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 Dofetilide was given at 250 mg once daily initially, t itrating to 500 mg twice daily, and reduced or withdrawn if creatinine clearance fell or QT c was 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. Reference: Lincoff et al. (1999). N Engl J Med 341:319 \200\223327. Simvastatin with or without ezetimibe hypercholesterolemia in familial ENHANCE Purpose: To compare the mean change in the intima-media thickness (IMT) measured at three s ites in the carotid arteries between patients with heterozygous familial hypercholesterolem ia (HeFH) treated with ezetimibe- simvastatin 10/80 mg vs. patients treated with high-dose simvastatin 80 mg alone, over a 2-year period. A total of 720 patients were enrolled with a mean age of 45.9 years. This was a randomized, double-blinded study. Follow-up: 24 months Results: They suggest that in patients with very high baseline LDL levels, such as those wi th HeFH, the combination of ezetimibe-simvastatin 10/80 mg does not result in signi \201 c ant changes in mean carotid IMT at 2 years compared with high- dose simvastatin 80 mg alone . There was no difference in incidence of cardiovascular mortality, nonfatal MI, nonfatal s troke, and need for revascularization, although the study was not powered to study clinical outcomes. The incidence of adverse events was similar. The LDL-lowering effect of ezetimib e-simvastatin was greater than that with high-dose simvastatin alone. Reference: Kastelein JJ, et al. (2008). N Engl J Med 358: 1431 \200\2231443. CHAPTER 15 Major trials in cardiology 616 European trial on Reduction Of cardiac events with Perindopril in stable coronary Artery di sease EUROPA Purpose: To evaluate the effect of perindopril on cardio- vascular risk in a low-risk popul ation and no overt heart failure. 12,218 patients with previous MI, angiographic evidence o f coronary disease, coronary revascularization, or a positive exercise test were randomized to receive perindopril 8 mg once daily or placebo. Concomitant treatment was with antiplat elet therapy (92%), B-blockers (62%), and lipid-lowering agents (58%). The primary end poin t was cardiovascular death, MI, or cardiac arrest. Follow-up: Mean 4.2 years Results: The primary end point was reached by 8% of the perindopril group and 10% of placeb o (p = 0.0003), representing a 20% risk reduction. Perindopril was well tolerated. Reference: The EUROPA Investigators (2003). Lancet 362:782 \200\223788. Fragmin during Instability in Coronary Artery Disease FRISC Purpose: To determine whether the addition of the low- molecular-weight heparin Fragmin (da lteparin) in \202 uences the recurrence of cardiac events in patients with unstable angina if added to aspirin and antianginal drugs. The study design was randomized, double blind, placebo controlled, parallel group. 1506 patients who were in the hospital with unstable an gina within 72 hours of having chest pain were given either placebo or Fragmin 120 U/kg eve ry 12 hours for the \201 rst 6 days, then 7500 U once a day for 35 \200\22345 days therea fter. All patients were on aspirin and B-blockers (unless contraindicated), with calcium an tagonists and nitrates as required. Follow-up: Up to 7 months Results: Mortality, need for revascularization, reinfarction, and need for IV heparin were lower in the \201 rst 6 days in the Fragmin group. There was also a signi \201 cant redu ction in the composite end point (death, revascularization, IV heparin use, MI), which pers isted for up to 40 days for nonsmokers (80% of the sample), but this effect was not carried 4 to 5 months after the end of treatment in the group as a whole. If the dose of Fragmin w as decreased, there was a risk of reinfarction that was greater in smokers. Reference: Fragmin during Instability in Coronary Artery Disease (FRISC) Study Group (1996) . Lancet 347: 561 \200\223568. MAJOR TRIALS IN CARDIOLOGY 617 Fragmin and Revascularization during Instability in Coronary Artery Disease Purpose: To eva luate the impact of 3 months continuous Fragmin (dalteparin, a low-molecular-weight heparin ) in patients with unstable angina, and to compare a direct invasive strategy with a stepwi se approach, preferably non-invasive. The study design was randomized, double blind, placeb o controlled. 