Aspirin in Secondary Prevention: Standing Strong?

Tricia Ward

Disclosures

October 29, 2014

Misunderstood?

A recent presentation at the Transcatheter Cardiovascular Therapeutics (TCT) 2014 meeting in Washington, DC, by Dr Anthony Bavry (University of Florida) was titled "Aspirin: the Most Understood and Misunderstood Antiplatelet Agent."[1] The role of aspirin in primary prevention has been an ongoing topic of debate, but its use in the secondary prevention of cardiovascular events has rarely been questioned since the ISIS-2 trial demonstrated a 23% reduction in mortality for acute myocardial infarction patients treated with aspirin.[2] The 2002 Antithrombotic Trialists' Collaboration[3] review of trials, involving more than 100,000 patients who had survived a prior occlusive vascular event, found that aspirin prevented approximately 25% of serious vascular events.

But these data largely come from the pre-statin era and before the use of more potent antiplatelets. Where does aspirin stand today as clinicians juggle the risk of bleeding with the potential ischemic benefits of contemporary antiplatelet choices?

Current Choices and Bleeding Risks

Patients who have an atherosclerotic event, such as acute coronary syndrome (ACS) or percutaneous coronary intervention (PCI) with stenting, now receive dual antiplatelet therapy. This often comprises aspirin and clopidogrel (Plavix®), but more potent agents, including prasugrel (Effient®) and ticagrelor (Brilinta®), are increasingly used. Additionally, many potential candidates for dual antiplatelet therapy are taking oral anticoagulation.

Like all antiplatelet therapies, aspirin doesn't come without a price. It is estimated that aspirin increases the risk for upper gastrointestinal (GI) bleeding by a factor of 1.5 to 2 over approximately 5 years.[4] Rates may be higher for patients older than 70 years of age. GI bleeding is independently associated with mortality and ischemic complications in patients with ACS.[5] It's not clear whether enteric-coated or buffered preparations reduce the risk for GI bleeding,[6,7] but lowering the aspirin dose appears to.[8]

Optimal Aspirin Dose?

The Antithrombotic Trialists concluded that aspirin doses in the range of 75 to 325 mg were as effective as very high doses (500-1500 mg) in terms of antithrombotic effect and were less likely to cause side effects.[3] Despite being one of the most widely prescribed cardiovascular drugs, an optimal dose within this 75-325 mg range has not been established, and inconsistent aspirin dosing has complicated the interpretation of trials on dual antiplatelet therapy.

Combining aspirin and a P2Y12 inhibitor (clopidogrel, prasugrel, or ticagrelor) carries a higher risk of bleeding than aspirin alone.[9,10] The CURE trial[11] which established the superiority of dual antiplatelet therapy over aspirin monotherapy in more than 12,500 patients with ACS, left aspirin dosing to physician discretion (within a recommended dose range of 75-325 mg). In a post-hoc analysis,[12] the incidence of major bleeding increased significantly with increasing aspirin dose in both the aspirin-placebo and the aspirin-clopidogrel treatment groups. For clopidogrel-treated patients, the rates were 3.0%, 3.4%, and 4.9% (P = .0009) for those treated with ≤ 100 mg, 101-199 mg, and ≥ 200 mg aspirin, respectively. There was no incremental ischemic benefit with these higher aspirin doses.

The PLATO trial[13] showed a 16% reduction in the composite of vascular death, MI, and stroke for ticagrelor vs clopidogrel in more than 18,500 patients with ACS, but again this was in the background of various aspirin dosing regimens. In a geographic analysis, clopidogrel appeared to outperform ticagrelor in patients randomly assigned in North America, a finding that is generally attributed to the higher aspirin doses typically used in North America.[14] Although the authors of that analysis acknowledge that the geographic anomaly could have been a chance finding, aspirin doses < 100 mg are mandated for long-term dual antiplatelet therapy with ticagrelor.

