Renin Antagonists: An Alternative to Controlling Hypertension

Dr. Arif is an assistant professor of pharmacy practice at Long Island University and an internal medicine specialist at James J. Peters Veterans Affairs Medical Center, Bronx, New York. Dr. Maggu is a primary care pharmacy specialist at the James J. Peters Veterans Affairs Medical Center, Bronx, New York.

Hypertension is one of the most common primary diagnoses in the United States, affecting >50 million Americans.¹ A direct relationship has been established between elevated blood pressure (BP) and cardiovascular disease (CVD), with adequate control of BP reducing the risk of stroke by 35% to 40%, myocardial infarction by 20% to 25%, and heart failure by 50%. Regardless of target BP goals (<140/90 mm Hg or <130/80 mm Hg for individuals with chronic kidney disease and diabetes mellitus), the ultimate outcome of therapy is the reduction of cardiovascular and renal morbidity and mortality.¹

According to the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High BP (JNC 7) guidelines, thiazide diuretics, though underused, prevent cardiovascular complications as well as enhance antihypertensive efficacy in multidrug regimens.¹ For compelling indications such as chronic kidney disease and diabetes mellitus, however, the use of drugs that inhibit the renin-angiotensinaldosterone system (RAAS) suspend the pathogenesis of cardiovascular and renal disorders.²

Renin, a small protein enzyme, is secreted by the kidneys in response to low arterial pressure and also plays a key role in controlling the rate-limiting step in the renin angiotensin system.^2,3 Renin cleaves angiotensinogen to form the inactive decapeptide angiotensin I. The potent and active octapeptide, angiotensin II, is then produced from angiotensin I by the angiotensinconverting enzyme (ACE). Via AT1 receptors, angiotensin II mediates an increased arterial tone, adrenal aldosterone secretion, renal sodium reabsorption, sympathetic neurotransmitters, and cellular growth.²

The RAAS can be inhibited in a variety of ways. ACE inhibitors reduce the conversion of angiotensin I to angiotensin II, a potent vasoconstrictor.² Peptides, including bradykinin and substance P, mediate the common side effects, such as cough and angioedema, and are also inhibited by the ACE inhibitors. Angiotensin receptor blockers (ARBs) are more specific in hindering the binding of angiotensin II to the AT1 receptor site. Direct renin inhibitors can halt the entire system at the origin.²

Within the RAAS, angiotensinogen II functions as a negative inhibitory feedback mediator to hinder the release of renin. Reduced angiotensin levels suppress the inhibitory feedback mechanism leading to increased plasma renin concentrations and renin activity that may negate ACE inhibitor and ARB therapy.² A renin inhibitor would be clinically significant as renin activity would be diminished.

Aliskiren

Aliskiren is the first in a new class of potent, oral renin inhibitors.⁴ In March 2007, the FDA approved aliskiren (Tekturna) for the treatment of hypertension as monotherapy or in combination with other antihypertensive agents.⁵ The once-daily, oral recommended starting dose is 150 mg, which may be increased to 300 mg once daily if BP is not adequately controlled. Doses >300 mg were not found to result in an increased BP response.⁴

In an 8-week, multicenter, randomized, placebo-controlled trial (n = 1123), a daily aliskiren dose of 300 mg significantly lowered mean sitting diastolic BP (msDBP) and mean sitting systolic BP (msSBP) compared with placebo, whereas tolerability was similar to placebo in patients with hypertension.⁶ Given as monotherapy, BP reductions proved to be similar to those provided by monotherapy with valsartan, losartan, and hydrochlorothiazide (HCTZ).⁵

Combination Treatments

Identification of aliskiren’s role in the management of hypertension has been the focus of several clinical trials. In order to discern possible pharmacologic synergy with dual RAAS inhibition, aliskiren combined with ACE inhibitors and with ARBs has been studied. Additionally, combination therapies with thiazide diuretics like HCTZ and calcium channel blockers have been evaluated.

Hydrochlorothiazide

In an 8-week, international, doubleblind, randomized, placebo-controlled trial (n = 2752), combinations of aliskiren 150- or 300-mg doses with HCTZ 6.25- to 25-mg doses were superior to placebo in reductions of msDBP and, with the exception of aliskiren/HCTZ 150 mg/6.25 mg, msSBP.⁷ Additionally, a greater proportion of patients reached a BP goal of <140/90 mm Hg than those on monotherapy alone.

