Hypertension (HTN) is the most prevalent cardiovascular risk factor in developed and developing countries.1 According to most recent guidelines, the goal of HTN management should be to reduce blood pressure (BP) to <140/90mmHg and even lower in patients with a high cardiovascular risk in order to lower the incidence of cardiovascular events such as stroke, myocardial infarction, congestive heart failure and end-stage renal disease, and consequently reduce cardiovascular deaths.2,3 These therapeutic goals have been defined based on the results of multiple clinical trials and meta-analyses that have shown, for example, that reductions in BP of approximately 10–12mmHg systolic and 5–6mmHg diastolic confer relative reductions in stroke risk and coronary heart disease of about 38 and 16%, respectively, within just a few years of beginning treatment.4 In most of the initial HTN trials, the major objective was to lower diastolic BP. In the Hypertension Outcomes Trial (HOT study), undertaken in 26 countries, lowering diastolic BP in patients with HTN was associated with a marked decrease of cardiovascular events and decreasing the diastolic level to <85mmHg was associated with an approximate 25% relative risk reduction.5 The effect of lowering diastolic BP to <80mmHg was particularly important in the diabetic subgroup.
Today, with an ageing population and the increased prevalence of isolated systolic HTN, attention has turned to the control of systolic pressure. There are several other reasons for this change: one is the observation that whatever the hypertensive population treated, systolic BP remains uncontrolled more often than diastolic BP.6 Moreover, the relative risk of developing a cardiovascular event correlates better with systolic than with diastolic BP. Recent evidence has shown that normalisation of systolic BP in patients with isolated systolic HTN is associated with a significant reduction in cardiovascular events, even in very old patients.7,8
Blood Pressure Control – An Unresolved Matter
Despite the recognised benefits of controlling HTN in clinical trials and epidemiological surveys, it is well-established that only a fraction of the hypertensive population is treated and has a normalised BP. The results of several national cross-sectional studies have shown that the percentage of hypertensive patients with a controlled BP ranges between <10 and 40–50% of treated patients. These figures are even worse if one considers patients with diabetes and chronic renal failure, for whom lower target BP has been ascribed. Moreover, one has to take into account the cross-sectional nature of these surveys. Hence, the measured BPs merely represent the values at one time-point in the management of the patients.
To have an impact on the incidence of cardiovascular events, it is crucial that BP is controlled over months and years. In this respect, Mancia et al. have examined the relationship between the incidence of cardiovascular events and the percentage of consultations with a normal BP in patients participating in a large prospective clinical trial, the International Verapamil-SR Trandolapril Study (INVEST).9 Interestingly, the post hoc analysis of the results showed that the greater the percentage of consultations with a normal BP, the greater the clinical benefits (see Figure 1). Unfortunately, very few such longitudinal surveys of BP control have been performed so far, probably because of their cost and complexity. Owing to the known poor persistence to antihypertensive therapy in HTN, lower percentages of sustained BP control may be expected in longitudinal compared with cross-sectional surveys.10 A low level of sustained HTN control in the population may account for the observation that treated hypertensive patients remain at higher risk of developing a cardiovascular complications than normotensive subjects.
The Barriers to Good Blood Pressure Control
HTN is a silent disease that can be cured only rarely and therefore needs lifelong treatment. In this context, numerous barriers to good BP control can occur during the long-term follow-up of a hypertensive patient. The major determinants of the success of antihypertensive therapy are related to several factors, including the acceptance by physicians of the recommended targets and their determination to achieve them, the compliance of patients and long-term persistence with the prescribed regimen and the efficacy and tolerability of the drug regimen.
