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Resistant Hypertension Best Practices
Best Practices in Resistant Hypertension: From Complexity to Control

Released: November 24, 2025

Wanpen Vongpatanasin
Wanpen Vongpatanasin, MD, FACC, FAHA
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Key Takeaways
  • Diagnosing true resistant hypertension requires patients to either have blood pressure above target despite use of 3 antihypertensive agents or use of 4 or more agents regardless of achieving control.
  • MRAs are strongly recommended for patients with an eGFR of ≥45 mL/min/1.73 m², and spironolactone is the preferred fourth-line therapy for resistant hypertension.
  • To help patients achieve control, healthcare professionals must simplify treatment by using combination therapy, expanding telemonitoring, and integrating team-based care models in their practice.

The management of resistant hypertension has advanced significantly with the 2025 American Heart Association (AHA)/American College of Cardiology (ACC) High Blood Pressure Guideline—reflecting a deeper understanding of its mechanisms and evolving treatment options. During a recent symposium titled “Pressure Points in Resistant Hypertension: Pioneering New Pathways to Control the Uncontrollable,” my colleagues and I explored the latest updates in diagnosing and managing this challenging condition. As the symposium unfolded, learners raised thought-provoking and frequently repeated questions: How do we truly define resistant hypertension? How do we integrate new therapeutic pathways? And what strategies best translate this science into everyday clinical care? 

These questions guided much of the discussion and revealed where healthcare professionals (HCPs) continue to seek clarity in their cardiology practice.

Defining Resistant Hypertension
The most common question asked by HCP leaners focused on defining and confirming true resistant hypertension. The 2025 AHA/ACC High Blood Pressure Guideline define it as either blood pressure above target despite use of 3 complementary agents, including a diuretic, at their maximally tolerated dose or blood pressure controlled with 4 or more complementary agents. Before labeling patients as having resistant hypertension, pseudoresistance first must be ruled out through accurate measurement, adherence assessment, and out-of-office monitoring. Ambulatory or home blood pressure monitoring is essential, as nearly one third of untreated cases are white-coat hypertension. This shift highlights the growing importance of diagnostic precision. The updated PREVENT risk calculator provides a more nuanced risk estimate that integrates kidney function, comorbidities, and blood pressure variability. 

Pharmacotherapy for Resistant Hypertension
The second major area of inquiry centered on the pharmacologic management of resistant hypertension. Spironolactone remains the preferred fourth-line therapy, supported by the PATHWAY-2 trial, which demonstrated its superiority to β- and α-blockers in reducing blood pressure. For patients with an estimated glomerular filtration rate of 45 mL/min/1.73 m² or greater and potassium less than 4.5 mEq/L, mineralocorticoid receptor antagonists (MRAs) are strongly recommended. Learners were particularly interested in alternatives for those who are intolerant to MRAs, and new data on amiloride and investigational aldosterone synthase inhibitors, such as baxdrostat and lorundrostat, generated significant discussion. These agents act upstream to block aldosterone synthesis directly, potentially overcoming many of the toxicities associated with steroidal MRAs. 

Another frequently asked question inquired about the role of novel therapeutics. The approval of aprocitentan, a dual endothelin A and B receptor antagonist, marks the first addition of a new drug class for resistant hypertension in years. The PRECISION trial showed sustained systolic blood pressure reduction, especially at night—a critical marker of cardiovascular risk. Equally exciting is zilebesiran, a small-interfering RNA that silences hepatic angiotensinogen production. It produced 6-month blood pressure reductions in the KARDIA-2 trial, which is an advancement that could transform treatment adherence via twice-yearly dosing. However, results from KARDIA-3 showed modest results with only -5 mm Hg reduction in systolic blood pressure with zilebesiran 300 mg compared with placebo.

Renal Considerations for Managing Resistant Hypertension
HCP learners also questioned why some of the renal denervation trials in this population did not meet their primary endpoint. The explanation may be multifactorial. First, the effects of renal denervation are relatively modest with an average -4.4 mm Hg reduction in 24-hour systolic blood pressure and -6.6 mm Hg reduction in office systolic blood pressure shown in a meta-analysis. Second, the sham arms often experience larger than expected reductions in blood pressure that are likely due to up titration in medications, which deviates from the study protocol. Third, the renal vascular bed only contributes 30% of systemic vascular resistance. Other regional sympathetic nerve activity (SNA) like mesenteric or skeletal muscle SNA are unaffected, which may contribute to persistently elevated blood pressure.

The learners then posed questions regarding the optimal approach to managing resistant hypertension in patients with chronic kidney disease or high hyperkalemia risk. The new guideline recommends chlorthalidone or indapamide over hydrochlorothiazide. Furthermore, SGLT2 inhibitors can be used in patients with resistant hypertension and diabetes or cardiorenal disease. Finally, universal screening for primary aldosteronism is now advised in all adults with resistant hypertension, even in the absence of hypokalemia.

Barriers to Achieving Control
The last of the discussion turned toward treatment adherence, care delivery, and persistent barriers to achieving blood pressure control. Less than half of patients with hypertension reach target blood pressure, often due to regimen complexity or cost. The guideline emphasizes simplifying treatment through combination therapy, expanded telemonitoring, and team-based care models that include pharmacists, nurses, and community health workers.

I believe the 2025 AHA/ACC High Blood Pressure Guideline mark a pivotal shift toward truly personalized and mechanism-driven management of resistant hypertension. As highlighted throughout the symposium, the challenge ahead is not the scarcity of therapeutic options but the precision of their application—translating scientific advances into consistent, patient-centered outcomes that achieve durable blood pressure control. The future holds great promise for HCPs to improve the care and quality of life of our patients. 

Your Thoughts
Are you applying the updated recommendations found in the 2025 AHA/ACC High Blood Pressure Guideline in your practice? You can get involved in the conversation by answering the poll question and posting a comment below.

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