2457 patients with anginal symptoms within 48 hours were randomized to have a n initial invasive or noninvasive strategy. Within these two groups, patients were randomiz ed to Fragmin or placebo for 3 months. All patients received aspirin and B-blockers (unless contra-indicated), as well as nitrates, calcium antagonists, statins, and ACE inhibitors, although these were optional. Follow-up: 6 months Results: There were signi \201 cantly fe wer deaths and MI in the early-revascularization group at 6 months in the invasive group, i ndependent of Fragmin treatment. There was a nonsigni \201 cant decrease in deaths when co nsidered separately. At 6 months, 23% of the noninvasive group had had an invasive procedur e. Reference: Invasive compared with non-invasive treatment in unstable coronary-artery dis ease: FRISC II prospective randomized multicentre study (1999). Lancet 354:708 \200\223715. FRISC II GISSI-I Gruppo Italiano per lo Studio della Streptochinasinell \200\231Infarto miocardio Purpose: To evaluate whether 1) streptokinase (SK) reduces in-hospital and 1-year mortality after AM I; 2) the effect of reduction, if present, depends on the interval between pain onset and t reatment; and 3) the risks of treatment are acceptable. 11521 patients with AMI were random ized to SK 1.5 MU over 1 hour or to control. Follow-up: 1 year Results: At 21 days there wa s an 18% reduction in mortality in the SK group as a whole (p = 0.0002). In those treated w ithin 3 hours, mortality was reduced by 23% (p = 0.0005). At 12 months, total mortality was 17.2% in the SK group vs. 19.0% in controls (relative risk 0.9, p = 0.0008). Reference: GI SSI Study Group ii:871 \200\223874. (1987). Lancet GISSI-2 Gruppo Italiano per lo Studio della Sopravviven- zanell \200\231Infarto miocardico Purpose: To compare streptokinase (SK) and alteplase (rt-PA) in 12,490 AMI patients and to evaluate the effects of heparin after thrombolysis with either agent on survival and postischemic e vents in a randomized, open-label, controlled 2x2 factorial design. Follow-up: 6 months CHAPTER 15 Major trials in cardiology 618 Results: There was no signi \201 cant difference in the combined end point of death and se vere left ventricular damage, rates of in-hospital complications (15 days post thrombolysis ), or rates of reinfarction in all groups, with or without heparin. Major bleeding occurred more frequently in the SK plus heparin group, but stroke rates were similar in all groups (1.14%); rt-PA was associated with a small but excess risk of stroke. Major bleeding was mo re frequent with SK than with rt-PA. Hypertensive patients had higher mortality throughout the follow-up period. GISSI-2 Reference: GISSI 2 Study Group (1996). J Hypertens 14: 743 \200\223750. Gruppo Italiano per lo Studio della Sopravviven- zanell \200\231Infarto miocardico GISSI-3 Purpose: To evaluate the independent and combined effects of lisinopril and nitrates on sur vival and LV function after AMI in 18,895 patients presenting within 24 hours of symptoms i n a randomized, open-label, controlled factorial trial. Nitrates were given initially as an NTG infusion, then as a patch or oral isosorbide mononitrate after 24 hours. Oral lisinopr il was started at a dose of 2.5 \200\2235 mg once daily and titrated up to 10 mg after 24 h ours. Controls were given neither drug. Trial drugs were continued for 6 weeks. Follow-up: 6 weeks and 6 months Results: Overall mortality and LV dysfunction at 6 weeks were signi \201 cantly reduced by lisinopril, although NTG did not in \202 uence outcome. At 6 months, overall mortality wa s 18.1% in the