Influence of beta-blockers on mortality in chronic heart failure

OBJECTIVE: To briefly discuss the pathophysiology of heart failure and the rationale for the use of beta-blockers in the treatment of chronic heart failure. Key morbidity reduction trials are briefly mentioned, and recent mortality reduction trials are reviewed. General recommendations regarding the use of beta-blockers in heart failure are also included to guide clinical practice. STUDY SELECTION/DATA EXTRACTION: Randomized, placebo-controlled clinical trials and meta-analyses evaluating mortality reduction with beta-blockers in the treatment of heart failure were identified using a MEDLINE search from January 1993 to March 2000. Abstracts and presented results from recent scientific meetings were also considered. DATA SYNTHESIS: Beta-blockers have been shown to decrease hospitalization for worsening heart failure, decrease the need for heart transplant, improve New York Heart Association (NYHA) functional class, and increase left-ventricular ejection fraction. A mortality benefit has recently been demonstrated for patients with chronic heart failure. Carvedilol, bisoprolol, and controlled-release/extended-release metoprolol decreased the risk of dying by 65%, 34%, and 34%, respectively, in patients with primarily NYHA functional class II or III and systolic dysfunction. The benefit of these agents in patients with class IV heart failure or determining whether one agent has an advantage over another is being investigated in ongoing clinical trials. CONCLUSIONS: Several beta-blockers have demonstrated mortality reduction in the treatment of patients with NYHA functional class II or III heart failure and systolic dysfunction. Beta-blockers should be considered in these patients when they are clinically stable and taking the current standard therapy of a diuretic plus an angiotensin-converting enzyme inhibitor or other vasodilator agent.     

Spironolactone use in patients with heart failure

BACKGROUND: The addition of spironolactone, an aldosterone antagonist, to standard therapy can reduce the risk of both morbidity and mortality in patients with severe heart failure. OBJECTIVE: To evaluate the use of spironolactone in class III and IV heart failure patients in four urban teaching hospitals. METHODS: We conducted a concurrent medical record review of 163 patients with documented heart failure admitted to a general medicine service over a 5-week period. Data retrieved included patient demographics, heart failure class, left ventricular ejection fraction, spironolactone contraindications, spironolactone use, dose and frequency, and other heart failure medication use, dose and frequency. All data reflected patients' baseline status. RESULTS: Our patient population was 80% white people, 61% male, with a mean age of 70 years (35-99). A total of 114 had class III or IV heart failure (70%). Angiotensin-converting enzyme inhibitors or appropriate alternative were prescribed in 117 (72%) patients, whereas beta-blockers were used in 121 (74%) patients. Fifty-seven patients met spironolactone ideal candidate criteria. Of these, eight (14%) were appropriately prescribed spironolactone. CONCLUSIONS: Three years after publication of the Randomized Aldactone Evaluation Study, spironolactone is underutilized in the treatment of heart failure. Results of this study indicated that the majority of patients in class III or IV heart failure were not prescribed spironolactone. Improvements in spironolactone prescribing are needed.     

Poster Session 2–3: Cardiac Resynchronization Therapy Monday, April 3, 2006, 4:00–5:30pm

Dr. Gabe Bleeker ¹ , Martin Schalij ¹ , Eduard Holman ¹ , Paul Steendijk ¹ , Ernst van der Wall ¹ , Jeroen Bax ^{1   1} Cardiology, Leiden University Medical Center, Leiden, The Netherlands
Background: Cardiac resynchronization therapy (CRT) is beneficial in selected patients with moderate-to-severe heart failure (New York Heart Association (NYHA) class III/IV). Patients with mildly symptomatic heart failure (NYHA class II) are currently not eligible for CRT and potential beneficial effects in these patients are not well studied. Methods: Fifty consecutive patients with NYHA class II heart failure and 50 consecutive NYHA class III/IV patients (control group) were prospectively included. All patients had left ventricular ejection fraction (LVEF) ≤ 35% and QRS duration >120 ms. The effects of CRT in NYHA class II patients were compared to results obtained in the control group. Results: The severity of baseline LV dyssynchrony was comparable between patients in NYHA class II vs NYHA class III/IV (83 ± 49 ms vs 96 ± 51 ms, ns), and resynchronization was achieved in both groups. NYHA class II patients showed a significant improvement in LVEF (from 25 ± 7% to 33 ± 10%, P < 0.001) and reduction in LV end-systolic volume (from 168 ± 55 ml to 132 ± 51 ml, P < 0.001) following CRT, similar to patients in NYHA class III/IV. In addition, only 8% of NYHA class II patients showed progression in heart failure symptoms. Conclusions: CRT has comparable effects in patients with NYHA class II and NYHA class III/IV heart failure in terms of LV resynchronization, improvement in LVEF, and LV reverse remodeling.     

