Combination Antithrombotic Therapy with Antiplatelet Agents and Anticoagulants for Patients with Atherosclerotic Heart Disease (

Continued from previous page Potential indications for combination therapy with aspirin plus warfarin Intracardiac thrombi usually form on inflamed or damaged valves, endocardium within an MI, in a dilated or dyskinetic cardiac chamber, or on prosthetic valves.^29–31 Coagulation is more important in the pathogenesis of intracardiac thrombi than platelet activation, although the latter plays a contributory role. The common factor in the thromboembolic potential of acute MI, left ventricular (LV) aneurysm and dilated cardiomyopathy is mural thrombus. This can be detected by two-dimensional echocardiography and/or indium-111 platelet scintigraphy.³⁰ According to the year 2001 guidelines from the American College of Chest Physicians on Antithrombotic Therapy, “if warfarin therapy is commenced in patients with acute MI and CAD, aspirin therapy should be discontinued until the planned course of therapy with warfarin is complete.”¹ However, the contemporary management of acute MI often involves primary coronary angioplasty and stenting. Coronary stenting necessitates therapy with the combination of aspirin plus clopidogrel for at least one month to prevent stent thrombosis.³² Omission of aspirin or clopidogrel can lead to stent thrombosis, which in turn leads to transmural MI in 90% and death in 25% of cases.³³ The general guideline of discontinuing aspirin or clopidogrel, as stated by the American College of Chest Physicians,¹ may not be the best approach in post-MI patients with indications for warfarin. Acute myocardial infarction and left ventricular aneurysm. Patients with anterior/apical MI are at greatest risk for infarct expansion and aneurysm formation. Patients who do not receive reperfusion therapy or in whom reperfusion therapy fails are at greater risk for aneurysm formation. Mural and occasionally protruding thrombi develop within the first week following acute anterior Q-wave MIs with akinetic or dyskinetic segments. The estimated incidence of LV thrombi in echocardiographic studies is approximately 33% for anterior MI and 31 LV thrombi are associated with increased risk for systemic embolization, when they are mobile and have a protruding appearance.³¹ In contrast, patients with chronic LV aneurysm (first documented at least one month after MI) are at low risk for systemic embolization.³⁴ Warfarin therapy (range, 2.0–3.0) is recommended for patients with anterior MI and LV aneurysm for a duration of 1–3 months.¹ Chronic LV aneurysm, by itself, does not justify the use of long-term anticoagulation therapy.¹ There are no data on the management of patients with acute MI who undergo coronary stenting, which requires therapy with aspirin and clopidogrel, and are noted to have LV aneurysm, which would require therapy with heparin followed by warfarin. Since such patients are at high risk for recurrent ischemic events, combination therapy with aspirin and warfarin (INR, 2.0–2.5) after 2–4 weeks of concomitant clopidogrel therapy for coronary stenting may be the most prudent approach. Acute myocardial infarction and atrial fibrillation. Atrial fibrillation (AF) occurs in up to 22% of patients with acute MI, particularly in elderly patients, and is an ominous sign.^35,36 In patients with AF, presence of any high-risk factor (age > 75 years, prior transient ischemic attack or stroke, prior systemic embolism, hypertension, poor LV systolic function and rheumatic mitral valve disease) mandates anticoagulation therapy with warfarin.^37–39 Patients with acute MI and CAD should be treated with daily aspirin indefinitely. Management of a patient with acute MI and AF who undergoes coronary stenting presents a therapeutic dilemma. Despite the recommendations from the American College of Chest Physicians on Antithrombotic Therapy,¹ aspirin therapy should not be discontinued after coronary stenting. Since there are no data on the efficacy and safety of combination therapy with aspirin and clopidogrel, plus warfarin, it would be prudent to individualize the antithrombotic regimen and maintain very close follow-up for at least 2–4 weeks. Acute myocardial infarction and left ventricular dysfunction. Patients with acute MI who develop LV dysfunction [ejection fraction (EF) 35%. The risk of stroke increased with decreasing LVEF, and anticoagulant therapy appeared to have a protective effect against stroke after MI.