Follow-up: 30 days and 6 months Results: Abciximab in conjunction with primary stenting improved early TIMI 3 \202 ow rat e, left ventricular function and 30-day mortality, recurrent MI, and rates of any revascula rization. There was excess minor bleeding in the abciximab group. Reference: ADMIRAL Investigators (2001). N Engl J Med 344: 1895 \200\2231903. AFCAPS/ TexCAPS Airforce/Texas Coronary Atherosclerosis Prevention Study Purpose: To determine if lovastatin 20 \200\22340 mg/day has a role in the primary preventi on of acute coronary events (MI, unstable angina, sudden cardiac death) in 5608 men and 997 women with normal or mildly elevated total or LDL cholesterol, low HDL cholesterol, and no clinically evident atherosclerotic disease, in a randomized, placebo- controlled trial. Follow-up: 5.2 years MAJOR TRIALS IN CARDIOLOGY 599 Results: Lovastatin reduced LDL cholesterol by 25% and increased HDL cholesterol by 6%. The incidences of \201 rst major acute coronary events, MI, unstable angina, coronary revasc ularization, and cardiovascular events were all signi \201 cantly reduced. There were too few fatal cardiovascular and fatal coronary heart disease events to perform a survival anal ysis. AFCAPS/ TexCAPS Reference: Downs JR, et al. (1998). JAMA 279:1615 \200\2231622. AFFIRM Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) Investigators Purpose: To evaluate two management strategies in treating AF: 1) cardioversion followed by drugs to maintain sinus rhythm (a choice of amiodarone, disopyramide, \202 ecainide, mor ocizine, procainamide, propafenone, quinidine, sotalol); 2) rate-control drugs, allowing AF to persist (a choice of B-blockers, verapamil, diltiazem, digoxin). Anticoagulation was re commended for both groups. 4060 patients with recent-onset AF and a high risk of stroke or death were randomized. The primary end point was overall mortality. 71% had hypertension, a nd 38% had coronary artery disease. 3311 had echocardiograms, and of these, 65% had enlarge d left atria, and 26% had impaired LV function. Follow-up: 5 years Results: Mortality at 5 years was 23.8% in the rhythm- control group and 21.3% in the rate- control group (hazard ratio 1.15, p = 0.08). More patients in the rhythm-control group were hospitalized and had more adverse drug effects. In both groups, most strokes occurred afte r warfarin had been stopped or if INR was subtherapeutic; this occurred more often in the r hythm-control group. During the course of the study, 594 patients assigned to the rhythm-co ntrol group crossed over to the rate-control group, mainly because of inability to maintain sinus rhythm and drug intolerance. Reference: The AFFIRM Investigators (2002). N Engl J Med 347:1825 \200\2231833. AHEFT African American Heart Failure Trial Purpose: To evaluate treatment with \201 xed-dose isosorbide dinitrate plus hydralazine c ompared with placebo among black patients with heart failure. 1050 patients were randomized to either \201 xed-dose hydralazine and isosorbide dinitrate vs. placebo. Randomization was strati \201 ed by B-blocker use. Initial dosing was 20 mg isosorbide dinitrate and 37. 5 mg hydralazine and titrated up to 120 mg isosorbide dinitrate and 225 mg hydralazine. Mos t patients were NYHA Class III, with a mean age of 57 years and a mean ejection fraction of 24%. Follow-up: Mean 18 months CHAPTER 15 Major trials in cardiology 600 Results: Mortality was lower in the combination-therapy group, 6.2% vs. placebo 10.2%. The survival difference began at 6 months after randomization and continued to diverge through follow-up. The primary composite score was signi \201 cantly improved in the combination-t herapy group compared with placebo ( \200\2230.1 1.9 vs. \200\2230.5 2.0, p = 0.01). Target dose was given in 68.0% of patients in the combination-therapy group and 88.9% of p atients in the placebo group (p < 0.001). Blood pressure (BP) was lower in the combination- therapy group than in the placebo group (systolic BP \200\2231.9 mmHg vs. +1.2 mmHg for pl acebo, p = 0.02; diastolic BP \200\2232.4 mmHg vs. +0.8 mmHg for placebo, p < 0.001). Adve rse events of headache (47.5% vs. 19.2%, p < 0.001) and dizziness (29.3% vs. 12.3%, p < 0.0 01) were higher in the combination-therapy group, but exacerbations of CHF were lower, incl uding all exacerbations (8.7% vs. 12.8%, p = 0.04) and severe exacerbations (3.1% vs. 7.0%, p = 0.005). AHEFT Reference: Taylor AL, et al. (2004). N Engl J Med 351:2049 \200\2232057. Acute Infarction Ramipril Ef \201 cacy Study AIRE Purpose: To evaluate the effect of ramipril on total mortality of AMI survivors with early clinical evidence of heart failure, and to assess progression to severe or resistant heart failure, nonfatal reinfarction, and stroke, compared to placebo. 