Percutaneous Revascularization for Ischemic Left Ventricular Dysfunction.

BACKGROUND: Whether revascularization by percutaneous coronary intervention (PCI) can improve event-free survival and left ventricular function in patients with severe ischemic left ventricular systolic dysfunction, as compared with optimal medical therapy (i.e., individually adjusted pharmacologic and device therapy for heart failure) alone, is unknown. METHODS: We randomly assigned patients with a left ventricular ejection fraction of 35% or less, extensive coronary artery disease amenable to PCI, and demonstrable myocardial viability to a strategy of either PCI plus optimal medical therapy (PCI group) or optimal medical therapy alone (optimal-medical-therapy group). The primary composite outcome was death from any cause or hospitalization for heart failure. Major secondary outcomes were left ventricular ejection fraction at 6 and 12 months and quality-of-life scores. RESULTS: A total of 700 patients underwent randomization - 347 were assigned to the PCI group and 353 to the optimal-medical-therapy group. Over a median of 41 months, a primary-outcome event occurred in 129 patients (37.2%) in the PCI group and in 134 patients (38.0%) in the optimal-medical-therapy group (hazard ratio, 0.99; 95% confidence interval [CI], 0.78 to 1.27; P = 0.96). The left ventricular ejection fraction was similar in the two groups at 6 months (mean difference, -1.6 percentage points; 95% CI, -3.7 to 0.5) and at 12 months (mean difference, 0.9 percentage points; 95% CI, -1.7 to 3.4). Quality-of-life scores at 6 and 12 months appeared to favor the PCI group, but the difference had diminished at 24 months. CONCLUSIONS: Among patients with severe ischemic left ventricular systolic dysfunction who received optimal medical therapy, revascularization by PCI did not result in a lower incidence of death from any cause or hospitalization for heart failure. (Funded by the National Institute for Health and Care Research Health Technology Assessment Program; REVIVED-BCIS2 ClinicalTrials.gov number, NCT01920048.).

Dynamic risk stratification using Markov chain modelling in patients with chronic heart failure.

AIMS: Risk changes with the progression of disease and the impact of treatment. We developed a dynamic risk stratification Markov chain model using artificial intelligence in patients with chronic heart failure (CHF). METHODS AND RESULTS: We described the pattern of behaviour among 7496 consecutive patients assessed for suspected HF. The following mutually exclusive health states were defined and assessed every 4 months: death, hospitalization, outpatient visit, no event, and leaving the service altogether (defined as no event at any point following assessment). The observed figures at the first transition (4 months) weres 427 (6%), 1559 (21%), 2254 (30%), 1414 (19%), and 1842 (25%), respectively. The probabilities derived from the first two transitions (i.e. from baseline to 4 months and from 4 to 8 months) were used to construct the model. An example of the model's prediction is that at cycle 4, the cumulative probability of death was 14%; leaving the system, 37%; being hospitalized between 12 and 16 months, 10%; having an outpatient visit, 8%; and having no event, 31%. The corresponding observed figures were 14%, 41%, 10%, 15%, and 21%, respectively. The model predicted that during the first 2 years, a patient had a probability of dying of 0.19, and the observed value was 0.18. CONCLUSIONS: A model derived from the first 8 months of follow-up is strongly predictive of future events in a population of patients with chronic heart failure. The course of CHF is more linear than is commonly supposed, and thus more predictable.

Biomarker-based assessment of collagen cross-linking identifies patients at risk of heart failure more likely to benefit from spironolactone effects on left atrial remodelling. Insights from the HOMAGE clinical trial.

