Showing papers by "Marc A. Pfeffer published in 2014"
University of Michigan1, Harvard University2, National Institutes of Health3, University of Minnesota4, Universidade Federal do Rio Grande do Sul5, Russian National Research Medical University6, New York Methodist Hospital7, Université de Montréal8, University of Washington9, Northwestern University10, University of Wisconsin-Madison11
TL;DR: In patients with heart failure and a preserved ejection fraction, treatment with spironolactone did not significantly reduce the incidence of the primary composite outcome of death from cardiovascular causes, aborted cardiac arrest, or hospitalization for the management of heart failure.
Abstract: Background Mineralocorticoid-receptor antagonists improve the prognosis for patients with heart failure and a reduced left ventricular ejection fraction. We evaluated the effects of spironolactone in patients with heart failure and a preserved left ventricular ejection fraction. Methods In this randomized, double-blind trial, we assigned 3445 patients with symptomatic heart failure and a left ventricular ejection fraction of 45% or more to receive either spironolactone (15 to 45 mg daily) or placebo. The primary outcome was a composite of death from cardiovascular causes, aborted cardiac arrest, or hospitalization for the management of heart failure. Results With a mean follow-up of 3.3 years, the primary outcome occurred in 320 of 1722 patients in the spironolactone group (18.6%) and 351 of 1723 patients in the placebo group (20.4%) (hazard ratio, 0.89; 95% confidence interval [CI], 0.77 to 1.04; P = 0.14). Of the components of the primary outcome, only hospitalization for heart failure had a significantly lower incidence in the spironolactone group than in the placebo group (206 patients [12.0%] vs. 245 patients [14.2%]; hazard ratio, 0.83; 95% CI, 0.69 to 0.99, P = 0.04). Neither total deaths nor hospitalizations for any reason were significantly reduced by spironolactone. Treatment with spiron olactone was associated with increased serum creatinine levels and a doubling of the rate of hyperkalemia (18.7%, vs. 9.1% in the placebo group) but reduced hypokalemia. With frequent monitoring, there were no significant differences in the incidence of serious adverse events, a serum creatinine level of 3.0 mg per deciliter (265 μmol per liter) or higher, or dialysis. Conclusions In patients with heart failure and a preserved ejection fraction, treatment with spironolactone did not significantly reduce the incidence of the primary composite outcome of death from cardiovascular causes, aborted cardiac arrest, or hospitalization for the management of heart failure. (Funded by the National Heart, Lung, and Blood Institute; TOPCAT ClinicalTrials.gov number, NCT00094302.)
1,930 citations
TL;DR: Patients enrolled in TOPCAT demonstrated heterogeneous patterns of ventricular remodeling, with high prevalence of structural heart disease, including left ventricular hypertrophy and left atrial enlargement, in addition to pulmonary hypertension, each of which has been associated with adverse outcomes in HFpEF.
Abstract: Background—Heart failure with preserved ejection fraction (HFpEF) is associated with substantial morbidity and mortality. Existing data on cardiac structure and function in HFpEF suggest significant heterogeneity in this population. Methods and Results—Echocardiograms were obtained from 935 patients with HFpEF (left ventricular ejection fraction ≥45%) enrolled in the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial before initiation of randomized therapy. Average age was 70±10 years, 49% were women, 14% were of African descent, and comorbidities were highly prevalent. Centralized quantitative analysis in a blinded core laboratory demonstrated a mean left ventricular ejection fraction of 59.3±7.9%, with prevalent concentric left ventricular remodeling (34%) and hypertrophy (43%), and left atrial enlargement (53%). Diastolic dysfunction was present in 66% of gradable participants and was significantly associated with greater left ventricular hypertrophy and...
357 citations
VU University Medical Center1, Cardiff University2, University of Navarra3, Brigham and Women's Hospital4, University of Oslo5, University of Milan6, University Health System7, Charité8, University of Brescia9, University of Michigan10, University of Göttingen11, University of Perugia12, Monash University13, University of Warwick14, Athens State University15, Northwestern University16, Boston University17, Campbell University18, Medical University of Graz19
TL;DR: To maximize the likelihood of identifying effective therapeutics for HF-PEF, lessons learned from the past decade of research should be applied to the design, conduct, and interpretation of future trials.