2006 patients aged (cid:11 6)18 years with con \201 rmed AMI 3 \200\22310 days prior to randomization with clinical e vidence of heart failure were given ramipril at a starting dose of 2.5 mg or placebo. Follow-up: Mean 15 months Results: All-cause mortality was signi \201 cantly lower at 30 days and maintained at the end of follow-up in the ramipril group (27% risk reduction), with 30% reduced risk of sudde n death. 38% of the reduction in overall mortality was in the sudden-death subgroup that ha d developed severe resistant heart failure. There was no alteration in risk of stroke or re infarction in the ramipril group. The study was continued in the AIREX study. Reference: Cleland J, et al. (1997). Eur Heart J 18:41 \200\22351. AIRE Extension Study AIREX Purpose: To assess the long-term (3 years after the end of AIRE) bene \201 t of ramipril i n the 603 UK patients from the AIRE study retrospectively, 302 initially on ramipril, 301 o n placebo. Follow-up: 3 years Results: All-cause mortality occurred in 27% of ramipril- treated patients compared to 39% of placebo controls, representing a relative risk reduction of 36%. Reference: Hall AS, et al. (1997). Lancet 349:1493 \200\2231497. MAJOR TRIALS IN CARDIOLOGY 601 ALLHAT Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial Purpose: To compare outcomes in high-risk hypertensive patients >55 years old in a prospect ive, randomized trial using standard antihypertensive drugs and newer agents as initial mon otherapy. Initially, more than 42,000 patients were randomized, but this number dropped to 33,357 after the doxazosin arm was halted because of increased morbidity (mainly stroke and heart failure) in this group compared to the chlorthalidone arm. The remainder was randomi zed to receive chlorthalidone, amlodipine, or lisinopril. 50% were women, and 35% were blac k. The primary end point was combined incidence of fatal CHD or nonfatal MI by intention to treat. Secondary outcomes were all-cause mortality, stroke, combined CHD (fatal CHD, nonfa tal MI, coronary revascularization, or angina with hospitalization), or combined cardiovasc ular disease (combined CHD plus stroke, treated angina without hospitalization, heart failu re, and peripheral arterial disease). Follow-up: Mean 4.9 years Results: All-cause mortality was not different between groups. Systolic pressures were high er with both amlodipine and lisinopril than with chlorthalidone, but diastolic pressures we re slightly better with amlodipine. Secondary outcome measures were also better with chlort halidone than with lisinopril. Reference: The ALLHAT Of \201 cers and Coordinators for the ALLHAT Collaborative Research Group (2000). JAMA 283:1967 \200\2231975. ASCOT-LLA Anglo-Scandinavian Cardiac Outcomes Trial \200\224Lipid Lowering Arm Purpose: To assess bene \201 ts of cholesterol lowering in the primary prevention of coron ary disease in hypertensive patients not conventionally deemed dyslipidaemic. 19,342 hypert ensive patients with at least three other cardiovascular risk factors were randomized to on e of two antihypertensive regimens (B-blocker plus diuretic, or calcium channel blocker plu s ACE inhibitor). Of these, 10,305 had cholesterol of >6.5 mmol/L (250 mg/dL) and were rand omized to atorvastatin 10 mg or placebo. The primary end point was death from coronary dise ase and nonfatal MI. Follow-up: Median 3.3 years CHAPTER 15 Major trials in cardiology 602 ASCOT-LLA Results: There was a signi \201 cant reduction in the primary end point in the a torvastatin group (hazard ratio 0.64, p = 0.0005), with the bene \201 t being seen by the \201 rst year of follow-up. There was a signi \201 cant reduction in fatal and nonfatal stroke, total cardiovascular events, and total coronary events in the atorvastatin group. A torvastatin lowered cholesterol by 1.1 mmol/L after 3-year follow-up compared to controls. Risk reduction in primary events was unrelated to baseline cholesterol levels. Reference: Sever P, et al. (2003). Lancet 361:1149 \200\2231158. ASSENT-1 Assessment of the Safety and Ef \201 cacy of a New Thrombolytic-1 Purpose: To evaluate the safety of different doses of TNK- tPA (tenecteplase) as a single b olus for AMI patients. 3235 patients with a mean age of 61 years were randomized to receive 30 mg (n = 1705), 40 mg (n = 1457), and 50 mg (n = 73) of TNK-tPA over 5 \200\22310 second s. Aspirin and IV heparin were given concomitantly. Follow-up: On hospital discharge, and at 30 days Results: Total stroke incidence at 30 days was 1.5%. Intracranial hemorrhage occurred in 0. 