Chronic Heart Failure Hospitalization Research Articles

Prevention of atrial fibrillation in patients with symptomatic chronic heart failure by candesartan in the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM) program

Atrial fibrillation (AF) is frequent in patients with chronic heart failure (CHF). Experimental and small patient studies have demonstrated that blocking the renin-angiotensin-aldosterone system may prevent AF. In the CHARM program, the effects of the angiotensin receptor blocker candesartan on cardiovascular mortality and morbidity were evaluated in a broad spectrum of patients with symptomatic CHF. CHARM provided the opportunity to prospectively determine the effect of candesartan on the incidence of new AF in this CHF population. 7601 patients with symptomatic CHF and reduced or preserved left ventricular systolic function were randomized to candesartan (target dose 32 mg once daily, mean dose 24 mg) or placebo in the 3 component trials of CHARM. The major outcomes were cardiovascular death or CHF hospitalization and all-cause mortality. The incidence of new AF was a prespecified secondary outcome. Median follow-up was 37.7 months. A conditional logistic regression model for stratified data was used. 6446 patients (84.8%) did not have AF on their baseline electrocardiogram. Of these, 392 (6.08%) developed AF during follow-up, 177 (5.55%) in the candesartan group and 215 (6.74%) in the placebo group (odds ratio 0.812, 95% CI 0.662-0.998, P = .048). After adjustment for baseline covariates, the odds ratio was 0.802 (95% CI 0.650-0.990, P = .039). There was no heterogeneity of the effects of candesartan in preventing AF between the 3 component trials (P = .57). Treatment with the angiotensin receptor blocker candesartan reduced the incidence of AF in a large, broadly-based, population of patients with symptomatic CHF.

Angiotensin receptor blockade with candesartan in heart failure: findings from the Candesartan in Heart failure — Assessment of Reduction in Mortality and morbidity (CHARM) programme

Randomized clinical trials in patients with chronic heart failure and reduced left ventricular ejection fraction (LVEF) have demonstrated the life-saving and symptomatic benefits of angiotensin-converting enzyme (ACE) inhibitors, beta-blockers, and, in more selected patients, spironolactone. Despite these major advancements, the prevalence of heart failure continues to increase mainly as a consequence of aging populations. The development of angiotensin II type 1 receptor blockers (ARBs) provides a pharmacologically distinct mechanism of inhibiting the renin-angiotensin-aldosterone system. ARBs offer the potential to produce further clinical improvements for patients with heart failure above and beyond ACE inhibitors, as well as an alternative for those intolerant to an ACE inhibitor. The Candesartan in Heart failure--Assessment of Reduction in Mortality and morbidity (CHARM) programme was designed as three parallel, randomized, double-blind, placebo-controlled clinical trials comparing candesartan with placebo in three different but complementary populations of patients with symptomatic heart failure. In patients with intolerance to an ACE inhibitor and an LVEF of 40% or less (the CHARM-Alternative trial), candesartan reduced cardiovascular mortality and hospitalizations for heart failure by 23% (P < 0.001). In patients with an LVEF of 40% or less treated with an ACE inhibitor (the CHARM-Added trial), candesartan reduced cardiovascular death and hospitalization for chronic heart failure by 15% (P = 0.011). In patients with a LVEF greater than 40% (the CHARM-Preserved trial), hospitalizations for heart failure and new-onset diabetes were significantly reduced. The CHARM programme, together with evidence from mechanistic studies and from other large trials with ARBs, constitutes a firm basis for including an ARB in the therapeutic arsenal in the treatment for chronic heart failure.

