Redefining HFpEF Care: Precision Therapies for an Inclusive Future

Executive Summary

Tricuspid regurgitation (TR), historically overshadowed by left-sided valvular diseases, is increasingly recognized as a significant contributor to heart failure (HF) symptoms, hospitalizations, and mortality. Despite its prevalence, TR often remains undiagnosed or untreated until advanced stages, exacerbating patient morbidity and diminishing quality of life (QoL).

TR arises from diverse mechanisms, broadly categorized into primary TR (stemming from intrinsic structural abnormalities like prolapse or myxomatous degeneration) and secondary TR (caused by functional impairments such as annular dilation, atrial enlargement, or ventricular dysfunction). Adding complexity, cardiac implantable electronic devices (CIEDs) can induce TR by interfering with valve apparatus, causing leaflet tethering or perforation.

Advances in therapies, particularly transcatheter tricuspid valve interventions (TTVI), are reshaping TR management. However, leveraging these innovations requires a thorough understanding of the mechanisms, phenotypes, and challenges of TR, which this blog aims to explore, thereby establishing the groundwork for a deeper exploration of TTVI in the subsequent blog.

Introduction: A Turning Point in HFpEF Care

HFpEF represents a critical unmet need in cardiovascular medicine, affecting a significant and growing portion of the HF population. Despite advances in diagnostics and pharmacologic treatments for heart failure with reduced ejection fraction (HFrEF), progress in HFpEF care has been slow and fragmented, leaving patients with few options beyond symptom management.

The financial burden of HFpEF is substantial, with the American Heart Association forecasting the total direct medical costs of HF to increase from $21 billion in 2012 to $53 billion in 2030 due to hospitalizations and management of associated comorbidities. A lack of effective treatments amplifies this economic strain, disproportionately impacting underrepresented and aging populations.

The heterogeneity of HFpEF has compounded the challenge. As a syndrome with varying phenotypes, it presents differently across patients, requiring precise approaches tailored to individual hemodynamic and clinical profiles. This complexity underscores the need for innovative, evidence-driven solutions that address the full spectrum of HFpEF.

Device-based therapies, such as IASDs, and novel approaches like SNA offer new hope for patients who experience persistent limitations despite optimized medical care. By targeting the pathophysiologic underpinnings of HFpEF including elevated LA pressures and pulmonary congestion, these therapies aim to improve QoL, exercise capacity, and reduce heart failure hospitalizations.

However, trials like REDUCE LAP-HF II and RELIEVE-HF have shown that patient selection, phenotypic stratification, and tailored endpoints are critical to success. Lessons learned from these trials provide a foundation for future studies that can refine treatment approaches, identify responder populations, and generate robust data for regulatory and reimbursement pathways.

Here we explore the state of HFpEF care, focusing on its clinical complexities, current treatment options, and the promise of device-based innovations. By analyzing successes and challenges in recent trials, RQM+ offers 10 forward-looking recommendations for clinical trial design that emphasize precision medicine, advanced technology integration, and payer-aligned strategies.

With a combination of clinical innovation, regulatory expertise, and strategic insight, RQM+ is uniquely positioned to guide medtech innovators in transforming HFpEF care. Together, we can unlock new possibilities for patients, ensuring that therapies are not only effective but also accessible and impactful. This is the moment to redefine what’s possible in HFpEF care, bridging today’s unmet needs with tomorrow’s breakthroughs.

Understanding HFpEF: Disease State and Target Patient Population

HFpEF is characterized by elevated LA pressure, resulting from impaired left ventricle (LV) filling due to diastolic dysfunction. This leads to pulmonary congestion and systemic symptoms such as exercise intolerance and breathlessness. While HFpEF primarily affects older adults, women, and patients with comorbidities like hypertension and obesity, it remains a heterogeneous syndrome with varying phenotypes, including:

1. Exercise-induced left atrial hypertension (EILAH): Patients experience elevated LA pressure during exertion despite normal resting pressures, often in earlier disease stages.
2. Resting left atrial hypertension (RELAH): Persistent LA pressure elevation, often seen in advanced stages of HFpEF with volume overload.
3. Combined pre- and post-capillary pulmonary hypertension (CpcPH): Associated with right ventricular (RV) dysfunction in late stage disease​.

Understanding these phenotypes provides a roadmap for personalized treatment, enabling therapies to address specific hemodynamic and clinical profiles. Such stratification improves trial efficiency and clinical outcomes, ensuring therapies align with real-world needs.

