Clinical Question:
Does intensive statin therapy reduce mortality in patients with acute coronary syndrome?

Bottom Line:
Intensive statin therapy following acute coronary syndrome (ACS) reduces cardiovascular and overall mortality.

Reference:
Murphy SA, Cannon CP, Wiviott SD, et al. Effect of intensive lipid-lowering therapy on mortality after acute coronary syndrome (a patient-level analysis of the Aggrastat to Zocor and Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 trials). Am J Cardiol 2007;100(7):1047-1051.

Study Design:
Meta-analysis (randomized controlled trials)

Synopsis:
Compared with moderate lipid lowering with standard-dose statin therapy, intensive lipid lowering with high-dose statin therapy after acute coronary syndromes (ACS) significantly reduces cardiovascular events. However, the 2 trials of high-dose versus standard-dose statin therapy in patients with ACS, Aggrastat to Zocor (A to Z) and Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis In Myocardial Infarction 22 (PROVE-IT-TIMI 22), were not individually powered to evaluate the impact on mortality alone. In this study, a pooled, patient-level analysis of these trials of 8,658 post-ACS patients was performed to provide a more robust estimate of the impact of intensive statin therapy on mortality. By 8 months, achieved low-density lipoprotein levels were lower in the group with intensive statin therapy (median 64 mg/dl, interquartile range 51 to 81) than in the group with moderate statin therapy (median 87 mg/dl, interquartile range 71 to 107) (p <0.001). All-cause mortality was significantly reduced in the group with intensive statin therapy compared with the group with moderate statin therapy (3.6% vs 4.9%, hazard ratio 0.77, 95% confidence interval 0.63 to 0.95, p = 0.015), without significant interaction by trial (interaction p = 0.63). The reduction in all-cause mortality with intensive statin therapy was consistent across key subgroups.

Clinical Question:
Does high-dose statin therapy provide additional benefit over moderate doses in patients with pre-existing heart disease?

Bottom Line:
Intensive statin therapy will decrease overall mortality rates compared with lower doses in patients with a recent history of acute coronary syndrome (ACS) but not in patients with stable coronary heart disease. However, 80 patients must be treated to prevent 1 additional death over 2 years. Intensive treatment decreases overall hospital admissions for heart failure in both groups and decreases major cardiac events in patients with stable coronary heart disease, but, again, the results are not striking.

Reference:
Afilalo J, Majdan AA, Eisenberg MJ. Intensive statin therapy in acute coronary syndromes and stable coronary heart disease: a comparative meta-analysis of randomised controlled trials. Heart 2007;93(8):914-921.
Study Design:

Meta-analysis (randomized controlled trials)
Funding:

Synopsis:
Intensive statin therapy reduces major adverse cardiovascular events (MACE), but the effect on mortality is unclear. The researchers determined whether intensive statin therapy reduces all-cause mortality compared with moderate statin therapy in patients with recent acute coronary syndromes (ACS) and stable coronary heart disease (CHD). Medline, Embase, the Cochrane Database, the internet, and conference proceedings from 1966 to 2006 were searched to identify relevant trials. Selection criteria were randomised allocation to intensive statin therapy (atorvastatin 80 mg/day, simvastatin 80 mg/day, or rosuvastatin 20-40 mg/day) versus moderate statin therapy, recent ACS or stable CHD at the time of randomisation, and > or =6 months of follow-up. Six trials, encompassing 110 271 patient-years, were pooled. In patients with recent ACS, intensive statin therapy reduced all-cause mortality from 4.6% to 3.5% over 2.0 years (OR = 0.75, 95% CI 0.61 to 0.93). In patients with stable CHD, intensive statin therapy had no effect on all-cause mortality over 4.7 years (OR = 0.99, 95% CI 0.89 to 1.11). Overall, intensive statin therapy was associated with a reduction in MACE (OR = 0.84, 95% CI 0.77 to 0.91) and admissions to hospital for heart failure (OR = 0.72, 95% CI 0.62 to 0.83). Intensive statin therapy was also associated with an increase in hepatic transaminases >3 times normal (OR = 3.73, 95% CI 2.11 to 6.58) and a trend towards increased creatine kinase >10 times normal and/or rhabdomyolysis (OR = 1.96, 95% CI 0.50 to 7.63).

Clinical Question:
Is idraparinux safe and effective for the treatment of acute venous thromboembolism?

Bottom Line:
In patients with deep venous thrombosis, once-weekly subcutaneous idraparinux for 3 or 6 months had an efficacy similar to that of heparin plus a vitamin K antagonist. However, in patients with pulmonary embolism, idraparinux was less efficacious than standard therapy.