lisinopril groups compared to 19.3% in those without lisinopril (p = 0.015); NTG produced no difference in mortality. Reference: GISSI 3 Study Group (1996). J Am Coll Cardiol 27:37 \200\22344. Gruppo Italiano per lo Studio della Sopravvivenza nell \200\231Infarto miocardico Prevenzio ne GISSI- Prevenzione Purpose: To evaluate the impact of the dietary supplements n-3 polyunsaturated fatty acids (PUFA) and vitamin E within 3 months of MI in 11,324 patients in a randomized, open paralle l group trial. Patients had concomitant therapy with aspirin, B-blockers, and ACE-I. Follow -up: 3.5 years Results: Vitamin E had no impact, either alone or in combination, on the risk of death, non fatal MI, or nonfatal stroke, but there was a signi \201 cant reduction in these end point s with PUFA (20% reduction in CVS death, nonfatal MI or nonfatal stroke), mainly attributab le to decrease in the risk of death and cardiovascular death. Reference: GISSI-Prevenzione Investigators (1999). Lancet 354:447 \200\223455. MAJOR TRIALS IN CARDIOLOGY 619 Global Utilization of Streptokinase and t-PA Occluded coronary arteries for GUSTO-1 Purpose: To compare in a randomized parallel group the effect of treatment with a) streptok inase (SK) and SC heparin vs. b) SK and IV heparin vs. c) rt-PA with IV heparin (accelerate d regimen) vs. d) rt-PA and SK and IV heparin simultaneously in the treatment of AMI in 41, 021 patients <6 hours after symptom onset. Concomitant therapy included aspirin and atenolo l. Follow-up: 30 days and 1 year Results: At both 30 days and 1 year, there was a 14% reduction in mortality in the accelera ted t-PA group compared to the two SK-only regimens. Combination of SK and t-PA led to no s igni \201 cant difference in 1-year mortality compared to SK only, and a marginal differen ce when compared to t-PA only. Although the accelerated t-PA group had signi \201 cantly m ore hemorrhagic strokes than the SK groups and the combination groups, overall there were f ewer complications in the accelerated t-PA group, as well as signi \201 cantly lower end p oint of death and disabling stroke at 1 year. However, in patients >75 years of age, those treated by accelerated t-PA had higher mortality at 30 days than that of younger patients b ut still had a greater absolute net bene \201 t. Older patients generally had a greater ri sk of mortality, stroke, bleeding, and reinfarction. Reference: White et al. (1996). Circulation 94:1826 \200\2231833. Global Use of Strategies To Open occluded coronary arteries IV \200\224Acute Coronary Syndr ome GUSTO IV-ACS Purpose: To investigate long-term effects of abciximab in patients with ACS without ST elev ation who were not scheduled for coronary intervention. 7800 patients with positive troponi n or persistent ST depression were randomized to abciximab bolus and 24-hour infusion, abci ximab bolus and 48-hour infusion, or placebo. Follow-up: 1 year Results: There was no survival bene \201 t in the abciximab group. In subgroups with low t roponin or high CRP, abciximab was associated with a higher mortality. Reference: Ottervanger JP, et al. (2003) Circulation 107: 437 \200\223442. CHAPTER 15 Major trials in cardiology 620 Heart Outcomes Prevention Evaluation Trial HOPE Purpose: To assess the role of the ACE inhibitor ramipril and vitamin E in patients at high risk of cardiovascular events who did not have LV dysfunction or heart failure. 