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Triple therapy consisting of a vitamin K antagonist and dual antiplatelet therapy is associated with a high risk of bleeding among patients with atrial fibrillation (A-fib) who need percutaneous coronary intervention (PCI) or suffer a myocardial infarction (MI), according to a Danish registry study published online August 6, 2012, ahead of print in Circulation.

Investigators led by Morten Lamberts, MD, of Copenhagen University Hospital Gentofte (Hellerup, Denmark), used national registry data to identify 11,480 patients with A-fib who were admitted with MI (n = 8,775, 17.3% of whom also underwent PCI) or simply underwent PCI (n = 2,705) between 2000 and 2009. The researchers compared the rates and timing of fatal and nonfatal bleeding based on the antithrombotic treatment regimen prescribed.

The regimens evaluated were:

• Triple therapy consisting of a vitamin K antagonist plus aspirin and clopidogrel (n = 1,495)
• Vitamin K antagonist plus aspirin or clopidogrel (n = 1,837)
• Vitamin K antagonist alone (n = 848)
• Dual antiplatelet therapy (n = 3,144)
• Aspirin or clopidogrel (n = 4,156)

Overall, 728 bleeding events occurred within 1 year of the MI or PCI. Of these, 79 were fatal, with 90% due to intracranial or gastrointestinal bleeding.

Bleeding Risk Rises with Potency of Regimen

At 1 year, rates of bleeding tended to increase with the intensity of antithrombotic therapy as rates of thromboembolic events (composite of cardiovascular death, MI, and stroke) decreased (table 1).

Table 1. One-Year Outcomes by Antithrombotic Regimen

After adjustment, triple therapy significantly increased risk for bleeding compared with a vitamin K antagonist plus a single antiplatelet drug (adjusted HR 1.41; 95% CI 1.10-1.81), while it provided no benefit with regard to the combined thromboembolic endpoint (adjusted HR 1.15; 95% CI 0.95-1.40).

The incidence of bleeding increased immediately after initiation of triple therapy and remained higher than for all other regimens regardless of time elapsed. In an adjusted landmark analysis, the risks for both early and late bleeding were greater with the use of triple therapy compared with a vitamin K antagonist plus 1 antiplatelet drug and compared with dual therapy (table 2).

Table 2. Landmark Analysis: Timing of Bleeding Risk by Antithrombotic Regimen

There was no difference between these groups with respect to thromboembolic risk.

“For atrial fibrillation patients suffering from myocardial infarction/coronary intervention, triple therapy . . . is associated with an immediate and persistent high risk of bleeding,” Dr. Lamberts told TCTMD in an e-mail communication. “Thus, no safe therapeutic window is present.”

In a telephone interview with TCTMD, Sorin J. Brener, MD, of Weill Cornell Medical College (New York, NY), noted that the observational nature of the study leaves some important questions unanswered. For example, “the fact that the bleeding risk is higher early on doesn’t make a lot of sense,” he said. “And the authors don’t indicate what the dose of aspirin is in any of the patients, so we don’t know if a lot of this bleeding risk is related to high-dose aspirin.”

Balancing Act

According to Dr. Lamberts, “balancing an individual patient’s bleeding risk with the risk of thrombosis is difficult.” Despite the limitations, prognostic algorithms such as the HAS-BLED score (based on clinical factors such as hypertension, renal and liver function, and bleeding history) used in the current study are “currently our best option for assessing each patient’s bleeding risk prior to initiation [or] change of antithrombotic treatment.”

In an e-mail communication with TCTMD, Sunil V. Rao, MD, of Duke University Medical Center (Durham, NC), commented that “we are in a relatively data-free zone [with regard to] patients who need long-term anticoagulation and revascularization, so clinical judgment is incredibly important. Interventionalists should make decisions regarding [dual antiplatelet therapy] on a case-by-case basis, with careful attention to bleeding risk. Patients at very high risk for bleeding are the most challenging, and strong consideration should be given to using bare-metal stents and very short-term [dual therapy]” followed by restarting warfarin.

This strategy is especially important early on since “this study demonstrates again that the highest risk for bleeding is early,” Dr. Rao added.

Triple Therapy May Be Right for Some

While triple therapy is risky, there are certain patients who may benefit, Dr. Lamberts noted. He offered the example of an individual with a history of multiple MIs who is considered at high risk for new infarctions but has no history of severe bleeding episodes on previous multiple antithrombotic treatments.

Dr. Brener agreed that triple therapy remains a possibility for patients who are at very high risk of ischemia and low risk for bleeding. “But you would want to limit the exposure time,” he noted. A possible candidate, he said, might be a young person with paroxysmal A-fib taking warfarin who experienced a STEMI with proximal LAD or left main disease and requires stenting.

Over time, pharmacological advances may well alter the role of triple therapy, Dr. Lamberts commented, speculating that newer anticoagulants could perhaps be more safely combined with dual therapy. Developments in stent technology are another potential game-changer, Dr. Rao added.

Source:

Lamberts M, Olesen JB, Ruwald MH, et al. Bleeding after initiation of multiple antithrombotic drugs, including triple therapy, in atrial fibrillation patients following myocardial infarction and coronary intervention: A nationwide cohort study. Circulation. 2012;Epub ahead of print.

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