Comparative effectiveness of beta-adrenergic antagonists (atenolol, metoprolol tartrate, carvedilol) on the risk of rehospitalization in adults with heart failure

Placebo-controlled randomized trials have demonstrated the efficacy of selected beta blockers on outcomes in chronic heart failure (HF), but the relative effectiveness of different beta blockers in usual clinical care is poorly understood. We compared 12-month risk of rehospitalization for HF associated with receipt of different beta blockers in 7,883 adults hospitalized for HF within 2 large health plans between January 1, 2001 and December 31, 2002. Beta-blocker use was ascertained from electronic pharmacy databases and readmissions within 12 months were identified from hospital discharge databases. Extended Cox regression was used to examine the association between receipt of different beta blockers and risk of readmission for HF after adjustment for potential confounders. During follow-up, there were 3,234 person-years of exposure to beta blockers (39.3% atenolol, 42.0% metoprolol tartrate, 12.3% carvedilol, and 6.4% other). Crude 12-month rates of readmissions for HF were high overall (42.6 per 100 person-years). After adjustment for potential confounders, cumulative exposure to each beta blocker, and propensity to receive carvedilol compared with atenolol, adjusted risks of readmission were not significantly different for metoprolol tartrate (adjusted hazard ratio 0.95, 95% confidence interval 0.85 to 1.05) or for carvedilol (adjusted hazard ratio 0.92, 95% confidence interval 0.74 to 1.14). In conclusion, in a contemporary cohort of high-risk patients hospitalized with HF, we found that adjusted risks of rehospitalization for HF within 12 months were not significantly different in patients receiving atenolol, shorter-acting metoprolol tartrate, or carvedilol.     

Carvedilol protects better against vascular events than metoprolol in heart failure: results from COMET.

OBJECTIVES: We explored whether vascular protection by carvedilol could contribute to its superior effects in the treatment of heart failure (HF) compared with metoprolol tartrate in the COMET (Carvedilol Or Metoprolol European Trial) study. BACKGROUND: Full adrenergic blockade by carvedilol and additional (e.g., antioxidative) properties may lead to vascular protection relative to beta-1 blockade alone, and contribute to its efficacy in HF treatment. METHODS: Three thousand twenty-nine patients with HF due to ischemic (51%) or idiopathic cardiomyopathy (44%) were randomized double-blind to carvedilol (n = 1,511) or metoprolol (n = 1,518) and followed for 58 months. Vascular end points were cardiovascular death, stroke, stroke death, myocardial infarction (MI), and unstable angina. RESULTS: The effect of carvedilol on cardiovascular death improved consistently in subgroups with prespecified baseline variables. Myocardial infarctions were reported in 69 carvedilol and 94 metoprolol patients (hazard ratio [HR] 0.71, 95% confidence interval [CI] 0.52 to 0.97, p = 0.03). Cardiovascular death or nonfatal MI combined were reduced by 19% in carvedilol (HR 0.81, 95% CI 0.72 to 0.92, p = 0.0009 vs. metoprolol). Unstable angina was reported as an adverse event in 56 carvedilol and in 77 metoprolol patients (HR 0.71, 95% CI 0.501 to 0.998, p = 0.049). A stroke occurred in 65 carvedilol and 80 metoprolol patients (HR 0.79, 95% CI 0.57 to 1.10). Stroke or MI combined occurred in 130 carvedilol and 168 metoprolol patients (HR 0.75, 95% CI 0.60 to 0.95, p = 0.015), and fatal MI or fatal stroke occurred in 34 carvedilol and in 72 metoprolol patients (HR 0.46, 95% CI 0.31 to 0.69, p = 0.0002). Death after a nonfatal MI or stroke occurred in 61 of 124 carvedilol and in 106 of 160 metoprolol patients (HR 0.66, 95% CI 0.48 to 0.90, p = 0.0086). CONCLUSIONS: Carvedilol improves vascular outcomes better than metoprolol. These results suggest a ubiquitous protective effect of carvedilol against major vascular events.     