77% at 30 days, with most of these occurring in the 30 mg group. The incidence of intracran ial hemorrhage was lower in those treated within 6 hours of symptom onset. The incidence of death, nonfatal stroke, and severe bleeding were 6.4%, 7.4%, and 1.6% for the 30 mg, 40 mg , and 50 mg groups respectively, without signi \201 cant differences between groups. Reference: Van de Werf F, et al. (1999). Am Heart J 1737: 786 \200\223791. ASSENT-2 Assessment of the Safety and Ef \201 cacy of a New Thrombolytic-2 Purpose: To compare single bolus tenecteplase (TNK-tpA) and alteplase (t-PA) infusion in tr eatment of AMI. 16,949 patients with symptom onset within 6 hours and median age 61 years w ere randomized to receive either drug. Aspirin and IV heparin were given concomitantly. Follow-up: 30 days Results: 30-day mortality, nonfatal stroke, and rates of intracranial hemorrhage were simil ar in the two groups, but there were fewer bleeding complications and less need for blood t ransfusion in the TNK-tPA group. Reference: Assessment of the Safety and Ef \201 cacy of a New Thrombolytic (ASSENT-2) Inve stigators (1999). Lancet 354:716 \200\223722. MAJOR TRIALS IN CARDIOLOGY 603 Assessment of the Safety and Ef \201 cacy of a New Thrombolytic \200\2233, Assessment of t he Safety and Ef \201 cacy of a New Thrombolytic \200\2233 PLUS ASSENT-3 and ASSENT-3 PLUS In ASSENT-3 the aim was to determine the safety and ef \201 cacy of in combination with en oxaparin, half-dose TNK-tPA plus abciximab plus low- dose unfractionated heparin, or full-d ose TNK-tPA plus weight-adjusted unfractionated heparin in the treatment of 6095 patients w ith STEMI presenting within 6 hours of symptom onset. This was the \201 rst large-scale t rial to investigate the use of low-molecular-weight heparin in thrombolysis. The combined e nd points of 30-day mortality, recurrent ischemia, recurrent MI, major bleeding, and intrac ranial hemorrhage were signi \201 cantly lower in the enoxaparin and abciximab group. Howe ver, if 30-day mortality was considered separately, there was no signi \201 cant differenc e between the groups. Major bleeding, mortality, and intracranial hemorrhage were higher in the abciximab group, and this effect was more pronounced in patients >75 years of age and in diabetics. full-dose TNK-tPA In ASSENT-3 PLUS, TNK-tPA was given to 1639 STEMI patients presenting within 6 hours with e ither enoxaparin or unfractionated heparin. Prehospital treatment with enoxaparin plus TNK provided no signi \201 cant bene \201 t over treatment with unfractionated heparin, altho ugh intracranial hemorrhage was greater in the enoxaparin-treated patients who were >75 yea rs old, female, and weighed <60 kg. 50% of patients were treated within 2 hours compared to just 29% in ASSENT-3. Earlier treatment was associated with better 30-day mortality. Reference: The ASSENT-3 Investigators (2001). Lancet 358:605 \200\223613. BARI Bypass Angioplasty Revascularization Investigation Purpose: To compare percutaneous and surgical revascularization strategies in patients with multivessel disease suitable for either procedure, working on the hypothesis that an initi al PTCA strategy does not result in a poorer 5-year clinical outcome than CABG. Patients wi th multivessel disease were randomized to an initial treatment strategy of CABG (n = 914) o r PTCA (n = 915). Follow-up: Mean 5.4 years Results: 5-year survival rates for CABG and PTCA were 89.3% and 86.3%, respectively (p = 0. 19), and the respective rates free from QWMI were 80.4% and 78.7%. 8% of patients in the CA BG group vs. 54% in the PTCA group underwent further revascularization procedures. 69% of t he PTCA group did not undergo subsequent CABG. CHAPTER 15 Major trials in cardiology 604 In diabetic patients, 5-year survival was 80.6% in the CABG group and 65.5% for the PTCA gr oup. The conclusion was that PTCA initially did not compromise 5-year survival compared to CABG in patients with multivessel disease, except in diabetics. PTCA-treated patients under went more frequent revascularization after initial randomization. BARI Reference: Aldermann E, et al. (1996). N Engl J Med 335: 217 \200\223225. Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications CADILLAC Purpose: To examine the impact of the platelet glycoprotein IIb/IIIa inhibitor abciximab as an adjunct in treating acute MI (AMI). 2082 patients with AMI were randomized in an open-l abel 2x2 factorial design trial of primary stenting vs. angioplasty, and abciximab treatmen t (n = 1052) vs. no abciximab treatment (n = 1030). Baseline characteristics were balanced between groups. Follow-up: 30 days and 1 year Results: At 30 days, abciximab treatment vs. no abciximab signi \201 cantly reduced the co mposite end point of death, MI, ischemia-led target vessel revascularization (TVR), or disa bling stroke (4.6% vs. 7.0%, p = 0.01). However, at 12 months, there was no signi \201 can t difference in composite end point. In an angiographic substudy (n = 656), restenosis, myo cardial salvage, and infarct-artery reocclusion were unaffected by abciximab. Reference: Tcheng JE, et al. (2003). Circulation 108: 1316 \200\2231323. Canadian Amiodarone Myocardial Infarction Trial CAMIAT Purpose: To evaluate the impact of amiodarone vs. placebo on risk of VF or death due to arr hythmia in 1202 patients who had MI in the previous 6 \200\22345 days with frequent ventric ular depolarizations ((cid:116)10/hr or (cid:116)1 run of sustained VT). Amiodarone was giv en initially at 10 mg/kg daily for 2 weeks, then as a maintenance dose 300 \200\223400 mg d aily for 3 \200\2235 months, 200 \200\223300 mg daily for 4 months, then 200 mg for 5 \200 \2237 days per week for 16 months. Patients had concomitant therapy with aspirin, B-blocker s, calcium antagonist, warfarin, digoxin, and ACE inhibitors. Follow-up: Mean 1.79 years Results: There was a relative risk reduction in the end points of 48.5% in the amiodarone g roup. Death occurred in 6.0% of the placebo group and 3.3% of the amiodarone group. Reference: Cairns AJ, et al. (1997). Lancet 349:675 \200\223682. MAJOR TRIALS IN CARDIOLOGY 605 Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events CAPRIE Purpose: To evaluate the relative effect of 75 \200\223325 mg aspirin and 75 mg clopidogrel in reducing the risk of a composite end point of ischemic stroke, MI, or vascular death in 19,185 patients with recent ischemic stroke, recent MI, or symptomatic peripheral vascular disease. Follow-up: Mean 1.9 years Results: Compared to aspirin, clopidogrel reduced the combined risk of ischemic stroke, MI, or vascular death by 8.7% (p = 0.043). There were no major differences in terms of safety or bleeding risk. Reference: Harker LA, et al. (1999). Drug Safety 4: 325 \200\223335. Chimeric 7E3 Antiplatelet Therapy in Unstable angina Refractory to standard treatment CAPTURE Purpose: To evaluate the effect of abciximab in mortality, incidence of AMI and urgent inte rvention for recurrent ischemia in 1265 patients with refractory unstable angina scheduled for PTCA in a randomized placebo controlled trial. Patients in the abciximab group were giv en a bolus and infusion beginning 18 \200\22324 hours before the PTCA and continuing 1 hour after PTCA. The primary end point was death, AMI, or urgent intervention within 30 days of enrolment. Follow-up: 30 days and 6 months Results: At 30 days the primary end point occurred in 11.3% of the abciximab group and 15.9 % of the placebo group (p = 0.012). The rate of MI was lower in the abciximab group than in the placebo group both before and during PTCA. Major bleeding occurred more frequently in the abciximab group than in placebo. At 6 months, there was no signi \201 cant difference in the rates of death, MI, or repeat intervention, however. Reference: The CAPTURE Investigators (1997). Lancet 349:1429 \200\2231435. Cholesterol And Recurrent Events CARE Purpose: To evaluate the effect of 40 mg pravastatin on fatal and nonfatal MI in patients w ith average cholesterol levels. 4159 patients were recruited in a randomized, double- blind , placebo-controlled trial who were aged 21 \200\22375 years and had MI 3 \200\22320 months before randomization. Plasma cholesterol was <240 mg/dL, LDL 115 \200\223274 mg/dL, and tr iglycerides <350 mg/dL. If LDL cholesterol increased during the study, dietary counseling w as offered as well as cholestyramine. CHAPTER 15 Major trials in cardiology 606 Follow-up: At least 5 years CARE Results: The pravastatin group had 24% lower risk of fatal and nonfatal MI, and the risk of CABG was reduced by 26% and risk of PTCA reduced by 23%. There was no reduction in coronar y events if baseline total cholesterol was <125 mg/dL. Reference: Sacks FM, et al. (1996). N Engl J Med 335: 1001 \200\2231009. The effect of Cardiac Resynchronization on morbidity and mortality in Heart Failure CARE HF cardiac Purpose: To evaluate optimal resynchronization pharmacological therapy in patients with advanced heart failure and cardiac dyssynchrony despite standard pharmacological thera py. A total of 813 patients were enrolled. Mean age was 67 years and mean left ventricular ejection fraction (LVEF) was 25%. the addition of (CRT) therapy to Follow-up: Mean 29.4 months Results: Treatment with CRT was associated with a reduction in the primary end point of all -cause mortality and hospitalization for major cardiovascular events compared with standard pharmacological therapy in this patient population. The reduction in mortality in the CRT was signi \201 cantly lower than with standard medical therapy alone in this study. Reference: Cleland JG, Daubert JC, Erdmann E, et al. (2005). N Engl J Med 352(15):1539 \200 \2231549. Carvedilol ACE inhibitor Remodeling Mild heart failure Evaluation trial CARMEN Purpose: To evaluate the effects of carvedilol and enalapril, either alone or in combinatio n, on 572 patients with LVEF <40% in a randomized, double-blind parallel group study. Prima ry outcome was measuring left ventricular end systolic volume index (LVESVI) using Echo at baseline and at 6, 12, and 18 months to represent changes in LV remodeling. Follow-up: 18 months Results: Combination therapy signi \201 cantly reduced LVESVI compared to enalapril alone, and carvedilol signi \201 cantly improved LVESVI compared to baseline, while enalapril di d not. Reference: Remme