Current Therapies: Benefits and Limitations

Pharmacologic Approaches:
Unlike HFrEF, HFpEF lacks robust evidence-based pharmacotherapies. Current treatments focus on symptom relief and comorbidity management (e.g., diuretics for volume overload). Emerging options, such as sodium-glucose cotransporter-2 (SGLT2) inhibitors, have shown modest benefits but do not fully address the underlying hemodynamic dysfunction​.

Interatrial Shunt Devices (IASDs)

• Mechanism: IASDs decompress the LA by creating a left-to-right shunt, mitigating pulmonary congestion and improving exercise tolerance.
• Clinical Trial Data: REDUCE LAP-HF II identified phenotypic responders with compliant pulmonary vasculature and exercise-induced LA hypertension, though non-responders diluted overall trial outcomes. RELIEVE-HF highlighted challenges in advanced HFpEF populations with RV dysfunction and pulmonary vascular resistance, where outcomes mirrored nonresponders in REDUCE LAP-HF II​.
• Implications: The success of IASDs hinges on careful patient selection and a balanced approach to trial inclusion criteria, ensuring alignment with both clinical and payer priorities.

Splanchnic Nerve Ablation (SNA)

• Mechanism: SNA targets the splanchnic vascular bed, redistributing blood volume and reducing LA pressure, particularly during exertion.
• Clinical Trial Data: The REBALANCE-HF trial revealed a subgroup of HFpEF patients who demonstrated significant improvements in exercise tolerance (6MWD) and quality of life (KCCQ). This aligns with the trial's focus on preload-dependent phenotypes, offering a new dimension in HFpEF management.
• Implications: SNA provides a viable option for patients unsuited for shunt-based therapies or refractory to GDMT, emphasizing the importance of tailoring interventions to patient-specific hemodynamics.

Limitations:

• Heterogeneous Patient Response: Not all HFpEF patients benefit equally; trials suggest better outcomes in early-stage disease with preserved RV function.
• Right Heart Overload Risks: Chronic left-to-right shunting risks RV strain over time, necessitating careful patient selection.
  
  

The Hits and Misses in HFpEF Trials

Here are some key items of note from recent clinical trials in HFpEF:

Hits:

• Responder Identification: Trials like REDUCE LAP-HF II effectively identified phenotypes most likely to benefit, paving the way for targeted therapies.
• Durability of Benefits: Data show stable RV function and sustained QoL improvements in responder groups over 2 to 3 years.
• Use of Real-World Data and Integration of Wearables in HFpEF Trials: Emerging studies, such as the REALIsM-HF trial, illustrate how wearable biosensors like the AVIVO patient patch and accelerometers are redefining HFpEF clinical trials. These devices enable continuous monitoring of physical activity, hemodynamic changes, and arrhythmias, complementing traditional endpoints such as hospitalizations and mortality. By correlating wearable data with biomarkers and patient-reported outcomes (ePROs), these tools provide a real-world perspective on treatment impact, early signs of deterioration, and daily symptom burden, paving the way for precision-driven HFpEF care.

Misses:

• Broad Inclusion Criteria: Trials including advanced HFpEF patients with significant RV dysfunction and pulmonary hypertension diluted overall effectiveness results due to inadequately powered subgroups.
• Inconsistent Endpoint Achievement: Multiple trials failed to meet hierarchical composite endpoints, underscoring the need for more refined, clinically relevant metrics.

Enhanced Recommendations for Future Clinical Trials

1. Prioritize Phenotype-Specific Enrollment

Recommendation: Stratify patients by phenotypes such as EILAH or those with compliant pulmonary vasculature. Include comorbidity-specific subgroups (e.g., obesity, chronic kidney disease).

Trial Design Suggestion: Conduct stratified multi-arm trials to compare outcomes across phenotypic groups, enabling tailored insights.

Rationale: This ensures trials focus on populations most likely to benefit, increasing statistical power and clinical relevance.

2. Expand Endpoint Selection

Recommendation: Think beyond hospitalization rates and mortality, so as to include:

• Dynamic hemodynamic monitoring during exercise
• Patient-reported outcomes (e.g., KCCQ)
• Physical function metrics (e.g., six-minute walk distance)

Trial Design Suggestion: Use composite endpoints combining hemodynamic, functional, and ePRO measures.

Rationale: This provides a holistic view of therapy impact, ensuring endpoints resonate with stakeholders.