Use of erythropoietin in heart failure management

OBJECTIVE: To review the use of erythropoietin for anemia in heart failure (HF). DATA SOURCES: Peer-reviewed articles in MEDLINE (1966-June 2004) were identified and citations from available articles were reviewed using the search terms anemia, erythropoietin, and heart failure. DATA SYNTHESIS: Anemia worsens HF prognosis. Clinical studies in patients with New York Heart Association Class III/IV HF who had hemoglobin <12 mg/dL and were refractory to maximal medical management showed that erythropoietin improves symptoms. Larger scale studies with mortality endpoints are required to confirm the benefits. CONCLUSIONS: In selected patients with severe, chronic HF, erythropoietin may be considered for functional improvement. However, routine use of this treatment strategy is not recommended until more data are available.     

Recent advances in cardiac resynchronization therapy

Cardiac resynchronization therapy (CRT) is an integral component of modern heart failure therapy for patients with severe symptoms (New York Heart Association [NYHA] class III or IV), a reduced ejection fraction (≤ 35%), and a wide QRS complex (> 120 ms). Results from recent trials have provided ample evidence that CRT may also reduce morbidity and mortality in patients with mildly symptomatic heart failure (NYHA class II). As a result, the 2010 European guidelines now recommend CRT for this patient population (level of evidence I, class A). This review summarizes and critically evaluates the landmark Resynchronization Reverses Remodeling in Systolic Left Ventricular Dysfunction (REVERSE), Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy (MADIT-CRT), and Resynchronization/Defibrillation for Ambulatory Heart Failure Trial (RAFT) studies, which comprise the suite of randomized controlled trials available today on this matter. Furthermore, we discuss the rationale and available evidence for other emerging indications for CRT, including its use in patients with a mildly reduced left ventricular ejection fraction (> 35%), in those with a narrow QRS complex (≤ 130 ms), or in patients with concomitant bradyarrhythmic pacemaker indications.     

The benefits of biventricular pacing in heart failure patients with narrow QRS, NYHA class II and right ventricular pacing

OBJECTIVE: To identify subgroups of heart failure patients who might benefit from biventricular pacing. BACKGROUND: Cardiac resynchronization therapy (CRT) improves the quality of life, New York Heart Association (NYHA) functional class, and exercise capacity and decreases hospitalizations for heart failure for patients who have severe heart failure and a wide QRS. It is unclear if other populations of heart failure patients would benefit from CRT. METHODS: One hundred forty-four consecutive heart failure patients who underwent CRT and completed 3 months of follow-up were reviewed. Demographic, echocardiographic, electrocardiographic, and clinical outcome data were analyzed to assess the relationship of functional class and QRS duration before device implantation to postimplant outcomes. RESULTS: There were 20, 88, and 36 patients in NYHA functional class II, III, and IV, respectively. Thirty-four patients had right ventricular pacing and another 29 patients had a QRS duration < or = 150 ms. Patients who were in NYHA functional class II at baseline had significant improvement in left ventricular ejection fraction and indices of left ventricular remodeling after CRT. Similar significant findings were seen in the subgroup with right ventricular pacing at baseline after CRT. However, in the subgroup with a narrow QRS duration, there were no significant changes in the indices of left ventricular remodeling or in the NYHA functional class and there was a significant increase in the QRS duration. For the study cohort as a whole, an improvement in NYHA functional class after CRT correlated with a significant decrease in adverse clinical outcomes. CONCLUSIONS: Heart failure patients who were in NYHA functional class II and those with right ventricular pacing appeared to benefit from CRT.     

