Highlights from the American College of Cardiology Annual Scientific Session 2005: March 6 to 9, 2005, Orlando, Florida

Study 

A Randomized Trial of Vitamin E in the Primary Prevention of Cardiovascular Disease in 39876 Women: The Women’s Health Study

Presenter 

Dr. Julie E. Buring, Brigham and Women’s Hospital, Boston, MA

Background 

The biological basis of using antioxidant supplements, including α-tocopherol (vitamin E), to prevent the initiation and progression of cardiovascular disease (CVD) is based on the oxidative-modification hypothesis, according to which peroxidation of low-density lipoprotein (LDL) cholesterol is the initiator of atherosclerosis. Supplementation of antioxidants capable of inhibiting the lipid peroxidation could lead to reduction in the risk of a first major cardiovascular event (MACE) as well as in the progression of established atherosclerotic disease.1,2

High doses of vitamin E can block lipid peroxidation and have additional effects that might reduce the risk of coronary heart disease (CHD).3 Epidemiologic cohort studies have suggested that vitamin E supplementation may prevent CVD and cancer. However, randomized, controlled trials have focused primarily on individuals with existing CHD, with inconsistent results. In fact, the actual value of vitamin E for primary prevention of CVD has been controversial. A meta-analysis of 7 trials of vitamin E,4 with a daily dose ranging from 50 to 800 IU and long-term follow-up of 1.4 to 12 years, included 81788 patients in either primary or secondary prevention. Compared with control, supplements of vitamin E did not provide survival benefit or significantly decrease risk of cardiovascular death or cerebrovascular accident. Furthermore, another large meta-analysis involving 135967 participants in 19 clinical trials evaluated the dose-response relationship between vitamin E supplementation and total mortality. Doses ranged from 16.5 to 2000 IU (median, 400 IU). A relationship between vitamin E dosage and all-cause mortality was observed, with increased risk above 150 IU daily.5

As a result, the U.S. Preventive Services Task Force could not determine the balance of benefits and harms of routine use of supplements of vitamin E, and concluded that the available evidence was insufficient to recommend for or against the use of supplements of vitamins A, C, or E, or antioxidant combinations for the prevention of cancer or CVD.6

The Women’s Health Study was a randomized, double-blind, placebo-controlled, 2 × 2 factorial trial funded by the National Heart, Lung, and Blood Institute and the National Cancer Institute to evaluate the risks and benefits of low-dose aspirin (100 mg every other day; supplied by Bayer Healthcare, Leverkusen, Germany) and vitamin E (600 IU every other day; supplied by the National Source Vitamin E Association, Washington, DC) in the primary prevention of CVD and cancer. After an initial questionnaire-based screening to assess willingness and eligibility and a 3-month run-in period to identify greater likelihood of long-term treatment compliance, a total of 39876 female health professionals aged ≥45 years without history of CVD, cancer, or other major chronic illness were randomized to receive aspirin or placebo, with subsequent randomization to vitamin E or placebo (mean follow-up, 10.1 years). The primary efficacy endpoint was a composite of MACE defined by nonfatal myocardial infarction (MI), nonfatal stroke, or cardiovascular death. Secondary endpoints included each of the primary endpoints as well as all-cause mortality.

Results 

In terms of MACE, there was no significant difference between vitamin E– and placebo-treated women (relative risk [RR], 0.93; 95% CI, 0.82-1.05; P = 0.26). Regarding individual endpoints, no significant differences were observed in the risk of stroke (RR, 0.98; 95% CI, 0.82-1.17; P = .82), MI (RR, 1.01; 95% CI, 0.82-1.23; P = .96), or all cause-mortality (RR, 1.04; 95% CI, 0.93-1.16; P = .53). By contrast, women in the vitamin E group had a 24% reduction in the risk of cardiovascular death (RR, 0.76; 95% CI, 0.59-0.98; P = .03) compared with women in the placebo group. Limited analysis of women with high compliance did not significantly alter the overall results. In addition, no significant differences were observed in terms of randomized aspirin assignment, subgroup analysis, or side effects.

Interpretation 

In this large, randomized trial in primary prevention, long-term treatment with a high-dosage vitamin E supplementation did not reduce the risk of major cardiovascular events. However, a significant reduction in the risk of cardiovascular death was observed among women treated with vitamin E, as compared with placebo-treated women. The mechanism to explain this finding is not known, because no beneficial effect was seen in the risk of MI and stroke. These results, taken together with the current evidence, do not support the use of vitamin E supplementation for primary prevention of CVD.