Are β-blockers needed in patients receiving spironolactone for severe chronic heart failure? An analysis of the COPERNICUS study

The beneficial effects of beta-blockers and aldosterone receptor antagonists are now well established in patients with severe systolic chronic heart failure (CHF). However, it is unclear whether beta-blockers are able to provide additional benefit in patients already receiving aldosterone antagonists. We therefore examined this question in the COPERNICUS study of 2289 patients with severe CHF receiving the beta1-beta2/alpha1 blocker carvedilol compared with placebo. Patients were divided post hoc into subgroups according to whether they were receiving spironolactone (n = 445) or not (n = 1844) at baseline. Consistency of the effect of carvedilol versus placebo was examined for these subgroups with respect to the predefined end points of all-cause mortality, death or CHF-related hospitalizations, death or cardiovascular hospitalizations, and death or all-cause hospitalizations. The beneficial effect of carvedilol was similar among patients who were or were not receiving spironolactone for each of the 4 efficacy measures. For all-cause mortality, the Cox model hazard ratio for carvedilol compared with placebo was 0.65 (95% CI 0.36-1.15) in patients receiving spironolactone and 0.65 (0.51-0.83) in patients not receiving spironolactone. Hazard ratios for death or all-cause hospitalization were 0.76 (0.55-1.05) versus 0.76 (0.66-0.88); for death or cardiovascular hospitalization, 0.61 (0.42-0.89) versus 0.75 (0.64-0.88); and for death or CHF hospitalization, 0.63 (0.43-0.94) versus 0.70 (0.59-0.84), in patients receiving and not receiving spironolactone, respectively. The safety and tolerability of treatment with carvedilol were also similar, regardless of background spironolactone. Carvedilol remained clinically efficacious in the COPERNICUS study of patients with severe CHF when added to background spironolactone in patients who were practically all receiving angiotensin-converting enzyme inhibitor (or angiotensin II antagonist) therapy. Therefore, the use of spironolactone in patients with severe CHF does not obviate the necessity of additional treatment that interferes with the adverse effects of sympathetic activation, specifically beta-blockade.

Adherence to guidelines is a predictor of outcome in chronic heart failure: the Mahler survey

Aims The impact on outcome of the implementation of European guidelines for the treatment of chronic heart failure (CHF) has not been evaluated. We investigated the consequences of adherence to care by cardiologists on the rate of CHF and cardiovascular (CV) hospitalizations and time to CV hospitalization. Methods and results We constructed class adherence indicators for angiotensin-converting enzyme (ACE) -inhibitors, beta-blockers, spironotactone, diuretics, and cardiac glycosides and GAls (GAl3 adherence to first three classes of heart failure medication, GAl5 adherence to five classes). In the study, 1410 evaluable patients (mean age 69, 69% mates, New York Heart Association (NYHA) II: 64%, III: 34%, IV: 2%) were enrolled and followed up for 6 months by 150 randomly selected cardiologists/cardiology departments from six European countries (France, Germany, Italy, The Netherlands, Spain, and UK). Overall, adherence to treatment guidelines was 60 (GAl3) and 63% (GAl5) and was better for ACE-] (88%) or diuretics (82%) than for cardiac gtycosides (52%), beta-blockers (58%), and spironolactone (36%). In the three tertites of the population defined by a decreasing mean adherence score value, CHF and CV hospitalization rates were, respectively, 6.7, 9.7, and 14.7% and 11. 2, 15.9, and 20.6% (P <0.002 and P <0.001, respectively). Global adherence indicator GAl3 was an independent predictor of time to CV hospitalization in a multi-variable model together with NYHA Class, history of CHF hospitalization, ischaemic aetiology, diabetes mellitus, and hypertension. Conclusion We demonstrate that adherence of physicians to treatment guidelines is a strong predictor of fewer CV hospitalizations in actual practice. There is a need to develop further quality improvement programmes in this condition.

