Clinical Trial Inclusion and Impact on Early Adoption of Medical Innovation in Diverse Populations.

BACKGROUND: Inadequate inclusion in clinical trial enrollment may contribute to health inequities by evaluating interventions in cohorts that do not fully represent target populations. OBJECTIVES: The aim of this study was to determine if characteristics of patients with heart failure (HF) enrolled in a pivotal trial are associated with who receives an intervention after approval. METHODS: Demographics from 2,017,107 Medicare patients hospitalized for HF were compared with those of the first 10,631 Medicare beneficiaries who received implantable pulmonary artery pressure sensors. Characteristics of the population studied in the pivotal CHAMPION (CardioMEMS Heart Sensor Allows Monitoring of Pressure to Improve Outcomes in NYHA Class III Heart Failure Patients) clinical trial (n = 550) were compared with those of both groups. All demographic data were analyzed nationally and in 4 U.S. regions. RESULTS: The Medicare HF cohort included 80.9% White, 13.3% African American, 1.9% Hispanic, 1.3% Asian, and 51.5% female patients. Medicare patients <65 years of age were more likely to be African American (33%) and male (58%), whereas older patients were mostly White (84%) and female (53%). Forty-one percent of U.S. HF hospitalizations occurred in the South; demographic characteristics varied significantly across all U.S. regions. The CHAMPION trial adequately represented African Americans (23% overall, 35% <65 years of age), Hispanic Americans (2%), and Asian Americans (1%) but underrepresented women (27%). The trial's population characteristics were similar to those of the first patients who received pulmonary artery sensors (82% White, 13% African American, 1% Asian, 1% Hispanic, and 29% female). CONCLUSIONS: Demographics of Centers for Medicare and Medicaid Services beneficiaries hospitalized with HF vary regionally and by age, which should be considered when defining "adequate" representation in clinical studies. Enrollment diversity in clinical trials may affect who receives early application of recently approved innovations.

Cost and Value in Contemporary Heart Failure Clinical Guidance Documents.

OBJECTIVES: This study sought to evaluate the frequency and nature of cost/value statements in contemporary heart failure (HF) clinical guidance documents (CGDs). BACKGROUND: In an era of rising health care costs and expanding therapeutic options, there is an increasing need for formal consideration of cost and value in the development of HF CGDs. METHODS: HF CGDs published by major professional cardiovascular organizations between January 2010 and February 2021 were reviewed for the inclusion of cost/value statements. RESULTS: Overall, 33 documents were identified, including 5 (15%) appropriate use criteria, 7 (21%) clinical practice guidelines, and 21 (64%) expert consensus documents. Most CGDs (27 of 33; 82%) included at least 1 cost/value statement, and 20 (61%) CGDs included at least 1 cost/value-related citation. Most of these statements were found in expert consensus documents (77.7%). Three (9%) documents reported estimated costs of recommended interventions, but only 1 estimated out-of-pocket cost. Of 179 cost/value-related statements observed, 116 (64.8%) highlighted the economic impact of HF or HF-related care, 6 (3.4%) advocated for cost/value issues, 15 (8.4%) reported gaps in cost/value evidence, and 42 (23.5%) supported clinical guidance recommendations. Over time, patterns of inclusion of statements and citations of cost/value have been largely stable. CONCLUSIONS: Although most contemporary HF CGDs contain at least 1 cost/value statement, most CGDs focus on the high economic impact of HF and its related care; explicit inclusion of cost/value to support clinical guidance recommendations remains infrequent. These results highlight key opportunities for the integration of formalized cost/value considerations in future HF-focused CGDs.

The Cost-Effectiveness of Palliative Care: Insights from the PAL-HF Trial.

