treated with clopidogrel and therefore contribute to clopidogrel response variability  .
There are, however, two relevant questions concerning clopidogrel response variability or "resistance": (1) Is treatment failure unrelated to a lack of clopidogrel effectiveness (because arterial thrombosis is multifactorial and not solely dependent on P2Y 12 -dependent signaling) or (2) platelet response variability? With regard to the latter possibility, there is evidence in both normal subjects and patients that preclopidogrel response to ADP predicts postclopidogrel response to ADP, as determined by a number of different platelet function assays (turbidometric platelet aggregation, platelet surface P-selectin, platelet surface activated integrin α-IIb β-3, monocyte-platelet aggregates, neutrophil-platelet aggregates) ,,,, .These data suggest that the variability lies, at least in part, within the platelet response to ADP rather than the platelet response to clopidogrel.
| How should a patient with clopidogrel hypo-responsiveness or 'resistance' be managed?|| |
Variability in clopidogrel-induced antiplatelet effects has become an emerging clinical entity with potentially severe consequences  . Therefore, it becomes imperative to question how a clinician can effectively manage this phenomenon. Unfortunately, not only the definition but also how to treat these patients remains undefined. An initial approach would be to correct the clinical factors that may be leading to poor responsiveness. Importantly, physicians must ensure proper patient compliance.
Interference by other drugs metabolized via cytochrome P450 may be a consideration. One hot topic which has gained attention and debate recently is the concomitant use of Clopidogrel and proton-pump inhibitors (PPIs). PPIs attenuate the benefits of antiplatelet therapy and increase the risk of future events. Among discharged acute coronary syndrome (ACS) patients prescribed the two drugs, there was an increased risk of adverse clinical outcomes compared with clopidogrel alone, including higher rates of death or rehospitalization for ACS. A study by David Juurlink and colleagues drew attention to the potential interactions between clopidogrel and proton pump inhibitors. The study examined only the effect of baseline omeprazole use and found that patients receiving clopidogrel in combination with omeprazole had a higher rate of death, myocardial infarction or urgent revascularization at twenty eight days than patients receiving clopidogrel alone (10.3% and 5.4%, respectively; p = 0.051). However, a number of important issues limit the general applicability of the study to clinical practice. Results from a case-control study do not seem to warrant statements regarding causation and they failed to mention the lack of association between proton pump inhibitors and major cardiovascular events in this study  .
A large and recent randomized trial of 3,627 patients, the (Clopidogrel and the Optimization of Gastrointestinal EveNTs) COGENT trial, indicated that the concomitant use of clopidogrel with omeprazole is not associated with an increase in adverse cardiovascular events, as has been suggested by ex-vivo platelet assays and observational studies. Based on the (COGENT) study and the TRITON-TIMI 38 analysis, clopidogrel-PPI interaction should currently be considered a nonissue for clinical practice. The evidence for a clinically important effect is not strong , .
Since there are no published studies addressing the clinical effectiveness of altering therapy based on a laboratory finding of clopidogrel resistance, the correct treatment, if any, of clopidogrel hypo-responsiveness or "resistance" remains unknown  . Nevertheless, the current American College of Cardiology/American Heart Association PCI guidelines have a Class IIb recommendation based on level C evidence that, in patients in whom subacute stent thrombosis may be catastrophic or lethal, platelet aggregation studies may be considered and the maintenance dose of clopidogrel increased from 75mg to 150mg per day if less than 50% inhibition of platelet aggregation is demonstrated  . Although there are as yet no published clinical outcome studies to support this approach, a 150mg daily maintenance dose of clopidogrel has recently been shown to provide more effective platelet inhibition (as determined by ADP-induced turbidometric platelet aggregation, the Verify Now P2Y 12 Assay, and VASP phosphorylation) than the current standard maintenance dose of 75mg daily , . However, even at the higher maintenance dose of 150mg daily there is still large variability in the degree of platelet inhibition , and the possible increased hemorrhagic risks of this approach have not been studied.
In the PCI setting, a loading dose of 600mg of clopidogrel, rather than the previous standard loading dose of 300mg, has been widely adopted based on small studies showing more rapid and profound inhibition of ADP induced turbidometric platelet aggregation, reduced myonecrosis markers, and reduced MACE at thirtydays ,, .. An increase in the clopidogrel loading dose from 600mg to 900mg may  or may not 32 result in an additional significant increase in inhibition of platelet function. However, even at these higher clopidogrel loading doses of 600mg and 900mg, there is still large variability in the degree of platelet inhibition ,,, .
