CASE Anthony D’s risk for stroke, infarction, and stent thrombosis—based on his history of diabetes and hypertension, atrial fibrillation, and PCI-S—and absence of independent bleeding risk factors make him a good candidate for triple therapy. Because the patient is at high risk, the physician starts him on 2 anticoagulants—warfarin (5 mg at bedtime) and enoxaparin (125 mg every 12 hours)—on the evening of his second day in the hospital. On Day 3, clinicians test Anthony’s prothrombin time/international normalized ratio (PT/INR) and P2Y12 function assay, which measure 14.9/1.1 and 8% platelet inhibition, respectively.
The patient is discharged on the following medication schedule: enoxaparin 125 mg every 12 hours, to be discontinued after 3 days; warfarin 5 mg daily, prasugrel 10 mg daily, and aspirin 81 mg daily; metoprolol succinate 100 mg daily; lisinopril 10 mg daily; rosuvastatin 10 mg daily; glyburide-metformin 5 mg/500 mg, 2 tablets twice daily; and insulin glargine 20 units at bedtime.
Safety and efficacy: Do the benefits outweigh the risk?
Safety is central to the continuing controversy surrounding the use of triple therapy.6,9 To date, however, no randomized prospective studies have evaluated its benefits and risks.
Numerous retrospective studies and case series have assessed the risk of bleeding associated with triple therapy.6 Several studies compared triple therapy with dual antiplatelet therapy without anticoagulation, and found a several-fold increase in both major and minor bleeding events in the triple therapy group.6
Few trials have assessed both the safety and the efficacy of triple therapy, however. One exception is a large retrospective trial, published in 2008.2 The researchers found that triple therapy significantly reduced the incidence of major cardiac events (death, acute MI, and target lesion revascularization); all-cause mortality; and major adverse effects (ie, any major cardiovascular event, major bleeding complication, and/or stroke), with no statistically significant increase in major bleeding events compared with patients on antiplatelet therapy without anticoagulation.2
The results of this trial, like those of other studies evaluating triple therapy, were weakened by variance in both the duration of antithrombotic therapy and the drug therapies studied. This limitation was off set, however, by multivariant analysis and well-documented follow-up.2 Despite the researchers’ findings, however, the results of other trials (and our knowledge of the mechanisms of action of the drug components) suggest that triple therapy significantly increases bleeding risk. For patients who would likely benefit from it but face an increased bleeding risk, there are ways to mitigate risk.
Prescribing triple therapy, while mitigating the risks
If bleeding is a serious concern in a patient who would benefit from triple therapy, the drug regimen may be adjusted. Options include:
- targeting a lower INR (2.0-2.5 vs the standard 2.0-3.0).6 While various trials have found a 2.0 to 3.0 range to reduce the risk of stroke, none has compared it with a lower range to evaluate reduction in bleeding risk.27 One potential benefit of trying to maintain a lower INR is the decrease in deviations into the 3.0 to 4.0 range, which is associated with an increased bleeding risk.28 However, lowering the INR target is not supported by any literature.1,18
- using low-dose aspirin therapy after PCI-S
- limiting the thienopyridine component of triple therapy to one month after ACS or PCI-S.6
When the risks of triple therapy outweigh the benefits because of an exceedingly high bleeding risk, single antiplatelet therapy with warfarin is another option to consider.
CASE [H17012] Anthony D’s discharge instructions called for an 81 mg daily dose of aspirin, as opposed to the 325-mg dose for the first 3 months of triple therapy after stent placement recommended by the American College of Cardiology/American Heart Association (ACC/AHA) guidelines for unstable angina/ non-ST segment elevated MI.1 Although the patient had no independent bleeding risk, his physician selected the lower dose of aspirin to mitigate the increased bleeding risk posed by the use of prasugrel as a component of triple therapy.6
Lower aspirin dose. Pharmacodynamic studies support the use of a lower dose of aspirin, finding that serum thromboxane is completely inhibited by a maintenance dose as low as 30 mg/d in healthy individuals and 50 mg/d for those with chronic stable angina.14 Using low-dose aspirin for the secondary prevention of ACS when triple therapy is indicated is likely to reduce GI toxicities as well as bleeding risk.
Reduce the duration of dual antiplatelet therapy. According to the ACC/AHA guidelines, thienopyridine therapy can be limited to one month in patients who are medically managed or have had a bare metal stent placed if there is concern about the patient’s risk of bleeding.6,10 Based on the findings of the one study that found triple therapy to be an independent predictor of major bleeds, this approach seems reasonable.1 It is called into question, however, by another recent trial, which found that patients on dual antiplatelet therapy for one year (vs one month) had a statistically significant improvement in cardiovascular outcomes.16