Marc Cohen, MD, FACC

Final Takeaways of Dual Endothelin Receptor Antagonists: Ideal Patients and Management Pearls

Health care providers managing resistant hypertension must begin with comprehensive patient reassessment rather than assuming previous evaluations were thorough or accurate. Dr Cohen emphasizes the importance of taking detailed histories regardless of prior documentation, ensuring that apparent treatment resistance isn’t actually due to medication nonadherence, lifestyle factors, or secondary causes that weren’t previously identified. This systematic approach prevents inappropriate medication escalation and ensures that patients receive appropriate care for their actual clinical situation.

The addition of endothelin dual pathway antagonism and aldosterone antagonist therapy represents 2 evidence-based approaches for patients with genuine resistant hypertension who have failed standard 3-drug combinations. These therapeutic options provide health care providers with effective tools for achieving blood pressure control in patients who previously had limited treatment options. The availability of these advanced therapies has transformed the outlook for patients with resistant hypertension from frustration to realistic hope for cardiovascular protection.

Successful resistant hypertension management requires integration of advanced pharmacological therapies with comprehensive lifestyle interventions and ongoing patient support. Health care providers must maintain focus on fundamental aspects of hypertension care including dietary sodium reduction, weight management, and exercise programs while incorporating newer therapeutic options. This comprehensive approach addresses both the immediate need for blood pressure control and the long-term cardiovascular health goals that drive resistant hypertension treatment efforts.

Videos

A panelist discusses the importance of comprehensive patient reassessment before advancing to dual endothelin receptor antagonists or aldosterone antagonists, emphasizing that successful resistant hypertension management requires integration of advanced pharmacological therapies with lifestyle interventions and ongoing patient support.

Aprocitentan in Practice: Real-World Insights from the Front Lines

Real-world clinical experience with aprocitentan demonstrates its effectiveness in patients with truly resistant hypertension who have failed multiple conventional therapies. Dr Cohen describes treating a patient already on 4 antihypertensive medications who experienced remarkable blood pressure improvement within 1 month of adding aprocitentan to her regimen. The patient achieved blood pressure readings that had not been seen with previous treatment combinations, demonstrating the medication’s ability to provide additional therapeutic benefit in heavily pretreated patients.

The side effect profile of aprocitentan appears manageable in clinical practice, with fluid retention being the most commonly observed adverse effect. Dr Cohen’s patient experienced mild ankle swelling that was successfully managed with as-needed diuretic dose adjustments rather than requiring medication discontinuation. This approach allows patients to continue benefiting from the blood pressure-lowering effects while managing predictable adverse effects through existing therapeutic relationships and medication adjustments.

One of the most valuable characteristics of aprocitentan in clinical practice is its ability to provide significant blood pressure reduction without causing excessive hypotension or overcorrection. Many advanced antihypertensive therapies risk causing blood pressure to drop too dramatically, leading to fatigue, kidney under-perfusion, and other complications. Dr Cohen appreciated that aprocitentan effectively “took the edge off” elevated blood pressures while maintaining stable, appropriate blood pressure ranges that didn’t compromise patient well-being or organ perfusion.

A panelist discusses real-world clinical experience with aprocitentan showing remarkable blood pressure improvements in heavily pretreated patients, with manageable side effects like mild fluid retention that can be addressed through diuretic adjustments.

Dual Endothelin Receptor Antagonists: A New Frontier in Resistant Hypertension

The endothelin pathway represents a significant breakthrough in understanding and treating resistant hypertension through targeted receptor antagonism. Endothelin functions as a powerful vasoconstrictor that causes arterial narrowing and subsequent blood pressure elevation, making it an ideal therapeutic target for patients who don’t respond to conventional treatments. While endothelin-mediated vasoconstriction serves important physiological functions such as bleeding control during injury, excessive activation can contribute to pathological blood pressure elevation in everyday situations.

Aprocitentan represents a dual endothelin receptor antagonist that blocks both endothelin A and endothelin B receptors, distinguishing it from single-receptor antagonists used in pulmonary arterial hypertension treatment. The PRECISION trial, published in 

, demonstrated significant blood pressure reductions when aprocitentan was added to existing 3-drug regimens in patients with confirmed resistant hypertension. This landmark study established the medication’s role in systemic hypertension treatment while differentiating its mechanism from pulmonary hypertension therapies.

The clinical significance of endothelin receptor antagonism extends beyond simple blood pressure reduction to meaningful cardiovascular risk reduction. Dr Cohen emphasizes that every 5 mm Hg reduction in blood pressure corresponds to approximately 10% reduction in adverse cardiovascular outcomes, making the substantial pressure reductions achieved with aprocitentan clinically meaningful. This relationship between blood pressure reduction and cardiovascular protection provides strong rationale for advancing to endothelin receptor antagonist therapy in patients with genuine treatment-resistant hypertension.

A panelist discusses how aprocitentan, a dual endothelin receptor antagonist, represents a breakthrough treatment that blocks both A and B receptors to achieve clinically meaningful blood pressure reductions in resistant hypertension patients.

Managing Resistant Hypertension: Unpacking Adherence and Polypharmacy

Managing patients on multiple antihypertensive medications presents significant practical challenges that extend beyond simple pharmacological considerations. Dr Cohen acknowledges the complexity of maintaining adherence to 3 or more daily medications while managing other life responsibilities including work obligations, family care, and additional health conditions. Health care providers must understand each patient’s daily routine and life circumstances to develop realistic medication schedules that fit within their existing lifestyle constraints and responsibilities.

The challenge of polypharmacy in resistant hypertension requires health care providers to move beyond simple medication prescribing to become lifestyle coaches and adherence specialists. Successful treatment demands understanding of individual patient circumstances, family dynamics, and social support systems that influence medication compliance. Providers must help patients integrate complex treatment regimens into their daily routines while addressing practical barriers such as work schedules, childcare responsibilities, and financial constraints that may impact treatment success.

Patient counseling and education become increasingly critical as treatment complexity increases with fourth- and fifth-line therapies. Health care providers must engage patients in forward-thinking discussions about long-term cardiovascular consequences of uncontrolled hypertension, helping them understand that current treatment challenges are investments in future health outcomes. This approach requires moving beyond immediate symptom management to help patients visualize their health trajectory and maintain motivation for complex treatment regimens that may not provide immediate symptomatic relief.

A panelist discusses how healthcare providers must become lifestyle coaches who understand patients' daily routines and circumstances to develop realistic medication schedules that address practical barriers to adherence in complex polypharmacy regimens.

Marc Cohen, MD, FACC

Articles