BACKGROUND: In a randomized control trial, Palliative Care in Heart Failure (PAL-HF) improved heart failure-related quality of life, though cost-effectiveness remains unknown. The aim of this study was to evaluate the cost-effectiveness of the PAL-HF trial, which provided outpatient palliative care to patients with advanced heart failure. METHODS AND RESULTS: Outcomes for usual care and PAL-HF strategies were compared using a Markov cohort model over 36 months from a payer perspective. The model parameters were informed by PAL-HF trial data and supplemented with meta-analyses and Medicare administrative data. Outcomes included hospitalization, place of death, Medicare expenditures, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios. Simulated mortality rates were the same for PAL-HF and usual care cohorts, at 89.7% at 36 months. In the base case analysis, the PAL-HF intervention resulted in an incremental gain of 0.03 QALYs and an incremental cost of $964 per patient for an incremental cost-effectiveness ratio of $29,041 per QALY. In 1-way sensitivity analyses, an intervention cost of up to $140 per month is cost effective at $50,000 per QALY. Of 1000 simulations, the PC intervention had a 66.1% probability of being cost effective at a $50,000 willingness-to-pay threshold assuming no decrease in hospitalization. In a scenario analysis, PAL-HF decreased payer spending through reductions in noncardiovascular hospitalizations. CONCLUSIONS: These results from this single-center trial are encouraging that palliative care for advanced heart failure is an economically attractive intervention. Confirmation of these findings in larger multicenter trials will be an important part of developing the evidence to support more widespread implementation of the PAL-HF palliative care intervention.

Geographical affiliation with top 10 NIH-funded academic medical centers and differences between mortality from cardiovascular disease and cancer.

Community engagement and rapid translation of findings for the benefit of patients has been noted as a major criterion for NIH decisions regarding allocation of funds for research priorities. We aimed to examine whether the presence of top NIH-funded institutions resulted in a benefit on the cardiovascular and cancer mortality of their local population. METHODS AND RESULTS: Based on the annual NIH funding of every academic medical from 1995 through 2014, the top 10 funded institutes were identified and the counties where they were located constituted the index group. The comparison group was created by matching each index county to another county which lacks an NIH-funded institute based on sociodemographic characteristics. We compared temporal trends of age-standardized cardiovascular mortality between the index counties and matched counties and states. This analysis was repeated for cancer mortality as a sensitivity analysis. From 1980 through 2014, the annual cardiovascular mortality rates declined in all counties. In the index group, the average decline in cardiovascular mortality rate was 51.5 per 100,000 population (95% CI, 46.8-56.2), compared to 49.7 per 100,000 population (95% CI, 45.9-53.5) in the matched group (P = .27). Trends in cardiovascular mortality of the index counties were similar to the cardiovascular mortality trends of their respective states. Cancer mortality rates declined at higher rates in counties with top NIH-funded medical centers (P < .001). CONCLUSIONS: Cardiovascular mortality rates have decreased with no apparent incremental benefit for communities with top NIH-funded institutions, underscoring the need for an increased focus on implementation science in cardiovascular diseases.

Challenges and Potential Improvements to Patient Access to Pharmaceuticals: Examples From Cardiology.

Patient access to a drug after US regulatory approval is controlled by complex interactions between governmental and third-party payers, pharmacy benefit managers, distributers, manufacturers, health systems, and pharmacies that together mediate the receipt of goods by patients after prescription by clinicians. Recent medication approvals highlight why and how the distribution of clinically beneficial novel therapies is controlled. Although imposed limitations on availability may be rational considering the fiduciary responsibilities of payers and escalating spending on health care and pharmaceuticals, transparency and communication are lacking, and some utilization management may disproportionately affect vulnerable populations. Analysis of the current health insurance landscape suggests mechanisms by which patient access to appropriate medications can be improved and patient and clinician frustration reduced while acknowledging the financial realities of the pharmaceutical marketplace. We propose creation of a shared, standardized, and transparent process for coverage decisions that minimizes administrative barriers and is defensible on the basis of clinical and cost-effectiveness evidence. These reforms would benefit patients and improve the efficiency of the pharmaceutical system.

Assessment of Limitations to Optimization of Guideline-Directed Medical Therapy in Heart Failure From the GUIDE-IT Trial: A Secondary Analysis of a Randomized Clinical Trial.

