Challenges and Perspectives in Optimising the Treatment of Arterial Hypertension: Role of the Ramipril-Amlodipine-Hydrochlorothiazide Single-Pill Combination
- Open Access
- 04.03.2026
- Review article
Abstract
1 Introduction
Globally, hypertension remains a major public health challenge, with suboptimal blood pressure (BP) control despite widespread treatment. Nationwide and global surveys show that between 40% and 70% of patients with hypertension who are receiving treatment do not achieve adequate BP control. In Italy, the latest studies available demonstrate relatively poor BP control [1‐3]. Therapeutic inertia, defined as the failure to intensify therapy when BP goals are unmet, is part of the problem, as approximately three-quarters of patients start on a single agent and more than half continue on monotherapy after 3 years [4, 5].
Because hypertension is driven by multiple physiological mechanisms, monotherapy often fails, even at high doses [6, 7]. Combining drugs that act through different pathways into single-pill combinations (SPCs) improves efficacy, allows lower doses of individual drugs and reduces dose-related adverse events (AEs) [6, 8]. SPCs also simplify regimens, an important determinant of long-term adherence [8, 9]. Starting therapy with two co-formulated drugs results in more rapid BP reduction and a higher likelihood of attaining targets than stepwise titration, which translates into better outcomes over time [7]. A recent real-world study including more than 1.4 million individuals in the UK who were eligible for dual combination therapy showed that treatment with dual therapy was associated with an 18% reduction in the composite endpoint of nonfatal myocardial infarction, nonfatal stroke, hospitalisation for heart failure, and cardiovascular (CV) death compared with current clinical practice, in which 57% of patients were treated with monotherapy. Over a 5-year follow-up, dual therapy was associated with a significantly lower risk of CV events (HR 0.82; 95% CI 0.81–0.83; p < 0.0001) [10].
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To address persisting shortfalls in BP control, the “LESS is BETTER” framework was developed as a pragmatic tool to support the application of contemporary hypertension guidelines in everyday clinical practice, overcome therapeutic inertia and improve patient outcomes. This framework summarises four key evidence-based principles to improve BP control: “L” for achieving lower targets, specifically systolic BP (SBP) of 120–129 mmHg, which is associated with significantly reduced cardiovascular risk; “E” for earlier control, emphasising the importance of achieving BP targets within 3 months of treatment initiation; “S” for stronger therapy, advocating the use of dual or triple drug combinations to maximise efficacy; and the second “S” for simpler regimens, encouraging the use of SPCs to improve adherence.
The 2018 European Society of Cardiology/European Society of Hypertension (ESC/ESH) guidelines introduced a new recommendation that most patients should initiate therapy with two-drug SPCs rather than with monotherapy [11]. The 2023 ESH guidelines reiterate this position, suggesting treatment should be initiated with a renin-angiotensin-aldosterone system (RAAS) inhibitor plus either a calcium channel blocker (CCB) or a thiazide-like diuretic, escalating to a three-drug SPC if needed (RAS inhibitor-CCB-diuretic) [12], which may be required by approximately one-third of patients with hypertension [13]. Treatment should aim to reduce SBP to < 140 mmHg in the first month and to < 130 mmHg within 3 months in most patients aged < 80 years, with a diastolic BP (DBP) target of < 80 mmHg, where tolerated [12]. The 2024 ESC guidelines and 2025 AHA/ACC guidelines on cardiovascular disease prevention supports the same strategy, recommending a blood pressure target of < 130/80 mmHg and, in appropriately selected high‑risk patients, encouraging intensification of therapy toward a systolic blood pressure < 120 mmHg when treatment is well tolerated and without adverse blood pressure, renal, or biochemical reactions [14, 15].
A triple SPC containing ramipril, amlodipine and hydrochlorothiazide and a dual combination of ramipril and amlodipine are available. These agents exert complementary antihypertensive effects through distinct mechanisms of action (Fig. 1), provide additive efficacy and have a favourable tolerability profile [14, 16, 17]. Ramipril is a long-acting angiotensin-converting-enzyme inhibitor (ACEi) that is converted to its active metabolite, ramiprilat, which lowers angiotensin II levels, promotes vasodilation and limits aldosterone-mediated sodium retention [18]. Amlodipine is a dihydropyridine CCB that inhibits L-type calcium channels in vascular smooth muscle, leading to potent and long-lasting arterial vasodilation due to its long half-life (30–50 h) [19]. Hydrochlorothiazide is a thiazide diuretic that exerts an antihypertensive effect, promoting natriuresis by inhibiting the distal tubular sodium-chloride cotransporter, thereby reducing plasma volume [20].
