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REFLECTIONS
Hypertension
Hypertension Global Newsletter #8 2025

TREATMENT Hypertension

Effect of single-pill versus free equivalent combinations on persistence and major
adverse cardiovascular events in hypertension: a real-world analysis
Simonyi G, et al. J Hypertens. 2025 Mar 1;43(3):405-412.

Over the last two decades, hypertension guidelines have consistently recommended the use of combination therapy of two or
more antihypertensive drugs; however, monotherapy is still used more frequently. Adherence to such antihypertensive treatments
is generally insufficient, resulting in suboptimal BP control and, therefore, health and economic consequences. Systematic reviews
have shown that treatment persistence is significantly better with single-pill combination (SPC) therapy versus free equivalent
combination (FEC) therapy. However, the reported effects of SPC versus FEC on BP control have been heterogeneous.

This Hungarian retrospective, observational cohort study used the financing and demographic databases of the National Health
Insurance Fund (NHIF) to investigate the effect of drug format (i.e., SPC versus FEC) of an angiotensin-converting enzyme inhibitor
(ACEi, ramipril) and a calcium channel blocker (CCB, amlodipine), administered in various combinations on long-term treatment
persistence in patients with hypertension. The secondary objective of the study was to determine the effect of drug format on the rate
of major adverse cardiovascular events (MACEs) and treatment adherence in patients with hypertension.

The analysis included 173,206 patients with hypertension who were split into groups by SPC or FEC and different ramipril/amlodipine
(R/A) dose combinations. The proportion of patients in the R/A SPC group (61%) was greater than that in the R/A FEC group (39%),
and among those, the R/A 5/5 mg group represented the largest group (62%). The mean (SD) ages in the R/A SPC and R/A FEC
groups were 61.31 (13.75) and 66.08 (13.10) years, respectively; 45.4% of the patients in the R/A SPC group and 43.1% of the R/A
FEC group were male.

In the R/A 5/5 mg dose combination, the non-persistence rate was significantly lower in the SPC group than in the FEC group from
Month 1 to Month 24 (P < 0.001), whereas it was significantly higher from Month 48 to Month 60 (P < 0.001). In the R/A 5/10, 10/5,
and 10/10 mg dose combinations, the non-persistence rate was significantly lower in the SPC groups than in the FEC groups during
the observation period (from Month 1 to Month 60; P < 0.05).

The rate of MACEs was significantly reduced with all doses of R/A SPC compared with R/A FEC (hazard ratio, 0.68–0.73; P ≤ 0.002).
In addition, the majority of patients proved to be adherent (i.e., had >80% proportion of days covered [PDC] values (percentage of
days a patient has access to their medication within a defined period) in both the R/A SPC and FEC groups. However, more patients
in the SPC group than in the FEC group were adherent regardless of the dosage combinations (PDC values in the SPC and FEC
groups were 82%–85% and 58%–73%, respectively).

These findings demonstrate that SPCs are associated with better long-term treatment persistence and a lower risk of MACEs than
FECs. This aligns with current hypertension guidelines that recommend using SPCs to improve patient adherence and outcomes.
The authors note some limitations to their study, mainly the absence of detailed clinical data (e.g., blood pressure) and the potential
for over/under-reporting health conditions in the database. Further research would benefit from incorporating more comprehensive
clinical data and exploring reasons behind the differing persistence patterns observed with the lowest dose combination.

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