Physicians have a crucial role to play in achieving adequate BP control; however, several recent studies have illustrated that medical inertia is a common phenomenon among physicians. Thus, Berlowitz et al. have shown that despite many annual visits (average of six), nearly half of a designated population of men still had uncontrolled BP, and changes or increases in their therapy occurred at fewer than 10% of visits.11 Physicians usually state many reasons why they do not intensify therapy when BP is not at goal; the most frequent comment is that they are satisfied with their treatment results despite the fact that BP goals were not being met and that they expect BP to decrease further with time.12,13
Several other reasons for this therapeutic inertia can be mentioned, including concerns about side effects with increased doses (particularly in elderly patients), perceived complexity of the regimen, lack of obvious symptoms and the physician’s acceptance of higher BP as representing adequate control. Of note, a decrease in this so-called therapeutic inertia by 50% could increase the percentage of patients with controlled HTN by almost one-fifth in one year.14
Another major obstacle for attaining BP control is patient compliance (adherence) and persistence with the prescribed therapy. Poor compliance and persistence are known to be major problems in all patients with chronic diseases and even more so when the disease is silent.10 It is estimated that 29–58% of patients are non-persistent with therapy (persistence defined as remaining on treatment for 12 months) and 24–51% are non-compliant (compliance defined as drugs available >80% of days in a year).15 In the US, an estimated 14% of all prescriptions are never filled and an additional 13% are filled but never taken.16 Compliance and persistence appear to have an inverse relationship with time. A large retrospective cohort study of over 2,000 new antihypertensive medication users over a 10-year period has illustrated this point and shown that the largest drop-off occurs in the first few years: among patients still in therapy after the first year, 50% stopped treatment within the next two years.17
Reasons for non-compliance are multiple: patients frequently report a lack of understanding of the instructions provided by physicians and adverse effects as their reasons for non-adherence. Other reasons include doubts over treatment benefits, individual characteristics and complex treatment regimens. Increasing compliance is a worthwhile goal and has been shown to have significant beneficial effects on cardiovascular outcomes.18,19 DiMatteo and colleagues reviewed patient adherence and the outcome of medical treatments in 63 clinical studies, six of which pertained to HTN. Their analysis included only studies with a definition of adherence and an objective method of measuring it, together with a measured outcome.18 Over all the disease areas studied, there was a 2.88 odds ratio of a better outcome among adherent patients, and in adherent HTN patients the odds ratio increased to 3.44 times more likely to have a better outcome. Good adherence to drug therapy has also been associated with a reduced mortality across diseases, provided the drugs are effective in lowering the risk of the disease.20
In a more recent study using the medication–possession ratio to classify patient compliance, highly compliant individuals were shown to be more likely to achieve BP control.21 In addition, better compliance and persistence can reduce the risk of myocardial infarction or stroke, decrease the risk of hospitalisation, reduce medical costs and reduce outpatient resource use. Interestingly, a post hoc analysis of the Candesartan in Heart Failure – Assessment of Reduction in Mortality and Morbidity (CHARM) study showed that mortality was reduced significantly in compliant patients with congestive heart failure whatever the randomised treatment (placebo or candesartan), suggesting that drug adherence is probably a personal attitude towards health problems and prevention strategies and not only a matter of taking drugs correctly or not.19
The 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. When investigating factors leading to poor BP control if drug efficacy is an obvious pre-requisite, the side-effect profile of drugs is identified as one the main factors for both physicians and patients. Thus, the acute and long-term tolerability profile of drugs appears to be essential for patients to remain on treatment and hence to achieve good BP control. The pill burden is another aspect of therapy that may have an unfavourable impact on the long-term results of antihypertensive therapy. The results of clinical trials in which a higher percentage of patients achieve target BP clearly demonstrate that the majority of patients need more than two drugs to effectively control their BP.22 In addition, patients often need additional therapies to control their cardiovascular risk, including aspirin, lipid-lowering drugs and antidiabetic agents, which contribute to further increasing the pill burden. As the number of therapeutic agents increases, patients feel sicker, which further increases the risk of non-adherence to drug therapy.