⁴⁰ In asymptomatic patients with severe LV dysfunction, the overall prevalence of cerebral microemboli is 31%, as detected by transcranial Doppler sonography.⁴¹ Patients with ASHD and ischemic cardiomyopathy may be candidates for combined aspirin plus warfarin. In the Warfarin/Aspirin Study of Heart Failure (WASH) trial, a total of 279 patients with congestive heart failure and LV dysfunction predominantly due to CAD were randomized to aspirin (300 mg/day), warfarin (target INR, 2.5) or no antithrombotic therapy.⁴² At a mean follow-up of 27 months, the primary endpoint of death, MI and stroke occurred in 26% in the warfarin group, 32% in the aspirin group and 27% in the control group (p = NS). Patients with acute MI complicated by severe LV dysfunction should receive long-term warfarin therapy (INR, 2.0–3.0) for 1–3 months.¹ Treatment of acute MI patients who undergo coronary stenting and are found to have LV dysfunction should be individualized. There is no randomized trial on concomitant therapy with aspirin, clopidogrel, plus warfarin in such patients. The Warfarin and Antiplatelet Therapy in Chronic Heart Failure (WATCH) trial, evaluating the efficacy of antithrombotic therapy with warfarin versus aspirin versus clopidogrel in patients with heart failure, is currently underway. Aortic atheroma and stroke. In addition to AF and CAD, atherosclerotic disease of the ascending aorta and aortic arch (“aortic atheroma”) has become recognized as an important source of cerebral emboli and “cryptogenic” stroke, thanks to imaging with transesophageal echocardiography (TEE).^43–48 The prevalence of aortic arch atheromas in patients with cerebral or peripheral embolic disease is 21–27%.⁴⁸ In the French Aortic Plaque in Stroke (FAPS) trial, atherosclerotic plaque >= 4 mm in thickness was found in 14.4% of the patients with ischemic stroke versus only 2% of the patients in the control group.45 After adjustment for other risk factors, the OR for ischemic stroke among patients with such plaques was 9.1 (95% CI, 3.3–25.2; p 48 A significant proportion (25–50%) of protruding aortic atheromas seen on TEE have mobile components that move freely with the blood flow and are in fact thrombi superimposed on atherosclerotic plaque.⁴⁸ Anticoagulation with warfarin may therefore be beneficial in reducing the risk of stroke in patients with protruding aortic atheromas. In a TEE study of patients with mobile lesions in the aorta, there was a higher incidence of vascular events in patients not treated with warfarin as compared to those given warfarin (45% versus 5%; p = 0.006).⁴⁷ In the echocardiographic substudy of the Stroke Prevention in Atrial Fibrillation (SPAF) trial, a total of 134 patients were found to have complex aortic plaque on TEE.⁴⁹ In these patients, adjusted-dose warfarin (INR, 2.0–3.0), as compared to fixed, low-dose warfarin (INR, 1.2–1.5), significantly reduced the risk of ischemic stroke by 75% (15.8% versus 4%; p = 0.02).⁵⁰ Since the presence of aortic atheroma correlates well with the presence of significant angiographic coronary artery stenosis,⁵¹ it would appear that the dilemma of needing both anticoagulation for the aortic debris, plus aspirin or clopidogrel for the coronary disease, has to be faced again. Newer Alternatives for Combination Antithrombotic Therapy Clopidogrel. One of the newer agents used in combination with aspirin for patients with CAD and non-ST elevation ACS is clopidogrel, a thienopyridine derivative. The efficacy of clopidogrel (75 mg daily) versus aspirin (325 mg daily) in reducing the risk of ischemic stroke, MI or vascular death was established in the Clopidogrel versus Aspirin at Risk of Ischemic Events (CAPRIE) trial of 19,185 patients with atherosclerotic vascular disease.9 The effect of combination therapy with aspirin plus clopidogrel, versus aspirin alone, was evaluated in the recent Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial of 12,562 patients with non-ST elevation ACS.