A single daily pill containing several blood-pressure medicines may help patients stay on treatment for years—and could be linked to substantially lower risks of heart attacks, strokes and death, according to a large real-world study from Italy. The analysis followed more than 24,000 adults receiving perindopril-based antihypertensive therapy and found a striking difference between people taking their medicines in one combined tablet and those taking equivalent drugs as separate pills. Across a decade of observation, at least 73 percent of single-pill users maintained high adherence in any given year, compared with no more than 44 percent of patients using separate tablets. The researchers also found that single-pill treatment was associated with a 27 percent lower risk of death from any cause, a 31 percent lower risk of cardiovascular events and a 46 percent lower risk of cerebrovascular events. Because the study was observational, it cannot prove that the pill format itself prevented these outcomes. But the findings provide unusually long-term evidence that simplifying treatment may help solve one of medicine’s most stubborn problems: patients not taking effective drugs consistently enough to control hypertension.
High blood pressure is often called a silent disease because it can damage arteries, the heart, brain and kidneys for years without producing obvious symptoms. It remains the leading modifiable risk factor for cardiovascular death worldwide, yet blood-pressure control is poor even where effective medicines and clinical guidelines are widely available. A global analysis covering 200 countries reported that only about 23 percent of women and 18 percent of men with hypertension achieved adequate control. One important reason is adherence, meaning how consistently a patient takes a medicine as prescribed. A related concept, persistence, describes how long the patient continues treatment before stopping. Both can deteriorate as regimens become more complicated, particularly when people must remember several tablets with different instructions, refill schedules or side effects. Single-pill combinations, also known as fixed-dose combinations, place two or three active ingredients in one tablet. In the Italian study, the combinations contained perindopril with amlodipine, indapamide, or both.
The medicines work through complementary biological pathways. Perindopril is an angiotensin-converting enzyme inhibitor, or ACE inhibitor, that reduces production of angiotensin II, a hormone that constricts blood vessels and stimulates salt retention. Lowering angiotensin II relaxes the vascular system and reduces the hormonal signals that push blood pressure upward. Amlodipine is a calcium-channel blocker. It limits calcium entry into the muscle cells lining arterial walls, promoting vasodilation and reducing resistance to blood flow. Indapamide is a thiazide-like diuretic that increases the kidney’s excretion of sodium and water, lowering circulating volume and, over time, vascular resistance. Combining drugs with different mechanisms can produce stronger and more balanced blood-pressure reduction than simply escalating one medicine. The therapeutic logic is well established; the practical challenge is ensuring that patients keep taking every component. With separate-pill treatment, missing one drug may effectively turn a carefully designed combination into an incomplete regimen. With a single pill, the components travel together.
To investigate whether the apparent convenience of a single tablet translated into durable benefits, researchers linked patient records across Italian Local Health Unit administrative databases. These records included demographic information, prescriptions and pharmacy dispensing, hospital diagnoses and procedures, and outpatient specialist services. The team identified adults with hypertension who began a perindopril-based combination between 2010 and 2022 and had at least one year of data before and after the first prescription. After exclusions designed to create more comparable treatment groups, the final analysis included 22,663 people prescribed a single-pill combination and 1,458 receiving the corresponding drugs as separate pills. The investigators selected perindopril-based regimens because they were among the first such combinations introduced in Italy, allowing the longest available follow-up. They adjusted the comparison using stabilised inverse probability weighting, a statistical method that reweights participants so that measured characteristics—such as age, sex, diabetes, kidney failure, previous cardiovascular disease, comorbidities and medication burden—are more evenly distributed between treatment groups.
The adherence results were consistent from year to year. The study measured the proportion of days covered, or PDC, using prescription and dispensing records. A PDC of at least 80 percent was classified as high adherence, 40 to 79 percent as moderate adherence and below 40 percent as low adherence. For a single-pill user, coverage meant having the combination tablet available. For a free-pill user, all the drugs in the intended combination had to be available, with refills within a 30-day window accounted for by the researchers’ algorithm. Between 2012 and 2021, 73 to 79 percent of single-pill users reached the high-adherence threshold, compared with 37 to 44 percent of separate-pill users. After statistical adjustment, single-pill treatment was associated each year with at least 4.5 times higher odds of high adherence. The finding suggests that the effect was not merely a short-lived burst of enthusiasm after treatment began; the gap persisted across the observation period.
Persistence showed an equally dramatic separation. Three years after starting treatment, 80 percent of people in the single-pill group remained on therapy, while only 50 percent of those taking separate pills did so. The median time to discontinuation was nine years for the single-pill group, compared with 3.1 years for the free-pill group. In this analysis, discontinuation occurred when no prescription was recorded during the final three months of observation; for patients using separate pills, interruption of one component counted as stopping the combination. That definition reflects the clinical reality that a combination regimen depends on all of its components. A patient who continues perindopril but stops amlodipine or indapamide may no longer receive the intended treatment strategy. The results offer a simple explanation for why treatment format could matter: one tablet reduces the number of decisions, opportunities for confusion and chances to forget that occur every day.
