Studies Of Left Ventricular Dysfunction Research Articles

Symptoms vs. pathology and outcomes in patients with reduced ejection fraction

Abstract Background After acute myocardial infarction (AMI), patients have similar mortality regardless of whether AMI is silent or not. Less is known about whether outcomes after left ventricular systolic dysfunction (LVSD) varies by absence or presence of heart failure (HF) symptoms (Stage B and C HF, respectively). Methods In Studies of Left Ventricular Dysfunction (SOLVD), patients with EF ≤35% were randomized to enalapril or placebo. We compared 4-year mortality in 2569 patients with HF symptoms (Stage C HF) enrolled in SOLVD-Treatment trial with that in 4228 patients without symptoms (Stage B) in SOLVD-Prevention trial, adjusting for 24 baseline characteristics including age, sex, race, EF, symptoms (as indexed by NYHA class). Results Patients in SOVLD-Treatment had a higher risk of death (HR, 2.63; 95% CI, 2.37–2.90; p<0.001), which remained significant after adjustment for 23 covariates except NYHA (HR, 1.35; 95% CI, 1.16–1.60; p<0.001; Figure, left panel). However, when NYHA was added to the model, the significant was lost (adjusted HR, 1.15; 95% CI, 0.97–1.36; p = 0.117; Figure, right panel). Conclusion These findings suggest that unlike in patients with AMI, in patients with reduced EF, those with HF symptoms have higher mortality, even after adjustment for other covariates.

Estimated quadratic inference function for correlated failure time data.

An estimated quadratic inference function method is proposed for correlated failure time data with auxiliary covariates. The proposed method makes efficient use of the auxiliary information for the incomplete exposure covariates and preserves the property of the quadratic inference function method that requires the covariates to be completely observed. It can improve the estimation efficiency and easily deal with the situation when the cluster size is large. The proposed estimator which minimizes the estimated quadratic inference function is shown to be consistent and asymptotically normal. A chi-squared test based on the estimated quadratic inference function is proposed to test hypotheses about the regression parameters. The small-sample performance of the proposed method is investigated through extensive simulation studies. The proposed method is then applied to analyze the Study of Left Ventricular Dysfunction (SOLVD) data as anillustration.

Why we love heart failure: an introduction to the universal definition of heart failure

“Stat rosa pristina nomine, nomina nuda tenemus” “The rose of old remains only through its name and we hold only bare names.” Umberto Eco. Il nome della rosa We both started to think about, and to research on, HF about 40 years ago, right with the publication of the first edition of Braunwald's textbook in 1980. That textbook was so clear. It was the first time for us that we found all essentials of pathophysiology, diagnosis and therapy of heart disease so clearly shown in one place.3 It was also the first time that we found a definition of HF usable in everyday clinical work and this was the time that we both fell in love with this syndrome. A name, a definition, may not be all, but it comes close. We define a syndrome. We have something to defeat. As more as we contemplate medicine, as more it seems that it is done by names and clear definitions. One of the most recent and devastating diseases we had, coronavirus disease 2019, was soon very clearly defined by a name, COVID-19, and while we still did not know anything of this disease, we could start searching in PubMed or Google for COVID-19 plus whatever is of interest and everything started coming out in increased clarity. HF was also not clear before we started having a definition. It was already clearly important but we did not have a clear enemy behind the name of HF. Dr Braunwald clearly defined HF and it was the first time we had something clear to fight against. Then, the methodology of randomized controlled trials was applied to HF and we had further definitions. The Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS) enrolled patients with a diagnosis of HF ‘… based on clinical criteria: a history of heart disease with symptoms of dyspnea or fatigue or both, together with signs of fluid retention and no evidence of primary pulmonary disease. The patients were symptomatic at rest (NYHA functional class IV). (…) Measurements of myocardial function were not required.’4 Better patients' characterization started in the Veterans Administration Cooperative Study comparing hydralazine–isosorbide dinitrate combination with prazosin and placebo.5 Eligibility for this trial ‘was based on evidence of cardiac dilatation at (…) chest x-ray film or (..) echocardiography or left ventricular (…) radionuclide ejection fraction <45% in association with reduced exercise tolerance, as assessed by a progressive maximal bicycle-ergometer exercise test’.5 Then, measurement of left ventricular ejection fraction (LVEF) became widely available through echocardiography and the Studies of Left Ventricular Dysfunction (SOLVD) introduced the criterion of a low LVEF, ‘of 0.35 or less’ as an integral component of the definition of HF.6 However, it was only in 1995 that the task force of the European Society of Cardiology (ESC) published guidelines for the diagnosis of HF which, as nicely stated by Braunwald, ‘went beyond symptoms’ and ‘also required objective evidence of cardiac dysfunction in the definition’.7 The figure in the Braunwald and Antman editorial outlines this: major discoveries and step forward in HF treatment went along with milestones in the definition of HF.2 Thus, nothing closer to truth than the quotation by Albert Einstein that Gregg Fonarow used in another enlightening recent editorial comment: ‘Many of the things you can count, don't count. Many of the things you can't count, really count.’8 There is no number in a definition, nothing that can be measured, but a definition can change our life and, hopefully, that of our patients, too.

