Marvin A Konstam

Tufts Medical Center, Boston, Massachusetts, United States

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Publications (349)2494.78 Total impact

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    ABSTRACT: We investigated the clinical profiles associated with serum uric acid (sUA) levels in a large cohort of patients hospitalized for worsening chronic heart failure with ejection fraction (EF) ≤40%, with specific focus on gender, race, and renal function based interactions. In 3,955 of 4,133 patients (96%) with baseline sUA data, clinical characteristics and outcomes were compared across sUA quartiles. The primary end points were all-cause mortality and a composite of cardiovascular mortality or heart failure hospitalization. Interaction analyses were performed for gender, race, and baseline renal function. Median follow-up was 9.9 months. Mean sUA was 9.1 ± 2.8 mg/dl and was higher in men than in women (9.3 ± 2.7 vs 8.7 ± 3.0 mg/dl, p <0.001) and in blacks than in whites (10.0 ± 2.7 vs 9.0 ± 2.8 mg/dl, p <0.001). Higher sUA was associated with lower systolic blood pressure and EF, higher natriuretic peptides, and more impaired renal function. After accounting for 24 baseline covariates, in patients with enrollment estimated glomerular filtration rate ≥30 ml/min/1.73 m(2), sUA was strongly associated with increased all-cause mortality (hazard ratio 1.44, 95% confidence interval 1.22 to 1.69, p <0.001) and the composite end point (hazard ratio 1.44, 95% confidence interval 1.26 to 1.64, p <0.001). However, in patients with estimated glomerular filtration rate <30 ml/min/1.73 m(2), sUA was not related with either end point (both p >0.4). Adjusted interaction analyses for gender, race, and admission allopurinol use were not significant. In conclusion, sUA is commonly elevated in patients hospitalized for worsening chronic heart failure and reduced EF, especially in men and blacks. The prognostic use of sUA differs by baseline renal function, suggesting different biologic and pathophysiologic significance of sUA among those with and without significant renal dysfunction.
    The American journal of cardiology. 09/2014;
  • Alanna A Morris, Javed Butler, Marvin A Konstam
    Journal of cardiac failure. 08/2014;
  • Journal of cardiac failure. 08/2014; 20(8S):S103-S104.
  • Journal of cardiac failure. 08/2014; 20(8S):S102.
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    ABSTRACT: Despite the well-established benefits of mineralocorticoid receptor agonists (MRAs) in heart failure with reduced ejection fraction, safety concerns remain in patients with concomitant diabetes mellitus (DM) because of common renal and electrolyte abnormalities in this population. We analyzed all-cause mortality and composite cardiovascular mortality and HF hospitalization over a median 9.9 months among 1,998 patients in the placebo arm of the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan (EVEREST) trial by DM status and discharge MRA use. Of the 750 patients with DM, 59.2% were receiving MRAs compared with 62.5% in the non-DM patients. DM patients not receiving MRAs were older, more likely to be men, with an ischemic heart failure etiology and slightly worse renal function compared with those receiving MRAs. After adjustment for baseline risk factors, among DM patients, MRA use was not associated with either mortality (hazard ratio [HR] 0.93; 95% confidence interval [CI] 0.75 to 1.15) or the composite end point (HR 0.94; 95% CI 0.80 to 1.10). Similar findings were seen in non-DM patients (mortality [HR 1.01; 95% CI 0.84 to 1.22] or the composite end point [HR 0.98; 95% CI 0.85 to 1.13] [p >0.43 for DM interaction]). In conclusion, in-hospital initiation of MRA therapy was low (15% to 20%), and overall discharge MRA use was only 60% (with regional variation), regardless of DM status. There does not appear to be clear, clinically significant in-hospital hemodynamic or even renal differences between those on and off MRA. Discharge MRA use was not associated with postdischarge end points in patients hospitalized for worsening heart failure with reduced ejection fraction and co-morbid DM. DM does not appear to influence the effectiveness of MRA therapy.
