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Patients with stage 2 systolic hypertension require sizable blood pressure (BP) reductions to achieve recommended targets. This randomized double-blind study compared a single-pill combination of the direct renin inhibitor aliskiren and hydrochlorothiazide (aliskiren/HCTZ) with HCTZ monotherapy in older patients (older than 55 years) with systolic BP ≥160 mm Hg and <200 mm Hg. After a 1- to 4-week washout, 451 patients were randomized to once-daily aliskiren/HCTZ 150/12.5 mg or HCTZ 12.5 mg for 1 week, and then double the doses for 7 weeks. Overall baseline BP was 168.8/91.4 mm Hg. At week 4 (primary) end point, aliskiren/HCTZ provided significantly greater BP reductions from baseline than HCTZ monotherapy (29.6/9.3 mm Hg vs 22.3/6.8 mm Hg) and resulted in a greater proportion of patients achieving BP goal of <140/90 mm Hg (51.1% vs 33.3%). Aliskiren/HCTZ therapy provides substantial BP reductions and may thus be a useful treatment option for older patients with stage 2 hypertension. J Clin Hypertens (Greenwich). 2011;13:162–169. © 2011 Wiley Periodicals, Inc.
Approximately a quarter of the 74.5 million adults with hypertension in the United States are affected by stage 2 hypertension (systolic blood pressure [SBP] >160 mm Hg).1 Isolated systolic hypertension (raised SBP but normal diastolic blood pressure [DBP]) is particularly common in older patients because of the natural physiologic changes that occur during the aging process: SBP rises as the vasculature stiffens and is remodelled with age.2 Thus, whereas most people with hypertension who are younger than 50 years have elevated DBP, those who are older than 50 years tend to have increased SBP.3
Current treatment guidelines advise lowering blood pressure (BP) to <140/90 mm Hg (or <130/80 mm Hg for patients with diabetes).4–6 To reach these BP goals, most patients require ≥2 antihypertensive agents, and therefore available treatment guidelines recommend first-line combination therapy for patients with stage 2 hypertension.6 Agents with complementary mechanisms of action, such as thiazide diuretics and agents that target the renin-angiotensin system, are logical choices to be used together4–6 and are available in single-pill combinations (SPCs).
The benefits of lowering BP in older patients with hypertension have been well documented in recent years. Several studies, including the Systolic Hypertension in the Elderly Program (SHEP), have demonstrated that BP reductions are associated with improvements in cardiovascular outcomes.7 A meta-analysis of 8 studies of patients 60 years and older with stage 2 systolic hypertension showed that antihypertensive therapy for a median duration of 3.8 years reduced stroke by 30%, cardiovascular death by 18%, and total mortality by 13%.8 Despite this, only 50% of treated patients older than 60 years and 31% of patients 80 years and older achieve BP goal, possibly reflecting the traditional reluctance of physicians to treat elderly patients aggressively because of the fear of treatment-related adverse events.9 The benefits of antihypertensive treatment, however, have clearly been shown to outweigh the risks by the landmark Hypertension in the Very Elderly Trial (HYVET).10 With an aging population, there is a growing need for BP-lowering therapies that combine large BP reductions with good tolerability in older patients.
Aliskiren-based regimens demonstrated superiority over established therapies based on angiotensin-converting enzyme (ACE) inhibitors in patients older than 60 years in the recently published Aliskiren for Geriatric Lowering of Systolic Hypertension (AGELESS) study.11 Here, we report the results of the Aliskiren HCTZ In Older Patients With Stage 2 Hypertension (ACTION) trial, a phase 4, randomized, controlled trial that evaluated the aliskiren/hydrochlorothiazide (HCTZ) SPC compared with HCTZ monotherapy in older patients (55 years and older) with stage 2 systolic hypertension.
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- Patients and Methods
The results of the ACTION study show that aliskiren/HCTZ SPC treatment is a highly effective option for BP reduction in older patients with stage 2 systolic hypertension. Patients receiving aliskiren/HCTZ had large SBP reductions of almost 30 mm Hg, on average, and more than half (51%) reached the recommended BP goal of <140/90 mm Hg after only 4 weeks of treatment. By contrast, patients receiving HCTZ monotherapy had significantly smaller reductions in SBP (approximately 22 mm Hg) and a significantly lower percentage reached BP goal (33%). The superiority of aliskiren/HCTZ over HCTZ monotherapy persisted after 8 weeks of treatment despite the optional addition of AML in patients with SBP ≥160 mm Hg. Aliskiren/HCTZ treatment was generally well tolerated. Adverse events were experienced by a similar proportion of patients to those receiving HCTZ monotherapy and most were mild in severity.
It is particularly noteworthy that a large proportion of aliskiren/HCTZ-treated patients rapidly achieved BP goal, with mean SBP falling to under 140 mm Hg within 4 weeks. Previous long-term outcome studies of other antihypertensive combinations in elderly populations, such as SHEP and the Systolic Hypertension in Europe (Syst-Eur) trial, showed marked BP reductions with active treatment, but mean SBP generally remained above 140 mm Hg.7,10,12 Although comparisons between studies with different enrollment criteria should be made with caution, mean baseline SBP (approximately 170 mm Hg) in these studies was similar to that in our study, as was the strategy of treatment escalation if patients did not achieve BP targets. In our study, SBP targets (<140 mm Hg) were more stringent than those of SHEP (<160 mm Hg for patients with baseline SBP of >180 mm Hg, or a reduction of 20 mm Hg for patients with baseline SBP of 160–180 mm Hg) and Syst-Eur (<150 mm Hg).