Fig. 1
Complementary mechanisms of antihypertensive drug classes [21]
BP can be determined by changes in cardiac output, total peripheral resistance and intravascular volume. The RAAS is one of the key regulators of BP, it works by increasing angiotensin II, a powerful systemic vasoconstrictor and one of the main intravascular volume regulators. Angiotensin II works by activating angiotensin II receptors, which are G-coupled. Angiotensin II works hand-in-hand with aldosterone to promote sodium and water reabsorption, and hence, maintaining intravascular volume as needed. Several drugs can lower BP by inhibiting different physiological mechanisms shown in this figure.
Adapted from Fig. 1 in Carlos-Escalante et al. Front Oncol 2021;11:660943 (doi: /https://doi.org/10.3389/fonc.2021.660943), which was published under a CC-BY 4.0 license (creativecommons.org/licenses/by/4.0). Adaptations included removing mechanism of actions for angiotensin receptor blockers, β-blockers and renin inhibitors, removing anatomical images and making other minor formatting changes.
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In addition to enhancing antihypertensive efficacy, the combined use of ramipril, amlodipine and hydrochlorothiazide mitigates common class-related AEs. Ramipril attenuates hydrochlorothiazide-induced RAAS activation and reduces amlodipine-associated peripheral oedema via ACEi-mediated sympatholytic effects [6, 22]. Amlodipine provides potent vasodilation without reflex tachycardia and may reduce the incidence and severity of ACEi-induced cough, possibly through prostaglandin inhibition and modulation of central cough reflex pathways [6, 22, 23]. Hydrochlorothiazide counteracts residual volume expansion and may attenuate ramipril-induced hyperkalaemia [20, 24].
The ramipril-amlodipine-hydrochlorothiazide combination is the first SPC based on their respective drug classes. The pharmacokinetic plasma concentration-time profiles of the three components are complementary (Fig. 2), resulting in consistent BP control and mitigation of class-specific AEs. The differential absorption and distribution of each component enables sustained 24-hour antihypertensive effects in the absence of excessive drops in BP [25]. In addition, SPCs improve treatment adherence and persistence, particularly in patients requiring multidrug regimens, and are recommended by international hypertension guidelines [12, 14].
Fig. 2
Representative normalised plasma concentration-time profiles of ramipril, ramiprilat, hydrochlorothiazide and amlodipine following oral administration. Normalised plasma concentrations are shown as a percentage of Cmax based on first-order absorption and elimination kinetics derived from published pharmacokinetic parameters [26‐28]. Data presented are estimates only. Cmax, maximum plasma concentration; NR, not reported; Tmax, time to maximum plasmaconcentration
The complementary mechanisms and tolerability benefits of the ramipril-amlodipine-hydrochlorothiazide triple SPC support its use in a wide range of patients with hypertension. In most cases, triple-drug SPCs should be considered a readily available, practical and straightforward treatment option. This narrative review synthesises current knowledge on hypertension management, with particular emphasis on the rationale, evidence and practical implications of SPCs, focusing on the ramipril-amlodipine-hydrochlorothiazide combination.
2 Methods
This review was developed by a multidisciplinary advisory board of five Italian clinicians with recognised expertise in hypertension management. The group was convened in Milan on 6 May 2025 to review the current evidence and provide expert input on the rationale, use and implementation of SPCs.
Literature sources were identified through a PubMed search. The search strategy combined MeSH terms and free-text keywords related to hypertension, fixed-dose or SPCs of ramipril, amlodipine and/or hydrochlorothiazide and the Italian setting using the following terms: (“Hypertension“[MeSH] OR “high blood pressure”) AND (“fixed-dose combination” OR “single-pill combination” OR “combination therapy”) AND (ramipril OR amlodipine OR hydrochlorothiazide). In addition, a targeted search for the Italian context was conducted by adding AND (“Italy”[MeSH] OR Italy OR Italian) to the original query. No publication date, language or study-type filters were applied.