WJ, et al. (2004). Cardiovasc Drugs Ther 18(1):57 \200\22366. MAJOR TRIALS IN CARDIOLOGY 607 Candesartan in Heart Failure CHARM Purpose: 7601 patients with symptomatic heart failure were entered into 3 individual compon ent randomized trials in which candesartan was used at 4 or 8 mg a day, titrated to target dose 32 mg vs. placebo: 1) CHARM added \200\224patients with LVEF (cid:100)40% and treated with an ACE inhibitor; 2) CHARM alternative \200\224patients with LVEF (cid:100)40% and ACE inhibitor intolerant; 3) CHARM preserved \200\224patients with LVEF (cid:100)40% with or w ithout ACE inhibitor. Primary outcome results were all-cause mortality for the trial as a w hole, or cardiovascular mortality/CHF hospitalization for component trials. Follow-up: Minimum 2 years Results: CHARM overall: lower cardiovascular mortality compared to placebo (23.3% vs. 24.9% , p = 0.055) and lower cardiovascular mortality/CHF hospitalizaton (30.2% vs. 34.5%, p < 0. 0001). CHARM added: lower cardiovascular mortality compared to placebo (23.7% vs. 27.3%, p = 0.02) and lower heart failure hospitalizations. CHARM alternative: lower mortality compar ed to placebo (21.6% vs. 24.8%, p = 0.072) and lower heart failure hospitalizations. CHARM preserved: non-signi \201 cant reduction in death and fewer heart failure hospitalizations . Reference: Pfeffer MA, et al. (2003). Lancet 362: 759 \200\223766. CIBIS Cardiac Insuf \201 ciency Bisoprolol Study Purpose: To evaluate effects on mortality in 641 of patients with NYHA Class III and IV hea rt failure and LVEF <40% using bisoprolol in a randomized double blind placebo- controlled trial. Follow-up: 2 years. Results: There was signi \201 cant reduction in hospitalization for heart failure in the b isoprolol group, and signi \201 cant improvement in functional class, but no signi \201 c ant difference in mortality, sudden death, or death related to VF or VT. Reference: CIBIS Investigators and Committees (1994). Circulation 90:1765 \200\2231773. CIBIS II Cardiac Insuf \201 ciency Bisoprolol Study II Purpose: To evaluate bisoprolol in reducing mortality in 2647 patients with NYHA Class III and IV heart failure in a randomized, double-blind, placebo-controlled trial, and to determ ine safety and ef \201 cacy using cardiovascular death and hospitalization. Follow-up: Mean 1.3 years CHAPTER 15 Major trials in cardiology 608 Results: All-cause mortality, hospital admission, and death were signi \201 cantly lower i n the bisoprolol group. All-cause mortality at 2 years was signi \201 cantly lower in wome n. CIBIS II Reference: Simon T, et al. (1999). Circulation 100 (Suppl I):1 \200\223297. Carvedilol Or Metoprolol European Trial Purpose: To determine if the B 1 blocking effect of carvedilol (target dose 25 mg bid), in addition to its effect of increasing insulin sensit ivity, confers a greater bene \201 t in heart failure compared to metoprolol tartrate (tar get dose 50 mg bid), with which it shares a B 1 blocking effect, in a randomized, double-bl ind, parallel group trial. 3028 patients had NYHA Class II \200\223IV, LVEF <35%, on optimu m therapy with ACE-I and diuretics. Primary end point was all-cause mortality, composite en d point was all-cause mortality or all-cause admission. COMET 2 receptor and A Follow-up: Mean 58 months Results: There was 17% reduction in all-cause mortality in the carvedilol group. Reference: Poole-Wilson PA, et al. (2003). Lancet 362 (9377):7 \200\22313. Comparison of Medical Therapy, Pacing, and De \201 brillation in Heart Failure Trial COM- PANION Purpose: To compare rates of hospitalization or death of >1600 patients with heart failure and evidence of conduction delay on surface ECG. Patients had NYHA Class III or IV, LVEF (c id:100)35%, QRS (cid:116)120 ms, PR>150 ms. They had been hospitalized at least once in the previous year. They were treated with optimal drug therapy alone (B-blockers, ACE inhibito rs, angiotensin receptor blockers, spironolactone), drug therapy plus a biventricular pacem aker (cardiac resynchronization), or drug therapy plus a de \201 brillator with resynchron ization capability. Follow-up: 12 months Results: The combination of all-cause death and all-cause hospitalization was reduced in bo th resynchronization groups, with a greater bene \201 t observed for the de \201 brillato r arm than the pacemaker arm (43.4% and 23.9% mortality reduction, respectively). No signi \201 cant difference in effect was found between patients with ischemic and nonischemic ca rdiomyopathy. Reference: Pinski SL (2003). JAMA 289(6):754 \200\223756. MAJOR TRIALS IN CARDIOLOGY 609 Carvedilol Prospective Randomized Cumulative Survival Trial COPERNICUS Purpose: To evaluate the impact of carvedilol on mortality in 2289 patients with severe hea rt failure, LVEF <25% in a randomized, double-blind, placebo-controlled trial. Follow-up: Mean 10.4 months Results: There was a 35% decrease in mortality in the carvedilol group compared to placebo. Reference: Packer M, et al. (2001). N Engl J Med 344: 1651 \200\2231658. Optimal medical therapy with or without PCI for stable coronary disease COURAGE Purpose: To evaluate the ef \201 cacy of percutaneous coronary intervention (PCI) compared with optimal medical therapy among patients with stable coronary artery disease. 