Effect of concomitant digoxin and carvedilol therapy on mortality and morbidity in patients with chronic heart failure

We retrospectively performed stepwise logistic regression analysis on 1,509 patients with chronic heart failure in 4 multicenter United States studies and 1 Australia-New Zealand study to examine the effect of digoxin in patients randomized to carvedilol or placebo. Patients receiving digoxin had more advanced heart failure, the incidence of hospitalization for any cause and the combination of all-cause death and all-cause hospitalization were the same in the digoxin versus no-digoxin groups.     

Prognostic relevance of atrial fibrillation in patients with chronic heart failure on long-term treatment with beta-blockers: results from COMET.

AIMS: Atrial fibrillation is common in patients with chronic heart failure (CHF). We analysed the risk associated with atrial fibrillation in a large cohort of patients with chronic heart failure all treated with a beta-blocker. METHODS AND RESULTS: In COMET, 3029 patients with CHF were randomized to carvedilol or metoprolol tartrate and followed for a mean of 58 months. We analysed the prognostic relevance on other outcomes of atrial fibrillation on the baseline electrocardiogram compared with no atrial fibrillation and the impact of new onset atrial fibrillation during follow-up. A multivariate analysis was performed using a Cox regression model where 10 baseline covariates were entered together with study treatment allocation. Six hundred patients (19.8%) had atrial fibrillation at baseline. These patients were older (65 vs. 61 years), included more men (88 vs.78%), had more severe symptoms [higher New York Heart Association (NYHA) class] and a longer duration of heart failure (all P<0.0001). Atrial fibrillation was associated with significantly increased mortality [relative risk (RR) 1.29: 95% CI 1.12-1.48; P<0.0001], higher all-cause death or hospitalization (RR 1.25: CI 1.13-1.38), and cardiovascular death or hospitalization for worsening heart failure (RR 1.34: CI 1.20-1.52), both P<0.0001. By multivariable analysis, atrial fibrillation no longer independently predicted mortality. Beneficial effects on mortality by carvedilol remained significant (RR 0.836: CI 0.74-0.94; P=0.0042). New onset atrial fibrillation during follow-up (n=580) was associated with significant increased risk for subsequent death in a time-dependent analysis (RR 1.90: CI 1.54-2.35; P<0.0001) regardless of treatment allocation and changes in NYHA class. CONCLUSION: In CHF, atrial fibrillation significantly increases the risk for death and heart failure hospitalization, but is not an independent risk factor for mortality after adjusting for other predictors of prognosis. Treatment with carvedilol compared with metoprolol offers additional benefits among patients with atrial fibrillation. Onset of new atrial fibrillation in patients on long-term beta-blocker therapy is associated with significant increased subsequent risk of mortality and morbidity.     

Carvedilol or Sustained-Release Metoprolol for Congestive Heart Failure: A Comparative Effectiveness Analysis

BackgroundRelative effectiveness of carvedilol and metoprolol succinate has never been compared in patients with heart failure (HF).Methods and ResultsFrom January 1998 to December 2008, 3,716 consecutive patients with ejection fraction (EF) ≤40%, initiated and maintained on carvedilol or metoprolol succinate, were enrolled and followed until June 2010. The primary end point was all-cause mortality, and the secondary end points were readmissions from HF and follow up EFs at 1, 3, and 5 years. HF etiology (ischemic or nonischemic) was a significant effect modifier, and separate analysis was performed for these subcohorts. Compared with those on carvedilol, patients on metoprolol succinate were less likely to experience mortality in the ischemic HF cohort (adjusted hazard ratio [aHR] 0.54, 95% confidence interval [CI] 0.43–0.66) but were more likely to die in the nonischemic HF cohort (aHR 1.18, 95% CI 1.10–1.28). Follow-up EF was similar by type of beta-blocker used in both ischemic and nonischemic HF cohorts. Furthermore, no significant difference was noted in the incidence of HF hospitalizations by beta-blocker type used in both ischemic and nonischemic HF cohorts.ConclusionsMetoprolol succinate was associated with an improved survival in patients with ischemic HF, and carvedilol was associated with an improved survival in patients with nonischemic HF.     

