ATLAS

Clinical Trial Commentary

Dr Eric TopolChairman and Professor, Department of CardiologyDirector of the Joseph J Jacobs Center for Thrombosis and Vascular Biology at the Cleveland Clinic

Dr Robert CaliffProfessor of Cardiology Associate Vice Chancellor for Clinical Research at Duke University

Dosage of enalapril for congestive heart failure in the USA

0 10 20 30 40 50

Patients (%)

30-40

15-20

7.5-10

<5

?

Mean daily dose inCONSENSUS I 18.4 mgV-HeFT II 15.0 mgSOLVD 16.6 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)

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

Study design

0 2 4 6 3.0 - 4.5YearsWeeks

2.5-5 mg

12.5-15 mg

22.5-25 mg

32.5 - 35 mg

2.5 - 5 mg

12.5-15 mg

Randomize

3178 pts (88%)

on ACE-i

405 pts (12%)

ACE-i naive

ATLASTime to death from any cause for patients in each treatment group

Treatment group

Low dose lisinopril

High dose lisinopril

0

20

40

60

80

100

120

0 6 12 18 24 30 36 42 48 54

Time to Death (months)

Pe

rce

nt

su

rviv

al .

ATLASDeath or hospitalization

for any reason

OddsLow 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)

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%

Results of ATLAS

8% reduction in risk of death15% reduction in all-cause mortality +

hospitalizations for heart failure

Results of SOLVD treatment trial

16% reduction in risk of death26% reduction in all-cause mortality +

hospitalizations for heart failure

ATLASAdverse reactions

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

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

?

RALESPatient population (n=1663)

Trial designrandomized 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

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)

Early discontinuation after mean follow-up of 24 months

Hospitalization 300/663 260/515 0.65p<0.001 for heart failure* (0.54-0.77)

* no. of patients/no. of events

Pitt B, et al. New Engl J Med 1999;341:709-717

Drop-out rates18% low dose17% high doseworsening heart failure, common reason for drop-out

Lisinopril titration strategyACE 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

ATLASAdverse

reactions

Cost-effectivenessincremental 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

ATLASAdverse 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