Initial use of fixed-dose angiotensin receptor blocker/hydrochlorothiazide therapy may improve hypertension management, reduce risk of cardiovascular disease, and decrease long-term healthcare expenditures.
Hypertension is the most prevalent risk factor for death worldwide,1 and a major modifiable risk factor for cardiovascular disease (CVD), the most common cause of death in the United States.2 About two-thirds of the cerebrovascular disease burden and one-half of the ischemic heart disease burden are attributable to poor blood pressure (BP) control.1 The correlation between BP and cardiovascular (CV) morbidity and mortality is steep, continuous, and independent of other risk factors.3,4
Numerous large-scale clinical trials in hypertension have shown that antihypertensive therapy is associated with significant improvements in CV outcomes.5-14 Hypertension treatment guidelines, therefore, recommend lowering BP to <140/90 mm Hg in most patients and to <130/80 mm Hg in those with specific additional CVD risk factors.1,4,15-19 However, these targets frequently are not met. According to the 1999 to 2004 National Health and Nutrition Examination Survey, approximately 67% of the 72 million people with hypertension in the United States in 20042 were aware of their condition, 54% were treated, and only 33% achieved their BP goal.20 Considering that BP control is routinely achieved in 48% to 65% of subjects in clinical trials,21 the National Health and Nutrition Examination Survey findings clearly suggest an opportunity for improved hypertension management in clinical practice. Thus, the US Department of Health and Human Services has set a target BP control rate of 50% by 2010.22
CVDs are responsible for decreased survival and impaired quality of life, and in the United States they account for the majority of the total healthcare expenditure. The estimated annual direct and indirect costs of hypertension and CVDs in the United States for 2007 are $66.4 billion and $431.8 billion, respectively.2 The clinical costs of uncontrolled hypertension are significant in terms of frequent physician visits to titrate and/or switch antihypertensive regimens, poor patient compliance with therapy due to perceived lack of benefit, and increased long-term CV complications. Because the clinical and economic benefits of treating hypertension are governed by early and effective BP control, and because the majority of patients fail to achieve their BP goal with monotherapy targeting 1 mechanism,23 greater use of multiple antihypertensive agents may be warranted to optimize individual patient care. Published guidelines recommend initiating treatment with 2-drug combinations in patients with a high CV risk who require urgent BP reduction, and in those who are unlikely to achieve BP control using monotherapy.
This review examines the possible reasons for poor BP control in clinical practice and evaluates the efficacy, safety, and implications for the reduction of CV risk and long-term healthcare expenditures of initial antihypertensive fixed-dose angiotensin receptor blocker/hydrochlorothiazide (ARB/HCTZ) combination therapy for patients with uncontrolled stage 2 hypertension. Stage 2 hypertension is systolic blood pressure (SBP) >160 mm Hg or diastolic blood pressure (DBP) >100 mm Hg, as defined by the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7).4
To identify articles for review, we conducted a literature search through the search engine PubMed utilizing key words such as ARB, HCTZ, stage 2 hypertension, combination therapy, and healthcare costs. Articles were evaluated for relevancy of efficacy, tolerability, and cost comparisons between initial fixed-dose combination therapy and monotherapy.
Cardiovascular Risk Associated With Uncontrolled Hypertension
It is well established that lowering BP can result in significant reductions in vascular disease risk in people with hypertension.3,6,7,9-14,24-26 A 20-mm Hg increase in SBP is associated with more than a 2-fold increase in the rate of death from stroke and a 2-fold increase in the rate of death from ischemic heart disease and other vascular causes,3 and a 5-mm Hg decrease in DBP is associated with an approximate 40% relative reduction in stroke death and a 30% relative reduction in death from ischemic heart disease or other vascular risk factors.24
Blood pressure control becomes increasingly more difficult and expensive to achieve as the severity of hypertension increases. Early, aggressive, and sustained BP lowering has the potential to reduce the progression from mild to more severe hypertension27 and the long-term consequences.28 The speed at which BP is reduced is now recognized as an important factor in the prevention of CV events,12,21,29,30 supporting the use of more aggressive treatment to get patients at high CV risk to a BP goal much faster.