    The American Journal of Cardiology 06/2014; · 3.21 Impact Factor
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    ABSTRACT: Angiotensin receptor antagonists (ARBs) improve outcomes in patients with heart failure (HF) with reduced left ventricular ejection fraction, but may induce hyperkalemia (HK) and/or a worsening of renal function (WRF). The incidence and risk factors of HK and its inter-relationship with WRF, as well as associations with clinical outcome (death or admission for HF i.e. the primary outcome) in 3846 HF patients enrolled in the double blind HEAAL trial (losartan 150mg/d vs. 50mg/d) were assessed. Worsening of renal function was defined as a decrease in eGFR >20% from baseline and HK as serum K >5.5 or >5mmol/L. Higher dose of losartan increased serum potassium. Episodes of HK >5mmol/L or WRF occurred at least once in about half of the patients. WRF was associated with higher occurrence of HK (HR 1.19 (1.06-1.34)) and vice versa (HR 1.35 (1.19-1.53)), but preceded HK in only about half of the events. High dose losartan improved outcome despite more frequent WRF and HK, both being independently associated with adverse outcomes in multivariate analyses. HK and WRF are common in HF patients. Both can be predicted from baseline risk factors and are therefore potentially preventable. Although associated with worse outcome, occurrence of any does not hinder the efficacy of high dose losartan. HK was associated with WRF and worse outcomes. Whether therapy targeting specifically HK may maximize the survival benefit derived from renin angiotensin aldosterone inhibitor use should be appropriately tested in future trials.
    International journal of cardiology 02/2014; · 6.18 Impact Factor
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    ABSTRACT: IMPORTANCE Small studies suggest that low-dose dopamine or low-dose nesiritide may enhance decongestion and preserve renal function in patients with acute heart failure and renal dysfunction; however, neither strategy has been rigorously tested. OBJECTIVE To test the 2 independent hypotheses that, compared with placebo, addition of low-dose dopamine (2 μg/kg/min) or low-dose nesiritide (0.005 μg/kg/min without bolus) to diuretic therapy will enhance decongestion and preserve renal function in patients with acute heart failure and renal dysfunction. DESIGN, SETTING, AND PARTICIPANTS Multicenter, double-blind, placebo-controlled clinical trial (Renal Optimization Strategies Evaluation [ROSE]) of 360 hospitalized patients with acute heart failure and renal dysfunction (estimated glomerular filtration rate of 15-60 mL/min/1.73 m2), randomized within 24 hours of admission. Enrollment occurred from September 2010 to March 2013 across 26 sites in North America. INTERVENTIONS Participants were randomized in an open, 1:1 allocation ratio to the dopamine or nesiritide strategy. Within each strategy, participants were randomized in a double-blind, 2:1 ratio to active treatment or placebo. The dopamine (n = 122) and nesiritide (n = 119) groups were independently compared with the pooled placebo group (n = 119). MAIN OUTCOMES AND MEASURES Coprimary end points included 72-hour cumulative urine volume (decongestion end point) and the change in serum cystatin C from enrollment to 72 hours (renal function end point). RESULTS Compared with placebo, low-dose dopamine had no significant effect on 72-hour cumulative urine volume (dopamine, 8524 mL; 95% CI, 7917-9131 vs placebo, 8296 mL; 95% CI, 7762-8830 ; difference, 229 mL; 95% CI, -714 to 1171 mL; P = .59) or on the change in cystatin C level (dopamine, 0.12 mg/L; 95% CI, 0.06-0.18 vs placebo, 0.11 mg/L; 95% CI, 0.06-0.16; difference, 0.01; 95% CI, -0.08 to 0.10; P = .72). Similarly, low-dose nesiritide had no significant effect on 72-hour cumulative urine volume (nesiritide, 8574 mL; 95% CI, 8014-9134 vs placebo, 8296mL; 95% CI, 7762-8830; difference, 279 mL; 95% CI, -618 to 1176 mL; P = .49) or on the change in cystatin C level (nesiritide, 0.07 mg/L; 95% CI, 0.01-0.13 vs placebo, 0.11 mg/L; 95% CI, 0.06-0.16; difference, -0.04; 95% CI, -0.13 to 0.05; P = .36). Compared with placebo, there was no effect of low-dose dopamine or nesiritide on secondary end points reflective of decongestion, renal function, or clinical outcomes. CONCLUSION AND RELEVANCE In participants with acute heart failure and renal dysfunction, neither low-dose dopamine nor low-dose nesiritide enhanced decongestion or improved renal function when added to diuretic therapy. TRIAL REGISTRATION Identifier: NCT01132846.
