Direct renin inhibition in the elderly

Hypertension may well be the most important public health issue facing society today. It is the most common outpatient diagnosis worldwide, affecting 1 billion patients, and contributes directly to 7.1 million deaths annually. Suboptimal blood pressure control is linked to approximately 60% of cerebrovascular events and 50% of ischemic heart disease cases.¹ Hypertension is a dependent, modifiable risk factor for cardiovascular disease and stroke, which are the first and third leading causes of death in the United States, respectively. Stroke is the top cause of long-term rehabilitation and nursing home admission in the United States.

Although causes of hypertension are multifactorial, age remains one of the more significant risk factors, and the prevalence of hypertension increases with age. One half of people aged 60 to 69 years and 75% of people over 70 years are hypertensive. Of normotensive patients aged 55 to 69 years, 90% will develop hypertension if they reach the age of 80 years.

Much of the morbidity and mortality associated with hypertension can be ameliorated through appropriate medical therapy. Benefits from blood pressure control have been noted in all age groups; therefore, hypertension management remains critical throughout a patient’s lifetime. Treatment of hypertension in elderly patients (>65 years) can be challenging because of comorbidities, high rates of polypharmacy, and higher rates of adverse reactions to medications. Although patients older than 65 years comprise approximately 15% of the population, they receive 33% of prescription medications. Approximately 25% of patients over the age of 65 years take 5 or more medications daily. Elderly patients are 2 to 3 times more likely to experience side effects from medications and are at risk for significantly more medication interactions because of the high rate of polypharmacy in this population.²

Several medication classes have demonstrated benefits in treating hypertension, including thiazide diuretics, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II type-1 receptor (AT1R) blockers, and dihydropyridine calcium channel blockers. A new class of medications that provide direct renin inhibition may offer additional options for treating hypertension.

We review the basis for inhibition of the renin-angiotensin-aldosterone (RAA) system in the treatment of hypertension and provide a brief review of the available data demonstrating efficacy of direct renin inhibitors in hypertension. Based on the currently available data, we make inferences regarding the utility of using such inhibitors in the elderly.

RAA system

The RAA system has been a target for developing pharmacologic agents since the discovery of ACE in 1957.³ Agents capable of interfering with multiple steps within the RAA system have been developed. The widespread use of ACE inhibitors and aldosterone antagonists has resulted in significant reductions in cardiovascular morbidity and mortality. Experimental and clinical evidence is overwhelming that RAA system manipulation with these agents improves blood pressure,⁴ reduces myocardial fibrosis,⁵ and slows the progression of chronic renal insufficiency in diabetic⁶ and nondiabetic chronic renal disease.⁷

ACE inhibitors and aldosterone antagonists have become an integral component of the treatment strategy in chronic congestive heart failure, postmyocardial infarction, left ventricular systolic dysfunction, and nonischemic cardiomyopathies. Nevertheless, a significant proportion of patients remain poorly responsive to or intolerant of currently available RAA system agents.

Skeggs and colleagues recognized that renin—the enzyme catalyzing the rate-limiting step in the RAA system responsible for Ang II and aldosterone production—was the ideal target for RAA system blockade.³ Aliskiren, the first direct renin inhibitor approved by the US Food and Drug Administration (FDA) in March 2007, is marketed for first-line and combination therapy of mild-to-moderate hypertension.

Direct renin inhibition: Battle of the escape phenomenon

The RAA system “escape” phenomenon describes the progressive rise of plasma renin concentrations and the resultant increase in plasma renin activity and in Ang II levels observed during therapy with ACE inhibitors and AT1R blockers. This increase in plasma renin concentration is compensatory because of interruption of the negative feedback effect of Ang II on renin release. Additionally, alternative enzymes in the kidneys, heart, and vascular endothelium convert Ang I to Ang II via ACE-independent pathways.^8,9 Initial investigations reported a rise in plasma renin activity after RAA system blockade, which appeared to be independent of the step in which the RAA system was blocked.¹⁰ Early clinical studies of patients treated with ACE inhibitors found Ang II levels were initially suppressed, but later returned to baseline concentrations despite continued therapy.¹¹

The reactive rise in plasma renin activity, plasma renin concentrations, and Ang II levels may explain why therapy with available RAA system inhibitors is sometimes suboptimal. The escape phenomenon has been proved responsible for deteriorated blood pressure control in patients with hypertension and for poor prognosis in patients with congestive heart failure treated with RAA system-modifying agents.^12,13 Although the hemodynamic effects of the escape phenomenon are related to increased Ang II levels, increased plasma renin concentrations and plasma renin activity may be equally important. Renin may have a direct vasculotoxic effect, and its pretreatment levels have been linked to an increased risk for myocardial infarction in hypertensive patients and in microvascular complications in diabetic patients.^14,15

The incomplete blockade of the RAA system by available agents sparked the investigation of higher doses of individual drugs,^16,17 multiple daily dosing of drugs,¹² and the combined administration of several RAA system agents, each of which acts at a different step,¹⁸ as a means to counteract the escape phenomenon. In contrast to ACE inhibitors, AT1Rs are able to block the effects of Ang II generated by both ACE-dependent and ACE-independent pathways; thus, combination therapy minimizes the escape seen with single-site RAA system agents.¹⁹ Clinical studies have shown that the addition of an AT1R antagonist to an ACE inhibitor—based treatment can improve morbidity and mortality in patients with heart failure.^19,20 Moreover, combinations of AT1R antagonists and ACE inhibitors have been shown to slow progression of diabetic and nondiabetic kidney disease beyond that achieved with monotherapy.²¹ Based on these and other findings, the magnitude of blockade of the RAA system appears to play a role in the clinical benefits derived from their administration. The ability to interrupt the RAA system at its rate-limiting step with a direct renin inhibitor offers an attractive therapeutic option for chronic cardiovascular and renal diseases.

