138 Creager Figure 8 Subgroup analysis for the primary endpoint of ischemic stroke, myocardial infarction, or vascular death in the CAPRIE trial. Of the patients with peripheral arterial disease, those randomized to aspirin had an event rate of 4.86% per year and those random- ized to clopidogrel had an event rate of 3.71% per year, accounting for relative risk reduc- tion of 23.8%. (Reproduced from Ref. 38.) eral arterial complications, bleeding, neutropenia, thrombocytopenia, or early drug discontinuation because of a noncardiac adverse event. This endpoint oc- curred in 4.6% of patients in the clopidogrel group compared to 9.1% of those assigned to ticlopidine. The incidence of major adverse cardiac events, defined as cardiac death, myocardial infarction, or target lesion revascularization occurred with a low, but similar, frequency in each treatment group, approximating 1.2% in those who received a clopidogrel loading dose plus maintenance therapy, 1.5% of those receiving maintenance clopidogrel without a load, and 0.9% of those receiving ticlopidine (Fig. 9). Thus, the efficacy of clopidogrel in preventing com- plications following coronary stenting was comparable to that of ticlopidine, yet there were fewer peripheral or bleeding complications with clopidogrel. Given evidence that aspirin or clopidogrel given alone reduces vascular event rates, it became critical to evaluate whether the combination of these two agents might provide further benefit for high-risk patients. This issue was ad- dressed in the recently completed Clopidogrel in Unstable angina to prevent Re- current Events (CURE) trial, which included 12,562 patients with acute coronary Aspirin, Ticlopidine, and Clopidogrel 139 Figure 9 The CLASSICS trial. The effect of clopidogrel plus aspirin to ticlopidine plus aspirin in patients undergoing coronary stenting. The incidence of major adverse cardio- vascular events, including cardiac death, myocardial infarction, or target lesion revascu- larization was comparable across treatment groups. (Adapted from Ref. 40.) syndromes without ST segment elevation (i.e., unstable angina or non-Q-wave myocardial infarction) who presented within 24 h of chest pain onset (39a). Pa- tients were required to have either ECG changes compatible with new ischemia (without ST segment elevation) or elevated cardiac enzymes or troponin I or T at least twice the upper limit of normal. Patients were randomly allocated to clopidogrel (300 mg loading dose fol- lowed by 75 mg daily) or placebo, both given in combination with aspirin (75 to 325 mg daily) and other standard therapies. Patients were treated and followed for 1 year. Overall, the combination of clopidogrel and aspirin resulted in a lower inci- dence of the primary trial outcome of cardiovascular death, MI, or stroke com- pared with the aspirin only group (9.3 vs. 11.4%; relative risk reduction 20%; 95% CI 10 to 28%; p Ͻ 0.001). When refractory ischemia was also included in this combined endpoint, there were 1040 events in the clopidogrel plus aspirin group as compared to 1196 events in the aspirin alone group, a relative risk reduction of 14 percent (95% CI 6 to 21%; p Ͻ 0.001). These benefits were seen in all major subgroups evaluated and were in addition to other standard treatments including heparin, glycoprotein IIb/IIIa inhibitors, beta-blockers, ACE inhibitors, and lipid-lowering agents. There was also a 25% reduction in severe ischemia during initial hospitalization and an 18% lower incidence of developing heart failure, although no difference was observed between treatment groups for refrac- tory ischemia after hospital discharge. The CURE trial data are likely to impact broadly on both the initial and long-term care of patients with acute coronary ischemia. Given the failure of oral 140 Creager glycoprotein IIb/IIIa inhibitors and the previously proven benefits of clopidogrel for initial management of in-stent thrombosis, it is probable that combined clopi- dogrel plus aspirin therapy will become a key addition to the care of high-risk patients. Compared with aspirin, however, the cost of clopidogrel is significant so the cost-effectiveness of this approach is currently uncertain for use beyond the first year. Several additional trials that are assessing the efficacy of clopidogrel in preventing cardiovascular events are currently taking place. These include: the Clopidogrel Reduction of Events During Extending Observation (CREDO) trial in which patients undergoing percutaneous revascularization will receive clopido- grel with aspirin for 1 year versus clopidogrel plus aspirin for 1 month followed by aspirin for another 11 months and the Warfarin and Antiplatelet Therapy in Chronic Heart Failure (WATCH) trial in which patients with congestive heart failure will be randomized to warfarin (titrated to an INR of 2.5–3.0), clopidogrel 75 mg/day, or aspirin 160 mg/day, and followed for up to 5 years. A. Adverse Effects of