Beyond Inclusion: Reimagining Equity and Real-World Impact in Heart Failure Trials

Introduction: A New Paradigm for Diversity in Heart Failure Trials

As the FDA prepares to implement groundbreaking diversity guidance in 2025, clinical trials must account for demographic metrics such as age, sex, race, and ethnicity. While this focus marks a pivotal step toward healthcare equity, addressing traditional diversity alone is insufficient for conditions as complex as heart failure (HF).

Conditions such as heart failure with preserved ejection fraction (HFpEF) and reduced ejection fraction (HFrEF) disproportionately affects underrepresented populations, with Black and Hispanic communities experiencing 2-3x higher HF-related hospitalizations compared to White populations yet remaining underrepresented in trials. Compounding this issue, HF research often overlooks disease heterogeneity and comorbidities central to patient outcomes. These include obesity, diabetes, chronic kidney disease (CKD), and pulmonary hypertension, factors that are frequently excluded to simplify trial design and regulatory pathways.

Such exclusions, while streamlining regulatory approval, fail to reflect real-world patient populations and payer demands for real-world effectiveness and economic value. To truly transform HF care, trials must embrace a holistic framework that integrates demographic, socioeconomic, and clinical diversity.
At RQM+, we recognize that inclusive trial designs serve both scientific rigor and strategic goals. By incorporating broader diversity into HF trials, manufacturers can achieve regulatory alignment, payer confidence, and expanded market access, while delivering transformative solutions for patients.

The Case for Expanding Equity and Diversity in HF Trials

Key Challenges in Current HF Trials

1. Demographic Underrepresentation
   • Intersectionality of Barriers: Women, Black, and Hispanic patients often face overlapping barriers such as limited access to trial sites, cultural mistrust of medical research, and socioeconomic constraints.
   • Women: Despite representing the majority of HFpEF cases, women are underrepresented in HF trials, limiting insights into sex-specific therapeutic responses.
   • Racial and Ethnic Minorities: Black and Hispanic populations face disproportionately high HF burdens but remain underrepresented, particularly in studies conducted in high-income countries.
2. Exclusion of Complex Patients
   • Missed Complexity: Patients with obesity, diabetes, CKD, or atrial fibrillation (AF) are often excluded due to procedural risks, despite representing large segments of the HF population.
   • Magnified Inequities: Intersectionality compounds disparities, such as a Black woman with CKD and HFpEF, who is unlikely to be included in traditional trial designs.
3. Geographic Imbalances
   • Disparity in Trial Locations: Most HF trials are concentrated in high-income countries, leaving low- and middle-income countries (LMICs) underrepresented despite rising HF prevalence. LMIC inclusion provides globally applicable data, vital for payer adoption in diverse markets.
4. Missed Subgroup Analyses
   • Opportunities for Precision Medicine: Even when diverse populations are included, outcomes are rarely stratified by demographics or comorbidities, limiting insights into therapeutic effectiveness across subgroups.