Early Effects of Starting Doses of Enalapril in Patients with Chronic Heart Failure in the SOLVD Treatment Trial

BackgroundIn the Studies of Left Ventricular Dysfunction (SOLVD) treatment trial, similar clinical benefits were observed between starting doses of enalapril and the target dose achieved by postrandomization up-titration. In our current analysis, protecting the randomization, we examined the early effects of starting doses of enalapril. MethodsThere were 2569 patients with mild-to-moderate chronic heart failure with reduced ejection fraction (ejection fraction ≤35%) randomized to receive starting doses (5-10 mg/day) of placebo (n = 1284) or enalapril (n = 1285). At day 14, both study drugs were blindly up-titrated to the target dose (20 mg/day). Overall, 96% (2458/2569) of the patients returned for dose up-titration, which was achieved in 59% (1444/2458), 48% (696/1444) of whom were in the enalapril group. Hazard ratios (HRs) and 95% confidence intervals (CIs) for outcomes in the enalapril group were estimated. ResultsHRs (95% CIs) for all-cause mortality, heart failure hospitalization, and the combined endpoint of heart failure hospitalization or all-cause mortality at 14 days after randomization were 0.80 (0.32-2.03), 0.63 (0.35-1.12), and 0.65 (0.39-1.06), respectively. Corresponding HRs (95% CIs) at 30 days were 0.82 (0.41-1.67), 0.43 (0.27-0.68), and 0.43 (0.27-0.68), respectively. The magnitude of these early effects of starting doses of enalapril is similar to its previously reported long-term effects at the target dose. ConclusionThese data suggest that in stable ambulatory patients with heart failure with reduced ejection fraction, the magnitude of the early effect of starting doses of enalapril is similar to that observed during longer-term therapy with the target doses of the drug.

Trends in Kidney Function Outcomes Following RAAS Inhibition in Patients With Heart Failure With Reduced Ejection Fraction

Angiotensin-converting enzyme (ACE) inhibitors are beneficial in heart failure with reduced ejection fraction (HFrEF). We sought to describe longitudinal trends in estimated glomerular filtration rate (eGFR) in HFrEF and how ACE-inhibitor therapy influences these changes. Post hoc analysis of trial data. Symptomatic (Treatment Trial, n=2,423) and asymptomatic (Prevention Trial, n=4,094) patients from the Studies of Left Ventricular Dysfunction (SOLVD). Enalapril versus placebo. Early and long-term eGFR slope (ie, within and after the first 6 weeks) and 4 kidney end points: (1) serum creatinine level increase by≥0.3mg/dL, (2)>30% eGFR decline, (3)>40% eGFR decline, and (4) incident eGFR<30mL/min/1.73m2. Shared parameter models, multivariable Cox regression models. Baseline mean eGFR was lower in the Treatment Trial than in the Prevention Trial, 69.5±19.8 (SD) versus 76.2±18.6mL/min/1.73m2. Following randomization, an early eGFR decline occurred in the enalapril group; however, slopes during the median 3-year follow-up were not statistically different by randomization arm in either the Treatment Trial (-0.84 in enalapril vs-1.36mL/min/1.73m2 per year in placebo; P=0.08) or Prevention Trial (-1.27 in enalapril vs-1.36mL/min/1.73m2 per year in placebo; P=0.7). Random assignment to enalapril treatment increased the risk for all 4 outcomes in the Treatment Trial in the first 6-week period (HRs were 1.48 [95% CI, 1.10-1.99] for creatinine increase by≥0.3mg/dL; 1.38 [95% CI, 0.98-1.94] for eGFR decline> 30%; 2.60 [95% CI, 1.30-5.21] for eGFR decline> 40%; and 4.71 [95% CI, 1.78-12.50] for eGFR<30mL/min/1.73m2), but after the first year was not significantly associated with increased risk. A similar albeit less pronounced pattern was observed in the Prevention Trial, with risks present only in the early period. Creatinine results were not blinded, making it possible that ACE-inhibitor/placebo dosing was influenced by creatinine level. Kidney function decline is slow in HFrEF. Although random assignment to enalapril treatment results in a statistically increased risk for kidney surrogates, the risk is limited to the early phase and late eGFR slopes and risks are not different by randomly assigned group.

