John F. Heitner

Spironolactone for Heart Failure with Preserved Ejection Fraction

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 spironolactone 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.).

Detection of Myocardial Damage in Patients With Sarcoidosis

Background— In patients with sarcoidosis, sudden death is a leading cause of mortality, which may represent unrecognized cardiac involvement. Delayed-enhancement cardiovascular magnetic resonance (DE-CMR) can detect minute amounts of myocardial damage. We sought to compare DE-CMR with standard clinical evaluation for the identification of cardiac involvement. Methods and Results— Eighty-one consecutive patients with biopsy-proven extracardiac sarcoidosis were prospectively recruited for a parallel and masked comparison of cardiac involvement between (1) DE-CMR and (2) standard clinical evaluation with the use of consensus criteria (modified Japanese Ministry of Health [JMH] guidelines). Standard evaluation included 12-lead ECG and at least 1 dedicated non-CMR cardiac study (echocardiography, radionuclide scintigraphy, or cardiac catheterization). Patients were followed for 21±8 months for major adverse events (death, defibrillator shock, or pacemaker requirement). Patients were predominantly middle-aged (46±11 years), female (62%), and black (73%) and had chronic sarcoidosis (median, 7 years) and preserved left ventricular ejection fraction (median, 56%). DE-CMR identified cardiac involvement in 21 patients (26%) and JMH criteria in 10 (12%, 8 overlapping), a >2-fold higher rate for DE-CMR (P=0.005). All patients with myocardial damage on DE-CMR had coronary disease excluded by x-ray angiography. Pathology evaluation in 15 patients (19%) identified 4 with cardiac sarcoidosis; all 4 were positive by DE-CMR, whereas 2 were JMH positive. On follow-up, 8 had adverse events, including 5 cardiac deaths. Patients with myocardial damage on DE-CMR had a 9-fold higher rate of adverse events and an 11.5-fold higher rate of cardiac death than patients without damage. Conclusions— In patients with sarcoidosis, DE-CMR is more than twice as sensitive for cardiac involvement as current consensus criteria. Myocardial damage detected by DE-CMR appears to be associated with future adverse events including cardiac death, but events were few, and this needs confirmation in a larger cohort.

Regional Variation in Patients and Outcomes in the Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist (TOPCAT) Trial

Background— Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist (TOPCAT) patients with heart failure and preserved left ventricular ejection fraction assigned to spironolactone did not achieve a significant reduction in the primary composite outcome (time to cardiovascular death, aborted cardiac arrest, or hospitalization for management of heart failure) compared with patients receiving placebo. In a post hoc analysis, an ≈4-fold difference was identified in this composite event rate between the 1678 patients randomized from Russia and Georgia compared with the 1767 enrolled from the United States, Canada, Brazil, and Argentina (the Americas). Methods and Results— To better understand this regional difference in clinical outcomes, demographic characteristics of these populations and their responses to spironolactone were explored. Patients from Russia/Georgia were younger, had less atrial fibrillation and diabetes mellitus, but were more likely to have had prior myocardial infarction or a hospitalization for heart failure. Russia/Georgia patients also had lower left ventricular ejection fraction and creatinine but higher diastolic blood pressure (all P<0.001). Hyperkalemia and doubling of creatinine were more likely and hypokalemia was less likely in patients receiving spironolactone in the Americas with no significant treatment effects in Russia/Georgia. All clinical event rates were markedly lower in Russia/Georgia, and there was no detectable impact of spironolactone on any outcomes. In contrast, in the Americas, the rates of the primary outcome, cardiovascular death, and hospitalization for heart failure were significantly reduced by spironolactone. Conclusions— This post hoc analysis demonstrated greater potassium and creatinine changes and possible clinical benefits with spironolactone in patients with heart failure and preserved ejection fraction from the Americas. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00094302.