3. Design Adaptive and Combination Trials

Recommendation: Implement adaptive designs allowing interim analyses to refine enrollment or endpoints. Test IASDs with pharmacologic agents like SGLT2 inhibitors or endothelin receptor antagonists. Combine SNA with pharmacologic agents like SGLT2 inhibitors for systemic and hemodynamic benefits.

Trial Design Suggestion: Multi-arm adaptive trials to evaluate IASDs (or SNA) alone, in combination with GDMT, and with adjunctive pharmacotherapies.

Rationale: This recommendation improves trial efficiency, reduces costs, and expands understanding of combination therapy potential.

4. Evaluate Long-Term Safety and Durability

Recommendation: Conduct long-term follow-up studies (5-10 years) assessing LA pressure control, RV remodeling, and adverse outcomes like pulmonary vascular disease.

Trial Design Suggestion: Include imaging-based assessments and follow-up visits to track device performance over time.

Rationale: This builds payer and clinician confidence in device safety and sustained patient benefits.

5. Leverage Digital Health and Remote Monitoring

Recommendation: Use remote monitoring tools to collect continuous hemodynamic data and patient activity levels.

Trial Design Suggestion: Include remote-adjusted endpoints to dynamically evaluate real-world patient responses.

Rationale: Such an approach reduces reliance on in-person visits, enhancing trial scalability and data collection.

6. Address Reimbursement Through Economic Endpoints

Recommendation: Capture cost-effectiveness metrics, such as QALYs gained and hospital cost reductions.

Trial Design Suggestion: Include subgroup-specific analyses to highlight cost savings in high-burden populations.

Rationale: This aligns trial outcomes with payer requirements, ensuring market adoption.

7. Explore Combination Endpoints to Reflect Real-World Complexity

Recommendation: Use hierarchical composite endpoints, balancing survival, symptom improvement, and functional capacity.

Trial Design Suggestion: Weight outcomes to reflect patient and clinician priorities, such as improved KCCQ scores and reduced hospitalizations.

Rationale: This captures the multidimensional impact of therapies, ensuring broader applicability.

8. Incorporate Global and Multicultural Trial Designs

Recommendation: Conduct trials in diverse regions, tailoring designs to reflect global healthcare disparities.

Trial Design Suggestion: Implement geographically stratified enrollment with region-specific analyses.

Rationale: This expands therapy access and generates insights into cultural and systemic variations in HFpEF care.

9. Develop Post-Market Evidence Strategies

Recommendation: Use registries and real-world studies to validate trial findings and support regulatory renewals.

Trial Design Suggestion: Create longitudinal registries tracking safety, effectiveness, and cost-effectiveness across diverse demographics.

Rationale: This recommendation strengthens evidence for long-term value, enhancing payer confidence and market penetration.

10. Integrate AI-Driven Diagnostics and Monitoring

Recommendation: Use AI for imaging analysis (echocardiography, MRI) to measure LV function, LA pressure changes, and RV strain. Utilize wearables for real-time monitoring of physical activity and hemodynamics.

Trial Design Suggestion: Incorporate dynamic imaging during exercise testing and real-world monitoring through wearables to assess therapy impact.

Rationale: Such an approach enhances precision in patient selection and provides granular, standardized data to evaluate device effectiveness.

Reimbursement Considerations

To secure reimbursement, future trials involving devices in the HFpEF space, must integrate both clinical and economic endpoints, demonstrating:

• Clinical Value: Trials must highlight hard endpoints (for e.g., reductions in hospitalizations and mortality) and responder subgroup benefits to convince payers of therapeutic effectiveness.
• Economic Analyses: Include cost-offset data, such as reduced hospitalizations and long-term economic savings through avoided complications, to justify coverage.
• Real-World Evidence: Post-market studies documenting real-world effectiveness across diverse populations will be critical to gaining payer trust and expanding access.

Conclusion: Bridging Innovation and Impact in HFpEF Care

The future of HFpEF care lies in therapies that embrace phenotypic diversity, innovative diagnostics, and real-world effectiveness. SNA and IASDs highlight the potential of tailored device-based interventions but underscore the need for precise trial designs. By broadening eligibility criteria (along with powered subgroups), integrating digital health tools, and addressing economic considerations, manufacturers can align regulatory success with payer confidence.

At RQM+, we empower medtech innovators to navigate these complexities, delivering solutions that are effective, equitable, and impactful. Together, we can shape a future where HFpEF care redefines standards and expands access to life-changing therapies.

The time is now; let’s advance HFpEF care through strategic innovation and collaboration. Contact us here.