    JAMA The Journal of the American Medical Association 11/2013; · 29.98 Impact Factor
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    ABSTRACT: Serum magnesium levels may be impacted by neurohormonal activation, renal function, and diuretics. The clinical profile and prognostic significance of serum magnesium level concentration in patients hospitalized for heart failure (HF) with reduced ejection fraction is unclear. In this retrospective analysis of the placebo group of the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan trial, we evaluated 1,982 patients hospitalized for worsening HF with ejection fractions ≤40%. Baseline magnesium levels were measured within 48 hours of admission and analyzed as a continuous variable and in quartiles. The primary end points of all-cause mortality (ACM) and cardiovascular mortality or HF rehospitalization were analyzed using Cox regression models. Mean baseline magnesium level was 2.1 ± 0.3 mg/dl. Compared with the lowest quartile, patients in the highest magnesium level quartile were more likely to be older, men, have lower heart rates and blood pressures, have ischemic HF origin, and have higher creatinine and natriuretic peptide levels (all p <0.003). During a median follow-up of 9.9 months, every 1-mg/dl increase in magnesium level was associated with higher ACM (hazard ratio [HR] 1.77; 95% confidence interval [CI] 1.35 to 2.32; p <0.001) and the composite end point (HR 1.44; 95% CI 1.15 to 1.81; p = 0.002). However, after adjustment for known baseline covariates, serum magnesium level was no longer an independent predictor of either ACM (HR 0.94, 95% CI 0.69 to 1.28; p = 0.7) or the composite end point (HR 1.01, 95% CI 0.79 to 1.30; p = 0.9). In conclusion, despite theoretical concerns, baseline magnesium level was not independently associated with worse outcomes in this cohort. Further research is needed to understand the importance of serum magnesium levels in specific HF patient populations.
    The American journal of cardiology 10/2013; · 3.58 Impact Factor
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    ABSTRACT: Haemoconcentration has been studied as a marker of decongestion in patients with hospitalization for heart failure (HHF). We describe the relationship between haemoconcentration, worsening renal function, post-discharge outcomes, and clinical and laboratory markers of congestion in a large multinational cohort of patients with HHF. In 1684 patients with HHF with ejection fraction (EF) ≤40% assigned to the placebo arm of the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVEREST) trial, absolute in-hospital haematocrit change was calculated as the change between baseline and discharge or day 7 (whichever occurred first). Patient characteristics, changes in renal function, and outcomes over a median follow-up of 9.9 months were compared by in-hospital haematocrit change. Overall, 26% of patients had evidence of haemoconcentration (i.e. ≥3% absolute increase in haematocrit). Patients with greater increases in haematocrit tended to have better baseline renal function. Haemoconcentration correlated with greater risk of in-hospital worsening renal function, but renal parameters generally returned to baseline within 4 weeks post-discharge. Patients with haemoconcentration were less likely to have clinical congestion at discharge, and experienced greater in-hospital decreases in body weight and natriuretic peptide levels. After adjustment for baseline clinical risk factors, every 5% increase of in-hospital haematocrit change was associated with a decreased risk of all-cause death [hazard ratio (HR) 0.81, 95% confidence interval (CI) 0.70-0.95]. Haematocrit change was also associated with decreased cardiovascular mortality or heart failure (HF) hospitalization at ≤100 days post-randomization (HR 0.73, 95% CI 0.71-0.76). In this large cohort of patients with HHF with reduced EF, haemoconcentration was associated with greater improvements in congestion and decreased mortality and HF re-hospitalization despite an increased risk of in-hospital worsening renal function.
