High dose lisinopril was more effective than low dose for reducing combined mortality and cardiovascular events in congestive heart failure
Packer M, Poole-Wilson PA, Armstrong PW, et al, on behalf of the ATLAS Study Group. Comparative effects of low and high doses of the angiotensin.converting enzyme inhibitor, lisinopril, on morbidity and mortality in chronic heart failure. Circulation 1999 Dec 7;100:2312-8
QUESTION: In patients with congestive heart failure (CHF), is high dose lisinopril more effective than low dose lisinopril for reducing mortality and admission to hospital rates?
Design
Randomised (allocation concealment unclear), blinded (patients, investigators, and outcome assessors), controlled trial with three year follow up.
Setting
287 hospitals in 19 countries.
Patients
3793 patients were screened, and 3164 (mean age 63.6
years, 80% men) were studied. Inclusion criteria were
New York Heart Association class II, III, or IV CHF,
despite use of diuretics for ³ 2 months, and left ventricular ejection fraction <30%. Exclusion criteria were
recent revascularisation procedure or ischaemic event,
history of ventricular tachycardia, intolerance to
angiotensin converting enzyme (ACE) inhibitors, serum
creatinine levels > 2.5 mg/dl, or non.cardiac disorders
that could limit survival. Follow up was 100%.
Intervention
Patients received their usual CHF medications and were
allocated to lisinopril, 2.5 or 5.0 mg/day (n = 1596), or
30 mg/day (n = 1568).
Main outcome measures
All cause mortality. Secondary endpoints were cardiovascular (CV) mortality and five combined endpoints.
Main results
The groups did not differ for all cause mortality (42.5%
for high dose v 44.9% for low dose lisinopril, P = 0.13) or
CV mortality (37.2% v 40.2%, P = 0.07). Patients in the
high dose group had lower rates of all cause mortality
combined with all cause admissions to hospital
(P = 0.002), CV admissions to hospital (P = 0.04), or CHF
admissions to hospital (P < 0.001) and lower rates of CV
mortality plus CV admissions to hospital (P = 0.03)
(table) than did patients in the low dose lisinopril group.
Conclusion
High dose lisinopril was more effective than low dose
lisinopril for reducing the combined endpoints of all
cause mortality combined with either all admissions to
hospital, CV admissions to hospital, or CHF admissions
to hospital and CV mortality plus CV admissions to hos.
pital for patients with CHF.
High dose v low dose lisinopril for congestive heart failure (CHF)
COMMENTARY
Large randomised controlled trials (RCTs) have shown that
high dose ACE inhibitors are generally safe in CHF. Many
clinicians remain concerned, however, about safety issues
and resort to the use of low dose ACE inhibitors. The
Assessment of Treatment with Lisinopril and Survival
(ATLAS) trial is the largest RCT comparing a high dose and
low dose ACE inhibitor in CHF. The results show a trend
toward decreased mortality and a modest reduction in
combined endpoints that include admission to hospital and
mortality. This finding is somewhat surprising because a
larger benefit with high dose ACE inhibitors was
anticipated. The only other RCT that evaluated a low dose
and high dose ACE inhibitor strategy in CHF was too small
and too short to provide clear answers.1 Although the
benefits in the ATLAS study seem relatively modest,
morbidity that includes admission to hospital is a major
consideration in CHF, both from the patient's and the
clinician's perspective.
How are clinicians to interpret the results of the ATLAS
trial? Firstly, the use of ACE inhibitors is well established as
firstline treatment in CHF, and every patient with clinical
manifestations or with asymptomatic left ventricular systolic
dysfunction should be considered for ACE inhibitor
treatment. Treatment should be initiated with caution, however, especially in elderly patients and in those with renal
dysfunction or low blood pressure. Patients should be
followed with careful and gradual increases in dose. If the
drug is tolerated, an attempt should be made to maximise
the ACE inhibitor dose. If side effects develop, however,
maintaining patients on a low or intermediate dose is far
better than withdrawing treatment.
In addition, as suggested by the ATLAS study and many
previous investigations, such symptoms as cough, hypoten.
sion, dizziness, and renal dysfunction are not always related
to ACE inhibitor use and may be caused by CHF, concomi.
tant illnesses, or other medications. Permanent withdrawal of
ACE inhibitors should be a last resort and considered only
in patients who clearly cannot tolerate this lifesaving
intervention.
Eva Lonn, Hamilton General Hospital McMaster Clinic, Hamilton, Ontario, Canada
- The NETWORK Investigators. Clinical outcome with enalapril in symptomatic chronic heart failure: a dose comparison. Eur Heart J 1998;19:481-9.
studentBMJ 2000;08:395-434 November ISSN 0966-6494
