Issues in blood pressure control and the potential role of single-pill combination therapies

Authors


  • Disclosures
    Development of this manuscript was sponsored by Novartis Pharma AG. Michel Burnier has not received an honorarium to author this manuscript. Ruth Brown is an employee of United BioSource. As a research organisation, United BioSource conducted the original literature review upon which this article is based. United BioSource has undertaken similar projects for other pharmaceutical companies. Siew Hwa Ong and Abdulkadir Keskinaslan are directly employed by Novartis Pharma AG, and Zeba M. Khan was directly employed by Novartis Pharmaceuticals Corporation during the development of this article. Editorial support was provided by Rx Communications Limited.

Michel Burnier,
Head of Division of Nephrology and Hypertension Consultation, CHUV, Rue du Bugnon 17, 1011 Lausanne, Switzerland
Tel.: + 41 21 314 11 54
Fax: + 41 21 314 11 39
Email: michel.burnier@chuv.ch

Summary

Hypertension (HTN) is a major risk factor for cardiovascular mortality, yet only a small proportion of hypertensive individuals receive appropriate therapy and achieve target blood pressure (BP) values. Factors influencing the success of antihypertensive therapy include physicians’ acceptance of guideline BP targets, the efficacy and tolerability of the drug regimen, and patient compliance and persistence with therapy. It is now well recognised that most hypertensive patients require at least two antihypertensive agents to achieve their target BP. However, complicated treatment regimens are a major contributory factor to poor patient compliance. The use of combination therapy for HTN offers a number of advantages over the use of monotherapy, including improved efficacy, as drug combinations with a synergistic mechanism of action can be used. This additive effect means that lower doses of the individual components can be used, which may translate into a decreased likelihood of adverse events. The use of single-pill combination therapy, in which two or more agents are combined in a single dosage form, offers all the benefits of free combination therapy (improved efficacy and tolerability over monotherapy) together with the added benefit of improved patient compliance because of the simplified treatment regimen. The use of single-pill combination therapy may also be associated with cost savings compared with the use of free combinations for reasons of cheaper drug costs, fewer physician visits and fewer hospitalisations for uncontrolled HTN and cardiovascular events. Thus, the use of single-pill combination therapy for HTN should help improve BP goal attainment through improved patient compliance, leading to reduced costs for cardiovascular-related care.

Review Criteria

How did you gather, select and analyse the information you considered in your review?

Relevant papers were identified through a literature search and were analysed in a descriptive manner.

Message for the Clinic

What is the take-home message for the clinician?

The use of single-pill combination therapy, in which two or more agents are combined in a single dosage form, offers all the benefits of free combination therapy (improved efficacy and tolerability) together with the added benefit of improved patient compliance due to the simplified treatment regimen. Such treatment should also help reduce the costs of cardiovascular-related care through cheaper drug costs, fewer physician visits and fewer hospitalisations.

Introduction

Hypertension (HTN) is a highly prevalent risk factor for cardiovascular disease. It is estimated that HTN currently affects approximately one billion people worldwide and predictions suggest that the prevalence of HTN will have increased by 60% by the year 2025 (1). This is a disturbing statistic for a preventable and treatable condition that is an undisputed risk factor for cardiovascular mortality the likelihood of which doubles with each 20/10 mmHg increase in blood pressure (BP) above 115/75 mmHg (2).

Current United States (US) and European Union guidelines define HTN as systolic BP of > 140 mmHg and/or diastolic BP of > 90 mmHg (3,4). They recommend that the management of HTN should aim to reduce BP to below these levels and that target BP values should be even lower in ‘high-risk’ patients (i.e. those with diabetes or chronic renal disease and proteinuria). In addition, the most recent US guidelines (JNC VII) now include a new category termed ‘prehypertension’, defined as systolic BP of 120–139 mmHg and/or diastolic BP of 80–89 mmHg (3). The inclusion of this new category is designed to emphasise the need for vigilance in individuals considered likely to develop HTN and the need to implement preventative measures in this category of subjects.