Acute declines in estimated glomerular filtration rate on enalapril and mortality and cardiovascular outcomes in patients with heart failure with reduced ejection fraction

Angiotensin-converting enzyme inhibitors are beneficial in heart failure with reduced ejection fraction but are associated with acute declines in estimated glomerular filtration rate (eGFR). Prior studies evaluating thresholds of eGFR decline while using angiotensin-converting enzyme inhibitors in heart failure with reduced ejection have not taken into account this medication-driven decline. Here we used data from the Studies of Left Ventricular Dysfunction (SOLVD) trial of 6245 patients and performed Cox proportional hazards regression models to calculate hazard ratios of all-cause mortality and heart failure hospitalization-associated with percent eGFR decline at two- and six-weeks after randomization to enalapril versus placebo. In reference to placebo with equal degree of percent eGFR decline, any eGFR decline in the enalapril arm was associated with lower hazard of both outcomes. Under a conservative estimate using zero percent eGFR decline in the placebo arm as the reference, up to a 10% decline with enalapril was associated with mortality benefit (hazard ratio 0.87 [95% confidence interval 0.77, 0.99]) while up to a 35% decline was associated with decreased risk of heart failure hospitalization (0.78 [0.61, 0.98]). Under an intermediate estimate, up to a 15% decline with enalapril was associated with a mortality benefit (0.86 [0.77, 0.97]) and all levels of eGFR decline were associated with decreased risk of heart failure hospitalization. There was no percent eGFR decline, including up to 40%, in any models at either two- or six-weeks where enalapril was associated with higher mortality risk. Thus, in patients with reduced ejection fraction heart failure, enalapril is associated with decreased risk of mortality and heart failure hospitalizations. Hence, compelling reasons beyond moderate eGFR decline ought to be considered before its use is withdrawn.

Semiparametric additive model for estimating risk difference in multicenter studies

ABSTRACTMany cancer studies are conducted in multiple centers. While they have the advantage of more patients and larger population, center-to-center heterogeneity could be significant such that it cannot be ignored in analysis. In this paper, we propose semiparametric additive risk models with a general link function to estimate risk effects while accounting for center-specific baseline function. We propose an estimating equation for inference and show that the derived estimators are consistent and asymptotically normal. Simulation studies demonstrate good small-sample performance of the proposed method. We apply the method to analyze data from the Study of Left Ventricular Dysfunction (SOLVD) in 1990 and discuss application to one-to-one matched design.

Similar clinical benefits from below-target and target dose enalapril in patients with heart failure in the SOLVD Treatment trial.

To examine associations of below-target and target dose of enalapril, an angiotensin-converting enzyme (ACE) inhibitor, with outcomes in patients with heart failure and reduced ejection fraction (HFrEF) in the Studies of Left Ventricular Dysfunction (SOLVD) Treatment trial. Two thousand five hundred and sixty-nine patients with HFrEF (ejection fraction ≤35%) were randomized to below-target (5-10 mg/day) dose placebo (n = 1284) or enalapril (n = 1285). One month post-randomization, blind up-titration to target (20 mg/day) dose was attempted for both study drugs in 2458 patients. Among the 1444 patients who achieved dose up-titration (placebo, n = 748; enalapril, n = 696; mean dose for both groups, 20.0 mg/day), target dose enalapril (vs. target dose placebo) was associated with a 9% absolute lower risk of the combined endpoint of heart failure hospitalization or all-cause mortality [adjusted hazard ratio (HR) 0.70; 95% confidence interval (CI) 0.60-0.81; P < 0.001] during 4 years of follow-up. Among the 1014 patients who could not achieve target dose (placebo, n = 486; enalapril, n = 528; mean dose for both groups, 8.8 mg/day), below-target dose enalapril (vs. below-target dose placebo) was associated with a 12% absolute lower risk of the combined endpoint of heart failure hospitalization or all-cause mortality (adjusted HR 0.68; 95% CI 0.57-0.81; P < 0.001). Among the 1224 patients receiving enalapril, target (vs. below-target) dose had no association with the combined endpoint of heart failure hospitalization or all-cause mortality (adjusted HR 1.04; 95% CI 0.87-1.23; P = 0.695). In patients with HFrEF, the clinical benefits of ACE inhibitors appear to be similar at both below-target and target doses.