9297 patie nts >55 years old with evidence of vascular disease (previous MI, angina, multivessel PTCA or CABG, multivessel coronary artery disease, peripheral vascular disease, cerebrovascular disease) or diabetes plus one other risk factor but not known to have a low LV EF or heart failure were randomly assigned to receive 10 mg ramipril (titrated up from 2.5 mg) or place bo, plus vitamin E 400 U/day or placebo. Primary outcome was composite of MI, stroke, or de ath from cardiovascular events. Secondary end points were death from any cause, need for re vascularization, hospitalization for unstable angina or heart failure, and complications of diabetes. Patients had approximately similar usage of aspirin, B-blockers, lipid- lowering agents, diuretics, and calcium channel blockers in the two groups. Follow-up: Mean 5 years Results: More people in the ramipril group stopped treatment due to cough, hypotension, or dizziness. However, there was a signi \201 cant reduction in the primary end points of MI, stroke, and death compared to placebo (14% vs. 17%), as well a reduction in total mortalit y. There was no signi \201 cant reduction in noncardiovascular death. In the ramipril grou p there was signi \201 cantly less need for revascularization, fewer complications of diab etes, less heart failure or worsening angina, and smaller incidence of new-onset diabetes. The reduction in the primary end point and cardiovascular death was even more striking in d iabetics (15.3% vs. 19.6%). There was a clear bene \201 t in the ramipril group in patient s with or without evidence of coronary artery disease, with or without history of MI and EF >40%. Bene \201 ts were also seen whether or not patients were taking aspirin, B-blockers , lipid-lowering agents, or anti-hypertensive drugs. In the vitamin E group there were no s igni \201 cant differences in primary or secondary end points. The study was stopped 6 mon ths early due to consistent observed bene \201 ts in primary end points. Reference: Yusuf S, et al. (2000). N Engl J Med 342: 145 \200\223153. Bivalirudin during primary PCI in acute myocardial infarction HORIZONS- AMI Purpose: To evaluate treatment with bivalirudin compared with heparin plus gpIIb/IIIa inhib itors among patients undergoing primary PCI for acute ST-elevation myocardial infarction (S TEMI). A total of 3602 patients were enrolled. MAJOR TRIALS IN CARDIOLOGY 621 Follow-up: 1 year HORIZONS- AMI Results: Among patients undergoing planned primary PCI for acute MI, use of bivalirudin was associated with a reduction in the composite end point of death, MI, target vessel revascu larization, stroke, or major bleeding at 30 days compared with heparin plus gpIIb/IIIa inhi bitors. This \201 nding was driven by a reduction in major bleeding, with no difference i n MACE. There was still a signi \201 cantly reduced incidence of the composite end point a t 12 months, but in addition to bleeding, a signi \201 cant reduction in mortality and non \200\223Q-wave MI was also noted. There was an increase in early (<24 hours) stent thrombo sis with the use of bivalirudin; however, there was no difference between study arms at the end of 1 year. Reference: Stone GW, et al. (2008). N Engl J Med 358: 2218 \200\2232230. Heart Protection Study HPS Purpose: To evaluate whether the lowering of blood concentrations of low-density lipoprotei n cholesterol (LDL-C), irrespective of the initial cholesterol measure, is associated with a lower cardiovascular risk. 20,536 patients with coronary disease, other occlusive arteria l disease, or diabetes were randomized to 40 mg simvastatin once daily or placebo. The aver age compliance in the statin group was 85%, and in the placebo group the average non-study statin use was 17%. Primary outcome measures were death, and fatal or nonfatal vascular eve nts. Follow-up: 5 years Results: All-cause mortality was signi \201 cantly reduced in the simvastatin group (12.9% vs. 14.7%, p = 0.0003) mainly due to an 18% reduction in the coronary death rate. There wa s a marginal reduction in other vascular deaths, and no signi \201 cant reduction in nonva scular deaths. There was a signi \201 cant reduction in the \201 rst-event rate for nonf atal MI or coronary death, nonfatal or fatal stroke, and for coronary revascularization. Th e proportional reduction in event rate was similar in each subcategory \200\224 that is, th ose with diagnosed coronary artery disease, cerebrovascular disease, peripheral vascular di sease, diabetes; and