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 Purpose: To evaluate the safety and ef \201 cacy of combined cardiac through biventricular pacing and implantable cardiac de \201 brillator (ICD) in 369 patients with NYHA Class II I (n = 328) or IV (n = 41) despite appropriate medical management. LVEF was (cid:100)35%, a nd QRS 130 ms. Of these 369 patients, 182 were controls (ICD on, CRT off), while 187 were i n the CRT group (ICD on, CRT on). Primary end points were quality of life, 6-minute walk di stance, and functional class compared to baseline. resynchronization therapy (CRT) Follow-up: 6 months MAJOR TRIALS IN CARDIOLOGY 629 Results: The CRT group had greater improvement in quality-of-life score and functional clas s compared to controls. There was no difference in 6-minute walk distance, but peak exercis e oxygen consumption and treadmill exercise duration increased in the CRT group. There was no difference in survival (15 deaths in control arm, 14 deaths in CRT arm), LV size or func tion, overall heart failure status, and rates of hospitalization. MIRACLE ICD Reference: Young JB, et al. (2003). JAMA 289:2719 \200\2232721. Mode Selection Trial in sinus-node dysfunction MOST Purpose: To evaluate whether dual-chamber pacing would provide better event-free survival a nd quality of life than single-chamber pacing for sinus node dysfunction. 2010 patients wer e randomized to dual-chamber or ventricular pacing. The primary end point was all-cause mor tality or nonfatal stroke. Secondary end points included the composite of death, stroke- or heart failure \200\223related hospitalization, AF, heart failure score, the pacemaker synd rome, and quality of life. Follow-up: Mean 33.1 months Results: Incidence of the primary end point did not differ between groups. The risk of AF w as lower in the dual- chamber group (hazard ratio 0.79, p = 0.0008) and heart failure score s were better, as were quality of life scores. Rates of hospitalization for heart failure, death, and stroke were not different. 16.5% of the ventricular pacing group experienced pac emaker syndrome and were crossed over to dual-chamber pacing. Reference: Lamas GA, et al. (2002). N Engl J Med 346: 1854 \200\2231862. Multisite Stimulation in Cardiomyopathies Trial MUSTIC Purpose: To evaluate the impact of biventricular pacing on 67 patients with severe heart fa ilure (NYHA III) and QRS >150 ms in a single-blind, controlled, randomized cross- over stud y. The primary end point was distance walked in 6 minutes, with secondary end points of qua lity of life measures, peak oxygen consumption, patients \200\231 treatment preference (act ive vs. inactive pacing), hospitalizations due to heart failure, and mortality. Follow-up: 6 months Results: Mean distance walked in 6 minutes was 23% longer in the active pacing group. 85% p referred the active pacing period. Quality-of-life score and peak oxygen uptake were both s igni \201 cantly improved, and hospitalizations were 66% less when paced. Longer follow-up was required to determine impact on mortality. Reference: Cazeau S, et al. (2001). N Engl J Med 344: 873 \200\223880. CHAPTER 15 Major trials in cardiology 630 Multicenter Unsustained Tachycardia Trial MUSTT Purpose: To identify individuals at greatest risk of sudden cardiac death using signal-aver aged ECG and electrophysiological then optimizing antiarrhythmic therapy on the basis of th e data to reduce sudden death and mortality. 2139 patients (cid:100)80 years old were enrol led with coronary heart disease, or MI more than 4 days previously, with LVEF (cid:100)40% and asymptomatic non-sustained VT. 704 patients had inducible sustained VT after electrophy siological testing and were entered into the randomized trial (184 drug therapy, 167 ICD, 3 53 no therapy). B-Blockers were recommended for all patients, but drug therapy varied and i ncluded sotalol, amiodarone, procainamide, dispyramide, propafenone, quinindine, and mexile tine. The remaining 1435 patients were entered into a registry. studies, and Follow-up: 5 years Results: B-Blockers reduced