Utility of Patient-Reported Outcome Instruments in Heart Failure.

Patient-reported outcomes (PRO) are defined as reports coming directly from patients about how they feel or function in relation to a health condition and its therapy. Although there are numerous compelling reasons why PRO could be an important help in clinical care, they have not evolved into clinical tools integrated into care. The purpose of this review is to assess existing PRO instruments for heart failure with respect to their psychometric properties and potential for use in clinical care. We performed a systematic search of articles published between July 2008 and January 2015 within the MEDLINE, PROMIS, PROQOLID, and Cochrane Library databases. Included instruments had to be developed and tested for heart failure and have had their development processes and psychometric properties described. A total of 31 instruments were identified, 9 of which met all inclusion criteria. After evaluating each remaining instrument in terms of psychometric and clinical criteria and symptom coverage, only 2 instruments-Minnesota Living with Heart Failure and Kansas City Cardiomyopathy questionnaire-met all evaluation criteria. Although clinically useful PRO instruments exist, increasing education to providers on the value and interpretability of PRO instruments, as well as a more streamlined approach to their implementation in the clinical setting is necessary. A clinical trial comparing the routine use of disease-specific PRO with clinical care could further support their incorporation into practice.

Agents with vasodilator properties in acute heart failure: how to design successful trials.

Agents with vasodilator properties (AVDs) are frequently used in the treatment of acute heart failure (AHF). AVDs rapidly reduce preload and afterload, improve left ventricle to aorta and right ventricle to pulmonary artery coupling, and may improve symptoms. Early biomarker changes after AVD administration have suggested potentially beneficial effects on cardiac stretch, vascular tone, and renal function. AVDs that reduce haemodynamic congestion without causing hypoperfusion might be effective in preventing worsening organ dysfunction. Existing AVDs have been associated with different results on outcomes in randomized clinical trials, and observational studies have suggested that AVDs may be associated with a clinical outcome benefit. Lessons have been learned from past AVD trials in AHF regarding preventing hypotension, selecting the optimal endpoint, refining dyspnoea measurements, and achieving early randomization and treatment initiation. These lessons have been applied to the design of ongoing pivotal clinical trials, which aim to ascertain if AVDs improve clinical outcomes. The developing body of evidence suggests that AVDs may be a clinically effective therapy to reduce symptoms, but more importantly to prevent end-organ damage and improve clinical outcomes for specific patients with AHF. The results of ongoing trials will provide more clarity on the role of AVDs in the treatment of AHF.

Improving cardiovascular clinical trials conduct in the United States: recommendation from clinicians, researchers, sponsors, and regulators.

Advances in medical therapies leading to improved patient outcomes are in large part related to successful conduct of clinical trials that offer critical information regarding the efficacy and safety of novel interventions. The conduct of clinical trials in the United States, however, continues to face increasing challenges with recruitment and retention. These trends are paralleled by an increasing shift toward more multinational trials where most participants are enrolled in countries outside the United States, bringing into question the generalizability of the results to the American population. This manuscript presents the perspectives and recommendations from clinicians, researchers, sponsors, and regulators who attended a meeting facilitated by the Food and Drug Administration to improve upon the current clinical trial trends in the United States.

Developing therapies for heart failure with preserved ejection fraction: current state and future directions.

The burden of heart failure with preserved ejection fraction (HFpEF) is considerable and is projected to worsen. To date, there are no approved therapies available for reducing mortality or hospitalizations for these patients. The pathophysiology of HFpEF is complex and includes alterations in cardiac structure and function, systemic and pulmonary vascular abnormalities, end-organ involvement, and comorbidities. There remain major gaps in our understanding of HFpEF pathophysiology. To facilitate a discussion of how to proceed effectively in future with development of therapies for HFpEF, a meeting was facilitated by the Food and Drug Administration and included representatives from academia, industry, and regulatory agencies. This document summarizes the proceedings from this meeting.

Antihypertensive drug development: current challenges and future opportunities.