Abstract: The management of heart failure with reduced ejection fraction (HF-REF) has improved significantly over the last two decades. In contrast, little or no progress has been made in identifying evidence-based, effective treatments for heart failure with preserved ejection fraction (HF-PEF). Despite the high prevalence, mortality, and cost of HF-PEF, large phase III international clinical trials investigating interventions to improve outcomes in HF-PEF have yielded disappointing results. Therefore, treatment of HF-PEF remains largely empiric, and almost no acknowledged standards exist. There is no single explanation for the negative results of past HF-PEF trials. Potential contributors include an incomplete understanding of HF-PEF pathophysiology, the heterogeneity of the patient population, inadequate diagnostic criteria, recruitment of patients without true heart failure or at early stages of the syndrome, poor matching of therapeutic mechanisms and primary pathophysiological processes, suboptimal study designs, or inadequate statistical power. Many novel agents are in various stages of research and development for potential use in patients with HF-PEF. To maximize the likelihood of identifying effective therapeutics for HF-PEF, lessons learned from the past decade of research should be applied to the design, conduct, and interpretation of future trials. This paper represents a synthesis of a workshop held in Bergamo, Italy, and it examines new and emerging therapies in the context of specific, targeted HF-PEF phenotypes where positive clinical benefit may be detected in clinical trials. Specific considerations related to patient and endpoint selection for future clinical trials design are also discussed.
302 citations
Emory University1, University of California, Los Angeles2, Medical University of South Carolina3, University Health System4, Bayer Corporation5, University of Pittsburgh6, Northwestern University7, University of Alabama at Birmingham8, Castle Hill Hospital9, Janssen Pharmaceutica10, Vanderbilt University11, Center for Drug Evaluation and Research12, Athens State University13, Novartis14, British Heart Foundation15, University of Brescia16, Duke University17, Harvard University18, Medical University of Graz19, University of Michigan20, Henry Ford Hospital21, University of California, San Francisco22
TL;DR: To facilitate a discussion of how to proceed effectively in future with development of therapies for HFpEF, a meeting was facilitated by the Food and Drug Administration and included representatives from academia, industry, and regulatory agencies.
Abstract: The burden of heart failure with preserved ejection fraction (HFpEF) is considerable and is projected to worsen. To date, there are no approved therapies available for reducing mortality or hospitalizations for these patients. The pathophysiology of HFpEF is complex and includes alterations in cardiac structure and function, systemic and pulmonary vascular abnormalities, end-organ involvement, and comorbidities. There remain major gaps in our understanding of HFpEF pathophysiology. To facilitate a discussion of how to proceed effectively in future with development of therapies for HFpEF, a meeting was facilitated by the Food and Drug Administration and included representatives from academia, industry, and regulatory agencies. This document summarizes the proceedings from this meeting.
295 citations
294 citations
University of Rochester1, Cedars-Sinai Medical Center2, Duke University3, Tufts University4, University of California, San Francisco5, Mount Sinai St. Luke's and Mount Sinai Roosevelt6, Sheba Medical Center7, Semmelweis University8, Harvard University9, University of Valencia10, Tel Aviv Sourasky Medical Center11, Tel Aviv University12, University of Bonn13, Loyola University Chicago14
TL;DR: The findings indicate that in patients with mild heart-failure symptoms, left ventricular dysfunction, and left bundle-branch block, early intervention with CRT-D was associated with a significant long-term survival benefit.
Abstract: BACKGROUND The Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy (MADIT-CRT) showed that early intervention with cardiac-resynchronization therapy with a defibrillator (CRT-D) in patients with an electrocardiographic pattern showing left bundle-branch block was associated with a significant reduction in heart-failure events over a median follow-up of 2.4 years, as compared with defibrillator therapy alone. METHODS We evaluated the effect of CRT-D on long-term survival in the MADIT-CRT population. Post-trial follow-up over a median period of 5.6 years was assessed among all 1691 surviving patients (phase 1) and subsequently among 854 patients who were enrolled in post-trial registries (phase 2). All reported analyses were performed on an intention-to-treat basis. RESULTS At 7 years of follow-up after initial enrollment, the cumulative rate of death from any cause among patients with left bundle-branch block was 18% among patients randomly assigned to CRT-D, as compared with 29% among those randomly assigned to defibrillator therapy alone (adjusted hazard ratio in the CRT-D group, 0.59; 95% confidence interval [CI], 0.43 to 0.80; P<0.001). The long-term survival benefit of CRT-D in patients with left bundle-branch block did not differ significantly according to sex, cause of cardiomyopathy, or QRS duration. In contrast, CRT-D was not associated with any clinical benefit and possibly with harm in patients without left bundlebranch block (adjusted hazard ratio for death from any cause, 1.57; 95% CI, 1.03 to 2.39; P = 0.04; P<0.001 for interaction of treatment with QRS morphologic findings). CONCLUSIONS Our findings indicate that in patients with mild heart-failure symptoms, left ventricular dysfunction, and left bundle-branch block, early intervention with CRT-D was associated with a significant long-term survival benefit. (Funded by Boston Scientific; ClinicalTrials.gov numbers, NCT00180271, NCT01294449, and NCT02060110.)