all-cause mortality in the whole cohort but did not in \202 uence death from arrhythmia or cardiac arrest. In patients with inducible sustained VT, incidence of death from cardiac arrest or arrhythmia was signi \201 cantly l ower in the EP-guided treatment group than in the no-treatment group; bene \201 t occurred only in those receiving ICDs. Similarly, the ICD group had signi \201 cantly reduced risk of arrhythmic death, cardiac arrest, and overall mortality compared to the other groups. Reference: Buxton AE, et al. (1999) N Engl J Med 341: 1882 \200\2231890. Optimal Therapy In Myocardial infarction with the Angiotensin II Antagonist Losartan OPTIMAAL Purpose: To compare the effects on all-cause mortality of losartan 50 mg once daily and cap topril 50 mg twice daily in 5477 patients with con \201 rmed acute MI, acute anterior QWMI , or reinfarction, and heart failure during acute phase. Patients were randomized in a doub le-blind, parallel method. Primary end point was all-cause mortality. Follow-up: 2.7 years Results: There was a nonsigni \201 cant difference in total mortality for captopril, but l osartan was better tolerated. Reference: Dickstein K, et al. (2002). Lancet 360:752 \200\223760. Pacemaker Selection in the Elderly PASE Purpose: To assess the effect of pacing mode (DDDR or VVIR) on long-term health-related qua lity of life of 407 elderly patients (65 \200\22396 years, mean age 76 years) with pacemake rs, randomized to one of these two modes. All patients were in sinus rhythm requiring pacin g for bradycardia. Primary end point was quality of life; secondary end points: all-cause m ortality, hospitalization for heart failure, nonfatal stroke, new AF, or pacemaker syndrome . MAJOR TRIALS IN CARDIOLOGY 631 Follow-up: 30 months PASE Results: Quality of life improved signi \201 cantly for both groups after implantation, bu t there was no signi \201 cant difference between groups in this end point, or in cardiova scular events or death. 26% of the VVIR group crossed over due to the pacemaker syndrome. P atients with sinus node disease, however, had an improved quality of life with dual-chamber compared to single-chamber pacing (explored more fully in MOST trial). Reference: Lamas GA, et al. (1998). N Engl J Med 338: 1097 \200\2231104. Percutaneous Coronary Intervention and Clopidogrel in Unstable angina to prevent Recurrent Events PCI-CURE Purpose: To evaluate the effect of pretreatment of patients undergoing PCI with clopidogrel followed by long-term therapy, in addition to concomitant use of aspirin. 2658 patients wi th NSTEMI undergoing PCI in the CURE study were randomly assigned double-blind treatment wi th clopidogrel or placebo. Patients were pretreated with aspirin and clopidogrel for a medi an of 10 days. After PCI, >80% of patients in both groups received open-label clopidogrel f or 4 weeks. After this, clopidogrel was restarted in the randomized individuals for a mean of 8 months (up to 1 year). Primary composite end point was cardiovascular death, MI, or ur gent target vessel revascularization within 30 days of PCI. Follow-up: Up to 1 year Results: There was a 30% reduction in cardiovascular death or MI in the clopidogrel group, as well as a lower rate of revascularization, without any signi \201 cant difference in ma jor bleeding. Reference: Mehta SR, et al. (2001). Lancet 358:527 \200\223533. Primary Angioplasty in AMI patients from General community hospitals transported to PCI Uni ts versus Emergency thrombolysis PRAGUE Trials PRAGUE 1: Long-term outcomes of three reperfusion strategies in 300 patients with acute STE MI presenting to community hospitals were compared: 1) thrombolysis alone in a community ho spital; 2) thrombolysis during immediate transportation for angioplasty; 3) immediate trans portation for angioplasty without thrombolysis. After 1 year, there were no signi \201 can t differences in total mortality in the 300 patients, but in a subset of patients randomize d within 2 hours of symptoms, total mortality was lower in the angioplasty group. Primary a ngioplasty