Antiplatelet Therapy in Anticoagulated Patients
Objective: To define the optimal antiplatelet regime in patients requiring long-term anticoagulation who undergo percutaneous coronary intervention.
Background: Antiplatelet therapy following coronary intervention consists of a regime of aspirin and clopidogrel for the prevention of subacute stent thrombosis. The optimal antiplatelet therapy post-coronary intervention in patients on ongoing anticoagulation therapy remains to be defined. Addition of aspirin and clopidogrel to patients already on warfarin increases the risk of bleeding, while withholding antiplatelet therapy increases the risk of stent thrombosis. Discontinuation of warfarin in turn increases the risk of thromboembolism.
Methods: We performed a systematic review and synthesis of the English language literature examining the risk of subacute thrombosis with various antiplatelet regimens and the risk for thromboembolism with and without warfarin. The risk of bleeding complications with various drug combinations were reviewed.
Conclusions: There are no data from randomized trials to clarify the optimum treatment in these patients; and the feasibility of such studies may be questionable. Hence, treatment decisions continue to be made on an individualized basis and should include assimilation of information on key factors, including the risk of bleeding and the risk of thromboembolism.

Percutaneous coronary stent implantation (PCI) is widely used for the treatment of acute coronary syndromes and chronic coronary artery disease. As stents are mostly made of stainless steel, they are a source for thrombus formation. One of the early and dreaded complications of coronary stent implantation is stent thrombosis. Stent thrombosis may occur within the first 24 hours (acute), or within the first month of stent placement (subacute). During the early stages of stent implantation the incidence of stent thrombosis varied from 24% in the Wallstent Study to 16% in the Palmaz-Schatz study. The antithrombotic regimes used in these studies included aspirin, dipyridamole, heparin and low-molecular weight dextran.

With the addition of warfarin to uninterrupted intravenous heparin, the incidence of stent thrombosis was reduced to 3.5%. However, the benefit was offset by an increase in hemorrhagic complications of 7.5% in the STRESS Study and 13.5% in the BENESTENT Study. In addition, aggressive anticoagulation was associated with increased hospital stays and costs.

With further refinement in stenting techniques, including optimal deployment at higher pressures with adequately-sized balloons and newer-generation stents, the incidence of stent thrombosis has been reduced. In addition, antiplatelet regimes for the prevention of stent thrombosis have replaced the cumbersome anticoagulation regimes. The landmark STARS Trial showed a regime of aspirin and ticlopidine to be superior to aspirin and warfarin (0.5% versus 2.7% in the reduction of stent thrombosis). This observation was confirmed in the Intracoronary Stenting and Antithrombotic Regimen (ISAR) Trial, which showed aspirin and ticlopidine to be superior to intense anticoagulation in regard to stent thrombosis (3.3% versus 21% in patients who underwent stenting for acute myocardial infarction). Ticlopidine has been largely replaced by clopidogrel due to the former's side effect profile of neutropenia and thrombotic thrombocytopenia purpura.

Clopidogrel has been shown to be as effective as ticlopidine in the prevention of stent thrombosis. A meta-analysis comparing the two drugs in 13,955 patients found that clopidogrel was associated with a lower incidence of major adverse cardiac events and a lower 30-day mortality rate (0.5% versus 1.1%). A few trials have shown a trend suggesting a benefit towards ticlopidine, while others have favored clopidogrel. However, data from the PCI-CURE (effects of pre-treatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing coronary intervention) and Clopidogrel for the Reduction of Events During Observation (CREDO) trials have established the safety and efficacy of clopidogrel. The PCI-CURE20 Trial showed that clopidogrel reduced the combined endpoint of cardiovascular death, myocardial infarction (MI), or urgent target vessel revascularization at 30 days in patients with non-ST elevation MI. There was no increase in major bleeding at 30 days. The CREDO Trial showed a significant reduction in the combined endpoint of MI, stroke and death at one year with the prolonged administration of clopidogrel in patients undergoing elective coronary stenting.

The advent of brachytherapy for the treatment of instent restenosis, and the implantation of drug-eluting stents have contributed to delayed endothelialization of stents, requiring longer duration of antiplatelet therapy to prevent late thrombosis. The incidence of late thrombosis without antiplatelet therapy at six months had been estimated to be 5–9%. The current practice is to use clopidogrel and aspirin for at least six months after radiation therapy, with many centers using clopidogrel for one year to an indefinite period after brachytherapy.

The advent of sirolimus-eluting stents and paclitaxel-eluting stents have altered the duration of antiplatelet therapy for the prevention of stent thrombosis. While there is no increase in the incidence of stent thrombosis, there is a need for prolonged antiplatelet therapy. This is due to delayed endothelialization secondary to inhibition of mitosis.

Current recommendations include three months of combined aspirin and clopidogrel in patients receiving the sirolimus stent and six months of aspirin and clopidogrel in patients receiving the paclitaxel stent.

Long-term anticoagulation is used in patients to prevent venous and arterial thromboembolism. The addition of antiplatelet therapy to this group of patients post-coronary intervention has not been studied. The optimal therapy for this group of patients is complex and will depend on individual patient risk factors for thromboembolism and bleeding. Prolonged antiplatelet therapy predisposes these patients to an increased risk of bleeding. In addition to life-threatening bleeding, even moderate bleeding episodes may require stopping anticoagulation, which in turn will predispose these patients to prosthetic valve thrombosis orthromboembolism.