288 citations
TL;DR: It is believed that heart failure should be systematically evaluated in cardiovascular outcome trials of all new glucose-lowering drugs.
274 citations
TL;DR: Left ventricular hypertrophy, higher left ventricular filling pressure, and higher pulmonary artery pressure were predictive of heart failure hospitalization, cardiovascular death, or aborted cardiac arrest independent of clinical and laboratory predictors.
Abstract: Background—Abnormalities in cardiac structure and function in heart failure with preserved ejection fraction may help identify patients at particularly high risk for cardiovascular morbidity and mortality. Methods and Results—Cardiac structure and function were assessed by echocardiography in a blinded core laboratory at baseline in 935 patients with heart failure with preserved ejection fraction (left ventricular ejection fraction ≥45%) enrolled in the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial and related to the primary composite outcome of cardiovascular death, heart failure hospitalization, or aborted cardiac arrest, and its components. At a median follow-up of 2.9 years, 244 patients experienced the primary outcome. Left ventricular hypertrophy (adjusted hazard ratio, 1.52; 95% confidence interval, 1.16–2.00), elevated left ventricular filling pressure (E/E′; adjusted hazard ratio 1.05 per 1 integer increase; 95% confidence interval, 1.02–1.07)...
210 citations
TL;DR: Methods of analysing repeat hospitalizations are described, and their value in one major trial is illustrated.
Abstract: AIMS: Heart failure is characterized by recurrent hospitalizations, but often only the first event is considered in clinical trial reports. In chronic diseases, such as heart failure, analysing all events gives a more complete picture of treatment benefit. We describe methods of analysing repeat hospitalizations, and illustrate their value in one major trial. METHODS AND RESULTS: The Candesartan in Heart failure Assessment of Reduction in Mortality and morbidity (CHARM)-Preserved study compared candesartan with placebo in 3023 patients with heart failure and preserved systolic function. The heart failure hospitalization rates were 12.5 and 8.9 per 100 patient-years in the placebo and candesartan groups, respectively. The repeat hospitalizations were analysed using the Andersen-Gill, Poisson, and negative binomial methods. Death was incorporated into analyses by treating it as an additional event. The win ratio method and a method that jointly models hospitalizations and mortality were also considered. Using repeat events gave larger treatment benefits than time to first event analysis. The negative binomial method for the composite of recurrent heart failure hospitalizations and cardiovascular death gave a rate ratio of 0.75 [95% confidence interval (CI) 0.62-0.91, P = 0.003], whereas the hazard ratio for time to first heart failure hospitalization or cardiovascular death was 0.86 (95% CI 0.74-1.00, P = 0.050). CONCLUSIONS: In patients with preserved EF, candesartan reduces the rate of admissions for worsening heart failure, to a greater extent than apparent from analysing only first hospitalizations. Recurrent events should be routinely incorporated into the analysis of future clinical trials in heart failure.
181 citations
TL;DR: Rates of cardiovascular death or HF hospitalization are greatest in those who have been previously hospitalized for HF, and recent HFospitalization identifies a high-risk population for future clinical trials in HF and reduced ejection fraction and HF with preserved ejections fraction.
Abstract: Background—Hospitalization for acute heart failure (HF) is associated with high rates of subsequent mortality and readmission. We assessed the influence of the time interval between previous HF hospitalization and randomization in the Candesartan in Heart failure: Reduction in Mortality and morbidity (CHARM) trials on clinical outcomes in patients with both reduced and preserved ejection fraction. Methods and Results—CHARM enrolled 7599 patients with New York Heart Association class II to IV HF, of whom 5426 had a history of previous HF hospitalization. Cox proportional hazards regression models were used to assess the association between time from previous HF hospitalization and randomization and the primary outcome of cardiovascular death or unplanned admission to hospital for the management of worsening HF during a median of 36.6 months. For patients with HF and reduced or preserved ejection fraction, rates of cardiovascular mortality and HF hospitalization were higher among patients with previous HF h...