AIMS: The HOMAGE randomized trial found that spironolactone reduced left atrial volume index (LAVI), E:A ratio, and a marker of collagen type I synthesis (procollagen type I C-terminal propeptide) in patients at risk of heart failure (HF). Previous trials showed that patients with HF, preserved ejection fraction and low serum collagen type I C-terminal telopeptide to matrix metalloproteinase-1 ratio (CITP:MMP-1), associated with high collagen cross-linking, had less improvement in diastolic function with spironolactone. We evaluated the interaction between serum CITP:MMP-1 and spironolactone on cardiac function in the HOMAGE trial. METHODS AND RESULTS: Patients at risk of HF were randomized to spironolactone (n = 260) or not (n = 255). Blood sampling and echocardiography were done at baseline, one and nine months. CITP:MMP-1 was used as an indirect measure of collagen cross-linking. Higher baseline CITP:MMP-1 (i.e. lower collagen cross-linking) was associated with greater reductions in LAVI with spironolactone at both one (p = 0.003) and nine (p = 0.01) months, but no interaction was observed for E:A ratio. Spironolactone reduced LAVI after one and nine months only for those patients in the third tertile of CITP:MMP-1 (estimated lowest collagen cross-linking) [mean differencesspiro/control : -1.77 (95% confidence interval, CI -2.94 to -0.59) and -2.52 (95% CI -4.46 to -0.58) mL/m2 ; interaction pacross-tertiles  = 0.005; interaction pthird tertile  = 0.008] with a similar trend for N-terminal pro-B-type natriuretic peptide which was consistently reduced by spironolactone only in the lowest collagen cross-linking tertile [mean differencesspiro/control : -0.47 (95% CI -0.66 to -0.28) and -0.31 (95% CI -0.59 to -0.04) ng/L; interaction pacross-tertiles  = 0.09; interaction pthird tertile < 0.001]. CONCLUSIONS: These findings suggest that, for patients at risk of HF, the effects of spironolactone on left atrial remodelling may be more prominent in patients with less collagen cross-linking (indirectly assessed by serum CITP:MMP-1).

Does home oxygen therapy (HOT) in addition to standard care reduce disease severity and improve symptoms in people with chronic heart failure? A randomised trial of home oxygen therapy for patients with chronic heart failure.

BACKGROUND: Home oxygen therapy (HOT) is commonly used for patients with severe chronic heart failure (CHF) who have intractable breathlessness. There is no trial evidence to support its use. OBJECTIVES: To detect whether or not there was a quality-of-life benefit from HOT given as long-term oxygen therapy (LTOT) for at least 15 hours per day in the home, including overnight hours, compared with best medical therapy (BMT) in patients with severely symptomatic CHF. DESIGN: A pragmatic, two-arm, randomised controlled trial recruiting patients with severe CHF. It included a linked qualitative substudy to assess the views of patients using home oxygen, and a free-standing substudy to assess the haemodynamic effects of acute oxygen administration. SETTING: Heart failure outpatient clinics in hospital or the community, in a range of urban and rural settings. PARTICIPANTS: Patients had to have heart failure from any aetiology, New York Heart Association (NYHA) class III/IV symptoms, at least moderate left ventricular systolic dysfunction, and be receiving maximally tolerated medical management. Patients were excluded if they had had a cardiac resynchronisation therapy device implanted within the past 3 months, chronic obstructive pulmonary disease fulfilling the criteria for LTOT or malignant disease that would impair survival or were using a device or medication that would impede their ability to use LTOT. INTERVENTIONS: Patients received BMT and were randomised (unblinded) to open-label LTOT, prescribed for 15 hours per day including overnight hours, or no oxygen therapy. MAIN OUTCOME MEASURES: The primary end point was quality of life as measured by the Minnesota Living with Heart Failure (MLwHF) questionnaire score at 6 months. Secondary outcomes included assessing the effect of LTOT on patient symptoms and disease severity, and assessing its acceptability to patients and carers. RESULTS: Between April 2012 and February 2014, 114 patients were randomised to receive either LTOT or BMT. The mean age was 72.3 years [standard deviation (SD) 11.3 years] and 70% were male. Ischaemic heart disease was the cause of heart failure in 84%; 95% were in NYHA class III; the mean left ventricular ejection fraction was 27.8%; and the median N-terminal pro-B-type natriuretic hormone was 2203 ng/l. The primary analysis used a covariance pattern mixed model which included patients only if they provided data for all baseline covariates adjusted for in the model and outcome data for at least one post-randomisation time point (n = 102: intervention, n = 51; control, n = 51). There was no difference in the MLwHF questionnaire score at 6 months between the two arms [at baseline the mean score was 54.0 (SD 18.4) for LTOT and 54.0 (SD 17.9) for BMT; at 6 months the mean score was 48.1 (SD 18.5) for LTOT and 49.0 (SD 20.2) for BMT; adjusted mean difference -0.10, 95% confidence interval (CI) -6.88 to 6.69; p = 0.98]. At 3 months, the adjusted mean MLwHF questionnaire score was lower in the LTOT group (-5.47, 95% CI -10.54 to -0.41; p = 0.03) and breathlessness scores improved, although the effect did not persist to 6 months. There was no effect of LTOT on any secondary measure. There was a greater number of deaths in the BMT arm (n = 12 vs. n = 6). Adherence was poor, with only 11% of patients reporting using the oxygen as prescribed. CONCLUSIONS: Although the study was significantly underpowered, HOT prescribed for 15 hours per day and subsequently used for a mean of 5.4 hours per day has no impact on quality of life as measured by the MLwHF questionnaire score at 6 months. Suggestions for future research include (1) a trial of patients with severe heart failure randomised to have emergency oxygen supply in the house, supplied by cylinders rather than an oxygen concentrator, powered to detect a reduction in admissions to hospital, and (2) a study of bed-bound patients with heart failure who are in the last few weeks of life, powered to detect changes in symptom severity. TRIAL REGISTRATION: Current Controlled Trials ISRCTN60260702. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 19, No. 75. See the NIHR Journals Library website for further project information.