Treatment Guideline Recommendations
In recognition of the association between BP level and CV risk, JNC 7 defines 3 levels of hypertension: (1) prehypertension (SBP 120-139 mm Hg or DBP 80-89 mm Hg); (2) stage 1 hypertension (SBP 140-159 mm Hg or DBP 90-99 mm Hg); and (3) stage 2 hypertension (SBP ≥160 mm Hg or DBP ≥100 mm Hg).4 In line with other hypertension treatment guidelines,1,15-19 the JNC 7 report recommends lowering BP to <140/90 mm Hg in most patients and <130/80 mm Hg in those with diabetes and renal impairment. Recently, the American Heart Association19 also recommended a BP goal of <130/80 mm Hg for patients with high coronary artery disease risk. An even lower goal of <120/80 mm Hg is recommended for patients with left ventricular dysfunction.19
Because many patients with hypertension have additional comorbidities that contribute to their CVD risk, the choice of treatment strategy should not be based solely on a patient’s BP level, but should also take into account any compelling indications that may help direct therapy.4 Studies have shown that the majority of patients (50%-60%) will fail to achieve their BP goal on any single antihypertensive agent targeting 1 mechanism.23 Hence, the more recent guidelines4,18,19 recommend initiating combination therapy in patients whose BP is >20/10 mm Hg above goal and in those with less severe hypertension but with a high CV risk, in whom rapid attainment of BP control is desirable (Table 1).4,15,17-19,31 Usually a combination of a thiazide diuretic with an angiotensin-converting enzyme (ACE) inhibitor, ARB, calcium channel blocker, or β-blocker is strongly suggested.4,12,13,28
Barriers to Effective Blood Pressure Control
Despite widespread availability of safe and effective antihypertensive agents and detailed guidelines, only about 30% of American adults with hypertension achieve their BP goal.20 This has been attributed to a number of factors, including lack of reimbursement from government/insurers, poor patient compliance/persistence with therapy, and poor adherence to guidelines by physicians.32-34
Compliance With Therapy. Poor compliance is a frequent problem in patients who experience slow or hidden treatment benefits or adverse effects,35 have complicated dosing patterns,36,37 or have high treatment costs.38,39 Failure to comply with long-term antihypertensive therapy has major implications for the prevention of CV events,12,40-42 as well as for healthcare expenditures.43,44 Real-world drug utilization patterns among 60,685 treatment-naive subjects within the United States indicate that approximately 30% to 50% of individuals stop using their prescribed antihypertensive medications for at least 60 days within the first year of treatment.41 In a study of Medicaid patients, the total medical cost of documented noncompliance with antihypertensive therapy was $873 higher per patient than for those who were compliant with treatment.45 The higher costs were primarily due to greater inpatient hospital expenditures, averaging $637 per patient. In fact, another study reported that 11% of hospital admissions among the elderly were due to noncompliance.38 Improving compliance rates, therefore, has implications for improving CV outcomes and reducing healthcare costs in patients with hypertension.
Physicians’ Adherence to Guidelines. In spite of hypertension treatment guidelines,4,18,19 many physicians fail to initiate therapy with multiple agents and/or prescribe additional antihypertensive medication when necessary.32-34,46 The Strategies of Treatment in Hypertension: Evaluation (STRATHE) study found that initial combination therapy was more effective for the reduction of BP than a sequential monotherapy or stepped-care strategy based on antihypertensive medications that are commonly used worldwide.47 In this study, initial treatment of hypertension with a low-dose ACE inhibitor/diuretic combination of perindopril and indapamide allowed significantly more patients to reach their BP goal of 140/90 mm Hg than either sequential β-blocker/ARB/calcium channel blocker monotherapy or a stepped-care ARB followed by a low-dose ARB/diuretic regimen (BP was reached by 62%, 49%, and 47% of patients, respectively).47 Therefore, use of combination therapy, either as initial treatment or early in the course of treating hypertensive patients, may reduce the need for frequent and multiple follow-up visits.