Evidence that rapid BP reductions are associated with beneficial outcomes comes from the Valsartan Antihypertensive Long-Term Use Evaluation (VALUE) trial, in which patients who responded to treatment (defined as previously untreated patients having a ≥10 mm Hg drop in SBP or previously treated patients not having an increase in BP) within a month of initiation had a 12% reduction in cardiac events (P<.01) and a 17% reduction in stroke (P<.05) compared with those who did not benefit from an immediate response to treatment.13 Although the VALUE trial did not enroll older patients exclusively, the mean patient age was approximately 67 years.14 The results of VALUE thus challenge the historical approach for the treatment of hypertension in older patients of “starting low and going slow” and suggest that physicians should aim to get these patients to BP goal as quickly as possible.
Importantly, our subgroup analyses showed that aliskiren/HCTZ provided large and rapid (ie, within 4 weeks) BP reductions consistently in the very elderly, those with very high BP, and those who were obese, populations that are all notoriously hard to treat effectively.9,15 These patient groups are also those at particularly high cardiovascular risk and thus may have the greatest need for effective treatments with good tolerability.
Our study demonstrates robust SBP reductions of 30 mm Hg after 4 weeks’ treatment with aliskiren/HCTZ combination therapy. Notably large SBP reductions (22 mm Hg) were also observed in the HCTZ monotherapy group, as might be expected in a study performed in patients with stage 2 hypertension at baseline. These reductions are broadly consistent with those observed in a post hoc subgroup analysis of patients with stage 2 hypertension from a placebo-controlled, multifactorial aliskiren/HCTZ study, in which aliskiren/HCTZ 300/25 mg combination therapy reduced SBP by 27.2 mm Hg and HCTZ 25 mg monotherapy reduced SBP by 18.9 mm Hg.16 Although the effect on absolute BP of adding aliskiren to HCTZ thus appears to be incremental (consistent with findings for combination of ARBs and HCTZ17,18), whether the effects of the two drugs in combination are additive requires the placebo effect to be taken into account. As the present study had no placebo arm, it is not possible to comment definitely on whether the addition of aliskiren to HCTZ had additive or incremental effects on BP. However, in the subgroup of patients with stage 2 hypertension in the previous multifactorial study, placebo-adjusted SBP reductions with aliskiren 300 mg, HCTZ 25 mg, and aliskiren/HCTZ 300/25 mg were 9.3 mm Hg, 8.8 mm Hg, and 17.1 mm Hg, respectively, suggesting additive effects of aliskiren and HCTZ on BP.16 Regarding the changes in BP at week 8 end point in the present study, it is important to note that between-treatment differences at this time point are less meaningful than those at the week 4 end point because optional add-on of AML at week 4 or 6 for patients who had not achieved SBP <160 mm Hg was used for a greater proportion of patients in the HCTZ group (22.0% vs 12.8% in the aliskiren/HCTZ group). The further reductions in mean BP and higher control rate in the aliskiren/HCTZ group at week 8 (62%) compared with week 4 (51%) reflect the addition of AML to the treatment regimen and demonstrate the effectiveness of the triple combination (aliskiren/HCTZ and AML) in patients who do not respond to combination therapy with two agents. The triple combination is thus likely to represent an important treatment option for patients with particularly hard-to-control hypertension.
Aliskiren/HCTZ combination therapy reduced PRA from baseline by 49% at week 4, and aliskiren/HCTZ±AML reduced PRA by 57% at week 8, confirming the ability of aliskiren to suppress diuretic- and calcium channel blocker–induced PRA increases. The present study did not evaluate the relationship between baseline PRA or on-treatment changes in PRA and observed changes in BP. Two published aliskiren studies have shown that changes in BP with aliskiren monotherapy are not related to PRA levels at baseline.19,20 Andersen and colleagues19 showed that the BP-lowering effect of aliskiren monotherapy was similar in patients with low (≤0.65 ng/mL/h) and high (>0.65 ng/mL/h) baseline PRA (−13.0/−12.5 and −13.7/−12.1 mm Hg, respectively). In addition, Richter and colleagues20 showed that the proportion of patients reaching target BP (<140/90 mm Hg [<130/80 mm Hg in patients with diabetes]) with aliskiren monotherapy, or aliskiren/HCTZ or aliskiren/HCTZ/AML combination therapy, was similar in patients with baseline PRA ≤0.65 ng/mL/h and >0.65 ng/mL/h. With regard to the relationship between changes in PRA and changes in BP, a modelling analysis of pooled data from 9 studies of aliskiren monotherapy in patients with stage 1 or 2 hypertension showed that the magnitude of the change in PRA on aliskiren treatment is predictive of the magnitude of the change in BP.21
Disclosures: This work was funded by Novartis Pharma-ceuticals Corporation, East Hanover, NJ. Jan Basile has received research support from Novartis, The National Heart, Lung and Blood Institute and Boehringer-Ingelheim; has acted as a consultant for Novartis, Abbott Laboratories, Boehringer-Ingelheim, Forest Laboratories, Daiichi-Sankyo and Takeda Pharmaceuticals; and has been a member of the speakers’ bureau for Novartis, Abbott Laboratories, AstraZeneca, Boehringer-Ingelheim, Forest Laboratories, GSK, Merck, Pfizer and Daiichi-Sankyo. Michael Lillestol has received research support from Novartis. Jaco Botha, Carol Yurkovic, and Richard Weitzman are employees of Novartis and are therefore eligible for Novartis stock and stock options.