The research team, led by Jesper N. Bech of the University Clinic in Nephrology and Hypertension at Gødstrup Hospital and Aarhus University in Denmark, together with colleagues from the United Kingdom, the United States, Germany, Spain, Israel, and Denmark, extracted data from de-identified electronic medical records, insurance claims, and national health registries covering the years 2018 through 2023, and through 2024 for Denmark. Their study population comprised 64,501 adults with diagnosed hypertension who had been maintained on a stable two-drug regimen and then initiated a third antihypertensive medication, a step that clinicians interpret as treatment intensification in patients whose blood pressure remains above goal. The third medication fell into one of six commonly prescribed classes: angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, calcium channel blockers, beta-blockers, diuretics, or mineralocorticoid receptor antagonists.

The headline result is stark. Across countries and drug classes, between 54 percent and 100 percent of patients had discontinued their third medication within 12 months of starting it, and between 67 percent and 100 percent had done so within 24 months. In most countries, the median time to discontinuation was remarkably short, ranging from just 0.1 to 0.5 years, meaning that half of patients in many cohorts had abandoned the new drug within roughly two to six months. Denmark stood out as the exception, with discontinuation rates of 54 to 67 percent at one year and median persistence of 0.5 to 0.8 years, a difference the investigators suggest may partly reflect differences in how Danish physicians prescribe and dispense medications, with prescriptions commonly issued for 100 days or more.

Adherence told a similarly sobering story. The researchers measured adherence using the proportion of days covered, a pharmacoepidemiological standard that tracks how much of a follow-up period a patient actually has medication available based on prescription fills and dispensations. Median adherence to the third drug declined steadily over time, and the proportion of patients achieving the conventional threshold of more than 80 percent adherence at six months was 66 to 79 percent in Denmark but only 8 to 52 percent elsewhere. By 24 months, the picture in most countries had deteriorated further. Notably, adherence and persistence patterns were broadly similar across the six drug classes within each country, suggesting that the problem is less about which particular medication is chosen and more about systemic factors governing how patients engage with complex multidrug regimens.

The blood pressure outcomes raise equally difficult questions. Among the subset of patients with recorded blood pressure measurements at 12 months, only 23 to 50 percent in the United States, 35 to 66 percent in the United Kingdom, 42 to 55 percent in Germany, 57 to 70 percent in Spain, 63 to 89 percent in Israel, and 35 to 71 percent in Denmark had blood pressure below their country-specific target, which was 130/80 mmHg in the United States and 140/90 mmHg everywhere else. Median reductions in systolic blood pressure over the first year were modest, ranging from essentially zero for some drug classes in some countries to around 14 mmHg for calcium channel blockers at best. At 24 months, many patients showed no meaningful improvement, and some experienced worsening systolic pressures relative to baseline.

Perhaps most striking was what the medication data revealed about dosing behavior. When the investigators plotted daily dose categories and discontinuation across the first 365 days after the index prescription, they found that up-titration to higher doses was uncommon. Patients overwhelmingly started on low or usual doses and stayed there, even as a substantial proportion remained above their blood pressure targets. In some cases, prescriptions fell below licensed doses altogether: at least half of patients receiving the mineralocorticoid receptor antagonist spironolactone in the UK, USA, and Spain were dispensed 25 mg or less, below the 50 mg threshold generally considered the licensed starting dose for hypertension, and a similar pattern appeared for eplerenone. The authors interpret this combination of low starting doses, minimal up-titration, and high discontinuation as a signature of therapeutic inertia, the well-documented clinical phenomenon in which providers fail to intensify treatment despite evidence that a patient’s condition remains uncontrolled.

The clinical stakes of this gap are considerable. Hypertension is the leading modifiable risk factor for cardiovascular and renal disease worldwide, and meta-analyses indicate that every 10 mmHg reduction in systolic blood pressure lowers the risk of major cardiovascular events by roughly 20 percent. Yet globally, only about one in five people with hypertension achieves guideline-recommended blood pressure control. Patients who require multiple medications and still fail to reach target face elevated risks of stroke, ischemic heart disease, heart failure, chronic kidney disease, diabetes, and death. The EnligHTN analysis also showed that many of these patients carried substantial comorbid disease at baseline: the prevalence of heart failure ranged from 2 to 56 percent across cohorts, chronic kidney disease from 14 to 84 percent, and type 2 diabetes from 8 to 38 percent, conditions that complicate blood pressure management both biologically and pharmacologically.

The authors are careful to note important limitations. Discontinuation was inferred from prescribing and dispensing records rather than direct measurement of medication intake, so the estimates reflect loss of observed treatment continuity rather than definitive proof that patients stopped taking their pills; gaps may also reflect clinician-directed strategy changes or incomplete data capture. Blood pressure measurements were missing for a majority of patients at follow-up, ranging from 50 to 90 percent at the 12- and 24-month time points, so control rates describe only those patients with documented monitoring and may not generalize to the full cohort. The setting in which readings were taken could not always be determined, leaving open the possibility of white-coat or pseudo-resistant effects, and some prescribed doses may have been intended for indications other than hypertension.

Even with those caveats, the scale and consistency of the findings across six distinct healthcare systems carry a clear message. High discontinuation, suboptimal adherence, and therapeutic inertia converge to leave many patients with harder-to-control hypertension undertreated and unprotected. The study’s authors argue that the field needs two parallel advances: adherence-focused strategies that reduce pill burden and support patients in staying on therapy, and new classes of antihypertensive agents that are better tolerated and more effective at targeting the underlying pathophysiology in patients who do not respond adequately to existing drugs. With newer pharmacological options entering the hypertension landscape, the real-world treatment patterns documented by EnligHTN provide a crucial benchmark against which any genuine improvement in persistence, adherence, and blood pressure control will have to be measured.

Subject of Research: Real-world antihypertensive medication adherence, discontinuation, and blood pressure control in patients with harder-to-control hypertension

Article Title: Antihypertensive Medication Patterns in Patients with Hypertension that is Harder to Control: Insights from the EnligHTN Study

Article References: Bech, J. N., McCormack, T., Bhalla, V., Ben Dor, N. R., Segura, J., Hougaard Christiansen, S., Andersen, I. T., Erhard, C., Rhodes, K. M., Norris, T., Coto, E., & Weil, J. (2026). Antihypertensive Medication Patterns in Patients with Hypertension that is Harder to Control: Insights from the EnligHTN Study. Advances in Therapy. https://doi.org/10.1007/s12325-026-03771-5

Image Credits: AI Generated

DOI: 10.1007/s12325-026-03771-5

Keywords: hypertension, antihypertensive medications, medication adherence, blood pressure control, treatment discontinuation, therapeutic inertia, EnligHTN study, real-world evidence, observational cohort study, treatment persistence, cardiovascular risk, polypharmacy

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