121 citations
TL;DR: Elevated levels of FGF-23 are associated with cardiovascular death and incident heart failure in patients with SIHD and identify patients who derive significant clinical benefit from angiotensin-converting enzyme inhibitor therapy regardless of renal function are identified.
TL;DR: MI survivors suffering a CV event experienced significantly worse HRQL than their previous trajectory, suggesting that generic instruments can be responsive to nonfatal events.
Abstract: Objectives The objective of this study was to determine the impact of nonfatal cardiovascular (CV) events on changes in health-related quality of life (HRQL) Background There is limited understanding of the impact of nonfatal CV events on long-term changes in HRQL in survivors of myocardial infarction (MI) Methods The VALIANT (Valsartan In Acute Myocardial Infarction) trial enrolled 14,703 patients post-MI complicated by Killip class II or higher (scale measuring heart failure severity post-MI ranging from class I to IV) and/or reduced ejection fraction The HRQL substudy included 2,556 (174%) patients who completed the EQ-5D with 5 questions, with responses mapped to utility weight on a scale of 0 to 1 and a visual analog scale (VAS) ranging from 0 (worst) to 100 (best) imaginable health state EQ-5D was administered at baseline and 6, 12, 20, and 24 months The trajectory of EQ-5D scores was developed by using linear mixed effects regression models with calculation of deviation from this trajectory after nonfatal CV events Patients who died before the next EQ-5D assessment were excluded Results Over a 2-year period, 597 patients experienced a nonfatal CV event and survived to have another EQ-5D assessment Their baseline EQ-5D scores were lower than patients without a subsequent nonfatal CV event (VAS 610 ± 19 vs 682 ± 18 [p Conclusions MI survivors suffering a CV event experienced significantly worse HRQL than their previous trajectory, suggesting that generic instruments can be responsive to nonfatal events Reduction in nonfatal CV events may affect longitudinal changes in HRQL
TL;DR: Whether outpatient management of HF exacerbation carries similar prognostic and therapeutic information is less well known, but could be important for the design of trials that use HF hospitalization as an endpoint.
Abstract: Aims
Hospitalization for worsening heart failure (HF) is known to increase mortality and morbidity risk and has been frequently used as an endpoint in randomized clinical trials. Whether outpatient management of HF exacerbation carries similar prognostic and therapeutic information is less well known, but could be important for the design of trials that use HF hospitalization as an endpoint.
Methods and results
MADIT-CRT randomized patients with mild HF symptoms to resynchronization therapy vs. control with an average follow-up of 3.3 years and a total of 191 deaths. HF events were centrally adjudicated for receiving i.v. decongestive therapy in an outpatient setting, or an augmented HF regimen during a hospital stay. Patients were compared according to whether their first HF was an out- or inpatient event. The first primary event was non-fatal outpatient HF, non-fatal inpatient HF, and death in 52, 331, and 78 patients, respectively. Patients with inpatient HF tended to be older and more likely to have HF of ischaemic aetiology than subjects who developed outpatient HF events. The risk of death following either type of non-fatal HF events was extremely high [hazard ratio (HR) 12.4, 95% confidence interval (CI) 9.1–16.9 for inpatient HF; HR 10.7, 95% CI 6.1–18.7 for outpatient HF] compared with subjects without non-fatal HF events. Allocation to CRT-D was associated with significant reduction in both types of HF.
Conclusion
Outpatient management of worsening HF portends a high risk of death, similar to inpatient HF events, and may be equally sensitive to the effects of therapy. These findings suggest that outpatient HF events should be considered in publicly reported outcomes measures and future HF clinical trials.
Trial Registration
NCT01294449.
TL;DR: Non-CV hospitalization is frequent in patients with symptomatic heart failure and associated with risk of subsequent mortality similar to CV hospitalization across the spectrum of EF, which may have implications for developing strategies to prevent readmissions.
Abstract: Background—Noncardiovascular (non-CV) comorbidities may contribute to hospitalizations in patients with heart failure (HF). We examined the incidence of mortality following hospitalization for cardiovascular (CV) versus non-CV reasons in the Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM) Program. Methods and Results—First hospitalizations for CV or non-CV reasons during the CHARM trial (N=7599) were related to subsequent risk of all-cause death using time-updated proportional hazards models. Over median 37.7 month follow-up, 2816 subjects (37.1%) were not hospitalized, 2893 (38.1%) were first hospitalized for CV reasons, and 1890 (24.9%) for non-CV reasons. The death rate (per 100 patient-years) among those not hospitalized was 2.8 compared with 17.8 after CV and 16.5 after non-CV hospitalization (both P<0.001 versus not hospitalized). Mortality at 30 days was higher after CV than non-CV hospitalization; however, among 30-day survivors of CV and non-CV hospitaliza...