The growing rate of obesity and diabetes, and an aging population has led to increased demand for new antihypertensive compounds. This review highlights the challenges and opportunities associated with each phase of drug discovery and development of novel antihypertensive agents. Discovery and development starts with identification of a protein hypothesized to be linked to hypertension. Using the information gathered during this early stage, several potential candidates are often synthesized and moved on through preclinical evaluations, eventually leading to selection of one or more compounds for testing in humans. The compounds then enter preclinical safety studies in laboratory animal species and subsequently are tested in tiered clinical studies. As the compounds enter clinical testing, there is an exponential increase in the investment of resources to demonstrate that a new compound is a viable and worthy therapeutic agent for hypertension. The review provides some forecasting of issues that are likely to impact drug development of novel antihypertensives in the future.

Anticipating risk for human subjects participating in clinical research: application of Failure Mode and Effects Analysis.

Failure Mode and Effects Analysis (FMEA) is a method applied in various industries to anticipate and mitigate risk. This methodology can be more systematically applied to the protection of human subjects in research. The purpose of FMEA is simple: prevent problems before they occur. By applying FMEA process analysis to the elements of a specific research protocol, the failure severity, occurrence, and detection rates can be estimated for calculation of a "risk priority number" (RPN). Methods can then be identified to reduce the RPN to levels where the risk/benefit ratio favors human subject benefit, to a greater magnitude than existed in the pre-analysis risk profile. At the very least, the approach provides a checklist of issues that can be individualized for specific research protocols or human subject populations.

Discharge education improves clinical outcomes in patients with chronic heart failure.

BACKGROUND: Although interventions combining patient education and postdischarge management have demonstrated benefits in patients with chronic heart failure, the benefit attributable to patient education alone is not known. We hypothesized that a patient discharge education program would improve clinical outcomes in patients with chronic heart failure. METHODS AND RESULTS: We conducted a randomized, controlled trial of 223 systolic heart failure patients and compared the effects of a 1-hour, one-on-one teaching session with a nurse educator to the standard discharge process. Subjects were contacted by telephone at 30, 90, and 180 days to collect information about clinical events, symptoms, and self-care practices. The primary end point of the study was the total number of days hospitalized or dead in the 180-day follow-up period. Subjects randomized to receive the teaching session (n=107) had fewer days hospitalized or dead in the follow-up period (0 and 10 days, median and 75th percentiles) than did controls (n=116, 4 and 19 days; P=0.009). Patients receiving the education intervention had a lower risk of rehospitalization or death (relative risk, 0.65; 95% confidence interval, 0.45 to 0.93; P=0.018). Costs of care, including the cost of the intervention, were lower in patients receiving the education intervention than in control subjects by 2823 dollars per patient (P=0.035). CONCLUSIONS: The addition of a 1-hour, nurse educator-delivered teaching session at the time of hospital discharge resulted in improved clinical outcomes, increased self-care measure adherence, and reduced cost of care in patients with systolic heart failure.

Impact of serial changes in cardiac hemodynamics on exercise performance in patients with heart failure due to ischemic and nonischemic cardiomyopathy.

Although prior studies have examined the role of central and peripheral hemodynamics on exercise tolerance within populations of patients with heart failure, a clear relation between hemodynamics and exercise has not been demonstrated. This may be due to the inability to control for other factors that may influence exercise performance. To isolate the impact of hemodynamics on exercise, we studied the relation between changes in these factors within individual patients studied on 2 occasions. A consecutive series of 133 ambulatory patients with heart failure were evaluated on 2 separate occasions with right-sided cardiac catheterization and treadmill cardiopulmonary exercise testing. Linear regression models were constructed and correlation coefficients were determined to examine the relation between changes in hemodynamic variables and changes in exercise variables over time for each patient. A significant correlation between peak oxygen consumption (VO(2)) and pulmonary arterial wedge pressure was found for both the first (r = -0.316, p <0.001) and second (r = -0.183, p = 0.029) tests. A stronger inverse correlation between the change in pulmonary arterial wedge pressure and change in peak VO(2) was observed in the study patients (r = -0.470, p <0.001). Similar correlations were found between change in peak VO(2) and changes in pulmonary arterial pressures. Changes in left ventricular filling pressure influence exercise tolerance in patients with heart failure due to left ventricular systolic dysfunction. Interpretation of cardiopulmonary exercise testing for the purpose of determining cardiac transplantation eligibility will be improved with knowledge of left ventricular filling pressure.

