Abstract
Background Endothelin-receptor blockade provides haemodynamic benefit in experimental and clinical heart failure. We aimed to measure the effects of long-term endothelin-blockade on left-ventricular (LV) remodelling and clinical outcomes in patients with chronic heart failure. Methods 642 patients with chronic heart failure were assigned the oral endothelin A-antagonist darusentan at 10, 25, 50, 100, or 300 mg daily or placebo for 24 weeks in addition to standard therapy in a randomised, double-blind, placebo-controlled trial. In the 50-300 mg groups, darusentan was uptitrated over 6 weeks. Primary endpoint was change in LV end-systolic volume (LVESV) at 24 weeks from baseline, measured by MRI. All patients for whom assessable MRI scans were available at baseline and follow-up were included in the analysis. Findings Darusentan was well tolerated. LVESV could be assessed in 485 (76%) patients with paired MRI data at baseline and 6 months. The change in LVESV was not significantly different from that with placebo at any dose (mean difference from placebo 1·27 mL [95% CI -9·9 to 12·4] with 10 mg dose, -1·84 mL [-13·0 to 9·3] with 25 mg, -5·68 mL [-16·9 to 5·6] with 50 mg, -4·05 mL [-15·5 to 7·4] with 100 mg, and -4·34 mL [-15·7 to 7·0] with 300 mg). Heart failure worsened in 71 (11·1%) patients, and 30 (4·7%) died during the study with no difference between groups. Interpretation Endothelin A blockade with darusentan did not improve cardiac remodelling or clinical symptoms or outcomes in patients with chronic heart failure receiving an angiotensin-converting-enzyme inhibitor, β blocker, or aldosterone antagonist. Thus, endothelin A blockade is unlikely to be useful as an add-on treatment in such patients.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 347-354 |
| Number of pages | 8 |
| Journal | Lancet |
| Volume | 364 |
| Issue number | 9431 |
| DOIs | |
| State | Published - Jul 24 2004 |
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Long-term effects of darusentan on left-ventricular remodelling and clinical outcomes in the Endothelin A Receptor Antagonist Trial in Heart Failure (EARTH) : Randomised, double-blind, placebo-controlled trial. / Anand, Prof Inder; McMurray, Prof John; Cohn, Prof Jay N.; Konstam, Prof Marvin A.; Notter, Thomas; Quitzau, Kurt; Ruschitzka, Frank; Lüscher, Prof Thomas F.
In: Lancet, Vol. 364, No. 9431, 24.07.2004, p. 347-354.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Long-term effects of darusentan on left-ventricular remodelling and clinical outcomes in the Endothelin A Receptor Antagonist Trial in Heart Failure (EARTH)
T2 - Randomised, double-blind, placebo-controlled trial
AU - Anand, Prof Inder
AU - McMurray, Prof John
AU - Cohn, Prof Jay N.
AU - Konstam, Prof Marvin A.
AU - Notter, Thomas
AU - Quitzau, Kurt
AU - Ruschitzka, Frank
AU - Lüscher, Prof Thomas F.
PY - 2004/7/24
Y1 - 2004/7/24
N2 - Background Endothelin-receptor blockade provides haemodynamic benefit in experimental and clinical heart failure. We aimed to measure the effects of long-term endothelin-blockade on left-ventricular (LV) remodelling and clinical outcomes in patients with chronic heart failure. Methods 642 patients with chronic heart failure were assigned the oral endothelin A-antagonist darusentan at 10, 25, 50, 100, or 300 mg daily or placebo for 24 weeks in addition to standard therapy in a randomised, double-blind, placebo-controlled trial. In the 50-300 mg groups, darusentan was uptitrated over 6 weeks. Primary endpoint was change in LV end-systolic volume (LVESV) at 24 weeks from baseline, measured by MRI. All patients for whom assessable MRI scans were available at baseline and follow-up were included in the analysis. Findings Darusentan was well tolerated. LVESV could be assessed in 485 (76%) patients with paired MRI data at baseline and 6 months. The change in LVESV was not significantly different from that with placebo at any dose (mean difference from placebo 1·27 mL [95% CI -9·9 to 12·4] with 10 mg dose, -1·84 mL [-13·0 to 9·3] with 25 mg, -5·68 mL [-16·9 to 5·6] with 50 mg, -4·05 mL [-15·5 to 7·4] with 100 mg, and -4·34 mL [-15·7 to 7·0] with 300 mg). Heart failure worsened in 71 (11·1%) patients, and 30 (4·7%) died during the study with no difference between groups. Interpretation Endothelin A blockade with darusentan did not improve cardiac remodelling or clinical symptoms or outcomes in patients with chronic heart failure receiving an angiotensin-converting-enzyme inhibitor, β blocker, or aldosterone antagonist. Thus, endothelin A blockade is unlikely to be useful as an add-on treatment in such patients.
AB - Background Endothelin-receptor blockade provides haemodynamic benefit in experimental and clinical heart failure. We aimed to measure the effects of long-term endothelin-blockade on left-ventricular (LV) remodelling and clinical outcomes in patients with chronic heart failure. Methods 642 patients with chronic heart failure were assigned the oral endothelin A-antagonist darusentan at 10, 25, 50, 100, or 300 mg daily or placebo for 24 weeks in addition to standard therapy in a randomised, double-blind, placebo-controlled trial. In the 50-300 mg groups, darusentan was uptitrated over 6 weeks. Primary endpoint was change in LV end-systolic volume (LVESV) at 24 weeks from baseline, measured by MRI. All patients for whom assessable MRI scans were available at baseline and follow-up were included in the analysis. Findings Darusentan was well tolerated. LVESV could be assessed in 485 (76%) patients with paired MRI data at baseline and 6 months. The change in LVESV was not significantly different from that with placebo at any dose (mean difference from placebo 1·27 mL [95% CI -9·9 to 12·4] with 10 mg dose, -1·84 mL [-13·0 to 9·3] with 25 mg, -5·68 mL [-16·9 to 5·6] with 50 mg, -4·05 mL [-15·5 to 7·4] with 100 mg, and -4·34 mL [-15·7 to 7·0] with 300 mg). Heart failure worsened in 71 (11·1%) patients, and 30 (4·7%) died during the study with no difference between groups. Interpretation Endothelin A blockade with darusentan did not improve cardiac remodelling or clinical symptoms or outcomes in patients with chronic heart failure receiving an angiotensin-converting-enzyme inhibitor, β blocker, or aldosterone antagonist. Thus, endothelin A blockade is unlikely to be useful as an add-on treatment in such patients.
UR - http://www.scopus.com/inward/record.url?scp=3242810591&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=3242810591&partnerID=8YFLogxK
U2 - 10.1016/S0140-6736(04)16723-8
DO - 10.1016/S0140-6736(04)16723-8
M3 - Article
C2 - 15276394
AN - SCOPUS:3242810591
VL - 364
SP - 347
EP - 354
JO - The Lancet
JF - The Lancet
SN - 0140-6736
IS - 9431
ER -