Influence of sex on treatment and outcome in chronic heart failure.

The population is aging, the prevalence of heart failure increases with age, and on average women live longer than men. There is evidence for sex-specific effects of individual, guideline-recommended drugs used for treatment of chronic heart failure. Women are underrepresented in most clinical trials and only a minority of drug applications to regulatory authorities have included sex analyses. The present review focuses on the potential female survival benefit in heart failure, the influence of sex on medical treatment in a broader sense, and the potential benefit to be derived from guideline recommended treatment and common adjunctive heart failure medication.

Clinical trials update from the European Society of Cardiology Heart Failure meeting 2011: TEHAF, WHICH, CARVIVA, and atrial fibrillation in GISSI-HF and EMPHASIS-HF.

This article provides information and a commentary on key trials relevant to the pathophysiology, prevention, and treatment of heart failure (HF) presented at the European Society of Cardiology Heart Failure meeting held in Gothenburg, Sweden in May 2011. Unpublished reports should be considered as preliminary, since analyses may change in the final publication. In the TEHAF study, use of the Health Buddy(®) monitoring system failed to reduce the number of HF admissions compared with usual care but a subgroup of patients with more recently diagnosed HF may have benefited. In the WHICH study, some reductions in the rate of hospital stay were observed in patients who underwent a nurse-led home-based intervention programme following a hospital admission for an acute HF exacerbation, compared with patients who were followed in a specialized outpatient clinic. Results from CARVIVA-HF suggest that ivabradine alone or in combination with carvedilol is safe and effective for improving exercise capacity and quality of life in HF patients on optimized angiotensin-converting enzyme inhibitor therapy. In the GISSI-HF study there was no difference in atrial fibrillation (AF) occurrence between the n-3 polyunsaturated fatty acids and placebo groups. In EMPHASIS-HF the incidence of new onset AF or flutter was reduced in patients with mild HF randomized to eplerenone compared with placebo.

UK guidelines for referral and assessment of adults for heart transplantation.

Patients with advanced heart failure have a dismal prognosis and poor quality of life. Heart transplantation provides an effective treatment for a subset of these patients. This article provides cardiologists with up-to-date information about referral for transplantation, the role of left ventricular assist devices prior to transplant, patient selection, waiting-list management and donor heart availability. Timing is of central importance; patients should be referred before complications (eg, cardiorenal syndrome or secondary pulmonary hypertension) have developed that will increase the risk of, or potentially contraindicate, transplantation. Issues related to heart failure aetiology, comorbidity and adherence to medical treatment are reviewed. Finally, the positive role that cardiologists can play in promoting and facilitating organ donation is discussed.

Relationship between right ventricular volumes measured by cardiac magnetic resonance imaging and prognosis in patients with chronic heart failure.

AIMS: The aim of this study was to investigate the prognostic impact of right ventricular (RV) size in patients with chronic heart failure. METHODS AND RESULTS: Normal volunteers (n = 80) and patients (n = 380) with left ventricular (LV) ejection fraction <45% on echocardiography and on optimal treatment for heart failure underwent cardiac magnetic resonance imaging with measurement of LV and RV volumes, mass and ejection fraction. The mean and the standard deviation (SD) of the RV end-systolic volume index in normal subjects were used to define the normal range as: mean RV end-systolic volume index +2 SD. Patients with dilated RV (>2 SD beyond the mean) (25%) had more frequent evidence of fluid overload in clinical examination and greater LV dimensions (P < 0.0001). During follow-up (median 45, interquartile range: 28-66 months), 37% of patients with and 24% without RV dilation died (log-rank test = 8.4; P = 0.004). In a multivariable Cox regression model, including 13 other clinical variables, RV (HR: 1.08/10 mL/m(2), 95% CI: 1.00-1.18, P = 0.044), but not LV, end-systolic volume index predicted a worse outcome. CONCLUSION: Twenty-five per cent of patients with heart failure due to LV systolic dysfunction have a dilated right ventricle. Greater RV dimensions predict mortality in patients with chronic heart failure. Treatments aimed at preserving or enhancing RV structure and function, possibly by unloading the RV by reducing pulmonary vascular resistance or left atrial pressure, should be investigated.