Aliskiren: The first commercially available renin inhibitor

Aliskiren (Tekturna) is the first of a new class of nonpeptide direct renin inhibitors developed with the aid of x-ray crystallographic analysis and molecular modeling of renin-inhibitor complexes.²² It is the first renin inhibitor to be approved by the FDA for the treatment of hypertension. Aliskiren is a highly selective, competitive inhibitor with a high specificity for the renin active site. Marked specificity reduces the likelihood for significant drug interactions and medication side effects. A high bioavailability and plasma half-life of 20 to 45 hours permits once-daily administration. Following oral administration, peak plasma concentration is reached 1 to 3 hours after ingestion, and steady-state blood levels are achieved 5 to 8 days after therapy initiation.

Aliskiren is metabolized via the CYP3A4 mechanism; however, multiple studies failed to demonstrate significant up- or down-regulation of the CYP system. No significant drug interactions have been noted between aliskiren and commonly used medications.

Direct renin inhibition and hypertension treatment

The ability of aliskiren to inhibit plasma renin activity, suppress production of Ang I and Ang II, and decrease plasma and urinary aldosterone secretions led investigators to initiate clinical studies as therapy for hypertension. Numerous clinical trials have evaluated aliskiren, as monotherapy or combined with other agents, for the treatment of hypertension. Dahlöf and associates reported a pooled analysis of 8481 patients who participated in double-blind, placebo-controlled clinical trials comparing the effects of 150 mg and 300 mg dosages of aliskiren monotherapy with placebo for 8 to 12 weeks.²³ Statistically significant reductions in systolic and diastolic blood pressures were achieved compared with placebo. The aliskiren arms tolerated treatment well, and reported side effects were comparable to those observed with placebo.^23-25

Aliskiren has been compared with many commonly prescribed antihypertensive agents, including RAA system—modifying agents, hydrochlorothiazide (HCTZ), and dihydropyridine calcium channel blockers. In a double-blind, placebo-controlled trial of hypertensive patients, Villamil and colleagues reported the antihypertensive effects of aliskiren compared with HCTZ, the combination of aliskiren with HCTZ, and placebo.²⁶ Aliskiren monotherapy had a blood pressure—lowering effect similar to HCTZ monotherapy. The combination arm demonstrated a synergistic lowering of blood pressure as compared with the monotherapy group. In addition, the renin inhibition achieved with aliskiren neutralized the observed compensatory rise in plasma renin activity induced by HCTZ therapy.^27,28 In obese hypertensive subjects, aliskiren in combination with HCTZ was shown to be as effective as irbesartan (Avapro) with HCTZ in lowering blood pressure in patients who failed to respond to HCTZ monotherapy.

²⁷

The ability to block the rate-limiting step of the RAA system with aliskiren in combination with other RAA system blockers has been proposed as the ideal combination to markedly reduce the contribution of the RAA system to systemic hypertension and its target-organ sequelae. The combination of aliskiren with ramipril (Altace) was studied in 837 patients with diabetes and hypertension. The blood pressure reduction observed with the combination was statistically greater than with either agent alone. As with HCTZ, the addition of aliskiren to ramipril blocked the rise in plasma renin activity seen with ramipril monotherapy.²⁵ In trials comparing aliskiren with various AT1R blockers, aliskiren compared favorably in terms of blood pressure reductions, side effects, and safety.^29-32 Additionally, rebound hypertension after withdrawal of aliskiren therapy has not been observed.^33,34

There has been only 1 double-blind, controlled clinical trial of aliskiren in patients over the age of 65 years. In this study by Verdecchia and associates, aliskiren monotherapy was compared with lisinopril (Prinivil) in 355 patients, and similar blood pressure reduction was noted in both groups.³⁵ The aliskiren group experienced no dose-related side effects and no instances of drug-drug interactions.

Extrapolating from the available data, researchers have written extensively about aliskiren’s theoretical benefits for preventing target-organ damage independent of its blood pressure—lowering effects. Several large clinical trials are either planned or under way to test its effectiveness for conditions such as chronic heart failure, left ventricular hypertrophy, and chronic renal insufficiency.

Conclusions

In patients with significant polypharmacy and multiple comorbid conditions, such as the elderly, direct renin inhibition with aliskiren alone or in combination with other medications appears to be a safe and effective option for treating hypertension. Aliskiren also holds promise for treating heart failure and chronic renal insufficiency in patients who are intolerant to other RAA system agents. It also provides another therapeutic option for patients in whom other medications have intolerable side effects or where additional medications are required to maintain blood pressure control.

Presumably, elderly patients will continue to derive morbidity and mortality benefits from blood pressure control alone, as noted with other classes of antihypertensives.¹ Since there is only 1 randomized trial examining the efficacy of aliskiren in elderly patients,³⁵ it is difficult to draw any broad conclusions about its safety and efficacy in this population. Nevertheless, based on the available data, aliskiren appears to be safe and effective for managing hypertension in the elderly. Additionally, while the potential class benefits of renin inhibitors in cases of end organ disease are enticing, there is currently no objective evidence by controlled trials demonstrating a reduction of morbidity and mortality attributable to their use.

Use of this new medication class should be tempered by the current lack of evidence demonstrating health benefits; the costs compared with other, equally effective medications; and concerns for long-term deleterious effects of direct renin inhibition, especially in patients with hyperreactive renin systems.³⁶ Until randomized clinical trials demonstrate superiority to other medications, it seems prudent to continue with the current treatment guidelines and use renin inhibitors in patients with refractory disease requiring additional medical therapy or in those who are intolerant to other medications.

Disclosure

The authors have no relationship with any commercial entity that might represent a conflict of interest with the content of this article.