SCReening Evaluation of the Evolution of New Heart Failure Study (SCREEN-HF): early detection of chronic heart failure in the workplace.

Objective The aim of the present study was to determine whether asymptomatic heart failure (HF) in the workplace is subject to the health worker effect, making screening using conventional risk factors combined with a cardiac biomarker, namely N-terminal pro B-type natriuretic peptide (NT-proBNP), as useful as in the general population. Methods Between June 2007 and December 2009 a 'well' population deemed at high risk for development of HF was identified through health insurance records. Blood was collected from volunteer participants for analysis of urea, electrolytes and creatinine, a full blood count and NT-proBNP. An echocardiogram was performed on selected participants based on high NT-proBNP concentrations. Results The mean left ventricular ejection fraction (LVEF) was significantly reduced in participants with the highest compared with the lowest NT-proBNP quintile. In multivariate analysis, log-transformed NT-proBNP was independently associated with impaired LVEF and with moderate to severe diastolic dysfunction after adjustment for age, sex, coronary artery disease, diabetes, hypertension and obesity. Conclusions A large burden of asymptomatic left ventricular dysfunction (AVLD) was observed in subjects aged 60 and over with plasma NT-proBNP in the top quintile that was independent of conventional risk factors and work status. HWE does not appear to operate in AVLD. NT-proBNP testing in a population with HF risk factors may cost-effectively identify those at greatest risk of developing HF in a working population and facilitate early diagnosis, treatment and maintenance of work capacity. What is known about the topic? Chronic heart failure (CHF) has several causes, the most common being hypertension and coronary ischaemia. CHF is a major health problem of increasing prevalence that severely impacts quality of life, shortens lives and reduces worker productivity. It is often not diagnosed early enough to take full advantage of ameliorating medication. What does this paper add? Population screening for CHF is not currently advocated. This may be because conventional risk factors must be used in combination and there is no useful biomarker available. Yet evidence (SOLVD (Studies of Left Ventricular Dysfunction trials) recommends early diagnosis. We believe the work place is an area of potential screening where there is little supporting evidence. This paper provides evidence that the biomarker NT-proBNP is a useful new tool that improves cost-effectiveness of screening in a selected population. Specifically, the paper recommends CHF screening in the population with the highest potential health gain (i.e. the working population) by the sector with the highest economic gain (i.e. employers). What are the implications for practitioners? The paper presents important health screening recommendations for medical and health and safety practitioners within a selected population of workers. We feel practitioners should consider screening for incipient heart failure, particularly within Australia's working population, to save lives, provide economic benefit and extend working longevity.

The risk of death associated with proteinuria in heart failure is restricted to patients with an elevated blood urea nitrogen to creatinine ratio

BackgroundRenal dysfunction (RD) is associated with reduced survival in HF; however, not all RD is mechanistically or prognostically equivalent. Notably, RD associated with “pre-renal” physiology, as identified by an elevated blood urea nitrogen to creatinine ratio (BUN/Cr), identifies a particularly high risk RD phenotype. Proteinuria, another domain of renal dysfunction, has also been associated with adverse events. Given that several different mechanisms can cause proteinuria, we sought to investigate whether the mechanism underlying proteinuria also affects survival in HF. Methods and ResultsSubjects in the Studies of Left Ventricular Dysfunction (SOLVD) trial with proteinuria assessed at baseline were studied (n=6439). All survival models were adjusted for baseline characteristics and estimated glomerular filtration rate (eGFR). Proteinuria (trace or 1+) was present in 26% and associated with increased mortality (HR=1.2; 95% CI, 1.1–1.3, p=0.006). Proteinuria >1+ was less common (2.5%) but demonstrated a stronger relationship with mortality (HR=1.9; 95% CI, 1.5–2.5, p<0.001). In patients with BUN/Cr in the top tertile (≥17.3), any proteinuria (HR=1.3; 95% CI, 1.1–1.5, p=0.008) and >1+ proteinuria (HR=2.3; 95% CI, 1.7–3.3, p<0.001) both remained associated with mortality. However, in patients with BUN/Cr in the bottom tertile (≤13.3), any proteinuria (HR=0.95; 95% CI, 0.77–1.2, p=0.63, p interaction=0.015) and >1+ proteinuria (HR=1.3; 95% CI, 0.79–2.2, p=0.29, p interaction=0.036) were not associated with worsened survival. ConclusionAnalogous to a reduced eGFR, the mechanism underlying proteinuria in HF may be important in determining the associated survival disadvantage.