Reference:
The van Gogh Investigators, Buller HR, Cohen AT, et al. Idraparinux versus standard therapy for venous thromboembolic disease. N Engl J Med 2007;357(11):1094-1104.

Study Design:
Randomized controlled trial (nonblinded)

Synopsis:
Venous thromboembolism is treated with unfractionated heparin or low-molecular-weight heparin, followed by a vitamin K antagonist. The authors investigated the potential use of idraparinux, a long-acting inhibitor of activated factor X, as a substitute for standard therapy. They conducted two randomized, open-label noninferiority trials involving 2904 patients with deep-vein thrombosis and 2215 patients with pulmonary embolism to compare the efficacy and safety of idraparinux versus standard therapy. Patients received either subcutaneous idraparinux (2.5 mg once weekly) or a heparin followed by an adjusted-dose vitamin K antagonist for either 3 or 6 months. The primary efficacy outcome was the 3-month incidence of symptomatic recurrent venous thromboembolism (nonfatal or fatal). In the study of patients with deep venous thrombosis, the incidence of recurrence at day 92 was 2.9% in the idraparinux group as compared with 3.0% in the standard-therapy group (odds ratio, 0.98; 95% confidence interval [CI], 0.63 to 1.50), a result that satisfied the prespecified noninferiority requirement. At 6 months, the hazard ratio for idraparinux was 1.01. The rates of clinically relevant bleeding at day 92 were 4.5% in the idraparinux group and 7.0% in the standard-therapy group (P=0.004). At 6 months, bleeding rates were similar. In the study of patients with pulmonary embolism, the incidence of recurrence at day 92 was 3.4% in the idraparinux group and 1.6% in the standard-therapy group (odds ratio, 2.14; 95% CI, 1.21 to 3.78), a finding that did not meet the noninferiority requirement.

Clinical Question:
Does epoetin alfa reduce the need for transfusions and improve clinical outcomes in critically ill patients?

Bottom Line:
Epoetin alfa did not reduce the need for transfusions in critically ill patients, but increased thrombotic events. Mortality was reduced among the trauma patients.

Reference:
Corwin HL, Gettinger A, Fabian TC, et al, for the EPO Critical Care Trials Group. Efficacy and safety of epoetin alfa in critically ill patients. N Engl J Med 2007;357(10):965-976.

Study Design:
Randomized controlled trial (double-blinded)

Synopsis:
Anemia, which is common in the critically ill, is often treated with red-cell transfusions, which are associated with poor clinical outcomes. The investigators hypothesized that therapy with recombinant human erythropoietin (epoetin alfa) might reduce the need for red-cell transfusions. In this prospective, randomized, placebo-controlled trial, they enrolled 1460 medical, surgical, or trauma patients between 48 and 96 hours after admission to the intensive care unit. Epoetin alfa (40,000 U) or placebo was administered weekly, for a maximum of 3 weeks; patients were followed for 140 days. The primary end point was the percentage of patients who received a red-cell transfusion. Secondary end points were the number of red-cell units transfused, mortality, and the change in hemoglobin concentration from baseline. As compared with the use of placebo, epoetin alfa therapy did not result in a decrease in either the number of patients who received a red-cell transfusion (relative risk for the epoetin alfa group vs. the placebo group, 0.95; 95% confidence interval [CI], 0.85 to 1.06) or the mean (+/-SD) number of red-cell units transfused (4.5+/-4.6 units in the epoetin alfa group and 4.3+/-4.8 units in the placebo group, P=0.42). However, the hemoglobin concentration at day 29 increased more in the epoetin alfa group than in the placebo group (1.6+/-2.0 g per deciliter vs. 1.2+/-1.8 g per deciliter, P<0.001). Mortality tended to be lower at day 29 among patients receiving epoetin alfa (adjusted hazard ratio, 0.79; 95% CI, 0.56 to 1.10); this effect was also seen in prespecified analyses in those with a diagnosis of trauma (adjusted hazard ratio, 0.37; 95% CI, 0.19 to 0.72). A similar pattern was seen at day 140 (adjusted hazard ratio, 0.86; 95% CI, 0.65 to 1.13), particularly in those with trauma (adjusted hazard ratio, 0.40; 95% CI, 0.23 to 0.69). As compared with placebo, epoetin alfa was associated with a significant increase in the incidence of thrombotic events (hazard ratio, 1.41; 95% CI, 1.06 to 1.86).

Clinical Question:
Will dronedarone help patients with atrial fibrillation to maintain sinus rhythm?