In the last 10 years, several large clinical trials have demonstrated the benefits of lowering BP to target levels in terms of reducing the incidence of cardiovascular events and lowering the mortality rate [HOT (5), ALLHAT (6), ASCOT BP arm (7) and VALUE (8)]. From the results of these trials, it has been estimated that an overall reduction in systolic BP of just 2 mmHg can reduce the risk of cardiovascular events by 7–10% (2), while reductions in systolic and diastolic BP of 10–12 and 5–6 mmHg respectively confer a relative reduction in the risk of stroke of about 38% and a relative reduction in the risk of coronary heart disease of about 16% within just a few years of starting treatment (9). In view of this, control of BP has become an important goal in the management of HTN (10). Furthermore, evidence suggests that normalisation of BP is not only an effective strategy in patients with isolated diastolic or combined systolic–diastolic HTN, but is also effective in elderly patients with isolated systolic HTN (11).

Despite the obvious benefits of BP control, only a small proportion of hypertensive individuals are properly treated and even fewer achieve guideline targets (11). In Europe, it is estimated that as many as 73% of hypertensive individuals remain untreated and that the attainment of BP goals in treated patients is equally poor, ranging from 19% in Spain to 40% in England (12). Thus, in practice, approximately seven out of 10 hypertensive patients in Europe are not reaching their target BP goals of < 140/90 mmHg (12), yet evidence from clinical trials indicates that it is possible for approximately two-thirds of patients, including the elderly patients and those with type 2 diabetes, to attain recommended BP goals (6,13,14).

For example, the ALLHAT study, which followed approximately 42,000 hypertensive patients treated with one of four alternative therapies over 5 years, showed that 66% of patients had a BP of < 140/90 mmHg at the end of the study (6). This discrepancy between the situation in clinical trials and that in actual clinical practice and the sheer magnitude of the uncontrolled HTN population indicate that there are real problems associated with the achievement of BP goals and that serious approaches are needed to overcome these problems. This paper considers the reasons why patients are not achieving BP goals and investigates the evidence to support the use of single-pill combination therapy in this context. A single-pill combination is defined here as a formulation of two or more active ingredients combined in a single dosage form.

Obstacles against achieving blood pressure goals

Why is there such a large discrepancy between clinical trial results and daily practice? Clinical trials suggest that treatment can result in the attainment of BP goals, yet in everyday practice, this does not appear to occur. There are numerous explanations for this discrepancy (15). The major determinants of the success of antihypertensive therapy are related to several factors including: physicians’ acceptance of the recommended targets and their determination to achieve them, the efficacy and tolerability of the drug regimen and patient compliance and long-term persistence with the prescribed regimen (15).

Several studies have shown that physicians have a crucial role to play in BP control. In a study of veterans in New England, Berlowitz et al. (16) showed that despite many annual general practitioner (GP) visits (average of six), nearly half (46%) of the population of men still had a BP of > 160/90 mmHg and changes or increases in their therapy occurred at fewer than 10% of visits (6.7%). Another study showed that 25% of US physicians surveyed would not treat a middle-aged patient with HTN unless diastolic BP was > 95 mmHg and 33% of them would not treat a middle-aged patient with HTN unless systolic BP was > 160 mmHg (17). A more recent analysis has shown that a 50% decrease in this so-called ‘therapeutic inertia’ (defined in the survey as provider’s failure to increase therapy when treatment goals are unmet) could increase the percentage of patients with controlled HTN by almost one-fifth in 1 year (18). There may be several reasons for this therapeutic inertia, including concerns about side effects with increased doses, particularly in elderly patients; perceived complexity of the treatment regimen; lack of obvious symptoms and the physician’s acceptance of a higher BP as representing adequate control.

Another obstacle to attaining BP control is patient compliance (also known as adherence) and persistence with the prescribed therapy. Compliance refers to the extent to which a patient acts in accordance with the prescribed dosing regimen and is usually reported as the proportion of prescribed doses taken in the prescribed time interval, whereas persistence refers to the continuing use (in time) of the prescribed therapy and is measured as the accumulation of time from initiation to discontinuation of therapy (19).