Clopidogrel In the CAPRIE trial, bleeding occurred with comparable frequency in the patients receiving clopidogrel compared to aspirin (9.27% vs. 9.28%, respectively) (38). In patients receiving clopidogrel, intracranial hemorrhage occurred in 0.35% and gastrointestinal hemorrhage in 1.99%, the latter being less frequent than in pa- tients receiving aspirin (38). In patients receiving clopidogrel, diarrhea occurred in 4.46% and rash occurred in 6.02%. Of patients receiving clopidogrel, neutro- penia (Ͻ1200/µL) was present in 0.1%, severe neutropenia (Ͻ450/µL) in 0.05%, thrombocytopenia (Ͻ100 ϫ 10 3 /µL) in 0.26%, and severe thrombocytopenia (Ͻ80 ϫ 10 3 /µL) in 0.19% of patients receiving clopidogrel. A recent report high- lighted the potential association of thrombotic thrombocytopenic purpura with clopidogrel (41). Eleven patients who had been treated with clopidogrel, 10 of whom had been treated for 14 days or less, were identified over a 2-year period by active surveillance of medical directors of blood banks, hematologists, and a surveillance overseen by pharmaceutical manufacturers. At the time of this report, the authors estimated that more than 3 million people had received clopidogrel. Idiopathic thrombotic thrombocytopenic purpura has been estimated to occur in approximately 3.7 per million persons per year (42). The CURE trial provides important information on expected side effects that are associated with clopidogrel 75 mg daily given in addition to aspirin. During 1 year of therapy, there was a statistically significant increase in major bleeding between the clopidgrel plus aspirin–treated group compared to the aspi- rin-alone group (3.7 vs. 2.7%; p ϭ 0.003). However, there was no statistically significant difference in the CURE trial for life-threatening bleeds between the two treatment groups. Aspirin, Ticlopidine, and Clopidogrel 141 Bleeding in the CURE trial was managed with either therapy interruption or transfusion; the principal sites for major bleeds were gastrointestinal and punc- ture sites. VI. CONCLUSION Platelets contribute to the thrombotic complications of atherosclerosis, and anti- platelet therapy reduces adverse cardiovascular events in patients with atheroscle- rosis. Both aspirin and clopidogrel are effective and relatively safe antiplatelet agents. 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Increasing mortality from thrombotic thrombo- cytopenic purpura in the United States—analysis of national mortality data, 1968– 1991. Am J Hematol 1995; 50:84–90. 8 Clinical Accomplishments of ACE Inhibition Therapy: With and Without Aspirin Marc A. Pfeffer Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts I. INTRODUCTION Inhibitors of converting enzyme, or kininase II, commonly called angiotensin- converting enzyme (ACE) inhibitors, were first developed in the late 1970s as a specific pharmacological treatment to lower blood pressure in a subset of hyper- tensive patients with elevated renin (1). Over the past two decades, as a conse- quence of intense basic and clinical investigations, it has now become clear that these agents have a much greater therapeutic effect than originally conceived. Indeed, ACE inhibitors are currently considered as life-saving and morbidity- reducing therapies for patients with heart failure, asymptomatic left ventricular dysfunction, acute and chronic myocardial infarction, diabetes, and other forms of nephropathy. Most recently, this list of beneficiaries has been expanded to the broad population of patients with vascular disease or diabetes and a concomitant risk factor. These impressive accomplishments stem from a series of international multicenter trials generating consistent information regarding survival and other important clinical outcome benefits with the use of these compounds. This chapter will provide an overview of these accomplishments and then focus on one of the current issues that is particularly relevant to these proceedings on thrombosis and thromboembolism—the question of a potential aspirin–ACE-inhibitor negative interaction. 145 146 Pfeffer II. ACCOMPLISHMENTS OF ACE INHIBITORS A. Heart Failure Heart failure was the first major area in which ACE inhibitors have proven their undisputed role in improving clinical outcomes, indeed, survival. In the early 1980s, the ‘‘vasodilator era,’’ then pioneering acute studies revealed that favor- able hemodynamic improvements could be obtained by ACE inhibitors in patients with severe heart failure (2,3). The first demonstration of a survival benefit with the use of an ACE inhibitor in any cohort of patients can be attributed to the Cooperative North Scandinavian ENalapril SUrvival Study (CONSENSUS), which randomized patients with severe heart failure (4). In this trial, despite the use of digitalis, diuretics, and other vasodilators, the placebo mortality rate was exceedingly high, approaching 50% at 6 months. Those randomized to the active therapy (enalapril) had a pronounced reduction in the risk of death. Indeed, the combination of the high placebo event rate and the relative effectiveness of ther- apy led to conclusive results in a population of approximately 500 patients. The Studies of Left Ventricular Dysfunction (SOLVD) greatly expanded the indications for ACE inhibitors as a consequence of their results in two parallel randomized trials collectively involving over 6000 patients (5,6). In the treatment arm, symptomatic heart failure patients with left ventricular dysfunction (ejection fraction Ͻ35%) of all etiologies were randomized to placebo or enalapril. Despite background therapy with digitalis or diuretics or both, the enalapril group experi- enced a 16% reduction in the risk of death and clear reductions in the need for rehospitalization for heart failure. The same screening procedures identified and randomized over 4000 patients who also had left ventricular dysfunction. However, the study investigators did not feel that these patients had sufficient symptoms to warrant therapy—the Prevention Arm. In this unique group, the randomization to enalapril showed a favorable trend for a reduction in fatal events with a clear reduction in the development of heart failure during the ap- proximately 4 years of follow-up. As a consequence of these and other smaller studies, ACE inhibitors had proven themselves as an essential, indeed, ‘‘corner- stone’’ therapy for the management of patients with heart failure (7). In some respects, the V-HeFT-II study put the icing on the cake for the use of ACE inhibi- tors in heart failure. It showed that, in a group of symptomatic heart failure pa- tients randomized to either the combination of hydralazine and nitrates (the first life-sustaining therapy for heart failure) versus enalapril, the ACE inhibitor re- sulted in superior survival even compared to a previously proven therapy for heart failure (8). Taken together, we now had clear evidence that the morbidity and mortality of heart failure could be effectively reduced by the use of an ACE inhibitor (9). ACE Inhibition Therapy 147 B. Myocardial Infarction The rationale for the treatment of patients with myocardial infarction with an ACE inhibitor stems from the pioneering work of the late Dr. Janice Pfeffer, beginning when she was a fellow in the Braunwald laboratory. Experimental models of infarctions were readily utilized to determine whether infarct size could be favorably modified by pharmacological therapy. Pfeffer explored the relation- ship between infarct size and ventricular function and incorporated important lessons from her doctoral training in hypertension at Edward Frohlich’s labora- tory to determine the long-term consequences of abrupt loss of myocardium from coronary ligation. Indeed, she demonstrated in the animal model that the loss of myocytes should be viewed as the beginning of an insidious phase of progressive ventricular enlargement (remodeling), which is related both to the extent of the histological damage as well as to the duration of time from the infarct (10). In- deed, the enlargement itself is a central component in the progressive worsening of dysfunction. Ventricular remodeling could also involve the normal remaining myocardium, which, as a consequence of unfavorable geometry and wall stress, could suffer an abnormal hemodynamic burden (11). These observations of ventricular remodeling provided a new therapeutic target for a novel use of ACE inhibition—to attenuate time-dependent ventricular enlargement following infarction. The use of ACE inhibitors was a natural exten- sion of her work in hypertension, where these agents were particularly effective in preventing hypertrophy and left ventricular chamber enlargement (12). In the myocardial infarction model, long-term administration of an ACE inhibitor did indeed attenuate ventricular enlargement as treated animals had smaller left ven- tricular cavities and more preserved ventricular pump function (13). In a subse- quent study, a prolongation of survival was demonstrated with ACE inhibitor treatment (14). These animal studies provided the rationale for initially small mechanistic studies, which confirmed both the process of progressive enlargement post–myo- cardial infarction and the attenuation of enlargement with the use of an ACE inhibitor (15,16). These mechanistic studies were soon followed by an extensive series of international multicenter randomized trials testing the hypothesis that administration of an ACE inhibitor to patients in the acute and chronic phases of myocardial infarction would lead to improved survival. The Survival and Ven- tricular Enlargement (SAVE) study, as suggested by the trial’s acronym, tested the hypothesis that attenuation of ventricular enlargement in high-risk patients post–myocardial infarction would lead to improved survival (17). The SAVE study demonstrated that the addition of captopril to a conventionally treated pa- tient who survived a myocardial infarction with an ejection fraction less than 40% without overt heart failure would lead not only to a reduction in the risk of [...]