LONG-TERM EFFECT OF EARLY ENALAPRIL THERAPY ON CAUSES OF DEATH IN PATIENTS WITH LEFT VENTRICULAR DYSFUNCTION: A 27-YEAR FOLLOW-UP OF SOLVD IN BELGIUM

In the Studies of Left Ventricular Dysfunction (SOLVD), treatment with enalapril reduced short-term mortality for patients with symptomatic but not asymptomatic left ventricular systolic dysfunction. We reported here data from a 27-year follow-up of SOLVD to determine the long-term effect of early

Baseline characteristics and treatment of patients in prospective comparison of ARNI with ACEI to determine impact on global mortality and morbidity in heart failure trial (PARADIGM-HF).

AimTo describe the baseline characteristics and treatment of the patients randomized in the PARADIGM-HF (Prospective comparison of ARNi with ACEi to Determine Impact on Global Mortality and morbidity in Heart Failure) trial, testing the hypothesis that the strategy of simultaneously blocking the renin–angiotensin–aldosterone system and augmenting natriuretic peptides with LCZ696 200 mg b.i.d. is superior to enalapril 10 mg b.i.d. in reducing mortality and morbidity in patients with heart failure and reduced ejection fraction.MethodsKey demographic, clinical and laboratory findings, along with baseline treatment, are reported and compared with those of patients in the treatment arm of the Studies Of Left Ventricular Dysfunction (SOLVD-T) and more contemporary drug and device trials in heart failure and reduced ejection fraction.ResultsThe mean age of the 8442 patients in PARADIGM-HF is 64 (SD 11) years and 78% are male, which is similar to SOLVD-T and more recent trials. Despite extensive background therapy with beta-blockers (93% patients) and mineralocorticoid receptor antagonists (60%), patients in PARADIGM-HF have persisting symptoms and signs, reduced health related quality of life, a low LVEF (mean 29 ± SD 6%) and elevated N-terminal-proB type-natriuretic peptide levels (median 1608 inter-quartile range 886–3221 pg/mL).ConclusionPARADIGM-HF will determine whether LCZ696 is more beneficial than enalapril when added to other disease-modifying therapies and if further augmentation of endogenous natriuretic peptides will reduce morbidity and mortality in heart failure and reduced ejection fraction.

Recent Trends in the Incidence, Treatment, and Prognosis of Patients With Heart Failure and Atrial Fibrillation (the Worcester Heart Failure Study)

Atrial fibrillation (AF) and heart failure (HF) are common cardiovascular diseases and the co-occurrence of AF and HF has been associated with reduced survival. Data are needed on the potentially changing trends in the characteristics, treatment, and prognosis of patients with acute decompensated HF (ADHF) and AF. The study population consisted of 9,748 patients hospitalized with ADHF at 11 hospitals in the Worcester, Massachusetts, metropolitan area during 4 study years (1995, 2000, 2002, and 2004). Of the 9,748 patients admitted with ADHF, 3,868 (39.7%) had a history of AF and 449 (4.6%) developed new-onset AF during hospitalization. The rates of new-onset AF remained stable (4.9% in 1995; 5.0% in 2004), but the proportion of patients with pre-existing AF (34.5% in 1995; 41.6% in 2004) increased over time. New-onset and pre-existing AF were associated with older age, but pre-existing AF was more closely linked to a greater co-morbid disease burden. The use of HF therapies did not differ greatly by AF status. Despite this, new-onset AF was associated with a longer length of stay (7.5 vs 6.1 days) and greater in-hospital death rates (11.4% vs 6.6%). In contrast, pre-existing AF was associated with lower rates of postdischarge survival compared to patients with no AF (p <0.05 for all). The mortality rates improved significantly over time in patients with AF. In conclusion, AF was common among patients with ADHF, and the proportion of ADHF patients with co-occurring AF increased during the study period. Despite improving trends in survival, patients with ADHF and AF are at increased risk of in-hospital and postdischarge mortality.