Risk of Emergent Bradycardia Associated with the Use of Carvedilol and Metoprolol in Routine Clinical Practice

BackgroundLarge randomized trials have reported mixed results regarding the risk of bradycardia between metoprolol and carvedilol. We compared the incidence of emergent bradycardia (measured by an emergency department visit or hospitalization due to bradycardia) for patients initiating metoprolol and carvedilol.MethodsAdult beneficiaries of Medi-Cal, the State of California Medicaid program, without a diagnosis of bradycardia who initiated metoprolol or carvedilol between May 1, 2004, and November 1, 2009, were included. Cox proportional hazard regression analysis was performed to model the time to first occurrence of emergent bradycardia after initiation of the study drugs as a dependent variable and the study drug (metoprolol vs carvedilol) as the primary predictor with adjustments for total daily metoprolol-equivalent dose, formulations, and use of nonstudy drugs as time-varying covariates, as well as demographics and comorbidities.ResultsAmong 38,186 subjects, 77.7% initiated metoprolol and 22.3% initiated carvedilol. The incidence of emergent bradycardia was low and comparable between the drugs (18.1 per 1000 person-years using metoprolol vs 17.7 per 100 person-years using carvedilol; unadjusted hazard ratio, 1.07; 95% confidence interval, 0.76-1.49). However, carvedilol users had substantially different population characteristics compared with metoprolol users. After adjustments for demographics, comorbidities, metoprolol-equivalent dose, formulations, and use of nonstudy drugs, initiation of metoprolol was associated with an increased risk of emergent bradycardia compared with that of carvedilol (adjusted hazard ratio, 1.64; 95% confidence interval, 1.14-2.36).ConclusionsInitiation of metoprolol is associated with an increased risk of emergent bradycardia compared with carvedilol, although the overall incidence of emergent bradycardia is low in routine clinical practice.     

Pharmacokinetics and Pharmacodynamics of Beta Blockers in Heart Failure

Although beta-blockers have been used for nearly three decades in the management of heart failure, only recent randomized clinical trials have demonstrated substantial benefit in reducing morbidity and mortality. Carvedilol, metoprolol succinate and bisprolol have evidence supporting their use in heart failure while other beta blockers either lack evidence supporting their use or have not been shown to be useful in heart failure. The only currently approved beta-blockers in the U.S. for heart failure are metoprolol succinate and carvedilol.Beta-blockers differ in their pharmacokinetic and pharmacodynamic properties. It should not be assumed that potential benefit in heart failure is a class effect since differences in the half-life, volume of distribution, protein binding, and route of elimination may give rise to differences in duration of beta blockade and potential drug interactions. Furthermore, pharmacodynamic differences exist because of selectivity for beta(1), beta(2) or alpha(1) adrenoreceptor blockade among the beta-blockers. Receptor kinetics also differ among the beta-blockers and this may influence the extent and duration of beta and alpha blockade across the category.Carvedilol is an inherently long-acting beta-blocker while the duration of beta blockade for metoprolol is dependent on the salt and formulation, which is used. Metoprolol tartrate is a short-acting form of metoprolol while metoprolol succinate is a longer acting salt and the commercially available product is designed as a once daily formulation. A recently published trial, the Carvedilol or Metoprolol European Trial (COMET) tested carvedilol given twice daily versus metoprolol tartrate given twice daily in patients with chronic heart failure. Although carvedilol reduced all cause mortality when compared with metoprolol tartrate, extrapolation to similar findings with metoprolol succinate are not possible since the pharmacokinetic and pharmacodynamic effects of these two formulations are different. Furthermore, the dosing of metoprolol tartrate in COMET may have been inadequate based on prior studies. Additional studies are needed to compare carvedilol directly to metoprolol succinate before concluding inequivalency exists for these two beta-blockers in heart failure.     

Differential effect of beta-blocker therapy on insulin resistance as a function of insulin sensitizer use: results from GEMINI.

