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Tekturna® (aliskiren): A New Antihypertensive
Hypertension occurs in approximately 25% of the US population and may lead to stroke, heart attack, kidney failure, heart failure, and death.1 According to the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7), prehypertension is defined as systolic blood pressure (SBP) 120-139 mm Hg or diastolic blood pressure (DBP) 80-89 mm Hg, and hypertension is SBP 140-159 mm Hg or DBP 90-99 mm Hg. Currently, hypertension is treated with diuretics, beta blockers, calcium channel blockers, angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and vasodilators.2
Aliskiren (Tekturna®) is a direct renin inhibitor that was FDA approved on March 6, 2007 for the treatment of hypertension.1 Aliskiren is a synthetic transition-state analog that binds with high specificity to the proteolytic active site of renin.3 Inhibition of renin results in reduced circulating levels of angiotensin I and II. Since aliskiren has a half-life of about a day, it effectively reduces plasma renin levels with one daily dose.3,4
A double-blind, randomized, placebo-controlled study evaluated the safety and efficacy of aliskiren in 652 patients with mild-to-moderate hypertension (mean sitting DBP >95 mm Hg and <110 mm Hg).5 Patients were excluded if they had severe hypertension (mean sitting DBP >110 mm Hg or mean sitting SBP >180 mmHg), secondary hypertension, type 1 or uncontrolled type 2 diabetes mellitus, a history of cardiovascular disease, or any medical condition that might significantly alter the pharmacokinetics of the study drugs. After a 2-week washout period of previous antihypertensive medication, followed by a 2- to 4-week placebo run-in period, patients were randomized to receive aliskiren 150 mg (n=127), aliskiren 300 mg (n=130), aliskiren 600 mg (n=130), irbesartan 150 mg (n=134), or placebo (n=131) once daily for eight weeks. The primary endpoint was the change from baseline in trough mean sitting DBP. Aliskiren 150 mg, 300mg, and 600 mg significantly lowered trough mean sitting DBP and mean sitting SBP compared to placebo (mean difference in DBP compared to placebo: 150 mg = -2.94 mm Hg, 300 mg = -5.43 mm Hg, 600 mg = -5.16 mm Hg; p<0.001). There was no difference between aliskiren 150 mg and irbesartan 150 mg. Aliskiren 300 mg and 600 mg lowered mean sitting DBP significantly more than irbesartan 150 mg (mean difference in DBP compared to irbesartan: 300 mg = -2.89 mm Hg; 600 mg = -2.63 mm Hg; p = 0.005 and p=0.01, respectively). Aliskiren was well tolerated with headache, dizziness, and diarrhea commonly reported. Sixty-six patients withdrew due to unsatisfactory therapeutic effect, adverse events, withdrawal of patient consent, protocol violation, or lost to follow-up. The authors concluded that aliskiren was both safe and effective for the treatment of mild-to-moderate hypertension. They also concluded that higher doses of aliskiren were more effective than irbesartan 150 mg. The study was limited by its short duration and inclusion of only patients with mild-to-moderate hypertension.5
Another randomized, double-blind, placebo-controlled trial evaluated the safety and efficacy of aliskiren in 1123 patients with mild-to-moderate hypertension.6 Patients were excluded if they had severe hypertension (mean sitting DBP >110 mm Hg or mean sitting SBP >180 mm Hg), secondary hypertension, type 1 or uncontrolled type 2 diabetes mellitus, history of severe cardiac or cerebrovascular disease, or any medical condition that might alter the pharmacokinetics of the study drugs. After discontinuation of prior antihypertensive medications and a 3- to 4-week placebo run-in period, patients were randomized to receive aliskiren monotherapy (75 mg, 150 mg, or 300 mg), valsartan monotherapy (80 mg, 160 mg, or 320 mg), aliskiren and valsartan in combination (75/80 mg, 150/160 mg, or 300/320 mg), valsartan/HCTZ 160/12.5 mg, or placebo once daily for eight weeks. The primary endpoint was the change from baseline in mean sitting DBP with aliskiren monotherapy compared to placebo. Secondary endpoints included the change from baseline in mean sitting SBP and efficacy of the combinations compared to aliskiren monotherapy and valsartan/HCTZ combination. Aliskiren 300 mg significantly lowered mean sitting DBP (-3.67 mm Hg + 0.87) and mean sitting SBP (-5.08 mm Hg + 1.34) compared to placebo (p<0.001 and p<0.01, respectively). Aliskiren 75 mg and 150 mg were no more effective than placebo. All three aliskiren/valsartan combinations significantly lowered mean sitting DBP and mean sitting SBP compared to placebo (p<0.05). The largest decreases in blood pressure were in the combination groups with valsartan/HCTZ showing the greatest mean change (-13.5 mm Hg ± 1.07). Common adverse effects included headache, fatigue, cough, back pain, and diarrhea. Eighty-nine patients dropped out due to adverse effects, unsatisfactory therapeutic effect, protocol violation, withdrawal of consent, or lost to follow-up. The authors concluded that aliskiren provided antihypertensive therapy comparable to an ARB with similar tolerability as placebo. The study was limited by its short duration, large placebo effect, and inclusion of only patients with mild-to-moderate hypertension.6
Aliskiren is a new antihypertensive medication with a novel mechanism of action. It is more effective than placebo at lowering blood pressure; however, it appears comparable to ARBs. Further studies comparing aliskiren to other antihypertensives are needed to determine its place in therapy, and long-term data is needed to evaluate its effect on morbidity/mortality and preventing hospitalizations.
By Clari Ramos, Pharm. D. Candidate
References:
- Food and Drug Administration. FDA approves new drug treatment for high blood pressure (4/6/07). Food and Drug Administration Web site. Available at: http://www.fda.gov/bbs/topics/NEWS/2007/NEW01580.html. Accessed April 10, 2007.
- Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7)-Complete report (8/2004). NIH publication No. 04-5290. National Heart, Lung, and Blood Web site. Available at: http://www.nhlbi.nih.gov/guidelines/hypertension/jnc7full.pdf. Accessed April 18, 2007.
- Van Tassell BW, Munger MA. Aliskiren for renin inhibition: a new class of antihypertensives. Ann Pharmacother 2007;41(3):456-464.
- Tekturna® [package insert]. East Hanover, NJ: Novartis Pharmaceuticals; 2007 March.
- Gradman AH, Schmieder RE, Lins RL, et al. Aliskiren, a novel orally effective renin inhibitor, provides dose-dependent antihypertensive efficacy and placebo-like tolerability in hypertensive patients. Circulation 2005;111(8):1012-1018.
- Pool JL, Schmieder RE, Aziz M, et al. Aliskiren, an orally effective renin inhibitor, provides antihypertensive efficacy alone and in combination with valsartan. Am J Hypertens 2007;20:11-20.