2287 pati ents were enrolled with a mean age of 62 years. Follow-up: Mean 4.6 years Results: Among patients with stable coronary artery disease, treatment with PCI was not ass ociated with a difference in death or MI compared with treatment with medical therapy throu gh 5 years of follow-up. PCI was performed in 94% of the PCI cohort, with successful PCI in 93%. At 5 years, use of ACE inhibitors was in 64% of patients, statins in 93%, aspirin in 95%, and B-blockers in 85%. LDL levels were reduced to a median of 71 mg/dL. Compliance wit h life style modi \201 cation was also high. Angina was signi \201 cantly reduced in both groups during follow-up. There was no difference in the reduction between PCI and medical therapy at 5 years in both groups (freedom from angina in 74% of the PCI group and 72% of t he medical therapy group, p = 0.35); however, there was a slightly higher rate of freedom f rom angina in the early time frame with PCI (at 1 year: 66% for PCI vs. 58% for medical the rapy, p < 0.001; at 3 years: 72% for PCI vs. 67% for medical therapy, p = 0.02). The majori ty of PCI patients did not receive drug- eluting stents. Reference: Boden WE, O \200\231Rourke RA, Teo KK, et al. (2007). N Engl J Med 356:1503 \200 \2231516. CHAPTER 15 Major trials in cardiology 610 Clopidogrel Observation for Reduction of Events During CREDO Purpose: To evaluate the bene \201 t of long-term clopidogrel after PCI combined with aspi rin, and to evaluate the bene \201 t of initiating clopidogrel with loading dose before th e procedure. 2116 patients with symptomatic coronary artery disease and objective evidence of ischemia who were undergoing elective PCI or were deemed highly likely to undergo PCI we re enrolled in 99 centers in North America. Patients were randomized to receive a 300 mg cl opidogrel loading dose (n = 1053) or placebo (n = 1063) 3 to 24 hours before PCI. After the procedure, all patients received clopidogrel 75 mg/day for 28 days. From day 29 to 12 mont hs, the loading-dose group received clopidogrel 75 mg/day, whereas placebo was given to the control group. The 1-year primary end point was a composite of death, myocardial infarctio n (MI), and stroke in the intent-to-treat population. Follow-up: 28 days, 6 months, and 1 year Results: At 1 year, there was a 26.9% risk reduction in the combined end point of the clopi dogrel-treated group. Pretreatment did not signi \201 cantly reduce the end point, but in a subgroup of patients receiving the loading dose more than 6 hours beforehand there was a signi \201 cant risk reduction. Reference: Steinhubl SR, et al. (2002) 2411 \200\2232420. JAMA 288: Canadian Trial Of Physiological Pacing CTOPP Purpose: To assess the potential bene \201 ts (measured by risk of cardiovascular death or stroke) of physiological (dual chamber) pacemakers compared with those of nonphysiological (single chamber) pacemakers over an extended period. 1474 patients requiring pacemakers fo r symptomatic bradycardia were randomized to receive one of the two modes of pacemaker. Follow-up: Initially 3 years, extended to a mean 6.4 years Results: There was no difference between groups in the primary outcome measures of cardiova scular death or stroke, or total mortality. However, there was a signi \201 cant reduction in the risk of developing atrial \201 brillation in the physiological pacing group (rela tive risk reduction 20.1%, p = 0.009). Reference: Kerr CR, et al. (2004). Circulation 109:357 \200\223362. MAJOR TRIALS IN CARDIOLOGY 611 Clopidogrel in Unstable angina to prevent Recurrent Events CURE Purpose: To evaluate the impact of clopidogrel on 12,562 patients presenting within 24 hour s of onset of acute coronary syndrome symptoms, either unstable angina (75%) or non-ST elev ation MI (25%). Patients were randomized to receive 75 mg clopidogrel or placebo, preceded by 75 \200\223325 mg aspirin. There were similar rates of use of IV heparin, low-molecular- weight heparin, ACE inhibitors, B-blockers, and lipid-lowering agents in the two groups. Follow-up: Mean 9 months Results: The clopidogrel group had a 20% overall reduction in the primary composite end poi nt of cardiovascular death, nonfatal MI, and nonfatal stroke, and this bene \201 t was see n within 30 days. There was also a reduction in the incidence of refractory ischemia by 14% and severe ischemia by 24% in the clopidogrel group. All subgroups bene \201 ted from clo pidogrel treatment. The incidence of major bleeding was 34% higher in the clopidogrel group (3.6% vs. 2.7%, p = 0.003), but life-threatening bleeding