Several new antihypertensive agents are reshaping the therapeutic strategies for patients with uncontrolled or resistant hypertension (RH). Agents such as baxdrostat, the first selective aldosterone synthase inhibitor, and aprocitentan, a dual endothelin receptor A and B antagonist, are paving the way for new drug combinations and a more personalized approach to blood pressure (BP) control.

Speaking at the 36th European Days of the French Society of Cardiology, professor Atul Pathak, MD, PhD, of the National Institute of Cardiac Surgery and Interventional Cardiology (Haerz Zenter) in Luxembourg City, Luxembourg, discussed these approaches as marking a significant evolution in hypertension management. The goals are to reduce adverse effects, improve long-term therapeutic adherence, and ensure effective reduction in BP.

A first-line tablet combining four low-dose drugs, including a beta-blocker, may be the next step.

For clinicians, these developments signal a potential shift from the traditional stepwise escalation model toward earlier multidrug strategies and targeted pathway inhibition in resistant diseases.

Single Pill

Although earlier intervention is recommended for hypertension, poor adherence remains a major challenge, Pathak noted. “It is estimated that 50% of patients prescribed at least three anti-hypertensive agents do not take their treatment,”. New therapeutic strategies “will probably help address these adherence problems,” he said.

Administering multiple antihypertensive agents in a single tablet is an emerging strategy for improving BP control. The FDA has recently approved Widaplik (George Medicines), a fixed-dose single-pill combination of telmisartan, an angiotensin II receptor blocker; amlodipine, a calcium channel blocker; and indapamide, a thiazide-like diuretic. The therapy is approved for the treatment of hypertension in adults, including as a first-line treatment.

Current guidelines recommend a stepwise strategy for the control of hypertension: initiate dual therapy for BP above 140/90 mm Hg, usually at low doses, and if BP targets are not achieved, escalate to triple therapy after 1-3 months. With this new triple therapy in a single tablet, “we are seeing a paradigm shift” that may influence future hypertension guidelines, according to Pathak.

The approval was based on the results of a phase 3 trial comparing a triple-combination pill with a placebo in untreated patients with hypertension. At 4 weeks, 70% of patients receiving low-dose triple therapy achieved BP below 140/90 mm Hg compared with 37% of those receiving placebo, with an average office systolic BP reduction of 9.4 mm Hg vs placebo.

Quadpill Approach

A first-line combination of four antihypertensive agents at low doses, or “quadpill” may represent the next step in hypertension management. The QUARTET trial demonstrated the superiority of this treatment over standard monotherapy. In this study, a single capsule containing irbesartan, amlodipine, indapamide, and the beta-blocker bisoprolol was compared with standard-dose monotherapy with irbesartan (150 mg) alone.

In the pilot trial, 591 patients with mild hypertension were randomly assigned to receive either a single, ultra-low-dose quadruple combination pill or a standard-dose monotherapy. During the 12 weeks, quadruple therapy reduced BP by 22 mm Hg, with a mean difference of 6.9 mm Hg between the groups. Severe adverse events did not differ significantly between the two strategies.

Thus, an initial strategy based on a combination of four antihypertensives at a quarter of the standard dose was shown to be more effective in controlling BP than a standard monotherapy approach at the standard dose, with no significant difference between the two strategies in terms of severe adverse effects.

Another quadruple combination in a single tablet recently demonstrated superiority in RH compared with triple therapy in RH. In the QUADRO trial, at 8 weeks, the combination of the angiotensin-converting enzyme inhibitor perindopril, amlodipine, indapamide, and bisoprolol achieved an additional 8 mm Hg reduction compared with triple therapy without the beta-blocker.

These results illustrate the value of combining several treatments that act synergistically in a single tablet, which should significantly improve treatment compliance. Pathak presented a possible evolution of the hypertension treatment algorithm that positioned the quadpill as the first-line therapy for all patients with hypertension.

In patients with chronic kidney disease (CKD) and an estimated glomerular filtration rate < 45 mL/min, finerenone, a nonsteroidal mineralocorticoid receptor antagonist that is not yet available in France, could be considered. Finerenone appears to be better tolerated in renal insufficiency than spironolactone, which remains recommended as a fourth-line treatment for RH in cases of preserved renal function.

Targeting Pathways

When the renin-angiotensin-aldosterone system activity is normal, aprocitentan may be added. Aprocitentan has shown benefits in RH defined as systolic BP 140 mm Hg or higher despite standardized background therapy, including three antihypertensive agents, one of which is a diuretic.

“Endothelin is a potent vasoconstrictor” previously targeted in pulmonary arterial hypertension, Pathak noted. In 2024, aprocitentan received European marketing authorization for RH based on the PRECISION trial, which reported an additional reduction of nearly 4 mm Hg vs placebo.

Beyond its modest BP effect, aprocitentan is associated with a risk for edema, which is usually mild-to-moderate. Its relatively high cost could also be a deterrent, leading to debates regarding its role as a fourth-line option.

In cases of RAAS dysregulation, “an aldosterone synthase inhibitorwill be more appropriate,” Pathak said. Baxdrostat is the first agent in this class to demonstrate efficacy in patients with uncontrolled RH. Recently, lorundrostat has shown efficacy.

These new drugs could offer an alternative to spironolactone, whose safety profile is limited by its low specificity for mineralocorticoid receptors. However, the use of this drug, which acts as an aldosterone antagonist, is restricted by its dose-dependent side effects. While spironolactone acts by inhibiting the action of aldosterone, baxdrostat and lorundrostat directly inhibit aldosterone production.

In the phase 3 BaxHTN trial, which included 796 patients with RH, once-daily administration of 1 mg and 2 mg of baxdrostat achieved placebo-adjusted mean changes in seated systolic BP of -8.7 mm Hg and -9.8 mm Hg, respectively, at 12 weeks.

“This decrease in blood pressure is the most significant observed with the addition of medication,” said Pathak. Hyperkalemia with serum potassium levels ≥ 6 mmol/L occurred in 1% of patients receiving baxdrostat. The drug was well tolerated and may alter practice in RH, as an alternative to spironolactone.

Other selective aldosterone synthase inhibitors, including lorundrostat and vicadrostat, showed similar results, suggesting a class effect.

Pathak also highlighted the role of SGLT2 inhibitors, which provide renal and cardiovascular protection in diabetes and exert clinically meaningful antihypertensive effects. GLP-1 receptor agonists also offer cardiometabolic benefits accompanied by a reduction in BP.

These emerging combinations reflect a shift toward “precision medicine” in the management of hypertension. Personalized care must also account for therapies targeting common comorbidities such as diabetes, CKD, heart failure, and obesity.

This story was translated from Medscape’s French edition.