separately, in women; in those whose presenting LDL-C was <3.0 mmol/L or total cholesterol <5 mmol/L. The bene \201 ts of simvastatin were in addition to existi ng treatments. There was a 0.01 annual excess risk of myopathy, and there were no signi \201 cant adverse effects on cancer incidence or hospitalization for any nonvascular causes . Reference: Heart Protection Study Collaborative Group (2002). Lancet 360:7 \200\22322. CHAPTER 15 Major trials in cardiology 622 Invasive versus Conservative Treatment in Unstable Coronary Syndromes (ICTUS) ICTUS Purpose: To evaluate the use of early invasive strategy compared with a more conservative, selective invasive in troponin-positive patients with non-ST strategy elevation myocardial infarction or acute coronary syndromes. A total of 1200 patients were randomized. The early invasive strategy included coronary angiography within 24 \200\22348 hours and percutaneou s coronary intervention (PCI) within 48 hours or coronary artery bypass grafting (CABG) as soon as possible. Follow-up: 3 years Results: Treatment with an early invasive strategy was not associated with a difference in the primary end point compared with a selective invasive strategy. Revascularization was pe rformed by hospital discharge in 76% of patients in the early-invasive group and 40% of pat ients in the selective-invasive group, with a shorter median time to revascularization in t he early-invasive group (19 hours vs. 142 hours). The rate of MI was higher in this trial t han in other similar trials, which likely re \202 ects periprocedural MI given the de \201 nition of MI of creatine kinase-MB >1 times the upper limit of normal. There was no difference in the primary composite end point of death, MI, or rehospitalizati on for ACS at 1 year (22.7% in early invasive vs. 21.2% in selective invasive, relative ris k [RR] 1.07, p = 0.33) between the two groups. There was no difference in mortality at 1 ye ar (2.5% each, p = 0.97). At 3-year follow-up, the composite of death, MI, or rehospitaliza tion for ACS did not signi \201 cantly differ for the invasive group compared with the con servative group (30.0% vs. 26.0%, HR 1.20, p = 0.10). There was no difference in all-cause mortality (7.9% vs. 7.7%, RR 1.11, p = 0.63) or cardiac death (5.0% vs. 4.5%, p = 0.92). Th e present trial results differ from the TACTICS-TIMI 18 trial and the FRISC-2 trial, which showed bene \201 t of an early invasive strategy over a conservative strategy in a similar patient population. Reference: de Winter RJ, et al. (2005). N Engl J Med 353: 1095 \200\2231104. A clinical trial of abciximab in elective percutaneous coronary intervention after pretreat ment with clopidogrel ISAR REACT Purpose: To evaluate whether treatment with gpIIb/IIIa inhibitor abciximab reduces postproc edure ischemic complications in low-risk patients pretreated with clopidogrel who undergo c oronary stenting. A total of 2159 patients were enrolled with a mean age of 66 years. MAJOR TRIALS IN CARDIOLOGY 623 Follow-up: Mean 30-day follow-up ISAR REACT Results: low-risk patients with coronary disease pretreated with high-dose clopidogrel and undergoing elective coronary stenting, treatment with the gpIIb/IIIa inhibitor abciximab wa s not associated with a reduction in the primary composite end point of death, MI, or urgen t TVR at 30 days. The trial patient population was at very low risk, excluding patients wit h insulin-dependent diabetes, acute coronary syndrome (ACS), and positive biomarkers. There was no difference in any component of the composite: death 0.3% in each arm; Q wave MI 0.4 % vs. 0.5%; non-Q wave MI 3.3% in each arm; urgent TVR 0.9% vs. 0.7% for abciximab vs. plac ebo, respectively, all p = NS. In Reference: Kastrati A, et al. (2004). N Engl J Med 350: 232 \200\223238. First International Study of Infarct Survival ISIS-1 Purpose: To assess the impact on mortality of early use of B-blockers (atenolol 5 \200\2231 0 mg IV over 5 minutes