Clopidogrel, the most commonly used agent for the purpose of secondary prevention, is the only thienopyridine with trial data for triple therapy.17 Clopidogrel’s antiplatelet effect, however, is highly dependent on specific cytochrome P-450 (CYP) enzymes for conversion to its active metabolite, and can be impaired by genetic variations in CYP 2C19, as well as by medication interactions. This has led to concern about the drug’s efficacy for secondary prevention of ACS.6,17,18 In 2010, the US Food and Drug Administration (FDA) added a black-box warning for clopidogrel, emphasizing the risk of myocardial infarction (MI), stroke, and cardiovascular death in patients with defective CYP 2C19 activity.19
Prasugrel, approved by the FDA in 2009,20 is useful for patients who respond poorly to clopidogrel. In fact, inadequate platelet inhibition with clopidogrel has prompted some physicians to choose prasugrel as a component of triple therapy.
While prasugrel may have greater efficacy compared with clopidogrel in preventing reinfarction, it appears to have a higher bleeding rate.15,17 Because of its bleeding profile, prasugrel is not recommended for patients >75 years unless they are at high risk for MI (prior MI or diabetes), and it is contraindicated for patients with a history of stroke. Caution is needed when prasugrel is prescribed for patients who weigh <132 lb (consider a maintenance dose of 5 mg/d rather than the usual 10 mg/d) or have an increased propensity to bleed.15
Warfarin provides the anticoagulant component of triple therapy
Until late last year, when dabigatran received FDA approval for use in stroke prevention,21 warfarin was the only oral anticoagulant available in the United States. (To learn more about dabigatran, which is not included in this review because of the lack of evidence regarding its use in triple therapy, see “Time to try this warfarin alternative?”.)
Because multiple drug, food, and disease state interactions can interfere with warfarin therapy, frequent monitoring to maintain a target international normalized ratio (INR) is required.22,23 (See Patient on warfarin? Steer clear of these drugs, in “Avoiding drug interactions: Here’s help,” J Fam Pract. 2010;59: 322-329).
Bridge therapy. Warfarin requires several days to reach its full effect, so anticoagulation with a more immediate-acting medication, such as a low-molecular-weight heparin or fondaparinux, is often used until the INR goal is reached.22,23 Thus, there are instances in which patients requiring triple therapy are actually receiving 4 drugs that increase bleeding risk.
When (or whether) to consider triple therapy
While triple therapy may be an option for patients with atrial fibrillation and ACS or PCI-S, there is no validated scoring system to aid in treatment decisions.24 As already noted, selecting the optimal therapy requires an individual assessment of the patient’s risk of reinfarction, stent thrombosis, stroke, and bleeding complications.
Risk factors for reinfarction and stent thrombosis are the same ones that increase the risk of ACS initially, and include diabetes mellitus, heart failure, smoking, hyperlipidemia, and hypertension.10,16 Advanced age; uncontrolled hypertension; chronic conditions such as peripheral vascular disease, anemia, and peptic ulcer disease; and a history of major bleeds are associated with an increased risk of bleeding. 24,25
In a retrospective trial evaluating independent predictors of major bleeding in patients with atrial fibrillation who underwent PCI-S,1 the researchers identified several factors that increased the risk of early major bleeding (within 48 hours of stent placement): the use of a glycoprotein IIb/IIIa inhibitor, stenting of ≥3 vessels, or left main artery disease. Factors that significantly increased the risk of major bleeding more than 48 hours after the procedure included triple therapy, an early major bleed, and baseline anemia.1
Drug combinations: What to consider
In addition to determining whether a patient is a good candidate for triple therapy, it is crucial to consider the choice of drugs. Benefits of prasugrel, compared with clopidogrel, include fewer drug interactions, less resistance to platelet inhibition, more rapid platelet inhibition after an oral loading dose, and higher levels of platelet inhibition during maintenance dosing.15,17
Improved outcomes are another potential benefit, according to TRITON-Thrombolysis in Myocardial Infarction (TIMI) 38,17 a large randomized prospective trial comparing the use of prasugrel with clopidogrel in triple therapy. Among study participants, the primary outcome rate—the combined incidence of death from cardiovascular causes, nonfatal MI, and nonfatal stroke—was 9.9% for those on prasugrel vs 12.1% for the clopidogrel group (hazard ratio [HR]=0.81; 95% confidence interval [CI], 0.73-0.90, P<.001).17 The rate of TIMI major bleeding, however, was higher among those on prasugrel (HR=1.32; 95% CI, 1.03-1.68, P=.03). The evidence suggests that for every 1000 patients treated with prasugrel vs clopidogrel, 24 primary outcomes would be prevented but there would be 10 additional bleeding events.17,26