    European Journal of Heart Failure 07/2013; · 5.25 Impact Factor
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    ABSTRACT: Endpoint selection is a critically important step in clinical trial design. It poses major challenges for investigators, regulators, and study sponsors, and it also has important clinical and practical implications for physicians and patients. Clinical outcomes of interest in heart failure trials include all-cause mortality, cause-specific mortality, relevant non-fatal morbidity (e.g. all-cause and cause-specific hospitalization), composites capturing both morbidity and mortality, safety, symptoms, functional capacity, and patient-reported outcomes. Each of these endpoints has strengths and weaknesses that create controversies regarding which is most appropriate in terms of clinical importance, sensitivity, reliability, and consistency. Not surprisingly, a lack of consensus exists within the scientific community regarding the optimal endpoint(s) for both acute and chronic heart failure trials. In an effort to address these issues, the Heart Failure Association of the European Society of Cardiology (HFA-ESC) convened a group of expert heart failure clinical investigators, biostatisticians, regulators, and pharmaceutical industry scientists (Nice, France, 12-13 February 2012) to evaluate the challenges of defining heart failure endpoints in clinical trials and to develop a consensus framework. This report summarizes the group's recommendations for achieving common views on heart failure endpoints in clinical trials.
    European Journal of Heart Failure 06/2013; · 5.25 Impact Factor
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    ABSTRACT: AIMS: Post-discharge morbidity and mortality for acute heart failure (AHF) patients remains high. Although the adverse effects of neurohormonal activation are well known in chronic HF, the prognostic significance of serum aldosterone in patients hospitalized for AHF has not been well studied. METHODS AND RESULTS: A secondary analysis was carried out of the placebo arm (n = 1850) from the EVEREST trial which had aldosterone measured at baseline. All patients were hospitalized for worsening HF and had an LVEF <40%. The median follow-up was 9.9 months. The association between serum aldosterone levels at baseline and the independently adjudicated outcomes [all-cause mortality (ACM) and the combined outcome of cardiovascular mortality (CVM) and HF re-hospitalization] were explored with multivariable Cox models. Median aldosterone levels increased during the hospital stay from 11 ng/dL at baseline to 15 ng/dL at discharge (P < 0.001) and remained increased after discharge (16 ng/dL at 24 weeks, P < 0.001). After adjusting for potential confounders, higher baseline aldosterone levels were associated with an increased risk for ACM and CVM or HF re-hospitalization [hazard ratio (HR) 1.49, 95% confidence intrerval (CI) 1.11-1.99; and HR 1.40, 95% CI 1.11-1.78, respectively, in the highest quartile when compared with the lowest]. CONCLUSION: In patients with LVEF <40% hospitalized for AHF and receiving standard therapy, serum aldosterone levels correlated with worse post-discharge outcomes. Aldosterone levels increase during AHF hospitalization and remain increased long after discharge. These results suggest that further modulation of the renin-angiotensin-aldosterone system in patients admitted with worsening HF might favourably improve post-discharge outcomes.
    European Journal of Heart Failure 06/2013; · 5.25 Impact Factor
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    ABSTRACT: Background Patients with decompensated heart failure, volume overload, and hyponatremia are challenging to manage. Relatively little has been documented regarding the clinical course of these patients during standard in-hospital management or with vasopressin antagonism.Methods and ResultsThe Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan database was examined to assess the short-term clinical course of patients hospitalized with heart failure and hyponatremia and the effect of tolvaptan on outcomes. In the placebo group, patients with hyponatremia (serum Na+ <135mEq/L; n = 232), compared with those with normonatremia at baseline (n = 1785), had less relief of dyspnea despite receiving higher doses of diuretics (59.2% vs 69.2% improved; P < .01) and worse long-term outcomes. In the hyponatremia subgroup from the entire trial cohort (n = 475), tolvaptan was associated with greater likelihood of normalization of serum sodium than placebo (58% vs 20% and 64% vs 29% for day 1 and discharge, respectively; P < .001 for both comparisons), greater weight reduction at day 1 and discharge (0.7 kg and 0.8 kg differences, respectively; P < .001 and P = .008), and greater relief of dyspnea (P = .03). Among all hyponatremic patients, there was no effect of tolvaptan on long-term outcomes compared with placebo. In patients with pronounced hyponatremia (<130 mEq/L; n = 92), tolvaptan was associated with reduced cardiovascular morbidity and mortality after discharge (P = .04).Conclusions In patients with decompensated heart failure and hyponatremia, standard therapy is associated with less weight loss and dyspnea relief, and unfavorable longer-term outcomes compared to those with normonatremia. Tolvaptan is associated with more favorable in-hospital effects and, possibly, long-term outcomes in patients with severe hyponatremia.