3 Clinical Evidence
The efficacy and safety of ramipril, amlodipine and hydrochlorothiazide are supported by a substantial body of clinical evidence when each drug is used alone and in various combinations, as demonstrated in dose-finding and placebo-controlled studies, as well as real-world, longer-term general practice studies (Supplementary Information).
3.1 Monotherapy with Ramipril, Amlodipine or Hydrochlorothiazide
Extensive data support the sustained antihypertensive efficacy of ramipril monotherapy, along with its cardiovascular and renal protective effects [29‐32]. Once-daily ramipril (1.25–10 mg) produced dose-dependent BP reductions (5–15%), maintained over 24 h and up to 2 years, comparable to other ACEi [33, 34]. Several 24-hour ambulatory BP monitoring (ABPM) studies of ramipril monotherapy demonstrate that once-daily dosing provides clinically relevant BP reduction across the entire dosing interval, with approximately 50% of peak effect maintained at 24 h, supporting a 24-hour antihypertensive duration [35‐38]. In the AIRE study, post-MI patients with heart failure showed reduced mortality at 15 months (22.6% to 16.9%) [29]. The HOPE trial reported a 22% reduction in cardiovascular events (CVEs), while the subgroup analysis MICRO-HOPE confirmed similar benefits in type 2 diabetes, including fewer microvascular complications [31, 32]. Additionally, the GISEN study demonstrated renal protection, slowing GFR decline in proteinuric nephropathy [30], although ramipril was compared with placebo while patients continued minimal-dose conventional antihypertensive therapy aimed at a diastolic BP < 90 mmHg, rather than being tested as pure monotherapy.
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Amlodipine’s efficacy and tolerability are well-established across varied populations [39‐42]. In general practice, it reduced BP by 23.7/17.3 mmHg in mild-to-moderate hypertension [41]. The ALLHAT study showed improved BP control over 5 years (from 146.2/83.9 to 134.7/74.6 mmHg; control rates from 27.6 to 66.3%) [43]. The CAMELOT study further showed that amlodipine reduced BP to 124/75 mmHg and significantly reduced CV events (16.6% vs. 23.1% placebo) [39], and the VALUE trial linked SBP < 135 mmHg with lower incidence of end-stage kidney disease [40]. A meta-analysis of five RCTs (47,558 patients) confirmed reduced visit-to-visit BP variability and slightly better SBP stability versus atenolol, lisinopril and enalapril [42].
Thiazide diuretics remain central to antihypertensive therapy. Hydrochlorothiazide lowers BP in a dose-dependent manner, as showed in Cochrane review [44]. Higher doses increased metabolic disturbances; however, hydrochlorothiazide showed the most favourable biochemical profile among thiazide-type diuretics [44]. In a large RCT (13,523 patients), hydrochlorothiazide (25–50 mg/day) offered similar CV protection to chlorthalidone (12.5–25 mg/day), but with less frequent hypokalaemia [45]. Despite its efficacy, diuretic monotherapy rarely ensures long-term control due to RAAS activation and metabolic effects. Expanded data on the clinical studies referenced are summarised in the Supplementary Information and in Supplementary TableS1.
Monotherapy with either ramipril, amlodipine or hydrochlorothiazide is often not sufficient to achieve BP targets even at the maximum recommended doses [6, 7]. Since multiple physiological mechanisms cause hypertension, combining treatments that will act on different pathways are now recommended by most guidelines [11, 12, 14, 15].
3.2 Dual SPCs
Ramipril-amlodipine combination therapy has been studied extensively. The ATAR study randomised 265 patients with mild-to-moderate hypertension to a fixed ramipril-amlodipine tablet (2.5/2.5 mg titrated to 10/10 mg) or amlodipine monotherapy for 18 weeks [46]. Office BP decreased by a mean 27.5/16.7 mmHg in the combination arm versus 22.8/14.0 mmHg with monotherapy. Target BP (< 140/90 mmHg) was achieved by 63% versus 47% of patients, respectively. Peripheral oedema occurred less often with the combination (7.6% vs. 18.7%;) and cough incidence was low in both groups [46].