Importance: Despite evidence that guideline-directed medical therapy (GDMT) improves outcomes in patients with heart failure (HF) and reduced ejection fraction, many patients are undertreated. The Guiding Evidence-Based Therapy Using Biomarker Intensified Treatment (GUIDE-IT) trial tested whether a strategy of using target concentrations of N-terminal pro-brain natriuretic peptide (NT-proBNP) to guide optimization of GDMT could improve outcomes. Objective: To examine medical therapy for HF in GUIDE-IT and potential reasons why the intervention did not produce improvements in medical therapy. Design, Setting, and Participants: GUIDE-IT, a randomized clinical trial performed at 45 sites in the United States and Canada, was conducted from January 16, 2013, to September 20, 2016. A total of 894 patients with HF and reduced ejection fraction (≤40%) were randomized to NT-proBNP-guided treatment with a goal to suppress NT-proBNP concentrations to less than 1000 pg/mL vs usual care. This secondary analysis examined the medical therapy titration and reasons why the intervention did not produce improvements in care and outcomes. Data were analyzed March 27 to June 28, 2019. Main Outcomes and Measures: For each encounter, medication titrations were captured. A reason was requested if a modification was not made. A Cox proportional hazards regression model was used to assess the independent association of drug class with outcomes. Results: Among the 838 patients available for analysis (566 men [67.5%]; median age, 62.0 years), 6223 visits occurred during 24 months. Adjustments of HF medication were made during 2847 of 5218 qualified visits (54.6%) (all usual care visits and all guided care visits with NT-proBNP level ≥1000 pg/mL) in 862 patients (96.4%). Most adjustments occurred within the first 6 months, primarily within the first 6 weeks. The most common reasons for not adjusting were "clinically stable" and "already at maximally tolerated therapy." Only 130 patients (15.5%) achieved optimal GDMT (≥50% of the target dose of ß-blockers or angiotensin-converting enzyme inhibitors/angiotensin receptor blockers or any dose of mineralocorticoid antagonists) at 6 months, an increase from the baseline (79 of 891 [8.9%]) but not different by treatment arm. Higher doses of ß-blockers were associated with reduced risk of the composite outcome of HF hospitalization and cardiovascular death (hazard ratio [HR], 0.98; 95% CI, 0.97-1.00; P = .008) and of all-cause death (HR, 0.97; 95% CI, 0.95-0.99; P = .01). Higher doses of angiotensin-converting enzyme inhibitors (HR, 0.84; 95% CI, 0.75-0.93; P < .001) and angiotensin receptor blockers (HR, 0.84; 95% CI, 0.71-0.99; P = .04) were associated with reduced risk of all-cause death. Increasing doses of mineralocorticoid antagonists did not appear to be associated with improved outcomes. Conclusions and Relevance: Despite a protocol-driven approach, many patients in GUIDE-IT did not receive medication adjustments and did not achieve optimal GDMT, including those with known elevated NT-proBNP concentrations. These results suggest that opportunities exist to titrate medications for maximal benefit in HF. GUIDE-IT may have failed to achieve treatment benefit because of therapeutic inertia in clinical practice, or current GDMT goals may be unrealistic. Trial Registration: ClinicalTrials.gov Identifier: NCT01685840.

Sex Differences in Quality of Life and Clinical Outcomes in Patients With Advanced Heart Failure: Insights From the PAL-HF Trial.

BACKGROUND: Palliative care improves quality of life in patients with heart failure. Whether men and women with heart failure derive similar benefit from palliative care interventions remains unknown. METHODS: In a secondary analysis of the PAL-HF trial (Palliative Care in Heart Failure), we analyzed differences in quality of life among men and women with heart failure and assessed for differential effects of the palliative care intervention by sex. Differences in clinical characteristics and quality-of-life metrics were compared between men and women at serial time points. The primary outcome was change in Kansas City Cardiomyopathy Questionnaire score between baseline and 24 weeks. RESULTS: Among the 71 women and 79 men, there was a significant difference in baseline Kansas City Cardiomyopathy Questionnaire (24.5 versus 36.2, respectively; P=0.04) but not Functional Assessment of Chronic Illness Therapy-Palliative Care scale (115.7 versus 120.3; P=0.27) scores. Among those who received the palliative care intervention (33 women and 42 men), women's quality-of-life score remained lower than that of men after enrollment. Treated men's scores were significantly higher than those untreated (6-month Kansas City Cardiomyopathy Questionnaire, 68.0 [interquartile range, 52.6-85.7] versus 41.1[interquartile range, 32.0-78.3]; P=0.047), whereas the difference between treated and untreated women was not significantly different (P=0.39). Rates of death and rehospitalization, as well as the composite end point, were similar between treated and untreated women and men. CONCLUSIONS: In the PAL-HF trial, women with heart failure experienced a greater symptom burden and poorer quality of life as compared with men. The change in treated men's Kansas City Cardiomyopathy Questionnaire score between baseline and 24 weeks was significantly higher than those untreated; this trend was not observed in women. Thus, there may be a sex disparity in response to palliative care intervention, suggesting that sex-specific approaches to palliative care may be needed to improve outcomes. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT0158960.

