Influence of order and type of drug (bisoprolol vs. enalapril) on outcome and adverse events in patients with chronic heart failure: a post hoc analysis of the CIBIS-III trial.

AIMS: Angiotensin-converting enzyme inhibitors (ACE-Is) and beta-blockers are associated with improved outcome in patients with chronic heart failure (CHF). In this post hoc analysis of the CIBIS III trial, we examined the influence of the order of drug administration on clinical events and achieved dose. We also assessed the relations between dose levels and baseline variables or adverse events. METHODS AND RESULTS: In the CIBIS III trial, 1010 patients (mean age: 72.4 years; mean ejection fraction: 28.8%; male: 68.2%) with stable CHF were randomized to up-titration of monotherapy with either bisoprolol (target dose 10 mg o.d.) or enalapril (target dose 10 mg b.i.d.) for 6 months, followed by their combination for 6-24 months. Endpoints were mortality or all-cause hospitalization, mortality alone and mortality or cardiovascular hospitalization. The study drug (ACE-I or beta-blocker) was last prescribed at ≥50% of target dose to significantly more patients for the first initiated drug in both treatment groups (both P< 0.001). Sixty per cent of endpoints were reached during the monotherapy phase and randomized treatment during monotherapy was not a predictor of the three assessed outcomes. Monotherapy phase was the strongest independent predictor of outcome (P< 0.0001 for all endpoints). Older age, NYHA class III, impaired renal function, lower body weight and blood pressure at baseline, and hypotension, bradycardia and heart failure during treatment were associated with the inability to reach high dose of both study drugs. CONCLUSION: The order of drug administration plays an important role in whether CHF patients reach target doses of bisoprolol and enalapril. For both study drugs, the dose level reached was associated with baseline characteristics and adverse events. In CHF patients not treated with an ACE-I or a beta-blocker, the duration of monotherapy with either type of drug should be shorter than 6 months.

The effect of treatment with bisoprolol-first versus enalapril-first on cardiac structure and function in heart failure.

BACKGROUND: In CIBIS III, initiating chronic heart failure (CHF) treatment with bisoprolol (target dose 10 mg q.d.) followed by combination therapy with enalapril (target dose 10 mg b.i.d.), compared to the opposite order, showed similar effects on survival and hospitalization. By echocardiography, we evaluated the effects of these treatment strategies on cardiac structure and function. METHODS: In a single-centre substudy, we compared the impact on left ventricular (LV) dimensions and ejection fraction (EF) of treatment with bisoprolol-first (n=21) and enalapril-first (n=19) in 40 beta-blocker and angiotensin-converting-enzyme-inhibitor naive patients, with stable, mild or moderate CHF (NYHA II-III) and LVEF ≤35%. Echocardiography was performed at baseline, after the 6-month monotherapy phase and after 12 months, i.e. after 6 months combination therapy. RESULTS: Baseline characteristics were similar across treatment groups. After 6 months LVEF increased by 5.1±4.0 EF-% (P<0.0001) with Bisoprolol and 4.0±4.0 EF-% (P=0.0005), with enalapril (between-group P=0.47). LV end-diastolic volume (LVEDV) decreased by 8.1±4.7 ml (P<0.0001) with bisoprolol and by 4.6±8.2 ml (P=0.03) with enalapril (between-group P=0.16). Mean wall thickness (WT) decreased by 0.31±0.43 mm (P=0.004) with bisoprolol and by 0.18±0.48 mm (P=0.11) with enalapril (between-group P=0.29). From baseline to 12 months, LVEF increased by 7.5±4.0 EF-% (P<0.0001) in Bisoprolol first group and 6.0±4.6 EF-% (P<0.0001), in the enalapril first group (between-group P=0.31). LVEDV decreased by 12.9±6.3 ml (P<0.0001) with bisoprolol-first and by 7.9±7.7 ml (P=0.0006) with enalapril-first (between-group P=0.16) and WT decreased by 0.38±0.44 mm (P=0.0008) and 0.59±0.54 mm (P=0.0004), respectively (between-group P=0.10). CONCLUSION: During both monotherapy and combined therapy, bisoprolol-first and enalapril-first similarly reversed cardiac remodelling and improved LVEF.

Should major vascular surgery be delayed because of preoperative cardiac testing in intermediate-risk patients receiving beta-blocker therapy with tight heart rate control?