⁵² The primary composite outcome of death, nonfatal MI or stroke occurred in 9.3% of the aspirin plus clopidogrel group and 11.4% of the aspirin alone group (p 52 In summary, combination therapy with aspirin plus clopidogrel is associated with better outcomes at a small price with regard to bleeding for patients with ACS. However, the cost-effectiveness of this combination therapy needs to be further elucidated.⁵³Ximelagatran. In recent studies, some of which are still on-going, ximelagatran, a novel oral direct thrombin inhibitor, was evaluated as an oral anticoagulant for patients with atrial fibrillation, deep vein thrombosis or pulmonary embolism.^54–58 In the Stroke Prevention by Oral Thrombin Inhibitor in Atrial Fibrillation (SPORTIF II) study, the tolerability and safety of 3 fixed doses of ximelagatran were compared to dose-adjusted warfarin in patients with non-valvular atrial fibrillation, who had at least one additional risk factors for stroke.⁵⁵ After 12 weeks, two of 187 patients on ximelagatran had thromboembolic events [1 transischemic attack (TIA) and 1 nonfatal ischemic stroke] and 2 of 67 patients in the warfarin group had TIAs. There were no major bleeds in any of the ximelagatran groups, but one major non-central nervous system bleed was observed in a patient receiving warfarin. This pilot trial indicated that fixed doses of ximelagatran (up to 60 mg twice daily) were well tolerated in patients with non-valvular atrial fibrillation during a 3-month treatment period.⁵⁵ The SPORTIF IV study was an open-label continuation of the 12-week randomized dose-guiding study (SPORTIF II) of ximelagatran compared with warfarin.⁵⁶ At 21–24 months follow-up, 1.8% of patients in the ximelagatran group versus 6.8% of patients in the warfarin group had experienced stroke or TIA. Major bleeding complications occurred in 0.9% of the patients in the ximelagatran group and 4.1% of the patients in the warfarin group. In the SPORTIF III study, a total of 3,410 patients with AF and one or more stroke risk factors were randomized to open-label warfarin (adjusted-dose INR, 2.3–3.0) or ximelagatran (fixed-dose, 36 mg twice daily).⁵⁷ During 4,941 patient-years of exposure (mean, 17.4 months), 96 patients had primary events (56 in the warfarin group versus 40 in the ximelagatran group). The primary event rate by intention to treat was 2.3% per year with warfarin and 1.6% per year with ximelagatran (p = 0.10). Rates of disabling or fatal stroke, mortality and major bleeding were similar between groups, but combined minor and major hemorrhages were lower with ximelagatran than with warfarin (29.8% versus 25.8% per year; p = 0.007). Raised serum alanine aminotransferase was more common with ximelagatran.57 Recently, the results of the SPORTIF V study were presented.⁵⁸ This study had a double-blind design to establish whether oral ximelagatran is noninferior to dose-adjusted warfarin, with a margin of 2% per year, in the prevention of stroke and systemic embolic events in 3,922 patients with nonvalvular atrial fibrillation and at least one additional risk factor for stroke. In 6,405 patient-years of exposure (mean, 20 months), a total of 88 patients developed primary events: 51 with ximelagatran (1.6%/year) and 37 with warfarin (1.2%/year; p = 0.089), for an absolute difference of 0.45% that confirmed the noninferiority of the new regimen by intention to treat analysis.⁵⁸ When the results of both SPORTIF III and V were pooled, ninety-one patients had events while taking ximelagatran (1.6%/year) and 93 had events while taking warfarin (1.6%/year).⁵⁸ These data suggest that fixed-dose ximelagatran (36 mg twice daily) is an effective and well-tolerated agent for prevention of stroke and systemic embolism in patients with atrial fibrillation. One of the most important aspects of therapy with ximelagatran is the fact that there is no need for routine coagulation monitoring. Ximelagatran has also been evaluated in patients with MI.