AIMS: To determine whether the beneficial effects of carvedilol on insulin resistance (IR) are affected by the concomitant use of insulin sensitizers [thiazolidinediones (TZDs) and metformin]. METHODS: Changes in HbA1c and homeostasis model assessment-insulin resistance (HOMA-IR) were assessed over 5 months, comparing carvedilol with metoprolol tartrate according to insulin sensitizer (TZDs and metformin) use. RESULTS: In TZD/metformin users, carvedilol patients showed a 5.4% decrease [95% confidence interval (CI) -11.9, 1.6; P = 0.13] and metoprolol tartrate patients showed a 2.8% decrease (95% CI -8.5, 3.2; P = 0.35) in HOMA-IR. The -2.6% difference between treatments was not significant (95% CI -10.7, 6.2; P = 0.55). In contrast, those not taking TZD/metformin experienced a 13.2% increase in HOMA-IR on metoprolol tartrate (95% CI 3.2, 24.1; P < 0.01) and a 4.8% decrease in HOMA-IR on carvedilol (95% CI -14.6, 6.0; P = 0.37), with a significant treatment difference of -15.9% favouring carvedilol (95% CI -26.6, -3.6; P = 0.01). There was no significant treatment interaction for the use of TZD/metformin and HbA1c. A statistically significant treatment difference was observed for HbA1c after 5 months favouring carvedilol after adjusting for insulin sensitizer use (-0.11%, 95% CI -0.214, -0.009; P = 0.03). CONCLUSIONS: In patients with diabetes and hypertension not taking insulin sensitizers, the use of metoprolol tartrate resulted in a worsening of insulin resistance, an effect not seen with carvedilol. However, in TZD/metformin users the difference between the beta-blockers was not statistically significant.     

Randomized, double-blind comparison of acute beta1-blockade with 50 mg metoprolol tartrate vs 25 mg carvedilol in normal subjects

Differential efficacy of immediate-release metoprolol tartrate and carvedilol in the treatment of congestive heart failure remains a subject of ongoing debate. The degree of beta1-blockade can be assessed by percentage reduction of exercise heart rate. Twelve healthy subjects underwent symptom-limited cardiopulmonary exercise testing repeated weekly and 2 hours after randomized, double-blind administration of 50 mg metoprolol tartrate vs 25 mg carvedilol. Baseline heart rate, heart rate at 40% and 70% peak O2 consumption, and maximal exercise were significantly blunted more by metoprolol tartrate than by carvedilol (P<.05 for all). Peak O2 consumption was significantly reduced by metoprolol tartrate (P<.03) but not by carvedilol (P=.054). The change in O2 consumption was significantly correlated with the degree of beta1-blockade (r =0.45; P<.05). In healthy subjects, a higher degree of beta1-blockade is achieved with 50 mg metoprolol tartrate compared with 25 mg carvedilol.     

Influence of heart rate, blood pressure, and beta-blocker dose on outcome and the differences in outcome between carvedilol and metoprolol tartrate in patients with chronic heart failure: results from the COMET trial.

AIMS: We studied the influence of heart rate (HR), systolic blood pressure (SBP), and beta-blocker dose on outcome in the 2599 out of 3029 patients in Carvedilol Or Metoprolol European Trial (COMET) who were alive and on study drug at 4 months after randomization (time of first visit on maintenance therapy). METHODS AND RESULTS: By multivariable analysis, baseline HR, baseline SBP, and their change after 4 months were not independently related to subsequent outcome. In a multivariable analysis including clinical variables, HR above and SBP below the median value achieved at 4 months predicted subsequent increased mortality [relative risk (RR) for HR>68 b.p.m. 1.333; 95% confidence intervals (CI) 1.152-1.542; P<0.0001 and RR for SBP>120 mmHg 0.78; 95% CI 0.671-0.907; P<0.0013]. Achieving target beta-blocker dose was associated with a better outcome (RR 0.779; 95% CI 0.662-0.916; P<0.0025). The superiority of carvedilol as compared to metoprolol tartrate was maintained in a multivariable model (RR 0.767; 95% CI 0.663-0.887; P=0.0004) and there was no interaction with HR, SBP, or beta-blocker dose. CONCLUSION: Beta-blocker dose, HR, and SBP achieved during beta-blocker therapy have independent prognostic value in heart failure. None of these factors influenced the beneficial effects of carvedilol when compared with metoprolol tartrate at the pre-defined target doses used in COMET.     