Rationale for Initial Fixed-Dose Combination Therapy in Patients With Uncontrolled Hypertension
Combinations of antihypertensive agents that reduce BP via different mechanisms, such as thiazide diuretics and ARBs or ACE inhibitors, result in additive or synergistic effects on BP reduction. For example, the Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension (ACCOMPLISH) trial reported similar BP control in patients receiving combination therapy with either an ACE inhibitor and a thiazide diuretic or a calcium channel blocker and a thiazide diuretic.48 Compared with the sequential addition of multiple single agents, fixed-dose combinations offer greater cost-effectiveness and improved treatment compliance.23,37,42,49 Furthermore, some antihypertensive agents have the potential to attenuate adverse events caused by other drugs. For example, concomitant administration of an ACE inhibitor or ARB may attenuate diuretic-induced alterations in potassium, serum cholesterol, and fasting glucose.50
Choice of Initial Therapy in Patients With Uncontrolled Hypertension
The choice of initial therapy should be based on several factors. First, the added benefits of some antihypertensive agents extend beyond BP control. For example, renin-angiotensin system inhibitors are renoprotective51-55 and have beneficial cardiometabolic effects that have been shown to reduce the incidence of new-onset diabetes.12,56-59 Treatment guidelines, therefore, recommend treating patients with hypertension and type 2 diabetes or renal disease with a combination of agents that includes an ACE inhibitor or an ARB.4,15-17,19 Second, compliance/persistence rates vary between therapeutic classes. For example, ARBs are associated with higher persistence rates at 1 year than ACE inhibitors, calcium channel blockers, diuretics, or β-blockers,41,60-63 whereas typical doses of diuretics are associated with higher rates of noncompliance and self-discontinuation.39 Thus, avoiding the typical 25-mg dose of HCTZ in favor of a lower dose combined with an ARB, for example, has the potential to improve patient compliance. Additional considerations for the choice of initial treatment should include compelling indications, tolerability, drug interactions, and cost.
The cost-effectiveness of antihypertensive treatment is significantly affected by treatment effectiveness, which in turn depends on compliance, drug tolerability, and dosing simplicity. A retrospective analysis of overall medical and pharmacy costs in a longitudinal pharmacy database demonstrated considerable annual cost savings among patients initiating ARB and ACE inhibitor therapy ($2780 and $3163, respectively). Annual pharmacy costs in the ARB and ACE inhibitor group were $893 and $955, respectively.64 Several studies have demonstrated the costeffectiveness of ARBs versus other antihypertensive drug classes in people with hypertension, type 2 diabetes, and microalbuminuria.65-67
Initial ARB/Diuretic Therapy Well Tolerated and Effective in Patients With Uncontrolled Hypertension
Data from numerous clinical trials have consistently shown the superiority of ACE inhibitors or ARBs combined with other agents over monotherapy in reaching BP goal in patients with mild-to-moderate (stage 1)4 hypertension and/or with additional CV risk factors.49,68-72 Although there are fewer studies in patients with more severe (stage 2)4 hypertension, the available data support the hypertension treatment guideline recommendations for a broader use of initial ARB/thiazide diuretic combination therapy (Table 2).48,73-77
Most studies of initial combination therapy versus monotherapy in patients with stage 2 hypertension showed that combination therapy resulted in greater BP reductions and higher goal attainment rates with a tolerability profile similar to that of monotherapy. For example, losartan/HCTZ combination therapy was associated with significant reductions (P <.001) in both SBP (—15.4 mm Hg) and DBP (–10.2 mm Hg) compared with ramipril monotherapy (SBP –9.2 mm Hg; DBP –6.4 mm Hg) in 312 patients with type 2 diabetes with BP ≥20/10 mm Hg above the recommended goal at baseline (Table 2).73 Similar results also were obtained from a double-blind trial in which 585 patients with severe hypertension (defined as mean sitting DBP ≥110 mm Hg and mean SBP ≤220 mm Hg) were randomized to receive either losartan/HCTZ combination therapy or losartan monotherapy, titrated as necessary (Table 2).74 In this study, significantly higher rates of goal BP attainment were achieved using combination therapy (SBP —25.1 mm Hg; DBP –17.8 mm Hg) versus monotherapy (SBP –14.1 mm Hg; DBP –11.9 mm Hg) (Table 2).
Similarly, a randomized study in patients with stage 2 or 3 systolic hypertension (SBP ≥160 mm Hg and ≤200 mm Hg) with or without other CV risk factors showed that monotherapy with valsartan 160 mg was effective (SBP —20.7 mm Hg; DBP –6.6 mm Hg), but significant additional reductions in SBP and DBP (P <.05) were achieved with valsartan/HCTZ combination therapy (SBP —28.3 mm Hg; DBP –10.1 mm Hg) (Table 2).75 The BP response rate was 56.9% in the monotherapy group compared with 74.4% and 75% in the 2 valsartan/HCTZ combination therapy groups (P <.05).75 In each of these studies, the adverse-event profile was similar in both the combination therapy and the monotherapy treatment groups.