did not differ between the group s. Reference: CURE Study Investigators (2000). Eur J Cardiol 21:2033 \200\2232041. Danish trial in Acute Myocardial Infarction DANAMI Purpose: To compare a deferred invasive strategy of PCI or CABG (n = 503, within 2 \200\223 5 weeks of discharge) with a conservative strategy (n = 505) in patients with inducible myo cardial ischemia (on exercise testing) within the \201 rst few weeks after receiving thro mbolysis for a \201 rst AMI. Primary end points were death, AMI, and admission with unsta ble angina. Follow-up: 2.4 years Results: In the invasive group, PCI was given to 53% and CABG to 29%. Mortality was not sig ni \201 cantly different at 2.4 years between the invasive and conservative groups. Howeve r, the invasive group had a lower incidence of AMI, unstable angina, and stable angina. The refore, the recommendation was to refer patients with inducible ischemia following AMI for a coronary angiogram revascularization. Reference: Madsen JK, et al. (1997). Circulation 96: 748 \200\223755. CHAPTER 15 Major trials in cardiology 612 Danish trial in Acute Myocardial Infarction II DANAMI II Purpose: To compare coronary angioplasty with thrombolysis in AMI in patients who require t ransportation from a community hospital to a center capable of PCI. 1572 patients with AMI were randomized to alteplase or angioplasty; of these, 443 were at an invasive-treatment ce nter. Platelet gpIIb/IIIa inhibitors were given at the discretion of the physician performi ng PCI; ticlopidine or clopidogrel was given to all patients undergoing PCI for at least 1 month. The primary end point was a composite of death, clinical evidence of infarction, or disabling stroke at 30 days. Results: In those patients randomized from community hospitals, the primary end point was r eached in 8.5% of the invasive group compared to 14.2% the thrombolysis group (p = 0.002). In invasive centers, the end point rates were 6.7% and 12.3% for invasive and thrombolysis groups, respectively (attributable mainly to lower rates of reinfarction). There was no sig ni \201 cant difference in death or stroke rates. 96% of patients were transferred from a community hospital to an invasive center within 2 hours. An invasive strategy is better tha n thrombolysis in patients at community hospitals if the transfer takes <2 hours. Reference: Henning R, et al. (2003). N Engl J Med 349: 733 \200\223742. Dual chamber And VVI Implantable De \201 brillator DAVID Purpose: To evaluate ef \201 cacy of dual chamber (DDDR) pacing compared with backup ventr icular pacing (VVI) in 506 patients with standard indications for ICD implantation but with out indications for antibradycardia pacing. All had LVEF <40%, no bradycardia indications f or pacing, and no persistent atrial arrhythmias. They were randomized to VVI at a backup ra te of 40/min or DDDR at a backup rate of 70/min. Optimum medical therapy was continued. Pri mary composite end point was time to death or \201 rst hospitalization for CCF. Follow-up: 1 year Results: The VVI group had 1-year survival-free rate of 83.9% vs. 73.3% for the DDDR group. The composite end point, mortality (6.5% in VVI vs. 10.1% DDDR), as well as hospitalizatio n for heart failure was also better in the VVI group. This suggests that in patients withou t bradycardia indications for pacing but with indications for ICD and LVEF <40%, the DDDR m ode may have no advantage and may prove detrimental over VVI. Reference: Wilkoff BL, et al. (2002). JAMA 288:3115 \200\2233123. MAJOR TRIALS IN CARDIOLOGY 613 Danish Investigations of Arrhythmia and Mortality On Dofetilide DIAMOND Purpose: To evaluate the prophylactic use of dofetilide in 3028 patients at high risk of su dden death. There were two arms: the CHF arm (n = 1518) and the AMI arm (n = 1510), with pa tients having had AMI within 7 days. Dofetilide was given at 250 mg once daily initially, t itrating to 500 mg twice daily, and reduced or withdrawn if creatinine clearance fell or QT c was >20% baseline or >550 ms. There were placebo. A substudy examined the effect of dofet ilide in the CHF arm on rates of cardioversion to sinus rhythm in patients who had AF. Foll ow-up: (cid:116)12 months Results: The 1-year mortality was 28% in the CHF arm and 22% in t he AMI arm. There were fewer hospitalizations for heart failure than with placebo, but ther e was no signi \201 cant difference in mortality between the dofetilide group as a whole a nd placebo. In the CHF arm, there was a signi \201 cantly greater conversion rate of patie nts to sinus rhythm compared to placebo. Reference: Torp-Pederson C, et al. (1999). N Engl J Med 341:857 \200\223865; Circulation 20 01; 104:292 \200\223296. Digitalis Investigation Group DIG Purpose: To evaluate the effect of digoxin vs. placebo on all-cause mortality in 7788 patie nts in sinus rhythm with symptoms of heart failure and with LVEF (cid:100)45%. Follow-up: M aximum 5 years Results: Overall mortality was not reduced by digoxin compared to placebo. T here was a signi \201 cant reduction in hospitalization for worsening heart failure (p < 0 .001). Reference: The Digitalis Investigation Group (1997). N Engl J Med 336:525 \200\22353 3. Diabetes mellitus Insulin-Glucose infusion in Acute Myocardial Infarction Purpose: To deter mine if insulin-glucose infusion in diabetic patients with AMI reduces initial high mortali ty rate, and if strict metabolic control during the early post-infarction period improves p rognosis. 