ATLAS Clinical Trial Commentary 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

Dosage of enalapril for congestive heart failure in the USA <5<5 ? Mean daily dose in CONSENSUS I18.4 mg V-HeFT II15.0 mg SOLVD16.6 mg Daily dose in mg FDA March 1992

ATLAS Objective 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)

ATLAS Patient 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

Study design Years Weeks mg mg mg mg mg mg Randomize 3178 pts (88%) on ACE-i 405 pts (12%) ACE-i naive

ATLAS Time to death from any cause for patients in each treatment group Treatment group Low dose lisinopril High dose lisinopril

ATLAS Death or hospitalization for any reason Odds Low doseHigh doseratiop Value Morbidity+ 1338/ / p=0.002 mortality (83.8%)(79.7%)( )

ATLAS Adverse reactions Low doseHigh dose Dizziness12%19% Hypotension7%11% Worsening renal function7%10% Cough13%11% Hyperkalemia4%6% Hypokalemia3%1%

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 ATLAS Adverse reactions

Conclusion When compared with low doses, the use of 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

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.

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

RALES Patient 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:

RALES Results Relative Placebo Spironolactoneriskp Value (n=841)(n=822) Mortality, p<0.001 deaths (%) (46%)(35%)( ) Early discontinuation after mean follow-up of 24 months Hospitalization 300/663260/ p<0.001 for heart failure* ( ) * no. of patients/no. of events Pitt B, et al. New Engl J Med 1999;341:

Drop-out rates 18% low dose 17% high dose worsening heart failure, common reason for drop-out Lisinopril titration strategy ACE naïve patients – 5 mg of lisinopril to start - build up to 12.5 – 15 mg for admission to trial - increased doses over months ATLAS Adverse 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 397High dose – ATLAS Adverse reaction s

- 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 Clinical pitfalls in the management of heart failure Adverse reactions