patients had a lower combined end point of total mortality and nonfatal reinfarc tion rate. Combining thrombolysis and PCI was not superior to PCI alone. CHAPTER 15 Major trials in cardiology 632 PRAGUE 2: 850 patients with STEMI <12 hours were randomized to thrombolysis in a community hospital without PCI, or immediate transportation for PCI. PCI strategy decreased mortality in patients presenting >3 hours after symptom onset, but in those presenting within 3 hour s, thrombolysis had similar results to PCI (primary end point was 30-day death, secondary e nd points were death, reinfarction, or stroke at 30 days. PRAGUE Trials PRAGUE 4: 400 patients scheduled for CABG were randomized to off-pump and on-pump surgery b y a cardiologist. The surgeon was allowed to change technique after randomization. Primary end point at 30 days was death, MI, stroke, or new renal failure needing dialysis. There wa s no signi \201 cant difference in the primary end point. The off-pump group had lower pos toperative CKMB levels, lower total hospital costs, less blood loss, and fewer distal anast amoses, suggesting that the off-pump technique was at least as clinically safe and effectiv e as on-pump surgery. References: Bedn r F, et al. (2003). Can J Cardiol 19(10): 1133 \200\2237. Widimsky P, et al. (2003). Eur Heart J 24:21 \200\2233. Straka Z, et al. (2004). Ann Thorac Surg 77:789 \200\223793. Platelet Receptor Management Inhibition Ischemic Syndrome PRISM Purpose: To compare tiro \201 ban with unfractionated heparin in 3232 patients with unstab le angina (last chest pain <24 hours, documented coronary artery disease) on aspirin in a d ouble-blind, randomized control trial. Follow-up: 48 hours and 30 days Results: At 48 hours, the incidence of death, MI, and refractory ischemia was lower in the tiro \201 ban group, but at 30 days theses rates were not signi \201 cantly different. In 2240 patients who were troponin T positive at 24 hours, mortality and the incidence of MI were lower at 30 days for the tiro \201 ban group. This bene \201 t was not seen in tropo nin- negative patients. Reference: Hamm CW, et al. (1999). Circulation 100 (Suppl I):1 \200\223775. Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstabl e Signs and Symptoms PRISM PLUS Purpose: To evaluate the effect of tiro \201 ban in the treatment of unstable angina and N QWMI. 1915 patients were randomized to tiro \201 ban, heparin, or tiro \201 ban and hepar in. The study drugs were infused for a mean of 71.3 hours, during which coronary angiograph y and intervention were performed when indicated after 48 hours. MAJOR TRIALS IN CARDIOLOGY 633 The drug infusion was maintained for 12 \200\22324 hours after an intervention The composit e primary end point was death, MI, or refractory ischemia within 7 days \200\231 randomizat ion. All patients were given aspirin unless there were any contraindications. PRISM PLUS Follow-up: 6 months Results: The study was stopped prematurely for the group who received tiro \201 ban alone because of excess mortality at 7 days. The composite end point was reached by fewer people in the tiro \201 ban plus heparin group than those who had heparin alone (12.9% vs. 17.9%, p = 0.004). The composite end point rates, as well as rates of death and MI, were lower in the tiro \201 ban plus heparin group than in the heparin-alone group at 30 days and at 6 months. There was no signi \201 cant difference in rates of bleeding between the tiro \201 ban plus heparin group and the heparin-alone group. Reference: The PRISM-PLUS Study Investigators (1998). N Engl J Med 338:1488 \200\2231497. Perindopril Protection against Recurrent Stroke Study PROGRESS Purpose: To evaluate the effects of BP reduction on risk of stroke in 6105 patients, normot ensive or hypertensive, with a proven TIA or stroke in the previous 5 years. Patients were randomized to perindopril 4 mg/day plus 2.5 mg indapamide if required, or placebos. Follow-up: 3.9 years Results: BP was reduced by 9/4 mmHg in the treatment group compared to placebo. There was a relative risk reduction in