Study 

A Randomized Trial of Low-Dose Aspirin in the Primary Prevention of Cardiovascular Disease in 39876 Women: The Women’s Health Study

Presenter 

Dr. Paul M. Ridker, Brigham and Women’s Hospital, Boston, MA

Background 

Although aspirin has been proven to be effective in the treatment of acute coronary syndromes and in the secondary prevention of cardiovascular disease (CVD), evidence about its use in primary prevention remains controversial.1 Overall, aspirin use is associated with a 32% reduction in the risk of MI, but less conclusive data for stroke and cardiovascular death are available. Furthermore, most trials have evaluated men exclusively, resulting in the availability of limited data about treatment effect in women.2

Results 

During follow-up, 477 major cardiovascular events (MACE) occurred in the aspirin group compared with 522 in the placebo group (relative risk [RR], 0.91; 95% CI, 0.80-1.03; P = .13). Regarding individual endpoints, there was a 17% reduction in the risk of stroke (RR, 0.83; 95% CI, 0.69-0.99; P = 0.04), with 24% reduction in the risk of ischemic stroke (RR, 0.76; 95% CI, 0.63-0.93; P = .009) and a nonsignificant increased risk of hemorrhagic stroke (RR, 1.24; 95% CI, 0.82-1.87; P = .31). Women treated with aspirin did not have a reduction in the risk of fatal or nonfatal MI (RR, 1.02; 95% CI, 0.84-1.25; P = .83) or death from cardiovascular causes (RR, 0.95; 95% CI, 0.74-1.22; P = .68) compared with women in the placebo group. By contrast, women in the aspirin group had significantly increased risk of gastrointestinal bleeding, including those requiring transfusion (RR, 1.40; 95% CI, 1.07-1.83; P = .02), peptic ulcer, hematuria, and epistaxis. Limited analysis to women with high compliance showed a greater reduction in the risk of MACE; no significant differences in treatment effect were observed in terms of randomized vitamin E assignment or various subgroup analyses. However, aspirin significantly reduced the risk of MACE by 26% (P = .008) among women aged ≥65 years and by 20% (P = .003) among former smokers and those who had never smoked.

Interpretation 

In this large, randomized trial in primary prevention, long-term treatment with low-dose aspirin did not reduce the risk of a first major cardiovascular event. A significant reduction in the risk of stroke was observed among women treated with aspirin compared with placebo-treated women. By contrast, aspirin did not provide any beneficial effect on the risk of fatal or nonfatal MI or death from cardiovascular causes, and it was associated with a significantly higher risk of side effects. The decision to incorporate low-dose aspirin in the primary prevention strategy among women, particularly among those older than 65 years, should be based on weighing benefits and risks.

Title 

Effect of Lowering Low Density Lipoprotein Cholesterol Substantially Below Currently Recommended Levels in Patients with Coronary Heart Disease: Results of the Treating to New Targets Study

Presenter 

Dr. John C. LaRosa, Brooklyn, NY

Background 

Recent statin trials1,2 have suggested that lowering low-density lipoprotein (LDL) cholesterol levels well below 100 mg/dL reduces the rate of coronary heart disease (CHD) events, prompting the National Cholesterol Education Program to endorse an optional target of 70 mg/dL for LDL cholesterol among individuals with CHD or CHD equivalents with additional very-high-risk features.3 However, whether intentionally lowering LDL cholesterol to such low targets reduces subsequent CHD events in patients with known, stable CHD has not been tested. The Treating to New Targets (TNT) trial was designed to test this hypothesis by randomizing patients with stable CHD either to high-dose atorvastatin (target LDL cholesterol of 75 mg/dL) or to low-dose atorvastatin (target LDL cholesterol of 100 mg/dL).

A total of 18469 patients were screened for the trial, of whom 15464 patients aged 35 to 75 years with clinically evident, stable CHD (previous myocardial infarction [MI], history of angina with evidence of obstructive coronary atherosclerosis, and/or history of coronary revascularization), LDL cholesterol of 130-250 mg/dL, and triglyceride level ≤600 mg/dL qualified for the open-label, run-in phase in which all patients received atorvastatin 10 mg for 8 weeks. Of these 15464 subjects, 5463 patients were excluded during the run-in phase for failure to meet additional randomization criteria: 648 failed to achieve an LDL cholesterol ≤130 mg on atorvastatin 10 mg (and were thus excluded for ethical reasons), 32 failed to achieve a triglyceride level ≤600 mg/dL, 96 had transaminase elevation >1.5× the upper limit of normal, 35 had myalgias, and the remaining 4650 subjects were excluded for other reasons. A total of 10001 patients (all of whom achieved an LDL cholesterol of ≤130 mg/dL on atorvastatin 10 mg) were randomized in a double-blind fashion to either continuation on atorvastatin 10 mg daily or to atorvastatin 80 mg daily. Patients were followed for a median of 4.9 years. The primary efficacy outcome was the occurrence of the first major cardiovascular event (death from CHD, nonfatal non–procedure-related MI, resuscitation after cardiac arrest, or fatal or nonfatal stroke). Secondary outcomes included a major coronary event (CHD death, nonfatal MI, or resuscitation after cardiac arrest), any cardiovascular event, and all-cause mortality. Analyses were performed by intention-to-treat.

Results 

The mean age of study participants was 61 years; 81% were male, 94% were white, 58% had prior MI, 15% had diabetes mellitus, and 5% had prior stroke. The mean LDL cholesterol levels before and after the 8-week run-in phase on atorvastatin 10 mg were 152 mg/dL and 98 mg/dL (35% reduction), respectively. After randomization, the mean LDL cholesterol levels were 101 mg/dL in the atorvastatin 10-mg arm and 77 mg/dL in the atorvastatin 80-mg arm. Efficacy and safety data are shown below.