followed by 100 mg orally once daily for 7 days) randomized in 16,02 7 patients with acute MI (<12 hours), in the \201 rst week and after longer follow-up. Follow-up: Mean 20 months Results: In the \201 rst 7 days, there was a 15% reduction (p < 0.02) in vascular deaths in the atenolol group, with greatest bene \201 t on day 1, due to reduction in acute myoca rdial rupture. A further reduction in deaths was observed after 1 year. Reference: Randomized trial of intravenous atenolol among 16027 cases of suspected acute my ocardial infarction: ISIS-1. Lancet 1986; ii:57 \200\22366. Second International Study of Infarct Survival ISIS-2 Purpose: To assess effects of IV streptokinase and oral aspirin either alone or in combinat ion in patients with suspected AMI (symptoms <24 hours, median 5 hours). 17,187 patients we re randomized. Follow-up: Up to 34 months Results: There was a reduction in 5-week mortality with streptokinase alone or aspirin alon e. There was a 25% odds reduction in death with streptokinase and 23% odds reduction with a spirin. There was a 42% odds reduction in death with aspirin and streptokinase combined, co mpared to the placebo group. Streptokinase was associated with more bleeding requiring bloo d transfusion (0.5% vs. 0.2% in placebo group) but fewer strokes (0.6% vs. 0.8% in placebo group). Aspirin signi \201 cantly reduced nonfatal reinfarction and nonfatal stroke. Reference: The ISIS-2 Collaborative Group (1988). Lancet ii:349 \200\223360. CHAPTER 15 Major trials in cardiology 624 Third International Study of Infarct Survival ISIS-3 Purpose: To compare streptokinase vs. rt-PA vs. anistreplase (APSAC), plus aspirin or aspir in plus heparin in 41,299 patients with de \201 nite or suspected AMI (symptom onset <24 h ours), in a randomized, double-blind, parallel- group factorial design. Follow-up: 6 months Results: The addition of heparin resulted in slightly fewer deaths and more major noncerebr al bleeds, but no signi \201 cant increase in cerebral hemorrhage; there was no signi \201 cant difference in mortality after 2 months. The APSAC group had more reports of aller gy and cerebral bleeds than the streptokinase group, with similar survival rates after 6 mo nths. In the rt-PA group, there were more cerebral bleeds, but fewer reinfarctions than in the streptokinase group, without any signi \201 cant difference in mortality between the g roups. Reference: The ISIS-3 (Third International Study of Infarct Survival) Collaborative Group ( 1992). Lancet 339:753 \200\223770. Fourth International Study of Infarct Survival ISIS-4 Purpose: To assess the effect on 5-week mortality of oral isosorbide mononitrate, oral capt opril or IV magnesium, separately or in combination, on 58,050 patients with de \201 nite or suspected AMI (symptom onset <24 hours) in addition to standard therapy. The study desig n was randomized, partly placebo controlled, partly open, 2x2x2 factorial. Follow-up: 5 weeks Results: In contrast to magnesium and nitrate, the captopril group had a small but signi \201 cant survival bene \201 t that was maintained after 1 year, with greatest bene \201 t in those at highest risk. Reference: Fourth International Study of Infarct Survival Collaborative Group (1995). Lance t 345:669 \200\223685. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein JUPITER Purpose: To assess whether apparently healthy persons with levels of low-density lipoprotei n (LDL) that do not mandate statin treatment, as per current guidelines (<130 mg/dL), but w ith levels of high-sensitivity C-reactive protein (hs-CRP) (cid:116)2 mg/L, would bene \201 t from taking rosuvastatin. A total of 17,802 patients were enrolled. Follow-up: Mean 1.9 years (terminated early, planned 5-year follow-up) MAJOR TRIALS IN CARDIOLOGY 625 Results: Rosuvastatin is associated with a signi \201 cant reduction in major cardiovascul ar events, including death, in apparently healthy persons with LDL cholesterol <130 mg/dL, but