Leitliniengerechte Herzinsuffizienzbehandlung in Deutschland

The MAHLER survey examined the impact of the European guidelines for the treatment of chronic heart failure (CHF). Especially, the trial addressed the question whether adherence to treatment guidelines leads to a reduction in the rate of CHF and cardiovascular (CV) hospitalization. The present sub-study presents the Germany specific data of the MAHLER study and compares the results with the results in other European countries.The gobal adherence index (GAI) shows the proportion of correctly prescribed heart failure medications per patient. Class adherence indicators for angiotensin-converting enzyme (AC)-inhibitors, beta-blockers, spironolactone, diuretics and cardiac glycosides and general adherence indicators (GAI3 adherence to first three classes of heart failure medications, GAI5 adherence to five classes) were constructed. In the German sub-study, 251 patient were included, who were seen by 21 cardiologists in private practice (mean age 68,6 + 10,4 years; 173 man, 78 woman; 158 NYHA II; 91 NYHA III, 2 NYHA IV).Mean adherence to CHF therapy guidelines was 63 % for GAI3, 62 % for GAI5. Compared to the other MAHLER-study countries, Germany was on place two and three concerning GAI3 and GAI5, respectively. Strong adherence to treatment guidelines in Germany led to a reduction of CHF and CV hospitalization rate by 40 % (p < 0.033). Thus, the German data confirm the results of the international study indicating that a good GAI3 performance is an independent predictor of time to hospitalization. Hitherto, the relative risk for hospitalization was higher for CHF patients in Germany than for patients in all other European countries.In Germany like in other European countries, guideline adherence for CHF therapy leads to a reduction in hospitalization rate.

Prognostic benefit of beta-blockers in patients not receiving ACE-Inhibitors

Beta-blockers (BBs) confer significant prognostic benefit in patients (pts) with systolic chronic heart failure (CHF). However, major trials have thus far studied BBs mainly in addition to ACE-Inhibitors or angiotensin receptor blockers (ARBs) as background therapy. The magnitude of the prognostic benefit of BBs in the absence of ACE-I or ARB has not as yet been determined. We performed a meta-analysis of all placebo-controlled BB studies in patients with CHF (n>200). Trials were identified via Medline literature searches, meeting abstracts, and contact with study organizations. Results for all-cause mortality and death or heart failure hospitalization were pooled using the Mantel-Haenszel (fixed effects) method. The impact of BB therapy on all-cause mortality in CHF, in the absence (4.8%) and presence (95.2%) of ACE-I (or ARB), was determined from six trials of 13 370 patients. The risk ratio (RR) for BBs vs. placebo was 0.73 [95% confidence interval (CI) 0.53-1.02] in the absence of ACE-I or ARB at baseline, compared with a RR of 0.76 (95% CI 0.71-0.83) in the presence of these agents. When ACE-Inhibitors were analysed in the same way (pre-BB), a RR of 0.89 (0.80-0.99) vs. placebo was observed in studies of >90 days. The impact of BB therapy on death or HF hospitalization in systolic CHF, in the absence and presence of ACE-I, was determined from three trials of 8988 patients. The RR for BBs vs. placebo was 0.81 (95% CI 0.61-1.08) in the absence of ACE-I or ARB at baseline, compared with a RR of 0.78 (95% CI 0.74-0.83) in the presence of these agents. When ACE-Is were analysed in the same way (pre-BB), a RR of 0.85 (95% CI 0.78-0.93) vs. placebo was observed in studies of >90 days. The magnitude of the prognostic benefit conferred by BBs in the absence of ACE-I appears to be similar to those of ACE-Is in systolic CHF. These data therefore suggest that either ACE-Is or BBs could be used as first-line neurohormonal therapy in patients with systolic CHF. Prospective studies directly comparing these agents are required to definitively address this issue.

Rate control versus rhythm control for patients with persistent atrial fibrillation with mild to moderate heart failure: Results from the RAte Control versus Electrical cardioversion (RACE) study

This study was conducted to compare rate- and rhythm-control therapy in patients with persistent atrial fibrillation (AF) and mild to moderate chronic heart failure (CHF). Rate control is not inferior to rhythm control in preventing mortality and morbidity in patients with AF. In CHF, this issue is still unsettled. In this predefined analysis of the RACE study, a total of 261 patients were in New York Heart Association (NYHA) classes II and III at baseline. These patients were analyzed. The primary end point was a composite of cardiovascular mortality, hospitalization for CHF, thromboembolic complications, bleeding, pacemaker implantation, and life-threatening drug side effects. Furthermore, quality of life was compared. After 2.3 +/- 0.6 years, the primary end point occurred in 29 (22.3%) of the 130 rate-control patients and in 32 (24.4%) of the 131 rhythm-control patients. More cardiovascular deaths, hospitalization for CHF, and bleeding occurred under rate control. Thromboembolic complications, drug side effects, and pacemaker implantation were more frequent under rhythm control. Quality of life did not differ between strategies. In patients successfully treated with rhythm control, the prevalence of end points was not different from those who were in AF at study end. However, the type of end point was different: mortality, bleeding, hospitalization for heart failure, and pacemaker implantation occurred less frequently. In patients with mild to moderate CHF, rate control is not inferior to rhythm control. However, if sinus rhythm can be maintained, outcome may be improved. A prospective randomized trial is necessary to confirm these results.