Bottom Line:
For every 9 patients who take dronedarone for 1 year, 1 fewer will experience a recurrence of atrial fibrillation (AF). What we really need are comparisons of this new drug with older drugs; longer studies; and studies that evaluate patient-oriented outcomes, such as symptom control and quality of life.

Reference:
Singh BN, Connolly SJ, Crijns HJ, et al, for the EURIDIS and ADONIS Investigators. Dronedarone for maintenance of sinus rhythm in atrial fibrillation or flutter. N Engl J Med 2007;357(10):987-999.

Study Design:
Randomized controlled trial (double-blinded)

Synopsis:
Amiodarone is effective in maintaining sinus rhythm in atrial fibrillation but is associated with potentially serious toxic effects. Dronedarone is a new antiarrhythmic agent pharmacologically related to amiodarone but developed to reduce the risk of side effects. In two identical multicenter, double-blind, randomized trials, one conducted in Europe (ClinicalTrials.gov number, NCT00259428 [ClinicalTrials.gov] ) and one conducted in the United States, Canada, Australia, South Africa, and Argentina (termed the non-European trial, NCT00259376 [ClinicalTrials.gov] ), the authors evaluated the efficacy of dronedarone, with 828 patients receiving 400 mg of the drug twice daily and 409 patients receiving placebo. Rhythm was monitored transtelephonically on days 2, 3, and 5; at 3, 5, 7, and 10 months; during recurrence of arrhythmia; and at nine scheduled visits during a 12-month period. The primary end point was the time to the first recurrence of atrial fibrillation or flutter. In the European trial, the median times to the recurrence of arrhythmia were 41 days in the placebo group and 96 days in the dronedarone group (P=0.01). The corresponding durations in the non-European trial were 59 and 158 days (P=0.002). At the recurrence of arrhythmia in the European trial, the mean (+/-SD) ventricular rate was 117.5+/-29.1 beats per minute in the placebo group and 102.3+/-24.7 beats per minute in the dronedarone group (P<0.001); the corresponding rates in the non-European trial were 116.6+/-31.9 and 104.6+/-27.1 beats per minute (P<0.001). Rates of pulmonary toxic effects and of thyroid and liver dysfunction were not significantly increased in the dronedarone group.

Clinical Question:
Is carvedilol beneficial in the management of children and adolescents with heart failure?

Bottom Line:
This study found no evidence for a benefit of carvedilol (Coreg) in the management of children and adolescents with heart failure.

Reference:
Shaddy RE, Boucek MM, Hsu DT, et al, for the Pediatric Carvedilol Study Group. Carvedilol for children and adolescents with heart failure. A randomized controlled trial. JAMA 2007;298(10):1171-1179.

Study Design:
Randomized controlled trial (double-blinded)

Synopsis:
Although beta-blockers improve symptoms and survival in adults with heart failure, little is known about these medications in children and adolescents. The authors prospectively evaluate the effects of carvedilol in children and adolescents with symptomatic systemic ventricular systolic dysfunction. A multicenter, randomized, double-blind, placebo-controlled study of 161 children and adolescents with symptomatic systolic heart failure from 26 US centers. In addition to treatment with conventional heart failure medications, patients were assigned to receive placebo or carvedilol. Enrollment began in June 2000 and the last dose was given in May 2005 (each patient received medication for 8 months). Patients were randomized in a 1:1:1 ratio to twice-daily dosing with placebo, low-dose carvedilol (0.2 mg/kg per dose if weight <62.5 kg or 12.5 mg per dose if weight > or =62.5 kg), or high-dose carvedilol (0.4 mg/kg per dose if weight <62.5 kg or 25 mg per dose if weight > or =62.5 kg) and were stratified according to whether each patient’s systemic ventricle was a left ventricle or not. The primary outcome was a composite measure of heart failure outcomes in patients receiving carvedilol (low- and high-dose combined) vs placebo. Secondary efficacy variables included individual components of this composite, echocardiographic measures, and plasma b-type natriuretic peptide levels. There was no statistically significant difference between groups for the composite end point based on the percentage of patients who improved, worsened, or were unchanged. Among 54 patients assigned to placebo, 30 improved (56%), 16 worsened (30%), and 8 were unchanged (15%); among 103 patients assigned to carvedilol, 58 improved (56%), 25 worsened (24%), and 20 were unchanged (19%). The rates of worsening were lower than expected. The odds ratio for worsened outcome for patients in the combined carvedilol group vs the placebo group was 0.79 (95% CI, 0.36-1.59; P = .47). A prespecified subgroup analysis noted significant interaction between treatment and ventricular morphology (P = .02), indicating a possible differential effect of treatment between patients with a systemic left ventricle (beneficial trend) and those whose systemic ventricle was not a left ventricle (nonbeneficial trend).

