Reducing Overall Mortality by Combining Three Antihypertensives into a Single Pill
Treating hypertension to recommended target blood pressure values often requires a combination of three antihypertensives. By simply combining these three substances into a single pill, it is possible to increase treatment adherence, reduce overall mortality in hypertensive patients, and lower healthcare costs within one year. This is demonstrated by a freshly published Italian real-world study.
Current Goals of Hypertension Treatment
Arterial hypertension is one of the most significant cardiovascular (CV) risk factors. Even though lifestyle adjustments can reduce blood pressure (BP) and CV risk, most hypertensive patients need lifelong pharmacological treatment. The benefit of such treatment in preventing CV diseases has been documented by many large randomized controlled trials. For every 5 mmHg reduction in systolic BP (SBP), a 10% reduction in CV event risk can be expected. Studies also show the preventive effect of BP reduction on kidney damage and there is growing evidence of its role in preventing cognitive decline and dementia.
Current European guidelines recognize four main classes of antihypertensives: renin-angiotensin-aldosterone system (RAAS) blockers (including angiotensin-converting enzyme inhibitors [ACEi] and angiotensin II receptor blockers [ARBs] or sartans), beta-blockers (BB), calcium channel blockers (CCB), and thiazide/thiazide-like diuretics (TD). The recommended target BP is < 130/80 mmHg for individuals aged 18–64 years, < 140/80 mmHg for those aged 65–79 years (if tolerated < 130/80 mmHg), and for patients over 80, the SBP should range between 140–150 mmHg (if well tolerated 130–139 mmHg).
The European Society of Hypertension (ESH) recommends starting hypertension treatment for most patients with a dual combination of antihypertensives, ideally in a single pill. If target BP values are not achieved with this dual combination, a triple combination is advised, again preferably in a fixed combination. Preferred classes include RAAS blockers + CCB or TD. The triple combination of antihypertensives achieves BP control in > 90% of patients not controlled by a dual combination. The combination of antihypertensives reduces the risk of side effects and the use of fixed combinations improves adherence to treatment.
Comparison of Fixed and Free Triple Combination of Antihypertensives in Real-Life Practice
The first fixed drug containing an ACEi, CCB, and TD was the triple combination of perindopril (PER)/indapamide (IND)/amlodipine (AML). The efficacy and tolerability of this fixed triple combination have been proven in clinical trials as well as in real-life practice. The aim of the cited Italian study was to evaluate adherence to this fixed combination and its impact on CV events, overall mortality, and healthcare costs in routine practice compared to the free combination of the same medicinal substances.
This was a retrospective observational analysis of data from Italian databases. Adult patients treated with PER, IND, and AML between 2010 and 2020 who had data available 1 year before and 1 year after starting this treatment were included. They were divided into 2 groups: those with the combination of the mentioned antihypertensives in a single pill (n = 12,150) and those with multiple pills (n = 6,105). The average age of patients in these groups was 66 and 68 years, respectively, 54% and 51% were men, and 12.2% and 13.5% had known CV disease at the time of starting the evaluated treatment. Adherence was defined by the proportion of days covered (< 40% = non-adherence; 40–79% = partial adherence; ≥ 80% = adherence). Mortality, incidence of CV events (ischemic heart disease, heart failure, stroke, peripheral arterial disease), and healthcare costs were evaluated during the first year of treatment.
The results showed significantly higher adherence in the single-pill group (59.9 vs. 26.9%; p < 0.001), and significantly lower overall mortality (29.9 vs. 33.7 per 1,000 patient-years; p < 0.05) and risk of the composite parameter including overall mortality and CV events (105.8 vs. 139.0 per 1,000 patient-years; p < 0.001) compared to the multiple-pill group. The triple combination of antihypertensives in a single pill was also associated with lower healthcare costs compared to the free combination (2970 vs. 3642 euros; p < 0.05), with the largest part of the costs being for medications and hospitalizations.
Conclusion
For many hypertensive patients, a triple combination of antihypertensives is necessary to achieve target BP levels. The Italian real-world study demonstrated significant benefits of the fixed combination of PER/IND/AML in a single pill compared to the free combination of these antihypertensives in terms of adherence, reduction in overall mortality, the combined parameter of overall mortality and CV events, and healthcare costs. Its results confirm similar findings from previous studies.
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Sources:
1. Snyman J. R., Bortolotto L. A., Degli Esposti L. et al. A real-world analysis of outcomes and healthcare costs of patients on perindopril/indapamide/amlodipine single-pill vs. multiple-pill combination in Italy. J Hypertens 2024 Jan 1; 42 (1): 136–142, doi: 10.1097/HJH.0000000000003570.
2. Mancia G., Kreutz R., Brunström M. et al. 2023 ESH Guidelines for the management of arterial hypertension The Task Force for the management of arterial hypertension of the European Society of Hypertension: endorsed by the International Society of Hypertension (ISH) and the European Renal Association (ERA). J Hypertens 2023 Dec 1; 41 (12): 1874–2071, doi: 10.1097/HJH.0000000000003480.
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