Poor compliance and persistence are known to be major problems in patients with HTN; it is estimated that 24–51% of HTN patients are non-compliant with therapy (compliance defined as drugs available for > 80% of the days in a year) and 29–58% of HTN patients are non-persistent with therapy (persistence defined as remaining on treatment for 12 months) (20). In the USA, an estimated 14% of all prescriptions are never filled and an additional 13% are filled but never taken (21). Compliance and persistence appear to show an inverse relationship with time; a large retrospective cohort study of over 2000 new antihypertensive medication users over a 10-year period illustrates this point and shows that the largest drop-off occurs in the first few years of treatment; among patients still in therapy after the first year, 50% stop treatment within the next 2 years (22). Reasons for non-compliance are multiple (23–27), but the main reasons appear to be the adverse effects of treatments and patients’ lack of understanding of the instructions provided by physicians (23).

Increasing compliance is a worthwhile goal and has been shown to have significant beneficial effects on cardiovascular outcomes (24,28–30). Good compliance with drug therapy has also been shown to reduce mortality across diseases, provided the drugs are effective in lowering the risk of the disease (31). A large study reviewed patient compliance and the outcome of medical treatment in 63 clinical studies, six of which pertained to HTN (24). The analysis only included studies with a definition of compliance and an objective method of measuring it, together with a measured outcome. Over all the disease areas studied, the odds ratio of a better outcome was 2.88 among compliant patients and this increased to 3.44 in compliant HTN patients.

In a more recent study, using the medication possession ratio (MPR) to classify patient compliance into high compliance (MPR = 80–100%), medium compliance (MPR = 50–79%) and low compliance (MPR ≤ 50%), highly compliant individuals were 45% more likely to achieve BP control than those showing medium or poor compliance (32). In addition, better compliance and persistence can reduce the risk of myocardial infarction or stroke (33), decrease medical costs (34), reduce outpatient resource use (35) and decrease the risk of hospitalisation (34) (Figure 1). Interestingly, a post hoc analysis of the CHARM study showed that mortality was significantly reduced in compliant patients with congestive heart failure whatever the treatment (placebo or candesartan), suggesting that compliance may reflect a personal attitude towards health problems and prevention strategies (30).

Figure 1.

 Better compliance with antihypertensive drugs leads to a decreased risk of hospitalisation (34)

The perceived and actual efficacy and safety of a drug regimen is of obvious importance to BP control, particularly when there are so many drug classes and agents that can be used. In recent years, there has been a shift away from the classic step-care approach, in which patients are started on low-dose monotherapy and titrated upwards and/or a second drug is added, as many patients remain only poorly controlled with this strategy (36). Evidence now suggests that the majority of patients will initially require at least two antihypertensive agents to achieve target systolic BP (7,37) and in patients considered as ‘high-risk’, the rationale for multiple-mechanism therapy is even stronger.

Bakris (37) showed that in patients with diabetes and HTN, more than 65% require two or more antihypertensive agents to reach a target BP of < 130/80 mmHg. As HTN is a multifactorial and polygenic disease, there are several good pathophysiological reasons why multiple-mechanism therapies provide greater efficacy in the control of BP in hypertensive patients, the main one being that the likelihood of normalising BP is higher if more than one BP control pathway is attacked. When combining therapeutic strategies, each strategy has the potential to neutralise counter regulatory mechanisms and the BP reductions that result are often additive (38–40). For example, an additive or synergistic effect is obtained with a combination of thiazide diuretics and blockers of the renin–angiotensin system and a combination of a calcium antagonist and a beta-blocker (38–41). In addition, with combination treatment, both agents can be given at lower doses than either drug alone, which should translate into improved tolerability (39,40).