The data monitoring experience in the Candesartan in Heart Failure Assessment of Reduction in Mortality and morbidity (CHARM) program

The CHARM program was designed as 3 separate randomized trials comparing candesartan with placebo in patients with chronic heart failure (CHF) who (1) were intolerant to angiotensin-converting enzyme inhibitor and had left ventricular ejection fraction (LVEF) < or =0.40; (2) were on angiotensin-converting enzyme inhibitor and had LVEF < or =0.40; or (3) had LVEF >0.40. CHARM provides an interesting example of the challenges faced by a Data and Safety Monitoring Committee (DSMC). Although the primary efficacy end point for each component trial was cardiovascular (CV) death or hospitalization for CHF, the primary outcome for the overall program was all-cause mortality. The DSMC received monthly safety reports and also met every 6 months (7 times in all) to review interim reports. Statistical stopping guidelines were predefined for all-cause mortality in the overall program. The overarching principle of the DSMC was proof beyond a reasonable doubt that would be likely to influence clinical practice. There were significant treatment differences in all-cause mortality for the overall program at several interim analyses, and the statistical stopping guideline was reached on one occasion. However, even a conventional level of statistical significance (P < .050) was achieved in only 1 of the 3 component trials. The DSMC consistently recommended that the program continue as planned. The final published result for all-cause death over a median of 3.1 years was a 9% reduction in hazard (95% CI 0%-17%, P = .055), whereas for CV death or hospitalization for CHF, there was a 16% reduction in hazard (95% CI 9%-23%, P < .0001). Subsequent exploratory analyses suggest that the hazard reduction in CV death was more marked in the first year after randomization and that, if real, this apparent treatment-time interaction offers a plausible explanation for why the interim mortality data showed statistically more extreme findings than the overall final results. The DSMC experience in the CHARM program illustrates the importance of continuing a trial to its scheduled completion unless there is proof beyond a reasonable doubt that would influence clinical practice rather than strict reliance on a statistical stopping guideline.

Adherence to guidelines is a predictor of outcome in chronic heart failure: the MAHLER survey

The impact on outcome of the implementation of European guidelines for the treatment of chronic heart failure (CHF) has not been evaluated. We investigated the consequences of adherence to care by cardiologists on the rate of CHF and cardiovascular (CV) hospitalizations and time to CV hospitalization. We constructed class adherence indicators for angiotensin-converting enzyme (ACE)-inhibitors, beta-blockers, spironolactone, diuretics, and cardiac glycosides and GAIs (GAI3 adherence to first three classes of heart failure medication, GAI5 adherence to five classes). In the study, 1410 evaluable patients (mean age 69, 69% males, New York Heart Association (NYHA) II: 64%, III: 34%, IV: 2%) were enrolled and followed up for 6 months by 150 randomly selected cardiologists/cardiology departments from six European countries (France, Germany, Italy, The Netherlands, Spain, and UK). Overall, adherence to treatment guidelines was 60 (GAI3) and 63% (GAI5) and was better for ACE-I (88%) or diuretics (82%) than for cardiac glycosides (52%), beta-blockers (58%), and spironolactone (36%). In the three tertiles of the population defined by a decreasing mean adherence score value, CHF and CV hospitalization rates were, respectively, 6.7, 9.7, and 14.7% and 11.2, 15.9, and 20.6% (P<0.002 and P<0.001, respectively). Global adherence indicator GAI3 was an independent predictor of time to CV hospitalization in a multi-variable model together with NYHA Class, history of CHF hospitalization, ischaemic aetiology, diabetes mellitus, and hypertension. We demonstrate that adherence of physicians to treatment guidelines is a strong predictor of fewer CV hospitalizations in actual practice. There is a need to develop further quality improvement programmes in this condition.