Renal, but not systemic, hemodynamic effects of dopamine are influenced by the severity of congestive heart failure

OBJECTIVE: To determine whether the short-term systemic and renal hemodynamic response to dopamine is influenced by clinical severity of congestive heart failure. DESIGN: Effects of increasing doses of dopamine were assessed in patients consecutively admitted for acutely decompensated congestive heart failure. SETTING: Intensive care unit. PATIENTS: We enrolled 16 congestive heart failure patients stratified by clinical severity (New York Heart Association [NYHA] class III, n = 8; NYHA class IV, n = 8) and two additional NYHA class III patients as controls. INTERVENTIONS: Measurements were carried out throughout five 20-min experimental periods: baseline, dopamine infusion at 2, 4, and 6 microg x kg(-1) x min(-1), and recovery. Controls received a similar amount of saline. MEASUREMENTS AND MAIN RESULTS: Systemic and renal hemodynamics were determined respectively by right cardiac catheterization and radioisotopes (iodine 131-labeled hippuran and iodine 125-labeled iothalamate clearance). The peak increase in heart rate and cardiac index occurred at a dopamine dose of 4-6 microg x kg(-1) x min(-1). The dose-response relation was similar in NYHA classes III and IV. Improvement in effective renal plasma flow and glomerular filtration rate, peaking at 4 microg x kg(-1) x min(-1), was more rapid and marked in NYHA class III than class IV patients, in whom the renal fraction of cardiac output failed to increase. The systemic and renal effects of dopamine were independent of age. No change occurred in controls. CONCLUSIONS: The dose of dopamine producing an optimal improvement of systemic and renal hemodynamics in congestive heart failure is higher than usually reported. A greater clinical severity of congestive heart failure impairs the renal effects of dopamine, probably through a selective loss in renal vasodilating capacity.     

The Management of Patients with Atrial Fibrillation and Dronedarone’s Place in Therapy

The pharmacologic management of atrial fibrillation (AF) includes rate and rhythm control strategies. Antiarrhythmic agents (eg, amiodarone, flecainide, and propafenone) are limited by serious toxicities (including proarrhythmic effects and pulmonary toxicity), which may lead to a reduced net clinical efficacy of rhythm control strategies. Dronedarone, a new antiarrhythmic agent, is effective in the maintenance of sinus rhythm. Dronedarone has also been shown to reduce ventricular rate and the incidence of hospitalization due to cardiovascular events. Dronedarone is recommended by the 2011 American College of Cardiology Foundation/American Heart Association/Heart Rhythm Society guidelines update for the management of AF patients with no or minimal heart disease, coronary artery disease, and hypertension with no left ventricular hypertrophy. Dronedarone is contraindicated in patients with New York Heart Association (NYHA) class IV heart failure or NYHA class II–III heart failure with a recent decompensation requiring hospitalization or referral to a specialized heart failure clinic.     

Treatment of edema

Edema is the result of an imbalance in the filtration system between the capillary and interstitial spaces. The kidneys play a key role in regulating extracellular fluid volume by adjusting sodium and water excretion. Major causes of edema include venous obstruction, increased capillary permeability, and increased plasma volume secondary to sodium and water retention. A systematic approach is warranted to determine the underlying diagnosis. Treatment includes sodium restriction, diuretic use, and appropriate management of the underlying disorder. Leg elevation may be helpful in some patients. Loop diuretics often are used alone or in combination. In patients with New York Heart Association class III and IV congestive heart failure, spironolactone has been found to reduce morbidity and mortality rates. In patients with cirrhosis, ascites is treated with paracentesis and spironolactone. Dihydropyridine-induced edema can be treated with an angiotensin-converting enzyme inhibitor or angiotensin-receptor blocker. Lymphedema occurs when a protein-rich fluid accumulates in the interstitium. Compression garments and range-of-motion exercises may be helpful in patients with this condition.     

