Combined Olmesartan, Amlodipine, and Hydrochlorothiazide Therapy in Randomized Patients with Hypertension: A Subgroup Analysis of the TRINITY Study by Age

The prevalence of hypertension rises with age [1‐4]. In the US, hypertension occurs in 70.8 % of women and 63.9 % of men 65–74 years of age and 80.1 % of women and 72.1 % of men ≥75 years of age, largely due to increased systolic blood pressure (SBP) [1]. Individuals over 60 years of age are also the most rapidly growing segment of the US population. By 2025, the worldwide prevalence of hypertension will reach 50.3 % in women and 46.0 % in men 60–69 years of age and 66.8 % in women and 57.1 % in men ≥70 years of age [5].

Adequately treating hypertension is important since cardiovascular disease risk is doubled with each 7 years of advancing age, 20-mmHg increment in SBP, or 10-mmHg increment in diastolic BP (DBP) [6]. National Health and Nutrition Examination Survey (NHANES) data indicate that only 53 % of individuals ≥60 years of age have adequate BP control [1]. In order to achieve adequate BP reduction, many elderly individuals require more than one drug [7]. If multiple-pill therapies adversely affect therapeutic adherence in this population [8, 9], many elderly patients with hypertension may benefit from single-pill, multiple-combination therapy [5, 10, 11].

In the Triple Therapy with Olmesartan Medoxomil, Amlodipine, and Hydrochlorothiazide in Hypertensive Patients Study (TRINITY; ClinicalTrials.gov Identifier: NCT00649389), the triple-combination treatment of olmesartan medoxomil (OM) 40 mg, amlodipine besylate (AML) 10 mg, and hydrochlorothiazide (HCTZ) 25 mg reduced both seated DBP (SeDBP) and seated SBP (SeSBP) to a greater degree than the 3 dual-combination treatments, enabling a greater proportion of study participants to reach BP goal (<140/90 mmHg [<130/80 mmHg in participants with diabetes, chronic kidney disease, or chronic cardiovascular disease]) [12]. The objective of the current prespecified TRINITY subgroup analysis was to evaluate the efficacy and safety of the OM 40/AML 10/HCTZ 25 mg triple-combination treatment compared with the 3 component dual-combination treatments in participants with hypertension who were <65 and ≥65 years of age. Within the ≥65 years of age subgroup, efficacy and safety were also summarized for participants ≥75 years of age.

This prespecified subgroup analysis of the TRINITY study demonstrated the efficacy and safety of triple-combination OM 40/AML 10/HCTZ 25 mg treatment in elderly participants with hypertension. Compared with the component dual-combination treatments, triple-combination treatment with OM/AML/HCTZ resulted in greater mean reductions in BP and enabled a larger proportion of study participants to achieve BP goals in all 3 age subgroups. All treatments were well tolerated. The largest BP reductions observed in this evaluation occurred in the very elderly (≥75 years of age) in participants receiving OM 40/AML 10/HCTZ 25 mg (n = 18). This subgroup was a subset of the ≥65 years of age subgroup, which may have contributed to the demonstrated efficacy. The ≥75 years of age subgroup also had the highest absolute rates of cardiovascular disease in patients receiving OM 40/AML 10/HCTZ 25 mg. The potential impact of these observations is substantial because epidemiologic data suggest that a reduction in SBP of 20 mmHg or DBP of 10 mmHg has the potential to reduce adverse events by as much as 50 % [6]. The favorable benefits observed in outcome trials have resulted in current guidance that hypertension should be treated vigorously in all patients, regardless of age [2]. In general, those with the best BP control also have the best outcomes. Thus, the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) recommends a BP goal of <140/90 mmHg (<130/80 mmHg in patients with diabetes or chronic kidney disease), regardless of age [2].

Numerous clinical trials have established the benefits of hypertension treatment in these patients [13‐24]. In the 1980s, the European Working Party on High Blood Pressure in the Elderly (EWPHE) demonstrated in a randomized, double-blind, placebo-controlled study that treating hypertension in participants ≥60 years of age significantly reduced cardiac (38 %, p = 0.036) and cardiovascular (27 %, p = 0.037) mortality [13]. More recently, the Hypertension in the Very Elderly Trial (HYVET) demonstrated that treating hypertension in participants ≥80 years of age to SBP values <150 mmHg reduced heart failure by 64 % (p < 0.001), stroke mortality by 39 % (p = 0.046), cardiovascular mortality by 23 % (p = 0.06), and all-cause mortality by 21 % (p = 0.02) [20]. Consistent with these findings, a meta-analysis of data from 15 trials found that treating hypertension in participants ≥60 years of age significantly reduced all-cause mortality (risk ratio [RR]: 0.90; 95 % confidence interval [CI]: 0.84–0.97), cardiovascular mortality (RR: 0.77; 95 % CI: 0.68–0.86), coronary heart disease mortality (RR: 0.77; 95 % CI: 0.65–0.90), and cerebrovascular mortality (RR: 0.66; 95 % CI: 0.53–0.82) [21].