	Outcome (n, %)	10 mg atorvastatin (n = 5006)	80 mg atorvastatin (n=4995)	Hazard ratio and 95% confidence intervals	P
	Major cardiovascular event (primary outcome)	548 (10.9)	434 (8.7)	0.78 (0.69-0.89)	<.001
	CHD death	127 (2.5)	101 (2.0)	0.80 (0.61-1.03)	.09
	Nonfatal nonprocedural MI	308 (6.2)	243 (4.9)	0.78 (0.66-0.93)	.004
	Fatal or nonfatal stroke	155 (3.1)	117 (2.3)	0.75 (0.59-0.96)	.02
	Major coronary event	418 (8.3)	334 (6.7)	0.80 (0.69-0.92)	.002
	Any cardiovascular event	1677 (33.5)	1405 (28.1)	0.81 (0.75-0.87)	<.001
	All-cause mortality	282 (5.6)	284 (5.7)	1.01 (0.85-1.19)	.92
	Cardiovascular mortality	155 (3.1)	126 (2.5)	0.80 (0.64-1.08)	.09
	Noncardiovascular mortality	127 (2.5)	158 (3.2)	1.25 (0.99-1.57)	.07
	Any adverse event	289 (5.8)	406 (8.1)		<.001
	Discontinuation due to treatment-related adverse events	5.3%	7.2%		<.001
	Treatment-related myalgias	234 (4.7)	241 (4.8)		.72
	Persistent transaminase elevation (>3× upper limit of normal)	9 (0.2)	60 (1.2)		<.001
	Persistent CK elevation (>10× the upper limit of normal)	0	0
	Rhabdomyolysis⁎	3	2

⁎ None of the cases of rhabdomyolysis were thought to be attributable to the study drug, based on ACC/AHA/NHLBI criteria for rhabdomyolysis induced by statin therapy.4

Interpretation 

The long-awaited TNT trial demonstrated that intensive statin therapy with a goal LDL cholesterol level of 75 mg/dL reduced major cardiovascular events by 22% compared with moderate-dose statin therapy with an LDL cholesterol goal of 100 mg/dL in stable CHD patients. It is noteworthy that intensive statin therapy not only substantially reduced the incidence of nonfatal MI, but also the risk of stroke, a major cause of morbidity among patients with CHD.

This is the first statin trial in which there were fewer deaths from cardiovascular causes than noncardiovascular causes among patients with known CHD, attesting to the great benefit of statin therapy in this population. The study was significantly underpowered to detect a difference in all-cause mortality (the trial would have required 34000 patients to be sufficiently powered for this endpoint). There were 31 more noncardiovascular deaths in the intensive statin arm, but because there was no single disease process or cancer type driving this trend, and because this was a post-hoc subgroup analysis, this finding may be due to chance. However, an editorial5 accompanying the early-release publication of the results of this trial6 questioned the safety profile of atorvastatin 80 mg daily. Only those patients who tolerated atorvastatin 10 mg were randomized to receive the 80-mg dose, and fully 35% of all patients who started the run-in phase on atorvastatin 10 mg were excluded from randomization for reasons that are not fully clear in the manuscript.6 Indeed, patients who had either myalgias or transaminase elevations of only 1.5× (as opposed to the standard 3×) the upper limit of normal on atorvastatin 10 mg during the run-in phase were excluded, indicating that the incidence of adverse events is likely to be higher in real-world practice than in this trial. For these reasons, starting all patients on low-dose atorvastatin and monitoring their tolerance to the medication before escalating the dose to 80 mg would be prudent practice. Nonetheless, the investigators are to be congratulated for completing a timely trial that contributes additional evidence in support of lowering the LDL cholesterol goals in patients with known CHD.

Study 

Efficacy of Gadoversetamide Enhanced MRI for the Diagnosis and Assessment of Myocardial Infarction: An International, Multicenter, Double-Masked, Randomized Phase 2 Trial

Presenter 

Dr. Raymond J. Kim, Duke University Medical Center, Durham, NC

Background 

The diagnosis of myocardial infarction is important for the clinical care of patients. Additionally, the extent of infarction has important implications for both therapeutic and prognostic purposes.

Recently, a new delayed contrast–enhancement technique for identifying myocardial infarction (MI) by cardiovascular magnetic resonance imaging (MRI) has been identified.1 This technique has been clinically used to identify the extent of MI and determine myocardial improvement after both acute MI and revascularization.2,3 The ability to detect MI and function has led to the use of cardiac MRI as an endpoint in clinical trials.4 However, the contrast agents used for cardiac MRI do not have a labeled indication for cardiac imaging. Additionally, the appropriate contrast dose for MI detection is not known. As a result, a phase 2 study was performed to determine the ability of contrast-enhanced MRI to identify MI and to evaluate the appropriate dose of contrast for detection.