A double-blind trial in patients with moderate-to-severe hypertension, defined as either newly diagnosed without previous treatment (mean DBP ≥110 mm Hg but ≤120 mm Hg and mean SBP ≥160 mm Hg) or inadequately controlled (DBP 90-110 mm Hg) on 1 or more antihypertensive agent, showed that olmesartan medoxomil 20 mg/HCTZ 12.5 mg (n = 308) produced greater BP reductions (SBP —29.3 mm Hg; DBP –17.6 mm Hg) than losartan 50 mg/HCTZ 12.5 mg (n = 305; SBP –24.9 mm Hg; DBP –16.5 mm Hg) (Table 2).76 By week 12, the difference between groups in mean DBP reductions (primary efficacy parameter) was only significant in the per-protocol group. The proportion of patients whose BP was controlled (BP <140/90 mm Hg) at week 12 (43.2% vs 32.1%; P <.002), and the reduction in pulse pressure (11.6 ± 9.4 vs 8.4 ± 9.4 mm Hg; P <.0001) was greater with olmesartan medoxomil/HCTZ than with losartan/HCTZ, indicating that olmesartan medoxomil 20 mg/HCTZ 12.5 mg offers better BP control in patients with moderate-to-severe hypertension. Both treatments were well tolerated.
Two further studies have recently demonstrated that initial irbesartan/HCTZ combination therapy is significantly more effective than irbesartan monotherapy in achieving rapid and sustained BP control, irrespective of the patient’s baseline BP (Table 2).49,77 In patients with untreated or uncontrolled moderate (SBP 160-180 mm Hg or DBP 100-110 mm Hg)77 or severe (DBP ≥110 mm Hg)49 hypertension, and in a post hoc pooled analysis of both studies78 irbesartan/HCTZ was generally associated with a greater likelihood of achieving SBP <140 mm Hg or DBP <90 mm Hg than irbesartan or HCTZ monotherapies across the range of BPs studied. The proportion of patients who achieved their BP goal decreased as the baseline BP increased; and although the majority of patients with SBP <160 mm Hg achieved their goal BP with irbesartan monotherapy, most subjects with moderate-to-severe hypertension (SBP ≥160 mm Hg) required combination therapy to achieve their goal. Results were consistent for a variety of goals, including SBP <130 mm Hg and DBP <80 mm Hg78 regardless of age, obesity, and type 2 diabetes.79
In a time-point analysis of the irbesartan/HCTZ versus irbesartan monotherapy study in patients with severe hypertension,80 SBP and DBP control rates were significantly greater for combination therapy versus monotherapy at all time points (weeks 3, 5, and 7); the BP reductions achieved with irbesartan monotherapy at week 7 were surpassed by irbesartan/HCTZ approximately 1 month earlier. Over 7 weeks, the probability of having SBP ≥110 mm Hg at least once during follow-up was 24.9% with monotherapy versus 16.4% with combination therapy, an absolute difference of 8.5%. For every 12 patients treated with combination versus monotherapy, exposure to SBP ≥110 mm Hg was significantly reduced by 26 weeks (P = .004).
Together, the results of these studies demonstrate that, compared with monotherapy, ARB/HCTZ combination therapy rapidly reduces BP levels and increases BP goal attainment rates in people with stage 2 hypertension,4 without affecting tolerability. Initial use of ARB/HCTZ combination treatment, therefore, has the potential to significantly improve hypertension management in people with uncontrolled stage 2 hypertension, thereby reducing healthcare costs.
Early and effective BP control has the potential to significantly reduce CV risk and its associated healthcare costs. However, despite the availability of safe and effective antihypertensive agents and detailed treatment guidelines, only around 30% of Americans with hypertension achieve their BP goal. This is largely due to poor treatment compliance and failure of physicians to adhere to the guidelines. Although the majority of people with hypertension, especially those with BP >20/10 mm Hg above goal, will require aggressive therapy with 1 or more antihypertensive agents, many physicians fail to prescribe adequate treatment. The initial use of fixed-dose ARB/HCTZ combination therapy, especially in patients with more severe hypertension (stage 2),4 has the potential to overcome many of the barriers to effective hypertension management, thereby reducing the risk of CVD and decreasing long-term healthcare expenditures to control and contain the pandemic of hypertension.