In an open-label, nonrandomized study, O’Brien and colleagues found the addition of HCTZ 25 mg to aliskiren 150 or 300 mg for 3 weeks significantly reduced daytime BP and inhibited plasma renin secretion when compared with aliskiren monotherapy in patients with mild-to-moderate hypertension.⁸ In early 2008, the FDA approved the combination of aliskiren and HCTZ (Tekturna HCT), which is marketed by Novartis.

Angiotensin-converting enzyme inhibitors

More recently, the combination treatment of aliskiren with an ACE inhibitor, ramipril, was studied in 1 randomized, double-blind trial (n = 837) focusing on hypertensive, diabetic patients.⁹ With a recommended BP goal of ≤130/80 mm Hg, patients were randomized to a daily treatment of aliskiren 150 mg (n = 282), ramipril 5 mg (n = 278), or aliskiren/ ramipril 150 mg/5 mg (n = 277) with dose titrations after 4 weeks to aliskiren 300 mg, ramipril 10 mg, or aliskiren/ ramipril 300/10 mg. After 8 weeks of treatment, significantly more patients on aliskiren monotherapy or ramipril/ aliskiren combination therapy had responded with a reduction in msSBP than those on ramipril alone.⁹

Angiotensin receptor blockers

To date, 3 clinical studies have focused on the additive antihypertensive effects of aliskiren combination therapy with ARBs. In an 8-week, randomized, double- blind, placebo-controlled study (n = 1797), the combination of aliskiren and valsartan at maximum recommended doses (300 and 320 mg, respectively) significantly reduced BP when compared with either agent as monotherapy or with placebo, with a tolerability profile similar to that with aliskiren and valsartan alone.¹⁰

Gradman and colleagues focused on treatment of mild-to-moderate hypertension in an 8-week, randomized, multicenter, double-blind, placebocontrolled, active-comparator trial (n = 652).¹¹ It was found that aliskiren 150 mg once daily was as effective as irbesartan 150 mg once daily and superior to placebo in lowering BP in patients without a history of diabetes and CVD (including heart failure, transient ischemic cerebral attacks, or myocardial infarctions). Aliskiren given as daily doses of 150 and 300 mg lowered DBP, but not SBP, more than irbesartan 150 mg, with the 600-mg daily dose not demonstrating further BP reductions.

Recently the Aliskirin in the Evaluation of Proteinuria in Diabetes (AVOID) study was published to evaluate aliskiren’s ability to reduce proteinuria use in patients with type 2 diabetes with nephropathy.¹² A total of 599 patients received 3 months of losartan 100 mg/day and were then randomized to 6 months of treatment with aliskiren 150 mg daily for 3 months, followed by 300 mg daily for 3 additional months versus placebo. The investigators found a 20% reduction in proteinuria, measured by the ratio of albumin to creatinine, in the aliskiren group compared with placebo (P <.0001).¹²

Calcium channel blockers

In a 6-week, randomized, double-blind, dose-escalating study, the addition of aliskiren 150 mg daily to amlodipine 5- mg-daily therapy demonstrated a significant reduction of msDBP and msSBP compared with amlodipine 5 mg alone. The overall efficacy was comparable with amlodipine 10-mg-daily treatment without the associated increased incidence of edema.¹³

Tolerability and Safety

Clinical studies have thus far presented aliskiren’s BP-lowering efficacy and a favorable side effect profile with rates of adverse events similar if not less in the aliskiren treatment arms. The most common adverse effects reported were diarrhea (2.3%), cough (1.1%), and rash (1%).5 Adverse effects are dose-dependent, with increases in doses resulting in increased incidences of diarrhea and minimal to no improvement in BP lowering with doses >300 mg.⁵

Aliskiren does not inhibit the breakdown of bradykinin as seen with ACE inhibitors; therefore, no subsequent increase in circulating bradykinin levels occurs, leading to a lower incidence of cough.¹⁴ Additionally, angioedema, the most serious side effect, is seen less often than with ACE inhibitors, with a reported 4 of 6460 patients.¹⁵

Precaution should be used with severe renal dysfunction and hyperkalemia when using aliskiren and should be avoided when the serum creatinine is 1.7 mg/dL for women and 2.0 mg/dL for men.⁵ Similar to other medications known to affect the RAAS, aliskiren also should be avoided during pregnancy, due to possible fetal injury or death.¹⁶ High-fat meals are known to decrease absorption with a peak concentration expected within 1 to 3 hours and oral bioavailability of 2.5%.⁵ Although aliskiren can be taken with or without meals, it is recommended that patients maintain a consistent meal pattern. With a half-life of 24 hours, the convenience of once-daily dosing makes adherence to therapy more plausible with maximum antihypertensive effects noted 2 weeks after initiation.^5,15