An international study was performed at 22 centers enrolling patients with both acute (≤16 days’ post-MI) and chronic (17 days–6 months), first-time MIs. Patients were then randomized to 1 of 4 masked doses (0.05, 0.1, 0.2, and 0.3 mmol/kg) of gadoversetamide for cardiac MRI images. Standard images were obtained before contrast administration (precontrast control images), and 10 and 30 minutes after contrast administration. For MRI analysis, precontrast and postcontrast images were separated, randomized, and then scored for the amount hyperenhanced regions by 3 independent readers not associated with the study. The perfusion territory for the infarct-related artery (IRA) was also scored at a separate core lab. All images were scored on the standard 17-segment model.

Results 

Five hundred fourteen patients (age 54 ± 11 years; 71% male) had 566 scans performed at 22 centers. All scans were performed using commercially available MRI machines, and no scans were removed from the study because of poor-quality images. The MI detection rate was significantly higher postcontrast compared with precontrast: 99% for acute and 95% for chronic at the 0.3-mmol dose vs <17% without contrast (P < 0.0001). When the MI was located postcontrast, the readers identified the location in 94% to 100% of the cases. Finally, peak CK-MB and troponin levels correlated significantly with infarct size as determined by MRI for doses >0.05 mmol/kg (P < .001).

Interpretation 

In this first, large, phase 2 study randomizing patients to different doses of gadoversetamide, the identification of MI in patients by MRI was 99% for acute infarcts and 95% for chronic infarcts at a dose of 0.3 mmol/kg. Additionally, there was a dose-response relationship between the identification of MI by MRI and increasing concentration. Finally, the ability to identify MI was correlated with location by angiography and independent of infarct age. These findings demonstrate that cardiac MRI is sensitive for the presence, location, and extent of MI when compared with angiography and biochemical markers.

Study 

COMMIT/CCS-2 (Clopidogrel and Metoprolol in Myocardial Infarction Trial/Second Chinese Cardiac Study)

Presenter 

Dr Zhengming Chen, University of Oxford, UK

Background 

Aspirin is effective in the treatment of acute myocardial infarction (AMI), reducing the risk of early death from vascular causes by approximately 25%.1 Clopidogrel, which blocks the platelet ADP receptor, acts synergistically with aspirin. Treatment with aspirin and clopidogrel has shown benefit in patients with acute coronary syndromes without ST elevation and in patients undergoing percutaneous coronary intervention (PCI).2,3

The COMMIT/CCS-2 trial was a randomized, double-blind, factorial (2 × 2) trial involving more than 45000 patients with AMI, recruited from 1250 hospitals throughout China. The trial was designed to evaluate the effect of clopidogrel plus aspirin as well as the effect of intravenous followed by oral metoprolol on the risk of death and serious nonfatal vascular events in this population.

The trial enrolled patients with suspected MI (e.g., ST elevation, ST depression or left bundle branch block) within 24 hours from symptom onset. Patients were eligible for the trial once the caring physician decided that there were no clear indications or contraindications to either clopidogrel or metoprolol. The protocol did not specify exclusion criteria but left that decision to the judgment of the caring physician. Ultimately, patients were excluded because of either a high risk of adverse effects with one of the trial treatments or a small likelihood of significant benefit (e.g., unconvincing history, normal electrocardiogram). Other reasons used to exclude patients were allergy to aspirin, cardiogenic shock, low systolic blood pressure (SBP) (e.g., persistently <100 mm Hg), low heart rate (e.g., persistently <50 beats/min), third-degree heart block, and active bleeding or history of hemostatic disorders.4

Patients were randomized to receive, in addition to 162 mg aspirin, clopidogrel 75 mg daily (without a loading dose) or matching placebo for the duration of hospital stay or up to 4 weeks. All other nontrial medications were left to the discretion of the caring physician.

Primary endpoints were death and death, reinfarction, or stroke at hospital discharge or up to 4 weeks.

Results 

The mean treatment duration and follow-up was 16 days. Among the patients in the study, 93% had ST elevation or left bundle branch block, 26% were older than age 70, 68% presented within 12 hours of symptom onset, and 50% received fibrinolytic treatment.

The clopidogrel-treated patients had a 9.3% rate of death, reinfarction, or stroke compared with 10.1% in the placebo group (9% relative reduction; P = 0.002). Among the single components of the composite endpoint, a small but significant reduction of in-hospital death (7.7% vs 8.1%; P = .03) and reinfarction (2.1% vs 2.4%; P = .02) were observed in the clopidogrel group. No differences were seen in the rate of stroke (0.9% vs. 1.1%; P > .1). The extent of benefit of clopidogrel on the composite endpoint was slightly greater in patients presenting within 6 hours from symptom onset (9.3% vs 10.9%) and in those receiving fibrinolysis (8.8% vs 9.9%). Finally, the benefit was consistent among sex and age subgroups.

The rate of major bleeding was low and similar between the clopidogrel (0.6%) and placebo (0.5%) groups. No increase in cerebral bleeding was observed in the clopidogrel group.

Interpretation 

Adding clopidogrel 75 mg daily to aspirin in patients with AMI resulted in a significant 0.8% absolute risk reduction in the composite endpoint without increasing the risk of major bleeding. Although the absolute benefit of clopidogrel in this study was modest, the consistent results of COMMIT/CCS-2 and CLARITY-TIMI 28, two trials that enrolled more than 50 000 patients, support the use clopidogrel in STEMI patients treated with fibrinolysis. Moreover, the results of the two trials call for a reconsideration of the optimal reperfusion strategy to be used, in particular when primary PCI cannot be performed quickly.