    Journal of Cardiac Failure. 06/2013; 19(6):390–397.
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    ABSTRACT: Combination therapy with hydralazine and nitrates can improve outcomes in patients with heart failure and low ejection fraction. However, this combination is underused in clinical practice for several reasons, including side effects related to hydralazine and polypharmacy. Some of the benefits seen with hydralazine, including afterload reduction and attenuation of nitrate tolerance, have also been observed with angiotensin-converting enzyme inhibitors. Demonstrating similar clinical benefits with nitrates plus angiotensin-converting enzyme inhibitor therapy alone, in the absence of hydralazine, may represent an opportunity to improve heart failure care by increasing the use of nitrates. In this paper, we summarize data that support studying such an approach.
    JACC: Heart Failure. 06/2013; 1(3):183–191.
  • Marvin A Konstam
    JACC. Heart failure. 04/2013; 1(2):178-180.
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    ABSTRACT: AIMS: Human stresscopin is a corticotropin-releasing factor (CRF) type 2 receptor (CRFR2) selective agonist and a member of the CRF peptide family. Stimulation of CRFR2 improves cardiac output and left ventricular ejection fraction (LVEF) in patients with stable heart failure (HF) with reduced LVEF. We examined the safety, pharmacokinetics, and effects on haemodynamics and serum biomarkers of intravenous human stresscopin acetate (JNJ-39588146) in patients with stable HF with LVEF ≤35% and cardiac index (CI) ≤2.5 L/min/m2. METHODS AND RESULTS: Sixty-two patients with HF and LVEF ≤35% were instrumented with a pulmonary artery catheter and randomly assigned (ratio 3:1) to receive an intravenous infusion of JNJ-39588146 or placebo. The main study was an ascending dose study of three doses (5, 15, and 30 ng/kg/min) of study drug or placebo administered in sequential 1 h intervals (3 h total). Statistically significant increases in CI and reduction in systemic vascular resistance (SVR) were observed with both the 15 ng/kg/min (2 h time point) and 30 ng/kg/min (3 h time point) doses of JNJ-39588146 without significant changes in heart rate (HR) or systolic blood pressure (SBP). No statistically significant reductions in pulmonary capillary wedge pressure (PCWP) were seen with any dose tested in the primary analysis, although a trend towards reduction was seen. CONCLUSION: In HF patients with reduced LVEF and CI, ascending doses of JNJ-39588146 were associated with progressive increases in CI and reductions in SVR without significant effects on PCWP, HR, or SBP.Trial registration: NCT01120210.
    European Journal of Heart Failure 03/2013; · 5.25 Impact Factor
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    ABSTRACT: Systolic blood pressure (SBP) is related to the pathophysiologic development and progression of heart failure (HF) and is inversely associated with adverse outcomes during hospitalization for HF (HHF). The prognostic value of SBP after initiating inhospital therapy and the mode of death and etiology of cardiovascular readmissions based on SBP have not been well characterized in HHF. A post hoc analysis was performed of the placebo group (n = 2061) of the EVEREST trial, which enrolled patients within 48 hours of admission for worsening HF with an ejection fraction (EF) ≤40% and an SBP ≥90 mm Hg, for a median follow-up of 9.9 months. Systolic blood pressure was measured at baseline, daily during hospitalization, and at discharge/day 7. Patients were divided into the following quartiles by SBP at baseline: ≤105, 106 to 119, 120 to 130, and ≥131 mm Hg. Outcomes were all-cause mortality (ACM) and the composite of cardiovascular mortality or HHF (CVM + HHF). The associations between baseline, discharge, and inhospital change in SBP and ACM and CVM + HHF were assessed using multivariable Cox proportional hazards regression models adjusted for known covariates. Median (25th, 75th) SBP at baseline was 120 (105, 130) mm Hg and ranged from 82 to 202 mm Hg. Patients with a lower SBP were younger and more likely to be male; had a higher prevalence of prior revascularization and ventricular arrhythmias; had a lower EF, worse renal function, higher natriuretic peptide concentrations, and wider QRS durations; and were more likely to require intravenous inotropes during hospitalization. Lower SBP was associated with increased mortality, driven by HF and sudden cardiac death, and cardiovascular hospitalization, primarily caused by HHF. After adjusting for potential confounders, SBP was inversely associated with risk of the coprimary end points both at baseline (ACM: hazard ratio [HR]/10-mm Hg decrease 1.15, 95% CI1.08-1.22; CVM + HHF: HR 1.09/10-mm Hg decrease, 95% CI 1.04-1.14) and at the time of discharge/day 7 (ACM: HR 1.15/10-mm Hg decrease, 95% CI 1.08-1.22; CVM + HHF: HR 1.07/10-mm Hg decrease, 95% CI 1.02-1.13), but the association with inhospital SBP change was not significant. Systolic blood pressure is an independent clinical predictor of morbidity and mortality after initial therapy during HHF with reduced EF.