Thus, the problems associated with a lack of achievement of BP goals are multifactorial; however, many are interrelated. For example, patient compliance with treatment is related to the convenience and simplicity of the treatment regimen as well as to the efficacy and safety of the antihypertensives prescribed (26,42–45). If the efficacy and safety of the treatment regimen could be improved alongside improvements in simplicity (resulting in increased compliance), BP targets might be more easily attainable. Perhaps an ideal treatment regimen would be a single agent that effectively and efficiently reduces BP over a 24-h period and causes minimal adverse effects.

As guidelines have now recognised that many patients need more than one drug to reach their BP goal (3,4), there is an indisputable rationale for the use of combination therapy in the management of hypertensive patients. American guidelines indicate that with stage 1 HTN, therapy might begin with a diuretic, but combination therapy can also be considered at this time; with stage 2 HTN, a combination of drugs can be prescribed as first-line therapy (3).

Improved efficacy with combination therapy

The most important rationale for using combination therapy in the treatment of HTN is to improve efficacy and numerous studies have shown that combination therapy offers equivalent or improved efficacy in terms of a reduction in BP compared with monotherapy (38–41,46–58). For example, a combination of the calcium channel antagonist (CCB) felodipine (5 mg) and the angiotensin receptor antagonist (ARB) candesartan (16 mg) was found to lower mean 24-h BP to a significantly (p < 0.005) greater extent (reduction in BP 21.0/11.2 mmHg) than monotherapy with felodipine (reduction in BP 11.9/5.7 mmHg) or candesartan (reduction in BP 12.2/7.5 mmHg) in elderly patients with systolic HTN (52). In addition, the responder rate was greater with combination therapy (90%) than with both monotherapies (55% for felodipine, 61% for candesartan). In another study of Japanese patients with essential HTN (57), the combination of losartan/hydrochlorothiazide (HCTZ; 50/12.5 mg) was significantly (p < 0.001) more effective than both monotherapies in reducing diastolic and systolic BP (reduction 12.7 and 18.0 mmHg, respectively, with combination therapy; 8.5 and 10.2 mmHg, respectively with losartan 50 mg; 7.8 and 11.7 mmHg, respectively with HCTZ 12.5 mg).

These findings were confirmed in a meta-analysis of 354 randomised, double-blind, placebo-controlled trials of five different categories of antihypertensive therapies (40). In this analysis, the reduction in BP with drug combinations was additive, with combinations of two or three drugs given at half the standard dose being preferable to one or two drugs given at standard dose. Interestingly, Stergiou et al. (41) showed that some drug combinations may be more effective than others. Thus, combining drugs that act on a similar BP control system may be less effective than combining drugs with different mechanisms of action.

The increased efficacy of combination therapy may be particularly relevant in the management of patients with a high cardiovascular risk, such as patients with severe HTN. For these patients, the ability to reach target BP faster may be a very important issue, as the results of the VALUE trial demonstrated a significantly reduced incidence of cardiovascular events in the amlodipine-treated vs. valsartan-treated group during the first 6 months due to better BP control (8). The Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension (ACCOMPLISH) trial aimed to compare the effects of two combination therapies (amlodipine/benazapril and benazapril/HCTZ) in preventing fatal and non-fatal cardiovascular outcomes in high-risk hypertensive patients. Interim data from this study presented at the Annual Scientific Session of the American College of Cardiology showed that combination therapy produced higher BP control rates than those achieved in other multinational studies: more than 70% of patients receiving combination therapy achieved the BP target of < 140/90 mmHg at 6 months regardless of the therapy used (59).

Improved tolerability with combination therapy

Combination therapy also offers important advantages over single agents in terms of tolerability. Except for angiotensin II receptor blockers, which have excellent tolerability, the adverse effects associated with antihypertensive drugs increase with higher drug doses (38,60–62). The additive effect of combination therapy with respect to efficacy means that lower doses of the individual components can be used, which translates into a reduced likelihood of adverse events (63).