Taken together, the problems associated with lack of achievement of BP goals are clearly multifactorial and interrelated. Patient compliance with the treatment and physician compliance with the guidelines are both related to the convenience and simplicity of the regimen, as well as to the efficacy and safety of the antihypertensives prescribed. It seems obvious that if the efficacy and safety of the treatment regimen could be improved alongside improvements in simplicity designed to increase compliance, BP targets may be more easily attained. Perhaps an ideal treatment regimen would be a single pill that could effectively and efficiently reduce BP over a 24-hour period, cause minimal adverse effects – particularly metabolic side effects – and be cost-effective.
Single-pill Combination Therapies – A Solution to Improve Blood Pressure Control?
In recent years, there has been a progressive shift from the classic step-care approach to the use of single-pill combinations as first-line therapy.23 This change in paradigm has resulted from evidence that the majority of patients included in large clinical trials require at least two antihypertensive agents acting on different mechanisms to achieve the pre-defined target BP. There are several good reasons why multiple-mechanism therapies have greater efficacy in controlling BP in hypertensive patients. The first is that the likelihood of normalising BP is higher if one attacks more than one BP-control pathway. In addition, when combining therapeutic strategies, each component has the potential to neutralise counter-regulatory mechanisms and the additional BP reductions that often result. The best example of such a synergism is the association of a renin–angiotensin system blocker and a thiazide diuretic. Moreover, with combination treatment both agents can often be given at lower doses than either one alone, which can translate into an improved tolerability profile.24
Single-pill combination therapies can offer all the advantages of a multiple-mechanism therapeutic strategy while potentially improving drug adherence, tolerability and costs. For these reasons, both American and European HTN guidelines have integrated the use of single-pill combinations into their therapeutic schemes.
Single-pill Combinations and Therapeutic Efficacy
One important rationale for using single-pill combinations as first-line therapies is to improve efficacy. There is no doubt that combination therapy is more effective lowering BP than monotherapy and that the likelihood of controlling BP is greater when starting with a single-pill combination. Whether a single-pill combination has superior antihypertensive efficacy to the same drugs taken separately is another question. Theoretically, there should be no difference between the two strategies because the same drugs are prescribed. Thus, at comparable compliance, the single-pill combination should be equivalent to the two-drug treatment. Interestingly, studies have not really supported this assumption as single-pill combinations have regularly been found to be more effective than the same drugs taken separately. This was confirmed in a meta-analysis of 354 randomised, double-blind, placebo-controlled trials of five different categories of antihypertensive therapy.24 In this analysis, the reduction in BP with drug combinations was additive, with combinations of two or three drugs at half standard dose being preferable to one or two drugs at standard dose.
In a recent Canadian randomised, controlled study, investigators compared a simplified algorithm for the treatment of HTN based on the initial use of a single-pill combination of a diuretic and a renin–angiotensin system blocker with the conventional guideline-based care recommending a step-care approach.25 The initial use of single-pill combinations was associated with a significantly higher proportion of patients achieving the target BP (64.7 versus 52.7%). These results tend to confirm the superiority of single-pill combinations over individual therapies. Of note, in the Avoiding CV Events through CoMbination therapy in Patients LIving with Systolic HTN (ACCOMPLISH) trial, the use of single-pill dual combinations led to a high percentage of well-controlled patients (>70%), regardless of the combination used (angiotensin-converting enzyme [ACE]–diuretic or ACE–calcium-channel blocker [CCB]).26 Of course, this study was not designed to test the superiority of a single-pill combination over individual drugs; nevertheless, it demonstrates the potential of single-pill combinations to achieve a high percentage of adequate BP control including in patients with high cardiovascular risk.
