Building the case for drug combinations as initial therapy in the management of hypertension: a long time coming

by R. D. Feldman, Canada

Discipline of Medicine, Memorial
University of Newfoundland
St. John’s, Newfoundland and
Labrador, CANADA

On a global basis, hypertension control remains a significant challenge with blood pressure control rates of less than 50% in most regions. The determinants of these low blood pressure control rates are multiple and include systems-based, health-care provider–based, and patient-based factors. In developed countries the most important factors are probably patient- and health-care provider–based factors related to both nonadherence and clinical inertia. Emerging evidence has demonstrated that the prescription of single-pill combinations in the management of hypertension improves outcomes. The use of low-dose single-pill combinations presents theoretical advantages in regards to superior effectiveness and safety as compared to conventional monotherapy-based regimens. The greater effectiveness of single-pill combinations versus free combinations relates, at least in part, to ameliorating the patient- and health-care provider–based determinants of inadequate blood pressure control. Single-pill combination prescription has been shown to improve adherence and blood pressure control. Further, the initial use of combination antihypertensive therapy is associated with decreased hypertension-related cardiovascular event rates. With greater appreciation of the effectiveness of treatment regimens featuring the use of single-pill combinations, there is a reasonable expectation that the early use of single-pill combinations will be increasingly incorporated into national and international hypertension guidelines and consequently implemented more broadly into clinical practice.

“Nothing is more powerful than an idea whose time has come.”
Victor Hugo—French novelist and poet (1802-1885)

In the context of the broader pharmacopeia used across medicine, the resistance to the use of low-dose single-pill combinations early in the management of hypertension can only be viewed as anomalous. For a range of disorders, initial combination therapy is the standard, including for the treatment of infections (trimethoprim/ sulfamethoxazole for urinary tract infections), for pain relief (nonsteroidal anti-inflammatory drugs/codeine), and for the management of asthma (βadrenergic agonists/ steroids). However, despite the continuing challenges that we have in achieving better blood pressure control on a global basis and the generalized appreciation that we need multidrug therapy for blood pressure control in the vast majority of patients with hypertension, health-care providers are reluctant to use single-pill combinations as their first-line choice. In this review I will summarize what I see as some of the key factors responsible for suboptimal blood pressure control and how the greater use of single-pill combination therapy as initial treatment may improve this situation.

Key determinants of suboptimal blood pressure control: patient and health-care provider factors

The major factors leading to suboptimal blood pressure control can probably be grouped into issues related to: (i) healthcare delivery barriers; (ii) financial barriers (both individual and societal); (iii) health-care professional–related factors; and (iv) patient-related factors. In most developed countries, the main factors remain patient-related and health-care professional– related. In regards to these latter two factors, the greater use of single-pill combination therapy in hypertension management would be an important advance.

Patient-related factors: nonadherence and therapeutic turbulence
The major patient-related factor impeding blood pressure control is nonadherence (also known as noncompliance, nonconvergence, or nonconcordance). Nonadherence leading to suboptimal disease management is common to a range of diseases, but especially notable for those diseases that are asymptomatic until complications supervene (like dyslipidemia, diabetes, and atrial fibrillation). In hypertension, nonadherence rates—reflecting both a failure to implement a dosing regimen and failure to continue therapy—have been reported at rates as high as 50% at one year.1 However, in the setting of patients with apparently resistant hypertension, the rate is probably closer to 10% to 20%.2 A number of factors have been implicated in predisposing to nonadherence with antihypertensive drug regimens. They include: (i) mistaken patient beliefs/attitudes, including the belief that long-term medication use is harmful or that hypertension is “cured” if blood pressure readings are normal; and (ii) treatment-ascribed symptoms (whether drug-related or not).

Beyond patients’ beliefs and attitudes, the complexity of antihypertensive medication regimens has also been an important determinant of poor adherence. Specifically, the risk of nonadherence increases both with increasing number of daily doses and increasing number of tablets.3,4 Further, our traditional approach of sequential replacement of monotherapies as the initial prescribing strategy for blood pressure control has been shown to reduce adherence. This approach of increasing the dose of monotherapy and, in the setting of a lack of or partial response, replacing one drug with a drug from another class, leads to reduced adherence and hence reduced blood pressure control. This phenomenon, termed “therapeutic turbulence,” has been shown to lead to an ≈25% increase in nonadherence consequent to two or more cycles of dose escalation and substitution.5