Probrain Natriuretic Peptide for assessment of efficacy in heart failure treatment

N-terminal probrain natriuretic peptide (NT-proBNP) is elevated in patients with heart failure. Numerous clinical trials have evaluated the efficacy of spironolactone in heart failure; however, no studies have directly examined the effects of spironolactone treatment on NT-proBNP level. This study investigated whether NT-proBNP levels decrease with daily spironolactone treatment. The study consisted of 117 adult patients with heart failure. All participants were divided into 3 groups, class I, class II, and class III, according to the New York Heart Association classification system. Patients were randomly assigned to receive spironolactone or were treated with another drug, other than spironolactone, as placebo. NT-proBNP plasma samples were taken at baseline and after 6 mo of treatment. A total of 62 patients were treated with daily spironolactone; 55 patients were followed with available treatment without spironolactone. The baseline demographic and laboratory parameters were similar for patients in all groups. At the end of 6 mo, spironolactonetreated patients had significantly lower NT-proBNP levels and significantly better ejection fractions than did patients in all New York Heart Association classes who were not treated with spironolactone. Results suggest that spironolactone decreases plasma NT-proBNP concentrations, and that the measurement of plasma NT-proBNP levels may be helpful in assessing therapeutic efficacy in patients who are treated for heart failure.     

Different β-adrenoceptor-effector coupling in human ventricular and atrial myocardium

To examine whether the downregulation of beta-adrenoceptors is accompanied by reduced beta-adrenoceptor-mediated effects in atrial as well as in ventricular myocardium, we investigated the beta-adrenoceptor-effector coupling in atrial and papillary muscle strips from patients with terminal heart failure (heart transplantation because of dilated cardiomyopathy; New York Heart Association Class IV, NYHA IV) and moderate heart failure (mitral valve replacement, NYHA II-III) and in tissue from non-failing hearts. The isometric force of contraction induced by isoprenaline (0.001-1 mumoll-1) or Ca2+ (1.8-15 mmoll-1) in atrial muscle strips and papillary muscle strips has been measured. We also examined the number of beta-adrenoceptors in both tissues by radioligand binding. The degree of heart failure affected neither the potency (EC50: control: 0.01 (0.001-0.082) mumoll-1; NYHA II-III: 0.01 (0.001-0.125) mumoll-1; NYHA IV: 0.01 (0.001-0.160) mumoll-1) nor the efficacy (NYHA IV: 7.8 +/- 1.0 mN; NYHA II-III: 6.1 +/- 0.7 mN; control: 7.7 +/- 0.9 mN) of the isoprenaline-mediated increase in force of contraction in atrial muscle strips. This is in spite of a reduced number of beta-adrenoceptors in moderately (NYHA II-III) and terminally (NYHA IV) failing atrial myocardium compared to non-failing atrial myocardium (P less than 0.05). In contrast, in papillary muscle strips increasing degrees of heart failure were accompanied by a progressive reduction of the isoprenaline-mediated increase in force of contraction (P less than 0.05) as well as by a progressive decrease of beta-adrenoceptors (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Reducing readmissions for congestive heart failure

Hospital admission for congestive heart failure is extremely common and quite expensive, although it is frequently preventable. New drugs and therapies have been reported to reduce admissions, decrease morbidity and mortality, and improve the quality of life for these patients. Patients with an ejection fraction less than 40 percent (decreased systolic function) should be treated with medication to improve symptoms and prevent progression of heart failure. Angiotensin-converting enzyme (ACE) inhibitors are a mainstay of treatment in patients who can tolerate them; in patients who cannot take these drugs, angiotensin II receptor blocking agents offer an alternative. Patients with New York Heart Association class II or III heart failure should also receive a beta blocker (metoprolol, carvedilol or bisoprolol). Recent research has shown that treatment with spironolactone improves mortality and hospital readmission rates. An exercise program should also be recommended for all patients with heart failure unless their condition is unstable.     