Study 

CLARITY-TIMI 28 (Clopidogrel as Adjunctive Reperfusion Therapy-Thrombolysis in Myocardial Infarction (TIMI) 28

Presenter 

Dr. Marc Sabatine, Brigham and Women’s Hospital, Boston, MA

Background 

Fibrinolytic therapy fails to achieve initial patency of the infarct-related artery in about 20% of patients with ST-segment elevation myocardial infarction (STEMI). Failure to obtain reperfusion is associated with a 3-fold increase in mortality.1,2 The ISIS-2 trial showed that antiplatelet therapy with aspirin strongly reduces the risk of major cardiovascular events in patients treated with fibrinolysis.3

Clopidogrel is a platelet ADP-receptor blocker that acts synergistically with aspirin. When added to aspirin, it has been shown to improve outcomes in patients with acute coronary syndromes without ST elevation and in patients undergoing percutaneous coronary intervention (PCI).4,5 No data were available regarding the benefit of the dual antiplatelet therapy in patients with STEMI treated with fibrinolysis.

The CLARITY-TIMI 28 was a double-blind, randomized, placebo-controlled trial that evaluated the effect of clopidogrel added to aspirin, in STEMI patients receiving fibrinolysis, on patency of the infarct-related artery and on ischemic complications. A total of 3491 patients were enrolled at 319 sites in 23 countries.

The inclusion criteria were: presence of chest pain longer than 20 minutes associated with electrocardiographic changes (ST-segment elevation ≥0.1 mV in at least two contiguous limb leads or ≥0.2 mV in at least two contiguous precordial leads or a previously unknown left bundle branch block), ability to randomize within 12 hours from symptom onset and planned fibrinolytic therapy. Exclusion criteria were: use of clopidogrel within 7 days before the randomization or planned treatment with clopidogrel, use of glycoprotein IIb/IIIa before angiography, contraindication to fibrinolytic therapy, cardiogenic shock, prior coronary artery bypass (CABG), plan to perform angiography within 48 hours without new clinical indication, weight ≤67 kg and receipt of >4000 U bolus of unfractionated heparin (UFH), weight >67 kg and receipt of >5000 U bolus of UFH and receipt of more than the standard dose of low-molecular-weight heparin (LMWH).

Patients were randomized to receive either clopidogrel (300-mg loading dose followed by 75 mg once daily) or placebo until the day of the mandatory angiography (performed 48 to 192 hours after the start of the study drug). Both clopidogrel and placebo patients who underwent PCI received open-label clopidogrel after angiography. Patients who were not treated with PCI received the study drug up to 8 days or until discharge, whichever came first. The choice of fibrinolytic agents was left to the investigator’s decision. Weight-adjusted UFH was recommended for patients receiving a fibrin-specific agent. Platelet glycoprotein IIb/IIIa inhibitors were permitted only after angiography unless clinically indicated.

The primary efficacy endpoint was the composite of an occluded infarct-related artery (defined by TIMI flow grade of 0 or 1), death from any cause before angiography could be performed and recurrent myocardial infarction before angiography. The primary safety endpoint was the rate of major bleeding (according to TIMI criteria) by the end of the day after angiography.

Results 

The rates of the primary efficacy endpoint were 15.0% and 21.7% in the clopidogrel and the placebo groups, respectively (OR, 0.64; 95% CI, 0.53-0.76). The reduction of the primary endpoint was driven by a significant reduction in the rate of occluded infarct-related arteries in the clopidogrel group (11.7% vs 18.4%; OR, 0.59; 95% CI, 0.48-0.72). A nonsignificant reduction in recurrent myocardial infarction was observed in the clopidogrel group (2.5% vs 3.5%; OR, 0.70; 95% CI, 0.47-1.04), whereas mortality did not differ between the groups (2.6% vs 2.2%; OR, 1.17; 95% CI, 0.75-1.82). The benefit of clopidogrel was consistent regardless of age, sex, type of fibrinolytic agent, type of heparin, or infarct location.

Patients treated with clopidogrel had a lower rate of the 30-day composite of death due to cardiovascular causes, recurrent MI, or recurrent ischemia leading to urgent revascularization (11.6% vs 14.1%; OR, 0.80; 95% CI, 0.65-0.97). The 30-day effect was mainly due to a significant 31% relative reduction in recurrent myocardial infarction. The rate of TIMI major bleeding did not differ between clopidogrel and placebo (1.3% vs 1.1; P = .64), including minor bleeding (1.0% vs 0.5%; P = .17) and intracranial hemorrhage (0.5% and 0.7%; P = .38). No significant increase in bleeding was seen in the small population (n = 136) who underwent CABG.

Interpretation 

In STEMI patients ≤75 years treated with fibrinolysis, a 300-mg loading dose of clopidogrel followed by 75 mg/d resulted in a 36% relative reduction in the odds of the composite endpoint of occluded infarct artery, death, or reinfarction.