As PLATO illustrated, US physicians tend to prescribe higher doses than their European counterparts. The CURRENT OASIS 7 trial[15] pitted low-dose (75-100 mg) vs high dose (≥ 300 mg) aspirin in more than 25,000 patients with ACS. Both doses were equivalent in terms of ischemic events and rates of major bleeding in the first month after stenting. Rates of minor bleeding were reduced with the low-dose regimen. "It is time for the proponents of higher-dose aspirin to concede defeat and modify clinical practice," commented Valentin Fuster (Mount Sinai School of Medicine, New York) to heartwire at the time.

The 2013 US guidelines for ST segment elevation myocardial infarction (STEMI) recommend a maintenance dose of 81 to 325 mg, noting that the 81-mg dose should be used with ticagrelor and is the preferred maintenance dose.[16] The 2014 European guidelines on myocardial revascularization specify a dose range of 75-100 mg for long-term aspirin therapy.[17]

It may take time for the low-dose message to take hold among US practitioners. Data from the National Cardiovascular Data Registry (NCDR) Acute Coronary Treatment and Intervention Outcomes Network (ACTION) Registry-Get with the Guidelines (GWTG)[18] on over 200,000 patients show that most survivors of STEMI or non-STEMI are discharged on high-dose aspirin, with only 35.6% receiving low-dose aspirin.

Triple Therapy Triple Threat

Many patients on oral anticoagulation develop an ACS or undergo PCI, making them potential candidates for triple therapy with aspirin, clopidogrel, and warfarin. In the absence of data, published guidance suggested strategies to drop either aspirin or clopidogrel after 3-6 months, depending on the bleeding risk of the patient and the stent used.[19]

Supporting data for dropping aspirin has since come from the single-center WOEST trial,[20] which found similar ischemic benefits and a reduced risk of bleeding for clopidogrel and oral anticoagulation, compared with triple therapy that included aspirin, in 563 patients with AF who underwent coronary stenting.

More recently, the ISAR-TRIPLE study[21] was presented at the 2014 TCT meeting in Washington, DC. This compared 6 months vs 6 weeks of triple therapy in over 600 patients on oral anticoagulation who underwent PCI. At the 6-week timepoint, the investigators took a slightly different tack from WOEST by stopping the clopidogrel and keeping patients on aspirin and warfarin. The primary endpoint was a statistical tie for shorter vs longer duration of therapy. There was also no difference in the rate of TIMI major bleeding, but there was a reduction in any BARC bleeding events in the 6-week group vs the 6-month group. Lead investigator Dr Nikolaus Sarafoff commented in an interview with Dr Seth Bilazarian that "After one to three months, I am willing to de-escalate triple therapy...while I would probably discontinue clopidogrel in a stable patient, I would discontinue aspirin in the patients with ACS."

How long after the index event should you continue any antiplatelet therapy in patients on warfarin? The observational CORONOR study[22] assessed more than 4000 patients with stable CAD who were over a year removed from an MI or coronary revascularization. More than 10% were on oral anticoagulation and three quarters of these patients were also taking antiplatelet therapy (mostly aspirin). This combination was associated with an increased risk of bleeding and no incremental ischemic benefit, leading the study authors to conclude that "when oral anticoagulation is required, concomitant antiplatelet therapy should not be prescribed in the absence of a recent cardiovascular event."

Duration of DAPT

What about patients who are not on oral anticoagulation? How long should they continue dual antiplatelet therapy? The DAPT study,[23] comparing 12 vs 30 months of dual antiplatelet therapy in patients undergoing PCI, was designed to answer this question which has vexed the cardiology community for years. It will be presented shortly at the American Heart Association meeting in November 2014.

As often happens in medicine, the goalposts have moved since this trial began, and the question du jour is whether dual antiplatelet therapy can be discontinued much earlier than 12 months. Studies so far[24,25,26] suggest that durations of 3 to 6 months are not associated with an excess risk for stent thrombosis or other cardiovascular events. Notably in these trials, clopidogrel was stopped and aspirin was continued indefinitely.

It would appear that the old-timer antiplatelet will be sticking around for a while.

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