Single-Pill Antihypertensive Combinations Reduce CV Outcomes and All-Cause Mortality

Risk for CV events and all-cause mortality is decreased in patients that receive combination therapy with up to 3 antihypertensive medications in a single pill.

Combination therapy with as many as 3 antihypertensive agents in 1 pill improves persistence to medication and reduces cardiovascular events and all-cause mortality compared with a multipill regimen, according to a study published in Hypertension.

These findings are based on data from patients who were treated with antihypertensive medications (renin-angiotensin system combinations) from 2012 to 2018. Data for patients aged 18 years or older who were diagnosed with arterial hypertension were obtained from AOK PLUS, a German statutory health fund. These patients were analyzed and followed up for 1 year or longer.

Patients receiving single-pill combinations were matched 1:1 with those receiving multipill combinations for each of 4 drug combinations. All-cause mortality was the primary objective.

After propensity score matching, the data of 28,999 hypertensive patients with single-pill combinations were compared with data from 28,999 hypertensive patients with identical drug combinations administered as multipill combinations. The cohorts were the following:

  • 10,801 patients received valsartan/amlodipine (VAL/AML)
  • 1026 patients received candesartan/amlodipine (CAN/AML)
  • 15,349 patients received ramipril/amlodipine (RAM/AML)
  • 1823 patients received valsartan/amlodipine/hydrochlorothiazide (VAL/AML/HCT)
These results strongly support the ESC/ESH, American College of Cardiology/American Heart Association, and International Society of Hypertension guidelines recommending the use of an SPC [single-pill combination] in favor of MPC [multipill combination].

Participants’ ages ranged from 65 to 72 years, with slightly more women included.

A lower mortality rate was observed for the single-pill combinations in all 4 comparisons vs multipill combinations. The VAL/AML incidence rate ratio (IRR) was 0.761 (95% CI, 0.683-0.848; P <.001). The CAN/AML IRR was 0.538 (95% CI, 0.284-0.980; P =.031). The RAMI/AML IRR was 0.526 (95% CI, 0.463-0.596; P <.001). The VAL/AML/HCT IRR was 0.515 (95% CI, 0.375-0.709; P <.001).

Lower hazard ratios with single-pill combinations compared with multipill combinations (all P <.001) were observed in the 4 drug combination groups regarding the composite outcome of all-cause death and all-cause hospitalization. In a comparison of the 4 drug combination groups, patients receiving single-pill combinations had a significantly reduced incidence (P <.05) of cardiovascular events in 15 of 20 IRRs analyzed and a trend in favor of single-pill combination in 5 IRR analyses compared with multipill combinations.

At 1 year, the percentage of patients who were persistent to antihypertensive drug combinations was significantly increased for those receiving single-pill combinations vs multipill combinations. Compared with each single-pill combination group, the proportion of patients with persistent medication was 20% less in the AML/VAL group for multipill combination, 24% less in the RAM/AML group for multipill combination, 30% less in the CAN/AML group for multipill combination, and 49% less in the AML/VAL/HCH group for multipill combination.

Limitations include potential residual bias. In addition, many participants who received multipill combinations were excluded from the analyses, and claims-based proxies were mostly used to identify the outcomes of interest attributed to hypertension-associated cardiovascular complications, including stroke and coronary heart disease. Furthermore, diagnosis or outcome misclassification may have occurred.

“These results strongly support the ESC/ESH [European Society of Cardiology/European Society of Hypertension], American College of Cardiology/American Heart Association, and ISH [International Society of Hypertension] guidelines recommending the use of an SPC [single-pill combination] in favor of MPC [multipill combination],” wrote the investigators. “These recommendations should be more rigorously implemented into daily clinical practice to improve the prognosis of hypertensive patients further.”

Disclosure: This analysis was supported by APONTIS PHARMA GmbH & Co. KG, Monheim, Germany. Some of the study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.


Schmieder RE, Wassmann S, Predel H-G, et al. Improved persistence to medication, decreased cardiovascular events and reduced all-cause mortality in hypertensive patients with use of single-pill combinations: results from the START-study. Hypertension. Published online March 29, 2023. doi: 10.1161/HYPERTENSIONAHA.122.20810