OBJECTIVES: The purpose of this study was to assess the value of preoperative cardiac testing in intermediate-risk patients receiving beta-blocker therapy with tight heart rate (HR) control scheduled for major vascular surgery. BACKGROUND: Treatment guidelines of the American College of Cardiology/American Heart Association recommend cardiac testing in these patients to identify subjects at increased risk. This policy delays surgery, even though test results might be redundant and beta-blockers with tight HR control provide sufficient myocardial protection. Furthermore, the benefit of revascularization in high-risk patients is ill-defined. METHODS: All 1,476 screened patients were stratified into low-risk (0 risk factors), intermediate-risk (1 to 2 risk factors), and high-risk (> or =3 risk factors). All patients received beta-blockers. The 770 intermediate-risk patients were randomly assigned to cardiac stress-testing (n = 386) or no testing. Test results influenced management. In patients with ischemia, physicians aimed to control HR below the ischemic threshold. Those with extensive stress-induced ischemia were considered for revascularization. The primary end point was cardiac death or myocardial infarction at 30-days after surgery. RESULTS: Testing showed no ischemia in 287 patients (74%); limited ischemia in 65 patients (17%), and extensive ischemia in 34 patients (8.8%). Of 34 patients with extensive ischemia, revascularization before surgery was feasible in 12 patients (35%). Patients assigned to no testing had similar incidence of the primary end point as those assigned to testing (1.8% vs. 2.3%; odds ratio [OR] 0.78; 95% confidence interval [CI] 0.28 to 2.1; p = 0.62). The strategy of no testing brought surgery almost 3 weeks forward. Regardless of allocated strategy, patients with a HR <65 beats/min had lower risk than the remaining patients (1.3% vs. 5.2%; OR 0.24; 95% CI 0.09 to 0.66; p = 0.003). CONCLUSIONS: Cardiac testing can safely be omitted in intermediate-risk patients, provided that beta-blockers aiming at tight HR control are prescribed.

Optimizing long-term cardiac management after major vascular surgery: Role of beta-blocker therapy, clinical characteristics, and dobutamine stress echocardiography to optimize long-term cardiac management after major vascular surgery.

BACKGROUND: Survivors of major vascular surgery are at increased risk of late cardiac complications. OBJECTIVE: To examine the cardioprotective effect of beta-blockers. METHODS: A follow-up study was conducted in 1286 patients who survived surgery for at least 30 days. Patients were screened for cardiac risk factors and dobutamine stress echocardiography (DSE) results; 1034 patients (80%) underwent preoperative DSE, and 370 (29%) received beta-blockers. The main outcome measure was late cardiac death or myocardial infarction. RESULTS: Seventy-four patients (5.8%) had late cardiac events. Cardiac event rates in patients with 0, 1 to 2, and 3 or more risk factors were 1.6%, 4.7%, and 19.2%, respectively. In patients without risk factors, beta-blockers were associated with improved event-free survival (2.8% vs 0%), and DSE had no additional prognostic value. In patients with 1 to 2 risk factors, the presence of ischemia during DSE increased cardiac events from 3.9% to 9.8%. However, if patients with ischemia were treated with beta-blockers, the risk decreased to 7.2%. In patients with 3 or more risk factors, DSE and beta-blockers stratified patients into intermediate- and high-risk groups. In patients without ischemia, beta-blockers reduced the cardiac event rate from 15.1% to 9.5%, whereas the cardioprotective effect was limited in patients with 3 or more risk factors and positive DSE findings. CONCLUSIONS: Long-term beta-blocker use is associated with a reduction in the cardiac event rate, except for patients with 3 or more risk factors and positive findings on DSE.

Increased plasma concentration of natriuretic peptides by selective beta1-blocker bisoprolol.

Beta-blocker therapy has been shown to be associated with an increase in the plasma concentration of A-type natriuretic peptide (ANP). Whether the plasma concentration of B-type natriuretic peptide (BNP), which is mainly derived from ventricular tissue, is also increased and whether this increase is caused by increased production or decreased metabolism by down-regulation of the natriuretic peptide-clearance receptor remains to be established. In a double-blind crossover study effects of 8 weeks' treatment of bisoprolol,10 mg once daily, and losartan, 50 mg once daily, on plasma concentrations of ANP, BNP, and N-terminal (Nt)-ANP and ambulatory blood pressure (ABP) were measured in 24 hypertensive patients. With bisoprolol plasma concentrations of ANP and BNP increased (P < 0.001) by 93 +/- 88% (mean +/- SD) and 148 +/- 117%, whereas these parameters did not change with losartan. Nt-ANP, which is not metabolized by the NP clearance receptor, increased by 83 +/- 45%, and increments in ANP and Nt-ANP were related (r =0.77, P < 0.001). The decrease in ABP was greater with bisoprolol than with losartan. Monotherapy with bisoprolol, but not with losartan, is associated with substantial increments in plasma concentrations of ANP, Nt-ANP, and BNP. As the magnitude of the increase in ANP and Nt-ANP was comparable, the beta-blocker-induced increase in NPs is not likely to be explained by a decrease in NP clearance receptor density.