Clinical Question:
In patients older than 75 years with atrial fibrillation, is warfarin more effective than aspirin at preventing strokes?

Bottom Line:
This study confirms that warfarin titrated to a target international normalized ratio (INR) of 2.0 to 3.0 is more effective than 75 mg aspirin in preventing strokes without significantly increasing the risk of bleeding complications.

Reference:
Mant J, Hobbs FD, Fletcher K, et al, for the BAFTA investigators; Midland Research Practices Network (MidReC). Warfarin versus aspirin for stroke prevention in an elderly community population with atrial fibrillation (the Birmingham Atrial Fibrillation Treatment of the Aged Study, BAFTA): a randomised controlled trial. Lancet 2007;370:493-503.

Study Design:
Randomized controlled trial (single-blinded)

Synopsis:
Anticoagulants are more effective than antiplatelet agents at reducing stroke risk in patients with atrial fibrillation, but whether this benefit outweighs the increased risk of bleeding in elderly patients is unknown. The investigators assessed whether warfarin reduced risk of major stroke, arterial embolism, or other intracranial haemorrhage compared with aspirin in elderly patients. 973 patients aged 75 years or over (mean age 81.5 years, SD 4.2) with atrial fibrillation were recruited from primary care and randomly assigned to warfarin (target international normalised ratio 2-3) or aspirin (75 mg per day). Follow-up was for a mean of 2.7 years (SD 1.2). The primary endpoint was fatal or disabling stroke (ischaemic or haemorrhagic), intracranial haemorrhage, or clinically significant arterial embolism. Analysis was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN89345269. There were 24 primary events (21 strokes, two other intracranial haemorrhages, and one systemic embolus) in people assigned to warfarin and 48 primary events (44 strokes, one other intracranial haemorrhage, and three systemic emboli) in people assigned to aspirin (yearly risk 1.8%vs 3.8%, relative risk 0.48, 95% CI 0.28-0.80, p=0.003; absolute yearly risk reduction 2%, 95% CI 0.7-3.2). Yearly risk of extracranial haemorrhage was 1.4% (warfarin) versus 1.6% (aspirin) (relative risk 0.87, 0.43-1.73; absolute risk reduction 0.2%, -0.7 to 1.2).

Clinical Question:
Are apolipoprotein levels and ratios useful in predicting the risk of coronary heart disease?

Bottom Line:
Measurement of the apolipoprotein B:apolipoprotein A-I ratio is comparable with, but does not offer any incremental utility to, standard lipid level ratios in predicting coronary heart disease (CHD). Routine measurement of apolipoprotein levels in clinical practice should be discouraged. (LOE = 1b)

Reference:
Ingelsson E, Schaefer EJ, Contois JH, et al. Clinical utility of different lipid measures for prediction of coronary heart disease in men and women. JAMA 2007;298:776-785.

Study Design:
Cohort (prospective)

Funding:

Synopsis:
Controversy exists regarding the value of measuring apolipoprotein levels for predicting CHD risk. As part of the Framingham Offspring Study, these investigators prospectively followed 3322 white adults (53% female), aged 30 to 74 years, initially attending an examination cycle from 1987 to 1991. Baseline evaluation included measuring standard lipid levels (total cholesterol, HDL cholesterol, LDL cholesterol), as well as non-HDL cholesterol, apolipoprotein A-I, and apolipoprotein B. None of the participants had cardiovascular disease at the beginning of the study. Three individuals assessed outcomes after review of hospital and physician office visit records; the authors do not specifically state if they were masked to baseline lipid levels. After a median of 15 years of follow-up, 291 subjects (198 men) developed CHD. Using multivariate prediction models adjusting for nonlipid risk factors, the apolipoprotein B:apolipoprotein A-I ratio was comparable with, without any incremental utility to, other standard lipid level ratios (eg, total cholesterol:HDL-cholesterol ratio) in predicting CHD.

Clinical Question:
Are apolipoprotein levels and ratios useful in predicting the risk of coronary heart disease?

Bottom Line:
Measurement of the apolipoprotein B:apolipoprotein A-I ratio is comparable with, but does not offer any incremental utility to, standard lipid level ratios in predicting coronary heart disease (CHD). Routine measurement of apolipoprotein levels in clinical practice should be discouraged.

Reference:
Ingelsson E, Schaefer EJ, Contois JH, et al. Clinical utility of different lipid measures for prediction of coronary heart disease in men and women. JAMA 2007;298:776-785.