In a study by Jamerson et al. (47), the incidence of peripheral oedema was significantly less with a combination of amlodipine besylate/benazepril (5/20 mg; 12.6%) than with amlodipine besylate (5 mg) monotherapy (23.0%; p = 0.01), while Saruta et al. (57) found that a combination of losartan/HCTZ (50/12.5 mg) was associated with improved hypokalaemia (p = 0.04) and improved hyperuricaemia (p < 0.001) compared with HCTZ alone (12.5 mg).

The INCLUSIVE trial (55) compared two doses of irbesartan and HCTZ (150/12.5 or 300/25 mg) with HCTZ monotherapy (12.5 mg) in previously uncontrolled HTN patients and found not only greater efficacy with irbesartan/HCTZ, but also similar tolerance with most adverse events being of mild or moderate intensity and transient in duration. Finally, a meta-analysis of 354 randomised trials of five different categories of antihypertensive agents showed that the incidence of adverse effects with drug combinations was significantly less than additive, suggesting that antihypertensive agents given in combination do not enhance the adverse effects of one another (40).

With respect to tolerability, combination therapy offers the added advantage that drug combinations may be able to counteract the adverse effects of each other. For example, a number of studies have shown that the addition of an angiotensin-converting enzyme (ACE) inhibitor or an ARB to a CCB reduces CCB-associated oedema (Figure 2) (38,47,48,53,63,64), while beta-blockers are less likely to cause cold extremities when combined with a CCB (65). Likewise, the addition of a potassium-sparing diuretic or an ACE inhibitor to a thiazide diuretic has been shown to limit the decrease in serum potassium and/or magnesium that can occur with thiazide diuretics (38,57,66–68).

Figure 2.

 A free combination of amlodipine/valsartan demonstrates superior tolerability (seen as a reduction in amlodipine-induced ankle oedema) to amlodipine monotherapy (53)

Rationale for single-pill combination therapy in hypertension

Single-pill combination therapy consists of treatment with two or more active drugs combined in a single tablet or capsule. It provides all of the advantages of multiple-mechanism therapy (improved efficacy and tolerability), with the added advantages of improved compliance and cost outcomes (see below). European guidelines also now include single-pill combination therapy as possible first-line treatment for HTN (4).

Are there potential risks when using single-pill combination therapy as first-line treatment for hypertensive patients? The potential risk is that of an excessive fall in BP, which may be harmful in some patients, for example elderly hypertensive patients with possible carotid artery stenosis or severe coronary heart disease. This risk is higher when the first dose of antihypertensive is taken. To avoid this type of side effect, single-pill combination therapies are available at different doses.

Improved compliance and persistence with single-pill combination therapy

Drug compliance is known to decrease with an increase in the frequency of dosing, such that compliance is almost 35% lower with a four-times-a-day regimen than with a once-a-day prescription (42). Single-pill combination therapy is likely to increase compliance and persistence compared with free combination therapy because it simplifies the treatment regimen to a single once-daily pill. Data are now accumulating which substantiate this hypothesis. Taylor and Shoheiber (26) conducted a retrospective US database analysis comparing compliance and medical resource use in patients (n = 2754) receiving single-pill combination therapy (amlodipine besylate/benazepril hydrochloride) with that in patients (n = 2978) receiving an ACE inhibitor and a long-acting dihydropyridine CCB as separate drugs. Over a 1-year period, the MPR was significantly higher in the single-pill combination group (80.8% vs. 73.8%; p < 0.001), signifying better compliance.

Another study has shown that single-pill combination therapy with a combination of amlodipine and benazepril provides significant beneficial effects in terms of compliance compared with individual component-based therapy with an ACE inhibitor and a dihydropyridine CCB (43). In this study, compliance improved regardless of concomitant medication use; indeed, as the number of concomitant medications increased, the compliance gap between those receiving single-pill combination therapy and those receiving separate agents increased (Figure 3). In a recent meta-analysis of published studies, non-compliance with study medication was reduced by around 25% in patients receiving single-pill combination therapy vs. free combinations (44).

Figure 3.

