Further information: Surgical Treatment of Coronary Heart Disease (see p1051) from Cardiovascular Medicine, 3rd Edn*

The Surgical Treatment for Ischemic Heart Failure (STICH) trial [1] is the largest surgical clinical trial ever conducted and its overall objective was to define the role of surgical ventricular reconstruction (SVR) in the treatment of patients with ischemic cardiomyopathy. Left ventricular (LV) remodeling can occur after a patient suffers a myocardial infarction (MI), leading to increased heart failure. Medical therapy has been found to have a positive effect on remodeling, and the use of SVR to reduce the LV volume has also had positive outcomes in reducing the progression of heart failure. The surgical procedure was specifically designed for patients who developed heart failure as a result of MI. The STICH trial was conducted to determine whether SVR that is performed in addition to coronary artery bypass surgery (CABG) would decrease the rate of hospitalization or death when compared with CABG alone.

A total of 1000 patients were randomized between September 2002 and January 2006 to undergo either CABG alone (n=499) patients or CABG with SVR (n=501) patients. Inclusion criteria were LV ejection fraction of 35% or less, coronary artery disease (CAD) that was amenable to CABG, and dominant anterior left ventricular dysfunction amenable to surgical reconstruction. Exclusion criteria were a recent MI, a need for aortic-valve replacement, a planned percutaneous coronary intervention (PCI), and coexisting noncardiac disease resulting in life expectancy of less than 3 years. The primary outcome was a composite of death from any cause and hospitalization for cardiac causes, and the median follow-up was 48 months.
SVR reduced end-systolic volume index by 19%, as compared with a reduction of 6% with CABG alone. Cardiac symptoms and exercise tolerance improved from baseline to a similar degree in the two groups. No significant difference was observed in the primary outcome, which occurred in 292 patients (59%) who were assigned to undergo CABG alone, and in 289 patients (58%) assigned to CABG and SVR. Although the addition of SVR resulted in a significantly greater reduction in LV volume than was achieved with CABG alone, this improvement in ventricular volume did not translate into a measurable benefit for the patient. There was no significant difference between the groups in the primary outcome of death or hospitalization for cardiac causes.

[1] Jones R H, Velazquez E J, Michler R E et al. Coronary bypass surgery with or without surgical ventricular reconstruction. N Engl J Med 2009;360:1705-1717

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Further information: The Medical Management of Heart Failure (see p1397) from Cardiovascular Medicine, 3rd Edn*

Heart Failure: A Controlled Trial Investigating Outcomes of exercise training (HF-ACTION) was a multicenter, randomized controlled trial of 2331 patients who were enrolled from April 2003 to February 2007. It represents the largest multicenter, randomized controlled trial of exercise training in heart failure (HF) to date and involved 82 centers within the United States, Canada, and France. Patients were randomized to either an exercise training (ET) group plus usual care or a usual care group, and all patients had left ventricular ejection fractions (LVEF) of 35% or less and New York Heart Association (NYHA) class II to IV symptoms, despite optimal HF therapy for at least 6 weeks.

The first paper [1] evaluated trial data to report the efficacy and safety of ET among patients with HF. Median follow-up was 30 months. The patients who were randomized to usual care plus an ET group received 36 sessions of supervised aerobic exercise, while the usual care group were not given a formal exercise program. Composite primary end-point was all-cause mortality or hospitalization and prespecified secondary end-points were all-cause mortality, cardiovascular mortality, or HF hospitalization.

A total of 759 patients (65%) in the ET group died or were hospitalized compared with 796 patients (68%) in the usual care group (hazard ratio [HR], 0.93; 95% confidence interval [CI], 0.84–1.02]; P=0.13). There were nonsignificant reductions in the ET group for mortality (189 patients [16%] in the ET group vs. 198 patients [17%] in the usual care group; HR, 0.96; 95% CI, 0.79–1.71; P=0.70, cardiovascular mortality or HF hospitalization (632 [55%] in the ET group vs. 677 [58%] in the usual care group; HR, 0.92; 95% CI, 0.83–1.03; P=0.14), and cardiovascular mortality or HF hospitalization (344 [30%] in the exercise training group vs. 393 [34%] in the usual care group; HR, 0.87; 95% CI, 0.75–1.00; P=0.06. In prespecified supplementary analyses adjusting for highly prognostic baseline characteristics, the HRs were 0.89 (95% CI, 0.81–0.99; P=0.03) for all-cause mortality or hospitalization, 0.91 (95% CI, 0.82–1.01; P=0.09) for cardiovascular mortality or cardiovascular hospitalization, and 0.85 (95% CI, 0.74–0.99; P=0.03) for cardiovascular mortality or HF hospitalization. Other adverse events were similar between the groups.

