Acetylsalicylic acid reduces niacin extended-release-induced flushing in patients with dyslipidemia.

BACKGROUND: Niacin extended-release (NER) is safe and effective for treatment of dyslipidemia. However, some patients discontinue NER treatment because of flushing, the most common adverse event associated with niacin therapy. OBJECTIVE: To evaluate the effect of daily oral acetylsalicylic acid (ASA) on NER-induced flushing in patients with dyslipidemia. METHODS: A randomized, double-blind, placebo-controlled, multicenter, 5-week study was conducted (ClinicalTrials.gov identifier: NCT00626392). Patients (n = 277) were randomly assigned to one of six treatment arms and received a 1-week run-in with ASA 325 mg or placebo followed by 4 weeks of ASA 325 mg or placebo 30 minutes before NER at a starting dose of 500 mg or 1000 mg; all patients were titrated to NER 2000 mg at week 3. The primary endpoint was the maximum severity of flushing events during week 1. RESULTS: In week 1, ASA run-in, ASA pretreatment, and a lower starting dosage of NER (500 mg/day) resulted in reductions in mean maximum severity of flushing; 48% fewer patients who received ASA experienced flushing episodes of moderate or greater intensity relative to placebo (absolute rates 15% vs 29%; p = 0.01). Over 4 weeks, ASA reduced the number of flushing episodes/patient/week by 42% relative to placebo. The discontinuation rate due to flushing was lower in the ASA group compared with placebo (1.8% vs 9.4%; p = 0.007). Overall safety was not different between groups. CONCLUSION: These data suggest that a clinically meaningful reduction in the severity and incidence of NER-induced flushing may be achieved with ASA use.

Effects of eplerenone versus losartan in patients with low-renin hypertension.

BACKGROUND: Sodium retention and volume expansion, mediated in part by aldosterone, are prominent features in low-renin hypertension. Agents that block aldosterone at its receptor sites, therefore, should have significant clinical benefit in patients with low-renin hypertension. METHODS: This 16-week, multicenter, double-blind, active-controlled, parallel-group, titration-to-effect trial compared the blood pressure and neurohumoral responses of the selective aldosterone blocker eplerenone (100-200 mg/d; n = 86) with those of the angiotensin receptor blocker losartan (50-100 mg/d; n = 82) in patients with low-renin hypertension (active renin < or = 25 pg/mL [< or = 42.5 mU/L]). Patients with diastolic blood pressure > or = 90 mm Hg after 8 weeks of monotherapy received add-on therapy with hydrochlorothiazide 12.5 to 25 mg daily. RESULTS: After 8 weeks of therapy, eplerenone reduced blood pressure to a greater extent than losartan (systolic blood pressure -15.8 vs -10.1 mm Hg, P = .017; diastolic blood pressure -9.3 vs -6.7 mm Hg, P = .05). After 16 weeks of therapy, significantly fewer eplerenone-treated patients (32.5%) than losartan-treated patients (55.6%) required add-on hydrochlorothiazide as allowed per protocol for blood pressure control (P = .003). Eplerenone consistently reduced blood pressure regardless of baseline active plasma renin levels whereas losartan reduced blood pressure more effectively in patients with higher baseline active renin levels. There were no differences between treatments in adverse events (reported by 62.8% of eplerenone patients and by 72.0% of losartan patients). CONCLUSIONS: These data show that eplerenone was more effective than losartan in reducing blood pressure in patients with low-renin hypertension. Further studies evaluating the efficacy of eplerenone in difficult-to-treat or resistant hypertension are needed.

Efficacy of eplerenone versus enalapril as monotherapy in systemic hypertension.