 Single-pill combinations improve compliance regardless of the use of concomitant medications (43)

Two studies have also shown better persistence with single-pill combination therapy at 12 months than with separate two-pill regimens (Figure 4) (25,69). In one of the studies (25), the percentage of patients persisting with a single-pill combination of lisinopril/HCTZ or enalapril/HCTZ at 12 months (69% and 70% respectively) was significantly greater (p < 0.05) than the percentage of patients persisting with lisinopril and a diuretic prescribed concurrently or enalapril and a diuretic prescribed concurrently (58% for both regimens). In the other study (69), patients were 2.09 times more likely to be non-compliant with two pills than with single-pill combination therapy, and nearly 1.5 times more likely to be non-persistent. Patients receiving a single-pill combination regimen of valsartan/HCTZ have also been shown to be more persistent with their treatment regimen than those assigned to a free combination of the same agents (70).

Figure 4.

 Improvement in persistence with single-pill combination therapies vs. co-administration of free combination therapies (25,69). Values are improvements in persistence in patients taking single-pill combinations expressed as percentages of the persistence in patients taking the same medications in separate doses

Improved cost outcomes with single-pill combination therapy

The global burden of uncontrolled HTN is immense; in 2000, 62% of all strokes, 49% of all ischaemic heart disease and 76% of all hypertensive disease (including hypertensive heart disease and hypertensive renal disease) were attributable to non-optimal BP control (defined as the theoretical minimum risk of an adverse health outcome and found to equate to a mean systolic BP of > 115 mmHg) (71). Worldwide, this equates to approximately 7.12 million deaths (12.8% of total deaths) and 64.3 million disability-adjusted life years (4.4% of the total) (71). Through enhanced antihypertensive efficacy and improved drug compliance, wider use of single-pill combination therapy should also reduce associated costs (72).

This hypothesis is supported by a retrospective database analysis which compared medication compliance, resource utilisation and costs in patients receiving a once-daily single capsule of amlodipine besylate/benazepril compared with a similar regimen of separate components (26). The results showed that the average total annual cost of cardiovascular-related care to a managed care organisation was significantly lower (p < 0.001) for patients receiving single-pill combination therapy (average total annual cost US $726 per subject) than for patients receiving the separate pill regimen (average total annual cost $1600 per subject). The reasons for the cost savings with single-pill combination therapy were fewer additional drugs, fewer physician visits and fewer hospitalisations for uncontrolled HTN and cardiovascular events.

In another retrospective cohort study, Dickson and Plauschinat (73) showed that single-pill combination therapy was associated with reduced costs to a managed care organisation, with average total costs of $3179 (2002 values) for elderly subjects receiving single-pill combination therapy with amlodipine/benazepril HCl (> 2300 patients) compared with $5236 for those receiving individual-component therapy with a CCB plus ACE inhibitor (> 3300 patients) (p < 0.0001). In this study, the reasons for the reduced costs with single-pill combination therapy were significantly lower ambulatory costs, drug costs and other costs (Medicare cross-over costs).

Similarly, a study of 84 African-American hypertensive patients showed that savings of $1080 per patient per year (1997 prices) would be realised by a managed care organisation if patients switched from a free combination of an ACE inhibitor and a CCB to a single-pill combination of amlodipine/benazepril (74). The savings realised were due to cheaper drug costs. Thus, in these studies, the reasons for cost savings with single-pill combination therapy included cheaper drug costs (73,74), fewer physician visits and fewer hospitalisations for uncontrolled HTN and cardiovascular events (26).

What is the potential for wider use of single-pill combination therapy?

The evidence that good compliance and persistence lead to better and less costly long-term outcomes is compelling and it seems reasonable to assume that encouraging such behaviour by using single-pill combination therapy is likely to increase the proportion of patients achieving their BP goals. Studies indicating lower persistence in patients who have had drugs added to their treatment regimen or who have switched drugs (75) support the growing view that initiating HTN treatment with well-tolerated combination therapy may lead to better BP control. Moreover, other studies have shown that achieving effective and rapid control of BP may be an important determinant of long-term persistence with treatment (76).