TL;DR: In a large cohort of patients with T2DM, CKD, and anemia, retinopathy was common but not independently associated with a higher risk of renal or cardiovascular morbidity or death.
Abstract: Objective: Retinopathy is an established microvascular complication of type 2 diabetes mellitus (T2DM), but its independent relationship with macrovascular and other microvascular complications is less well defined across the spectrum of kidney disease in T2DM. We examined the prognostic value of retinopathy in assessing the risk of developing endstage renal disease (ESRD), cardiovascular morbidity or death among patients in the Trial to Reduce cardiovascular Events with Aranesp Therapy (TREAT). Design: TREAT enrolled 4038 patients with T2DM, chronic kidney disease (CKD) and moderate anemia. Patients were grouped by baseline history of retinopathy. Proportional hazards regression models were utilized to assess the association between retinopathy and subsequent ESRD, cardiovascular morbidity or death over an average of 2.4 years. Results: Although younger, the 1895 (47%) patients with retinopathy had longer duration of diabetes, lower estimated glomerular filtration rate, more proteinuria, and more microvascular complications. In univariate analysis, retinopathy was associated with a higher rate of ESRD, but not with cardiovascular events or mortality. After adjustment, retinopathy was no longer statistically significant for the prediction of ESRD or any clinical endpoint. Conclusions: In a large cohort of patients with T2DM, CKD, and anemia, retinopathy was common but not independently associated with a higher risk of renal or cardiovascular morbidity or death. Trial registration number: NCT00093015
TL;DR: In clinically stable chronically supported LVAD patients, intrinsic cardiac structure, function, and myocardial viability did not significantly change over the pre-specified time frame, and was unchanged on repeat imaging while at reduced LVAD speed.
Abstract: Background Chronically supported left ventricular assist device (LVAD) patients may be candidates for novel therapies aimed at promoting reverse remodeling and myocardial recovery. However, the effect of hemodynamic unloading with a LVAD on myocardial viability and LV function in chronically supported LVAD patients has not been fully characterized. We aimed to develop a non-invasive imaging protocol to serially quantify native cardiac structure, function, and myocardial viability while at reduced LVAD support. Methods Clinically stable ( n = 18) ambulatory patients (83% men, median age, 61 years) supported by a HeartMate II (Thoratec, Pleasanton, CA) LVAD (median durations of heart failure 4.6 years and LVAD support 7 months) were evaluated by echocardiography and technetium-99m ( 99m Tc)-sestamibi single photon emission computed tomography (SPECT) imaging at baseline and after an interval of 2 to 3 months. Echocardiographic measures of LV size and function, including speckle tracking–derived circumferential strain, were compared between ambulatory and reduced LVAD support at baseline and between baseline and follow-up at reduced LVAD support. The extent of myocardial viability by SPECT was compared between baseline and follow-up at reduced LVAD support. Results With reduction in LVAD speeds (6,600 rpm; interquartile range: 6,200, 7,400 rpm), LV size increased, LV systolic function remained stable, and filling pressures nominally worsened. After a median 2.1 months, cardiac structure, function, and the extent of viable myocardium, globally and regionally, was unchanged on repeat imaging while at reduced LVAD speed. Conclusions In clinically stable chronically supported LVAD patients, intrinsic cardiac structure, function, and myocardial viability did not significantly change over the pre-specified time frame. Echocardiographic circumferential strain and 99m Tc-sestamibi SPECT myocardial viability imaging may provide useful non-invasive end points for the assessment of cardiac structure and function, particularly for phase II studies of novel therapies aimed at promoting reverse remodeling and myocardial recovery in LVAD patients.
TL;DR: Sizeable reductions in BP, with potential for substantial CVD reduction, can be safely achieved using combinations of BP drugs in the elderly with normal high and Stage 1 hypertension.
Abstract: Aims We studied the unclear question whether blood pressure (BP) lowering reduces cardiovascular disease (CVD) in elderly individuals with systolic BP <160 mm Hg.