Ruling out heart failure in primary-care: the cost-benefit of pre-screening using NT-proBNP and QRS width.

BACKGROUND: Half of the patients presenting to primary-care with signs and symptoms of heart failure (HF) are found not to have serious heart disease after echocardiographic assessment. This places an unnecessary burden on hospital services. We sought to assess the cost-benefit of screening for left ventricular systolic dysfunction (LVSD) and major structural heart disease (SHD) using N-terminal pro-B-type natriuretic peptide (NT-proBNP) and QRS-width from an electrocardiogram in patients presenting with suspected HF to primary-care physicians (PCP). METHODS: Patients were recruited from a community-based service pilot. Blood samples for NT-proBNP measurement were obtained in primary-care. All patients were referred irrespective of the NT-proBNP result, with echocardiograms reviewed by a cardiologist blinded to the NT-proBNP result. RESULTS: NT-proBNP<180 pg/ml (21 pmol/l) 'ruled-out' major-LVSD avoiding 38% of echoes and 23% of cost compared with direct referral for echocardiography. NT-proBNP<93 pg/ml (11 pmol/l) 'ruled-out' major-SHD, avoiding 20% of echoes and 8% of cost. A QRS<84 ms 'ruled-out' major-LVSD, avoiding 28% of echoes and 17% of cost. A QRS<82 ms 'ruled-out' major-SHD avoiding 20% of echoes and 9% of cost. Intermediate values of NT-proBNP were often associated with equivocal echocardiography and in some scenarios NT-proBNP testing might avoid 61% of echocardiograms and 46% of cost. CONCLUSION: Use of NT-proBNP by PCPs to detect major-LVSD and major-SHD in patients with suspected HF could reduce referrals for specialist HF-assessment, provide cost-avoidance compared to direct referral and improve the efficiency of care. QRS-width is less effective as a diagnostic test and adds little cost-benefit when combined with NT-proBNP.

Screening for left ventricular systolic dysfunction in high-risk patients in primary-care: a cost-benefit analysis.

BACKGROUND: Appropriate screening strategies are needed to cost effectively identify patients with undiagnosed and untreated left ventricular systolic dysfunction (LVSD). AIM: To investigate the cost-benefit of screening high-risk patients in primary-care for LVSD (EF<40%) using various screening strategies. METHODS: Patients considered at high-risk of developing LVSD were recruited from three primary-care practices. Patients with known LVSD were excluded. Echocardiography, electrocardiography and blood tests were performed blinded to an NT-proBNP result. Logistic regression (LR) and receiver-operating characteristic analysis were used to assess the univariate and multivariable utility of NT-proBNP, QRS duration, symptoms and evidence of myocardial infarction (MI) to detect LVSD. RESULTS: 427 patients were assessed. 7.5% had undiagnosed LVSD. NT-proBNP, QRS, symptoms and MI were independent predictors of LVSD (p<0.014) and the resultant LR-model had an area-under-the-curve of 0.89 (0.84-0.94) and specificity of 54% (51-79%) at a sensitivity of 100%. The LR-model avoided 24.1% (18.1- 48.3%) of the cost and 50.1% (44.1-74.3%) of the echocardiograms compared to screening using echocardiography alone. CONCLUSIONS: Screening high-risk groups in primary-care increases the pick-up rate for undiagnosed LVSD and using an LR-model combining NT-proBNP, QRS, symptoms and evidence of MI has significant cost benefits.

Six minute corridor walk test as an outcome measure for the assessment of treatment in randomized, blinded intervention trials of chronic heart failure: a systematic review.

