Robert T. Cole

Isosorbide mononitrate in heart failure with preserved ejection fraction

BACKGROUND Nitrates are commonly prescribed to enhance activity tolerance in patients with heart failure and a preserved ejection fraction. We compared the effect of isosorbide mononitrate or placebo on daily activity in such patients. METHODS In this multicenter, double-blind, crossover study, 110 patients with heart failure and a preserved ejection fraction were randomly assigned to a 6-week dose-escalation regimen of isosorbide mononitrate (from 30 mg to 60 mg to 120 mg once daily) or placebo, with subsequent crossover to the other group for 6 weeks. The primary end point was the daily activity level, quantified as the average daily accelerometer units during the 120-mg phase, as assessed by patient-worn accelerometers. Secondary end points included hours of activity per day during the 120-mg phase, daily accelerometer units during all three dose regimens, quality-of-life scores, 6-minute walk distance, and levels of N-terminal pro-brain natriuretic peptide (NT-proBNP). RESULTS In the group receiving the 120-mg dose of isosorbide mononitrate, as compared with the placebo group, there was a nonsignificant trend toward lower daily activity (-381 accelerometer units; 95% confidence interval [CI], -780 to 17; P=0.06) and a significant decrease in hours of activity per day (-0.30 hours; 95% CI, -0.55 to -0.05; P=0.02). During all dose regimens, activity in the isosorbide mononitrate group was lower than that in the placebo group (-439 accelerometer units; 95% CI, -792 to -86; P=0.02). Activity levels decreased progressively and significantly with increased doses of isosorbide mononitrate (but not placebo). There were no significant between-group differences in the 6-minute walk distance, quality-of-life scores, or NT-proBNP levels. CONCLUSIONS Patients with heart failure and a preserved ejection fraction who received isosorbide mononitrate were less active and did not have better quality of life or submaximal exercise capacity than did patients who received placebo. (Funded by the National Heart, Lung, and Blood Institute; ClinicalTrials.gov number, NCT02053493.).

Effects of Liraglutide on Clinical Stability Among Patients With Advanced Heart Failure and Reduced Ejection Fraction: A Randomized Clinical Trial

IMPORTANCE Abnormal cardiac metabolism contributes to the pathophysiology of advanced heart failure with reduced left ventricular ejection fraction (LVEF). Glucagon-like peptide 1 (GLP-1) agonists have shown cardioprotective effects in early clinical studies of patients with advanced heart failure, irrespective of type 2 diabetes status. OBJECTIVE To test whether therapy with a GLP-1 agonist improves clinical stability following hospitalization for acute heart failure. DESIGN, SETTING, AND PARTICIPANTS Phase 2, double-blind, placebo-controlled randomized clinical trial of patients with established heart failure and reduced LVEF who were recently hospitalized. Patients were enrolled between August 2013 and March 2015 at 24 US sites. INTERVENTIONS The GLP-1 agonist liraglutide (n = 154) or placebo (n = 146) via a daily subcutaneous injection; study drug was advanced to a dosage of 1.8 mg/d during the first 30 days as tolerated and continued for 180 days. MAIN OUTCOMES AND MEASURES The primary end point was a global rank score in which all patients, regardless of treatment assignment, were ranked across 3 hierarchical tiers: time to death, time to rehospitalization for heart failure, and time-averaged proportional change in N-terminal pro-B-type natriuretic peptide level from baseline to 180 days. Higher values indicate better health (stability). Exploratory secondary outcomes included primary end point components, cardiac structure and function, 6-minute walk distance, quality of life, and combined events. RESULTS Among the 300 patients who were randomized (median age, 61 years [interquartile range {IQR}, 52-68 years]; 64 [21%] women; 178 [59%] with type 2 diabetes; median LVEF of 25% [IQR, 19%-33%]; median N-terminal pro-B-type natriuretic peptide level of 2049 pg/mL [IQR, 1054-4235 pg/mL]), 271 completed the study. Compared with placebo, liraglutide had no significant effect on the primary end point (mean rank of 146 for the liraglutide group vs 156 for the placebo group, P = .31). There were no significant between-group differences in the number of deaths (19 [12%] in the liraglutide group vs 16 [11%] in the placebo group; hazard ratio, 1.10 [95% CI, 0.57-2.14]; P = .78) or rehospitalizations for heart failure (63 [41%] vs 50 [34%], respectively; hazard ratio, 1.30 [95% CI, 0.89-1.88]; P = .17) or for the exploratory secondary end points. Prespecified subgroup analyses in patients with diabetes did not reveal any significant between-group differences. The number of investigator-reported hyperglycemic events was 16 (10%) in the liraglutide group vs 27 (18%) in the placebo group and hypoglycemic events were infrequent (2 [1%] vs 4 [3%], respectively). CONCLUSIONS AND RELEVANCE Among patients recently hospitalized with heart failure and reduced LVEF, the use of liraglutide did not lead to greater posthospitalization clinical stability. These findings do not support the use of liraglutide in this clinical situation. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01800968.