^59,60 The Efficacy and Safety of the Oral Direct Thrombin Inhibitor Ximelagatran in Patients with Recent Myocardial Damage (ESTEEM) trial was a placebo-controlled, double-blind, dose-guiding study of 1,883 patients who had recent ST-elevation or non-ST elevation MI.⁵⁹ Within 14 days after the index event, patients were randomized to aspirin plus oral ximelagatran at doses of 24 mg, 36 mg, 48 mg or 60 mg twice daily, or aspirin plus placebo. The primary event was a composite of death, non-fatal MI, and severe recurrent ischemia. At 6-month follow-up, oral ximelagatran plus aspirin, as compared with aspirin alone, significantly reduced the risk for the primary endpoint from 16.3% (102/638) to 12.7% (154/1,245) (hazard ratio, 0.76; 95% CI, 0.59–0.98; p = 0.036). There was no indication of a dose response between the ximelagatran groups. Major bleeding events were rare — 1.8% and 0.9% in the combined ximelagatran and placebo groups, respectively (hazard ratio, 1.97; 95% CI, 0.80–4.84).59 At 1-year follow-up, the beneficial effect of ximelagatran was still evident, with a 24% reduction of primary endpoint (16.3% versus 12.7%; p = 0.36).⁶⁰ These preliminary data indicate that oral ximelagatran may be an effective therapeutic agent for reduction of cardiovascular events in MI patients. Oral glycoprotein (GP) IIb/IIIa inhibitors. The success of short-term therapy with intravenous GP IIb/IIIa inhibitors led to the development of oral platelet GP IIb/IIIa inhibitors (xemilofiban, orbofiban, sibrafiban) with the intention of extending the initial benefits to long-term care. However, these oral agents failed to show any beneficial effects in several trials.61 In fact, in a recent meta-analysis of 4 randomized trials involving 33,326 patients followed for > 30 days, therapy with oral platelet GP IIb/IIIa inhibitors was associated with a significant increase in mortality (OR, 1.37; 95% CI, 1.13–1.66).⁶¹ Summary Primary prevention. In individuals without symptomatic cardiovascular disease, therapy with aspirin is associated with significant reduction in the risk of nonfatal MI, especially in hypertensive patients and diabetics. In subjects with multiple risk factors who are at high risk for cardiovascular disease, combination therapy with aspirin plus low-intensity warfarin (INR, 1.5) provides additional benefits (Table 1). This is at the expense of some increased risk of bleeding. Secondary prevention. In patients with established CAD, despite the use of antiplatelet agents (aspirin), the rates of recurrent cardiovascular events remain high. Based on the available data (Table 1), combination therapy with aspirin (81 mg/day) plus moderate-intensity warfarin (INR, 2.0–3.0) is superior to aspirin alone in preventing death, nonfatal MI, recurrent angina and ischemic stroke, provided there is a good compliance rate (>= 70%) with warfarin therapy and the target INR of 2.0–3.0 is achieved (Figure 1). This beneficial effect of combination therapy is associated with a modest increase in the rate of bleeding, mostly minor bleeds (Figure 2). Other potential indications for combination therapy with aspirin and warfarin include MI associated with acute left ventricular aneurysm and protruding thrombus, atrial fibrillation, severe left ventricular systolic dysfunction and high-grade aortic debris (Figure 3). While combination therapy with aspirin plus warfarin may be justified in selected patients, there are no data regarding clopidogrel plus warfarin. It is also possible that the combination of aspirin plus clopidogrel may offer therapeutic appeal.⁶² Available data on ximelagatran indicate that this oral direct thrombin inhibitor is promising in patients with non-valvular atrial fibrillation and MI. Acknowledgment. We dedicate this manuscript to Dr. Robert Lee, who worked at Dupont Pharmaceuticals and dedicated the latter years of his life to the concept of combination antithrombotic therapy.