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Clinical Trial Commentary

Clinical Trial Commentary. ATLAS. Dr Eric Topol Chairman and Professor, Department of Cardiology Director of the Joseph J Jacobs Center for Thrombosis and Vascular Biology at the Cleveland Clinic Dr Robert Califf Professor of Cardiology Associate Vice Chancellor for

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Clinical Trial Commentary

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  1. Clinical Trial Commentary ATLAS Dr Eric Topol Chairman and Professor, Department of Cardiology Director of the Joseph J Jacobs Center for Thrombosis and Vascular Biology at the Cleveland Clinic Dr Robert Califf Professor of Cardiology Associate Vice Chancellor for Clinical Research at Duke University

  2. Dosage of enalapril for congestive heart failure in the USA Daily dose in mg Mean daily dose in CONSENSUS I 18.4 mgV-HeFT II 15.0 mgSOLVD 16.6 mg 30-40 15-20 7.5-10 <5 ? FDA March 1992

  3. ATLASObjective • To compare the effects of low doses and high doses of ACE inhibitors on the risk of death and the risk of major events in chronic heart failure • low-dose lisinopril (2.5 – 5.0 mg daily) • high-dose lisinopril (32.5 – 35.0 mg daily)

  4. ATLASPatient population (n=3164) • Inclusion criteria • class II, III and IV heart failure • if class II, hospitalization for CHF within 6 months • LV ejection fraction < 30% • receiving digitalis & diuretics ± ACE inhibitor • Exclusion criteria • recent MI, unstable angina or revascularization • history of sustained VT • IV positive inotropic drugs within 48 hours

  5. Study design 32.5 - 35 mg 22.5- 25 mg 12.5-15 mg 3178 pts (88%)on ACE-i 12.5- 15 mg 2.5- 5 mg 405 pts (12%)ACE-i naive 2.5 - 5 mg 0 2 4 6 3.0 - 4.5 Years Weeks Randomize

  6. ATLASTime to death from any cause for patients in each treatment group Treatment group Low dose lisinopril High dose lisinopril

  7. ATLASDeath or hospitalizationfor any reason • Odds • Low dose High dose ratio p Value • Morbidity+ 1338/1596 1250/1568 0.88 p=0.002 • mortality (83.8%) (79.7%) (0.82-0.96)

  8. ATLASAdverse reactions • Low dose High dose • Dizziness 12% 19% • Hypotension 7% 11% • Worsening renal function 7% 10% • Cough 13% 11% • Hyperkalemia 4% 6% • Hypokalemia 3% 1%

  9. ATLASAdverse reactions • Results of ATLAS • 8% reduction in risk of death • 15% reduction in all-cause mortality + hospitalizations for heart failure • Results of SOLVD treatment trial • 16% reduction in risk of death • 26% reduction in all-cause mortality + hospitalizations for heart failure

  10. Conclusion • When compared with low doses, the useof high doses of lisinopril (up to 35 mg/day) is associated with a • 12% reduction in the risk of death and hospitalization for any cause • 24% reduction in the frequency of hospitalizations for heart failure • In the US, use of high doses instead of low doses would: • prevent 100,000 patients from being hospitalized or dying each year • prevent nearly 250,000 hospitalizations for CHF

  11. Outcome-based dose comparison • For most drugs, dose ranging is based on surrogate measures. • Occasionally, a single outcome-based trial is performed, usually at a single dose. • Multi-dose trials are often constructed with a strategy that doesn’t take both doses to completion.

  12. Ideal therapy for congestive heart failure Beta-blocker ACE inhibitor ? Digoxin Spironolactone

  13. RALESPatient population (n=1663) • Trial design • randomized double-blind study • 25 mg spironolactone QD vs placebo • Primary endpoint • death from all causes • Inclusion criteria • class II and III heart failure • diagnosis of heart failure > 6 weeks • on ACE inhibitor if tolerated • EF < 35% for at least 6 months • Exclusion criteria • life threatening comorbidity • operable, valvular or congenital heart disease • unstable angina Pitt B, et al. New Engl J Med 1999;341:709-717

  14. RALESResults • Relative • Placebo Spironolactone risk p Value (n=841) (n=822) • Mortality, 386 284 0.70 p<0.001 • deaths (%) (46%) (35%) (0.60-0.82) Hospitalization 300/663 260/515 0.65 p<0.001 for heart failure* (0.54-0.77) * no. of patients/no. of events Early discontinuation after mean follow-up of 24 months Pitt B, et al. New Engl J Med 1999;341:709-717

  15. ATLASAdverse reactions • Drop-out rates • 18% low dose • 17% high dose • worsening heart failure, common reason for drop-out • Lisinopril titration strategy • ACE naïve patients • - 2.5 – 5 mg of lisinopril to start • - build up to 12.5 – 15 mg for admission to trial • - increased doses over months

  16. ATLASAdverse reactions • Cost-effectiveness • incremental cost of additional hospitalizations in low dose group outweighs incremental cost of high dose • Hospitalizations for any reason • Low dose – 4 397 High dose – 3 819

  17. Clinical pitfalls in the management of heart failureAdverse reactions • - dose limiting ACE inhibitors because of cough, when this symptom is due to heart failure or infection • - withholding ACE inhibitors for a low blood pressure auscultated by Korotkoff sound in the absence of postural symptoms

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