Cardiac Structure and Function in Heart Failure With Preserved Ejection Fraction: Baseline Findings From the Echocardiographic Study of the Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial

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 a higher prevalence of left atrial enlargement. Doppler evidence of pulmonary hypertension was present in 36%. At least 1 measure of structural heart disease was present in 93% of patients. Conclusions— 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. Diastolic function was normal in approximately one third of gradable participants, highlighting the heterogeneity of the cardiac phenotype in this syndrome. These findings deepen our understanding of the TOPCAT trial population and expand our knowledge of the diversity of the cardiac phenotype in HFpEF. Clinical Trial Registration—URL: . Unique identifier: [NCT00094302][1]. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00094302&atom=%2Fcirchf%2F7%2F1%2F104.atomBackground— 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 a higher prevalence of left atrial enlargement. Doppler evidence of pulmonary hypertension was present in 36%. At least 1 measure of structural heart disease was present in 93% of patients. Conclusions— 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. Diastolic function was normal in approximately one third of gradable participants, highlighting the heterogeneity of the cardiac phenotype in this syndrome. These findings deepen our understanding of the TOPCAT trial population and expand our knowledge of the diversity of the cardiac phenotype in HFpEF. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00094302.

Intravenous Erythropoietin in Patients With ST-Segment Elevation Myocardial Infarction: REVEAL: A Randomized Controlled Trial

CONTEXT Acute ST-segment elevation myocardial infarction (STEMI) is a leading cause of morbidity and mortality. In experimental models of MI, erythropoietin reduces infarct size and improves left ventricular (LV) function. OBJECTIVE To evaluate the safety and efficacy of a single intravenous bolus of epoetin alfa in patients with STEMI. DESIGN, SETTING, AND PATIENTS A prospective, randomized, double-blind, placebo-controlled trial with a dose-escalation safety phase and a single dose (60,000 U of epoetin alfa) efficacy phase; the Reduction of Infarct Expansion and Ventricular Remodeling With Erythropoietin After Large Myocardial Infarction (REVEAL) trial was conducted at 28 US sites between October 2006 and February 2010, and included 222 patients with STEMI who underwent successful percutaneous coronary intervention (PCI) as a primary or rescue reperfusion strategy. INTERVENTION Participants were randomly assigned to treatment with intravenous epoetin alfa or matching saline placebo administered within 4 hours of reperfusion. MAIN OUTCOME MEASURE Infarct size, expressed as percentage of LV mass, assessed by cardiac magnetic resonance (CMR) imaging performed 2 to 6 days after study medication administration (first CMR) and again 12 ± 2 weeks later (second CMR). RESULTS In the efficacy cohort, the infarct size did not differ between groups on either the first CMR scan (n = 136; 15.8% LV mass [95% confidence interval {CI}, 13.3-18.2% LV mass] for the epoetin alfa group vs 15.0% LV mass [95% CI, 12.6-17.3% LV mass] for the placebo group; P = .67) or on the second CMR scan (n = 124; 10.6% LV mass [95% CI, 8.4-12.8% LV mass] vs 10.4% LV mass [95% CI, 8.5-12.3% LV mass], respectively; P = .89). In a prespecified analysis of patients aged 70 years or older (n = 21), the mean infarct size within the first week (first CMR) was larger in the epoetin alfa group (19.9% LV mass; 95% CI, 14.0-25.7% LV mass) than in the placebo group (11.7% LV mass; 95% CI, 7.2-16.1% LV mass) (P = .03). In the safety cohort, of the 125 patients who received epoetin alfa, the composite outcome of death, MI, stroke, or stent thrombosis occurred in 5 (4.0%; 95% CI, 1.31%-9.09%) but in none of the 97 who received placebo (P = .04). CONCLUSIONS In patients with STEMI who had successful reperfusion with primary or rescue PCI, a single intravenous bolus of epoetin alfa within 4 hours of PCI did not reduce infarct size and was associated with higher rates of adverse cardiovascular events. Subgroup analyses raised concerns about an increase in infarct size among older patients. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00378352.