stroke of 28% in the treatment group (p < 0.0001), and the risk of total vascular events was also lower in the treatment group. Risk of stroke was reduced in both normotensive and hypertensive patients. The combination of perindopril and indapam ide reduced BP by 12/5 mmHg and stroke risk by 43%, but in the perindopril-alone group BP w as reduced by 5/3 mmHg and did not lead to a reduced stroke risk. Reference: PROGRESS Collaborative Group (2001). Lancet 358:1033 \200\2231041. Platelet gpIIb/IIIa Underpinning the Receptor Suppression of Unstable Ischemia Trial for PURSUIT Purpose: To evaluate the effects of integrelin on the frequency and duration of ischemia in 227 patients with unstable angina in a randomized, double-blind, placebo- controlled trial . PCI was performed in 11.2% of patients during a period of medical therapy with integrelin that lasted for 72 hours in total and for 24 hours after the intervention. All patients re ceived IV heparin. Follow-up: 72 hours CHAPTER 15 Major trials in cardiology 634 Results: Holter monitoring measured ischemic episodes, and their frequency and duration wer e lower in the integrelin group, as were refractory ischemia and MI. There was no excess bl eeding risk in the integrelin group. PURSUIT Reference: Schulman SP, et al. (1996). Circulation 94: 2083 \200\2232089. Rate control versus electrical cardioversion persistent atrial \201 brillation for RACE Purpose: To evaluate whether ventricular rate control in AF is inferior to maintenance of s inus rhythm. There were 522 patients with persistent AF after electrical cardioversion in t he rate control or rhythm control group. The end point was a composite of death from cardio vascular disease, heart failure, thromboembolism, bleeding, permanent pacemaker implantatio n, and adverse drug effects. Rate control was achieved by digoxin, calcium channel blockers (non-dihydropyridine), and B-blockers, either alone or in combination, to achieve a target heart rate <100/min. All patients were orally anticoagulated unless contraindicated. The r hythm control group underwent DCCV without prior treatment with antiarrhythmics. Then they were placed on sotalol. If AF recurred within 6 months, DCCV was repeated and sotalol was r eplaced by \202 ecainide or propafenone. If further AF recurred, a loading dose of amioda rone was given at 600 mg daily for 4 weeks, then DCCV was repeated and the antiarrhythmic d rug continued. Patients were orally anticoagulated until 1 month of sinus rhythm was mainta ined, after which the anticoagulant was stopped or changed to aspirin. Aspirin was allowed in the rate control group if <65 years old without underlying cardiac disease. Follow-up: Mean 2.3 years Results: 39% of the rhythm control vs. 10% of the rate control group were in sinus rhythm, The primary end point occurred in 17.2% of the rate control vs. 22.6% of the rhythm control group, indicating that rate control was not inferior to rhythm control for preventing deat h and morbidity from cardiovascular causes in patients with recurrent AF after DCCV. Reference: Van Gelder IC, et al. (2002). N Engl J Med 347:1834 \200\2231840. Randomized Aldactone Evaluation Study mortality trial RALES Purpose: To evaluate the effect of adding 25 mg spironolactone in 1663 patients with LVEF < 35%, already on ACE inhibitors and loop diuretic, and most also on digoxin. The primary end point was all-cause mortality. Follow-up: Mean 24 months MAJOR TRIALS IN CARDIOLOGY 635 in the Results: There was a 30% risk reduction spironolactone group, p < 0.001, due to lowe r deaths from both sudden cardiac death and progressive heart failure. There was also 35% l ess frequent hospitalization in the spironolactone group; this group had a signi \201 cant improvement in NYHA functional class. There was a 10% incidence of gynecomastia and breast pain in men treated with spironolactone. There was minimal risk of serious hyperkalemia in either group. The trial was discontinued early after an interim analysis showed spironolac tone to be ef \201 cacious. RALES Reference: Pitt B, et