Expanding the Definition of Diversity: Beyond Demographics

Populations Typically Excluded in HF Trials

1. Obesity-Associated HFpEF
   • Rationale: Obesity drives unique metabolic and hemodynamic dysfunctions.
   • Opportunity: Evaluating device therapies in this population can demonstrate real-world effectiveness, particularly in reducing hospitalizations and improving QoL. Obesity-specific endpoints, such as weight-adjusted functional capacity, could further strengthen the evidence base for payers (thus aligning better with payer interests) and improving real-world applicability.
2. Diabetes Mellitus
   • Rationale: Diabetes exacerbates HF but is often excluded due to complication risks.
   • Opportunity: Combining device therapies with pharmacologic agents like SGLT2 inhibitors could show synergistic benefits and appeal to payers. This would address a significant unmet need, as diabetic HF patients represent a rapidly growing and high-cost subgroup.
3. Chronic Kidney Disease (CKD)
   • Rationale: CKD complicates HF management due to volume overload and reduced clearance.
   • Opportunity: Trials including CKD patients can highlight cost-effectiveness in this high-cost group. Real-world studies of CKD patients could also demonstrate long-term savings by reducing dialysis dependence and hospitalizations.
4. Combined Pre- and Post-Capillary Pulmonary Hypertension (CpcPH)
   • Rationale: Advanced HF populations with pulmonary hypertension have few therapeutic options.
   • Opportunity: Demonstrating effectiveness in reducing RV strain and improving hemodynamics could expand device indications.
5. Frailty and Sarcopenia
   • Rationale: Frail patients face unique challenges but represent a high-symptom burden subgroup.
   • Opportunity: Trials targeting mobility and QoL outcomes can showcase device benefits beyond survival endpoints. Including this population would align trial designs with the goals of value-based care, where improving QoL is a key metric.
6. Atrial Fibrillation (AF)
   • Rationale: AF is a common HF comorbidity but often excluded due to rhythm-device interactions.
   • Opportunity: Including AF patients can validate therapies that address rhythm and hemodynamic dysfunction simultaneously.

Designing Inclusive Trials for Better Effectiveness and Reimbursement

1. Broaden Eligibility Criteria
   • Include comorbid populations such as those with obesity, CKD, and AF to better reflect real-world complexity.
   • Incorporate adaptive trial designs to adjust cohort composition in real-time based on interim analyses.
   • Bold Addition: Use stratified enrollment strategies to capture a broader spectrum of disease phenotypes.
2. Leverage Wearables and Remote Monitoring
   • Collect real-time data on patient activity and hemodynamics to capture QoL improvements, a key metric for payers.
   • Bold Addition: Incorporate advanced wearables like implantable sensors for continuous monitoring of arrhythmias and exercise capacity.
3. Expand Geographic Representation
   • Conduct trials in LMICs to generate globally relevant data and address disparities.
   • Build collaborations with local health systems and NGOs to overcome logistical barriers in LMICs.
   • Bold Addition: Build cross-continental trial networks to balance equity and market alignment.
4. Prioritize Subgroup Analyses and Long-Term Outcomes
   • Stratify results by demographic and comorbidity variables to build a precision medicine narrative.
   • Bold Addition: Extend follow-ups beyond 5-10 years to address durability concerns in heterogenous populations, for both regulatory and payer needs.
5. Integrate Social Determinants of Health (SDOH)
   • Include data on socioeconomic status to understand barriers to treatment adherence and outcomes. SDOH metrics, such as access to care or transportation, can help refine implementation strategies post-approval.
   • Leverage AI models to analyze SDOH factors, offering actionable insights into improving trial accessibility and outcomes.

Strategic Benefits for Medtech Manufacturers

1. Regulatory Success: Inclusive trials align with FDA and EU Health Technology Assessment (HTA) expectations, minimizing approval delays.
2. Reimbursement Confidence: Real-world evidence strengthens the case for payer support, particularly in high-cost populations. For example, trials that demonstrate cost savings in CKD or diabetic patients could secure favorable reimbursement terms.
3. Global Market Adoption: Broader trial populations enhance global applicability, increasing clinician and patient adoption.
4. Ethical Leadership: Addressing equity builds trust among underrepresented communities and stakeholders.
5. Risk Mitigation: Comprehensive trial data reduces post-market risks, such as adverse events or product recalls, safeguarding long-term success.

Conclusion: A Broader Vision for Heart Failure Trials

As the FDA’s 2025 diversity guidance approaches, MedTech manufacturers must move beyond traditional diversity metrics to include the heterogeneity and comorbidities that define real-world HF populations. Innovative trial designs leveraging advanced technologies and global networks offer a pathway to transformative HF care.

RQM+ excels at designing inclusive trials that meet regulatory standards, generate payer-aligned data, and deliver impactful patient outcomes. Together, we can redefine HF research, ensuring innovative therapies are accessible and equitable for all.

Let’s lead the future of HF care with innovation, inclusion, and impact.

Contact us here.