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Real-world evidence from the RAMONA study supports the use of the ramipril-amlodipine combination in patients with type 2 diabetes (T2D) and uncontrolled hypertension [47]. Among 1276 patients who switched to a ramipril-amlodipine SPC, mean BP decreased significantly from 157.5/91.3 mmHg at baseline to 130.9/79.6 mmHg at 4 months. Target BP (< 140/85 mmHg) was achieved by 69.8% of patients with T2D. The treatment was well tolerated, with no AEs related to the medication reported [47]. Support for dual SPCs also comes from a meta-analysis that included 10,968 participants from 42 randomised controlled trials (RCTs), which found that combining drugs from different classes, such as an ACEi plus CCB, is approximately five times more effective in lowering BP than simply doubling the dose of a single agent [17].
Cough is a well-known class effect of ACEis and may affect adherence to therapy in clinical practice. In a randomised crossover study of patients with benazepril-induced cough, the addition of amlodipine was found to significantly reduce cough frequency and intensity compared with placebo. Sixty-one per cent of patients reported a significant reduction of at least 10%, and 6% experienced complete resolution [23]. These findings suggest that CCBs, such as amlodipine, may attenuate cough through prostaglandin synthesis modulation or central reflex suppression mechanisms.
The ACCOMPLISH trial compared benazepril-amlodipine with benazepril-hydrochlorothiazide in 11,506 patients with high-risk hypertension [48]. The study aimed to evaluate whether, at comparable BP targets, the two drug combinations exerted differing effects on cardiovascular outcomes, with the underlying hypothesis that benazepril–amlodipine may offer target organ protection beyond its BP–lowering properties. Indeed, the benazepril-amlodipine combination was associated with a significant reduction in the primary composite endpoint of CVEs over a mean follow-up of 30 months (9.6% vs. 11.8%). This benefit included reductions in fatal or nonfatal myocardial infarction and coronary revascularisation (HR 0.86; 95% CI 0.74–1.00; p = 0.04). Mean BP was 131.6/73.3 mmHg with benazepril-amlodipine versus 132.5/74.4 mmHg with benazepril-hydrochlorothiazide [48].
Beyond haemodynamic effects, the ACEi-CBB combination may also provide complementary vascular benefits [49]. ACEis enhance endothelial function by increasing bradykinin availability and stimulating nitric oxide production, which contributes to vasodilation, anti-inflammatory activity and plaque stability. These effects are distinct from, but potentially additive to, the vasodilatory and anti-remodelling properties of CCBs, such as amlodipine. Evidence also suggests that ACEis exert broader anti-atherosclerotic effects through inhibition of oxidative stress, modulation of inflammatory pathways and improvements in endothelial repair mechanisms. These “pleiotropic” properties support the use of ACEi-CCB combinations as a rational therapeutic strategy to reduce cardiovascular risk in patients with hypertension [49].
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3.3 Triple SPCs
Triple therapy has been shown to produce greater BP reductions and improved cardiovascular outcomes compared to monotherapy or dual therapy. A 2020 network meta-analysis of 46 RCTs comprising over 240,000 participant-years compared major antihypertensive classes and drug combinations [50]. Triple therapy with ACEi-CCB-diuretic combinations produced the largest mean BP reduction (by 18.5/11.5 mmHg) and the greatest relative risk reduction for major CVEs (approximately 34%) compared with monotherapy [50].
These findings are supported by projections from a meta-analysis of 354 RCTs that included over 400,000 participants [51]. The analysis demonstrated that combining three antihypertensive drugs from different classes at half-standard doses can reduce SBP/DBP by an estimated 19.9/10.7 mmHg, with significant reductions in the risk of stroke (by 63%) and ischaemic heart disease events (by 49%) [51]. The additive effect of drug combinations with different mechanisms of action underpins the rationale for triple SPCs in patients requiring robust and sustained BP control.
Clinical data supporting the efficacy of a ramipril-amlodipine-hydrochlorothiazide combination stem from a randomized, double-blind study in 205 hypertensive patients with T2D and left ventricular hypertrophy inadequately controlled by dual therapy [52]. Patients received ramipril (5–10 mg) in addition to amlodipine 10 mg and hydrochlorothiazide 12.5 mg for 1 year. Clinic BP was reduced by a mean of − 13.4/−10.4 mmHg, the regimen was well tolerated, with no significant impact on metabolic parameters [52].