Extended-release metoprolol succinate in chronic heart failure

OBJECTIVE: To review the pharmacology, pharmacokinetics, efficacy, and tolerability of extended-release (ER) metoprolol succinate and its role in the management of chronic heart failure. DATA SOURCES: A MEDLINE search of English-language literature (1990-October 2002) was conducted using congestive heart failure and metoprolol CR/XL or metoprolol CR/ZOK as search terms to identify pertinent studies. STUDY SELECTION/DATA EXTRACTION: All of the articles identified from the data sources were evaluated, with priority given to randomized, double-blind, placebo-controlled studies. DATA SYNTHESIS: ER metoprolol succinate is a controlled-release tablet designed to produce even and consistent beta(1)-blockade throughout the 24-hour dosing interval, with less fluctuation in metoprolol plasma concentrations compared with immediate-release metoprolol. Three randomized, double-blind, placebo-controlled trials have evaluated the efficacy of ER metoprolol succinate in the treatment of patients with chronic heart failure. The MERIT-HF (Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure) study, the largest of these trials and the largest randomized mortality trial with beta-blockers in heart failure to date, demonstrated that ER metoprolol succinate reduced the relative risk of all-cause mortality by 34% versus placebo. Furthermore, the relative risk of the combined endpoint of mortality plus all-cause hospitalizations was reduced by 19% and sudden death was reduced by 41%. The benefits of therapy were evident in various patient subgroups, including elderly patients and those with diabetes mellitus. ER metoprolol succinate was generally well tolerated, with a similar proportion of patients discontinuing therapy due to adverse events relative to placebo (9.8% and 11.7%, respectively). CONCLUSIONS: ER metoprolol succinate therapy provides substantial mortality and morbidity benefits in patients with New York Heart Association class II and III heart failure who are stabilized on angiotensin-converting enzyme inhibitors and diuretics. ER metoprolol succinate is administered once daily, is well tolerated, and provides consistent beta(1)-blockade over the 24-hour dosing interval.     

Adaptation of guidelines for the treatment of chronic heart failure in a specialized heart failure clinic

BACKGROUND: Chronic heart failure is associated with high mortality and morbidity. In spite of a number of trials showing significant improvement in survival and reduction in hospitalization for patients who received ACE inhibitors/AT1 receptor antagonists (ACEI/ARB), beta-blockers and spironolactone, and notwithstanding the recommendations of national and international guidelines for the management of heart failure, substantial proportions of patients are not receiving this treatment. The aim of our study was to analyse 1. the efficiency of a specialized heart failure clinic in translating guidelines into clinical practice, and 2. the effect of optimized neurohormonal therapy on patient outcome. METHODS AND RESULTS: The data of patients with systolic heart failure and an ejection fraction < or = 35% referred to the Innsbruck Heart Failure and Transplantation Program between February 2000 and October 2001 were analysed. The number of patients treated with ACEI/ARB, beta-blocker and spironolactone increased significantly in the investigation period (p < 0.05). Equivalent dose for captopril and bisoprolol per patient developed from 66.4 +/- 42.8 to 96.5 +/- 41.9 mg (p < 0.001) and from 2.0 +/- 2.9 to 6.3 +/- 4.0 mg (p < 0.001), respectively. Optimization of neurohormonal therapy was associated with a significant improvement in NYHA class (2.5 +/- 0.8 vs. 1.9 +/- 0.8; p < 0.001). No relevant changes were noticed for blood pressure, serum creatinine, serum sodium, and serum potassium, whereas heart rate dropped significantly. Kaplan-Meier curves examining the time to first event of the combined end point of mortality and hospitalisation for worsening heart failure revealed a clear benefit for patients on combined neurohormonal therapy (ACEI/ARB and beta-blocker, n = 86) when compared with patients on neurohormonal monotherapy (ACEI/ARB or beta-blocker, n = 35), (p < or = 0.001). Differences remained significant (p = 0.022) after adjusting for NYHA class at referral, age, gender, etiology of the underlying cardiomyopathy, ejection fraction, and atrial fibrillation in Cox regression analysis. CONCLUSION: Guidelines for the management of chronic heart failure patients can be translated efficiently into clinical practice by a specialized heart failure clinic. Optimization of therapy is associated with an improvement in functional status and a decrease in mortality or hospitalization for worsening heart failure. Therefore the nationwide installation of specialized heart failure clinics is required.     