Methods and results We initiated a randomized placebo-controlled stratified 2 × 2 factorial clinical trial evaluating the effects of BP lowering in 11 000 elderly individuals with systolic blood pressure (SBP) between 130 and 159 mm Hg, for 5 years. Following 5-week active run-in, participants were randomized to aliskiren (300 mg) or placebo, and to an additional antihypertensive [hydrochlorothiazide (25 mg) or amlodipine (5 mg)], or their respective placeboes. Study was terminated by sponsor after 1759 subjects (age 72.1 ± 5.2 years, 88% receiving at least one antihypertensive) were randomized and followed for 0.6 year. Study drugs were well tolerated with few serious adverse events during run-in and after randomization, with no significant differences between treatment groups. By design, three levels of BP reductions were achieved, adjusted mean BP reductions of 3.5/1.7 mm Hg ( P < 0.001) by aliskiren, 6.8/3.3 mm Hg ( P < 0.001) by hydrochlorothiazide or amlodipine, and 10.3/5.0 mm Hg ( P < 0.001) by double therapy compared with placebo. Twenty-five major CVD events occurred. Non-significant trends towards fewer CVD events with greater BP reductions are evident: hazard ratios (HR) 0.82 [95% confidence interval (CI): 0.37–1.81] for 3.5 mm Hg SBP reduction; HR 0.45 (95% CI: 0.19–1.04) for 6.8 mm Hg; and HR 0.25 (0.05–1.18) for 10.3 mm Hg reduction for primary composite of CV death, MI, stroke, or significant heart failure.
Conclusions Sizeable reductions in BP, with potential for substantial CVD reduction, can be safely achieved using combinations of BP drugs in the elderly with normal high and Stage 1 hypertension.
Clinical trial registration NCT01259297.
TL;DR: Creative approaches are needed for the engagement of DMC members to increase the transparency such that they are neither employees of nor consultants to the sponsor of the trial; meaningful conflicts of interest should be identified and addressed.
Abstract: Data monitoring committees (DMCs) have important roles in safeguarding patient interests and enhancing trial integrity and credibility. To effectively fulfill their responsibilities, DMCs should be independent of study sponsors, study investigators, and caregivers managing study participants. Unfortunately, in real-world settings where DMCs are in place, there are some practices that threaten to diminish the level of independence of these committees. To address this, some important approaches should be considered: A DMC charter should outline the roles and responsibilities of the DMC without appearing to be a legal contract; the meetings of the DMC should be led by its chair, ideally with a meeting format that ensures independence from the investigators and sponsor; the DMC and those having leadership roles in the monitoring process should have adequate training and experience; procedures should be in place to enable the DMC to have access to interim safety and efficacy data that are accurate, current, an...
TL;DR: This editorial refers to ‘Right heart dysfunction in heart failure with preserved ejection fraction’, by V. Melenovsky et al, to appropriately call the attention to the importance of RV dysfunction as a contributing mechanism.
Abstract: This editorial refers to ‘Right heart dysfunction in heart failure with preserved ejection fraction’, by V. Melenovsky et al. , on page doi:10.1093/eurheartj/ehu193
In heart failure (HF) with reduced ejection fraction (HFrEF), the magnitude of left ventricular (LV) contractile dysfunction which defines this group has proven an important prognostic marker and effective target for therapy. Measures of right ventricular (RV) contraction are not commonly quantified, but when they are they provide additional prognostic information. It is now well recognized that up to half of HF patients have more preserved contractile function as measured by LVEF (HFpEF),1 demonstrate rates of HF re-hospitalization and functional decline similar to HFrEF,2 and have a higher risk of death compared with age-matched controls.3 While abnormal cardiac performance is implied in the HF diagnosis, the mechanisms underlying HFpEF are clearly multifactorial, with contributions of age, arterial stiffening, renal dysfunction, atrial fibrillation, and obesity, among others ( Figure 1 ). Even within the heart, while LV diastolic dysfunction is an important underlying cardiac perturbation, additional abnormalities of cardiac function may contribute, including subtle abnormalities of LV systolic function, dyssynchronous ventricular contraction and/or relaxation, impaired left atrial (LA) function, pulmonary vascular dysfunction, chronotropic incompetence, and impaired peripheral oxygen extraction.4 In addition to aetiological heterogeneity, phenotypic heterogeneity and the prominent contribution of co-morbidities make understanding this syndrome particularly challenging. Melenovsky et al . now appropriately call our attention to the importance of RV dysfunction as a contributing mechanism.5
Operating in parallel with the left ventricle, the right ventricle is also intimately coupled to the left ventricle via the interventricular septum and pericardium. The right ventricle normally …
TL;DR: This work investigated the relationship of kidney function and long‐term cardiovascular outcomes in patients with high risk myocardial infarction and found that renal dysfunction is associated with poor cardiovascular outcome.