The population of this trial was highly selected, as suggested by the restrictive inclusion criteria and by the low mortality rate. Moreover, the reduction in the primary endpoint was driven mainly by an increased rate of patency, a surrogate for major cardiac events. The observed reduction in MI at 30 days could be at least in part explained by the effect of clopidogrel pretreatment in patient receiving PCI. Despite these limitations, the results of this study represent a major advance in the adjuvant therapy of STEMI patients receiving fibrinolysis.

The results of the CLARITY-TIMI 28 trial raise the question of whether fibrinolytic therapy administered with aspirin and clopidogrel followed by routine elective catheterization may offer advantages compared with primary PCI.

Study 

COMMIT/CCS-2 Clopidogrel and Metoprolol in Myocardial Infarction Trial/Second Chinese Cardiac Study

Presenter 

Dr. Rory Collins, Clinical Trials Unit, Oxford, UK

Background 

Few studies in the literature provide data about the early use of intravenous (IV) followed by oral β-blockers in the treatment of acute myocardial infarction (AMI). In the ISIS-1 trial, a small reduction in mortality was observed with early treatment with atenolol in AMI patients.1 The MIAMI trial showed a lower mortality rate among high-risk AMI patients treated with IV metoprolol, whereas in lower-risk patients, there was no difference.2

The COMMIT/CCS-2 was a randomized, double-blind, factorial (2 × 2) trial that enrolled nearly 46000 patients with suspected AMI at 1250 Chinese hospitals. The factorial design was adopted to answer two questions: the effect of clopidogrel in addition to aspirin and the effect of IV metoprolol followed by oral administration in reducing the risk of death and serious nonfatal cardiovascular events during the index hospitalization.

All patients presenting within 24 hours from symptom onset, and with electrocardiographic (ECG) signs of suspected myocardial infarction (ST elevation, ST depression, left bundle branch block), were eligible for the study if a clear indication or contraindication to either study medication was not existent in the opinion of the responsible physician. The protocol did not define specific exclusion criteria. Patients were excluded if, according to the responsible physician, there was either a high risk of adverse effects with one of the trial treatments or a small likelihood of significant benefit (e.g., unconvincing history, normal ECG). The following were listed as possible criteria for high risk of adverse effects: allergy to aspirin, cardiogenic shock, low systolic blood pressure (SBP) (e.g., persistently <100 mm Hg), low heart rate (e.g., persistently <50 beats/min), third-degree heart block, and active bleeding or history of hemostatic disorders.3

Patients were randomized to receive metoprolol 15 mg (or matching placebo) intravenously over 15 minutes. The first 50-mg tablet of metoprolol (or matching placebo) was to be given 15 minutes after the last IV dose and repeated every 6 hours for the first 2 days. From the third day, a single 200-mg, controlled-release tablet of metoprolol (or matching placebo) was used.

The primary endpoints were death and the composite of death, reinfarction, or cardiac arrest by hospital discharge or up to 4 weeks.

Results 

The mean treatment duration and follow-up was 16 days. Twenty-six percent of the patients were older than 70 years, 50% had anterior myocardial infarctions, 34% had SBP <120 mm Hg, and 24% were in class Killip II-III. Half of the patients were treated with fibrinolytic therapy.

No significant difference was reported in in-hospital mortality (7.7% metoprolol vs 7.8% placebo; P > .1) and in the composite primary endpoint (9.5% metoprolol vs 9.9%; P > .1). Metoprolol-treated patients had an 18% relative reduction in the risk of reinfarction (2.0% vs 2.5%; P = 0.002) and a 17% relative reduction in the risk of ventricular fibrillation (2.5% vs 3.0%; P < .001). However, the overall rate of in-hospital cardiac arrest was similar in the two groups (5.5% metoprolol vs. 5.8% placebo; P > .1).

Patients receiving metoprolol had a significant increase in the rate of cardiogenic shock (5.0% vs 3.9%; P < .001), resulting in a significant increase of deaths (2.2% vs 1.7%). The increase in cardiogenic shock associated with metoprolol was particularly evident on day 0 (2.1% vs 1.4%) and in patients with Killip class II (7.9% vs 6.5%) and class III (16.2% vs 10.4%). However, Killip class I patients receiving metoprolol had a significantly higher rate of cardiogenic shock (3.5% vs 2.8%).

Interpretation 

This study showed that in patients with AMI, 15 mg IV metoprolol followed by oral nontitrated 200 mg/d did not reduce the in-hospital mortality rate, decreased the risk of reinfarction and ventricular fibrillation but at a cost of a 29% relative increase in cardiogenic shock. The increased risk of shock appeared to be particularly related to the IV dose of metoprolol. The rise in cardiogenic shock was dramatic in patients with signs of heart failure. This finding contrasts with the results of trials with β-blockers in chronic heart failure and points out the importance of a careful dose titration in patients with heart failure.

The COMMIT/CCS-2 trial gave an answer regarding the efficacy and safety of an aggressive metoprolol dosing regimen in patients with AMI. However, using a more cautious, patient-titrated dosing regimen in the same population may show a different efficacy and safety profile.

