Trifecta or Triple Threat? The Challenge of Post-PCI Management in Patients Receiving Chronic Oral Anticoagulant Therapy

Abstract

We are fortunate to practice in an era of medicine which has many proven therapies. However, we are increasingly faced with coadministration of therapies whose combined effects have not been fully evaluated. Perhaps the most common and difficult of these scenarios is the use of dual antiplatelet therapy in patients who require chronic oral anticoagulation. Although each of these treatments has clear benefits,1Hart R.G. Benavente O. McBride R. Pearce L.A. Antithrombotic therapy to prevent stroke in patients with atrial fibrillation: a meta-analysis.Ann Intern Med. 1999; 131: 492-501Crossref PubMed Scopus (1489) Google Scholar, 2Skanes A.C. Healey J.S. Cairns J.A. et al.Focused 2012 update of the Canadian Cardiovascular Society atrial fibrillation guidelines: recommendations for stroke prevention and rate/rhythm control.Can J Cardiol. 2012; 28: 125-136Abstract Full Text Full Text PDF PubMed Scopus (411) Google Scholar, 3Bell A.D. Roussin A. Cartier A. et al.The use of antiplatelet therapy in the outpatient setting: Canadian Cardiovascular Society Guidelines Executive Summary.Can J Cardiol. 2011; 27: 221Abstract Full Text Full Text PDF Scopus (42) Google Scholar, 4Connolly S.J. Ezekowitz M.D. Yusuf S. et al.Dabigatran versus warfarin in patients with atrial fibrillation.N Engl J Med. 2009; 361: 1139-1151Crossref PubMed Scopus (8573) Google Scholar there is concern about bleeding risk when they are used together. Physicians are forced to choose between risking a thromboembolic or a bleeding complication. To best serve our patients, we must consider not only our initial reaction to do no harm, but go through the slower process5Kahneman D. Thinking Fast and Slow. Farrar, Straus and Giroux, New York2011Google Scholar of calculating the risk and severity of all possible adverse effects. However, for this process to succeed, we need robust data on which to base these calculations. This issue of the Canadian Journal of Cardiology (CJC) contains 2 articles which provide much-needed data. In the first, Ho and colleagues study the most common group of patients requiring chronic anticoagulation—individuals with atrial fibrillation.6Ho K.W. Ivanov J. Freixa X. et al.Antithrombotic therapy after coronary stenting in patients with nonvalvular atrial fibrillation.Can J Cardiol. 2013; 29: 213-218Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar Their single-centre Canadian study included 602 patients with atrial fibrillation as their only indication for anticoagulation who underwent percutaneous coronary intervention (PCI) between 2008 and 2009. All were treated with dual antiplatelet therapy using aspirin and clopidogrel. The study was not randomized; however, physicians elected to treat 382 patients with triple therapy (ie, continued warfarin along with dual antiplatelet therapy), and 220 patients received dual antiplatelet therapy alone.6Ho K.W. Ivanov J. Freixa X. et al.Antithrombotic therapy after coronary stenting in patients with nonvalvular atrial fibrillation.Can J Cardiol. 2013; 29: 213-218Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar Physicians clearly favoured triple therapy among patients with a higher risk of stroke, as patients receiving triple therapy were older (72.9 vs 70.5 years, P = 0.039), were more likely to have suffered a previous stroke (14.4% vs 6.4%, P = 0.01) and had a higher Congestive Heart Failure, Hypertension, Age, Diabetes, Stroke/Transient Ischemic Attack CHADS2 score (2.6 vs 2.1; P < 0.001).6Ho K.W. Ivanov J. Freixa X. et al.Antithrombotic therapy after coronary stenting in patients with nonvalvular atrial fibrillation.Can J Cardiol. 2013; 29: 213-218Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar The risk of stroke in Ho's series was similar for patients treated with dual antiplatelet therapy and triple therapy; approximately 1%.6Ho K.W. Ivanov J. Freixa X. et al.Antithrombotic therapy after coronary stenting in patients with nonvalvular atrial fibrillation.Can J Cardiol. 2013; 29: 213-218Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar However, with such a low event rate, this study did not have sufficient statistical power to detect any meaningful difference in stroke between treatment strategies. The rates of major bleeding and of bleeding requiring blood transfusion were approximately 10%; however, again there was no difference between treatment groups. The authors did report a significantly increased risk of gastrointestinal bleeding with triple therapy (2.6% vs 0.5%; P = 0.045)6Ho K.W. Ivanov J. Freixa X. et al.Antithrombotic therapy after coronary stenting in patients with nonvalvular atrial fibrillation.Can J Cardiol. 