AIMS: The 6 min walk test (6MWT) is commonly used in clinical trials to assess treatments for heart failure, but its ability to distinguish between effective and ineffective treatments is questionable. The aim of this study is to investigate, using a systematic literature review, the utility of the 6MWT as a measure of the effectiveness of treatment in randomized controlled trials of heart failure. METHODS AND RESULTS: A literature search was performed using Medline, EMBASE, CINAHL, and Biological abstracts for randomized controlled trials that measured 6MWT between 1988 and 31 May 2004. A significant increase in 6MWT distance was observed in only 9 of 47 randomized controlled trials of pharmacological therapy; 2 of 6 trials of ACE-inhibitors; 3 of 17 trials of beta-blockers; 1 of 4 trials of digoxin; one trial of ibopamine; one trial of l-arginine; one trial of beriberine; and one trial showed superiority of captopril over flosequinan. A significant increase in 6MWT was observed in four out of six placebo-controlled trials of cardiac resynchronization. Smaller pharmacological trials with fewer centres were more likely to be positive; six out of nine positive pharmacological trials had four or less participating centres, raising the possibility of publication bias. Pharmacological trials including patients with more severe heart failure were more likely to show a significant improvement with therapy than trials of milder heart failure. Five out of seven pharmacological trials that reported an improvement in symptoms also reported an improvement in 6MWT distance. Of 30 pharmacological trials, 29 that reported no improvement in symptoms also reported no improvement in 6MWT. Using mean values in these trials, the age of patients appeared a more important determinant of 6MWT distance than New York Heart Association classification. CONCLUSION: The 6MWT has not yet been proven to be a robust test for the identification of effective pharmacological interventions although it appears useful for the assessment of cardiac resynchronization therapy. The results of the 6MWT were concordant with changes in symptoms, suggesting that it may be used as supportive evidence for symptom benefit. The test may be of greater value in patients with more advanced heart failure, where it may function as a maximal exercise test.

Clinical trials update from the American Heart Association meeting: ACORN-CSD, primary care trial of chronic disease management, PEACE, CREATE, SHIELD, A-HeFT, GEMINI, vitamin E meta-analysis, ESCAPE, CARP, and SCD-HeFT cost-effectiveness study.

This article provides information and a commentary on landmark trials presented at the American Heart Association meeting held in November 2004, relevant to the pathophysiology, prevention, and treatment of heart failure. An open trial of the ACORN Cardiac Support Device (CSD) showed encouraging preliminary results in patients with severe heart failure. The PEACE (Prevention of Events with Angiotensin-Converting Enzyme inhibition) study supports data from previous studies showing that ACE inhibitors reduce vascular events in patients at increased risk. The CREATE (clinical trial of metabolic modulation in acute MI treatment evaluation) study of patients with acute myocardial infarction (MI) showed no mortality benefit of a glucose/insulin/potassium regimen, but treatment with reviparin reduced the incidence of death, MI, or stroke. Azimilide was not associated with a significant reduction in shocks, but reduced the shocks or episodes of markedly symptomatic ventricular tachycardia terminated by pacing in the SHIELD (Shock Inhibition Evaluation with Azimilide) study. The addition of isosorbide dinitrate plus hydralazine to standard therapy improved survival in black heart failure patients in the A-HeFT (African-American Heart Failure Trial) study. In an investigation of hypertensive patients with diabetes, carvedilol had fewer adverse effects on diabetic control than metoprolol. A meta-analysis of high-dose vitamin E supplementation suggested an association with increased mortality. The ESCAPE (Evaluation Study of CHF and Pulmonary Artery Catheterisation Effectiveness) study showed no benefit of pulmonary artery catheterisation over clinical management in patients with severe heart failure. Routine prophylactic coronary revascularisation for stable coronary disease prior to major vascular surgery showed no benefit in the CARP (Coronary Artery Revascularization Prophylaxis) study. Analysis of data from SCD-HeFT supports the cost-effectiveness of ICDs in heart failure, although overall cost implications may be prohibitive.

Diastolic heart failure: a difficult problem in the elderly.

Heart failure with normal systolic function has been equated to diastolic heart failure (DHF). DHF appears to be quite common in the elderly, especially in elderly women with hypertension. Recent epidemiologic studies suggest that 30%-50% of patients with heart failure may have DHF. Morbidity for DHF is considerable and comparable to that of heart failure with left ventricular systolic dysfunction. Both groups of patients have similar rates of recurrent hospitalization and cost of care. Long-term mortality also appears to be similar in the two groups of patients. With the aging of the population, the numbers of patients with DHF will continue to rise and are likely to contribute significantly to the burden of disease caused by heart failure. Unfortunately, as yet, no reliable definition has been found for DHF. Currently the diagnosis of DHF is often made by exclusion, and treatment is empirical and unsatisfactory because of the lack of large-scale, randomized, controlled trials in this area; however, several large and other smaller trials are currently in progress that will hopefully provide some answers.