Dr. Mustafa Lütfi Yavuz, Dr. Mehmet Aydoğan

Study Title: QUADRO - A single 4-drug combination in hypertension

Published at Conference: ESC - 2024

Link:  https://www.escardio.org/The-ESC/Press-Office/Press-releases/A-single-tablet-with-4-blood-pressure-lowering-drugs-can-be-more-effective-than-taking-3-drugs-in-separate-pills

Introduction:
Managing resistant hypertension often requires the use of multiple pharmacological treatments to achieve effective blood pressure control. However, increasing the number of medications in a treatment regimen can significantly reduce patient adherence to therapy.

Objective:
This study aims to evaluate the efficacy and safety of a four-drug combination pill, consisting of low doses of perindopril, indapamide, amlodipine, and bisoprolol, in the management of resistant hypertension. The focus is on assessing the impact of adding bisoprolol to this combination compared to a three-drug regimen in terms of treatment effectiveness.

Methods:
The QUADRO study is a double-blind, randomized controlled trial conducted in patients with resistant hypertension. Initially, patients underwent an 8-week lead-in phase, during which they received a triple combination therapy with perindopril, indapamide, and amlodipine. After eight weeks, patients whose blood pressure remained uncontrolled were randomly assigned to either continue with the same regimen or switch to the four-drug combination pill, which included bisoprolol. To maintain blinding, both groups received an identical number of pills. The primary outcome was defined as the change in office systolic blood pressure, with secondary outcomes including 24-hour ambulatory blood pressure monitoring and overall blood pressure control.

Results:
A total of 183 patients from 49 centers across 13 countries participated in the study. The mean age of the participants was 57 years, with 47% being female. At baseline, the average office systolic blood pressure was recorded at 150.3 mmHg, while the average diastolic blood pressure was 90 mmHg. After eight weeks, the office systolic blood pressure in the four-drug combination group decreased by an average of 20.67 mmHg, compared to a reduction of 11.32 mmHg in the triple therapy group. This difference was statistically significant in favor of the four-drug combination (-8.04 mmHg; p<0.0001). Furthermore, the four-drug group showed a significantly greater reduction in 24-hour ambulatory systolic blood pressure (-7.53 mmHg; 95% CI -10.95 to -4.11; p<0.0001) and office diastolic blood pressure (-6.14 mmHg; 95% CI -9.00 to -3.27; p<0.0001) compared to the triple therapy group. Overall, office blood pressure control (<140/90 mmHg) was achieved in 66.3% of patients in the four-drug group, compared to 42.7% in the triple therapy group (p=0.001). Ambulatory blood pressure normalization (24-hour average <130/80 mmHg) was achieved in 51.2% of patients in the four-drug group, versus 20.7% in the triple therapy group (p<0.0001). Home blood pressure normalization (<135/85 mmHg) was observed in 60.7% of patients on the four-drug combination, compared to 25.4% in the triple therapy group (p<0.0001). There were no significant differences in adverse events between the two groups, and no serious adverse events were reported.

Conclusion:
The addition of bisoprolol to a triple-drug regimen, forming a quadruple single-pill combination, was found to be more effective in lowering blood pressure in resistant hypertension patients compared to the use of separate drugs. This combination showed superior blood pressure reduction across various measurement methods and improved treatment adherence, resulting in better blood pressure control.

Commentary:
The quadruple single-pill combination offers notable advantages in both efficacy and adherence compared to separate medications in the management of resistant hypertension. The inclusion of bisoprolol enhances blood pressure control while also improving patient compliance with the treatment regimen. The lack of significant differences in adverse effects supports this therapeutic approach as a safe option. These results suggest that the quadruple single-pill combination is a viable and effective alternative in the management of resistant hypertension.