The results showed that regular ET was safe, but it produced nonsignificant reductions in the primary and secondary end points. However, in protocol-specified supplementary analyses adjusted for prognostic factors, the treatment effect was statistically significant, and the HF-ACTION results support a prescribed ET program for patients with reduced LVF and HF.

The second paper [2] evaluated trial data to report the effects of ET on health status among patients with HF. The Kansas City Cardiomyopathy Questionnaire (KCCQ) was used to measure health status every 3 months for 12 months, and annually thereafter for 4 years The KCCQ scored patients from 0 to 100, and higher scores corresponded to better health status.

At 3 months, usual care plus ET led to greater improvement in the KCCQ overall summary score (mean, 5.21; 95% confidence interval [CI], 4.42–6.00) compared with usual care alone (3.28; 95% CI, 2.48–4.09). The additional 1.93-point increase (95% CI, 0.84–3.01) in the ET group was statistically significant (P<0.001). After 3 months, there were no further significant chances in KCCQ score for either group (P=0.85 for the difference between slopes), resulting in a sustained, greater improvement overall for the entire ET group (P<0.001) Results were similar on the KCCQ subscales, and no subgroup interactions were detected. Results of the trial indicated that participation in an exercise program provided a modest, but significant improvement on patient-reported health status.

[1] O’Connor C M, Whellan D J, Lee K L et al. Efficacy and safety of exercise training in patients with chronic heart failure HF-ACTION randomized controlled trial. JAMA 2009;301(14):1439-1450

[2] Flynn K E, Pina I L, Whellan D J et al. Effects of exercise training on health status in patients with chronic heart failure: HF-ACTION randomized controlled trial. JAMA 2009;301(14):1451-1459

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Further information: Peripheral Arterial Disease (see p1681) and Hypertension (see p1833) from Cardiovascular Medicine, 3rd Edn*

The Prevention Regimen For Effectively avoiding Second Strokes (PRoFESS) trial was a double-blind, two-by-two factorial, active, and placebo-controlled study in patients who had suffered a recent ischemic stroke. Two studies from the trial were published in a recent issue of The New England Journal of Medicine [1,2].

One of the articles primarily focused on patients randomized to receive 25 mg of aspirin plus 200 mg of extended-release dipyridamole (ASA-ERDP) twice a day or 75 mg of clopidogrel once-daily in order to study the efficacy and safety of the two antiplatelet regimens [1]. The same group of patients received either telmisartan (80 mg once-daily) or placebo for control of blood pressure (BP), a study that was the primary focus of the second article [2]. The primary outcome was first recurrence of stroke. The secondary outcome was a composite of stroke, myocardial infarction (MI), or death from vascular causes. A total of 20,332 patients were followed for a mean of 2.5 years. Recurrent stroke occurred in 916 patients (9.0%) receiving ASA-ERDP and in 898 patients (8.8%) receiving clopidogrel (HR 1.01; 95% CI, 0.92–1.11). The secondary outcome occurred in 1333 patients (13.1%) in each group (HR for ASA-ERDP, 0.99; 95% CI, 0.92–1.07). There were more major hemorrhagic events among ASA-EDRP recipients (419 [4.1%]) than among clopidogrel recipients (365 [3.6%]) (HR, 1.15; 95% CI, 1.00–1.32), including intracranial hemorrhage (HR, 1.42; 95% CI, 1.11–1.83). The net risk of recurrent stroke or major hemorrhagic event was similar in the two groups (1194 ASA-EDRP recipients [11.7%] vs. 1156 clopidogrel recipients [11.4%]; HR, 1.03; 95% CI, 0.95–1.11).

The trial showed that in the group of patients studied, i.e. patients having suffered a recent ischemic stroke, the risks of recurrent stroke, MI, or death from vascular causes were similar in patients receiving ASA-ERDP and in those receiving clopidogrel. In those receiving ASA-ETDP versus ones receiving clopidogrel, there was an increase in hemorrhagic stroke, but the net benefit in regard to the risk of recurrent stroke or major hemorrhagic events was similar. There was no significant difference between the two treatments in the risk of fatal or disabling strokes. These findings provide additional safety and efficacy data that physicians can use to make individual treatment decisions for prevention of recurrent stroke.

