Efficacy and Safety of Combined Use of Aliskiren and Valsartan in Patients With Hypertension

What Does This Important Study Show? 

Almost 4,000 subjects with mild to moderate hypertension underwent a 1- to 2-week washout period, followed by a 3- to 4-week run-in period to establish eligibility. Patients with severe cerebrovascular or cardiovascular disease or systolic blood pressure (SBP) greater than 180 mm Hg at any time during the study were excluded. Of the recruited patients, 1,797 patients were randomly assigned to receive once-daily aliskiren, 150 mg; valsartan, 160 mg; a combination of aliskiren, 150 mg, and valsartan, 160 mg; or placebo for 4 weeks, after which doses were doubled for an additional 4 weeks. Patients with severe CKD, nephrotic syndrome or a history of dialysis were excluded from the study.

The primary outcome was change in mean sitting diastolic blood pressure (DBP) from baseline to study end. Secondary outcomes included changes in SBP, treatment success (DBP < 90 mm Hg, >10 mm Hg decrease in DBP), blood pressure (BP) control (SBP/DBP < 140/90 mm Hg), change in ambulatory BP, and changes in plasma renin and aldosterone levels.

At 8 weeks, combination therapy decreased mean sitting BP by 4.2/3.2 mm Hg and 4.4/2.5 mm Hg compared with aliskiren and valsartan monotherapy, respectively. This effect was consistent at each 2-week interval. The primary end point, mean sitting DBP, was significantly lower in the combination-therapy group. Ambulatory BP was measured in 354 subjects. Mean 24-hour SBPs were 14.4, 10.1, 9.8, and 1.3 mm Hg less than baseline measurements in the aliskiren/valsartan, valsartan, aliskiren, and placebo groups, respectively. Ambulatory BP decreases were sustained throughout the 24-hour period.

Not surprisingly, plasma renin concentration at 8 weeks significantly increased in those treated with aliskiren/valsartan (55.2 ng/mL) compared with the valsartan (12.2 ng/mL), aliskiren (25.3 ng/mL), and placebo groups (6.2 ng/mL). However, plasma renin activity dramatically decreased in patients treated with aliskiren (0.13 ng/mL/h with monotherapy; 0.30 in combination with valsartan) versus valsartan (1.28 ng/mL/h) and placebo (0.73 ng/mL/h). Although valsartan alone and in combination with aliskiren significantly decreased serum aldosterone levels compared with placebo, aliskiren monotherapy failed to do so.

Incidents of hyperkalemia and increased serum creatinine levels were similar in all groups and did not demand discontinuation of treatment. Adverse events were similar across groups, except for headache, which was higher in the placebo group.

Unfortunately, effects on albuminuria were not reported and may not have been measured. Also, only adverse effects on creatinine levels were reported, and none were significant enough to warrant discontinuation of the study drug. Thus, the more detailed renal actions of renin blockade, if any, cannot be gleaned from this report.

How Does This Study Compare With Prior Studies? 

Previous studies explored the efficacy and safety of aliskiren alone or in combination. Pool et al2 randomly assigned more than 1,100 patients to aliskiren, 75, 150, or 300 mg/d; valsartan, 80, 160, or 320 mg/d; combination aliskiren/valsartan, 75/80, 150/160, or 300/320 mg/d; and valsartan/hydrochlorothiazide, 160/12.5 mg/d. Combination therapy yielded decreases in BP similar to those seen in the study by Oparil et al1 and similar to valsartan/hydrochlorothiazide, without significant adverse effects. The effect of aliskiren alone and in combination on RAAS biomarkers have been previously studied. Azizi et al3, 4 reported that in both sodium-depleted3 and sodium-replete4 normotensive volunteers, aliskiren was able to suppress serum levels of angiotensin I and angiotensin II and urine aldosterone excretion more effectively than valsartan alone.

To date, no clinical trials have been published describing the effects of aliskiren on CKD progression or proteinuria. However, an abstract describing the Aliskiren in the Evaluation of Proteinuria in Diabetes (AVOID) trial was recently presented that showed that 3 months of treatment with aliskiren, 150 mg/d, followed by 3 months of aliskiren, 300 mg/d, added to losartan monotherapy yielded a 20% decrease in microalbuminuria versus valsartan and placebo. Additional trials designed to study renoprotective and cardioprotective properties of aliskiren in patients post–myocardial infarction are ongoing (ASPIRE HIGHER, sponsored by the manufacturer).

Some effort, scattered mostly among small trials, has tested the role of dual RAAS blockade in the treatment of patients with CKD with proteinuria. Two recent meta-analyses have supported the contention that ACE inhibitors and ARBs in combination decrease proteinuria better than monotherapy, especially in patients with greater proteinuria.5, 6 These meta-analyses of heterogeneous trials failed to distinguish whether the effect of dual therapy on proteinuria was a result of improved BP control or intrinsic properties of treatment medications. Results of the combination treatment of angiotensin II receptor blocker and angiotensin-converting-enzyme inhibitor in nondiabetic renal disease (COOPERATE) trial further support the use of dual therapy for slowing the progression of CKD with proteinuria.7 Conversely, a relatively large randomized controlled trial of hypertensive patients with modest proteinuria (mean protein < 500 mg) failed to show improvement in protein excretion with dual therapy over monotherapy and placebo.8 Dual RAAS inhibition with enalapril and eplerenone produced a significant decrease in proteinuria, albeit with high rates of hyperkalemia.9

One rationale for more specific inhibition of renin activity is based in large part on in vitro data. Renin, as well as (pro)renin, may, independently of angiotensin and aldosterone, but directly though a renin receptor, stimulate production of transforming growth factor β, plasminogen activator inhibitor 1, fibronectin, and collagen through the angiotensin-independent extracellular signal-regulated kinase 1 and 2 (ERK 1/2) pathway in rat mesangial cells. This pathway is not blocked by angiotensin II type 1 receptor blocker.10 However, current ACE-inhibitor and ARB treatments increase renin levels, but are beneficial. If renin were deleterious, one would predict otherwise. Thus, the role of independent actions of renin, although intriguing, remains of uncertain pathophysiological and clinical importance.

What Should Clinicians and Researchers Do? 

Clearly, there are not enough data to recommend aliskiren for first-line routine clinical use at this time. Whether the potential theoretical benefit of blocking the RAAS at its origin translates into clinical gain may be known better as ongoing clinical trials are published. However, the current work in aliskiren highlights the many unknowns regarding agents that have been in clinical use for a decade or more. We still do not know whether the combination of ACE inhibitors and ARBs is beneficial. However, a Veterans Administration study is addressing this in patients with type 2 diabetes.11 Also, very high doses of ARBs may have advantages over standard doses, but definitive data are lacking. Aldosterone blockade, although showing promise in limited clinical trials and in animal models, has not been adequately studied. Even more amazing, we do not know whether the usual diuretics enhance the renal protection of ACE inhibitors or ARBs. Because many people with CKD do not receive diuretics, perhaps for lack of evidence, a trial of their efficacy in combination with ACE inhibitors or ARBs would be useful. From a cost perspective, data from such a trial could lead to less expensive combination therapy than the addition of a renin blocker to ACE inhibitors or ARBs. Because the commercial value of diuretics is small, we cannot expect a pharmaceutical company to support it. Aliskiren may some day take its place among the agents currently in use. In the meantime, resources should be applied to understanding our present armamentarium.