Role of aldosterone blockade for resistant hypertension
It has been established that resistant hypertension is associated with increased CV morbidity and mortality. Resistant hypertension is defined as elevated BP remaining uncontrolled despite treatment with three or more optimally dosed antihypertensive agents, including a diuretic, or controlled BP requiring four or more medications. The exact prevalence of resistant hypertension is unknown; however, it is estimated to be present in 10% to 30% of hypertensive patients. Rates of resistant hypertension and, therefore, a rise in CV morbidity and mortality are likely to increase as the US population continues to age and the incidence of obesity continues to grow.
Aldosterone plays an important role in the development and severity of resistant hypertension. Upon activation by aldosterone, mineralocorticoid receptors promote inflammation, oxidative stress, fibrosis, insulin resistance and endothelial dysfunction. It is known that elevated aldosterone levels, obesity and insulin resistance contribute to salt retention, volume expansion, inflammation and oxidative stress, all of which can contribute to resistant hypertension and lead to CV remodeling.
Benefits of aldosterone blockade
Blockade of the renin-angiotensin-aldosterone system with an ACE inhibitor or angiotensin receptor blocker is often utilized in hypertensive patients, especially those with indications such as CVD and diabetes. Treatment with an ACE inhibitor or angiotensin receptor blocker may result in an early drop in aldosterone, which can be followed by a return to baseline or elevation of aldosterone, known as aldosterone breakthrough. Aldosterone breakthrough often results in worsened CV outcomes. It has been postulated that the addition of an aldosterone antagonist will block the aldosterone breakthrough effect.
Treatment with the aldosterone blockers spironolactone and eplerenone results in reduced vascular stiffness and diuresis, causing a decrease in BP. Reduction in vascular stiffness may yield a greater reduction in systolic BP vs. diastolic BP. One benefit of eplerenone over spironolactone is its high selectivity for the aldosterone receptor. This high selectivity results in fewer troublesome adverse effects when compared with spironolactone, mainly gynecomastia and breast pain.
Many small studies have shown that aldosterone receptor antagonists lower BP in patients with resistant hypertension. However, these studies had multiple confounding factors, making the results difficult to interpret, and none of the studies included a control group for comparison purposes. It should be noted that the maximal antihypertensive effect following treatment with an aldosterone blocker may take up to 7 weeks to occur, making adequate study follow-up important. Dose is also an important consideration; for spironolactone, doses greater than 50 mg daily do not provide additional BP lowering, but can result in greater adverse effects.
The BP-lowering arm of the ASCOT trial was one of the first large trials to evaluate the efficacy of aldosterone antagonism in resistant hypertension. Researchers evaluated a cohort of 1,411 patients enrolled in ASCOT who had resistant hypertension and were taking a mean of 2.9 antihypertensive medications. The addition of spironolactone 25 mg daily decreased systolic BP by 21.8 mm Hg and diastolic BP by 9.5 mm Hg. In subgroup analyses, the presence of metabolic syndrome, BMI, fasting plasma glucose, lipid panel and changes in body weight did not alter response to spironolactone. The most frequent adverse effects associated with spironolactone were gynecomastia/breast discomfort, which occurred in 6% of patients and resulted in discontinuation in 3% of patients (all men), and serious hyperkalemia (potassium >6 mmol/L) in 2% of patients. Limitations of this study include its observational design and lack of placebo control. In addition, patients assigned spironolactone had higher baseline systolic BP and were more likely to have left ventricular hypertrophy.
ASPIRANT was the first randomized trial to assess the effect of spironolactone in resistant hypertension. In this trial, 117 patients with resistant hypertension, treated with at least three antihypertensive agents, were randomly assigned spironolactone 25 mg daily or placebo for 8 weeks. Patients were taking a mean of 4.5 antihypertensive medications at the time of randomization. Spironolactone decreased systolic BP by 5.4 mm Hg; diastolic BP was not significantly decreased. In subgroup analyses, baseline aldosterone/renin ratio (ARR) predicted BP response. Patients with a baseline ARR >7 experienced a significant drop in both systolic BP (13 mm Hg-15 mm Hg) and diastolic BP (5 mm Hg-7 mm Hg), whereas those with ARR ≤7 experienced no significant drop in either systolic or diastolic BP. No patients experienced serious hyperkalemia. Although placebo controlled, this study is limited by the small sample size.
Eplerenone also was evaluated in an open-label study of patients with resistant hypertension. In this trial, 52 patients received eplerenone 50 mg daily with the option of dose increase to 50 mg twice daily. Patients were assigned a mean of 3.7 antihypertensive medications at baseline. BP was measured in clinic as well as with a 24-hour ambulatory monitor. Eplerenone decreased clinic- and ambulatory-monitored systolic BP by 17.6 mm Hg/7.9 mm Hg and diastolic BP by 12.2 mm Hg/6 mm Hg, respectively. No serious adverse events or deaths were reported. The most common adverse effect was dizziness, which occurred in 7.6% of patients. Tapering the antihypertensive doses or discontinuation of one of the original antihypertensive medications resolved this issue. Serum potassium rose by a mean of 0.3 mEq/L, with only two patients experiencing levels >5.5 mEq/L. Limitations of this study include its open-label design, small sample size and lack of placebo control.
Treatment initiation, monitoring
Aldosterone receptor antagonists have been shown to decrease BP in patients with resistant hypertension. However, little data are available regarding their effect of clinical outcomes.
Based on available data, aldosterone receptor antagonists such as spironolactone or eplerenone may be a beneficial adjunctive treatment for patients with resistant hypertension. Treatment can be initiated with either spironolactone 25 mg daily or eplerenone 50 mg daily. Potassium and creatinine should be monitored; however, in most patients studied, these agents were well tolerated. It may be possible to use baseline ARR to determine which patients are most likely to respond well to these agents.
Disclosure: Lusk reports no relevant financial disclosures.