The risks are mitigated when low-dose hydrochlorothiazide is combined with an ACEi, which counteracts the renin surge, preserves potassium levels and reduces the risk of hyperuricaemia [6]. Long-term observational data from the Brisighella Heart Study evaluated 185 patients with hypertension receiving different triple combinations [53]. Patients treated with an ACEi-CCB-diuretic combination achieved the most stable BP control over 8 years, with 68% on target at baseline and 65% at the end of follow-up, which was higher than other triple-drug regimens. No cases of incident T2D or need for treatment intensification were observed in this group, and uric acid levels remained stable, suggesting a favourable long-term metabolic profile [53].
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A triple SPC is not affected by food intake, allowing it to be taken at any time of day, thus offering flexibility and better adherence to patient needs. Steady-state plasma concentrations of amlodipine are typically reached after 7 to 8 days of consecutive daily dosing, and the combination reaches steady-state levels rapidly, making the ramipril-amlodipine-hydrochlorothiazide combination a suitable option for achieving early BP control [19].
Together, these findings provide compelling reasons to use triple SPCs, such as ramipril-amlodipine-hydrochlorothiazide, to manage hypertension. This is particularly important for patients who require rapid and sustained BP control, or who are at high risk of cardiovascular and renal complications.
4 LESS Framework
The “LESS is BETTER” mnemonic summarises four key evidence-based principles to improve BP control. Together, these elements offer a structured approach to overcoming therapeutic inertia and improving outcomes in patients with hypertension.
4.1 Lower
The first pillar of the LESS framework advocates lowering office SBP to the 120–129 mmHg range (with DBP < 80 mmHg), whenever this is clinically tolerated. Contemporary guidelines have converged on these thresholds because the relationship between BP and cardiovascular risk is continuous and log-linear across the usual spectrum of readings found in clinical practice [12, 14]. In a meta-analysis that pooled data from 613,815 participants from 123 RCTs, each 10 mmHg reduction in SBP lowered the relative risk of major CVEs by 20%, fatal or non-fatal stroke by 27%, coronary heart disease by 17% and heart failure by 28% [54]. Proportional benefits were preserved down to mean baseline pressures of 130 mmHg, indicating that active treatment remains worthwhile even for patients whose starting BP would previously have been considered mild hypertension [54].
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Individual-participant data confirm these findings, as shown by a meta-analysis of 344,716 patients, which found that a 5 mmHg reduction in SBP translated into a 10% reduction in major CVEs, irrespective of baseline SBP [55].
RCTs further support the clinical importance of pursuing intensive targets. In the BPROAD study of 12,821 Chinese adults with T2D, aiming for an SBP < 120 mmHg reduced the composite of cardiovascular death, stroke, MI or heart-failure hospitalisation by 21% versus an SBP < 140 mmHg strategy after 4.2 years, with only mild increases in hypotension and hyperkalaemia [56]. Robust BP lowering has therefore become a cornerstone of primary and secondary cardiovascular prevention. A modelling analysis suggests that aiming for a BP of 120/70 mmHg rather than < 140/90 mmHg would avoid 63% of strokes and 46% of ischaemic heart-disease events in typical 60- to 69-year-old individuals [51].
Nevertheless, excessively low BP may be harmful in selected subgroups. Observational datasets have described J- or U-shaped curves in the very elderly and in patients with symptomatic coronary disease, where an SBP < 120 mmHg or DBP < 70 mmHg were associated with higher event rates [57‐59]. Clinicians should therefore titrate therapy cautiously in frail individuals, assess orthostatic change and prioritise symptoms over rigid numerical goals. Patients with chronic kidney disease may also show a paradoxical increase in renal morbidity when low BP regimens are achieved, although the concurrent reduction in CVEs provides a net benefit [60]. Visit-to-visit variability in BP also modifies risk. Higher standard deviations in clinic SBP were independently associated with stroke and all-cause mortality in the ALLHAT study, emphasising the value of achieving consistently low, rather than intermittently low, BP [61].
In practice, SPCs facilitate the achievement of these targets. National Health and Nutrition Examination Survey data show that patients receiving fixed-dose combinations (FDCs) are nearly twice as likely to achieve guideline targets compared with those on multiple separate tablets [62]. Furthermore, FDCs help in reducing CVEs.
Taken together, the evidence strongly supports the “Lower” principle – aiming at achieving and maintaining guideline-recommended BP targets without hesitation.