Study Design:
Cohort (prospective)

Synopsis:
Evidence is conflicting regarding the performance of apolipoproteins vs traditional lipids for predicting coronary heart disease (CHD) risk. To settle the conflict the authors compared performance of different lipid measures for CHD prediction using discrimination and calibration characteristics and reclassification of risk categories; to assess incremental utility of apolipoproteins over traditional lipids for CHD prediction. They did a population-based, prospective cohort from, Framingham, Massachusetts. They evaluated serum total cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), non-HDL-C, apolipoprotein (apo) A-I and apo B, and 3 lipid ratios (total cholesterol:HDL-C, LDL-C:HDL-C, and apo B:apo A-I) in 3322 middle-aged white participants who attended the fourth offspring examination cycle (1987-1991) and were without cardiovascular disease. Fifty-three percent of the participants were women. Incidence of first CHD event (recognized or unrecognized myocardial infarction, angina pectoris, coronary insufficiency, or coronary heart disease death). After a median follow-up of 15.0 years, 291 participants, 198 of whom were men, developed CHD. In multivariate models adjusting for nonlipid risk factors, the apo B:apo A-I ratio predicted CHD (hazard ratio [HR] per SD increment, 1.39; 95% confidence interval [CI], 1.23-1.58 in men and HR, 1.40; 95% CI, 1.16-1.67 in women), but risk ratios were similar for total cholesterol:HDL-C (HR, 1.39; 95% CI, 1.22-1.58 in men and HR, 1.39; 95% CI, 1.17-1.66 in women) and for LDL-C:HDL-C (HR, 1.35; 95% CI, 1.18-1.54 in men and HR, 1.36; 95% CI 1.14-1.63 in women). In both sexes, models using the apo B:apo A-I ratio demonstrated performance characteristics comparable with but not better than that for other lipid ratios. The apo B:apo A-I ratio did not predict CHD risk in a model containing all components of the Framingham risk score including total cholesterol:HDL-C (P = .12 in men; P = .58 in women).

Clinical Question:
In patients with asymptomatic ischemia following myocardial infarction, is percutaneous coronary intervention superior to medical therapy for preventing adverse cardiac events?

Bottom Line:
In patients with silent ischemia following myocardial infarction (MI), percutaneous angioplasty is more effective than medical treatment for reducing long-term adverse cardiac events and cardiac death, and for improving exercise tolerance.

Reference:
Erne P, Schoenenberger AW, Burckhardt D, et al. Effects of percutaneous coronary interventions in silent ischemia after myocardial infarction: the SWISS II randomized controlled trial. JAMA 2007;297:1985-1991.

Study Design:
Randomized controlled trial (nonblinded)

Synopsis:
The effect of a percutaneous coronary intervention (PCI) on the long-term prognosis of patients with silent ischemia after a myocardial infarction (MI) is not known. The investigators determined whether PCI compared with drug therapy improves long-term outcome of asymptomatic patients with silent ischemia after an MI. They did a randomized, unblinded, controlled trial (Swiss Interventional Study on Silent Ischemia Type II [SWISSI II]) conducted from May 2, 1991, to February 25, 1997, at 3 public hospitals in Switzerland of 201 patients with a recent MI, silent myocardial ischemia verified by stress imaging, and 1- or 2-vessel coronary artery disease. Follow-up ended on May 23, 2006. Percutaneous coronary intervention aimed at full revascularization (n = 96) or intensive anti-ischemic drug therapy (n = 105). All patients received 100 mg/d of aspirin and a statin. Survival free of major adverse cardiac events defined as cardiac death, nonfatal MI, and/or symptom-driven revascularization. Secondary measures included exercise-induced ischemia and resting left ventricular ejection fraction during follow-up. During a mean (SD) follow-up of 10.2 (2.6) years, 27 major adverse cardiac events occurred in the PCI group and 67 events occurred in the anti-ischemic drug therapy group (adjusted hazard ratio, 0.33; 95% confidence interval, 0.20-0.55; P<.001), which corresponds to an absolute event reduction of 6.3% per year (95% confidence interval, 3.7%-8.9%; P<.001). Patients in the PCI group had lower rates of ischemia (11.6% vs 28.9% in patients in the drug therapy group at final follow-up; P = .03) despite fewer drugs. Left ventricular ejection fraction remained preserved in PCI patients (mean [SD] of 53.9% [9.9%] at baseline to 55.6% [8.1%] at final follow-up) and decreased significantly (P<.001) in drug therapy patients (mean [SD] of 59.7% [11.8%] at baseline to 48.8% [7.9%] at final follow-up).