Heart Failure Site-Based Research in the United States: Results of the Heart Failure Society of America Research Network Survey.

OBJECTIVES: This study sought to determine clinician and scientist involvement in heart failure (HF) clinical research and to describe the challenges of conducting clinical trials in the United States. BACKGROUND: Improvements in the current capability, potential, and deficiencies of the HF clinical research infrastructure in the United States are needed in order to enhance efficiency and impact. METHODS: The Heart Failure Society of America (HFSA) distributed an electronic survey regarding HF clinical trial activity for the purpose of understanding the barriers that exist to conducting high-quality HF clinical research. RESULTS: Overall, 1,794 HFSA members were queried, and 434 members (24%) completed surveys, whereas a total of 7,589 individuals with interest in HF were queried, and 615 completed surveys. Of the respondents, 410 (67%) were actively engaged in HF research and 120 (20%) were interested in research. Most respondents, 270, were physicians (44%); 311 of the total (76% of the total and 80% of physicians) practiced in academic institutions; 333 respondents (81%) had served as principal investigators and 73 (18%) as site coordinators. Respondents active in clinical research usually participated in 1 to 5 trials and enrolled 1 to 20 patients annually. Institutional review board (IRB) approval typically required 3 months, and contract completion required 3 to 6 months per site. The greatest barriers to research were insufficient site budgets, delay in contracting, inability to find participants meeting trial entry criteria, and unavailability of qualified study coordinators. CONCLUSIONS: Many U.S. clinical research sites are constrained by budgetary, staffing, and contractual issues. The HFSA Research Network seeks to unify interested sites and deconstruct barriers to permit high-value HF research.

Economic and Quality-of-Life Outcomes of Natriuretic Peptide-Guided Therapy for Heart Failure.

BACKGROUND: The GUIDE-IT (GUIDing Evidence Based Therapy Using Biomarker Intensified Treatment in Heart Failure) trial prospectively compared the efficacy of an N-terminal pro-B-type natriuretic peptide (NT-proBNP)-guided heart failure treatment strategy (target NT-proBNP level <1,000 pg/ml) with optimal medical therapy alone in high-risk patients with heart failure and reduced ejection fraction. When the study was stopped for futility, 894 patients had been enrolled. OBJECTIVES: The purpose of this study was to assess treatment-related quality-of-life (QOL) and economic outcomes in the GUIDE-IT trial. METHODS: The authors prospectively collected a battery of QOL instruments at baseline and 3, 6, 12, and 24 months post-randomization (collection rates 90% to 99% of those eligible). The principal pre-specified QOL measures were the Kansas City Cardiomyopathy Questionnaire (KCCQ) Overall Summary Score and the Duke Activity Status Index (DASI). Cost data were collected for 735 (97%) U.S. RESULTS: Baseline variables were well balanced in the 446 patients randomized to the NT-proBNP-guided therapy and 448 to usual care. Both the KCCQ and the DASI improved over the first 6 months, but no evidence was found for a strategy-related difference (mean difference [biomarker-guided - usual care] at 24 months of follow-up 2.0 for DASI [95% confidence interval (CI): -1.3 to 5.3] and 1.1 for KCCQ [95% CI: -3.7 to 5.9]). Total winsorized costs averaged $5,919 higher in the biomarker-guided strategy (95% CI: -$1,795, +$13,602) over 15-month median follow-up. CONCLUSIONS: A strategy of NT-proBNP-guided HF therapy had higher total costs and was not more effective than usual care in improving QOL outcomes in patients with heart failure and a reduced ejection fraction. (Guiding Evidence Based Therapy Using Biomarker Intensified Treatment [GUIDE-IT]; NCT01685840).