4.2 Earlier
Timely achievement of target BP is a critical determinant of cardiovascular protection. Current guidelines recommend reducing SBP to < 140 mmHg within the first month of treatment, and to < 130 mmHg within 3 months for most patients [12, 14]. This approach is supported by RCT evidence. In the VALUE study, which enrolled 15,314 patients with hypertension and high cardiovascular risk, those treated with an amlodipine-based regimen achieved faster BP control than those on a valsartan-based regimen, with a 2–3 mmHg advantage in both SBP and DBP during the early phase of treatment [63]. Although average BP was similar over the full 4.2-year follow-up, the amlodipine group experienced significantly fewer MIs in the initial months [63]. The post-hoc analysis of other important RCTs, such as the ALLHAT and ASCOT studies, support the concept that earlier and faster achievement of BP control results in better cardiovascular outcomes [64]. This is also supported by both ESH and ESC Guidelines, which recommend achieving BP control within 3 months [12, 14].
Observational and interventional studies consistently demonstrate that delays in reaching BP targets may compromise clinical benefit. In a retrospective cohort study of 88,756 patients with hypertension from the UK THIN primary-care database, patients whose treatment was intensified promptly (within approximately 1 month) had significantly lower risks of CVEs and all-cause mortality compared with those experiencing delays [65]. Risk increased steadily with longer delays, reaching a hazard ratio (HR) of 1.25 for delays ≥ 15.3 months [65].
A Canadian cohort study of 354,312 patients with newly diagnosed hypertension examined the impact of early BP control on long-term outcomes [66]. Patients who failed to achieve SBP < 140 mmHg within 12 months had a higher risk of major CVEs over a median 7.8 years of follow-up. Event curves diverged within the first year and remained separated, suggesting that delayed control confers lasting excess risk [66].
Taken together, these data support the “Earlier” principle of the LESS framework.
4.3 Stronger
Stronger antihypertensive effects can be achieved by using combination therapy rather than monotherapy, and this benefit extends further with the addition of a third agent when needed.
In a double-blind RCT conducted in Brazil, an amlodipine-ramipril FDC was compared with amlodipine monotherapy in patients with stage 1–2 hypertension [46]. The combination resulted in significantly greater reductions in ambulatory SBP and DBP and the rates of peripheral oedema were lower in the combination group; the relative risk of developing peripheral oedema in the amlodipine-only group was approximately 2.5-fold higher than in the FDC group [46].
A meta-analysis showed that an ACEi-CCB combination is approximately five times more effective in lowering BP than simply doubling the dose of a single agent [17]. Real-world findings from the UK CPRD database also favour early use of combination therapy. In a cohort of more than 54,000 adults, initial treatment with two antihypertensive agents was associated with significantly better BP than monotherapy (HR 1.17), with the effect more pronounced in those with grade 2–3 hypertension and in users of ACEi-CCB combinations [67].
For patients whose BP remains uncontrolled on dual therapy, a third agent can offer further benefit. A meta-analysis of 14 RCTs (N = 11,457) showed that triple therapy can reduce BP by an additional 5.4/3.2 mmHg compared with dual therapy, and improve control rates (58% vs. 45%) without a meaningful increase in AE-related withdrawals [68]. Notably, the addition of a third drug achieved four times greater BP reduction than simply doubling the dose of the existing agents.
These findings support the “Stronger” component of the LESS framework: combining complementary agents, especially early in treatment, yields greater and more consistent reductions in BP compared with stepwise monotherapy escalation.
4.4 Simpler
Complexity of treatment is a well-established barrier to long-term adherence. Therefore, simplifying antihypertensive regimens using SPCs improves adherence, persistence and BP control.
Evidence from meta-analyses supports the benefits of SPCs over equivalent individual drug components administered separately. In a pooled analysis of 15 studies (N = 32,331), SPC use was associated with a 21% absolute increase in adherence compared with individual drug components, with no significant difference in AEs or BP reduction [69]. A meta-analysis of 61 studies (N = 62,481) reported an 84% improvement in persistence with SPCs and a 15% increase in adherence [70].
Real-world studies have demonstrated that SPCs decrease the time to BP control and reduce the risk of CVEs. In an electronic health records study of 106,621 untreated patients with hypertension in the United States, initiating therapy with an SPC reduced time to BP control by 53% compared with monotherapy and by 14% compared with individual drug components (HR 1.53 and 1.34, respectively) [71]. In the START study, which included 57,998 patients with German insurance claims data, SPCs were associated with higher 1-year persistence and a significantly lower risk of CVEs and all-cause mortality than individual drug components, regardless of the drug pair used [72].