Hydralazine and Isosorbide Dinitrate in Heart Failure Historical Perspective, Mechanisms, and Future Directions

Until the 1970s, treatment options for heart failure were limited to digitalis and diuretics.1 Although effective for symptoms, there was no evidence of mortality benefit with this combination, and it was an inadequate option for many patients with advanced symptoms. The search for more effective options led to strategies that modulated hemodynamics.1 Numerous physiological studies showed the dependence of ventricular function on vascular resistance, and drugs that reduced systemic vascular resistance improved cardiac performance.2,–,5 A pivotal study by Franciosa et al6 showed that sodium nitroprusside in patients with heart failure in the setting of acute myocardial infarction reduced left ventricular filling pressures from 22.7±2.0 to 11.3±1.6 mm Hg and led to a modest increase in cardiac output. A subsequent study revealed more striking improvements in patients with refractory heart failure, in whom nitroprusside reduced systemic vascular resistance by 50%, increased cardiac output by 56%, and reduced left ventricular filling pressure by 47%.7 These hemodynamic benefits with nitroprusside led to studies with oral agents, including hydralazine, isosorbide dinitrate (ISDN), prazosin, phentolamine, and minoxidil. Although these drugs did affect hemodynamics, none was as effective as nitroprusside individually.8,–,12 In 1977, Massie et al13 studied the combination of 2 oral agents, hydralazine and ISDN (H-ISDN) in class III to IV heart failure patients, proposing that simultaneously reducing preload with ISDN and afterload with hydralazine would result in a better response than with either drug individually. They found that H-ISDN reduced left ventricular filling pressure by 36%, increased cardiac index by 58%, and reduced systemic vascular resistance by 34%. Later, Pierpont et al14 compared H-ISDN with nitroprusside and showed that the 2 therapies had similar effects on wedge pressure reduction and cardiac index increase. Considering these hemodynamic benefits with …

Comparison of myocardial velocities obtained with magnetic resonance phase velocity mapping and tissue doppler imaging in normal subjects and patients with left ventricular dyssynchrony

To compare longitudinal myocardial velocity and time to peak longitudinal velocity obtained with magnetic resonance phase velocity mapping (MR‐PVM) and tissue Doppler imaging (TDI), and to assess the reproducibility of each method.

Gender differences in the risk of stroke during support with continuous-flow left ventricular assist device

BACKGROUND There is increasing recognition that the risk of stroke after left ventricular assist device (LVAD) implantation varies based on gender, with a higher risk in female patients. We reviewed our own data to determine gender differences in the risk of stroke. METHODS Frequency of stroke, including intracranial hemorrhage and ischemic stroke, was retrospectively evaluated in 110 heart failure patients (mean age 49.6 ± 13.6 years, 32% women) discharged from the hospital after implantation of a HeartMate II (N = 74) or HeartWare (N = 36) LVAD. Competing outcomes analysis was used to determine which clinical risk factors were associated with the risk of stroke and death, with the primary end-point being time to first stroke event. RESULTS During a median follow-up of 1.3 years, 26 patients had a stroke (23.6%, 0.14 case per person-year). The median time to first stroke was 0.7 (interquartile range 0.3 to 1.4) years. After adjusting for covariates, risk of stroke was higher for women than for men (hazard ratio 3.1, 95% confidence interval 1.4 to 6.9; p = 0.007). There was no difference in overall survival between men and women. CONCLUSION The risk of stroke after LVAD varies based on gender, with a higher risk in female patients. More research is needed to fully understand these differences, and whether device management strategies should be tailored based on gender.