Clinical trials update from the European Society of Cardiology Heart Failure meeting: COMET,COMPANION, Tezosentan and SHAPE

This article continues a series of reports on recent research developments in the field of heart failure. Key presentations made at the European Society of Cardiology Heart Failure Update meeting, held in Strasbourg, France are described. The COMET study showed a 17% relative risk reduction in all-cause mortality with carvedilol compared with metoprolol tartrate. The COMPANION study, as previously reported, showed encouraging results for the use of cardiac resynchronisation and implantable defibrillator therapy in patients with heart failure, but further evidence is awaited. The results of a study on tezosentan suggest that lower doses of this endothelin antagonist may be clinically more effective with fewer adverse effects compared with higher doses. The SHAPE survey of heart failure awareness in Europe identified a need for further heart failure education amongst the public, patients, their carers and primary care physicians.     

Comparison of carvedilol and metoprolol on serum lipid concentration in diabetic hypertensive patients

Context: Vasoconstricting beta‐blocker use is associated with a reduction in HDL cholesterol, higher triglyceride, total cholesterol and LDL cholesterol levels, whereas carvedilol, a vasodilating beta‐blocker, has not been associated with these effects. Objective: To compare in a randomized, double‐blind study, the effects of the beta 1‐blocker metoprolol tartrate with the combined alpha 1, beta‐blocker carvedilol on serum lipid concentrations. Methods: A prospective randomized, double‐blind, parallel‐group trial compared the effects of carvedilol and metoprolol on total cholesterol, triglycerides, calculated LDL, HDL and non‐HDL cholesterol levels at baseline and after 5 months of therapy as a secondary objective in the Glycemic Effects in Diabetes Mellitus: Carvedilol‐Metoprolol Comparison in Hypertensive (GEMINI) study. In this study, 1235 participants with type 2 diabetes and hypertension who were receiving renin‐angiotensin system blockers were randomized either to carvedilol, receiving 6.25–25 mg twice daily, or to metoprolol tartrate, receiving 50–200 mg twice daily. If needed, hydrochlorothiazide and a dihydropyridine calcium channel blocker were added to achieve blood pressure goals. Results: In the metoprolol tartrate group, triglycerides and non‐HDL cholesterol increased and both the LDL and the HDL cholesterol levels decreased. In the carvedilol group, total LDL and HDL cholesterol decreased, non‐HDL cholesterol was unchanged and triglycerides increased. Comparing the carvedilol and metoprolol tartrate groups, there was no statistically significant difference in LDL and HDL cholesterol levels, but there was a significantly greater decreases with carvedilol in total cholesterol [?2.9%, 95% confidence interval (CI) ?4.60 to ?1.15, p < 0.001], triglycerides (?9.8%, 95% CI ?13.7, ?5.75%, p < 0.001) and non‐HDL cholesterol (?4.03%, 95% CI ?6.3 to ?1.8, p < 0.0006). At the end of the study, significantly more participants in the metoprolol tartrate group had had initiation of statin therapy or the statin dose increased than those in the carvedilol group (11 vs. 32%, p = 0.04). Conclusions: In patients with type 2 diabetes currently receiving a renin‐angiotensin blocker, compared with metoprolol tartrate, the addition of carvedilol for blood pressure control resulted in a significant decrease in triglyceride, total cholesterol and non‐HDL cholesterol levels. The use of metoprolol resulted in a significantly greater rate of initiation of statin therapy or an increase in the dose of existing statin therapy when compared with carvedilol utilization.     

Do metoprolol and carvedilol have equivalent effects on diurnal heart rate in patients with chronic heart failure?