The second article [2] primarily focused on patients randomized to receive either telmisartan (80 mg once-daily) or placebo for control of BP. The primary outcome was first recurrence of stroke. The secondary outcome was a composite of stroke, myocardial infarction (MI), or death from vascular causes. Of the of total of 20,332 patients, 10,146 were randomized to receive 80 mg daily of telmisartan, a renin-angiotensin system inhibitor (ARB), and 10,186 to receive placebo. The median interval for initiation of therapy was 15 days after an ischemic stroke and continued for 2.5 years.

The mean BP was 3.8/2.0 mmHg lower in the ARB group than in the placebo group. A total of 880 patients (8.7%) in the ARB group and 934 patients (9.2%) in placebo had a subsequent stroke (hazard ratio [HR] in the ARB group, 0.95% confidence interval [CI], 0.86–1.04; P=0.23). Major cardiovascular events occurred in 1367 patients (13.5%) in the ARB group and 1463 patients (14.4 %) in placebo (HR, 0.94; 95% CI, 0.87–1.01; P=0.11). New-onset diabetes occurred in 1.7% of the ARB group and 2.1% in the placebo group (HR, 0.82; 95% CI, 0.65–1.04; P=0.10). Results showed that the addition of ARB therapy to the use of other antihypertensive drugs soon after a stroke and continued for a mean of 2.5 years did not significantly reduce the risk of subsequent stroke, major cardiovascular events, or new-onset diabetes.

[1] Sacco RL, Diener HC, Yusuf S et al. Aspirin and extended-release dipyridamole versus clopidogrel for recurrent stroke. N Engl J Med 2008;359:1238-51

[2] Yusuf S, Diener HC, Sacco RL et al. Telmisartan to prevent recurrent stroke and cardiovascular events. N Engl J Med 2008;359:1225-37

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Further information: Hypertension (see p1833) from Cardiovascular Medicine, 3rd Edn*

The purpose of this trial [1], the third European Cooperative Acute Stroke Study (ECASS III), was to test the hypotheses that the efficacy of alteplase administered in patients with acute ischemic stroke could safely extend to 3–4.5 hours after the onset of stroke symptoms.

ECASS III was a double-blind, parallel-group trial that enrolled patients from multiple centers across Europe. Patients were 18–80 years of age, had received a clinical diagnosis of acute ischemic stroke, had not suffered a brain hemorrhage or major infarction, and were randomized in a 1:1 double-blind fashion to receive treatment with intravenous alteplase (0.9 mg per kilogram of body weight) or placebo. The primary end point was disability at 90 days, dichotomized as a favorable outcome (a score of 0 or 1 on the modified Rankin scale, range=0–6, with 0 indicating no symptoms and 6 indicating death) or an unfavorable outcome (2–6 on the modified Rankin scale). The secondary end point was a global outcome analysis of four neurologic and disability scores combined. Safety end points were death, symptomatic intracranial hemorrhage, or other adverse events. A total of 821 patients were enrolled, and 418 received alteplase and 403 received placebo. The median time for administration of alteplase was 3 hours 59 minutes.

More patients in the alteplase group than in placebo had a favorable outcome (52.4% vs. 45.2%; odds ratio [OR], 1.34; 95% confidence interval [CI], 1.02–1.76; P=0.04). In the global analysis, the outcome was also improved with alteplase as compared with placebo (OR, 1.28; 95% CI, 1.00–1.65; P<0.05). The incidence of intracranial hemorrhage was higher with alteplase than with placebo (for intracranial hemorrhage, 27% vs. 17.6%; P=0.001; for symptomatic intracranial hemorrhage, 2.4% vs. 0.2%; P=0.008). Mortality did not differ significantly between the alteplase and placebo groups (77.7% and 8.4%, respectively; P=0.68). No significant differences were indicated in the rates of other serious adverse events.

Although the results of the trial showed a modestly significant improvement in the clinical outcome of patients presenting with acute ischemic stroke who were treated with intravenous alteplase 3–4.5 hours after onset of symptoms, the investigators emphasized that patients should be treated with alteplase as early as possible to maximize the benefit of the treatment.

[1] Hacke W, Kaste M, Bluhmke E et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med 2008;359:1317-29

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Further information: Management of Cholesterol Disorders (see p2667) from Cardiovascular Medicine, 3rd Edn*

This paper [1] presents a prospective, subanalysis study using the data obtained from 15,548 initially healthy men and women who participated in the Justification for the Use of statins in Prevention: an Interventional Trial Evaluating Rosuvastatin (JUPITER) trial (87% of the total number), and was intended to examine the effects of rosuvastatin 20 mg versus placebo on rates of non-fatal myocardial infarction, non-fatal stroke, admission for unstable angina, arterial revascularization, or cardiovascular death during follow-up of 5 years.