    American heart journal 02/2013; 165(2):216-25. · 4.65 Impact Factor
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    ABSTRACT: AimsSigns and symptoms of congestion are the most common cause for hospitalization for heart failure (HHF). The clinical course and prognostic value of congestion during HHF has not been systemically characterized.Methods and resultsA post hoc analysis was performed of the placebo group (n = 2061) of the EVEREST trial, which enrolled patients within 48 h of admission (median ∼24 h) for worsening HF with an EF ≤40% and two or more signs or symptoms of fluid overload [dyspnoea, oedema, or jugular venous distension (JVD)] for a median follow-up of 9.9 months. Clinician-investigators assessed patients daily for dyspnoea, orthopnoea, fatigue, rales, pedal oedema, and JVD and rated signs and symptoms on a standardized 4-point scale ranging from 0 to 3. A modified composite congestion score (CCS) was calculated by summing the individual scores for orthopnoea, JVD, and pedal oedema. Endpoints were HHF, all-cause mortality (ACM), and ACM + HHF. Multivariable Cox regression models were used to evaluate the risk of CCS at discharge on outcomes at 30 days and for the entire follow-up period. The mean CCS obtained after initial therapy decreased from the mean ± SD of 4.07 ± 1.84 and the median (25th, 75th) of 4 (3, 5) at baseline to 1.11 ± 1.42 and 1 (0, 2) at discharge. At discharge, nearly three-quarters of study participants had a CCS of 0 or 1 and fewer than 10% of patients had a CCS >3. B-type natriuretic peptide (BNP) and amino terminal-proBNP, respectively, decreased from 734 (313, 1523) pg/mL and 4857 (2251, 9642) pg/mL at baseline to 477 (199, 1079) pg/mL, and 2834 (1218, 6075) pg/mL at discharge/Day 7. A CCS at discharge was associated with increased risk (HR/point CCS, 95% CI) for a subset of endpoints at 30 days (HHF: 1.06, 0.95-1.19; ACM: 1.34, 1.14-1.58; and ACM + HHF: 1.13, 1.03-1.25) and all outcomes for the overall study period (HHF: 1.07, 1.01-1.14; ACM: 1.16, 1.09-1.24; and ACM + HHF 1.11, 1.06-1.17). Patients with a CCS of 0 at discharge experienced HHF of 26.2% and ACM of 19.1% during the follow-up.Conclusion Among patients admitted for worsening signs and symptoms of HF and reduced EF, congestion improves substantially during hospitalization in response to standard therapy alone. However, patients with absent or minimal resting signs and symptoms at discharge still experienced a high mortality and readmission rate.