al. (1999). N Engl J Med 341:709 \200\223717. A randomized (double blind) study with the sirolimus coated BX velocity balloon expandable stent (cipher) in the treatment of patients with de novo native coronary lesions RAVEL Purpose: 237 patients with single de novo lesions <18 mm in length and 2.5 \200\2233.5 mm i n diameter received clopidogrel for a 2-month period and were randomized to receive either a Cipher or bare-metal stent. All patients underwent angiography at the end of the study. Follow-up: 6 months Results: Event-free survival was 97% at 6 months compared to 72% in the bare-metal stent gr oup. There was no restenosis in the Cipher group compared to 26% in the control group. Ther e were no reported cases of subacute thrombosis in the Cipher group. Reference: Regar E, et al. (2002). Circulation 106: 1949 \200\2231956. Reversal of Atherosclerosis with Aggressive Lipid Lowering REVERSAL Purpose: To evaluate the effect of two different lipid- lowering drugs on coronary atheroma burden and progression. Patients who were enrolled required coronary angiography for a cli nical indication and demonstrated at least 1 obstruction with angiographic luminal narrowin g of (cid:116)20%. Lipid criteria required a low-density cholesterol level (LDL-C) of 3.24 \200\2235.44 mmol/L after a 4- to 10-week washout period. 654 patients were initially rando mized in a double-blinded manner to receive the study drug, either 40 mg pravastatin or 80 mg atorvastatin. 502 patients had intravascular ultrasound (IVUS) examinations that could b e evaluated both at baseline and after 18 months treatment. The target vessel for IVUS must not have undergone angioplasty or have a luminal narrowing of >50% throughout a target seg ment with a minimum length of 30 mm. CHAPTER 15 Major trials in cardiology 636 The main outcome measure was percentage change in atheroma volume. A secondary outcome meas ure was change in percentage atheroma volume, a measure of absolute, not relative, change i n atheroma volume. REVERSAL Follow-up: 18 months Results: Baseline LDL-C value (mean 3.89 mmol/L in both groups) was reduced to 2.85 mmol/L in the pravastatin group and 2.05 mmol/L in the atorvastatin group (p <0.001). C-reactive p rotein (CRP) decreased 5.2% in the pravastatin group and 36.4% with atorvastatin. There was a signi \201 cantly lower reduction in progression of percentage change in atheroma volum e (primary end point) in the atorvastatin group compared with pravastatin. No signi \201 c ant progression of atheroma burden occurred in the atorvastatin group, but it did in the pr avastatin group compared to baseline. These changes may be related to reduction in LDL-C an d CRP. There were no signi \201 cant numbers of adverse drug reactions in either group. Reference: Nissen SE, et al. (2004). JAMA 291:1071 \200\2231080. Second Randomized Intervention Treatment of Angina RITA-2 Purpose: To compare long-term consequences in 1018 patients with unstable angina randomized to PTCA vs. conservative therapy. Follow-up: Median 7 years Results: Death or MI occurred in 14.5% PTCA patients and in 12.3% medical patients, which w as not signi \201 cantly different. CABG and repeat arteriography were more common in the PTCA group. The PTCA group had improved exercise tolerance and anginal symptoms. References: Lancet 1997; 350(9076):461 \200\223468; Henderson RA, et al. (2003). J Am Coll Cardiol 42:1161 \200\2231170. Amiodarone versus sotalol for atrial \201 brillation SAFE T Purpose: To evaluate the safety and ef \201 cacy of amiodarone compared with sotalol for r estoration and maintenance of sinus rhythm among patients with atrial \201 brillation. A total of 6582 patients were screened for the study, however, only 665 were enrolled. Follow-up: Mean 12 \200\22354 months Results: The primary end point of time to \201 rst recurrence of atrial \201 brillation was longer in the amiodarone group (median 487 days, 48% by 1 year) than in either the sot alol group (median 74 days, 68% by 1 year, p = 0.002) or placebo group (median 6 days, 87% by 1 year, p < 0.001 