Use of beta-blockers in congestive heart failure

While beta-adrenergic blockers have been used for decades in a variety of cardiovascular illnesses, they have traditionally been avoided in chronic heart failure. In spite of significant advances in management, mortality in patients suffering from heart failure remains unacceptably high and new therapies are urgently needed. Recently, several large clinical trials have shown a significant reduction in both morbidity and mortality in heart failure patients when beta-blockers are added to standard therapy. While further investigation is warranted in certain subgroups, the use of beta-adrenergic blockers in New York Heart Association (NYHA) class II to IV heart failure should now be considered routine. The purpose of this article is to outline and review the five major clinical trials of beta-blocker therapy in chronic heart failure; the US Carvedilol heart failure Program (USCP), the Cardiac Insufficiency Bisoprolol Study II (CIBIS-II), the Metoprolol CR/XL Randomized Intervention Trial in chronic Heart Failure (MERIT-HF), the Beta-blocker Evaluation of Survival Trial (BEST) and the Carvedilol Prospective Randomized Cumulative Survival trial (COPERNICUS), and to aid the reader in the selection of appropriate candidates for beta-blocker therapy.     

Digoxin remains useful in the management of chronic heart failure

Despite the introduction of a variety of new classes of drugs for the management of heart failure, digoxin continues to have an important role in long-term outpatient management. A wide variety of placebo-controlled clinical trials have unequivocally shown that treatment with digoxin can improve symptoms, quality of life, and exercise tolerance in patients with mild, moderate, or severe heart failure. These benefits are evident regardless of the underlying rhythm (normal sinus rhythm or atrial fibrillation), etiology of the heart failure, or concomitant therapy (eg. ACE inhibitors). Unlike other agents with positive inotropic properties, digoxin does not increase all-cause mortality and has a substantial benefit in reducing heart failure hospitalizations. Consensus guidelines have recently been published by the Heart Failure Society of America and the American College of Cardiology/American Heart Association, and they contain the following recommendations for digoxin treatment: 1. Digoxin should be considered for the outpatient treatment of all patients who have persistent symptoms of heart failure (NYHA class II-IV) despite conventional pharmacologic therapy with diuretics, ACE inhibitors, and a beta-blocker when the heart failure is caused by systolic dysfunction (the strength of evidence = A for NYHA class II and III; strength of evidence = C for NYHA class IV). 2. Digoxin is not indicated as primary treatment for the stabilization of patients with acutely decompensated heart failure. (Strength of evidence = B). Digoxin may be initiated after emergent treatment of heart failure has been completed in an effort to establish a long-term treatment strategy. 3. Digoxin should not be administered to patients who have significant sinus or atrioventricular block, unless the block has been treated with a permanent pacemaker (strength of evidence = B). The drug should be used cautiously in patients who receive other agents known to depress sinus or atrioventricular nodal function (such as amiodarone or a beta-blocker) (strength of evidence = B). 4. The dosage of digoxin should be 0.125-0.25 mg daily in the majority of patients (strength of evidence = C). The lower dose should be used in patients over 70 years of age, those with impaired renal function, or those with a low lean body mass. Higher doses (eg, digoxin 0.375-0.50 mg daily) are rarely needed. Loading doses of digoxin are not necessary during initiation of therapy for patients with chronic heart failure. 5. Serial assessment of serum digoxin levels is unnecessary in most patients. The radioimmunoassay was developed to assist in the evaluation of toxicity, not the efficacy of the drug. There appears to be little relationship between serum digoxin concentration and the drug's therapeutic effects. 6. Digoxin toxicity is commonly associated with serum levels >2 ng/mL but may occur with lower digoxin levels if hypokalemia, hypomagnesemia, or hypothyroidism coexist. Likewise, the concomitant use of agents such as quinidine, verapamil, spironolactone, flecainide, and amiodarone can increase serum digoxin levels and increase the likelihood of digoxin toxicity. 7. For patients with heart failure and atrial fibrillation with a rapid ventricular response, the administration of high doses of digoxin (>0.25 mg daily) for the purpose of rate control is not recommended. When necessary, additional rate control should be achieved by the addition of beta-blocker therapy or amiodarone (strength of evidence = C). If amiodarone is added, the dose of digoxin should be reduced. Digitalis preparations are now entering their fourth century of clinical use for the treatment of chronic heart failure symptoms. Its clinical efficacy can no longer be doubted and its safety has been verified by the multicenter DIG trial. Future advances in pharmacogenetics should facilitate identification of those patients most likely to benefit from its pharmacologic effects.     