The Effects of β-Adrenergic Blockers in African Americans with Chronic Heart Failure

Objective: To review the available literature regarding the use of β-adrenergic blockers in African Americans with heart failure. Data Sources: Primary literature was located via MEDLINE (1966–January 2004). Key search terms were β-adrenergic blockers; heart failure, congestive; carvedilol; metoprolol; bisoprolol; and bucindolol. Data Synthesis: In African Americans, the prevalence of chronic heart failure (CHF) is nearly twice that of white people. African Americans exhibit symptoms of CHF at an earlier age, develop more marked functional decline after hospitalization for CHF, and have almost a twofold higher mortality rate compared with white patients. Sympathetic nervous system activation is a key pathophysiologic response in CHF; by attenuating this system, β-blockers have been shown to decrease mortality. Unfortunately, minority populations have been underrepresented in many of the trials evaluating β-blockers. Of the 4 β-blockers assessed in CHF, bucindolol has shown detrimental effects when used in African Americans. Metoprolol and bisoprolol have not been sufficiently evaluated to determine if response varies by race. Carvedilol has the best documented benefit in this population. Conclusions: Response to β-adrenergic blockers in CHF varies by race. Bucindolol has shown detrimental effects when used in African Americans. Further investigation is warranted to determine if metoprolol and bisoprolol are equally efficacious to carvedilol in African American patients with CHF.

Cardiac resynchronization therapy reduced all-cause death and hospitalization in chronic heart failure

Cardiac resynchronization therapy reduced all-cause death and hospitalization in chronic heart failure

Association between chronic heart failure and inhaled β-2-adrenoceptor agonists

Background Recent reports suggest an association between β-agonists and the risk of incident chronic heart failure (CHF). We sought to examine the association between inhaled β-agonists and risk of incident and nonincident heart failure. Methods We performed a nested case-control study within the Ambulatory Care Quality Improvement Project (ACQUIP). Case subjects were defined as having had a hospitalization with a primary discharge diagnosis of CHF. Controls were randomly selected from the ACQUIP cohort. The exposure was the number of β-agonist canisters filled in the 90 days before an index date. Results After adjusting for potentially confounding factors, there appeared to be no association between the use of inhaled β-agonists and the risk of heart failure (1–2 canisters per month, OR 1.3 [95% CI 0.9, 1.8], ≥3 canisters per month, 1.1 [95% CI 0.8, 1.6]). However, among the cohort that had a history of CHF, there appeared to be a dose-response association between the number of inhaled β-agonists and the risk of hospitalization for chronic heart failure (1–2 canisters per month, adjusted OR 1.8 [95% CI 1.1, 3.0], ≥3 canisters per month, adjusted OR 2.1 [95% CI 1.2, 3.8]). Conclusion β-Agonists did not appear to be associated with incident heart failure but were associated with risk of CHF hospitalization among those subjects with a previous CHF diagnosis. Although a causal relationship cannot be inferred from these findings, further research is warranted to determine the safety and effectiveness of inhaled β-agonists for patients with CHF.

Mortality and Morbidity Reduction With Candesartan in Patients With Chronic Heart Failure and Left Ventricular Systolic Dysfunction