Intravenous Allogeneic Mesenchymal Stem Cells for Nonischemic CardiomyopathyNovelty and Significance: Safety and Efficacy Results of a Phase II-A Randomized Trial

Rationale: Potential benefits of mesenchymal stem cell (MSC) therapy in heart failure may be related to paracrine properties and systemic effects, including anti-inflammatory activities. If this hypothesis is valid, intravenous administration of MSCs should improve outcomes in heart failure, an entity in which excessive chronic inflammation may play a pivotal role. Objective: To assess the safety and preliminary efficacy of intravenously administered ischemia-tolerant MSCs (itMSCs) in patients with nonischemic cardiomyopathy. Methods and Results: This was a single-blind, placebo-controlled, crossover, randomized phase II-a trial of nonischemic cardiomyopathy patients with left ventricular ejection fraction ≤40% and absent hyperenhancement on cardiac magnetic resonance imaging. Patients were randomized to intravenously administered itMSCs (1.5×106 cells/kg) or placebo; at 90 days, each group received the alternative treatment. Overall, 22 patients were randomized to itMSC (n=10) and placebo (n=12) at baseline. After crossover, data were available for 22 itMSC patients. No major differences in death, hospitalization, or serious adverse events were noted between the 2 treatments. Change from baseline in left ventricular ejection fraction and ventricular volumes was not significantly different between therapies. Compared with placebo, itMSC therapy increased 6-minute walk distance (+36.47 m, 95% confidence interval 5.98–66.97; P =0.02) and improved Kansas City Cardiomyopathy clinical summary (+5.22, 95% confidence interval 0.70–9.74; P =0.02) and functional status scores (+5.65, 95% confidence interval −0.11 to 11.41; P =0.06). The data demonstrated MSC-induced immunomodulatory effects, the magnitude of which correlated with improvement in left ventricular ejection fraction. Conclusions: In this pilot study of patients with nonischemic cardiomyopathy, itMSC therapy was safe, caused immunomodulatory effects, and was associated with improvements in health status and functional capacity. Clinical Trial Registration: URL: . Unique identifier: [NCT02467387][1]. # Novelty and Significance {#article-title-23} [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT02467387&atom=%2Fcircresaha%2F120%2F2%2F332.atomRationale: Potential benefits of mesenchymal stem cell (MSC) therapy in heart failure may be related to paracrine properties and systemic effects, including anti-inflammatory activities. If this hypothesis is valid, intravenous administration of MSCs should improve outcomes in heart failure, an entity in which excessive chronic inflammation may play a pivotal role. Objective: To assess the safety and preliminary efficacy of intravenously administered ischemia-tolerant MSCs (itMSCs) in patients with nonischemic cardiomyopathy. Methods and Results: This was a single-blind, placebo-controlled, crossover, randomized phase II-a trial of nonischemic cardiomyopathy patients with left ventricular ejection fraction ⩽40% and absent hyperenhancement on cardiac magnetic resonance imaging. Patients were randomized to intravenously administered itMSCs (1.5×106 cells/kg) or placebo; at 90 days, each group received the alternative treatment. Overall, 22 patients were randomized to itMSC (n=10) and placebo (n=12) at baseline. After crossover, data were available for 22 itMSC patients. No major differences in death, hospitalization, or serious adverse events were noted between the 2 treatments. Change from baseline in left ventricular ejection fraction and ventricular volumes was not significantly different between therapies. Compared with placebo, itMSC therapy increased 6-minute walk distance (+36.47 m, 95% confidence interval 5.98–66.97; P=0.02) and improved Kansas City Cardiomyopathy clinical summary (+5.22, 95% confidence interval 0.70–9.74; P=0.02) and functional status scores (+5.65, 95% confidence interval −0.11 to 11.41; P=0.06). The data demonstrated MSC-induced immunomodulatory effects, the magnitude of which correlated with improvement in left ventricular ejection fraction. Conclusions: In this pilot study of patients with nonischemic cardiomyopathy, itMSC therapy was safe, caused immunomodulatory effects, and was associated with improvements in health status and functional capacity. Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02467387.