Combined therapy with an angiotensin II receptor blocker and an angiotensin-converting enzyme inhibitor in heart failure

OBJECTIVE: To evaluate the safety, tolerability, and efficacy of chronic combination therapy with an angiotensin-converting enzyme (ACE) inhibitor and an angiotensin II receptor blocker (ARB) in the management of heart failure. DATA SOURCES: Clinical literature was accessed through MEDLINE (January 1966-June 2000). Key search terms included angiotensin-converting enzyme inhibitor; losartan; combined modality therapy; drug effects; heart failure, congestive; and receptors, angiotensin. DATA SYNTHESIS: Heart failure is widely prevalent and continues to be associated with high morbidity and mortality, even with currently recommended care. At the moderate doses studied for patients with mild heart failure in brief trials, combined ACE inhibitor and ARB therapy was well tolerated and had an additive effect in reducing blood pressure and relieving symptoms of heart failure. CONCLUSIONS: An ARB combined with an ACE inhibitor may benefit heart failure patients who are receiving all other recommended therapies. Further trials are needed to evaluate long-term safety effectiveness, quality of life, and survival before the combination can be recommended for routine use.     

High-versus low-dose ACE inhibitor therapy in chronic heart failure

OBJECTIVE: To discuss the controversy associated with the optimal dosing of angiotensin-converting enzyme (ACE) inhibitors in the management of patients with systolic heart failure; specifically, to review data related to the use of high-dose ACE inhibitors related to both neurohormonal and clinical outcomes associated with doses similar to, lower than, and higher than those used in the large, randomized clinical trials. DATA SOURCES: Primary, review, and meta-analysis articles were identified by MEDLINE search (1987-September 2002) and through secondary sources. STUDY SELECTION AND DATA EXTRACTION: All of the articles identified from the data sources were evaluated, and all information deemed relevant was included in this discussion. All available comparative dose trials, both prospective and retrospective, were evaluated for clinical and neurohormonal outcomes. DATA SYNTHESIS: The majority of data comparing the effect of high- with low-dose ACE inhibitors on neurohormonal outcomes demonstrate dose-related reduction in various neurohormonal measurements including plasma ACE, aldosterone, atrial natriuretic peptide, B-type natriuretic peptide, and interleukin-6 levels. Clinical endpoints including New York Heart Association class and heart failure-related hospitalizations were reduced by higher doses, but a dose-related survival benefit has not been demonstrated. Differences in duration of therapy and study design may account for variability in neurohormonal and morbidity results among various studies. CONCLUSIONS: Despite documented underutilization in clinical practice of doses of ACE inhibitors demonstrated in large controlled trials to improve morbidity and mortality, clinicians should attempt to reach these target doses if possible in patients with heart failure. Higher doses may improve surrogate markers for heart failure without impacting survival.     

Effect of posterolateral left ventricular scar on mortality and morbidity following cardiac resynchronization therapy

OBJECTIVES: To determine the effect of a posterolateral (PL) left ventricular scar on mortality and morbidity following cardiac resynchronization therapy (CRT). METHODS: Sixty-two patients with heart failure (age 67.3 +/- 9.6 yrs [mean +/- SD], 45 males, New York Heart Association class [NYHA] class III or IV, left ventricular ejection fraction [LVEF]= 35%, left bundle branch block, QRS > or = 120 ms) underwent late gadolinium enhancement cardiovascular magnetic resonance (LGE-CMR) for scar imaging. Patients were followed up for 741 (75-1602) days (mean [range]). RESULTS: The presence of a PL scar emerged as an independent predictor of the composite endpoint of cardiovascular death or hospitalization for worsening heart failure (HR: 3.06 [1.63, 7.7, P < 0.0001]) as well as the endpoint of cardiovascular death (HR: 2.63 [1.39, 6.65], P = 0.0016). A transmural PL scar was the strongest predictor of these endpoints (both P < 0.0001). The symptomatic responder rate (improvement by > or =1 NYHA classes or > or =25% in 6-min walking distance) was 83% in the group with non-PL scars, but only 47% in the group with transmural PL scars (P < 0.0001). Pacing over the scar was associated with a higher mortality and morbidity than pacing outside the scar (all P < 0.05). CONCLUSIONS: A PL scar is associated with a worse clinical outcome following CRT, particularly if it is transmural. Pacing scarred left ventricular myocardium carries a greater risk of mortality and morbidity than pacing nonscarred myocardium.