Agent-specific evidence further supports the use of SPCs. In a Hungarian insurance database analysis, patients receiving a ramipril-amlodipine SPC had a two-fold higher likelihood of 12-month persistence compared with those receiving the same drugs as separate pills [9]. A retrospective cohort study using Australian Pharmaceutical Benefits Scheme data found that mortality at 48 months was significantly lower in patients receiving an SPC of ACEi-CCB compared with those receiving the two drugs separately (8% vs. 18%; adjusted HR 1.83) and median persistence was six times longer [73]. A real-world analysis of 173,206 Hungarian patients showed that all dose strengths of ramipril-amlodipine SPCs were associated with lower rates of discontinuation and fewer major adverse CVEs than individual drugs over 5 years of follow-up [8].
The use of triple SPCs also appears to be cost saving. An Italian microsimulation analysis based on 95,989 patients estimated that a ACEi-CCB-diuretic SPC would extend life expectancy by 0.86 years and reduce lifetime healthcare costs relative to a two-pill equivalent, primarily due to averted hospitalisations [74].
The four elements of “Lower”, “Earlier”, “Stronger” and “Simpler”, when considered together, offer a structured approach that supports the routine use of SPCs. This approach simplifies treatment regimens, overcomes treatment inertia and improves outcomes in patients with hypertension.
5 Barriers to Treatment
Therapeutic inertia represents a significant barrier to optimal hypertension control (Fig. 3). This manifests as a prevalent cultural habit to initiate and maintain monotherapy despite guideline recommendations for early combination regimens [4, 5]. Overcoming this requires addressing these behavioural and systemic factors to facilitate a cultural shift towards SPCs.
Fig. 3
Barriers to SPC uptake and strategies to address them. ABPM, ambulatory blood pressure monitoring; BP, blood pressure; LESS, Lower, Earlier, Stronger, Simpler; SPC, single-pill combination
Clinicians often voice concerns regarding the risk of hypotension, especially in elderly patients, and a perceived loss of titration flexibility with SPCs [75]. However, studies on initial combination therapy generally do not report excessive hypotensive events [46]. Lower doses within SPCs can mitigate dose-dependent AEs, and the availability of multiple dose strengths for many SPCs allows for tailored and adjustable therapy, dispelling misconceptions about lost flexibility and offering predictable BP control [69]. Treatment-related AEs with more intensive BP lowering appear quantitatively infrequent when expressed as number needed to harm, and remain outweighed by CV benefit across higher‑risk groups, even at lower systolic targets [60, 76, 77]. Intensive BP control confers greater absolute reductions in major CV events and improves survival, despite an increased risk of treatment‑related AEs [60, 77, 78]. Thus, pointing to a balanced, net-benefit approach in which lower systolic BP targets (< 120 mmHg) remain appropriate when treatment is well tolerated, supported by careful patient selection and monitoring.
Further barriers include the limited use of ABPM and an under-appreciation of medico-legal protections from guideline adherence. ABPM is the gold standard for accurate hypertension diagnosis and 24-hour BP assessment, crucial for identifying masked or white-coat hypertension [79]. However, its routine use in primary care is often constrained by cost and logistics, leading to treatment decisions based solely on less accurate office BP measurements. Current ESH and other international guidelines acknowledge home BP monitoring (HBPM) as a practical tool for diagnosing and managing hypertension, particularly where ABPM is not available or impractical. HBPM offers repeated measurements in the patient’s usual environment and can enhance adherence and patient engagement with treatment [12]. Although ABPM remains the reference standard assessment, highlighting HBPM as a guideline‑endorsed, feasible option could help overcome organisational and patient‑related barriers.
Finally, communication gaps between doctors and patients significantly impede medication adherence and BP control. When patients lack full understanding of their condition, treatment rationale or the importance of consistent medication use, their engagement diminishes [80]. This transforms a collaborative alliance into a passive compliance challenge. It is important to clarify the inaccurate belief that antihypertensive agents should be administered at different times of the day. In fact, current guidelines recommend their simultaneous administration in a single-pill combination, as this approach is both clinically rational and effective.