The CURRENT/OASIS 7 (Clopidogrel optimal loading dose Usage to Reduce Recurrent EveNTs/Optimal Antiplatelet Strategy for InterventionS 7) trial, which was presented in European Society of Cardiology( ESC) 2009 randomized 25,087 unstable angina or acute MI patients who were scheduled to undergo angiography within 72 hours of hospital arrival to a high dose regimen (600mg loading dose of clopidogrel, followed by 150mg per day for seven days) or the standard regimen (300mg on the first day followed by 75mg/day). At thirty days, the primary endpoint, the combined rate of cardiovascular death, MI, and stroke occurred in 4.4% of patients on the standard-dose Plavix compared to 4.2% of patients on the high dose. The difference did not achieve statistical significance. A little more than two-thirds of the study patients underwent PCI. Among the PCI patients, the risk of stent thrombosis was reduced by 30% and the risk of MI was reduced by 22% in the group that received the high dose group compared to the group that received the standard dose. The high dose group had more major bleeding, but there was no increase in intracerebral or fatal bleeds. No benefit of the higher dose was found in the group of patients who did not have PCI. In a second randomization, patients received either highdose (300-325mg once daily) or low-dose (75-100mg once daily) aspirin. There were no significant differences in outcome between these two groups. This study concluded that the combination of high-dose clopidogrel combined with usual doses of aspirin may be the optimal treatment strategy in PCI patients.
Recently, it was shown that the administration of a 600mg loading dose in patients already on chronic clopidogrel therapy results in an additional significant increase in inhibition of ADP-induced platelet aggregation, suggesting that the current recommended maintenance dose of clopidogrel may be insufficient in producing optimal platelet inhibition  . The currently used maintenance dose for chronic clopidogrel therapy (75mg/day) was chosen because a degree of platelet inhibition is reached similar to that achieved with ticlopidine 250mg twice daily  . Therefore, it has been suggested that increasing the maintenance dose to 150mg/day may improve individual responsiveness to clopidogrel in selected patient populations.
The ISAR CHOICE-2 (Intracoronary Stenting and Antithrombotic Regimen: Choose a High Oral maintenance dose for Intensified Clopidogrel Effect) showed that in an unselected cohort of patients, a 150mg maintenance dose resulted in enhanced platelet inhibition compared with a standard 75mg maintenance dose regimen 1 month after undergoing low-risk PCI  . The OPTIMUS (Optimizing anti-Platelet Therapy In diabetes MellitUS) study selectively studied diabetes mellitus patients with high posttreatment platelet reactivity while in their chronic phase of treatment . In these patients, although a 150mg clopidogrel maintenance dose resulted in marked platelet inhibition of numerous platelet function measures compared with a 75mg dose, a considerable number of patients still remained above the therapeutic threshold of posttreatment platelet reactivity used in this study, suggesting the need for more potent P2Y 12 inhibitors or alternative antithombotic regimens in these high-risk patients.
| Future directions|| |
The current therapeutic alternative for treatment of patients with poor clopidogrel response remains limited. Novel P2Y 12 receptor antagonists with more potent antiplatelet effects are currently under clinical investigation'. These novel molecules are all characterized by more potent antiplatelet effects, reduced interindividual response variability, and therefore less likely to lead to resistance. The P2Y 12 receptor antagonists under clinical investigation include prasugrel, AZD6140, and cangrelor [Table 3].
Prasugrel is an investigational orallyadministered thienopyridine pro-drug that, like clopidogrel, is metabolized via cytochrome P450 in the liver , . The active metabolite of prasugrel irreversibly inhibits the platelet P2Y 12 receptor to a similar extent to the active metabolite of clopidogrel  . However, there is much more efficient in vivo generation of the active metabolite of prasugrel than of the active metabolite of clopidogrel  . As a result, a prasugrel 60mg loading dose results in a much more rapid, potent, and consistent inhibition of platelet function than the standard clopidogrel loading dose of 300mg , and the more recently adopted clopidogrel loading dose of 600mg  . Furthermore, a maintenance dose of prasugrel 10mg daily results in a more potent and consistent inhibition of platelet function than the standard clopidogrel maintenance dose of 75mg daily  .