Health-care provider–related factors: therapeutic inertia and the prescription of suboptimal medication regimens
Of perhaps the greatest importance as a health provider–centered determinant of suboptimal blood pressure control is the phenomenon of clinical inertia, ie, the failure of a health-care provider to initiate or intensify therapy when therapeutic goals are not reached. Clinical inertia is a major factor leading to delayed treatment initiation, follow-up, and ultimately blood pressure control and to increased risk of an acute cardiovascular event or death.6 It has been estimated to occur in as many as two thirds of clinic visits of patients with hypertension.1,3,4

Multiple factors have been suggested to contribute to clinical inertia, including overestimation of the impact of provided care, assuming elevated clinic blood pressures represent whitecoat effects, overreliance on health behavior change strategies, and knowledge gaps.1,7 The complexity of antihypertensive regimens required to achieve blood pressure control would also be expected to be a significant contributing effect to the development of clinical inertia. This complexity primarily relates to: (i) the number of medications required to achieve blood pressure control, eg, three to four drugs required to reach the lower blood pressure targets recommended for higher risk (SPRINT [Systolic blood PRessure INtervention Trial]– type) patients8; and (ii) the number of medications currently available for blood pressure treatment and the thousands of combinations and permutations of drugs to choose among, compounded by the competing voices of guidelines organizations and pharmaceutical companies on how best to manage patients with hypertension. However, regardless of the determinants of clinical inertia, its impact on blood pressure control rates on a practicewide basis is enormous. As illustrated by Okonofua and colleagues,9 the difference between blood pressure control rates in practices with the highest extent of clinical inertia versus those practices with the lowest was greater than 70%, ie, control rates of less than 10% in the practices demonstrating the greatest extent of clinical inertia versus more than 70% in those practices exhibiting the least. The prescription of suboptimal therapeutic regimens by healthcare providers is probably the most underappreciated contributor to suboptimal blood pressure control. The impact of suboptimal therapeutic regimens on blood pressure control was perhaps best illustrated by the study of Garg and colleagues.2 In their survey of patients with apparently “resistant hypertension” they found that for almost 60% of them the primary determinant of poor blood pressure control could be ascribed to “drug-related causes”—predominantly the prescription of a suboptimal medical regimen.

The rest of this review will focus on how the early use of lowdose single-pill combinations in the management of hypertension can ameliorate both patient-centered and health-care professional–centered determinants of suboptimal blood pressure control. This will include consideration of their: (i) greater efficacy (versus monotherapy); (ii) more favorable safety profile, greater global effectiveness (ie, in the context of racial differences in antihypertensive drug responses); (iii) greater effectiveness in achieving blood pressure control from a practicewide perspective; and (iv) greater effectiveness in reducing hypertension-related cardiovascular complications.

Combining antihypertensive drugs is always more effective than doubling the dose of monotherapy

It is a pharmacological truism that at maximal doses of a monotherapy, adding a second antihypertensive drug leads to greater blood pressure lowering. But even down to subtherapeutic doses, combining agents is three to five times more effective than dose-doubling.10 Further, whereas there are racial differences in the antihypertensive effectiveness of specific classes of antihypertensive drugs (eg, reduced effectiveness of angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) in black patients with hypertension), no such racial differences are evident when those agents are combined with an antihypertensive agent from a different class (eg, as with the use of an ACE inhibitor/ diuretic combination).11

Lower incidence of adverse effects with combinations, especially at low doses, than with doubling the dose of monotherapy

For most antihypertensive drugs the dose relationship for their most common adverse effects (eg, peripheral edema with calcium channel blockers) occurs over the same range as their antihypertensive effects. However, at half standard doses (typically approximating the starting dose) the aggregate adverse effects of most antihypertensive drugs approximates zero (versus placebo) and increases to ≈10% above placebo as dosage is increased to a standard dose level.12 Thus when a monotherapy dose is doubled it is expected that the probability of an adverse effect will increase by 10%. However, if instead, that drug (used at a starting or, even better, at a subtherapeutic dose) is combined with a low dose of another antihypertensive drug it would be expected that the aggregate probability of an adverse effect would still approximate that of placebo, ie, the probability of an adverse effect would be far lower than if a monotherapy dose were doubled. Further, when combined, there may be a lower incidence of some of the side effects of those specific drugs had they been used as monotherapies. For example, the incidence of disorders in serum potassium concentrations of both diuretics and reninangiotensin system (RAS) inhibitors are reduced when they are combined. Likewise, the incidence of peripheral edema with calcium channel blockers is significantly reduced when combined with a RAS inhibitor.13

In summary, from the perspectives of effectiveness and safety, greater use of single-pill combinations would seem to be warranted.