Patients with symptomatic chronic heart failure (CHF) and reduced left ventricular ejection fraction (LVEF) have a high risk of death and hospitalization for CHF deterioration despite therapies with angiotensin-converting enzyme (ACE) inhibitors, beta-blockers, and even an aldosterone antagonist. To determine whether the angiotensin-receptor blocker (ARB) candesartan decreases cardiovascular mortality, morbidity, and all-cause mortality in patients with CHF and depressed LVEF, a prespecified analysis of the combined Candesartan in Heart Failure Assessment of Reduction in Mortality and morbidity (CHARM) low LVEF trials was performed. CHARM is a randomized, double-blind, placebo-controlled, multicenter, international trial program. New York Heart Association (NYHA) class II through IV CHF patients with an LVEF of < or =40% were randomized to candesartan or placebo in 2 complementary parallel trials (CHARM-Alternative, for patients who cannot tolerate ACE inhibitors, and CHARM-Added, for patients who were receiving ACE inhibitors). Mortality and morbidity were determined in 4576 low LVEF patients (2289 candesartan and 2287 placebo), titrated as tolerated to a target dose of 32 mg once daily, and observed for 2 to 4 years (median, 40 months). The primary outcome (time to first event by intention to treat) was cardiovascular death or CHF hospitalization for each trial, with all-cause mortality a secondary end point in the pooled analysis of the low LVEF trials. Of the patients in the candesartan group, 817 (35.7%) experienced cardiovascular death or a CHF hospitalization as compared with 944 (41.3%) in the placebo group (HR 0.82; 95% CI 0.74 to 0.90; P<0.001) with reduced risk for both cardiovascular deaths (521 [22.8%] versus 599 [26.2%]; HR 0.84 [95% CI 0.75 to 0.95]; P=0.005) and CHF hospitalizations (516 [22.5%] versus 642 [28.1%]; HR 0.76 [95% CI 0.68 to 0.85]; P<0.001). It is important to note that all-cause mortality also was significantly reduced by candesartan (642 [28.0%] versus 708 [31.0%]; HR 0.88 [95% CI 0.79 to 0.98]; P=0.018). No significant heterogeneity for the beneficial effects of candesartan was found across prespecified and subsequently identified subgroups including treatment with ACE inhibitors, beta-blockers, an aldosterone antagonist, or their combinations. The study drug was discontinued because of adverse effects by 23.1% of patients in the candesartan group and 18.8% in the placebo group; the reasons included increased creatinine (7.1% versus 3.5%), hypotension (4.2% versus 2.1%), and hyperkalemia (2.8% versus 0.5%), respectively (all P<0.001). Candesartan significantly reduces all-cause mortality, cardiovascular death, and heart failure hospitalizations in patients with CHF and LVEF < or =40% when added to standard therapies including ACE inhibitors, beta-blockers, and an aldosterone antagonist. Routine monitoring of blood pressure, serum creatinine, and serum potassium is warranted.

Characterizing variability in cardiovascular drug responses

Characterizing variability in cardiovascular drug responses

Targeted Anticytokine Therapy in Patients With Chronic Heart Failure

Studies in experimental models and preliminary clinical experience suggested a possible therapeutic role for the soluble tumor necrosis factor antagonist etanercept in heart failure. Patients with New York Heart Association class II to IV chronic heart failure and a left ventricular ejection fraction < or =0.30 were enrolled in 2 clinical trials that differed only in the doses of etanercept used. In RECOVER, patients received placebo (n=373) or subcutaneous etanercept in doses of 25 mg every week (n=375) or 25 mg twice per week (n=375). In RENAISSANCE, patients received placebo (n=309), etanercept 25 mg twice per week (n=308), or etanercept 25 mg 3 times per week (n=308). The primary end point of each individual trial was clinical status at 24 weeks. Analysis of the effect of the 2 higher doses of etanercept on the combined outcome of death or hospitalization due to chronic heart failure from the 2 studies was also planned (RENEWAL). On the basis of prespecified stopping rules, both trials were terminated prematurely owing to lack of benefit. Etanercept had no effect on clinical status in RENAISSANCE (P=0.17) or RECOVER (P=0.34) and had no effect on the death or chronic heart failure hospitalization end point in RENEWAL (etanercept to placebo relative risk=1.1, 95% CI 0.91 to 1.33, P=0.33). The results of RENEWAL rule out a clinically relevant benefit of etanercept on the rate of death or hospitalization due to chronic heart failure.