    European Heart Journal 01/2013; · 14.72 Impact Factor
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    ABSTRACT: Objectives This study was designed to test the hypothesis of whether amlodipine reduces the risk for death in patients with heart failure due to a nonischemic cardiomyopathy. Background A pre-specified subgroup analysis in an earlier, large-scale, placebo-controlled study suggested that amlodipine might reduce the risk for death in patients with heart failure due to a nonischemic cardiomyopathy. Methods To evaluate this hypothesis, 1654 patients with severe heart failure due to a nonischemic cardiomyopathy (ejection fraction <30%) were randomly assigned to amlodipine (target dose: 10 mg/d) or placebo added to conventional therapy for heart failure for a median of 33 months. Results There were 278 deaths in the amlodipine group and 262 deaths in the placebo group (hazard ratio: 1.09; 95% confidence interval [CI]: 0.92 to 1.29; p = 0.33). The differences between the 2 groups in the risks for cardiovascular death and hospitalization were also not significant. When the results from patients with a nonischemic cardiomyopathy in both the earlier trial and in the current study were combined, there was no evidence of a favorable or unfavorable effect of amlodipine on mortality (hazard ratio: 0.97; 95% CI: 0.83 to 1.13; p = 0.66). Both trials, however, observed higher frequencies of peripheral edema and pulmonary edema and lower frequencies of uncontrolled hypertension and chest pain in patients treated with amlodipine. Conclusions These results of the current trial, viewed together with the results from the earlier study, indicate that amlodipine does not exert favorable effects on the clinical course of patients with heart failure, regardless of the presence or absence of underlying coronary artery disease. These findings indicate the need for great caution when striking benefits are observed in subgroups of patients or in trials not primarily designed to assess such effects.
    JACC: Heart Failure. 01/2013; 1(4):308–314.
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    ABSTRACT: Objectives The purpose of this study was to characterize the relationship between heart rate and post-discharge outcomes in patients with hospitalization for heart failure (HHF) with reduced ejection fraction (EF) in sinus rhythm. Background A reduction in heart rate improves clinical outcomes in patients with chronic heart failure and in sinus rhythm, but the association between heart rate and post-discharge outcomes in patients with HHF is presently unclear. Methods This post-hoc analysis of the EVEREST (Efficacy of Vasopressin Antagonism in Heart Failure: Outcome Study With Tolvaptan) trial examined 1,947 patients with HHF and EF ≤40% not in atrial fibrillation/flutter or pacemaker dependent. Results The median follow-up period was 9.9 months. At baseline, patients with a higher heart rate tended to be younger with lower EF and were more likely to have worse New York Heart Association functional class and higher natriuretic peptide levels. After adjustment for clinical risk factors, baseline heart rate was not predictive of all-cause mortality (p ≥ 0.066). However, at ≥70 beats/min, every 5-beat increase in 1-week post-discharge heart rate was independently associated with increased all-cause mortality (hazard ratio: 1.13 [95% confidence interval: 1.05 to 1.22]; p = 0.002). Similarly, every 5-beat increase ≥70 beats/min in 4-week post-discharge heart rate was predictive of all-cause mortality (hazard ratio: 1.12 [95% confidence interval: 1.05 to 1.19]; p = 0.001). Conclusions In this large cohort of patients with HHF with reduced EF and in sinus rhythm, baseline heart rate did not correlate with all-cause mortality. In contrast, at ≥70 beats/min, higher heart rate in the early post-discharge period was independently predictive of death during subsequent follow-up. Further study of post-discharge heart rate as a potential therapeutic target in this high-risk population is encouraged.
    JACC: Heart Failure. 01/2013; 1(6):488–496.
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    ABSTRACT: BACKGROUND: -Arginine vasopressin (AVP) levels are elevated in proportion to heart failure (HF) severity and are associated with higher cardiovascular mortality in ambulatory patients. However, the relationship between baseline and trends in AVP with outcomes in patients hospitalized for worsening HF with reduced ejection fraction (EF) is unclear. METHODS AND RESULTS: -The Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVEREST) trial investigated the effects of tolvaptan in patients with worsening HF and EF≤40%. The present analysis examined baseline and follow-up AVP levels in 3,196 EVEREST patients with valid AVP measurements. Co-primary endpoints included all-cause mortality (ACM), and the composite of cardiovascular mortality or HF hospitalization (CVM/H). Median follow-up was 9.9 months. Times to events were compared with univariate log-rank tests and multivariable Cox regression models, adjusted for baseline risk factors. After adjusting for baseline covariates, elevated AVP levels were associated with increased ACM (hazard ratio [HR] 1.33, 95% confidence interval [CI] 1.13-1.55) and CVM/H (HR 1.23, 95% CI 1.08-1.39). There was no interaction of baseline AVP with treatment assignment in terms of survival (p=0.515). Tolvaptan therapy increased the proportion of patients with elevated AVP (p<0.001), but this had no effect on mortality (HR 0.95, 95% CI 0.72-1.24). CONCLUSIONS: -Elevated baseline AVP level was independently predictive of mortality, but did not identify a group of patients who had improved outcomes with tolvaptan treatment. Tolvaptan treatment increased AVP levels during follow-up, but this incremental increase was not associated with worsened outcomes.
