ORIGINAL CONTRIBUTIONS

Efficacy of Modified Dual Antiplatelet Therapy Combined with Warfarin Following Percutaneous (FULL TITLE BELOW)

Usman Baber, MD, Mohammed Akhter, MD, Sharad Kothari, MD, Samin K. Sharma, MD, Annapoorna Kini, MD
Usman Baber, MD, Mohammed Akhter, MD, Sharad Kothari, MD, Samin K. Sharma, MD, Annapoorna Kini, MD
ABSTRACT: Background. The optimal combination of anticoagulant and antiplatelet therapy following percutaneous coronary intervention with stenting (PCI-S) among patients requiring oral anticoagulation (OAC) is unknown. Objectives. We sought to compare the efficacy of a modified dual-antiplatelet regimen (daily aspirin and every other day clopidogrel) to conventional treatment (daily aspirin and daily clopidogrel) following percutaneous coronary intervention (PCI) with drug-eluting stents (DES) among patients who are also discharged on warfarin. Methods. We performed a single-center, retrospective analysis of consecutive patients (n = 454) who underwent PCI-S with DES and were discharged on warfarin and either a conventional (n = 170) or modified (n = 284) antiplatelet regimen between March 2003 and May 2007. In-hospital and 1-year events were compared between the two groups. Results. There were no differences in 1-year rates of death, myocardial infarction, stent thrombosis or target lesion revascularization between patients receiving a conventional compared to a modified antiplatelet regimen. In-hospital bleeding rates were also similar between the two groups. Conclusions. An antiplatelet regimen of aspirin with every-other-day clopidogrel may be as efficacious as daily aspirin and clopidogrel among patients receiving warfarin following PCI-S with DES.

J INVASIVE CARDIOL 2010;22:80–83

Key words: antithrombotic regimens, clopidogrel, aspirin, combination therapies

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Multiple randomized controlled trials evaluating antithrombotic regimens following coronary artery stenting with bare-metal stents have clearly shown that treatment with aspirin and a thienopyridine is safer and more efficacious than either aspirin alone or aspirin combined with warfarin.1,2 The optimal combination of antiplatelet and/or anticoagulant agents following percutaneous coronary intervention with stenting (PCI-S) among patients who have a concurrent indication for oral anticoagulants (OAC) was not addressed by these earlier studies and remains unclear. Balancing efficacy with safety is made more difficult in the drug-eluting stent (DES) era as current guidelines recommend prolonged dual-antiplatelet therapy due to concerns of late and very late stent thrombosis.3 Modifying the anitplatelet regimen while continuing warfarin following PCI-S among such patients may provide a similar degree of protection against ischemic complications at a lower bleeding risk. To investigate this issue further, particularly in the context of DES, we evaluated clinical outcomes among patients following PCI-S with DES who were discharged on warfarin and either daily aspirin and clopidogrel or daily aspirin with every-other-day clopidogrel.