Prognostic significance of mitral regurgitation and tricuspid regurgitation in patients with left ventricular systolic dysfunction.

BACKGROUND: Mitral regurgitation (MR) and tricuspid regurgitation (TR) frequently develop in patients with left ventricular systolic dysfunction (LVSD). Ventricular volume overload that occurs in patients with MR and TR may lead to progression of myocardial dysfunction. We hypothesized that MR and TR would provide markers of risk in patients with LVSD. METHODS: We reviewed clinical, electrocardiographic, and echocardiographic data on 1421 consecutive patients with LVSD (left ventricular ejection fraction < or =35%). Predictors of survival (freedom from death or United Network for Organ Sharing [UNOS]-1 transplantation) were identified in a multivariable analysis with a Cox proportional hazards analysis. The impact of MR and TR (none to mild, moderate, or severe) then was assessed separately with Kaplan-Meier survival analysis. RESULTS: During the follow-up period (mean +/- SD, 365 +/-364 days), death occurred in 435 study subjects (31%) and UNOS-1 transplantation in 28 subjects (2%). Multivariable predictors of poor outcome included increasing MR and TR grade, cancer, coronary artery disease, and absence of an implantable cardiac defibrillator. Relative risk was 1.84 (95% CI 1.43-2.38) for severe MR and 1.55 (95% CI 1.14-2.11) for severe TR. Survival with Kaplan-Meier analysis related inversely to MR grade (none to mild 1004 +/-31 days, moderate 795 +/-34 days, severe 628 +/-47 days, P <.0001) and TR grade (none to mild 977 +/-28 days, moderate 737 +/-40 days, severe 658 +/-55 days, P =.0001). CONCLUSION: Patients with severe MR or TR represent high-risk subsets of patients with LVSD. Future study is warranted to determine whether pharmaceutical or surgical strategies to relieve MR and TR have a favorable impact on survival.

Safety and efficacy of atorvastatin in heart transplant recipients.

BACKGROUND: Pravastatin and simvastatin prolong survival and reduce transplant-related coronary vasculopathy, although low-density lipoprotein (LDL) lowering with these agents is only modest. The objective of this study was to assess the safety of moderate dose atorvastatin and its efficacy when prior treatment with another statin had failed to lower LDL to < 100 mg/dl. METHODS: Data from 185 patients were retrospectively evaluated for adverse events, duration of exposure (person-days), and the mean atorvastatin dose exposure. Changes in lipid parameters, and prednisone and cyclosporine doses were determined. SAFETY: 48 patients received atorvastatin for 24,240 person-days at a mean dose exposure of 21 +/- 10 mg. Rhabdomyolysis, myositis, myalgias, and hepatotoxicity occurred in 0, 2, 2, and 0 patients, respectively. All events occurred at the 10-mg dose, within the first 3 months, and were rapidly reversible with atorvastatin discontinuation. EFFICACY: Thirty-four patients evaluable for efficacy analyses had a pre-atorvastatin LDL of 145 +/- 38 mg/dl on the following statins: pravastatin (n = 30, 40 +/- 0mg), fluvastatin (n = 3, 33 +/- 12 mg), simvastatin (n = 1, 40 mg). After atorvastatin (21 +/- 9 mg/day) for 133 +/- 67 days, LDL was reduced to 97 +/- 24 mg/dl (relative reduction 31 +/- 20%, p < 0.0001). At the end of the observation period (418 +/- 229 days, atorvastatin final dose 24 +/- 14 mg/day), LDL was further decreased to 88 +/- 23 mg (relative reduction 37 +/- 17%, p < 0.0001). CONCLUSION: Atorvastatin, when used at moderate doses and with close biochemical and clinical monitoring, appears to be safe and is effective in aggressively lowering LDL in heart transplant recipients when treatment with other statins has failed to achieve LDL goals.