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In stented patients at elevated stroke risk, the addition of warfarin to dual antiplatelet therapy (DAPT) increases major bleeding complications—regardless of how often the oral anticoagulant is maintained within therapeutic range, according to a registry study published online August 13, 2013, ahead of print in Circulation: Cardiovascular Interventions.

Investigators led by Akira Sato, MD, of the University of Tsukuba (Ibaraki, Japan), analyzed data from 2,648 patients who underwent stenting (about 70% with DES) and were enrolled in the multicenter Ibaraki Cardiovascular Assessment Study registry between April 2007 and August 2010. Patients were discharged on clopidogrel (75 mg daily) and aspirin (100-200 mg daily). Clopidogrel was to continue for at least 1 year and the aspirin for life.

In addition, 182 patients (7%) received warfarin. Reasons included A-fib (n = 143), deep vein thrombus (n = 16), mechanical heart valve (n = 14), and intraventricular thrombus (n = 9).

Triple Therapy More than Triples Major Bleeding

After a median follow-up of 25 months and 5,517 patient-years, 48 patients (2%) had experienced a major bleeding complication (primary endpoint; defined as a cerebral hemorrhage or GI bleeding). Rates of major bleeding, GI bleeding, and all bleeding complications were higher in the triple therapy group than the double therapy group. Although cerebral hemorrhage was no more frequent overall in patients on triple therapy, fatal events were (table 1).

Table 1. Bleeding Outcomes at 25 Months

On multivariable analysis, independent predictors of increased risk of major bleeding complications were:

• Male sex (HR 2.64; 95% CI 1.09-6.43; P < 0.05)
• Warfarin administration (HR 3.83; 95% CI 1.82-8.06; P < 0.001)
• Emergent PCI (HR 1.95; 95% CI 1.06-3.60; P < 0.05)

In contrast, hemoglobin level predicted reduced risk (HR 0.845; P < 0.01).

Overall, the median time in therapeutic range (TTR) was 76% (IQR 49%-87%). Importantly, the TTR of patients on warfarin who experienced a major bleeding complication did not differ from that of those who were free of major bleeding (83% vs. 75%; P = 0.7). However, in 6 of the 9 patients who had major bleeding, mean INR at the time of occurrence was above 2.5.

The prevalence of MACCE (cardiac death, MI, stent thrombosis, stroke, and TVR) and its component endpoints did not differ between the triple and double therapy groups, while all-cause death was higher among patients receiving warfarin (table 2).

Table 2. Ischemic Outcomes at 25 Months

Multivariable analysis showed that warfarin administration was not an independent predictor of all-cause death, stroke, or MACE. CHADS2 score predicted increased stroke risk (P < 0.001), while use of calcium channel blockers and DES predicted reduced occurrence (P < 0.05 and P < 0.01, respectively).

Among 214 patients with A-fib, 143 took warfarin. Of the 71 A-fib patients not on the anticoagulant, the CHADS2 score was less than 2 in 53 patients and 2 or greater in the remaining 18. Yet stroke incidence was similar among all 3 groups at 2.35, 0.90, and 5.26 per 100 person-years, respectively (P = 0.3).

INR More Important than TTR

In a telephone interview with TCTMD, Sandeep Nathan, MD, of the University of Chicago Pritzker School of Medicine (Chicago, IL), noted that the major bleeding rate with triple therapy was “relatively low” compared with a Danish registry that found an annualized rate of rehospitalization for bleeding of 12% (Sørensen R, et al. Lancet. 2009;374:1967-1974). In addition, both the TTR (> 70%, which is on the high end of estimates for American patients) and the targeted INR (1.6-2.5, compared to 2.0-3.0 in the United States) make application of these Japanese findings to the US setting questionable.

“What I take home from the study is that higher INRs are associated in the triple therapy realm with more major bleeding. [But] we don’t necessarily have to be as concerned about time in therapeutic range,” Dr. Nathan said.

Interestingly, he observed, 2 expected effects of triple therapy were not seen. It did not provide added protection against stroke, but on the other hand, the increased major bleeding did not dramatically raise MACE risk.

The bottom line is that “in the absence of good data suggesting that more anticoagulation is more protective against thromboembolic events, the lowest possible [exposure] is what we should be aiming for,” Dr. Nathan said. A variety of strategies may be employed. On the anticoagulant side, tightly regulating INR is helpful, he noted, while on the antiplatelet side, avoiding long-term DAPT by using BMS or balloon angioplasty, especially to treat simple lesions, should be considered.

An alternate approach, which showed promise in the recent WOEST trial, is to forgo aspirin. While acknowledging some evidence that aspirin may not offer much protection yet enhances bleeding risk, Dr. Nathan pointed out that in the aforementioned Danish study, major bleeding was actually somewhat higher with warfarin and clopidogrel alone than with triple therapy. Moreover, he noted, most of the proven benefit of antiplatelet therapy for prevention of stent thrombosis rests with DAPT including aspirin.

Avoid Prasugrel, Ticagrelor

In general, Dr. Nathan said, antiplatelet therapy should steer clear of more potent thienopyridines or P2Y12 inhibitors such as prasugrel and ticagrelor, which carry increased bleeding risk. However, “once you’ve resigned yourself to clopidogrel,” platelet function testing may be useful to rule out resistance, he added.

As yet it is unclear how the availability of the novel oral anticoagulants will affect the risk-benefit calculus of triple therapy, Dr. Nathan said, particularly given the different dosing regimens and all the permutations of these dosages used in combination with different antiplatelet drugs. However, he noted, the novel anticoagulants are a boon in terms of avoiding over-anticoagulation since titration is not an issue.

In the end, the choice of combination therapy often comes down to assessing the risk profile of an individual patient using tools like the HAS-BLED and CHADS2 scores, Dr. Nathan observed.

“The compelling indication usually rests with anticoagulation,” he said, and “that’s where my clinical decision making process begins.” He also factors in a patient’s TTR on warfarin and the complexity of the cardiovascular disease, asking whether “I can get away with a BMS or second-generation DES where I might feel comfortable with truncated antiplatelet therapy.

“The bottom line is minimizing the time you have to have all 3 agents on board,” he concluded.

 

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Source:
Naruse Y, Sato A, Hoshi T, et al. Triple antithrombotic therapy is the independent predictor for the occurrence of major bleeding complications: Analysis of percent time in therapeutic range. Circ Cardiovasc Interv. 2013;Epub ahead of print.

 

 

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