Methods

Beginning July 1, 1999, all patients undergoing PCI at the Mount Sinai Hospital in New York City were enrolled in an outcomes registry. The population for the current analysis was limited to adult patients, 18 years of age and older, who underwent PCI with DES and were discharged on warfarin and dual-antiplatelet (aspirin and clopidogrel) therapy between March 2, 2003, and May 31, 2007 (n = 454). Patients were classified into two groups based on the prescribed antiplatelet regimen at discharge: conventional (daily aspirin and daily clopidogrel) or modified (daily aspirin with every-other-day clopidogrel). The decision to continue patients on either a conventional or modified regimen following PCI was made by the responsible clinical cardiologist. Multiple cardiologists prescribed a modified regimen during the time period of the present study. For patients who underwent PCI more than once, the earliest presentation was used as the index event. All data were collected using standardized methods and recorded onto forms designed for the PCI registry. The presence of comorbid conditions was ascertained using a standardized chart abstraction form. Medications being taken by patients upon hospital admission were abstracted from medical charts by research staff. Thrombolysis in myocardial infarction (TIMI) major bleeding was defined as a hemoglobin drop > 5 g/dl with or without an identified site or intracranial hemorrhage or cardiac tamponade. TIMI minor bleeding was defined as a hemoglobin drop > 3 g/dl but Results Baseline characteristics of the study population are shown in Table 1 by antiplatelet group. Other than older age and higher use of statins in the conventional group, there were no significant differences in the frequency of other clinical risk factors, clinical presentations or medication use between the two groups. The clinical indications for warfarin are listed in Table 2 by antiplatelet group. The most common indication in both groups was atrial fibrillation, which was more common in the modified versus conventional group (60% vs. 40%, p Discussion In this single-center, retrospective analysis of patients who underwent PCI with DES discharged on warfarin and dual-antiplatelet therapy, we found no differences in 1-year clinical outcomes between patients who were discharged on daily aspirin and clopidogrel compared to daily aspirin with alternate-day clopidogrel. Our study extends earlier observations comparing antithrombotic regimens following PCI-S by including a heterogenous patient population with multiple indications for OAC who underwent PCI with DES only. Previous studies have shown that triple antithrombotic therapy with aspirin, clopidogrel and warfarin is associated with a high risk of bleeding and/or ischemic complications.5–8 These analyses, however, compared outcomes between patients treated with triple therapy to those treated with either antiplatelet therapy alone, or warfarin with antiplatelet monotherapy. In at least two studies, patients receiving warfarin had a higher burden of baseline cardiovascular risk factors, which may have contributed to the increased risk of adverse events following PCI-S.6,8 Our study differs importantly from these earlier investigations, as all patients in the present analysis were discharged on warfarin and outcomes were compared between patients receiving one of two different antiplatelet regimens. In addition, baseline risk factors were well balanced between the two treatment groups. Recent data suggest that discontinuing warfarin following PCI-S among patients treated with OAC is associated with a prohibitively increased risk of death and/or stroke.6,9 Among 426 patients with atrial fibrillation who underwent PCI-S, for example, Ruiz-Nodar et al found that nonanticoagulation with coumarins was associated with a 3-fold increased risk of death.9 In a separate analysis that reported clinical outcomes among patients who were on OAC at the time of PCI-S, the 1-year stroke rate was 8.8% among patients discharged on antiplatelet therapy alone compared to 3% among those discharged on a regimen containing warfarin.6 In addition, warfarin was superior to dual-antiplatelet therapy with aspirin and clopidogrel in preventing thromboembolic complications among patients with atrial fibrillation.10 Accordingly, most patients with indications for OAC who undergo PCI-S are treated with triple-antithrombotic therapy including warfarin, aspirin and a thienopyridine,7,9 despite a higher likelihood of bleeding complications compared to less intense antithrombotic treatments.5–7 A potential alternative to reducing the inherent bleeding risk associated with triple-antithrombotic therapy while maintaining efficacy includes modifying the intensity of antiplatelet treatment while continuing warfarin. To date, only one other study has evaluated such an approach.11 Nguyen et al analyzed outcomes among patients presenting with acute coronary syndromes (ACS) who underwent PCI-S and were discharged on either warfarin and dual-antiplatelet therapy or warfarin and antiplatelet monotherapy. Most patients underwent PCI with bare-metal stents and were followed for 6 months. Although ischemic events were more frequent in the antiplatelet monotherapy group, the difference in event rates between the two groups did not reach statistical significance.11 In-hospital bleeding rates were also similar between the two groups.11 Similar to these findings, we also found that a less intense antiplatelet regimen of aspirin with every-other-day clopidogrel may be as efficacious as daily aspirin and clopidogrel when combined with warfarin following PCI-S. Our study also extends the observations of Nguyen et al by including patients who underwent PCI with DES alone and were followed for 1 year. Although there was no difference in in-hospital bleeding rates between the two groups in the present study, we were unable to determine whether or not long-term safety is improved with this less intense antiplatelet regimen. Overall bleeding rates were lower in our cohort compared to other studies. Differences in bleeding definitions and patient populations may account for these findings. Study limitations. Our study is limited by its retrospective, single-center design. The decision to continue patients on either a conventional or modified antiplatelet regimen was made by the treating cardiologist, which can introduce bias by an imbalance of risk factors. In addition, we were unable to compare the long-term safety between the two treatment regimens. Due to these limitations, our results should be considered hypothesis generating and require further evaluation in adequately powered, prospective studies.

References

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_________________________________________ From the Mount Sinai Hospital School of Medicine, New York, New York. The authors report no conflicts of interest related to the content herein. Manuscript submitted August 31, 2009, provisional acceptance given September 9, 2009, final version accepted September 15, 2009. Address for correspondence: Samin K. Sharma, MD, FACC, Mount Sinai Hospital, Cardiac Cath Lab & Intervention, One Gustave L. Levy Place, New York, NY 10029. E-mail: samin.sharma@mountsinai.org