Low-dose carvedilol improves left ventricular function and reduces cardiovascular hospitalization in Japanese patients with chronic heart failure: the Multicenter Carvedilol Heart Failure Dose Assessment (MUCHA) trial

Background The efficacy and optimum dose of β-blockers have not been established in Japanese patients with chronic heart failure (CHF). The efficacy and safety of two doses of carvedilol, a β-blocker with vasodilator and antioxidant actions, were investigated in Japanese patients with CHF. Methods After screening and a carvedilol challenge phase, 174 patients with mild to moderate CHF were randomly assigned (double-blinded) to placebo, 2.5 mg of carvedilol twice daily, or 10 mg of carvedilol twice daily. After a 2- to 4-week uptitration phase, maintenance treatment was continued for 24 to 48 weeks. The primary end point was improvement of the global assessment of CHF by the attending physician. Secondary end points were death or hospitalization for cardiovascular disease, cardiovascular hospitalization, hospitalization for heart failure, change of left ventricular ejection fraction, and change in New York Heart Association class. Results Carvedilol therapy achieved dose-dependent improvement of all end points ( P for linear trend, range .002 to <.001). Both carvedilol groups showed marked risk reduction (71% to 91%) for cardiovascular and CHF hospitalization and for death or cardiovascular hospitalization ( P range, .024 to <.001 for pairwise comparisons with placebo). No significant differences were observed for noncardiovascular hospitalization or adverse events. Conclusions In Japanese patients with mild or moderate CHF, carvedilol achieved dose-related improvement of CHF and left ventricular ejection fraction; cardiovascular hospitalization was markedly reduced. At 5 mg/d, carvedilol conferred an important patient benefit, less than at 20 mg/d.

Myocardial contractile reserve by dobutamine stress echocardiography predicts improvement in ejection fraction with beta-blockade in patients with heart failure: the Beta-Blocker Evaluation of Survival Trial (BEST).

beta-Blockers improve survival and reduce hospitalization in chronic heart failure (CHF) by biologically improving left ventricular ejection fraction (LVEF). However, a good predictor of improvement with this therapy has not been identified. This substudy of BEST examined whether myocardial contractile reserve, as determined by dobutamine stress echocardiography, predicts improvement in LVEF. Seventy-nine patients with class III/IV CHF underwent dobutamine stress echocardiography before treatment with bucindolol (n=41) or placebo (n=38). Regional wall motion score index (WMSI) was calculated as the sum of the scores in each segment divided by the total number of segments visualized. WMSI was compared with change in LVEF after 3 months of therapy as determined by gated radionuclide scan. Change in WMSI correlated inversely with change in LVEF after 3 months of bucindolol (r=-0.72, P<0.0001) and was the most significant multivariate predictor of change in LVEF (P=0.0002). Patients with contractile reserve had demographics similar to those of patients without contractile reserve, including RVEF, LVEF, systolic blood pressure, and CHF duration. However, patients without contractile reserve had higher baseline plasma norepinephrine levels (687+/-333 versus 420+/-246 pg/mL, P<0.05) and greater decrease in plasma norepinephrine in response to bucindolol (-249+/-171 versus -35+/-277 pg/mL, P<0.05). This study suggests a direct relationship between contractile reserve and improvement in LVEF with beta-blocker therapy in patients with advanced CHF. Patients without contractile reserve have higher resting adrenergic drive, as reflected by plasma norepinephrine, and may experience greater sympatholytic effects from bucindolol.

Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-Preserved Trial

Half of patients with chronic heart failure (CHF) have preserved left-ventricular ejection fraction (LVEF), but few treatments have specifically been assessed in such patients. In previous studies of patients with CHF and low LVEF or vascular disease and preserved LVEF, inhibition of the renin-angiotensin system is beneficial. We investigated the effect of addition of an angiotensin-receptor blocker to current treatments. Between March, 1999, and July, 2000, we randomly assigned 3023 patients candesartan (n=1514, target dose 32 mg once daily) or matching placebo (n=1509). Patients had New York Heart Association functional class II-IV CHF and LVEF higher than 40%. The primary outcome was cardiovascular death or admission to hospital for CHF. Analysis was done by intention to treat. Median follow-up was 36.6 months. 333 (22%) patients in the candesartan and 366 (24%) in the placebo group experienced the primary outcome (unadjusted hazard ratio 0.89 [95% CI 0.77-1.03], p=0.118; covariate adjusted 0.86 [0.74-1.0], p=0.051). Cardiovascular death did not differ between groups (170 vs 170), but fewer patients in the candesartan group than in the placebo group were admitted to hospital for CHF once (230 vs 279, p=0.017) or multiple times. Composite outcomes that included non-fatal myocardial infarction and non-fatal stroke showed similar results to the primary composite (388 vs 429; unadjusted 0.88 [0.77-1.01], p=0.078; covariate adjusted 0.86 [0.75-0.99], p=0.037). Candesartan has a moderate impact in preventing admissions for CHF among patients who have heart failure and LVEF higher than 40%.