Single-pill combinations outperform “free combinations” in respect to adherence

Two recent systematic reviews have both concluded that there is superior patient adherence with the use of single-pill combinations versus the use of “free” equivalents.14,15 Further, as illustrated by the study of Taylor and colleagues, greater use of single-pill combinations would be expected to translate into both improved adherence and decreased medical resource utilization.16

Initial low-dose single-pill combination strategies outperform initial monotherapy-based strategies for blood pressure control

Initiating antihypertensive therapy with a single-pill combination has been previously shown in more rigorous clinical trial settings.17,18 These studies utilized strict protocol-driven dosage adjustments when single-pill combinations were prescribed and at closely monitored fixed intervals. Thus, it might be argued that the greater blood pressure–lowering effectiveness seen in patients randomized to the single-pill combination treatment arms was due to intrinsic differences in antihypertensive effectiveness between treatment arms (ie, the more rapid introduction of a more efficacious two-drug–therapy regimen in the combination group, with more rapid titration) rather than superiority of the single-pill combination formulation versus the free combination alternative. In that context the STITCH (Simplified Treatment Intervention To Control Hypertension) study was a more naturalistic comparison of the effectiveness of a single-pill combination strategy versus a traditional sequential monotherapy strategy.19

The STITCH study used a more pragmatic design than the preceding single-pill combination effectiveness studies. In it, practices were randomized to either being instructed to manage patients using a more traditional approach as outlined by the Canadian Hypertension Education Program recommendations— focusing on initial monotherapy (in most cases) versus managing patients utilizing the STITCH algorithm that featured the initial use of low-dose single-pill combinations, started at a dose simulating the antihypertensive effect of initial monotherapy. The effectiveness of the competing strategies could be examined in the absence of the requirement of a rigid clinical trial dosing protocol as used in conventional clinical trials. In the STITCH study the primary outcome was the practice-based 6-month blood pressure control rates in the subset of practice patients with uncontrolled hypertension at study entry in the STITCH-care versus guidelines-care group. In the STITCH study, in those practices randomized to instruction on the utility of the initial use of low-dose single-pill combinations, practicewide blood pressure control was significantly greater than in those practices instructed on a more traditional guidelines-based strategy, with a 23% greater relative improvement. Further, on average, blood pressure reduction in patients in practices randomized to the STITCHcare arm was 6/3 mm Hg greater.

Box 1. Potential advantages of initial single-pill combination–based
antihypertensive treatment.
*Preferred choices include angiotensin receptor blocker/diuretic and angiotensin-
converting enzyme inhibitor/calcium channel blocker.

Does initial therapy with single-pill combinations “work” outside of clinical trial settings?

The real-life utility of the early use of single-pill combinations, regardless of the stage of hypertension, is most evident from the experience of the Kaiser Permanente health system. In their guidelines for hypertension management, a single-pill combination is the preferred form of treatment in both stage 1 and stage 2 hypertension—analogous to the STITCH care management pathway. Utilizing this strategy, the Kaiser Permanente hypertension program reports blood pressure control rates in excess of 80%20,21—the highest reported healthcare system hypertension control rates globally.

Initiation of combination therapy versus monotherapy in reducing hypertension-related cardiovascular complications

The relative utility of initiating therapy with drug combinations versus monotherapy in regards to hypertension-related cardiovascular risk reduction has been examined in two cohort studies. In the first, Corrao and colleagues performed a population- based case-control study from a cohort of 209 650 patients from Lombardy, Italy, studying the 10 668 patients hospitalized for cardiovascular disease.22 Patients starting on combination therapy had an 11% reduction in cardiovascular risk compared to those initiated with monotherapy. In the second study, Gradman and colleagues examined the record of 1762 patients with hypertension who were initiated on combination therapy matched 1:1 with similar patients initiated on monotherapy and then subsequently transitioned to combination therapy. They reported that those patients on initial combination therapy had a 34% lower cardiovascular event rate (fatal and nonfatal) compared to those initiated on monotherapy. 23 These studies, although both observational in design, support on aggregate the benefit of initial combination therapy on harder cardiovascular disease outcomes.