for both amiodarone and sotalol comparisons). Spontaneous cardioversio n in the \201 rst 28 days was similar in the amiodarone and sotalol groups, both of which were higher than the placebo group. Reference: Singh BN, et al. (2005). N Engl J Med 352: 1861 \200\2231872. MAJOR TRIALS IN CARDIOLOGY 637 Stenting and Angioplasty with Protection in Patients at High Risk for Endarterectomy (SAPPH IRE) SAPPHIRE Purpose: To compare stenting with protection vs. endarterectomy in patients with severe sym ptomatic or asymptomatic carotid artery stenosis. The rate of the composite end point of de ath, myocardial infarction, or stroke at 30 days and ipsilateral stroke or death from neuro logical causes within 31 days to 1 year was studied in 334 patients. Mean age of patients w as 72 years. Follow-up: 3 years Results: Among patients with severe atherosclerotic carotid artery stenosis, treatment with stenting was noninferior compared to carotid endarterectomy (CEA) for the composite of dea th, stroke, or MI at 30 days plus ipsilateral stroke or death from neurological causes with in 31 days to 1 year. The directionality of the individual end points at 1 year all favored stenting, none reached signi \201 cance (death 7.4% vs. 13.5%, p = 0.08; MI 3.0% vs. 7.5% , p = 0.07; stroke 6.2% vs. 7.9%, p = 0.60). There was no signi \201 cant difference in tr ansient ischemic attack or major bleed between the 2 arms. However, the rate of cranial ner ve injury was higher in the CEA arm (0% vs. 4.9%, p < 0.01). The trial was discontinued pre maturely secondary to low enrollment. Long-term results of the trial through 3 years are pe nding. Reference: Yadav JS, et al. (2004). N Engl J Med 351: 1493 \200\2231501. Survival And Ventricular Enlargement Study SAVE Purpose: To evaluate the effect of captopril starting 3 \200\22316 days after MI in improvi ng mortality and left ventricular function in 2231 patients with LVEF <40% but no overt hea rt failure. Follow-up: Mean 42 months Results: All-cause mortality risk was reduced in the captopril arm by 19%. Recurrent MI ris k was reduced by 25% and death after recurrent MI by 32%. Patients in the captopril arm wer e less likely to require coronary revascularization but there was no difference in hospital ization rates compared to placebo. Symptoms of cough, dizziness, diarrhea, and taste altera tion were more common in the captopril group. Reference: Rutherford JD, et al. (1994). Circulation 90: 1731 \200\2231738. CHAPTER 15 Major trials in cardiology 638 A randomized trial of a sirolimus-eluting stent versus a standard stent in patients at high risk of coronary restenosis SIRIUS Purpose: To evaluate the effect of sirolimus drug-eluting stents vs. bare-metal stents on 1 058 patients with de novo coronary artery stenosis. Follow-up: 12 months Results: At 9 months, clinical restenosis (target lesion revascularization) was 4.1% in the sirolimus limb and 16.6% in the control (p < 0.001); at 12 months values were 4.9% and 20% , respectively (p <0.001). There were no differences in death or MI rates. In high-risk sub sets and in presence of diabetes, there was a reduction of 70% \200\22380% clinical resteno sis at 1 year. At 9 months, clinical restenosis (target lesion revascularization) was 4.1% in the sirolimus limb and 16.6% in the control (p < 0.001). At 12 months these values were 4.9% and 20%, respectively (p < 0.001). There were no differences in death or MI rates. Reference: Holmes DR Jr, et al. (2004) Circulation 105: 634 \200\223640. Studies Of Left Ventricular Dysfunction SOLVD Purpose: To evaluate the impact of enalapril on long- term survival in patients with LVEF ( cid:100)0.35 with or without a history of cardiac failure, and on LV function and volume, a rrhythmias, and quality of life. Study design was randomized, double blind, placebo control led. 4228 patients aged 21 \200\22380 years had no overt congestive cardiac failure, and 25 68 patients had overt cardiac failure. Both groups were randomized to receive enalapril (st arting at 2.5 mg twice daily, titrating to 10 mg twice daily) or