Risk of Mortality and Heart Failure Exacerbations Associated With Inhaled β-Adrenoceptor Agonists Among Patients With Known Left Ventricular Systolic Dysfunction

Recent studies suggest that myocardial beta(2)-adrenoceptors may be important in chronic heart failure. We sought to determine if use of selective beta(2)-agonists was associated with hospitalization for heart failure and all-cause mortality. We studied a cohort of patients with left ventricular systolic dysfunction (LVSD). The outcome was the first hospitalization with a primary diagnosis of chronic heart failure or death from any cause. The exposure was the average number of beta-agonist canisters filled per month in the 90 days prior to and 15 days after enrollment. Among 1,529 subjects, the relative risk (RR) of chronic heart failure hospital admission associated with inhaled beta-agonists followed a dose-response relationship: RR for one canister per month, 1.4 (95% confidence interval [CI], 0.9 to 2.0), RR for two canisters per month, 1.7 (95% CI, 1.2 to 2.5), and RR for three canisters per month, 2.1 (95% CI, 1.4 to 3.1). The RR of death demonstrated a similar finding: RR for one canister per month, 0.9 (95% CI, 0.5 to 1.5), RR for two canisters per month, 1.3 (95% CI, 0.9 to 2.1), and RR for three canisters per month, 2.0 (95% CI, 1.3 to 3.1). Adjusting for potential confounding factors did not affect the estimates. Among subjects with LVSD, inhaled beta-agonists were associated with an increased risk of heart failure hospitalization, and all-cause mortality. Clinicians should carefully consider the etiology of dyspnea when prescribing beta-agonists to patients with LVSD.

Ongoing right ventricular hemodynamics in heart failure: clinical value of measurements derived from an implantable monitoring system

ObjectivesThis study examined the characteristics of continuously measured right ventricular (RV) hemodynamic information derived from an implantable hemodynamic monitor (IHM) in heart failure patients. BackgroundHemodynamic monitoring might improve the day-to-day management of patients with chronic heart failure (CHF). Little is known about the characteristics of long-term hemodynamic information in patients with CHF or how such information relates to meaningful clinical events. MethodsThirty-two patients with CHF received a permanent RV IHM system similar to a single-lead pacemaker. Right ventricular systolic and diastolic pressures, heart rate, and pressure derivatives were continuously measured for nine months without using the data for clinical decision-making or management of patients. Data were then made available to clinical providers, and the patients were followed up for 17 months. Pressure characteristics during optimal volume, clinically determined volume-overload exacerbations, and volume depletion events were examined. The effect of IHM on hospitalizations was examined using the patients’ historical controls. ResultsLong-term RV pressure measurements had either marked variability or minimal time-related changes. During 36 volume-overload events, RV systolic pressures increased by 25 ± 4% (p < 0.05) and heart rate increased by 11 ± 2% (p < 0.05). Pressure increases occurred in 9 of 12 events 4 ± 2 days before the exacerbations requiring hospitalization. Hospitalizations before using IHM data for clinical management averaged 1.08 per patient year and decreased to 0.47 per patient-year (57% reduction, p < 0.01) after hemodynamic data were used. ConclusionsLong-term ambulatory pressure measurements from an IHM may be helpful in guiding day-to-day clinical management, with a potentially favorable impact on CHF hospitalizations.