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Drug–drug interactions involving antiplatelet agents

Eric R Bates, Debabrata Mukherjee, Wei C Lau
DOI: http://dx.doi.org/10.1016/S0195-668X(03)00470-6 1707-1709 First published online: 1 October 2003

See doi:10.1016/S1095-668X(03)00442-1 for the article to which this editorial refers

Antiplatelet therapy used to be a simple proposition. ‘An aspirin a day keeps the cardiologist away’ is a modified aphorism that has been true for more than two decades. This is now evidence-based, with the Antithrombotic Trialists’ Collaboration confirming that antiplatelet therapy in patients with atherosclerotic vascular disease reduces non-fatal myocardial infarction by one third, non-fatal stroke by one quarter, and vascular mortality by one sixth.1No other pharmacologic agent can challenge the risk-benefit or cost-benefit ratios of aspirin therapy. Aspirin is mandatory treatment for secondary prevention of cardiovascular events.

However, antiplatelet therapy has become more complex. In recent years, aspirin has been proscribed for the primary prevention of cardiovascular events in low risk patients because of a small risk for gastrointestinal bleeding and hemorrhagic stroke. Additionally, specific cyclooxygenase (COX)-2 inhibitors (coxibs) have become attractive anti-inflammatory drug alternatives to aspirin, a COX-1 inhibitor, because they cause less gastrointestinal bleeding, although they may not be as effective in preventing thrombotic events. Now, aspirin resistance has been described and has been defined either as the failure of aspirin to prevent individuals from clinical thrombotic complications or as the failure to produce an expected response on a laboratory measurement of platelet activation or aggregation.

Potential drug–drug interactions have also been described with aspirin. Aspirin inhibits the synthesis of vasodilating prostaglandins, whereas angiotensin converting enzyme inhibitors (ACEi) increase prostaglandin production by inhibiting the breakdown of bradykinin. Co-administration could reduce the prostaglandin mediated decrease in arterial pressure associated with ACEi and potentiate depression of renal function by decreasing synthesis of renal vasodilatory prostaglandins, resulting in increased sodium and water retention. Although some retrospective analyses have suggested that co-administration of these drugs decreases the mortality benefit associated with ACEi therapy in patients with heart failure or ischaemic heart disease, others have not.

A potential drug–drug interaction between aspirin and ibuprofen has also been noted2and associated with increased mortality risk in one retrospective study.3Ibuprofen seems to inhibit the access of aspirin to the acetylation site in platelet COX-1, antagonizing irreversible platelet inhibition.

Clopidogrel, a thienopyridine, is a platelet ADP receptor inhibitor. Like aspirin, it reduces cardiovascular events4and appears to have added benefit when given with aspirin as dual antiplatelet therapy in patients with acute coronary syndromes or undergoing percutaneous coronary intervention (PCI).5,6Interestingly, clopidogrel was approved for clinical use before dosing studies were published or its mechanism of action was elucidated. As with aspirin, clopidogrel resistance has been described.7We recently demonstrated that clopidogrel, a prodrug, needs to be activated by the hepatic cytochrome P450 (CYP) 3A4 enzyme system and that its platelet aggregation inhibition efficacy could be perturbed by inhibitors, inducers, and substrates of CYP3A4 activity.8,9Specifically, we showed that atorvastatin, another CYP3A4 substrate, competitively inhibits this activation in a dose-dependent manner, whereas pravastatin, which is not metabolized by the liver, did not.9

In this issue of the European Heart Journal, Neubauer and colleagues10offer flow cytometry evidence that atorvastatin interferes with clopidogrel activation by CYP3A4. Their work complements the previous observations made with ex vivo platelet aggregation8and genetically engineered human microsomes9and additionally suggests that simvastatin may also interact with clopidogrel. Small subgroup sample sizes and theinclusion of clopidogrel non-responders and poorresponders make it difficult to further evaluate the dose-response relationship we previously noted.8Nevertheless, it is increasingly obvious that a drug–drug interaction exists and that its impact on clinical events needs to be defined.

There are disturbing reports that suggest this interaction is clinically important. A retrospective review of the CREDO study showed a trend towards greater absolute and relative risk reduction in one year rates of death, myocardial infarction, and stroke when clopidogrel was given to patients taking pravastatin instead of atorvastatin, despite the claim that no interaction was present.11Mueller et al.12demonstrated a higher rate of cardiovascular death in patients taking clopidogrel versus ticlopidine after coronary stenting: importantly, 86% of the patients were on statin therapy and only 9% received GP IIb/IIIa inhibitors. Other studies after PCI have also shown a slight excess of events with clopidogrel compared with ticlopidine, a drug not metabolized byCYP3A4.13

United States cardiologists recently received a letter from Cordis Corporation warning about the risk of subacute stent thrombosis after implantation of the Cypher™ sirolimus-eluting coronary stent. It should be noted that sirolimus is a metabolic substrate for CYP3A4 and that it promotes platelet aggregation.14Any combination of inadequate stent strut apposition, tissue protrusion, residual dissection, or pre-existing thrombus with local sirolimus release and reduced aspirin and/or clopidogrel activity secondary to drug resistance or drug–drug interactions theoretically could increase the risk for subacute stent thrombosis.

So, what should the prudent clinician do? First, we would suggest that the chronic daily antiplatelet aspirin dose should be 75 or 81mg. In the AntithromboticTrialists’ Collaboration, this dose had equal efficacy and lower bleeding complication rates compared with higher doses. A similar observation was made when aspirin was administered in combination with clopidogrel in the CURE trial. Moreover, if there is an interaction between aspirin and ACEi, it should be minimized with a lower aspirin dose. Second, patients at high risk for vascular events should not forego the potential clinical benefit of aspirin prophylaxis by using rofecoxib without aspirin or ibuprofen with aspirin. Rather, acetominophen or other substitutes should be prescribed so that inhibition of the COX-1 enzyme and thromboxane production by aspirin is successfully achieved. Third, higher doses of atorvastatin, and perhaps simvastatin, should not be prescribed for patients taking clopidogrel, particularly patients recovering from an acute coronary syndrome, stent (particularly a drug-eluting stent) implantation, or brachytherapy. Pravastatin or rosuvastatin may be the preferred agent in these patients. Fourth, patients undergoing PCI without platelet GP IIb/IIIa inhibitor therapy should be pretreated with a 600mg loading dose of clopidogrel and given 75mg BID during hospitalization to assure that maximal platelet aggregationinhibition is achieved during the periprocedural period. This dose was as good as GP IIb/IIIa inhibitors in low and medium risk patients undergoing PCI in the ISAR-REACT study.15

No loss of antiinflammatory, anti-atherosclerotic, or anti-thrombotic drug efficacy will result by following these suggestions in treating arthritis, dyslipidemia, or coronary artery disease. Only market shares of drugs that inhibit antiplatelet drug efficacy will be influenced. In fact, better outcomes might be expected because of better antiplatelet therapy. There appears to be a publication bias towards post-hoc analyses of studies attempting to refute the concern about these issues.11,16The burden of proof should not be with those who offer these sentinel reports on potential drug–drug interactions with antiplatelet agents. Rather, the medical community and government regulators should demand that the pharmaceutical industry perform appropriate prospective randomized clinical trials to prove that these biologically plausible drug–drug interactions do not result in increased rates of myocardial infarction, stroke, and death because of compromised antiplatelet therapy.