Four-drug pill beats three separate meds in difficult-to-treat hypertension

For individuals with difficult-to-treat hypertension who are struggling with three separate medications, a single pill that combines four blood pressure (BP)-lowering drugs may help with BP control, as shown in the phase III QUADRO trial.

In a cohort of 183 patients with resistant hypertension, 8 weeks of treatment with a single-pill combination containing perindopril, indapamide, amlodipine, and bisoprolol yielded significantly greater reductions in the primary endpoint of office sitting systolic BP (SBP) as compared with triple therapy with perindopril, indapamide, and amlodipine (mean change from baseline, –20.67 vs –11.32 mm Hg; difference, –8.04 mm Hg; p<0.0001), reported principal investigator Professor Stefano Taddei from the University of Pisa, Italy. [Taddei S, et al, ESC 2024]

Single-pill quadruple therapy likewise had greater effects on secondary endpoints such as ambulatory SBP over the 24-hour period (mean change from baseline, –14.09 vs –6.97 mm Hg; difference, –7.53 mm Hg; p<0.0001) and office sitting diastolic BP (DBP; mean change from baseline, –10.50 vs –5.31 mm Hg; difference, –6.14 mm Hg; p<0.0001).

At week 8, more patients in the single-pill quadruple therapy group than in the triple therapy group achieved office sitting BP control (66.3 percent vs 42.7 percent; p=0.001), 24-h ambulatory BP normalization (SBP <130 mm Hg, DBP <80 mm Hg; 51.2 percent vs 20.7 percent; p<0.0001), and 24-h home BP normalization (SBP <135 mm Hg, DBP <85 mm Hg; 60.7 percent vs 25.4 percent; p<0.0001).

The rate of adverse events (AEs) was comparable in the two treatment groups, and no serious AEs were observed, Taddei noted.

The most common AE was orthostatic hypotension, occurring in 11.4 percent of patients in the single-pill quadruple therapy group and in 8.4 percent of those in the triple therapy group. In terms of treatment-related emergent AE, one case of bradycardia and one case of palpitations were documented in the respective groups. A case of acute sinusitis in the triple therapy group led to treatment withdrawal, although Taddei pointed out that the event was not related to the study drugs.

“Patients with resistant hypertension on three BP medications, namely a diuretic, a renin-angiotensin system inhibitor, and a calcium channel blocker, require the addition of a fourth medication. However, adherence decreases with the number of pills prescribed,” Taddei noted. [Hypertension 2017;69:1113-1120]

To address the challenge of decreased adherence with multiple medications, guidelines promote single-pill combinations to enhance BP control, he added. Indeed, the findings demonstrate the superiority of the single-pill quadruple therapy over triple therapy, whichever BP measurement method was used, with a good safety profile.

According to Taddei, no quadruple single-pill combination has been available so far, and QUADRO fills this gap. The four-drug pill described in the trial will become the first of its kind to be available for patients with treatment-resistant hypertension.

The patients (mean age 57.4 years, 47.0 percent female, 96.2 percent Caucasian) who participated in QUADRO were enrolled from 13 countries. These patients initially received the triple combination of perindopril, indapamide, and amlodipine at optimal doses for 8 weeks during the run-in period. Those who still had uncontrolled BP after 8 weeks (office systolic BP ≥140 mm Hg and 24-hour ambulatory systolic BP ≥130 mm Hg), while being adherent to the therapy, were randomly assigned either to continue the same triple therapy (n=94) or to receive a single-pill combination containing perindopril, indapamide, amlodipine, and bisoprolol (at either 10/2.5/5/5 mg or 10/2.5/10/5 mg daily) for 8 weeks.