Mitchell A. Psotka

Ivabradine Role in the Chronic Heart Failure Armamentarium

Ivabradine is approved to reduce hospitalizations for patients with symptomatic heart failure, reduced ejection fraction, and persistently elevated heart rate despite otherwise maximal medical therapy. However, the eligible patient population is a small fraction of those with heart failure overall. This review summarizes the major clinical evidence supporting the use of ivabradine, identifies and discusses areas of uncertainty from the clinical trial data, helps describe the population most likely to benefit, and attempts to place ivabradine within the multifaceted treatment scheme currently used for patients with heart failure and reduced ejection fraction.

Strategies to Prevent Postdischarge Adverse Events Among Hospitalized Patients with Heart Failure

Hospitalizations for heart failure (HF) are increasing, and HF is the primary cause of readmission for all Medicare patients. Inpatient HF mortality is poor, but most morbidity and mortality occurs after hospital discharge. Readmissions attributable to HF persist or increase over time after discharge, and past HF admissions predict both readmission and mortality. The heightened risk of readmission dissipates slowly after discharge, suggesting that any intervention should be part of a lasting care package in the outpatient setting. Interventions that apply to multiple common medical comorbidities may be more likely to reduce overall adverse events.

Improving Heart Failure Therapeutics Development in the United States: The Heart Failure Collaboratory.

The current heart failure clinical trial environment is strained by increasing complexity and cost, regulatory requirements, competing demands on stakeholders, implementation challenges, and decreasing patient and investigator participation. To begin the process of developing potentially effective strategies and tactics, stakeholders including patients; investigators; academic leaders; pharmaceutical and device industry representatives; society representatives; third-party payers; and government representatives from the U.S. Food and Drug Administration, National Institutes of Health, and Centers for Medicare and Medicaid Services convened in March of 2017. This paper summarizes the discussions, outlines current challenges and actionable opportunities, and makes targeted recommendations to achieve the goals of improving efficiency in clinical trials and speeding the development of effective heart failure therapies, including the formation of an organized Heart Failure Collaboratory.

Palliative Care in Heart Failure: What Triggers Specialist Consultation?

Heart failure (HF) continues to cause substantial death and suffering despite the availability of numerous medical, surgical, and technological therapeutic advancements. As a patient-centered holistic discipline focused on improving quality of life and decreasing anguish, palliative care (PC) has a crucial role in the care of HF patients that has been acknowledged by multiple international guidelines. PC can be provided by all members of the HF care team, including but not limited to practitioners with specialty PC training. Unfortunately, despite recommendations to routinely include PC techniques and providers in the care of HF patients, use of general PC strategies as well as expert PC consultation is limited by a dearth of evidence-based interventions in the HF population and knowledge as to when to initiate these interventions, uncertainty regarding patient desires, prognosis, and the respective roles of each member of the care team, and a general shortage of specialist PC providers. This review seeks to provide guidance as to when to employ the limited resource of specialist PC practitioners, in combination with services from other members of the care team, to best tend to HF patients as their disease progresses and eventually overcomes.

Direct Myosin Activation by Omecamtiv Mecarbil for Heart Failure with Reduced Ejection Fraction

Myosin is the indispensable molecular motor that utilizes chemical energy to produce force for contraction within the cardiac myocyte. Myosin activity is gated by intracellular calcium levels which are regulated by multiple upstream signaling cascades that can be altered for clinical utility using inotropic medications. In contrast to clinically available cardiac inotropes, omecamtiv mecarbil is a novel direct myosin activator developed to augment left ventricular systolic function without the undesirable secondary effects of altered calcium homeostasis. Its identification and synthesis followed high-throughput screening of a reconstituted sarcomere, deliberate optimization, exquisite biochemical evaluation, and subsequently promising effects in animal models were demonstrated. Physiologically, it prolonged the duration of left ventricular systole in animal models, healthy adults, and patients with heart failure with reduced ejection fraction (HFrEF) without changing the velocity of pressure development, as assessed in animal models. It has been formulated for both intravenous and oral administration, and in both acute and chronic settings produced similar alterations in the duration of systole associated with beneficial increases in cardiac output, improvements in left ventricular volumes, and reductions in heart rate and often of natriuretic peptides. Small, asymptomatic increases in troponin were also observed in the absence of clinically evident ischemia. Clinically, the question remains as to whether the possible harm of this minimal troponin release is outweighed by the potential benefits of reduced neurohormonal activation, increased stroke volume and cardiac output, and improved ventricular remodeling in patients treated with omecamtiv mecarbil. The resolution of this question is being addressed by a phase III outcomes trial of this potential novel therapy for heart failure.

Aspirin for Primary Prevention: What’s a Clinician to Do?