Barriers to wider acceptance of single-pill combinations as initial therapy for the management of hypertension

From a hypertension guidelines perspective, internationally there has only been limited acceptance of the role of singlepill combinations as initial therapy in the management of hypertension and then only under specific conditions. Several national guidelines do recommend the initial use of singlepill combinations when blood pressures are more than 20 mm Hg above target for systolic blood pressure or 10 mm Hg above target for diastolic.24 However, there is little appreciation of the utility of low-dose combinations as initial therapy for stage 1 hypertension based on their superior performance in terms of adherence, effectiveness, or safety. In some guidelines systems, the road block to greater adoption of singlepill combinations earlier in the management of hypertension has been the lack of adequate clinical trials evidence demonstrating the effectiveness of combination therapy as the “lead treatment” (ie, either in initiating therapy or as an add-on) in large cardiovascular event-driven (hard outcome) randomized clinical trials. This barrier has been viewed by many to have been surmounted with the publication of the HOPE-3 (Heart Outcomes Prevention Evaluation–3) study.25

Box 1. Potential advantages of initial single-pill combination–based
antihypertensive treatment.
*Preferred choices include angiotensin receptor blocker/diuretic and angiotensin-
converting enzyme inhibitor/calcium channel blocker.

The overall results of this study on the effectiveness of achieving lower target blood pressures in this intermediate-risk patient population were admittedly neutral. However, in the subgroup of patients with the highest tertile of blood pressures on entry (ie, greater than 143 mm Hg systolic, a prespecified subgroup), those randomized to the active treatment arm, who received the single-pill combination of candesartan/hydrochlorothiazide, demonstrated an approximately 25% reduction in cardiovascular events. These findings support the case for initial therapy with a single-pill combination as an effective way to reduce both blood pressure and cardiovascular event rates—in other words, the findings meet the minimum requirements of guidelines writers for the evidence needed to recommend a single-pill combination as a first-line choice.

Is there a preferred single-pill combination?

Using the Canadian guidelines standard that a first-line hypertension treatment must be shown both to reduce blood pressure and cardiovascular risk, the HOPE-3 study would support the recommendation of a diuretic/ARB combination as the preferred first-line single-pill combination choice. However, findings from the ACCOMPLISH (Avoiding Cardiovascular events through COMbination therapy in Patients LIving with Systolic Hypertension) study would support the designation of an ACE inhibitor/calcium channel blocker single-pill combination as a preferred choice as well.25 In the ACCOMPLISH study, patients randomized to the benazepril/amlodipine single-pill combination had a 20% lower cardiovascular event rate versus those randomized to therapy with the benazepril/ hydrochlorothiazide single-pill combination.26 Based on the ACCOMPLISH study, both the Canadian Hypertension Education Program guidelines27 and the UK National Institute for Health and Care Excellence guidelines28 have recommended a RAS inhibitor/calcium channel blocker combination as the preferred single-pill combination choice. Notably, the development of these recommendations preceded the publication of HOPE-3. Thus, in the absence of direct head-tohead studies, the evidence to date supports the recommendation of both ARB/diuretic and ACE inhibitor/calcium channel blocker as the preferred single-pill combinations for initiating antihypertensive therapy (Box 1).


Despite the significant advances we have made in hypertension control and the wide availability of a range of effective antihypertensive drugs, we are still far short of the levels of blood pressure control achievable under the most optimal conditions (ie, in the setting of rigorous clinical trials protocols). Key factors contributing to this treatment gap include: patient-centered factors, such as nonadherence; as well as health-care provider–centered factors, which include clinical inertia and the prescription of suboptimal treatment regimens. The use of low-dose single-pill combinations presents theoretical advantages in regards to superior effectiveness and safety as compared to conventional monotherapy-based regimens. Further, single-pill combination therapy leads to improved adherence and overall higher rates of blood pressure control in hypertensive patient populations. Additionally, those patients initiated on combination antihypertensive therapy demonstrate lower rates of cardiovascular events.

With greater appreciation of the effectiveness of treatment regimens featuring the use of single-pill combinations, there is a reasonable expectation that the early use of single-pill combinations will increasingly be incorporated into national and international hypertension guidelines and consequently implemented more broadly into clinical practice. ■

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Keywords: hypertension; initial therapy; nonadherence; therapeutic turbulence; therapeutic inertia; suboptimal medication regimen; blood pressure control; single-pill combination; cardiovascular complication