placebo. Follow-up: 3 years Results: In the group without heart failure there was no statistically signi \201 cant dec rease in mortality, either all-cause or related to cardiovascular disease. There was, howev er, a 29% risk reduction in the combined incidence of death and development of overt cardia c failure. In the group with symptoms of heart failure, there was a 16% risk reduction in a ll-cause mortality. There was no change in quality of life in either group compared to plac ebo after 1 year, or in the incidence of ventricular arrhythmias. However, left ventricular end diastolic volumes and left ventricular mass increased in the placebo group but not in the enalapril- treated groups. Enalapril-treated patients lived 0.16 years longer than the placebo group, translating into a lifetime increase of 0.4 years over placebo. The enalapri l groups had signi \201 cantly fewer hospitalizations than the placebo group. Reference: Glick H, et al. (1995). J Card Fail 1:371 \200\223380. MAJOR TRIALS IN CARDIOLOGY 639 Scandinavian Simvastatin Survival Study SSSS (4S) Purpose: To evaluate the impact of 20 mg simvastatin in patients with total serum cholester ol 5.5 \200\2238 mmol/L (after 8 weeks of dietary therapy) on mortality and the incidence o f major coronary artery disease. 4444 patients aged 35 \200\22369 years were in the study. Follow-up: Median 5.4 years Results: There was a 30% relative risk reduction in all-cause mortality, 42% reduction in c oronary mortality, 34% reduction in coronary events, 32% reduction in cost of hospitalizati on, and 37% reduction in revascularization procedures in the simvastatin group. Simvastatin signi \201 cantly reduced the risk of major coronary events in all quartiles of baseline total, LDL, and HDL cholesterol to a comparable degree in each quartile. There was one case of reversible myopathy that was the most serious drug-related adverse event. Reference: J nsson B, et al. (1996) Eur Heart J 17: 1001 \200\2231007. Trials evaluating a slow-release paclitaxel-eluting stent (TAXUS) for coronary lesions TAXUS TAXUS 1: This trial was to evaluate the safety and feasibility of a TAXUS stent delivering paclitaxel locally to coronary plaques via a slow-release polymer coating, compared to a ba re-metal control stent. 61 patients with de novo or restenotic lesions ((cid:100)12 mm) wer e randomized to receive a TAXUS stent or control stent that was non-drug eluting (diameters 3.0 or 3.5 mm). The primary end point, 30-day major adverse clinical event (MACE), rate wa s 0% in both groups. At 12 months, the MACE rate was 3% in the TAXUS group and 10% in the c ontrol. The restenosis rate measured by QCA was 0% in the TAXUS group vs. 10% in controls a t 6 months. IVUS showed signi \201 cant improvements in normalized neointimal hyperplasia in the TAXUS group compared to controls. TAXUS 2: A comparison of slow-release (SR) and moderate- release (MR) paclitaxel-eluting st ents with control bare- metal stents (BMS). All 536 patients had post-procedure and 6-month follow-up with IVUS. There was signi \201 cant reduction in MACE rates, in-stent restenos is (ISR), and in-stent volume reduction with SR or MR stents compared to controls. There wa s no signi \201 cant difference between the TAXUS groups. TAXUS 3: 28 patients with ISR with lesions <30 mm in length and 50% \200\22399% diameter st enosis in 3.0 \200\2233.5 mm vessels were treated with one or more TAXUS stents. 25 people completed the angiographic follow-up at 6 months. The MACE rate was 29% (8 patients). IVUS was recommended to ensure good stent deployment and complete coverage of target lesion. CHAPTER 15 Major trials in cardiology 640 TAXUS 4: This trial evaluated the safety and ef \201 cacy of slow-release polymer-based pa clitaxel stents after implantation in de novo coronary lesions after 1 year. 1314 patients with de novo coronary lesions 10 \200\22328 mm length, diameter 2.5 \200\2233.75 mm, covera ble by a single stent, were randomized to a TAXUS or bare metal (EXPRESS) stent. At 1 year, MACE rates and target vessel