BACKGROUND: Carvedilol exerted a greater reduction in mortality than metoprolol tartrate in the Carvedilol or Metoprolol European Trial (COMET). However, it is unclear if the degree and time course of beta1-blockade during a 24-h period was similar with each agent at the doses used. Therefore we analyzed 24-h ECG Holter recordings from a study which compared the long-term clinical efficacy of metoprolol tartrate to carvedilol in chronic heart failure patients using the same dosing regimen as in COMET. METHODS AND RESULTS: Fifty-one patients with chronic heart failure with a mean LVEF 26+/-1.8% were randomized in a double-blind fashion to receive metoprolol tartrate 50 mg bid or carvedilol 25 mg bid. 24-h ECG monitoring (Holter) was performed at baseline, 12 weeks and 1 year. Adequate quality recordings for analysis were obtained from 43 subjects at baseline, 42 at 12 weeks and 29 subjects at 1 year. Both drugs produced a fall in average 24-h heart rate from baseline at 12 weeks and at 1 year: metoprolol 88+/-3 to 71+/-2 and 69+/-3 bpm; carvedilol 83+/-3 to 70+/-2 and 70+/-3 bpm respectively (all p<0.001). The pattern of suppression of heart rate during the 24-h period was similar for both drugs. CONCLUSION: Metoprolol tartrate 50 mg bid and carvedilol 25 mg bid had similar effects on 24-h heart rate. This result suggests that the degree of beta1-blockade produced by these two drugs in these doses is comparable and the superior survival effect of carvedilol compared to metoprolol seen in COMET is likely to be due to actions of carvedilol other than beta1-blockade.     

Health care and medication costs and use among older adults with heart failure

BACKGROUND: Heart failure disproportionately affects older adults for whom multiple medications are prescribed to prevent exacerbations and hospitalization. To target interventions effectively, it is important to understand the association of medication acquisition with health care utilization and costs. METHODS: We used electronic medical records from an urban public health care system to identify patients aged >/=50 years who had a diagnosis of heart failure. We assessed the association between inappropriate or appropriate medication supplies and hospitalization and costs using multivariable analyses that adjusted for demographic characteristics, prior health care use, health status, and insurance status. RESULTS: Total health care costs for treating 1554 patients with heart failure from 1996 to 2000 were 36.6 million dollars (in 2000 dollars). Less than a third of patients received appropriate medication supplies (between 90% and 110% of the supplies needed) annually. Compared with patients with appropriate supplies, the odds of hospitalization were greater among those with undersupplies (odds ratio [OR] = 3.1; 95% confidence interval [CI]: 2.3 to 4.2; P <0.0001) or oversupplies (OR = 2.0; 95% CI: 1.7 to 2.4; P <0.0001). Total costs were 25% higher for patients with undersupplies (95% CI: 8% to 46%; P = 0.004) and 18% higher for those with oversupplies (95% CI: 7% to 30%; P = 0.0009) than for those with appropriate supplies. CONCLUSION: Among adults with heart failure, inappropriate medication supplies were associated with increased hospitalization and higher costs. Monitoring medication supplies from electronic medical records may be a useful component of programs aiming to improve care while managing costs.     

Association of diastolic dysfunction and outcomes in ambulatory older adults with chronic heart failure

BACKGROUND: Studies of patients with heart failure and preserved systolic function report variable outcomes compared with those of patients with impaired systolic function. OBJECTIVE: To study outcomes of diastolic (vs systolic) heart failure in older adults with chronic heart failure. METHODS: Patients were ambulatory chronic heart failure patients 65 years and older (N = 3984) who participated in the Digitalis Investigation Group trial. Of these, 3405 had systolic heart failure (ejection fraction < or =45%) and 579 had diastolic heart failure (ejection fraction >45%). By using a 1:1 match by age, sex, and race, 571 diastolic heart failure patients were matched with 571 systolic heart failure patients. Kaplan-Meier survival analyses and multivariable Cox proportional hazard analyses were used to estimate the risk of various outcomes between the groups. RESULTS: During the 1044 mean days of follow up, compared with 41% of systolic heart failure patients, 27% of diastolic heart failure patients died (p <.001). Presence of diastolic heart failure was independently associated with a 27% decreased risk of all-cause death (adjusted hazard ratio [HR] = 0.73; 95% confidence interval [CI], 0.58-0.91) and a 32% reduction in risk of hospitalization due to heart failure (adjusted HR = 0.68; 95% CI, 0.52-0.88). There was no difference in overall hospitalization between the groups. However, compared with systolic heart failure patients, diastolic heart failure patients were more likely to be hospitalized due to noncardiovascular causes (adjusted HR = 1.38; 95% CI, 1.02-1.88). CONCLUSIONS: Older adults with diastolic heart failure had lower risk of all-cause mortality and heart failure-related hospitalizations, but higher risk of noncardiovascular hospitalization.     