hs-CRP (cid:116)2 mg/L. Rosuvastatin was associated with a signi \201 cant reduction i n the incidence of the primary end point of nonfatal myocardial infarction (MI), nonfatal s troke, unstable angina, arterial revascularization, or cardiovascular death, compared with placebo (0.77 vs. 1.36 events per 100 person-years [PY] of follow-up, hazard ratio [HR] 0.5 6; 95% con \201 dence interval [CI] 0.46 \200\223 0.69, p < 0.00001). The number needed to treat based on these data with rosuvastatin is 95 patients for 2 years, and 31 patients fo r 4 years. Rosuvastatin was associated with a signi \201 cant reduction in the levels of h s-CRP (median: 1.8 vs. 3.3 mg/L, p < 0.0001), LDL (median: 55 vs. 109 mg/dL), and triglycer ides (99 vs. 118 mg/dL, p < 0.0001), but not HDL (50 vs. 50 mg/dL, p = 0.34). There was a h igher incidence of physician-reported diabetes in the rosuvastatin arm (3.0% vs. 2.4%, p = 0.01) and a higher median glycated hemoglobin at 2 years with rosuvastatin (5.9% vs. 5.8%, p = 0.001). JUPITER Reference: Ridker PM, et al. (2008). N Engl J Med 359: 2195 \200\2232207. Losartan Hypertension Intervention For Endpoint Reduction in LIFE Purpose: To evaluate the long-term effects of once-daily losartan compared with those of at enolol in patients with diabetes, hypertension, and ECG-documented LVH, with respect to the incidence of cardiovascular morbidity and mortality (cardiovascular death, stroke, or myoc ardial infarction). 1195 patients with mean blood pressure 177/96 mmHg after placebo run-in were randomized to losartan or atenolol on the basis of treatment. Follow-up: Mean 4.7 years Results: All-cause mortality and cardiovascular death were signi \201 cantly lower in the losartan group. However, there was no difference in the risk of stroke or myocardial infarc tion. Losartan decreased ECG LVH better than atenolol. Losartan seemed to have bene \201 t s beyond BP reduction alone. Reference: Lindholm LH, et 359:1004 \200\2231010. al. (2002). Lancet CHAPTER 15 Major trials in cardiology 626 Long-term Intervention with Pravastatin in IHD LIPID Purpose: To evaluate the impact of long-term treatment with 40 mg pravastatin on mortality and morbidity in patients with a history of AMI, and unstable angina within 3 \200\22336 mo nths of starting the trial with baseline cholesterol 4 \200\2237 mmol/L. A total of 9014 pa tients aged 31 \200\22375 years were enrolled in the trial, which was randomized, double bl ind, and placebo controlled. Follow-up: Mean 6.1 years Results: In the pravastatin group there was a relative risk reduction of 24% in death from coronary disease, and 22% relative risk reduction in all-cause mortality. There was also a signi \201 cant reduction in incidence of nonfatal MI, stroke, and coronary revascularizat ion. Reference: The LIPID Study Group (1998). N Engl J Med 339:1349 \200\2231357. Multicenter Automatic De \201 brillator Implantation Trial MADIT Purpose: To determine if patients at high risk of sudden cardiac death would have reduced m ortality if they had an AICD implanted, compared with conventional drug therapy. 300 patien ts with a history of ventricular tachycardia or QWMI (>1 month previously) and LVEF <35% we re randomized to receive either AICD or drug therapy (most commonly amiodarone). Follow-up: Mean 27 months Results: There was a 54% reduction in all-cause mortality in the AICD group compared with t he non-device group. Reference: MADIT Executive Committee (1991). Pacing Clin Electrophysiol 14:920 \200\223927. Multicenter Automatic De \201 brillator Implantation Trial II MADIT II Purpose: To evaluate the impact of prophylactic ICD therapy in patients with MI at lest 30 days prior to enrollment and poor LV EF ((cid:100)30%). 