Effects of enalapril in systolic heart failure patients with and without chronic kidney disease: Insights from the SOLVD Treatment trial

BackgroundAngiotensin-converting enzyme inhibitors improve outcomes in systolic heart failure (SHF). However, doubts linger about their effect in SHF patients with chronic kidney disease (CKD). MethodsIn the Studies of Left Ventricular Dysfunction (SOLVD) Treatment trial, 2569 ambulatory chronic HF patients with left ventricular ejection fraction ≤35% and serum creatinine level ≤2.5mg/dl were randomized to receive either placebo (n=1284) or enalapril (n=1285). Of the 2502 patients with baseline serum creatinine data, 1036 had CKD (estimated glomerular filtration rate <60ml/min/1.73m2). ResultsOverall, during 35months of median follow-up, all-cause mortality occurred in 40% (502/1252) and 35% (440/1250) of placebo and enalapril patients, respectively (hazard ratio {HR}, 0.84; 95% confidence interval {CI}, 0.74–0.95; p=0.007). All-cause mortality occurred in 45% and 42% of patients with CKD (HR, 0.88; 95% CI, 0.73–1.06; p=0.164), and 36% and 31% of non-CKD patients (HR, 0.82; 95% CI, 0.69–0.98; p=0.028) in the placebo and enalapril groups, respectively (p for interaction=0.615). Enalapril reduced cardiovascular hospitalization in those with CKD (HR, 0.77; 95% CI, 0.66–0.90; p<0.001) and without CKD (HR, 0.80; 95% CI, 0.70–0.91; p<0.001). Among patients in the enalapril group, serum creatinine elevation was significantly higher in those without CKD (0.09 versus 0.04mg/dl in CKD; p=0.003) during first year of follow-up, but there was no differences in changes in systolic blood pressure (mean drop, 7mm Hg, both) and serum potassium (mean increase, 0.2mEq/L, both). ConclusionsEnalapril reduces mortality and hospitalization in SHF patients without significant heterogeneity between those with and without CKD.

Influence of renal dysfunction phenotype on mortality in the setting of cardiac dysfunction: analysis of three randomized controlled trials

Renal neurohormonal activation leading to a reduction in glomerular filtration rate (GFR) has been suggested as a mechanism for renal insufficiency (RI) in the setting of heart failure. We hypothesized that RI occurring in the presence of renal neurohormonal activation may be prognostically more important than RI in the absence of renal neurohormonal activation. Subjects in the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE) trial (n = 429), Beta-Blocker Evaluation of Survival Trial (BEST) (n = 2691), and Studies Of Left Ventricular Dysfunction (SOLVD) trial (n = 6782) limited datasets were studied. The blood urea nitrogen to creatinine ratio (BUN/Creatinine) was employed as a surrogate for renal neurohormonal activation and the primary outcome was the interaction between BUN/Creatinine and RI associated mortality. Baseline RI (GFR < 60 mL/min/1.73 m&sup2;) was associated with mortality in all study populations (P < 0.001). In patients with higher BUN/Creatinine, the risk of mortality was consistently greater in patients with RI [adjusted hazard ratio (HR) ESCAPE = 2.8, 95% confidence interval (CI) 1.3-14.3, P = 0.019; BEST = 1.6, 95% CI 1.2-2.2, P = 0.002; SOLVD = 1.6, 95% CI 1.3-2.0, P = 0.001]. However, in patients with lower BUN/Creatinine, the risk of mortality was not elevated in patients with RI (adjusted HR ESCAPE = 0.94, 95% CI 0.35-2.4, P = 0.90, P interaction = 0.005; BEST = 0.97, 95% CI 0.64-1.4, P = 0.90, P interaction = 0.02; SOLVD = 1.0, 95% CI 0.8-1.3, P = 0.71, P interaction = 0.005). The association between RI and poor survival observed in heart failure populations appears to be contingent not simply on the presence of a reduced GFR, but possibly on the mechanism by which GFR is reduced.