Usefulness of noninvasive estimate of pulmonary vascular resistance to predict mortality, heart failure, and adverse cardiovascular events in Patients With stable coronary artery disease (from the Heart and Soul Study)

Pulmonary vascular resistance (PVR) is an important hemodynamic variable that affects prognosis and therapy in a wide range of cardiovascular and pulmonary conditions. We sought to determine whether a noninvasive estimate of PVR predicts adverse outcomes in patients with stable coronary artery disease. Using Doppler echocardiography we measured the estimated PVR (defined as the ratio of the tricuspid regurgitant velocity [TRV] to the velocity-time integral [VTI] of the right ventricular outflow tract [RVOT]) in 795 ambulatory patients with stable coronary artery disease. Participants were categorized by quartiles of the TRV/VTI RVOT ratio. Hazard ratios (HRs) and 95% confidence intervals were calculated for all-cause mortality, heart failure hospitalization, and adverse cardiovascular events (cardiovascular death, nonfatal myocardial infarction, or stroke). After 4.3 years of follow-up there were 161 deaths, 44 deaths from cardiovascular causes, 103 heart failure hospitalizations, and 120 adverse cardiovascular events. Compared with patients in the lowest TRV/VTI RVOT quartile, those in the highest quartile were at increased risk of all-cause mortality (unadjusted HR 1.8, 95% confidence interval 1.3 to 2.5), heart failure hospitalization (unadjusted HR 2.9, 95% confidence interval 2.0 to 4.3), and adverse cardiovascular events (unadjusted HR 2.0, 95% confidence interval 1.4 to 2.9). After multivariate adjustment, patients in the highest quartile were at increased risk of heart failure hospitalizations (adjusted HR 2.5, 95% confidence interval 1.3 to 4.7). In conclusion, a noninvasive estimate of PVR (TRV/VTI RVOT ratio) predicts mortality, heart failure hospitalization, and adverse cardiovascular events in patients with stable coronary artery disease.     

Cost-effectiveness of beta-blocker therapy with metoprolol or with carvedilol for treatment of heart failure in Canada

OBJECTIVE: The purpose of this study was to estimate the cost-effectiveness of beta-blocker therapy with either metoprolol or carvedilol in addition to conventional therapy for patients with heart failure (HF) in Canada. DESIGN: A Markov simulation was used to estimate the costs and life expectancy for treating patients with conventional therapy alone and with the addition of metoprolol or carvedilol. Although carvedilol has been marketed in Canada since 1999, metoprolol succinate has yet to be marketed there, so the price is unknown. Therefore we input a Canadian price based on the price ratio of the 2 drugs in the United States. RESULTS: For subjects aged 60 years at HF onset, the expected years of life are 4.53 years for those treated with conventional therapy alone, 5.70 years for those who receive conventional therapy plus metoprolol, and 6.21 years for those who receive conventional therapy plus carvedilol. The expected costs (in 1999 Canadian dollars) are $8,989, $13,833, and $18,114, respectively. This yields incremental cost-effectiveness ratios (ICERs) for metoprolol relative to conventional therapy alone of $4,140 per life-year gained, and for carvedilol relative to metoprolol, the ICER is $8,394 per life-year gained. CONCLUSIONS: In addition to conventional therapy with furosemide and angiotensin converting enzyme inhibitors, treatment with either metoprolol or carvedilol confers a survival benefit that is attractive from a cost-effectiveness point of view. Until better information becomes available, it is not possible to distinguish between the two beta-blockers on the basis of cost-effectiveness. This means that the choice of beta-blockers for HF should be based largely on clinical considerations because both beta-blockers prolong life at relatively low cost.