Study 

Cardiac Resynchronisation in Heart Failure (CARE HF)

Presenter 

Dr. John G.F. Cleland, University of Hull, Kingston upon Hull, UK

Background 

Cardiac dyssynchrony is a common finding in patients with heart failure (HF) secondary to left ventricular systolic dysfunction (LVSD).1 Cardiac resynchronization therapy (CRT) has been shown to be hemodynamically effective in these patients and to improve symptoms, quality of life (QOL), and exercise capacity.2 However, its effects on rehospitalization and mortality remain uncertain.

The CARE HF trial was designed to: 1) assess the effect on morbidity and mortality of adding CRT to patients treated with optimal medical therapy (OMT) with moderate-to-severe HF due to LVSD and cardiac dyssynchrony; and 2) investigate the mechanism underlying the observed effect to identify predictive markers of success or failure. Major inclusion criteria were HF for at least 6 weeks requiring diuretics; current NYHA class III/IV; optimal medical treatment; LVSD and dilatation; ejection fraction (EF) <35% and end-diastolic diameter (EDD) >30 mm (indexed to height) QRS >120 msec; and, for patients with QRS <150 msec, dyssynchrony must be confirmed by echocardiogram (aortic pre-ejection delay >140 msec, intraventricular (IV) mechanical delay >40 msec, and delayed activation of posterolateral wall of the left ventricle. Exclusion criteria were permanent atrial fibrillation and permanent pacing.

Patients randomized to CRT underwent surgery to implant the pacing device following standard techniques (right ventricular lead on apex, left ventricular lead on lateral or posterolateral free wall via coronary sinus); optimal IV delay was assessed by echocardiogram. The device did not include a defibrillator function. The primary endpoint was a composite of all mortality or unplanned hospitalization for a major cardiovascular event. The secondary endpoint was all-cause mortality. Additional endpoints were all-cause mortality and rehospitalization for HF at 90 days, symptoms, QOL assessment, and neuroendocrine function, among others.

From January 2001 to March 2003, in 82 centers in 12 European countries, patients were enrolled and randomized to continue OMT alone or to add CRT. The device implant was successful in 96%. Median time to implant was 4 days. At completion of the study, there was <5% crossover before the primary endpoint. Mean follow-up time was 29 months.

Results 

From a total of 813 patients, 404 were randomized to continue OMT, whereas 409 were assigned to add CRT. There were no significant differences in baseline characteristic between the groups. There were no differences in non–device-related serious adverse events (SAE) in the groups. The most common SAEs in the CRT group were lead displacement, coronary-sinus dissection, and pocket erosion. The primary endpoint was reached by 39% of patients in the CRT group vs 55% in the OMT group (HR, 0.63; 95% CI, 0.55-0.77; P < .001). Analyses of the primary endpoint in all subgroups (such as gender, age, etc) favored CRT. Mortality in the CRT group was 20% vs 30% in OMT group (HR, 0.63; 95% CI, 0.48-0.85; P < .002). Analyses for additional secondary endpoints, such as symptoms, QOL, EF, left ventricular end-systolic volume, area of the regurgitant mitral jet, and level of brain natriuretic peptide showed benefits for the use of CRT in all of them (P < .001).

Interpretation 

The CARE HF trial showed that the use of CRT in patients with advanced HF treated with optimal medical therapy reduces morbidity, improves symptoms, QOL, survival, cardiac function, and cardiac efficiency. Notably, this is the first trial to show benefits of CRT in terms of survival in a long-term (18-month) analysis and in neuro-hormonal activation. CARE HF, along with another trial,2 demonstrates the benefits of CRT in this clinical setting. It is important to note that approximately 30% of the deaths in both the CRT and OMT groups were sudden, which confirms that the use of CRT with the defibrillator function instead of pacing alone is preferable in these patients. In conclusion, the use of CRT should be considered in patients in sinus rhythm with moderate-to-severe HF despite optimal therapy and with evidence of dyssynchrony.

Study 

U.S. Multicenter Pivotal Study of the HELEX Septal Occluder

Presenter 

Dr. Thomas K. Jones, Children’s Hospital & Regional Medical Center, Seattle, WA

Background 

The HELEX™ Septal Occluder (HSO) is a low-profile, double-disk occluder device for percutaneous closure of secundum atrial septal defect (ASD). This device is prepackaged with the delivery system attached and is delivered through a 9-Fr sheath in the femoral vein. The device consists of a Gortex membrane bound to a Nitinol wire frame and is positioned so that the atrial septum is sandwiched between the two discs. The study compared the safety and efficacy of the HSO versus surgical repair of ASD.

This was a multicenter, nonrandomized, controlled trial in which 450 patients were enrolled from 14 U.S. sites from March 2001 to April 2003. Each patient was followed for 1 year postprocedure. The first 3 HSO patients at each site were considered training cases and were excluded from the analysis. The HSO patients were enrolled prospectively; the patients in the surgical arm were both prospectively and retrospectively enrolled. Clinical success was defined as no or clinically insignificant residual shunt with no major adverse events or repeat procedure after 1 year. Inclusion criteria were secundum atrial septal defect with evidence of right ventricular volume overload and, for the device group, a defect <22 mm by balloon-sizing, a septal rim present around at least 75% of the defect, and femoral access.