Renal Function and Heart Failure Treatment

A number of studies have demonstrated a linkage between renal dysfunction and adverse clinical outcomes in both acute and chronic heart failure.1–3 Heart failure treatments can affect renal function in a variety of ways, with decreased glomerular filtration rate (GFR) during treatment often denoting a poorer prognosis.4–6 Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) reduce GFR through intrarenal mechanisms yet convey reduced rates of morbidity and mortality, presenting the hypothesis that the association between change in GFR and clinical outcomes depends on the factors that drive that change more than on GFR itself. In this issue of Circulation: Heart Failure , Testani et al7 present evidence that supports this hypothesis, showing that within the SOLVD (Studies of Left Ventricular Dysfunction) study, early reduction in GFR was associated with increased mortality within the placebo group but not in the enalapril group. It is reasonable to conclude that inhibiting the renin-angiotensin system (RAS) reduces GFR through a mechanism that does not convey an adverse prognosis. In evaluating new therapies, focus should be placed on clarifying the pathways through which agents influence renal function. Article see p 685 Within the SOLVD study, despite exclusion of patients with serum creatinine of >2.0 mg/dL, baseline renal impairment was associated with reduced survival.2,3 Patients randomized to enalapril showed slight, but statistically significant mean increases in serum creatinine during treatment relative to those receiving placebo.8,9 There exist a number of putative mechanisms whereby heart failure therapies may influence renal function. Diuretics may predispose to prerenal azotemia through intravascular volume depletion, excessive cardiac preload reduction, and a resulting reduction in cardiac output. Loop diuretics also induce intrarenal mechanisms for reducing GFR, principally through adenosine release and diminished glomerular blood flow …

Prognostic Importance of Early Worsening Renal Function After Initiation of Angiotensin-Converting Enzyme Inhibitor Therapy in Patients With Cardiac Dysfunction

Worsening renal function (WRF) in the setting of heart failure has been associated with increased mortality. However, it is unclear if this decreased survival is a direct result of the reduction in glomerular filtration rate (GFR) or if the mechanism underlying the deterioration in GFR is driving prognosis. Given that WRF in the setting of angiotensin-converting enzyme inhibitor (ACE-I) initiation is likely mechanistically distinct from spontaneously occurring WRF, we investigated the relative early WRF-associated mortality rates in subjects randomized to ACE-I or placebo. Subjects in the Studies Of Left Ventricular Dysfunction (SOLVD) limited data set (n=6337) were studied. The interaction between early WRF (decrease in estimated GFR ≥20% at 14 days), randomization to enalapril, and mortality was the primary end point. In the overall population, early WRF was associated with increased mortality (adjusted hazard ratio [HR], 1.2; 95% CI, 1.0-1.4; P=0.037). When analysis was restricted to the placebo group, this association strengthened (adjusted HR, 1.4; 95% CI, 1.1-1.8; P=0.004). However, in the enalapril group, early WRF had no adverse prognostic significance (adjusted HR, 1.0; 95% CI, 0.8-1.3; P=1.0; P=0.09 for the interaction). In patients who continued to receive study drug despite early WRF, a survival advantage remained with enalapril therapy (adjusted HR, 0.66; 95% CI, 0.5-0.9; P=0.018). These data support the notion that the mechanism underlying WRF is important in determining its prognostic significance. Specifically, early WRF in the setting of ACE-I initiation appears to represent a benign event that is not associated with a loss of benefit from continued ACE-I therapy.

Early Enalapril Therapy on Long-Term Mortality in Patients with Asymptomatic Left Ventricular Systolic Dysfunction: A 22-Year Follow-Up of SOLVD in Belgium