... the renin-angiotensin system and the balance between thrombolysis and thrombosis An infusion of angiotensin-II raised plasminogen activator inhibitor-1 (PAI-1), which would alter the fibrinolytic balance toward thrombosis (34) The randomized use of ACE inhibitors in patients with acute myocardial infarction did indeed lower PAI-1 levels and, particularly, the balance of PAI-1 to intrinsic tPA ( 35) Augmented... SAVE, AIRE, TRACE, SOLVD (Selective LongTerm Trials) Death ASA: yes no Death, HF, MI ASA: yes no ACE inhibitor odds ratio 1699/ 759 7 (22.3%) 0. 85 (0.76 Ϫ 0. 95) 1 457 /51 58 (28.6%) 0. 75 (0.67 Ϫ 0. 85) test for heterogeneity NS; p ϭ 0.23 257 1/ 759 7 (33.8%) 0.76 (0.69 Ϫ 0.84) 21 95/ 5 158 (42.6%) 0.68 (0.60 Ϫ 0.76) test for heterogeneity NS; p ϭ 0.20 ASA use at baseline; ACE inhibitor odds ratio Source: From Ref... M, Hall A, Murray G, Torp-Pedersen C, ´ Ball S, Pogue J, Moye L, Braunwald E, for the ACE-inhibitor Myocardial Infarction Collaborative Group Long-term ACE-inhibitor therapy in patients with heart failure ACE Inhibition Therapy 25 26 27 28 29 30 31 32 33 34 35 157 or left-ventricular dysfunction: a systematic overview of data from individual patients Lancet 2000; 355 : 157 5– 158 1 Pfeffer MA ACE inhibitors... infarction: ISIS-2 Lancet 1988; 2:349– 360 Hall D, Zeitler H, Rudolph W Counteraction of the vasodilator effects of enalapril by aspirin in severe heart failure J Am Coll Cardiol 1992; 20: 154 9– 155 5 Spaulding C, Charbonnier B, Cohen-Solal A, Juilliere Y, Kromer EP, Benhamda K, Cador R, Weber S Acute hemodynamic interaction of aspirin and ticlopidine ACE Inhibition Therapy 49 50 51 52 53 54 159 with enalapril... double-blind, randomized comparative trial Circulation 1998; 98: 757 –7 65 Brown J, Dollery C, Valdes G Interaction of nonsteroidal anti-inflammatory drugs with antihypertensive and diuretic agents Control of vascular reactivity by endogenous prostanoids Am J Med 1986; 25: 43 57 Hall D The aspirin-angiotensin-converting enzyme inhibitor tradeoff: to halve and halve not [editorial] J Am Coll Cardiol 2000; 35: 1808–1812... lesions Ultrasound Med Biol 19 85; 11(3) :51 5 52 1 10 Allard L, Cloutier G, Guo Z, Durand LG Review of the assessment of single level and multilevel arterial occlusive disease in lower limbs by duplex ultrasound Ultrasound Med Biol 1999; 25( 4):4 95 50 2 11 Roth SM, Bandyk DF Duplex imaging of lower extremity bypasses, angioplasties, and stents Semin Vasc Surg 1999; 12(4):2 75 284 12 Allard L, Cloutier G Power... selection and timing [editorial] Circulation 1998; 97:2192–2194 ISIS-4 Collaborative Group ISIS-4 A randomised factorial trial assessing early oral captopril, oral mononitrate, and intravenous magnesium sulphate in 58 , 050 patients with suspected acute myocardial infarction Lancet 19 95; 3 45: 669–6 85 Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico GISSI3 Effects of lisinopril and transdermal... estimates and to particularly probe prospective subgroup analyses for both efficacy and safety The ACE Inhibitor Myocardial Infarction Collaborative group prospectively determined that the broad-inclusion, short-term studies should be analyzed separately from the elective-inclusion, long-term studies Both of these systematic overviews (metanalysis) have been completed and recently published (54 ,24) In... Engl J Med 2000; 342:1 45 153 Lonn E, Yusuf S, Dzavik V, Doris C, Yi Q, Smith S, Moore-Cox A, Bosch J, Riley W, Teo K Effects of ramipril and Vitamin E on atherosclerosis: Results of the study to evaluate carotid ultrasound changes in patients treated with ramipril and vitamin E (SECURE) Circulation 2001; 103:919–9 25 Hennekens CH, Buring JE, Sandercock P, Collins R, Peto R Aspirin and other antiplatelet... enalapril and aspirin on mortality after acute myocardial infarction: subgroup analysis of the Cooperative New Scandinavian Enalapril Survival Study II (CONSENSUS II) Am J Cardiol 1997; 79:1 15 119 Leor J, Reicher-Reiss H, Goldbourt U, Boyko V, Gottlieb S, Battler A, Behar S Aspirin and mortality in patients treated with angiotensin-converting enzyme inhibitors J Am Coll Cardiol 1999; 33:1920–19 25 Anti-Platelet . important interface between the renin-angiotensin system and the balance between throm- bolysis and thrombosis. An infusion of angiotensin-II raised plasminogen activa- tor inhibitor-1 (PAI-1), which would alter. AIRE, TRACE, SOLVD (Selective Long- Term Trials) Death ACE inhibitor odds ratio ASA: yes 1699/ 759 7 (22.3%) 0. 85 (0.76 Ϫ 0. 95) no 1 457 /51 58 (28.6%) 0. 75 (0.67 Ϫ 0. 85) test for heterogeneity NS; p. heart failure ACE Inhibition Therapy 157 or left-ventricular dysfunction: a systematic overview of data from individual pa- tients Lancet 2000; 355 : 157 5– 158 1. 25. Pfeffer MA. ACE inhibitors in acute