2013; 29: 213-218Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar; however, it should be noted that this was a secondary outcome and the P value was borderline and unadjusted for multiple testing. The authors then conducted 2 sophisticated analyses to evaluate the net clinical benefit for triple therapy compared with dual antiplatelet therapy and to determine if it varied in relation to patients' baseline stroke risk. Several methods have been proposed to compare stroke and major bleeding on a common scale; however, the authors selected the method used in the Atrial Fibrillation Clopidogrel Trial With Irbesartan for Prevention of Vascular Events (ACTIVE) study.7Connolly S.J. Eikelboom J.W. Ng J. et al.Net clinical benefit of adding clopidogrel to aspirin therapy in patients with atrial fibrillation for whom vitamin K antagonists are unsuitable.Ann Intern Med. 2011; 155: 579-586Crossref PubMed Scopus (118) Google Scholar This method assigns a weight of 1.0 for strokes and 0.67 for major bleeds, based on the relative association of these 2 outcomes to the outcome of death or disability.7Connolly S.J. Eikelboom J.W. Ng J. et al.Net clinical benefit of adding clopidogrel to aspirin therapy in patients with atrial fibrillation for whom vitamin K antagonists are unsuitable.Ann Intern Med. 2011; 155: 579-586Crossref PubMed Scopus (118) Google Scholar Using this method, they found that the sum of stroke and bleeding events favoured triple therapy among patients at higher risk of stroke (specifically a CHADS2 score > 2), but favoured dual antiplatelet therapy for those with a lower stroke risk.6Ho K.W. Ivanov J. Freixa X. et al.Antithrombotic therapy after coronary stenting in patients with nonvalvular atrial fibrillation.Can J Cardiol. 2013; 29: 213-218Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar Although Ho's study is too small to precisely compare stroke and bleeding rates between treatment strategies, it is sufficiently large to estimate the absolute event rates and to generate the hypothesis that patients with a higher risk of stroke may benefit more from triple therapy. The second report from Andrade and colleagues is a systematic review and meta-analysis of observational studies evaluating the risk of major bleeding with dual antiplatelet therapy compared with triple therapy, in a variety of patient populations.8Andrade J.G. Deyell M.W. Khoo C. Lee M. Humprhries K. Cairns J.A. Risk of bleeding on triple antithrombotic therapy following percutaneous coronary intervention/stenting: a systematic review and meta-analysis.Can J Cardiol. 2013; 29: 204-212Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar Like most meta-analyses, this study includes large numbers of patients on which to base a more precise estimate of the relative risk of major bleeding; however, does so at the expense of some uncertainty because of the differences in patient populations and outcome ascertainment between included studies. Andrade and colleagues identified 18 observational studies which included 2499 patients treated with triple therapy. Their pooled estimate of the included studies suggested that major bleeding9Connolly S. et al.Active Steering Committee; ACTIVE InvestigatorsRationale and design of ACTIVE: the atrial fibrillation clopidogrel trial with irbesartan for prevention of vascular events.Am Heart J. 2006; 151: 1187-1193Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar was increased with triple therapy, both at 30 days (odds ratio, 2.38; 95% confidence interval, 1.05-5.38) and 6 months (odds ratio, 2.87, 95% confidence interval, 1.47-5.62) after PCI.8Andrade J.G. Deyell M.W. Khoo C. Lee M. Humprhries K. Cairns J.A. Risk of bleeding on triple antithrombotic therapy following percutaneous coronary intervention/stenting: a systematic review and meta-analysis.Can J Cardiol. 2013; 29: 204-212Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar Unlike the Ho study, they did not report on stroke risk, as many of the included studies did not report thromboembolic complications or did so in a nonuniform fashion. The ideal strategy of antiplatelet and antithrombotic therapy for an individual patient involves not only the choice between dual and triple therapy, but the selection of agents, dose, and duration, and in the case of PCI, the choice of stent. In virtually all patients with a stent, the risk and consequences of stent thrombosis10Schwalm J.D. Ahmad M. Velianou J.L. Pericak D. Natarajan M.K. Long-term outcomes with paclitaxel-eluting stents versus bare metal stents in everyday practice: a Canadian experience.Can J Cardiol. 2010; 26: e40-e44Abstract Full Text PDF PubMed Scopus (7) Google Scholar make the use of dual antiplatelet therapy essential. However, the decision to continue oral anticoagulation is based on the risk of thromboembolic complications because of the underlying indication for this therapy. In the case of mechanical valves or recent venous thromboembolism, continuation of anticoagulation is generally favoured.11Lip G.Y. Huber K. Andreotti F. et al.Management of antithrombotic therapy in atrial fibrillation patients presenting with acute coronary syndrome and/or undergoing percutaneous coronary intervention/stenting.Thrombo Haemost. 