T he United States Preventive Services Task Force (USPSTF) 2009 recommendations regarding the use of aspirin for primary prevention of cardiovascular disease (CVD) were intended to provide concise evidence-based management strategies. They endorsed the use of aspirin for primary prevention of myocardial infarction in men and for primary prevention of stroke in women when the benefits outweighed the potential harms. However, these guidelines were rapidly undermined by additional data, new reviews of previous trials, conflicting conclusions even among concurrent analyses, and varying thresholds for aspirin therapy among guidelines, professional societies, and other authoritative bodies. In this issue of JGIM, Fiscella and colleagues reveal that, based on patient report, the USPSTF recommendations are followed in relatively few patients. The authors analyzed National Health and Nutrition Examination Survey (NHANES) data from 2011 to 2012, 2 years after publication of the guidelines. Men between the ages of 45 and 79 years and women between 55 and 79 years, none of whom had known CVD, were included. To determine whether aspirin was merited by the published risk cutoffs, their 10-year risk for CVD was calculated based on Framingham equations, as the USPSTF intended. Among those deemed eligible for aspirin therapy, only 34% of men and 42 % of women reported that their physicians advised them to take it. In contrast, 76 % of participants eligible for secondary prevention of CVD reported a physician recommendation for aspirin. Conversely, 24 % of men and 28 % of women who were not eligible for aspirin reported a physician recommendation to take it. USPSTF guidelinebased aspirin eligibility did not predict aspirin recommendation in multivariable logistic regression. Positive associations with older age, comorbidities such as diabetes mellitus, and access to healthcare suggest that traditional risk factors were employed for decisionmaking, rather than the calculations and cutoffs recommended by the USPSTF. The study is limited, most notably by relying on self-report, and by the fact that the authors did not have access to whether there were contraindications to aspirin therapy, such as a history of gastrointestinal bleeding. Given that hemorrhagic events are the predominant hazard that offsets the risk-benefit balance for aspirin use in primary prevention, this limitation is significant. Even so, that three-quarters of subjects eligible for secondary prevention recalled being advised to take aspirin suggests that neither failed report nor bleeding risk completely explain the low rates of aspirin recommendation reported in the primary prevention group. So why are clinicians apparently not following the USPSTF guidelines fully? New data and analyses of the risks and benefits of aspirin therapy released shortly after the USPTSF guidelines may be partly responsible. The authors describe this changing landscape of published literature. The 2009 USPSTF guidelines had been published for only a few months when a novel individual participant data meta-analysis was published. This study demonstrated little if any benefit to aspirin for primary prevention, despite using data from the same six randomized controlled trials (RCTs) and over 90,000 subjects as prior investigations. This inquiry also debunked any improvement in stroke or a gender difference for primary prevention aspirin, tenets of the USPSTF publication. Multiple publications over the subsequent years further altered the playing field. Three additional small RCTs and four meta-analyses were published before the end of 2012. The results were disparate. While all found that aspirin decreased major cardiac events, they did not agree on whether it decreased CVD mortality, and those that evaluated adverse events found that there was modest net benefit, given a substantial increase in bleeding. If there was a benefit for aspirin as primary prevention, it was small, with a number needed to treat (NNT) of 120 over 6 years to avoid one CVD event, and 162 to avoid one nonfatal myocardial infarction (MI). The comparative number needed to harm (NNH) to cause one nontrivial bleeding event was 73, which included fatal, cerebrovascular, retinal, or hollow viscous bleeding, any bleeding requiring hospitalization or transfusion, and bleeding termed “major” in the primary study. Based on these investigations, the data for aspirin for primary prevention of CVD in 2011–2012 were murky at best, which was reflected in varying thresholds for treatment among authoritative guidelines. In contrast to the USPSTF, the American College of Chest Physicians (ACCP) recommended in 2012 that aspirin for persons over 50 years of age as primary prevention was a weak Grade 2B recommendation. Published online December 2, 2014

Cardiac myosin activators: up and coming

This article refers to ‘Ribonucleotide reductase-mediated increase in dATP improves cardiac performance via myosin activation in a large animal model of heart failure’, by S. Kadota et al., published in this issue on pages 772–781. Despite the central role of decreased contractile function in the pathogenesis of heart failure with reduced ejection fraction (HFrEF), many promising inotropic agents have failed to demonstrate clinical benefits outside of cardiogenic shock.1 The dissociation between improved inotropy and clinical outcomes with these agents may be due to their mechanisms of action and effect on cellular energetics and calcium handling rather than a requisite adverse impact of increased myocardial contractility. Improved contractile function thus remains a viable therapeutic target. Myocardial contractility is produced at the cellular level by the interaction of myosin and actin filaments, with their relationship dynamics modulated by ATP, calcium, and regulatory proteins.2 The details of the myosin cycle are informative. Overall, the chemical energy of ATP hydrolysis is coupled to mechanical movement of ∼10 nm by each activated myosin head. In resting myocardium, troponin and tropomyosin bind to actin and prevent myosin attachment. Following myocyte depolarization, calcium is released from the sarcoplasmic reticulum as well as imported from the extracellular space. The increased calcium binds troponin, allowing the myosin cycle to proceed. ATP binding releases myosin in its strongly bound post-contraction state from actin. Hydrolysis of ATP to ADP resets the myosin lever arm to a cocked position. Release of the hydrolysed phosphate occurs concomitant with actin binding and is coupled to the force producing movement of the myosin lever arm. The cycle then ends with the dissociation of ADP from the myosin and the myosin–actin complex awaiting the arrival of the next ATP. Currently available inotropic agents including beta-adrenergic agonists, phosphodiesterase inhibitors, and levosimendan, as well as many in the development pipeline including nitroxyl donors, modify this system either by increasing cellular calcium or by sensitizing the cardiomyocyte to endogenous calcium fluxes.1 Increased cytoplasmic calcium augments sarcomere activation and the velocity of contraction development (dP/dt). However, it also induces