Place in Therapy

The addition of aliskiren to the pharmacotherapeutic options in the management of hypertension allows for a novel approach to RAAS inhibition. Although several clinical trials have demonstrated aliskiren’s dose-dependent BP reduction with few side effects, it may be too premature for this to translate into improved long-term outcomes related to morbidity and mortality. Ongoing trials with primary cardiovascular and renal end points are in progress. ¹⁷ The Aliskiren Observation of Heart Failure Treatment (ALOFT) trial recently published has shown that the addition of aliskiren to an ACE inhibitor or ARB and a beta-blocker leads to favorable effects on neurohormonal actions in heart failure patients. Other ongoing trials include the Aliskiren Left Ventricular Assessment of Hypertrophy (ALLAY), Aliskiren in Post Myocardial Infarction Patients (ASPIRE), Aliskiren Trial in Visceral Obesity at Risk Patients Outcomes Research (AVIATOR), Type 2 Diabetic Nephropathy (ALTITUDE).¹⁸ The data generated from the completion of such trials will undoubtedly be analyzed for consideration in developing future hypertension treatment guidelines. â– 

References

1. Chobanian AV, Bakris GL, Black HR, et al: The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. JAMA. 2004;289(19):1560-2571.

2. Staesson JA, Li Y, Richart T. Oral renin inhibitors. Lancet. 2006; 368(9585):1449-1455.

3. Guyton AC, Hall JE. Textbook of Medical Physiology. 10th ed. Philadelphia: WB Saunders; 2000:201.

4. Oh B, Mitchell J, Herron JR, et al. Aliskiren, an oral renin inhibitor, provides dose-dependent efficacy and sustained 24-hour blood pressure control in patients with hypertension. Hypertension. 2007;49(11):1157-1164.

5. Tekturna [package insert]: East Hanover, NJ: Novartis Pharmaceuticals; 2007.

6. Pool JL, Schmieder RE, Azizi M, et al. Aliskiren, an orally effective renin inhibitor, provides antihypertensive efficacy alone and in combination with valsartan. Am J Hypertens. 2007;20(1):11-20.

7. Villamil A, Chrysant SG, Calhoun D, et al. Renin inhibition with aliskiren provides additive antihypertensive efficacy when used in combination with hydrochlorothiazide. J Hypertens. 2007;25(1):217-226.

8. O’Brien E, Barton J, Nussberger J, et al. Aliskiren reduces blood pressure and suppresses plasma renin activity in combination with a thiazide diuretic, an angiotensin-converting enzyme inhibitor, or an angiotension receptor blocker. Hypertension. 2007;49(2):276-284.

9. Uresin Y, Taylor A, Kilo C, et al. Efficacy and safety of the direct renin inhibitor aliskiren and ramipril alone or in combination in patients with diabetes and hypertension. J Renin Angiotensin Aldosterone Syst. 2007;8(4):190-198.

10. Oparil S, Yarows S, Patel S, Fang H, Zhang J, Satlin A. Efficacy and safety of combined use of aliskiren and valsartan in patients with hypertension: a randomized, double-blind trial. Lancet. 2007;370(9583):221-229.

11. Gradman AH, Schmieder RE, Lins RL, Nussberger J, Chiang Y, Bedigian MP. 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.

12. Parving HH, Persson F, Lewis JB, Lewis EJ, Hollenberg NK. Aliskiren combined with losartan in type 2 diabetes and nephropathy. New Engl J Med 2008;358(23):2433-2446.

13. Drummond W, Munger MA, Essop, Maboudian M, Khan M, Keefe DL. Antihypertensive efficacy of oral direct renin inhibitor aliskiren add-on therapy in patients not responding to amlodipine montherapy. J Clin Hypertens. 2007;9(10):742-750.

14. Azizi M, Webb R, Nussberger J, Hollenberg NK. Renin inhibition with aliskiren: where are we now, and where are we going? J Hypertens. 2006; 24(2):243-256.

15. Venkata, CS, Ram S. Renin inhibitors: a new approach to antihypertensive drug treatment. J Clin Hypertens. 2007;9(8):615-621.

16. Aliskiren Drug Monograph. Lexi-Comp Online. Hudson, OH: Lexi-Comp Inc. Accessed December 4, 2007.

17. Pool J. Direct renin inhibition: focus on aliskiren. J Manag Care Pharm. 2007;13(8 suppl B):S21-S33.

18. Institute for Safe Medication Practices Web site. www.ismp.org. Accessed December 15, 2007.