Animal studies have shown that prasugrel has a much more potent antithrombotic effect than clopidogre  and phase II studies of prasugrel in humans showed no significant increase in bleeding compared with clopidogrel  . The 13,608-patient phase III trial, TRITON-TIMI 38 (TRial to assess Improvement in Therapeutic Outcomes by optimizing platelet inhibitioN with prasugrel), was recently completed  . This trial demonstrated that in patients with acute coronary syndromes with scheduled PCI, prasugrel (60mg loading dose and a 10mg daily maintenance dose), as compared with approved doses of clopidogrel (300mg loading dose and a 75mg daily maintenance dose), was associated with significantly reduced rates of ischemic events, including stent thrombosis, but with an increased risk of major bleeding, including fatal bleeding. The primary efficacy end point occurred in 12.1% of patients receiving clopidogrel and 9.9% of patients receiving prasugrel (hazard ratio for prasugrel versus clopidogrel, 0.81;95% confidence interval [CI], 0.73 to 0.90; P < 0.001). There were also significant reductions in the prasugrel group in the rates of myocardial infarction (9.7% for clopidogrel versus 7.4% for prasugrel; P < 0.001), urgent target-vessel revascularization (3.7% versus 2.5%; P < 0.001), and stent thrombosis (2.4% versus 1.1%; P < 0.001). Major bleeding was observed in 2.4% of patients receiving prasugrel and in 1.8% of patients receiving clopidogrel (hazard ratio, 1.32; 95% CI, 1.03 to 1.68; P < 0.03). Also greater in the prasugrel group was the rate of life threatening bleeding (1.4% versus 0.9%; P < 0.01), including nonfatal bleeding (1.1% versus 0.9%; hazard ratio, 1.25; P < 0.23) and fatal bleeding (0.4% versus 0.1%; P < 0.002). A post hoc subgroup exploratory analysis of the data identified 3 subgroups of interest that had less clinical efficacy and greater absolute levels of bleeding than the overall cohort, resulting in less net clinical benefit or in clinical harm. These subgroups were: patients with a history of stroke or transient ischemic attack, age older than or equal to 75 years, and body weight < 60 kg(44).
The PRINCIPLE-TIMI 44 trial demonstrated that, among patients undergoing cardiac catheterization with planned PCI, a 60mg prasugrel loading dose resulted in greater platelet inhibition than the now widely used higher clopidogrel loading dose of 600mg  . Maintenance therapy with prasugrel 10mg daily resulted in a greater antiplatelet effect than the high clopidogrel maintenance dose of 150mg daily. This trial was not powered for clinical outcomes  . Prasugrel has been recently approved in Europe and has received the endorsement of the FDA Advisory Panel and is likely to see widespread use in patients with STEMI and non-STEMI in the near future. A major concern with prasugrel is increased bleeding. Further studies are needed to define the optimal patient subgroups with STEMI who would benefit from use of prasugrel.
AZD6140 (AstraZeneca) is another investigational P2Y 12 antagonist [Table 2]. To increase oral bioavailability, the structure of AZD6140 was modified from AR-C109318XX46. Unlike ticlopidine, clopidogrel, and prasugrel, AZD6140 is (1) not a thienopyridine but an ATP analog , (2) a direct P2Y12 antagonist (i.e., no metabolism of a prodrug is required), and (3) a reversible P2Y12 antagonist  . Like prasugrel, AZD6140: (1) results in a more rapid onset of action and greater degree of platelet inhibition than clopidogrel, (2) maintenance therapy results in more potent inhibition of platelet function than the standard clopidogrel maintenance dose of 75mg daily, (3) showed no significant increase in bleeding compared with clopidogrel in phase II studies ,, . In these phase II studies, dyspnea was greater, in patients on AZD6140 compared with patients on clopidogrel. Dyspnea apparently occurred in a dose-dependent manner. AZD6140 is given orally twice a day and is currently in a phase III trial: PLATO (PLATelet inhibition and patient Outcomes).
Cangrelor (The Medicines Company) is an investigational, direct-acting, reversible P2Y 12 antagonist. Unlike the above-described orallyadministered P2Y 12 antagonists (ticlopidine, clopidogrel, prasugrel, and AZD6140), cangrelor is administered intravenously, which, together with the rapid reversal of its effects after the end of the infusion, may be potentially advantageous in the PCI setting. Like prasugrel and AZD6140, cangrelor results in a more rapid onset of action and greater degree of platelet inhibition than clopidogrel, and showed no significant increase in bleeding compared with clopidogrel in phase II studies , . Cangrelor is currently in phase III trials: CHAMPION-PCI and CHAMPIONPLATFORM.
PRT060128 (Portola) is an investigational, direct-acting, reversible P2Y 12 antagonist with a novel structure  . PRT060128, which can potentially be administered orally or intravenously, has completed phase I clinical studies.
| Conclusions|| |
The P2Y 12 antagonist clopidogrel has a wellestablished role as an antithrombotic agent in the settings of PCI and acute coronary syndromes. However, several challenges remain, including the relatively slow onset of action of clopidogrel. Current available data show that about 4% to 30% of patients treated with conventional doses of clopidogrel do not display adequate antiplatelet response. Clopidogrel resistance is a term widely used but not clearly defined. So far, it has been used to reflect failure of clopidogrel to achieve its platelet inhibition effect.
The terms of clopidogrel resistance, nonresponse, and low response to clopidogrel are used synonymously, which may confuse readers. The response to clopidogrel has been mostly evaluated by platelet function tests, these terms can be considered as interchangeable as they reflect failure of clopidogrel to achieve its expected antiplatelet effect.
NovelP2Y 12 antagonists, including prasugrel, AZD6140, and cangrelor have a faster onset of action, as well as more potent, and less variable, inhibition of platelet function ex vivo. Whether this promise will be translated into clinical benefit for patients will be determined by the results of phase III clinical trials.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3]