    Circulation Heart Failure 12/2012; · 6.68 Impact Factor

Publication Stats

13k Citations
2,494.78 Total Impact Points


  • 1983–2014
    • Tufts Medical Center
      • • Division of Cardiology
      • • Department of Medicine
      Boston, Massachusetts, United States
  • 2013
    • Stanford Medicine
      • Department of Medicine
      Stanford, CA, United States
  • 2012–2013
    • Harvard Medical School
      • Department of Medicine
      Boston, MA, United States
    • Stanford University
      • Department of Medicine
      Stanford, CA, United States
    • Emory University
      • Division of Cardiology
      Atlanta, Georgia, United States
    • Henry Ford Hospital
      Detroit, Michigan, United States
  • 1984–2013
    • Tufts University
      • • Division of Cardiology
      • • Tufts Center for Conservation Medicine
      • • Department of Medicine
      Georgia, United States
  • 2010–2012
    • Duke University Medical Center
      • Division of Cardiology
      Durham, NC, United States
    • University of Pittsburgh
      Pittsburgh, Pennsylvania, United States
    • Medical University of South Carolina
      Charleston, South Carolina, United States
    • Sahlgrenska University Hospital
      Goeteborg, Västra Götaland, Sweden
    • Mayo Clinic - Rochester
      • Department of Cardiovascular Diseases
      Rochester, Minnesota, United States
  • 2008–2012
    • University of Illinois at Chicago
      • Section of Cardiology
      Chicago, Illinois, United States
    • National Heart, Lung, and Blood Institute
      Maryland, United States
  • 2006–2012
    • Northwestern University
      • • Center for Cardiovascular Innovation
      • • Department of Emergency Medicine
      • • Division of Cardiology (Dept. of Medicine)
      • • Feinberg School of Medicine
      Evanston, IL, United States
  • 1985–2012
    • University of Massachusetts Boston
      • Department of Counseling and School Psychology
      Boston, Massachusetts, United States
  • 2011
    • Wilford Hall Ambulatory Surgery Center
      Lackland Air Force Base, Texas, United States
  • 2003–2011
    • University of Colorado
      • Division of Cardiology
      Denver, Colorado, United States
    • RAND Corporation
      Santa Monica, California, United States
    • Duke University
      Durham, North Carolina, United States
    • University of Minnesota Duluth
      Duluth, Minnesota, United States
  • 1990–2011
    • University of Massachusetts Medical School
      • • Division of Cardiovascular
      • • Department of Medicine
      Worcester, MA, United States
  • 2007–2008
    • University of California, San Diego
      San Diego, California, United States
    • Thomas Jefferson University Hospitals
      Philadelphia, Pennsylvania, United States
    • Thomas Jefferson University
      Philadelphia, Pennsylvania, United States
  • 1997–2006
    • New England Baptist Hospital
      Boston, Massachusetts, United States
  • 2005
    • University of Minnesota Twin Cities
      • Division of Biostatistics
      Minneapolis, MN, United States
    • Blue Water Task Force
      Big Sky, Montana, United States
  • 2004
    • University of California, Los Angeles
      Los Angeles, California, United States
  • 2001
    • CUNY Graduate Center
      New York City, New York, United States
  • 2000
    • University of Michigan
      • Division of Pediatric Cardiology
      Ann Arbor, MI, United States
  • 1991–2000
    • Beverly Hospital, Boston MA
      Beverly, Massachusetts, United States
  • 1998–1999
    • Concordia University–Ann Arbor
      Ann Arbor, Michigan, United States
    • Vanderbilt University
      • Department of Medicine
      Nashville, MI, United States
  • 1996
    • University of Texas Medical School
      Houston, Texas, United States
  • 1995
    • U.S. Department of Health and Human Services
      Washington, Washington, D.C., United States
  • 1984–1985
    • Boston University
      • Department of Chemistry
      Boston, MA, United States