Jennifer V. Linseman

Divergent Results Using Clinic and Ambulatory Blood Pressures: Report of a Darusentan-Resistant Hypertension Trial

Patients with resistant hypertension are at increased risk for cardiovascular events. The addition of new treatments to existing therapies will help achieve blood pressure (BP) goals in more resistant hypertension patients. In the current trial, 849 patients with resistant hypertension receiving ≥3 antihypertensive drugs, including a diuretic, at optimized doses were randomized to the selective endothelin A receptor antagonist darusentan, placebo, or the central &agr;-2 agonist guanfacine. The coprimary end points of the study were changes from baseline to week 14 in trough, sitting systolic BP, and diastolic BP measured in the clinic. Decreases from baseline to week 14 in systolic BP for darusentan (−15±14 mm Hg) were greater than for guanfacine (−12±13 mm Hg; P<0.05) but not greater than placebo (−14±14 mm Hg). Darusentan, however, reduced mean 24-hour systolic BP (−9±12 mm Hg) more than placebo (−2±12 mm Hg) or guanfacine (−4±12 mm Hg) after 14 weeks of treatment (P<0.001 for each comparison). The most frequent adverse event associated with darusentan was fluid retention/edema at 28% versus 12% in each of the other groups. More patients withdrew because of adverse events on darusentan as compared with placebo or guanfacine. We conclude that darusentan provided greater reduction in systolic BP in resistant hypertension patients as assessed by ambulatory BP monitoring, in spite of not meeting its coprimary end points. The results of this trial highlight the importance of ambulatory BP monitoring in the design of hypertension clinical studies.

Effects of low-dose oral enoximone administration on mortality, morbidity, and exercise capacity in patients with advanced heart failure: the randomized, double-blind, placebo-controlled, parallel group ESSENTIAL trials.

Aims Use of inotropic agents in patients with heart failure (HF) has been limited by adverse effects on outcomes. However, administration of positive inotropes at lower doses and concomitant treatment with beta-blockers might increase benefit–risk ratio. We investigated the effects of low doses of the positive inotrope enoximone on symptoms, exercise capacity, and major clinical outcomes in patients with advanced HF who were also treated with beta-blockers and other guideline-recommended background therapy. Methods and results The Studies of Oral Enoximone Therapy in Advanced HF (ESSENTIAL) programme consisted of two identical, randomized, double-blind, placebo-controlled trials that differed only by geographic location (North and South America: ESSENTIAL-I; Europe: ESSENTIAL-II). Patients with New York Heart Association class III–IV HF symptoms, left ventricular ejection fraction ≤30%, and one hospitalization or two ambulatory visits for worsening HF in the previous year were eligible for participation in the trials. The trials had three co-primary endpoints: (i) the composite of time to all-cause mortality or cardiovascular hospitalization, analysed in the two ESSENTIAL trials combined; (ii) the 6 month change from baseline in the 6 min walk test distance (6MWTD); and (iii) the Patient Global Assessment (PGA) at 6 months, both analysed in each trial separately. ESSENTIAL-I and -II randomized 1854 subjects at 211 sites in 16 countries. In the combined trials, all-cause mortality and the composite, first co-primary endpoint did not differ between the two treatment groups [hazard ratio (HR) 0.97; 95% confidence interval (CI) 0.80–1.17; and HR 0.98; 95% CI 0.86–1.12, respectively, for enoximone vs. placebo]. The two other co-primary endpoints were analysed separately in the two ESSENTIAL trials, as prospectively designed in the protocol. The 6MWTD increased with enoximone, compared with placebo, in ESSENTIAL-I (P = 0.025, not reaching, however, the pre-specified criterion for statistical significance of P < 0.020), but not in ESSENTIAL-II. No difference in PGA was observed in either trial. Conclusion Although low-dose enoximone appears to be safe in patients with advanced HF, major clinical outcomes are not improved.

Efficacy and safety of darusentan in patients with resistant hypertension: results from a randomized, double-blind, placebo-controlled dose-ranging study.

In this phase 2, randomized, double‐blind, placebo‐controlled forced dose‐titration study, 115 patients with resistant hypertension, receiving background therapy with ≥3 antihypertensive medications including a diuretic at full doses, were randomized 2:1 to increasing doses of darusentan (10, 50, 100, 150, and 300 mg), a selective endothelin receptor antagonist, or matching placebo once daily for 10 weeks. Darusentan treatment decreased mean systolic and diastolic blood pressure levels in a dose‐dependent fashion compared with placebo; the largest reductions were observed at week 10 (300‐mg dose) (systolic, −11.5±3.1 mm Hg [P=.015]; diastolic, −6.3±2.0 mm Hg [P=.002]). Darusentan (300 mg) also decreased mean 24‐hour, daytime, and nighttime ambulatory blood pressures from baseline to week 10. Darusentan was generally well tolerated; mild to moderate edema and headache were the most common adverse events. This study demonstrates a clinical benefit from a new class of antihypertensive agent in patients classified as resistant by the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure guidelines.

Drug Therapy and Heart Failure Prevention

There are at least 5 million people in the United States living with chronic heart failure (CHF) today.1 Approximately 550 000 new cases of heart failure are identified in this country each year.1 In addition, there are tens of millions more people living with one or more risk factors for the development of heart failure, including coronary artery disease, hypertension, dyslipidemia, obesity, and diabetes, and these numbers are presently on the rise. Clinical research conducted over the last decade has focused primarily on enhancing treatment options for patients with known left ventricular (LV) dysfunction, with or without heart failure symptoms. Thanks to the treatments identified by such studies as Studies of Left Ventricular Dysfunction (SOLVD),2 Randomized Aldactone Evaluation Study (RALES),3 The Cardiac Insufficiency Bisoprolol Study II (CIBIS II),4 Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure (MERIT-HF),5 Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS),6 and many others, the risk of morbidity and mortality after heart failure diagnosis has been substantially lowered, provided that patients with CHF are actually treated with inhibitors of the renin-angiotensin-aldosterone system and -blockers. In contrast, very little is known about what interventions can be utilized to improve and/or prolong the lives of the much larger and broader group of patients mentioned above, who are at risk of developing left ventricular dysfunction and CHF. Aside from appropriately treating prevailing conditions, what else, if anything, can be done to impact the future health status of these at-risk patients?

Darusentan treatment significantly decreases blood pressure and results in better systolic blood pressure control when added to multi-drug therapy in patients with resistant hypertension

Darusentan treatment significantly decreases blood pressure and results in better systolic blood pressure control when added to multi-drug therapy in patients with resistant hypertension

Inhibition of endothelin-1 with darusentan: a novel antihypertensive approach for the treatment of resistant hypertension

Darusentan is an ETA-selective endothelin receptor antagonist that is currently in Phase III clinical development for the treatment of resistant hypertension (RHTN). Current hypertension treatment guidelines describe RHTN as the failure to achieve goal blood pressure despite treatment with full or adequate doses of an appropriate three-drug regimen that includes a diuretic. The exact prevalence of RHTN in the hypertensive community is unknown; however, recent clinical trials suggest that as many as a third of enrolled subjects may demonstrate treatment resistance. While the mechanisms responsible for the development of RHTN are also unknown, one of the few vasoconstrictive signaling pathways that remain unopposed, even in the presence of aggressive treatment with currently available antihypertensive agents, is the endothelin pathway. The efficacy and safety of darusentan, added on to full-dose background therapy including three or more medications, has recently been demonstrated in a randomized, placebo-c...