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Antithrombotic therapy in patients with AF undergoing PCI

Two is company, three is a crowd.

Issue: June 2014

ByMichael B. Bottorff, PharmD, FCCP, FNLA, CLS

ByBrandon Cave, PharmD candidate

BySarah A. Spinler, PharmD, FCCP, FAHA, FASHP, AACC, BCPS (AQ Cardiology)

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There is a shortage of randomized clinical trial evidence on the preferred treatment strategy to minimize risks for stroke, stent thrombosis and major bleeding for patients with nonvalvular atrial fibrillation undergoing PCI with stenting.

Treatment options are changing rapidly with the introduction of novel oral anticoagulants and newer oral P2Y12 inhibitor antiplatelet drugs as well as advancements in stent materials, which may necessitate a shorter duration of dual antiplatelet therapy after PCI. All things considered, an important question surrounds the optimal combination of agents that will give patients adequate coverage for prevention of ischemic events and acceptable safety in regard to bleeding, and the recommended duration of therapy after PCI.

Evaluation of bleeding risk

Historically, the solution has been to treat patients with oral anticoagulation, usually warfarin, and DAPT with aspirin and clopidogrel. These drugs are class IA/IB recommended treatments for the respective indications of AF and PCI, according to the American College of Cardiology Foundation/American Heart Association Guideline for the Management of STEMI.

Brandon Cave

Michael B. Bottorff

However, this combination, commonly known as triple therapy, alters the risk-benefit ratio that these agents have alone and significantly increases the risk for bleeding above the additive individual risk. The heightened risk for major bleeding is evident despite optimal management with a high time in therapeutic range. The addition of the second antiplatelet agent to warfarin, most often clopidogrel, appears to double the risk that accompanies aspirin and warfarin therapy; together, all three agents are associated with high annual risks of 4% to 16% for fatal and nonfatal bleeding. Studies have shown that triple therapy vs. aspirin alone results in four times the rate of bleeding, with no improvement on survival, as well as an 80% increase compared with warfarin alone.

In one Denmark cohort study published by Hansen and colleagues in 2010, triple therapy increased the risk for nonfatal and fatal bleeding by more than threefold vs. warfarin alone and increased the risk for death due to nonfatal bleeding. Compared with a baseline annual bleeding risk of 3.9% on warfarin alone, the researchers reported an increase of nearly 12% per patient-year with triple therapy. Hence, numerous strategies may be considered to reduce these risks without compromising stroke.

Strategies to reduce bleeding

Guidelines and consensus documents have been published to determine strategies for reduction of the dramatic increase in bleeding associated with triple therapy. Although there are some minor differences between expert panels, there is much agreement between the documents.

Experts agree that bare-metal stents are preferred over drug-eluting stents due to the shorter required length of DAPT needed to prevent stent thrombosis. Also, although not evidence-based, it is recommended that physicians manage warfarin to a conservative goal INR of 2 to 2.5 to optimize stroke prevention and minimize bleeding. It is also recommended that aspirin be limited to 81 mg daily because it has been proven as effective as higher doses with significantly less bleeding. Proton pump inhibitors are recommended to reduce gastrointestinal bleeding risk.

The minor differences between recommendations from Europe and North America appear in regard to therapy duration in relation to type of stenting and individual risk. According to North American recommendations, a patient would receive only 1 month of triple therapy for a BMS and either a low stent thrombosis risk or high bleeding risk; a patient would receive 6 months of triple therapy for a BMS with a high stent thrombosis risk and low bleeding risk or a DES with both a low stent thrombosis and low bleeding risk; a patient would receive 12 months of triple therapy with a DES and a high stent thrombosis risk and low bleeding risk. A DES in patients at high bleeding risk is not recommended. After the recommended triple therapy duration, patients can be managed with warfarin and one antiplatelet agent (dual therapy).

European recommendations differ in the further stratification of elective vs. ACS stenting and the type of DES. One month of triple therapy is recommended for patients with elective BMS. Those with high bleeding risk should continue therapy with only a vitamin K antagonist; patients with low bleeding risk should continue with dual therapy. Three months of triple therapy is appropriate for patients with an elective “-olimus” DES and low bleeding risk vs. 6 months for patients with an elective paclitaxel DES or any stent in the setting of ACS with low bleeding risk. A patient with ACS and high bleeding risk should receive a BMS stent and triple therapy for 1 month. Again, except where noted, the remainder of therapy duration is completed with dual therapy.