This study compared the efficacy and tolerability of eplerenone and enalapril in 499 patients with stage 1 or 2 hypertension who were randomized to receive eplerenone or enalapril for 6 months in a 3-step titration-to-effect study. After 6 months, patients whose diastolic blood pressure (BP) was <90 mm Hg had their dosages down-titrated were followed for an additional 6 months. Diastolic BP was the primary end point. Eplerenone was as effective as enalapril in reducing both systolic BP (eplerenone, -14.5 mm Hg; enalapril, -12.7 mm Hg; p = 0.199) and diastolic BP (eplerenone, -11.2 mm Hg; enalapril, -11.3 mm Hg; p = 0.910) at 6 months. BP reductions at 12 months were also similar between groups (-16.5/-13.3 mm Hg for eplerenone, -14.8/-14.1 mm Hg for enalapril; p = 0.251 and 0.331, respectively). Withdrawal rates for adverse events (eplerenone 7.9%, enalapril 9.3% at 6 months) and treatment failures (eplerenone 23.3%, enalapril 22.8% at 6 months) were also equivalent. Approximately 2/3 of each group had normal BP with monotherapy treatment at 6 months. BP response was independent of renin levels in the eplerenone group, but not in the enalapril group. Both agents reduced albuminuria in patients who had an elevated value at baseline, with significantly greater improvement in patients treated with eplerenone versus enalapril (-61.5% vs -25.7%; p = 0.01). Both agents were similarly well tolerated, and there was no increased incidence of any sexual adverse events in the eplerenone group. Patients taking enalapril had a higher rate of cough. Both agents increased serum potassium levels, but <1% in each group reported adverse events from hyperkalemia. Eplerenone was as effective as enalapril as monotherapy in patients with stage 1 or 2 hypertension, was more effective in reducing albuminuria, and was well tolerated for 12 months.

Can renin status predict the antihypertensive efficacy of eplerenone add-on therapy?

Since neither angiotensin-converting enzyme inhibitors (ACE-I) nor angiotensin II receptor blockers (ARB) can completely suppress aldosterone levels, there is a need for alternative/supplementary antihypertensive medications, such as the selective aldosterone blocker eplerenone (Inspra). This multicenter study measured the safety and efficacy of add-on eplerenone therapy to reduce blood pressure not controlled by ACE-I or ARB monotherapy. An ad hoc analysis evaluated whether active plasma renin or serum aldosterone levels could predict blood pressure response to eplerenone therapy. Patients (N = 341) with a diastolic blood pressure > 95 mmHg on a fixed dose of ACE-I or ARB were randomized to 8 weeks of double-blind treatment with eplerenone 50 mg qd or placebo. If blood pressure remained uncontrolled following 2, 4, or 6 weeks of treatment, the eplerenone dose was increased to 100 mg qd. In a combined cohort analysis of these patients, the placebo-adjusted change in systolic and diastolic blood pressure was -5.9/-2.4 mmHg (p< 0.001 and p = 0.006, respectively). While adding eplerenone to an ACE-I or ARB is safe and effective for blood pressure reduction, there was no baseline value or range of values of active plasma renin, serum aldosterone, or their ratio that predicted a favorable response to either of these drug combinations.

Symptoms and the distress they cause: comparison of an aldosterone antagonist and a calcium channel blocking agent in patients with systolic hypertension.

BACKGROUND: Although there has been increasing recognition that a substantial part of the cardiovascular, central nervous system, and renal conditions induced by renin-angiotensin-aldosterone system activation reflects an action of aldosterone, the potential influence of therapy designed to block aldosterone has been limited by the fact that spironolactone (until recently the only aldosterone antagonist available) exerts a substantial array of adverse effects. We sought to compare the magnitude of the distress induced by a widely used calcium channel blocking agent, amlodipine, and a new aldosterone antagonist, eplerenone, in patients treated for systolic hypertension. METHODS: A total of 269 patients older than 50 years with systolic hypertension were randomized to either eplerenone, 50 mg/d, or amlodipine, 2.5 mg/d, and titrated to a maximum 200-mg eplerenone dose or 10-mg amlodipine dose. Patients were followed up for 24 weeks. Quality-of-life questionnaires (SF-36 Health Survey) and a validated instrument for assessing symptom distress (Symptom Distress Index) were administered at randomization and 24 weeks after starting treatment. RESULTS: The systolic blood pressure response to eplerenone and amlodipine did not differ (eplerenone = -20.5 mm Hg and amlodipine = -20.1 mm Hg). For the quality-of-life analysis, 119 patients were randomized to eplerenone and 122 to amlodipine. No significant treatment group differences in the Symptom Distress Index were detected at baseline. There was an overall significant treatment effect on symptom distress in favor of eplerenone (P =.03). Indeed, Symptom Distress Index showed significant worsening distress in 36 of 71 symptoms in the amlodipine arm and none in the eplerenone arm. Significant treatment effect in favor of eplerenone was observed in 5 symptoms: ankle swelling, weight gain, nocturia, increased urination, and shortness of breath. Patients with symptom distress also showed an erosion of psychosocial measures of quality of life (P<.001). CONCLUSIONS: The aldosterone antagonist eplerenone is substantially better tolerated than the widely used calcium-channel blocking agent amlodipine, with comparable reductions in systolic blood pressure. This feature should improve therapeutics in patients in whom blockade of aldosterone's effect would be helpful.