Detection of Left Ventricular Thrombus by Delayed-Enhancement Cardiovascular Magnetic Resonance : Prevalence and Markers in Patients With Systolic Dysfunction

OBJECTIVES This study sought to assess the prevalence and markers of left ventricular (LV) thrombus among patients with systolic dysfunction. BACKGROUND Prior studies have yielded discordant findings regarding prevalence and markers of LV thrombus. Delayed-enhancement cardiovascular magnetic resonance (DE-CMR) identifies thrombus on the basis of tissue characteristics rather than just anatomical appearance and is potentially highly accurate. METHODS Prevalence of thrombus by DE-CMR was determined in 784 consecutive patients with systolic dysfunction (left ventricular ejection fraction [LVEF] <50%) imaged between July 2002 and July 2004. Patients were recruited from 2 separate institutions: a tertiary-care referral center and an outpatient clinic. Comparison to cine-cardiovascular magnetic resonance (CMR) was performed. Follow-up was undertaken for thrombus verification via pathology evaluation or documented embolic event within 6 months after CMR. Clinical and imaging parameters were assessed to determine risk factors for thrombus. RESULTS Among this at-risk population (age 60 +/- 14 years; LVEF 32 +/- 11%), DE-CMR detected thrombus in 7% (55 patients) and cine-CMR in 4.7% (37 patients, p < 0.005). Follow-up was consistent with DE-CMR as a better reference standard than cine-CMR, including 100% detection among 5 patients with thrombus verified by pathology (cine-CMR, 40% detection), and logistic regression analysis testing the contributions of DE-CMR and cine-CMR simultaneously, which showed that only the presence of thrombus by DE-CMR was associated with follow-up end points (p < 0.005). Cine-CMR generally missed small intracavitary and small or large mural thrombus. In addition to traditional indices such as low LVEF and ischemic cardiomyopathy, multivariable analysis showed that increased myocardial scarring, an additional parameter available from DE-CMR, was an independent risk factor for thrombus. CONCLUSIONS In a broad cross section of patients with systolic dysfunction, thrombus prevalence was 7% by DE-CMR and included small intracavitary and small or large mural thrombus missed by cine-CMR. Prevalence increased with worse LVEF, ischemic etiology, and increased myocardial scarring.

Baseline Characteristics of Patients in the Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial

Background—Treatment of Preserved Cardiac Function with an Aldosterone Antagonist (TOPCAT) is an ongoing randomized controlled trial of spironolactone versus placebo for heart failure with preserved ejection fraction (HFpEF). We sought to describe the baseline clinical characteristics of subjects enrolled in TOPCAT relative to other contemporary observational studies and randomized clinical trials of HFpEF. Methods and Results—Between August 2006 and January 2012, 3445 patients with symptomatic HFpEF from 270 sites in 6 countries were enrolled in TOPCAT. At the baseline study visit, all subjects provided a detailed medical history and underwent physical examination, electrocardiography, quality of life, and laboratory assessment. Key parameters were compared with other large, contemporary HFpEF studies. The mean age was 68.6±9.6 years with a slight female predominance (52%); mean body mass index was 32 kg/m2; and comorbidities were common. History of hypertension (91% prevalence in TOPCAT) exceeded all other major HFpEF clinical trials. However, baseline blood pressure was well controlled (129/76 mm Hg; systolic blood pressure 7–16 mm Hg lower than other similar trials). Other common comorbidities included coronary artery disease (57%), atrial fibrillation (35%), chronic kidney disease (38%) and diabetes mellitus (32%). Self-reported activity levels were low, quality of life scores were comparable with those reported for patients with end-stage renal disease, and the prevalence of moderate or greater depression was 27%. Conclusions—TOPCAT subjects share many common characteristics with contemporary HFpEF cohorts. Low activity level, significantly decreased quality of life, and depression were common at baseline in TOPCAT, underscoring the continued unmet need for evidence-based treatment strategies in HFpEF. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00094302.

Cardiac Structure and Function and Prognosis in Heart Failure With Preserved Ejection Fraction

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), and higher pulmonary artery pressure assessed by the tricuspid regurgitation velocity (hazard ratio, 1.23 per 0.5 m/s increase; 95% confidence interval, 1.02–1.49) were associated with the composite outcome and heart failure hospitalization alone after adjusting for clinical and laboratory variables. The risk of adverse outcome associated with left ventricular hypertrophy was additive to the risk associated with elevated E/E′. Conclusions—Among heart failure with preserved ejection fraction patients enrolled in TOPCAT, 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. These features, both alone and in combination, identify heart failure with preserved ejection fraction patients at particularly high risk for cardiovascular morbidity and mortality. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00094302.