In the Studies of Left Ventricular Dysfunction (SOLVD), enalapril therapy did not reduce mortality in patients with left ventricular systolic dysfunction but without clinical heart failure. We reported here the 22-year mortality outcomes of such patients previously enrolled in SOLVD in Belgium. Among the 398 Belgian patients originally enrolled in the SOLVD Prevention Trial, post-trial mortality data were prospectively collected on all 336 survivors (165 in enalapril vs. 171 in placebo group) at trial closeout. All patients were placed on enalapril after the trial ended. Use of enalapril was classified as either “early” if started in trial or “delayed” if started post trial. The median delay in therapy was 3.3 years. No patients were lost to follow-up. The median duration of follow-up was 21.7 years from the time of randomization or 18.9 years from the time of closeout. The overall 5-, 10-, 15-, and 20-year cumulative survival rates were 74%, 50%, 32%, and 20% respectively. All-cause Kaplan-Meier mortality did not differ over the entire follow-up period between patients who received early as compared to delayed enalapril therapy (82% vs. 87%, p=0.12) but differed significantly over the post-trial period in favor of patients who received early therapy (78% vs. 88%, p=0.007). Early therapy was associated with a significant 24% risk reduction in all-cause mortality over the post-trial period (95% CI 3-40%, p=0.03). This corresponded to a significant increase in life expectancy of 34.1 months (95% CI 4.6-73.5 months) among patients who were treated early as compared to late (p=0.02). Post-trial use of ACE inhibitors (78%) was similar between the two groups. In an extended follow-up of SOLVD, early therapy with enalapril improved late survival in patients with asymptomatic left ventricular systolic dysfunction.

Thromboembolism and Antithrombotic Therapy in Patients With Heart Failure in Sinus Rhythm

Heart failure (HF) represents a major and growing public health problem because of its prevalence, incidence, morbidity, mortality, and economic costs. The prevalence of HF is 2% to 3% of the general population.1 Five million Americans are affected, with >550 000 cases diagnosed each year.2 The mortality rate from severe HF remains >60% within 5 years of diagnosis, and 50% of hospitalized patients with HF require readmission within 6 months of discharge. In the US estimated costs amount to > $35 billion per year.3 Although several therapies (eg, β-blockers, angiotensin-converting enzyme [ACE] inhibitors, and cardiac resynchronization therapy) have been proven effective in improving HF outcomes, many unanswered questions about optimal treatment remain. One area of ongoing uncertainty is the appropriate role for antithrombotic therapy in patients with HF. Observational data suggest that patients with HF have an increased venous thromboembolism (VTE) risk (deep venous thromboembolism [DVT], pulmonary embolism [PE], peripheral arterial thromboembolism, and stroke).4 These epidemiological findings are supported by multiple mechanisms that can contribute to a hypercoagulable state in patients with HF. Despite this increased risk of VTE, the role of antithrombotic therapy remains unclear. In this article, we provide an overview of epidemiology, pathophysiology, clinical trial data, and therapeutic recommendations for prevention of thromboembolism in HF. We searched PubMed for articles published between 1958 and 2010 using the following search terms: epidemiology of heart failure , thromboembolism and heart failure , thrombogenesis and heart failure , anticoagulation in heart failure , antiplatelet agent and heart failure , aspirin and heart failure , bleeding risk and anticoagulation , and aspirin and angiotensin-converting enzyme inhibitors . We also studied abstracts from national and international cardiovascular meetings to identify unpublished studies using the key words anticoagulation and dilated cardiomyopathy . Data from published observational studies and secondary …

The vanishing story of angiotensin II receptor blockers in the treatment of atrial fibrillation

This editorial refers to ‘Randomized trial of angiotensin II-receptor blocker vs. dihydropiridine calcium channel blocker in the treatment of paroxysmal atrial fibrillation with hypertension (J-RHYTHM II Study)’ by T. Yamashita et al. , on page 473. Pharmacological inhibition of the renin–angiotensin system (RAS) is a safe and beneficial intervention in patients with structural heart disease. Furthermore, there is good experimental evidence that AT-1 receptor blocker (ARB) therapy can prevent atrial structural remodelling in atrial fibrillation (AF).1–4 Experiments have proved that by angiotensin-converting enzyme (ACE) inhibitors and ARBs, the degree of atrial fibrosis and thereby the inducibility of AF can be reduced.2–4 In these settings, ACE inhibitors and ARBs were similarly effective. Of note, antiarrhythmic effects of ACE inhibitors and ARBs to prevent AF are supported by retrospective analyses of clinical trials including TRACE (Trandolapril Cardiac Evaluation), ValHeFT (Valsartan Heart Failure Trial), SOLVD (Studies of Left Ventricular Dysfunction), CHARM (Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity), and LIFE (Losartan Intervention For Endpoint reduction in hypertension).1,5 Given the observation that AF induces atrial fibrosis and contributes to electrophysiological changes, ARBs appear as a reasonable and safe additive antiarrhythmic therapy in AF, which is supported by recent meta-analyses.1,5 Yamashita et al .6 present the important data of J-RHYTHM II (Japanese Rhythm Management Trial II for Atrial …