Investigators sought to validate the hypothesis that asymptomatic individuals with normal LDL cholesterol concentrations, but with evidence of increased inflammation by measurement of C-reactive protein, would benefit from a statin. Compared with placebo, men and women who achieved LDL cholesterol less than 1.8 mmol/l had a 55% reduction in vascular events (event rate [ER] 1.11 vs. 0.51 per 100 person-years; hazard ratio [HR] 0.45, 95% confidence interval [CI] 0.34–0.60, P<0.0001), and those achieving hsCRP less than 2 mg/l a 62% reduction (ER 0.42 per 100 person-years; HR 0.38, 95% CI 0.26–0.56, P<0.0001). LDL cholesterol and hsCRP reductions were only weakly correlated in individual patients (r<0.15), but we recorded a 65% reduction in vascular events in patients who received rosuvastatin who achieved both LDL cholesterol less than 1.8 mmol/l and hsCRP less than 2 mg/l (ER 0.38 per 100 person-years; adjusted HR 0.35, 95% CI 0.23–0.54) versus a 33% reduction in those who achieved one or neither target (ER 0.74 per 100 person-years; HR 0.67, 95% CI 0.52–0.87) (across treatment groups P<0.0001). Individuals who achieved LDL cholesterol less than 1.8 mmol/l and hsCRP less than 1 mg/l had a 79% reduction (ER 0.24 per 100 person-years; HR 0.21, 95% CI, 0.09–0.52). Achieved hsCRP concentrations were predictive of event rates irrespective of the lipid endpoint used, including the apolipoprotein B to apolipoprotein A1 ratio.

The mechanism by which statins reduce cholesterol is known to be the inhibition of the hydroxymethyl-glutaryl-coenzyme A (HMG-CoA) reductase pathway. The data from this study have now shown insight into the mechanism of a statin’s ability to reduce inflammation. Statins reduce inflammatory cell adhesion and monocyte recruitment to endothelial cells, change smooth muscle migration in developing plaques, and favorably affect matrix metalloproteinases, leading to plaque stabilization, and the extent to which these inflammatory properties affect clinical outcomes, and whether or not they are independent of LDL cholesterol, still must be evaluated in future studies.

[1] Ridker PM, Danielson E, Fonseca FAH et al. Reduction in C-reactive protein and LDL cholesterol and cardiovascular event rates after initiation of rosuvastatin: a prospective study of the JUPITER trial. Lancet 2009; 373:1175-1182

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Further information: Venous Disease (see p1705) from Cardiovascular Medicine, 3rd Edn*

Justification for the Use of statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) is the first randomized trial [1] to evaluate statin therapy in the prevention of venous thromboembolism (VTE). The trial recruited 17,802 apparently healthy men and women with low-density lipoprotein (LDL) cholesterol levels of less than 130 mg/ dL and high-sensitivity C-reactive protein (hsCRP) levels of 2.0 mg/L or higher, randomly assigning them to 20 mg/day of rosuvastatin or placebo. VTE is a common, but serious and potentially fatal condition. Although statins are well-known in the prevention of heart attack and stroke, data from JUPITER have now shown that they also are effective in preventing VTE.

In the median follow-up of 1.9 years (maximum 5.0), symptomatic VTE occurred in 34 patients in the rosuvastatin group and 60 patients in the placebo group developed systematic VTE. The rates of VTE were 0.18 and 0.32 events per 100 person-years of follow-up in the rosuvastatin and placebo groups respectively (hazard ratio [HR] with rosuvastatin, 0.57; 95% confidence interval [CI], 0.37–0.86; P=0.007). The corresponding rates for unprovoked VTE (occurring in the absence of malignancy, trauma, hospitalization, or surgery) were 0.10 and 0.17 (HR, 0.61; 95% CI, 0.35–1.09; P=0.09) and for provoked VTE (occurring with malignancy, during trauma, hospitalization, or surgery) they were 0.08 and 0.16 (HR, 0.52; 95% CI, 0.28–0.96; P=0.03). Rates of pulmonary embolism (PE) were 0.09 in the rosuvastatin group and 0.12 in the placebo group (HR, 0.77; 95% CI, 0.41–1.45; P=0.42), whereas the rates of deep-vein thrombosis only were 0.09 and 0.20, respectively (HR, 0.45; 95% CI, 0.25–0.79; P=0.004). Risk reductions were seen for both VTE and PE. These risk reductions through the use of statins appear to be an independent benefit of its use.

[1] Glynn RJ, Danielson E, Fonseca FAH et al. A randomized trial of rosuvastatin in the prevention of venous thromboembolism. N Engl J Med 2009;360:1851-1861

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