Single-pill Combinations and Drug Adherence
One of the major reasons why single-pill combinations may provide greater benefits in terms of BP control is certainly linked to drug adherence. Drug adherence is known to decrease in proportion to the frequency of the dose regimen with an almost 35% lower adherence in a four-times-a-day regimen versus a once-a-day prescription.27 Single-pill combinations are likely to increase compliance and persistence because they simplify the treatment regimen and reduce the pill burden. Data are now accumulating that substantiate this hypothesis. In a retrospective US database analysis comparing adherence and medical resource use of patients (n=2,754) receiving a single-pill combination of amlodipine desylate and benazepril hydrochloric acid (HCl) with that of patients (n=2,978) receiving an ACE inhibitor and a long-acting dihydropyridine CCB as separate drugs, one-year persistence on therapy was better in patients receiving the single-pill combination.28 This observation is supported by several other publications indicating significantly greater adherence in terms of pill possession or persistence among patients receiving a single-pill combination compared with separate two-pill regimens. Thus, patients were twice as likely to be non-adherent with two pills compared with a single-pill combination and nearly 1.5 times more likely to be non-persistent.29 In a recent meta-analysis, non-compliance to the study medication was reduced by around 25% in patients receiving a single-pill combination versus free drug combinations (see Figure 2).30
Single-pill Combination and Tolerability Profile
Single-pill combinations are often advantageous over single agents in terms of tolerability. Except for angiotensin II receptor blockers, the occurrence of adverse effects associated with antihypertensive drugs increases with higher drug doses. Single-pill combinations usually combine lower doses of the individual components and this translates into a reduced likelihood of adverse events. Again, there is a wealth of data to support this statement. For example, hyperkalaemia is less common with the combination of aldactone and hydrochlorothiazide (HCTZ) than with aldactone alone, and peripheral oedema is less frequent when CCBs are associated with renin–angiotensin system blockers.31 In one study,32 elderly nursing home residents were switched from a free combination of CCB and ACE therapies to a single-pill combination. After two months there were fewer reports of drug-related adverse events (75% less oedema) and significantly lower per-patient costs. In a large meta-analysis of five different categories of antihypertensive agent, the incidence of adverse effects with drug combinations was significantly less than additive, suggesting that antihypertensive agents given in fixed dose combinations do not potentiate the adverse effects of one another.24
One may also argue that the use of single-pill combinations is associated with an increased risk of some side effects, for example orthostatic hypotension and dizziness. In some elderly patients, the initial use of a single-pill combination may indeed be associated with an excessive fall in BP, which would be deleterious if the patient suffered from a carotid artery stenosis or severe coronary heart disease. This risk is higher when the first dose of the drug is taken. To avoid this type of side effect, combinations should be available at different doses. Alternatively, in such patients it may be wiser to start with a monotherapy and use single-pill combinations as a second-line therapy once the therapeutic situation has been stabilised.
Single-pill Combination and Costs
Uncontrolled HTN imposes a major health and financial burden on society. Through a simplified therapeutic regimen, the use of single-pill combinations can increase compliance and persistence, thus delivering enhanced effectiveness compared with their equivalent monocomponents administered as separate pills. As a result, single-pill combination therapies can help more patients reach target BP, thereby reducing cardiovascular morbidity and mortality.
In turn, this may translate into reduced numbers of physician visits and hospital admissions, shortened hospital stays, reduced non-drug and overall healthcare expenditure and improved productivity. Thus, a wider use of single-pill combinations could potentially reduce the overall cost of treatments.33 Whether this is indeed the case has not definitively been proved. Today, there are large variations among countries in the way single-pill combination therapies are paid for, and several financial barriers exist in some countries that limit wider use of these combinations.
Conclusions
Single-pill combinations have been shown to be valuable tools for the management of several medical conditions such as asthma, diabetes and dyslipidaemia. They represent effective and convenient alternatives to multidrug therapies with the individual components. HTN represents another field where many single-pill combinations are available with the potential to improve compliance and therefore outcomes. Considering the fact that a substantial proportion of hypertensive patients are inadequately controlled despite the availability of effective antihypertensive drugs because patients do not stay on therapy, wider use of single-pill combinations should improve BP control by simplifying treatment and reducing the pill burden. Today, most single-pill combinations involve dual therapies within one therapeutic area. In the last few years, the first combination therapies across diseases (for example HTN and lipid disorders) have appeared on the market and could become increasingly popular.34 In the near future, single-pill combinations will probably include more than two components in each pill; this could bring us to the expected polypill, which may further simplify the management of cardiovascular risk factors.