Abstract: We studied 27 610 patients from four randomized trials of acute myocardial infarction complicated by heart failure and/or LV dysfunction (LVEF ≤40%). Two trials excluded patients with serum creatinine ≥2.5 mg/dL. Patients were grouped by estimated glomerular filtration rate (eGFR) using the four-component Modification of Diet in Renal Disease equation. We used adjusted Cox proportional hazard models to compare mortality and composite cardiovascular events among eGFR groups. Median follow-up was 23 months. The eGFR was approximately normally distributed, with a mean ± SD of 69.1 ± 20.2 mL/min/1.73 m 2 . Co-morbidities were more prevalent with lower eGFR. The risk of death or composite outcome of cardiovascular death, myocardial infarction, stroke, or heart failure hospitalization increased with declining eGFR. Below 75 mL/min/1.73 m 2 , each 10 unit reduction of eGFR was associated with an adjusted hazard ratio for death of 1.13 (95% confidence interval, 1.11–1.15) and composite cardiovascular outcome of 1.09 (95% confidence interval, 1.08–1.10). Older patients (≥75 years) with low LVEF (<30%) had a higher incidence of mortality and adverse cardiovascular events across eGFR categories.
TL;DR: Electrocardiographic left ventricular hypertrophy was identified as one of the earliest “factors of risk” in patients at heightened risk for cardiovascular events before the advent of noninvasive imaging.
Abstract: Alterations in cardiac structure and function have long been recognized as markers of heightened risk for cardiovascular events. Indeed, even before the advent of noninvasive imaging, electrocardiographic left ventricular hypertrophy (LVH) was identified as one of the earliest “factors of risk”
Journal Article•
TL;DR: The Trial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT) demonstrated a heightened risk of stroke associated with Darbepoetin alfa use, and this finding raised significant patient safety concerns.
Journal Article•
TL;DR: Impaired LS, defined as an absolute LS < 15.8%, was present in 53% of patients and was associated with the composite outcome of cardiovascular (CV) death, HF hospitalization, or aborted cardiac arrest, and its components.
Abstract: Introduction: Left ventricular (LV) systolic function by strain imaging is impaired in heart failure with preserved ejection fraction (HFpEF) but its prognostic relevance is not known. Hypothesis: We hypothesized that worse longitudinal strain (LS) is independently associated with adverse outcomes. Methods: LS was assessed by 2D speckle-tracking echocardiography in a blinded core laboratory at baseline in 447 patients with HFpEF (left ventricular ejection fraction [LVEF] ≥45%) enrolled in the Treatment Of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial and was related to the primary composite outcome of cardiovascular (CV) death, HF hospitalization, or aborted cardiac arrest, and its components. Results: At a median follow-up of 2.6 (IQR 1.5-3.9) years, 115 patients experienced the primary outcome. Impaired LS, defined as an absolute LS < 15.8%, was present in 53% of patients and was associated with the composite outcome (adjusted HR 2.14, 95% CI 1.26-3.66; p=0.005),...
TL;DR: The relationship between β-blocker use and outcomes in HFPEF was explored with a sophisticated analysis of data from the Swedish heart failure registry, an administrative database that includes inpatient, outpatient, pharmacy, and outcomes information collected from individuals across the entire country.