2010; 103: 13-28Crossref PubMed Scopus (266) Google Scholar Among patients with atrial fibrillation, it is reasonable to use risk stratification schemes such as CHADS2 to define the best strategy; considering the net clinical benefit as done by Ho and colleagues. In patients with a CHADS2 score of ≥ 2, triple therapy appears to be the preferred option, assuming the patient does not have other factors placing them at an increased risk of bleeding complications.2Skanes A.C. Healey J.S. Cairns J.A. et al.Focused 2012 update of the Canadian Cardiovascular Society atrial fibrillation guidelines: recommendations for stroke prevention and rate/rhythm control.Can J Cardiol. 2012; 28: 125-136Abstract Full Text Full Text PDF PubMed Scopus (411) Google Scholar For patients with a CHADS2 score of < 2, dual anti-platelet therapy alone is preferred for most patients, given the lower absolute risk of thromboembolic complications. Although dual antiplatelet therapy does not reduce stroke to the same extent as oral anticoagulation,12Connolly S. Pogue J. Hart R. et al.Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE W): a randomised controlled trial.Lancet. 2006; 367: 1903-1912Abstract Full Text Full Text PDF PubMed Scopus (1704) Google Scholar even in patients with a CHADS2 score of 1,13Healey J.S. Hart R.G. Pogue J. et al.Risks and benefits of oral anticoagulation compared with clopidogrel plus aspirin in patients with atrial fibrillation according to stroke risk: the Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE-W).Stroke. 2008; 39: 1482-1486Crossref PubMed Scopus (153) Google Scholar it is reassuring that dual antiplatelet therapy provides additional stroke protection beyond aspirin alone.14Connolly S.J. Pogue J. et al.ACTIVE InvestigatorsEffect of clopidogrel added to aspirin in patients with atrial fibrillation.N Engl J Med. 2009; 30: 2066-2078Google Scholar Of course, this proposed approach to therapy based on CHADS2 stratification is merely a suggested starting point. Individual patients and physicians who place different relative values on bleeding and thromboembolic complications may choose a different course. Along with a decision to use triple-therapy, several steps can be taken to minimize the bleeding risk of this strategy. First, if technically appropriate, bare metal stents can be used as they would require a shorter duration of triple therapy.11Lip G.Y. Huber K. Andreotti F. et al.Management of antithrombotic therapy in atrial fibrillation patients presenting with acute coronary syndrome and/or undergoing percutaneous coronary intervention/stenting.Thrombo Haemost. 2010; 103: 13-28Crossref PubMed Scopus (266) Google Scholar Next, although technically challenging, a lower international normalized ratio range (2.0-2.5) may be used in patients receiving warfarin. However; a more practical option is now to use 1 of the new oral anticoagulants which have lower rates of bleeding than warfarin; specifically dabigatran 110 mg twice per day4Connolly S.J. Ezekowitz M.D. Yusuf S. et al.Dabigatran versus warfarin in patients with atrial fibrillation.N Engl J Med. 2009; 361: 1139-1151Crossref PubMed Scopus (8573) Google Scholar and when available in Canada, apixaban 5 mg daily.15Connolly S.J. Eikelboom J. Joyner C. et al.Apixaban in patients with atrial fibrillation.N Engl J Med. 2012; 364: 806-817Crossref Scopus (1982) Google Scholar Similarly with the introduction of 2 new antiplatelet agents for the management of patients after PCI, if appropriate from a stent perspective, the agent with the lowest risk of bleeding (ie, standard-dose clopidogrel or ticagrelol16Steiner S. Moretl D. Chen L. Coyle D. Wells G.A. Network meta-analysis of prasugrel, ticagrelor, high- and standard-dose clopidogrel in patients scheduled for percuatenous coronary interventions.Thrombo Haemost. 2012; 108: 318-327Crossref PubMed Scopus (32) Google Scholar) should be preferred when triple therapy is desired. The wide range of currently available antiplatelet and anticoagulant medications coupled with relatively low rate of early postprocedural stroke in the PCI population6Ho K.W. Ivanov J. Freixa X. et al.Antithrombotic therapy after coronary stenting in patients with nonvalvular atrial fibrillation.Can J Cardiol. 2013; 29: 213-218Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar make it highly unlikely that a high-quality prospective, randomized trial will ever be conducted to evaluate the ideal combination of antiplatelet and anticoagulant medications which should be given to patients after PCI. However, the 2 studies in this issue of CJC, along with earlier work and clinical practice guidelines2Skanes A.C. Healey J.S. Cairns J.A. et al.Focused 2012 update of the Canadian Cardiovascular Society atrial fibrillation guidelines: recommendations for stroke prevention and rate/rhythm control.Can J Cardiol. 2012; 28: 125-136Abstract Full Text Full Text PDF PubMed Scopus (411) Google Scholar, 11Lip G.Y. Huber K. Andreotti F. et al.Management of antithrombotic therapy in atrial fibrillation patients presenting with acute coronary syndrome and/or undergoing percutaneous coronary intervention/stenting.Thrombo Haemost. 2010; 103: 13-28Crossref PubMed Scopus (266) Google Scholar now provide reasonable guidance for clinicians who must face these difficult decisions. The author has no conflicts of interest to disclose.