Renal dysfunction in heart failure.

Renal dysfunction is a common, important comorbidity in patients with both chronic and acute heart failure (HF). Chronic kidney disease and worsening renal function (WRF) are associated with worse outcomes, but our understanding of the complex bidirectional interactions between the heart and kidney remains poor. When addressing these interactions, one must consider the impact of intrinsic renal disease resulting from medical comorbidities on HF outcomes. WRF may result from any number of important processes. Understanding the role of each of these factors and their interplay are essential in understanding how to improve outcomes in patients with renal dysfunction and HF.

Tolvaptan in Patients Hospitalized With Acute Heart Failure Rationale and Design of the TACTICS and the SECRET of CHF Trials

Congestion is a primary reason for hospitalization in patients with acute heart failure (AHF). Despite inpatient diuretics and vasodilators targeting decongestion, persistent congestion is present in many AHF patients at discharge and more severe congestion is associated with increased morbidity and mortality. Moreover, hospitalized AHF patients may have renal insufficiency, hyponatremia, or an inadequate response to traditional diuretic therapy despite dose escalation. Current alternative treatment strategies to relieve congestion, such as ultrafiltration, may also result in renal dysfunction to a greater extent than medical therapy in certain AHF populations. Truly novel approaches to volume management would be advantageous to improve dyspnea and clinical outcomes while minimizing the risks of worsening renal function and electrolyte abnormalities. One effective new strategy may be utilization of aquaretic vasopressin antagonists. A member of this class, the oral vasopressin-2 receptor antagonist tolvaptan, provides benefits related to decongestion and symptom relief in AHF patients. Tolvaptan may allow for less intensification of loop diuretic therapy and a lower incidence of worsening renal function during decongestion. In this article, we summarize evidence for decongestion benefits with tolvaptan in AHF and describe the design of the Targeting Acute Congestion With Tolvaptan in Congestive Heart Failure Study (TACTICS) and Study to Evaluate Challenging Responses to Therapy in Congestive Heart Failure (SECRET of CHF) trials.

Medical therapy for acute decompensated heart failure: what recent clinical trials have taught us about diuretics and vasodilators.

Diuretics and vasodilators have been the cornerstone of heart failure (HF) therapy for decades. Although not shown to reduce mortality, diuretic and vasodilator therapy remain commonplace for treating acute decompensated HF, with diuretics being the mainstay of therapy for the removal of excess fluid in all patients with HF. This article discusses results of recent trials concerning diuretic or vasodilator therapy and HF, including the Diuretic Optimization Strategies Evaluation (DOSE) trial, the Placebo-Controlled Randomized Study of the Selective A1 Adenosine Receptor Antagonist Rolofylline for Patients Hospitalized With Acute Decompensated Heart Failure and Volume Overload to Assess Treatment Effect on Congestion and Renal Function (PROTECT), and the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVEREST), as well as results from the Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure (ASCEND-HF) trial and the Preliminary Study of Relaxin in Acute Heart Failure (Pre-RELAX-AHF).

Nonadherence in the Advanced Heart Failure Population

The number of patients living with heart failure (HF) in the USA now exceeds 5 million. Although HF is a disease readily treated by medications and lifestyle interventions, nonadherence is common, leading to worse clinical outcomes and increased healthcare costs. While adherence to medical therapy and clinician recommendations is key in the management of HF, it is perhaps more critical in patients with the most advanced disease, including those receiving home inotropic infusion, heart transplantation, or a left ventricular assist device. Yet, there is a paucity of data on the effects of nonadherence on the advanced heart failure population and little information on the most effective management strategies in these patients. Future studies of nonadherence in HF should utilize uniform definitions of adherence and, ideally, more objective measurements of adherence such as the novel “digital pill” technology.