Abstract: Heart failure with preserved ejection fraction (HFPEF) poses just as daunting a challenge for physicians and patients as heart failure with reduced ejection fraction (HFREF) but without nearly as defined a course for how to best treat affected patients. Although potential new therapies for treating HFPEF are being investigated, it is always worth revisiting existing therapies to evaluate their potential as available and costeffective options for care. This sentiment has motivated several studies of β-blockers and their association with important outcomes for patients with HFPEF,1,2 including the observational analysis by Lund and colleagues3 in this issue of JAMA. Beginning in the 1970s, Swedish investigators originally introduced the concept of β-blocker use to treat chronic heart failure through a series of case reports and small studies.4 These compelling early data inspired major clinical trials that convincingly demonstrated that β-blocker therapy could reduce hospitalizations and mortality across the spectrum of disease severity in HFREF.5-8 Because the presentation of heart failure with either reduced or preserved ejection fraction involves myocardial demand in excess of reserve, it is reasonable to postulate that the benefits of β-blocker therapy in HFREF might also apply to HFPEF. To explore the relationship between β-blocker use and outcomes in HFPEF, Lund et al performed a sophisticated analysis of data from the Swedish heart failure registry, an administrative database that includes inpatient, outpatient, pharmacy, and outcomes information collected from individuals across the entire country. The authors identified 19 083 adults diagnosed with heart failure and an ejection fraction of at least 40% and included extensive variables describing the characteristics of this HFPEF cohort (Tables 1 through 3 in the article). Uncharacteristic of findings reported from other HFPEF cohorts,9 individuals with HFPEF in this study were more likely to be men than women and the vast majority were living independently in the community. In addition, more than half had atrial fibrillation, almost double the rate of that reported in other HFPEF cohorts.9 Perhaps a related finding, β-blockers were the most frequently prescribed cardiac medication (83%) for these patients, followed closely by diuretics (79%) and renin-angiotensin antagonists (78%). As expected, the large proportion of HFPEF patients treated with β-blockers were significantly different from the smaller proportion of those not treated with β-blockers across multiple characteristics in the cohort. Therefore, to compare outcomes between treated and nontreated individuals, a propensity score–matching process was required to create a subsample of treated and untreated patients who appeared more balanced in terms of their demographic and clinical characteristics. Ultimately, a total of 8244 patients were matched 2:1 (β-blocker:no β-blocker) based on age, sex, and propensity for being prescribed a β-blocker. When the matched groups were compared, presence of β-blocker therapy was associated with an absolute 3% and a relative 8% lower risk of all-cause mortality at 5 years (P = .02) . However, this association was nonsignificant in the total HFPEF cohort when the analyses were adjusted for propensity score. Notably, there was no relation of β-blocker use with the composite outcome of death or heart failure hospitalization in either the matched sample or the total HFPEF cohort. As the authors have shown, the propensity score approach can fail to match many potentially eligible patients. Thus, whereas the advantage of an administrative database is to capture information across a large sample of the population, a substantial proportion of the sample—more than half in this case—were excluded from the primary analysis. That a large number of individuals treated with β-blockers could not be matched to patients not treated with β-blockers on propensity score indicates the presence of a strong selection bias in β-blocker prescribing patterns. In other words, many clinicians in Sweden apparently used similar criteria for deciding which HFPEF patients should receive β-blocker therapy, making it difficult to find treated and untreated individuals who otherwise appeared demographically and clinically alike. Even the most careful attempts to match and adjust are unable to account for known and unknown confounders in the manner achieved by randomization. Although patients in the primary analysis were matched based on a propensity score that comprised more than 50 variables, many additional unmeasured factors could have influenced both the likelihood of being prescribed a β-blocker and the outcome. Examples of such factors include chronotropic incompetence (impaired heart rate response to physical activity which contributes to symptoms), burden of comorbidities, and overall health status and quality of life. In this cohort, persons taking β-blocker therapy were also more likely to be already taking multiple other medications and so could represent individuals more likely to adhere to medications in general. Data from prior trials indicate that patients with heart failure who have higher levRelated article page 2008 Opinion
01 Jan 2014
TL;DR: The parallelisms between the concepts, surrogate outcomes, and more definitive randomized placebo-controlled trials addressing clinical outcome for the use of angiotensin-converting enzyme (ACE) inhibitors in asymptomatic individuals with left ventricular dysfunction are presented.
Abstract: The establishment of hypertension as a risk factor for premature fatal and nonfatal cardiovascular diseases by epidemiological studies was the first step in developing a management strategy to improve prognosis. The demonstration in randomized, placebo- controlled trials that chronic antihypertensive therapy could reduce this risk provided the impetus for an ongoing educational program to motivate both physicians and patients to use pharmacologic agents to treat this asymptomatic condition in order to prevent future adverse cardiovascular events. The parallelisms between the concepts, surrogate outcomes, and more definitive randomized placebo-controlled trials addressing clinical outcome for the use of angiotensin-converting enzyme (ACE) inhibitors in asymptomatic individuals with left ventricular dysfunction are presented. In both cases, the combination of definitive outcomes and safety data coupled with a supportive educational program are needed for physicians and patients to accept and continue lifelong therapy for asymptomatic conditions.