The recent AHA/ACC/Heart Rhythm Society Guideline for the Management of Patients with AF states that it may be “reasonable” to use 75 mg clopidogrel daily and anticoagulation without aspirin in patients who recently underwent coronary revascularization (class IIB recommendation).

Evidence supporting this recommendation comes from the prospective WOEST trial, which evaluated 573 patients with an indication for anticoagulation and DAPT for PCI. Compared with triple therapy, warfarin and clopidogrel were associated with a lower event rate across several bleeding definitions, a relative risk reduction of 64%, and a reduction in the combined efficacy endpoint of death, MI, stroke, target vessel revascularization and stent thrombosis. Further, a Danish registry of more than 12,000 patients with AF undergoing PCI demonstrated that oral anticoagulation and clopidogrel was associated with a lower occurrence of MI or coronary death and a lower incidence of bleeding compared with triple therapy, although neither outcome achieved statistical significance. Oral anticoagulation plus aspirin was significant for less bleeding; however, it was also significant for an increase in all-cause mortality. These data suggest the addition clopidogrel to a vitamin K antagonist is at least equal to triple therapy and perhaps a better option in a patient with high risk for bleeding. This, however, is contrary to the recommendations in the current PCI guidelines, which recommend discontinuing the P2Y12 component. Meta-analyses are controversial regarding the superiority of triple therapy over dual therapy in regard to efficacy. But, the increased risk for bleeding is undeniable, especially in the gastrointestinal tract.

Areas in which data are lacking

There are fewer data with the target-specific oral anticoagulant agents. However, early reports indicate an advantage of dual therapy over triple therapy.

RE-LY was the only AF trial to allow use of both antiplatelet agents, and in a post-hoc analysis, major bleeding risk was more than doubled with DAPT compared with a 60% increased risk with a single antiplatelet agent. A meta-analysis of ACS trials using novel anticoagulants suggested that the addition of a single antiplatelet agent is favorable with regard to efficacy and limiting bleeding risk. The addition of the second antiplatelet agent only prevented five major adverse cardiac events but was associated with an additional 42 bleeding events per 1,000 patients. However, these data are difficult to interpret due to the use of lower doses of anticoagulant in some of the trials.

Also unclear is the risk-benefit ratio in this setting with the substitution of prasugrel (Effient, Eli Lilly/Daiichi Sankyo) or ticagrelor (Brilinta, AstraZeneca) for clopidogrel due to the established superiority over clopidogrel with stronger and less variable platelet inhibition, which may lead to increased bleeding.

The available evidence with either of these agents as a part of triple therapy is restricted to a small study by Wallentin and colleagues of 377 patients with DES receiving triple therapy containing either prasugrel or clopidogrel for 6 months. Prasugrel significantly increased TIMI major bleeding (HR=6.1; 95% CI 1.6-22.1) compared with clopidogrel, without a corresponding benefit in efficacy (14.3% vs. 2.8%, respectively). The risk of ticagrelor as part of triple therapy is unknown. However, in the PLATO trial, researchers reported a significant risk in non-CABG related bleeding compared with clopidogrel as part of a dual antiplatelet regimen.

More research, experience needed

Triple therapy is clearly indicated for its efficacy because warfarin alone is insufficient for prevention of stent thrombosis and DAPT is insufficient for prevention of cardioembolic stroke, but the risk-benefit ratio of triple therapy is still hampered by the well-defined increase in bleeding risk.

Additional research and further supportive studies are needed to have a definitive answer to this clinical “catch-22.” Until then, to reduce bleeding risk and pill burden, and maintain acceptable efficacy against thrombotic events in patients with a high bleeding risk, an aggressive yet rational approach is to remove the aspirin component of triple therapy until clopidogrel therapy is no longer necessary.

Disclosure: Bottorff reports serving as a member of speakers’ bureaus for AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb and Pfizer. Cave reports no relevant financial disclosures.