In a study of an initial single-pill combination of olmesartan/HCTZ or losartan/HCTZ in patients with moderate-to-severe HTN who were either not previously treated or had not reached their BP goals, the single-pill combinations were associated with substantial reductions in systolic and diastolic BP, with 43% and 32% of patients respectively achieving their BP targets by week 12. In addition, the single-pill combinations were well tolerated (77). This and other studies using a combination of agents as first-line therapy for HTN are setting the stage for earlier prescribing of single-pill combination therapy, which has the added benefit of improved compliance. Initially, interest in single-pill combination therapy focused on the development of low-dose combinations, with the aim of increasing efficacy but reducing the incidence of side effects. With the development of new drug classes with improved tolerability profiles, such as ARBs, the concept of low-dose single-pill combination therapy should be challenged because it should now be possible to improve further the efficacy of drug combinations without the addition of side effects.

In terms of single-pill combination therapies that are currently available, the combination of ARBs [considered to be at least as effective as other antihypertensive drugs with a tolerability profile comparable to that of placebo (78)] and HCTZ provides advantages associated with the two drug classes: reduction of angiotensin II-mediated sodium retention and vasoconstriction with ARBs and the volume-reducing benefits of diuretics. Monotherapy with a CCB is often the preferred treatment for patients with moderate-to-severe HTN, but peripheral oedema limits its titration (36). A CCB in combination with ARBs, however, leads to additive efficacy (41) with a reduction in peripheral oedema compared with CCB monotherapy (Figure 2) (53), thus providing another valuable choice for the treatment of HTN.

Concluding remarks

Surveys of the prevalence of HTN in Western countries indicate that a substantial proportion of individuals thought to have HTN are either not receiving treatment or are not reaching their BP goals. HTN may be poorly controlled partly not only because of its asymptomatic nature (79), but also because of a lack of compliance and persistence with prescribed medications (24,26,80). According to several retrospective database studies, compliance is improved if medications are limited to single daily doses (45), and compliance and persistence are improved when adverse events are minimised (81). Persistence is also better when target BP is reached (76). Importantly, improved compliance/persistence may improve outcomes and help reduce the economic burden caused by treatment discontinuation and drug switching (27).

Experience from clinical trials (5,6) and clinical practice (82) has shown that many patients require more than one antihypertensive agent to achieve target BP levels. Compliance with single-pill combination therapy has been shown to be better than that with two separate pills (25). Thus, prescribing single pills for the treatment of HTN may help improve treatment compliance, which, in turn, may increase the level of BP control and decrease overall healthcare costs (72). Improved HTN control should reduce healthcare costs despite an overall increase in pill consumption (due to better compliance) as a result of fewer hospital admissions, physician visits and ultimately, cardiovascular events (72). Better control may also increase personal productivity and decrease disability days, resulting in better patient quality of life (83). One study has also shown advantages associated with single-pill combination therapy as first-line treatment in moderate-to-severe HTN, such as substantial reductions in systolic and diastolic BP, a large proportion of patients achieving their BP targets and good tolerability (77).

In summary, single-pill combination therapy for HTN offers all the advantages of free combination therapy (improved efficacy and tolerability compared with monotherapy) together with the benefit of increased patient compliance and persistence with therapy. The resulting improvement in the control of HTN should, in turn, lead to reduced costs for cardiovascular-related care.

Author contributions

Michel Burnier drafted the manuscript, critically reviewed the edited manuscript and approved the final version of the manuscript. Ruth Brown performed the qualitative review, drafted the manuscript, critically reviewed the edited manuscript and approved the final version of the manuscript. Siew Hwa Ong and Abdulkadir Keskinaslan helped with the concept, provided funding, critically reviewed the edited manuscript and approved the final version of the manuscript. Zeba Khan helped with the concept, critically reviewed the edited manuscript and approved the final version of the manuscript.

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