Marc Cohen, MD, FACC

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.

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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.

Treatment Strategies for Resistant Hypertension: A Multipronged Balancing Act 

The standard treatment approach for resistant hypertension follows a systematic three-drug foundation using distinct medication classes that target different physiological pathways. The initial regimen typically includes thiazide-type diuretics like hydrochlorothiazide or chlorthalidone, calcium channel blockers such as amlodipine or nifedipine, and ACE inhibitors or ARBs including valsartan, losartan, or lisinopril. This combination targets the primary mechanisms of blood pressure regulation while minimizing overlapping adverse effects and maximizing therapeutic synergy.

When patients remain hypertensive despite optimal doses of the 3-drug foundation, health care providers must advance to fourth-line therapies targeting additional physiological pathways. Two primary approaches have emerged as evidence-based options: endothelin receptor antagonists like aprocitentan and aldosterone antagonists such as spironolactone or finerenone. These medications work through different mechanisms than the initial 3-drug combination, providing new therapeutic targets for blood pressure reduction in treatment-resistant patients.

The success of advanced resistant hypertension treatment requires careful patient selection and monitoring to ensure appropriate medication escalation. Health care providers must verify that patients have truly optimized lifestyle modifications including weight loss, sodium reduction, and regular exercise before declaring treatment failure with standard therapies. The availability of newer medication classes provides hope for patients with genuine treatment resistance, but success depends on comprehensive care that addresses both pharmacological and nonpharmacological factors contributing to elevated blood pressure.

A panelist discusses how treatment strategies progress from standard 3-drug regimens (thiazide diuretics, calcium channel blockers, and ACE inhibitors/ARBs) to fourth-line options like endothelin antagonists or aldosterone antagonists, while addressing information overload and the need for weight management drugs.

Marc Cohen, MD, FACC

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