Results 

One hundred thirty-two patients in the HSO arm and 124 patients in the surgical arm met criteria for evaluation. The HSO and surgical groups were similar with statistical but clinically unimportant differences in median age (6.8 vs 4.7 years), weight (24.3 kg vs 17.2 kg), and preprocedural echocardiographic defect size (10.5 mm vs 15 mm), respectively. Patients were evaluated at time of discharge, 1 month, 6 months’, and 12 months’ postprocedure. Clinical success was achieved in 90.6% of patients in the HSO arm and 83.5% with a surgical repair. Therefore, the noninferiority hypothesis was satisfied. Anesthesia and length of hospitalization were significantly shorter in the HSO group. Adverse-events rates were not statistically different. The most common major adverse event for the HSO group was device embolization requiring catheter retrieval. Six patients (5%) had evidence of wire-frame fractures, all well tolerated and associated with no or clinically insignificant residual shunts. Eight patients in the surgical group developed postpericardiotomy syndrome requiring treatment, and 1 died due to cardiac tamponade.

Interpretation 

The HELEX™ Septal Occluder is a safe and effective therapy for repair of secundum ASD. Closure of ASD with the HSO compares favorably to surgical repair with reduced anesthesia time and hospital stay.

Study 

BRAVE-2 (Beyond 12 hours Reperfusion Alternative Evaluation Trial). A multicenter, randomized trial assessing the value of mechanical reperfusion in patients with acute myocardial infarction presenting >12 hours from onset of symptoms

Presenter 

Dr Adnan Kastrati, Deutsches Herzzentrum, Munich, Germany

Background 

Despite increased public awareness of cardiovascular symptoms, a substantial proportion of patients with acute myocardial infarction (AMI) present more than 12 hours after symptom onset.1 Time from symptom onset to reperfusion is an important predictor of infarct size and patient outcome following ST-segment elevation myocardial infarction.2,3 Current ACC/AHA guidelines do not support mechanical reperfusion in asymptomatic patients presenting more than 12 hours after symptom onset if they are clinically, hemodynamically, and electrically stable.4 However, these recommendations are based on observational data, because no randomized, clinical trials have evaluated an acute invasive strategy in this group of asymptomatic and late-presenting patients.

The BRAVE-2 trial was a European, multicenter, randomized trial designed to evaluate whether an acute invasive strategy had a favorable impact on infarct size. Stable patients who sustained an AMI within the preceding 12 to 48 hours were considered for inclusion. Patients with ongoing or stuttering symptoms and congestive heart failure were excluded. All randomized patients were treated with aspirin, a thienopyridine, and heparin. The invasive group received abciximab when they underwent percutaneous coronary intervention (PCI).

The primary endpoint of this trial was infarct size (expressed as a percentage of the left ventricle) determined by SPECT scintigraphy performed 5 to 10 days after randomization. The secondary endpoint was a composite of all-cause mortality, recurrent myocardial infarction, and stroke within 30 days after randomization. Accordingly, a total of 365 patients were randomized to an invasive arm or a conservative arm. The invasive group underwent angiography followed by PCI if necessary, whereas the conservative group was initially treated with conventional medical therapy. The study had 80% power to detect a 30% reduction in infarct size in the primary endpoint, assuming a mean infarct size of 20% in the conservative group.

Results 

The two study arms had comparable baseline demographic and clinical characteristics. Median age was 66 years, most patients were men (74%), 24% had diabetes mellitus, 38% presented with a late anterior AMI, and the majority (82%) were in Killip class 1. The median time from pain onset to randomization was 23 hours in the overall cohort, and the median time from randomization to angiography in the invasive arm was 1.5 hours. The majority (94%) of patients in the invasive group underwent PCI, whereas 4% were referred for coronary artery bypass grafting, and 2% were treated medically. Among patients in the invasive group, only 20% had Thrombolysis In Myocardial Infarction (TIMI) flow grade 3 upon initial angiography. TIMI flow grade 3 was restored in 87% of those patients following PCI.

SPECT scintigraphy was available in 95% of all randomized patients. The median infarct size was significantly reduced in the invasive group (8% vs 13%, invasive and conservative groups, respectively; P = .0002). In addition, a trend toward improved 30-day combined clinical outcomes was noted in the invasive group (4% vs 6.6%; P = .37). The investigators also reported that subsequent clinically driven “unplanned” PCI was performed in a much lower proportion of patients randomized to the invasive arm (1% vs 33%).

Interpretation 

This is the first randomized trial of prompt mechanical reperfusion in asymptomatic AMI patients presenting late after symptom onset. The investigators should be commended for performing this time-consuming trial. This trial undoubtedly challenges conventional thinking regarding the lack of benefits associated with late reperfusion in stable AMI patients. Although the reduction in infarct size shown in BRAVE-2 is clinically relevant, the trial was clearly underpowered to examine the effects of this strategy on “harder” clinical endpoints such as death or recurrent myocardial infarction. Nevertheless, these results provide evidence for the consideration of a prompt invasive strategy in AMI patients presenting very late after symptom onset.