Efficacy and tolerability of eplerenone and losartan in hypertensive black and white patients.

OBJECTIVES: The purpose of this study was to evaluate the efficacy and tolerability of monotherapy with the selective aldosterone blocker eplerenone in both black and white patients with hypertension. BACKGROUND: Essential hypertension and cardiovascular-renal-target organ damage is more prevalent in black than white adults in the U.S. METHODS: Black (n = 348) and white (n = 203) patients with mild-to-moderate hypertension were randomized to double-blind treatment with eplerenone 50 mg, the angiotensin II receptor antagonist losartan 50 mg, or placebo once daily. Doses were increased if blood pressure remained uncontrolled. The primary end point was change in mean diastolic blood pressure (DBP) after 16 weeks of therapy. RESULTS: Adjusted mean changes from baseline in DBP were -5.3 +/- 0.7, -10.3 +/- 0.7, and -6.9 +/- 0.6 mm Hg in the placebo, eplerenone-treated, and losartan-treated groups, respectively (mean +/- SE, p < 0.001 eplerenone vs. placebo, p < 0.001 eplerenone vs. losartan). In black patients, DBP decreased by -4.8 +/- 1.0, -10.2 +/- 0.9, and -6.0 +/- 0.9 mm Hg for the placebo, eplerenone-treated, and losartan-treated groups, respectively (mean +/- SE, p < 0.001 eplerenone vs. placebo, p < 0.001 eplerenone vs. losartan), whereas in white patients, DBP decreased by -6.4 +/- 1.0, -11.1 +/- 1.1, and -8.4 +/- 1.0 mm Hg, respectively (p = 0.001 eplerenone vs. placebo, p = 0.068 for eplerenone vs. losartan). For reduction of systolic blood pressure (SBP), eplerenone was superior to placebo and losartan in all patients combined and in black patients, and was superior to placebo in white patients. Eplerenone was as effective as losartan in reducing SBP and DBP in the high renin patient, but more effective than losartan in the low renin patient. Similarly, eplerenone was at least as effective as losartan in patients with differing baseline levels of aldosterone. Both eplerenone and losartan were well tolerated. CONCLUSIONS: The antihypertensive effect of eplerenone was equal in black and white patients and was superior to losartan in black patients.

Eplerenone, a selective aldosterone blocker, in mild-to-moderate hypertension.

BACKGROUND: Eplerenone, a selective aldosterone blocker (SAB) that is highly specific for the aldosterone receptor, has the potential to be efficacious in the treatment of hypertension. METHODS: This 8-week, multicenter, double-blind, placebo-controlled trial assessed the efficacy, safety, and tolerability of eplerenone in eligible patients randomized to eplerenone 50, 100, or 400 mg once daily; eplerenone 25, 50, or 200 mg twice daily; spironolactone 50 mg twice daily; or placebo. The primary efficacy variable was the adjusted mean change in baseline to final visit for seated diastolic blood pressure (DBP). RESULTS: Of 417 randomized patients, 409 were evaluated for efficacy. The adjusted mean change from baseline to final visit in seated and standing systolic blood pressure (SBP) and DBP was significantly greater (P < .05) in all eplerenone groups than in the placebo group. The adjusted mean change in 24-h ambulatory blood pressure monitoring (ABPM) measurements of SBP and DBP also documented a 24-h duration significantly greater (P < .05) than placebo in eplerenone-treated patients. For all measurements, the antihypertensive effect of eplerenone increased in a dose-response fashion. Eplerenone (100 mg) reduced BP by 75% compared with spironolactone (100 mg) and had an adverse events incidence rate similar to placebo. No antiandrogenic or progestational effects or clinically relevant safety issues were observed in eplerenone-treated patients. However, one spironolactone-treated patient reported menstrual irregularities. CONCLUSIONS: Eplerenone doses of 50 to 400 mg once daily are well tolerated and effective in reducing BP in patients with mild-to-moderate hypertension during a 24-h period.