620 diabetic patients with suspected AMI and glucose >11 mmol/L were randomized t o receive insulin-glucose infusion and, subsequently, subcutaneous insulin for (cid:116)3 m onths. Follow-up: 12 months DIGAMI Results: At 12 months there was a relative mortality reduction of 29% in the insulin-glucos e group. This risk reduction was most pronounced in patients with a low cardiovascular risk pro \201 le who were not previously on insulin, with a relative risk reduction of 52% at 3 months (p = 0.046) and 52% at 1 year (p = 0.2). Reference: Malmberg K, et al. (1995). J A m Coll Cardiol 26:57 \200\22365. CHAPTER 15 Major trials in cardiology 614 De \201 brillator (DINAMIT) In Acute Myocardial Infarction Trial DINAMIT Purpose: To evaluate the effects of prophylactic implantable cardioverter de \201 brillato r (ICD) early in high-risk patients after acute MI with the hypothesis that mortality would be lower in the ICD therapy group. A total of 674 patients were followed with a mean age o f 62 years and mean EF of 28%. Follow-up: Mean follow-up 2.5 years Results: Anterior MI was present in 72% of patients, and 48% of patients had chronic heart failure (CHF) associated with the index MI. Acute reperfusion therapy angioplasty, (percuta neous thrombolytic, or both) was performed in 62% of patients. The primary end point of all -cause mortality was not different between the ICD therapy and medical therapy. Prophylacti c implantable de \201 brillator therapy was not associated with a reduction in the primary end point of all-cause mortality compared with optimal medical therapy. The frequency of a rrhythmia deaths was lower in the prophylactic ICD therapy arm. Nonarrhythmic deaths were h igher in the ICD arm. transluminal coronary Reference: Hohnloser SH, et al. (2004). N Engl J Med 351:2481 \200\2232488. European Myocardial Infarction Amiodarone Trial EMIAT Purpose: To evaluate the effect of amiodarone on mortality in 1486 patients enrolled 5 \200 \22321 days post-MI with LVEF <40% in a randomized, double-blind, placebo-controlled manner . Follow-up: Median 21 months Results: All-cause mortality and cardiac mortality did not differ between groups, but there was a 35% risk reduction in arrhythmic deaths in the amiodarone group (p = 0.05). Reference: Julian DG, et al. (1997). Lancet 349:667 \200\223674. Evaluation in PTCA to Improve Long-term Outcome with abciximab GpIIb/IIIA blockade EPILOG Purpose: To determine the effect of the glycoprotein receptor blocker cF7E3 (abciximab) on mortality and morbidity when used during percutaneous coronary intervention. In a randomize d, double-blind, placebo-controlled trial, 2792 patients were given IV unfractionated hepar in as a bolus, and were randomly assigned to receive either placebo or abciximab. Within th e abciximab group, patients could receive either an additional bolus of heparin alone or an additional bolus plus an infusion of heparin. Follow-up: 30 days MAJOR TRIALS IN CARDIOLOGY 615 Results: There was a signi \201 cant reduction in the composite event rate in the abcixima b group, with no signi \201 cant difference between the high- or low-dose heparin subgroup s within the abciximab group. There was no difference in the risk of major bleeding, althou gh minor bleeding was more frequent in the abciximab group. The trial was stopped after the interim analysis showed a reduction in death and MI that exceeded the predetermined stoppi ng level in the abciximab group. EPILOG Reference: The EPILOG investigators (1997). N Engl J Med 336:1689 \200\2231696. Evaluation of Platelet gpIIb/IIIa Inhibition in Stenting EPISTENT Purpose: To evaluate the in \202 uence of platelet glycoprotein inhibitor cF7E3 on coronar y disease treated by PTCA or stenting. Study design was randomized, double blinded, part pl acebo controlled. 2399 patients who were to undergo elective or urgent intervention, either balloon angioplasty alone or stenting, were randomized to receive abciximab or placebo. As pirin and heparin were given to all patients, with ticlopidine given at physician \200\231s discretion. Follow-up: 6 months Results: Death, MI, or need for urgent revascularization was lower within 30 days in both a bciximab groups than with placebo. Within the abciximab group, these rates were lower in th e stenting group than in the PTCA group alone. These trends were also observed at 6 months.