6 Strategies to Overcome Barriers
According to the 2023 ESH guidelines, a three-drug combination can achieve BP control in up to 90% of patients [12], a rate significantly higher than current control levels across Europe. This highlights the need to overcome therapeutic inertia through targeted educational and systemic interventions. Educational outreach can significantly improve BP control and adherence. Disseminating updated guidelines and robust evidence on SPC efficacy and safety can bridge knowledge gaps, addressing specific clinician concerns about hypotension or flexibility by highlighting the real-world benefits of SPCs.
Increased ABPM use can demonstrate the superior 24-hour BP stability of long-acting SPCs. Visualising consistent BP control can reassure clinicians and address concerns about titration flexibility. ABPM also aids in identifying hypotensive effects, enabling data-driven dose adjustments and offers legal reassurance by documenting guideline-aligned treatment effectiveness objectively. Moreover, ABPM confirms the absence of significant BP fluctuations, demonstrating improved overall control, and highlighting the benefits of stable hypertension management.
Emphasising the availability of flexible dose strengths within SPC ranges can directly address perceived limitations in dose adjustment. This allows for tailored therapy, reassuring clinicians that SPCs offer sufficient adaptability for personalised patient management and maintaining effective BP control.
Developing structured counselling scripts based on the “LESS is BETTER” framework can empower general practitioners and specialists to communicate effectively with patients, explaining the rationale and benefits of combination therapy and SPCs. This fosters patient empowerment and shared decision-making. A schematic table directly addressing common general practice barriers with evidence-backed counterarguments can further serve as a practical tool to accelerate SPC adoption.
Healthcare system policies, including reimbursement and formulary placement, significantly influence SPC adoption. Triple SPCs are projected to be cost-effective, primarily due to indirect savings from improved patient outcomes and reduced healthcare utilisation [74].
7 Conclusions
Even though there are well-established evidence and guidelines in support of the use of SPCs, the control of hypertension remains suboptimal due to therapeutic inertia, misconceptions about SPCs, and barriers to their systemic implementation. Triple (ramipril-amlodipine-hydrochlorothiazide) and dual (ramipril-amlodipine) SPCs are options that offer a clinically and economically rational approach to improving BP control, with extensive data supporting their efficacy, safety and adherence benefits. The “LESS is BETTER” framework, emphasising “Lower” targets, “Earlier” control, “Stronger” therapy and “Simpler” regimens, provides a practical, evidence-based model to help clinicians overcome therapeutic inertia, better manage treatment options and align their practice with current guidelines. It will be essential to address these barriers through education, communication tools, the use of ABPM and system-level policy support to realise the full potential of SPC-based strategies within all healthcare systems.
Acknowledgements
We would like to thank Georgii Filatov who assisted in the preparation of the outline and first draft of this manuscript on behalf of Springer Healthcare Italia. This medical writing assistance was funded by Neopharmed Gentili.
Declarations
Ethical Approval
This article is a review and does not contain any studies with human participants or animals performed by any of the authors. Therefore, ethical approval was not required.
Consent to Participate
This article does not contain any studies with human participants or animals performed by the authors. All cited studies are properly referenced and comply with ethical standards as reported by their respective authors.
Conflict of interest
Maria Lorenza Muiesan has received honoraria/reimbursements for participation on advisory boards from Sandoz, AstraZeneca, Neopharmed Gentili, Novartis and Daiichi-Sankyo; and travel grants from Menarini Italy and Servier. Aldo P. Maggioni has received personal fees unrelated to the present work for participating in study committees sponsored by AstraZeneca, Novartis, Sanofi and Bayer; and honoraria for participation on an advisory board from Neopharmed Gentili. Roberto Pontremoli has received honoraria from AstraZeneca, Boehringer-Ingelheim, Lilly, MSD, Organon, Novartis, Menarini, Bayer, NovoNordisk, Vifor and Recordati. Alberto Corsini has received research funding and/or honoraria from Amgen, Daiichi-Sankyo Europe, Amarin, DOC, MSD, Novartis, Recordati S.p.A., Sanofi and Viatris; and has received a grant from Sharper for writing a manuscript on combination therapy. Massimo Volpe has received honoraria for the speakers’ bureaus or advisory boards from Menarini Int, Servier, Sandoz, AstraZeneca, Sanofi, Neopharmed Gentili and Novartis.
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