revascularization rates were lower in the TAXUS group. Rates of cardiac death, MI, and subacute thrombosis were not signi \201 cantly different. TAXUS References: Grube E, et al. (2003). Circulation 107:38 \200\22342; Columbo A, et al. (2003) Circulation 108:788 \200\223794; Tanabe K, et al. (2003). Circulation 107:559 \200\223564; Stone GW, et al. (2004) Circulation 109:1942 \200\2231947. Ef \201 cacy of tPA (with IV heparin) was compared to streptokinase in achieving reperfusi on in 290 patients presenting with acute STEMI <6 hours after symptom onset. All patients u nderwent baseline coronary angiography after randomization. Signi \201 cantly higher rates of perfusion were found in the TPA arm. Patients with a patent artery at 90 minutes after starting reperfusing therapy had lower 6-month and 1-year mortality regardless of treatment group. TIMI 1 Patients with acute MI were given tPA within 4 hours of symptom onset and randomized to an immediate invasive (angiogram within 2 hours), delayed invasive (within 18 \200\22348 hours ), and conservative (angiogram if ETT positive at 6 weeks or further ischemia) strategy. Th ey were then given a predischarge angiogram and 6-week ETT, and followed up at 1 year. At 6 weeks there was no difference between the groups in death or reinfarction. Infarct-related artery patency at time of discharge was similar in all groups, with more complications in the invasive arms. TIMI 2A 3339 patients with AMI were given tPA within 4 hours of symptom onset and randomized to an invasive strategy (angiogram within 18 \200\22348 hours) or a conservative strategy (angiog ram if ETT positive at 6 weeks or further ischemia). Patients were also randomized to immed iate IV followed by oral B-blockade, or deferred B-blockade. There was no difference in the composite end point of death or recurrent MI at 42 days between the invasive and conservat ive groups. But those in the invasive arm were twice as likely to need PTCA or CABG at 1 ye ar. In the early B-blockade group, there was signi \201 cantly lower reinfarction and recu rrent ischemia at 6 weeks. TIMI 2B MAJOR TRIALS IN CARDIOLOGY 641 391 patients with unstable angina or NQWMI were given aspirin, IV heparin, B-blockers, nitr ates and calcium antagonists, and then randomized to receive tPA or placebo after baseline angiography had excluded patients with left main stem disease or no coronary disease. They then underwent repeat angiography at 18 \200\22336 hours and were followed up at 6 weeks wi th an ETT. Baseline angiography showed 35% had apparent thrombus, and 30% had possible thro mbus, with no difference in the degree of lesion improvement at angiography after randomiza tion (25% tPA vs. 19% placebo). TIMI 3A 1473 patients with unstable angina or NQWMI were treated with maximal medical therapy and r andomized in a 2x2 factorial design to receive tPA or placebo, and to follow invasive or co nservative strategies. There was no difference in composite end points of death, infarction , or ischemia in tPA and placebo groups, although the risk of MI, death, or cerebral bleedi ng was higher in the tPA group. Similarly, there was no difference between the conservative and invasive groups in the primary end points, although the invasive group required more r eadmission to the hospital for angina. The TIMI 3 registry showed that ST deviation was a p rognostic indicator in unstable angina, whereas new T-wave inversion was not. TIMI 3B 382 patients with AMI <6 hours were randomized to tPA, APSAC, or a combination of the two ( at reduced dosage). Each underwent angiograms at 90 minutes, and at 18 \200\22336 hours. tP A was shown to have higher patency than APSAC or the combination, fewer unsatisfactory outc omes prior to discharge, and lower mortality at 1 year. TIMI 4 Patients with AMI <6 hours were randomized to hirudin (a direct thrombin inhibitor) or unfr actionated heparin, combined with aspirin and tPA, followed by angiography at 90 minutes an d 18 \200\22336 hours. The hirudin arm had higher TIMI 3 \202 ow rates and fewer re-occlu sions. TIMI 5