Aliskiren and Valsartan for Hypertension
Abstract & Commentary
By Michael H. Crawford, MD, Professor of Medicine, Chief of Cardiology, University of California, San Francisco. Dr. Crawford is on the speaker's bureau for Pfizer.
Synopsis: Efficacy and safety of combined use of aliskiren and valsartan in patients with hypertension: a randomized, double-blind trial.
Source: Oparil S, et al. Efficacy and safety of combined use of aliskiren and valsartan in patients with hypertension: a randomized, double-blind trial. Lancet. 2007;370:221-229.
Aliskiren is a new class of drugs that directly inhibit renin and is approved in the USA for the treatment of hypertension. Valsartan is the best-selling antihypertensive medication in the world. Little is known about the combination of these 2 drugs on blood pressure. Thus, Oparil and colleagues conducted a double-blind, placebo-controlled parallel group, dose escalation study at 312 centers in the USA, Spain, and Germany in 1797 patients with hypertension, but no severe cardiovascular disease. Patients were given once-daily oral aliskiren 150 mg or valsartan 160 mg or the combination or placebo for 4 weeks. Then they were force titrated to double the dose of each agent for 4 weeks. The primary end-point was a change in mean sitting diastolic blood pressure from baseline to week 8. Secondary end-points included systolic blood pressure measurements, the 4-week results and plasma levels of renin, renin activity and aldosterone. Overall 11% of the patients withdrew early from the study mostly because of inadequate blood pressure control.
Premature discontinuation was least common in the combination therapy group and most common in the placebo group. Both mean sitting blood pressure and mean 24-hour ambulatory blood pressure decreased most on combination therapy and less but equally on both monotherapies. All 3 active drug groups decreased significantly vs placebo. Mean sitting systolic blood pressure decreased 4.6 mmHg on placebo, 13 mmHg on each monotherapy, and 17.2 on combination therapy. Plasma renin levels were increased by all 3 active therapies, but most by aliskiren. Plasma renin activity was reduced by aliskiren alone or in combination, but was elevated by valsartan monotherapy. Aldosterone levels were not changed on aliskiren monotherapy, but were reduced by valsartan and combination therapy. Adverse events occurred in 2-3% of patients in each group. Potassium levels >5.5 mmol/L occurred in 2-4% of patients more in the combined therapy group. The authors concluded that the combination of aliskiren and valsartan in maximum recommended doses results in greater blood pressure lowering than does monotherapy with either agent in patients with hypertension. Also, combination therapy exhibited a low adverse event rate that was similar to monotherapy.
Commentary
It is unusual to see pharmacologic treatment studies that combine maximum doses of 2 drugs. Most are done with less than maximum doses, leaving the question of what would happen if one drug was increased maximally, rather than adding another drug. The major rationale for using multiple drugs at low doses is to avoid adverse effects that may be seen at higher doses of one drug. This assumes that the added drug is from a different class of agents with a different adverse effect profile. Although this theory sounds good, it has never been convincingly proved in clinical trials. In fact, some studies have shown the opposite, that adverse effects tend to increase in frequency the more drugs you give. Thus, this study was interesting because all these issues were challenged. Maximum doses were used as monotherapy and in combination, and the 2 agents chosen had similar adverse-effect profiles. The results showed that combination therapy with aliskiren and valsartan was superior to monotherapy with either drug, with a similar adverse effect frequency.
One strength of the study was the use of an 8-hour ambulatory blood pressure recording to weed out the white coat hypertensives. This is important because they tend to get better over time, which results in greater placebo effects. Also, 24-hour ambulatory blood pressure measures were done and correlated well with the mean sitting blood pressure results. The major adverse effect observed was an increase in creatinine, which was seen in 4 patients on combination therapy (0.9%), 2 on valsartan, one on aliskiren and none on placebo. However, this was not accompanied by an increase in blood urea nitrogen and serum potassium levels > 5.5 mmol/L, and were not significantly different between the 4 groups (3% placebo, 2% aliskiren, 2% valsartan and 4% combination). None of these patients had events that lead to study drug discontinuation.
The biochemical results are also interesting. Plasma renin levels increased in all 3 therapeutic groups as might be expected from drugs that block its activity downstream. However, only aliskiren and combination therapy reduced renin activity. What, if any, effects elevated renin and renin activity have in patients on angiotensin receptor blockers (ARB) is unknown, but blocking renin's effect with aliskiren did further reduce blood pressure. Perhaps the observed inconsistent effect of adding an ARB to an ACE inhibitor on blood pressure is due to increased renin activity. Also, combination therapy and ARB monotherapy reduced aldosterone levels which would be expected to help reduce blood pressure. Thus, this may be an especially potent drug combination for favorably altering the renin angiotensin aldosterone system.
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