Losmapimod, a novel p38 mitogen-activated protein kinase inhibitor, in non-ST-segment elevation myocardial infarction: a randomised phase 2 trial

BACKGROUND p38 MAPK inhibition has potential myocardial protective effects. We assessed losmapimod, a potent oral p38 MAPK inhibitor, in patients with non-ST-segment elevation myocardial infarction (NSTEMI) in a double-blind, randomised, placebo-controlled trial. METHODS From October, 2009, to November, 2011, NSTEMI patients were assigned oral losmapimod (7·5 mg or 15·0 mg loading dose followed by 7·5 mg twice daily) or matching placebo in a 3:3:2 ratio. Safety outcomes were serious adverse events and alanine aminotransferase (ALT) concentrations over 12 weeks, and cardiac events (death, myocardial infarction, recurrent ischaemia, stroke, and heart failure) at 90 days. Efficacy outcomes were high-sensitivity C-reactive protein (hsCRP) and B-type natriuretic peptide (BNP) concentrations at 72 h and 12 weeks, and troponin I area under the curve (AUC) over 72 h. The losmapimod groups were pooled for analysis. This trial is registered with ClinicalTrials.gov, number NCT00910962. FINDINGS Of 535 patients enrolled, 526 (98%) received at least one dose of study treatment (losmapimod n=388 and placebo n=138). Safety outcomes did not differ between groups. HsCRP concentrations at 72 h were lower in the losmapimod group than in the placebo group (geometric mean 64·1 nmol/L, 95% CI 53·0-77·6 vs 110·8 nmol/L, 83·1-147·7; p=0·0009) but were similar at 12 weeks. Early geometric mean BNP concentrations were similar at 72 h but significantly lower in the losmapimod group at 12 weeks (37·2 ng/L, 95% CI 32·3-42·9 vs 49·4 ng/L, 38·7-63·0; p=0·04). Mean troponin I AUC values did not differ. INTERPRETATION p38 MAPK inhibition with oral losmapimod was well tolerated in NSTEMI patients and might improve outcomes after acute coronary syndromes. FUNDING GlaxoSmithKline.

Value of Cardiovascular Magnetic Resonance Stress Perfusion Testing for the Detection of Coronary Artery Disease in Women

OBJECTIVES We wanted to assess the value of cardiovascular magnetic resonance (CMR) stress testing for evaluation of women with suspected coronary artery disease (CAD). BACKGROUND A combined perfusion and infarction CMR examination can accurately diagnose CAD in the clinical setting in a mixed gender population. METHODS We prospectively enrolled 147 consecutive women with chest pain or other symptoms suggestive of CAD at 2 centers (Duke University Medical Center, Robert-Bosch-Krankenhaus). Each patient underwent a comprehensive clinical evaluation, a CMR stress test consisting of cine rest function, adenosine-stress and rest perfusion, and delayed-enhancement CMR infarction imaging, and X-ray coronary angiography within 24 h. The components of the CMR test were analyzed visually both in isolation and combined using a pre-specified algorithm. Coronary artery disease was defined as stenosis > or =70% on quantitative analysis of coronary angiography. RESULTS Cardiovascular magnetic resonance imaging was completed in 136 females (63.0 +/- 11.1 years), 37 (27%) women had CAD on coronary angiography. The combined CMR stress test had a sensitivity, specificity, and accuracy of 84%, 88%, and 87%, respectively, for the diagnosis of CAD. Diagnostic accuracy was high at both sites (Duke University Medical Center 82%, Robert-Bosch-Krankenhaus 90%; p = 0.18). The accuracy for the detection of CAD was reduced when intermediate grade stenoses were included (82% vs. 87%; p = 0.01 compared the cutoff of stenosis > or =50% vs. > or =70%). The sensitivity was lower in women with single-vessel disease (71% vs. 100%; p = 0.06 compared with multivessel disease) and small left ventricular mass (69% vs. 95%; p = 0.04 for left ventricular mass < or =97 g vs. >97 g). The latter difference was even more significant after accounting for end-diastolic volumes (70% vs. 100%; p = 0.02 for left ventricular mass indexed to end-diastolic volume < or =1.15 g/ml vs. >1.15 g/ml). CONCLUSIONS A multicomponent CMR stress test can accurately diagnose CAD in women. Detection of CAD in women with intermediate grade stenosis, single-vessel disease, and with small hearts is challenging.