The researchers then examined outcomes beginning one year after treatment initiation, using the first year to assess adherence and excluding patients who died during that period from the outcome analyses. Compared with free-pill therapy, single-pill use was associated with a 27 percent lower risk of all-cause mortality, corresponding to a hazard ratio of 0.73. The risk of the composite cardiovascular outcome was 31 percent lower, with a hazard ratio of 0.69. Ischaemic heart disease risk was 22 percent lower, cerebrovascular-event risk was 46 percent lower, and the combined risk of cardiovascular events or death was 29 percent lower. Adherence itself displayed a similar pattern regardless of formulation: compared with low or moderate adherence, high adherence was associated with 22 percent lower all-cause mortality, 21 percent lower cardiovascular risk, 17 percent lower ischaemic-heart-disease risk, 33 percent lower cerebrovascular risk and 22 percent lower risk of cardiovascular events or death. These are relative associations, not guarantees for individual patients, but their consistency strengthens the case for adherence as a key link between treatment and outcomes.
The study also revealed a paradox that could shape future prescribing. Before adjustment, patients receiving single-pill combinations were generally younger, had fewer cardiovascular diagnoses, fewer kidney problems and a lower overall comorbidity burden than those receiving separate pills. This may indicate that clinicians are more hesitant to prescribe combined tablets to older or medically complex patients, perhaps because they want greater flexibility to change individual doses or discontinue one ingredient if side effects occur. Yet these are precisely the patients who often face the greatest difficulty managing multiple medicines and the highest underlying cardiovascular risk. The analysis found that older age, male sex, greater comorbidity and a larger medication burden predicted worse clinical outcomes. Surprisingly, higher pill burden also predicted better adherence in the model, contrary to much previous research. The authors suggest that patients taking many medicines may have more regular contact with healthcare professionals or more established medication routines, showing that adherence is shaped by more than pill count alone.
The findings come with important limitations. Administrative databases record prescriptions and dispensations, not whether a tablet was actually swallowed, so PDC measures medication availability rather than confirmed ingestion. The records also lacked blood-pressure readings, drug doses, dose changes, reasons for treatment selection, reasons for discontinuation, lifestyle factors and the intensity of clinical monitoring. Even sophisticated weighting cannot remove confounding from factors that were never recorded. Physicians may have selected single-pill therapy for patients who were already more engaged with care, more able to manage treatment or less severely ill. The single-pill group also combined several different regimens rather than one identical product. In addition, the study excluded people who died within the first year from later outcome analyses, creating a possible survivorship bias, although these patients represented 3.1 percent of otherwise eligible participants. The research was conducted in Italy and focused on perindopril combinations, so the results may not apply identically to every antihypertensive combination or healthcare system. Funding, writing support and open-access costs were provided by Servier, which markets perindopril-based products, and several authors reported related consulting or honoraria.
Even with those caveats, the study offers a powerful real-world message: an effective hypertension regimen is useful only if people can sustain it. Randomised trials are designed to test drug efficacy under controlled conditions, but administrative data reveal what happens amid ordinary lives, competing illnesses, missed appointments and refill delays. The authors argue that single-pill combinations should be considered more broadly, including for older adults and patients with multiple conditions who may benefit most from simplification. The approach is not a substitute for individual clinical judgement: fixed-dose tablets can reduce flexibility, and clinicians still need to monitor blood pressure, kidney function, electrolytes and adverse effects. Nor should patients alter treatment without medical advice. But if putting several complementary medicines into one tablet helps preserve treatment continuity, the benefit could extend beyond convenience to fewer strokes, heart complications and premature deaths. Published in Advances in Therapy, the analysis turns an everyday object—the pill bottle—into a reminder that the design of treatment can be almost as important as the pharmacology inside it.
Subject of Research: Long-term adherence, persistence and cardiovascular outcomes associated with perindopril-based single-pill versus free-pill antihypertensive combinations in Italy
Article Title: A Retrospective, Observational Study of Adherence, Persistence and Clinical Outcomes with Perindopril-Based Single-Pill or Free-Pill Antihypertensive Treatments in Italy
Article References: Vintila AM, Masi S, Degli Esposti L, et al. “A Retrospective, Observational Study of Adherence, Persistence and Clinical Outcomes with Perindopril-Based Single-Pill or Free-Pill Antihypertensive Treatments in Italy.” Advances in Therapy (2026). Original research article
Image Credits: AI Generated
DOI: 10.1007/s12325-026-03765-3
Keywords: hypertension, perindopril, single-pill combinations, medication adherence, treatment persistence, cardiovascular events, stroke risk, real-world evidence
Tags: Benefits of combined antihypertensive pillsEffectiveness of simplified medication regimensHypertension treatment adherenceImpact of medication simplification on cardiovascular riskLong-term outcomes of blood pressure managementLongitudinal study of antihypertensive treatmentManaging silent hypertension and associated healthPatient compliance in hypertension therapyPerindopril-based antihypertensive therapyReal-world observational study on hypertensionReducing stroke and heart attack risks with medication adherenceSingle-pill vs. separate medication regimens