Improving Medication Adherence in Cardiometabolic Disease: Practical and Regulatory Implications.

Medication nonadherence, a major problem in cardiovascular disease (CVD), contributes yearly to approximately 125,000 preventable deaths, which is partly attributable to only about one-half of CVD patients consistently taking prescribed life-saving medications. Current interest has focused on how labeling and education influence adherence. This paper summarizes the scope of CVD nonadherence, describes key U.S. Food and Drug Administration initiatives, and identifies potential targets for improvement. We describe key adherence factors, methods, and technological applications for simplifying regimens and enhancing adherence, and 4 areas where additional collaborative research and implementation involving the regulatory system and clinical community could substantially reduce nonadherence: 1) identifying monitoring methods; 2) improving the evidence base to better understand adherence; 3) developing patient/health provider team-based engagement strategies; and 4) alleviating health disparities. Alignment of U.S. Food and Drug Administration approaches to dissemination of information about appropriate use with clinical practice could improve adherence, and thereby reduce CVD death and disability.

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.

The palliative care in heart failure trial: rationale and design.

BACKGROUND: The progressive nature of heart failure (HF) coupled with high mortality and poor quality of life mandates greater attention to palliative care as a routine component of advanced HF management. Limited evidence exists from randomized, controlled trials supporting the use of interdisciplinary palliative care in HF. METHODS: PAL-HF is a prospective, controlled, unblinded, single-center study of an interdisciplinary palliative care intervention in 200 patients with advanced HF estimated to have a high likelihood of mortality or rehospitalization in the ensuing 6 months. The 6-month PAL-HF intervention focuses on physical and psychosocial symptom relief, attention to spiritual concerns, and advanced care planning. The primary end point is health-related quality of life measured by the Kansas City Cardiomyopathy Questionnaire and the Functional Assessment of Chronic Illness Therapy with Palliative Care Subscale score at 6 months. Secondary end points include changes in anxiety/depression, spiritual well-being, caregiver satisfaction, cost and resource utilization, and a composite of death, HF hospitalization, and quality of life. CONCLUSIONS: PAL-HF is a randomized, controlled clinical trial that will help evaluate the efficacy and cost effectiveness of palliative care in advanced HF using a patient-centered outcome as well as clinical and economic end points.

Link between decisions regarding resuscitation and preferences for quality over length of life with heart failure.

AIMS: Survival preferences, ascertained from time-trade-off utilities, have not been studied in heart failure patients who designate a 'do not resuscitate' (DNR) status. Therefore, the aim of this study was to determine the association of heart failure patients' resuscitation preferences with survival preferences and mortality in the ESCAPE trial. METHODS AND RESULTS: We analysed the association of resuscitation orders at 1 month with time-trade-off utilities and 6-month mortality. There were 26 and 349 patients with a DNR order and Full Code order, respectively. DNR patients were older, had more coronary artery disease, hypertension, renal impairment, and poorer exercise capacity than Full Code patients. DNR patients also experienced longer hospitalization and higher 6-month mortality. In multivariate analysis, DNR preference was associated with 10-fold higher odds of willingness to trade survival time (lower time-trade-off utility) in favour of improved quality of life [odds ratio 10.33, 95% confidence interval (CI) 1.65-64.80]. DNR preference was the best predictor of mortality (χ(2) 26.12, P < 0.0001, hazard ratio 6.88, 95% CI 3.28-14.41), despite adjustment for known predictors including brain natriuretic peptide. CONCLUSIONS: Heart failure patients' requests to forego resuscitation may signify more than simply 'what-if' directives for emergency care. DNR decisions may reflect preferences for intervention to enhance quality rather than prolong survival, which is particularly important as these patients have high early mortality.