Combination therapy is an attractive approach [2]. Successfully applying advanced BP goals in elderly patients remains challenging [1, 2]: only about 20 % of these patients achieve the recommended BP targets [2]. In hypertension, the etiology of BP elevation is usually multifactorial, making it unlikely that BP control can be achieved by modulating a single mechanism [4, 25]. The JNC 7 guidelines state that most patients with hypertension require 2 or more antihypertensive medications to achieve BP goal but overall, at least 75 % of patients with hypertension will require at least 2 agents and at least 25 % need at least 3 agents to achieve BP goal (these percentages represent data from a controlled environment of a clinical trial and findings cannot be extrapolated to the general population) [2, 7, 25‐29]. In the Study on Cognition and Prognosis in the Elderly (SCOPE), 49 % of participants randomized to active treatment were receiving at least 3 antihypertensive agents by study end [7]. Similarly, in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA), 78 % of participants with hypertension and ≥3 other cardiovascular risk factors were receiving at least 2 and 61 % at least 3 antihypertensive agents by study end; addition of a third antihypertensive agent resulted in approximately 30 % of participants with previously uncontrolled hypertension achieving BP goal (<140/90 mmHg [<130/80 mmHg in participants with diabetes]) [30, 31]. Thus, the American College of Cardiology Foundation (ACCF)/American Heart Association (AHA) 2011 Expert Consensus Document on Hypertension in the Elderly recommends adding a third drug from another class if the antihypertensive response is inadequate compared to full doses of 2 drugs from different classes [4].

BP control in the elderly is also complicated by adverse events, such as hypotension, and drug interactions [4]. Elderly patients are also more likely to have end organ damage that may influence drug selection and response to therapy [2, 4]. In addition, pathophysiologic, lifestyle, and treatment-related factors in these patients may adversely affect compliance with any antihypertensive therapeutic regimen [4].

In the present study, triple-combination treatment was well tolerated in participants <65 and ≥65 years of age, with a similar prevalence of TEAEs (57.7 and 61.0 %), drug-related TEAEs (27.6 and 30.5 %), and study drug discontinuations due to a TEAE (3.9 and 4.2 %). The incidence of hypotension was similar across age groups (<65 years of age: 0.4 %; ≥65 years of age: 0.7 %); however, more participants ≥75 years of age (4.2 %) discontinued their study medication due to an adverse event compared with participants <65 years of age (2.2 %) and ≥65 years of age (2.9 %). OM either as monotherapy or in combination with HCTZ and/or AML is an effective and safe treatment for hypertension in a broad range of patients, including the elderly [32‐36]. In one study, 52–67 % of study participants ≥65 years of age receiving OM/HCTZ combination therapy achieved the SeBP goal of <140/90 mmHg, while in another study, 61 % of participants ≥65 years of age receiving OM/AML combination therapy, with or without HCTZ, achieved the SeBP goal of <140/90 mmHg (<130/80 mmHg in participants with diabetes) [32, 34]. In patients with diabetes, chronic kidney disease, or chronic cardiovascular disease, short-term (12 weeks) and long-term treatment with OM 40/AML 10/HCTZ 25 mg was well tolerated, lowered BP more effectively, and enabled more participants to reach BP goal than the corresponding dual-combination therapies [37]. Furthermore, in another multinational, phase 3 study, adding HCTZ to a range of OM/AML dose combinations was well tolerated and improved BP control by significantly lowering BP in patients with moderate-to-severe hypertension [38].

A critical factor in achieving benefit is adherence to therapy, which has been shown to correlate inversely with the number of pills in a therapeutic regimen [8, 9, 39]. Nonadherence is a major contributing factor to inadequate BP control [40‐42] and can be particularly problematic in elderly individuals taking polypharmacotherapy (often with 6 or more medications) for multiple comorbidities [4]. The ACC/AHA 2011 Expert Consensus states that potential benefits of single-pill combination therapy include increased efficacy, reduced adverse events, and additive target organ protection [4]. Furthermore, by decreasing the number of copayments required, this therapy could reduce out-of-pocket costs, an important consideration in the elderly due to lower incomes [4, 43]. Thus, single-pill combination therapy provides a convenient and effective option for many patients that may increase adherence and persistence [44‐49].

Certain limitations exist in this study. While the evaluation of the elderly (≥75 years of age and ≥65 years of age) and non-elderly subgroups (<65 years of age) was pre-defined, statistical analyses between these subgroups was not completed because of the unequal participant numbers in the subgroups. Achieved SeBP reductions were comparable with treatment cohorts and the age subgroups and did not warrant further analyses between subgroups. Participants with various illnesses, including active heart disease and poorly controlled diabetes (i.e., HbA_1c >9 %), were excluded from participation; therefore, caution must be exercised regarding generalizability of these data to the overall population. In addition, the TRINITY study evaluated only a single dose for each agent used and therefore does not provide information on the efficacy or safety of these regimens using different dosing schemes. Also, in clinical practice, patients are likely to be titrated from no drugs to 1 drug, 2 drugs, and then a regimen with 3 drugs. While the TRINITY 12-week study is not designed in this way, it is reasonable to assume that if patients were titrated in the study as they are in clinical practice, the total BP reduction would be similar.

This prespecified subgroup analysis of the TRINITY study demonstrated that OM 40/AML 10/HCTZ 25 mg triple-combination treatment was both safe and effective in study participants with hypertension, regardless of age. Triple-combination treatment resulted in greater reductions in SeSBP and SeDBP and, as a result, was more effective in enabling study participants to reach BP goal compared with the component dual-combination treatments in all age subgroups. Triple-combination treatment was well tolerated, with low prevalences of hypotension and few discontinuations due to drug-related TEAEs in both the <65 and ≥65 years of age subgroups. Triple-combination treatment with OM 40/AML 10/HCTZ 25 mg may provide a safe and effective treatment option for elderly patients whose BP is not adequately controlled with dual-combination treatment. Other combinations of similar classes of medications may be efficacious at reducing BP, but will need to be evaluated.