1232 patients were randomized to re ceive conventional drug therapy alone (490 patients) or a combination of both ICD and drug therapy (742 patients). Follow-up: Mean 20 months Results: Mortality rates were 19.8% and 14.2% in the conventional and ICD groups, respectiv ely, and there was a 31% reduction in death at any interval in the ICD group. Reference: Moss A, et al., for the MADIT II Investigators (2002). N Engl J Med 346:877 \200 \223883. MAJOR TRIALS IN CARDIOLOGY 627 Metoprolol Trial I \200\224Heart Failure CR/XL Randomized Intervention MERIT-HF Purpose: To evaluate the impact of metoprolol succinate when added to standard therapy for chronic heart failure in 3991 patients with LVEF (cid:100)40% and NYHA Class II \200\223IV, when compared to placebo. Metoprolol was started at 12.5 or 25 mg once daily, aiming to ti trate up to 200 mg once daily. Follow-up: 1 year Results: At 1 year, the trial was terminated early because of the signi \201 cant reductio n in all-cause mortality with metoprolol compared to placebo (7.2% vs. 11.0%, p = 0.00009), including reductions in cardiovascular death, sudden death, and death from worsening heart failure. Reference: Hjalmarson A, et al. (2000) 1295 \200\223302. JAMA 283: Microalbuminuria, Cardiovascular and Renal Outcomes in the Heart Outcomes Prevention Evalua tion MICRO- HOPE Purpose: To evaluate the impact of Ramipril and vitamin E in the development of diabetic ne phropathy in patients with microalbuminuria, or the development of new-onset microalbuminur ia in the diabetic subset of patients from the HOPE study. Of the HOPE cohort, 3577 were di abetic, and 1129 had microalbuminuria. Follow-up: Mean 4 years Results: 7% of the ramipril group and 8% of the placebo group (p = 0.027) developed protein uria. There was a trend for reduction in risk of new-onset microalbuminuria, although this was not statistically signi \201 cant (p = 0.17). Ramipril reduced the risk of overt nephr opathy, dialysis, or laser therapy by 16%. Reference: Heart Outcomes Prevention Evaluation (HOPE) Study Investigators (2000). Lancet 3 55:253 \200\223259. Myocardial Cholesterol Lowering Ischemia Reduction with Aggressive MIRACL Purpose: To determine whether atorvastatin 80 mg once daily initiated 24 \200\22396 hours a fter an acute coronary syndrome (ACS) reduces death, nonfatal MI, cardiac arrest, or recurr ent symptomatic myocardial ischemia requiring emergent hospitalization (the primary end poi nts) in 3086 patients in a randomized, placebo-controlled trial. Follow-up: 16 weeks CHAPTER 15 Major trials in cardiology 628 Results: The primary end point occurred in 14.8% of the atorvastatin group and 17.4% of the placebo group (p = 0.48). There were no signi \201 cant differences in risk of death, non fatal MI, or cardiac arrest between the two groups. However, the atorvastatin group had a l ower risk of recurrent ischemic events requiring hospitalization. MIRACL Reference: Schwartz GG, et al. (2001). JAMA 285: 1711 \200\2231718. Multicentre Insync Randomized Clinical Evaluation Trial MIRACLE Purpose: To evaluate whether cardiac resynchronization therapy (CRT) through atrial-synchro nized biventricular pacing produces clinical bene \201 t in patients with heart failure an d IV conduction delay. 453 patients with NYHA Class III and IV heart failure, LVEF (cid:100 )35%, and QRS >130 ms were randomized to a CRT group (n = 228) or a control group (n = 225) , while continuing optimal medical therapy. Primary end points were 6-minute walk distance and NYHA functional class. Follow-up: 6 months Results: Patients in the resynchronization group had signi \201 cantly improved walking di stance, quality of life score, and NYHA class after 1 month, which was maintained throughou t the study, compared to nonpaced controls. Signi \201 cant improvements were also seen in secondary end points of LVEF, peak oxygen consumption, total exercise time, and duration o f the QRS interval. The risk of major clinical events (death and hospitalization for heart failure) was also signi \201 cantly lower. Reference: Abraham WT, et al. (2002) N Engl J Med 346: 1845 \200\2231853. Multicentre Evaluation Insync ICD Randomized Clinical MIRACLE ICD