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Toleration of High Doses of Angiotensin-Converting Enzyme Inhibitors in Patients With Chronic Heart Failure
Results From the ATLAS Trial
Barry M. Massie, MD;
Paul W. Armstrong, MD;
John G. F. Cleland, MD;
John D. Horowitz, MD;
Milton Packer, MD;
Philip A. Poole-Wilson, MD;
Lars Rydén, MD
Arch Intern Med. 2001;161:165-171.
ABSTRACT
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Background Treatment with angiotensin-converting enzyme (ACE) inhibitors reduces
mortality and morbidity in patients with chronic heart failure (CHF), but
most affected patients are not receiving these agents or are being treated
with doses lower than those found to be efficacious in trials, primarily because
of concerns about the safety and tolerability of these agents, especially
at the recommended doses. The present study examines the safety and tolerability
of high- compared with low-dose lisinopril in CHF.
Methods The Assessment of Lisinopril and Survival study was a multicenter, randomized,
double-blind trial in which patients with or without previous ACE inhibitor
treatment were stabilized receiving medium-dose lisinopril (12.5 or 15.0 mg
once daily [OD]) for 2 to 4 weeks and then randomized to high- (35.0 or 32.5
mg OD) or low-dose (5.0 or 2.5 mg OD) groups. Patients with New York Heart
Association classes II to IV CHF and left ventricular ejection fractions of
no greater than 0.30 (n = 3164) were randomized and followed up for a median
of 46 months. We examined the occurrence of adverse events and the need for
discontinuation and dose reduction during treatment, with a focus on hypotension
and renal dysfunction.
Results Of 405 patients not previously receiving an ACE inhibitor, doses in
only 4.2% could not be titrated to the medium doses required for randomization
because of symptoms possibly related to hypotension (2.0%) or because of renal
dysfunction or hyperkalemia (2.3%). Doses in more than 90% of randomized patients
in the high- and low-dose groups were titrated to their assigned target, and
the mean doses of blinded medication in both groups remained similar throughout
the study. Withdrawals occurred in 27.1% of the high- and 30.7% of the low-dose
groups. Subgroups presumed to be at higher risk for ACE inhibitor intolerance
(blood pressure, <120 mm Hg; creatinine,  132.6 µmol/L [1.5
mg/dL]; age, 70 years; and patients with diabetes) generally tolerated
the high-dose strategy.
Conclusions These findings demonstrate that ACE inhibitor therapy in most patients
with CHF can be successfully titrated to and maintained at high doses, and
that more aggressive use of these agents is warranted.
INTRODUCTION
DURING THE past 15 years, a series of studies and large clinical trials
have established the efficacy of angiotensin-converting enzyme (ACE) inhibitors
in patients with chronic heart failure (CHF) and left ventricular systolic
dysfunction,1, 2, 3
as well as in those with asymptomatic4 and
postmyocardial infarction left ventricular systolic dysfunction.5, 6
These trials demonstrated that ACE inhibitors prolong survival, prevent hospitalizations,
improve clinical status, and prevent progressive left ventricular dysfunction.
Despite the overwhelming evidence supporting the routine administration of
ACE inhibitors and recommendations by professional organizations and governmental
authorities for their use,7, 8, 9, 10
a substantial number of appropriate patients remain untreated,11, 12, 13, 14, 15, 16
and more are receiving low doses of ACE inhibitors that have never been demonstrated
to be effective in clinical studies.13, 16, 17, 18
The most frequently observed and cited reasons for not using ACE inhibitors
in general, and the higher doses used in clinical trials in particular, are
concerns about excessive reductions in blood pressure, renal dysfunction,
and safety in older patients.12, 13, 15, 16, 19
The Assessment of Treatment with Lisinopril and Survival (ATLAS) trial
demonstrated that treatment with high doses of the ACE inhibitor lisinopril
(target dose, 32.5-35.0 mg once daily [OD]), when compared with the lower
doses often prescribed (2.5-5.0 mg OD), was associated with a trend toward
reduced mortality (-7.9%; 96.1% confidence interval [CI], -17.6%
to 3.0%; P = .13) and a significantly lower risk
for death or hospitalization for any cause (-11.6%; 95% CI, -4.5%
to -18.2%; P = .002).20
The present study addresses in depth the second critical dimension of this
issue, ie, whether a strategy of using these high doses can be implemented
with acceptable safety and tolerability.
PATIENTS AND METHODS
PATIENT POPULATION
The ATLAS trial commenced recruitment on October 1, 1992 and terminated
on September 15, 1997. Patients were recruited from 287 centers in 19 countries
in North America, Europe, and Australia.20, 21
The primary inclusion criteria for this trial were the presence of symptomatic
CHF (New York Heart Association class II-IV) with diuretic treatment for at
least 2 months and a left ventricular ejection fraction (EF) of no greater
than 0.30. To qualify for enrollment, patients with class II symptoms must
have had a hospitalization or emergency department visit for decompensated
CHF within the previous 6 months. Patients of all ages were eligible whether
or not they were receiving ACE inhibitors at the time of entry. Other medications
for heart failure, including digitalis, vasodilators, and ß-blockers,
were permitted but not required.
Major exclusion criteria included myocardial infarction, unstable angina,
or cardiac surgery within the previous 2 months; clinical instability as indicated
by treatment with intravenous positive inotropic drugs or mechanical or ventilatory
assistance within 48 hours; current listing for cardiac transplantation; symptomatic
hypotension; serum creatinine level of greater than 221.0 µmol/L (2.5
mg/dL); or the presence of a noncardiac condition with an expected survival
shorter than the study period. In addition, patients who were receiving long-term
treatment with nonsteroidal anti-inflammatory agents (other than aspirin)
or who had known intolerance of ACE inhibitors were excluded.
The protocol was approved by the ethics committees of all participating
centers, and written informed consent was obtained from all patients.
STUDY DESIGN
The study design is illustrated in Figure 1 and consisted of an open-label lisinopril tolerability
phase of 4 weeks, a 4-week double-blind titration period, and a double-blind
chronic maintenance phase. Patients who were not taking ACE inhibitors at
the time of entry started open-label lisinopril therapy at a dosage of 2.5
or 5.0 mg OD for 2 weeks. The low dose was selected by the investigator as
the smallest tablet size available in their country that was considered effective;
it was 5.0 mg in 85% of patients. If the low dose was tolerated, an additional
10 mg of open-label lisinopril was added for 2 more weeks. In patients previously
receiving maintainence therapy using an ACE inhibitor, lisinopril dosage was
converted to 12.5 or 15.0 mg (the lowest dose considered effective plus 10
mg) and maintained for 4 weeks. Blood pressure and renal function were monitored
at 2 and 4 weeks thereafter.
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Figure 1. Schematic of the study design.
A total of 3793 patients entered the open-label tolerability period in which
patients who did not previously use an angiotensin-converting enzyme (ACE)
inhibitor initially received 2.5 or 5.0 mg of lisinopril daily, titrated to
12.5 or 15.0 mg daily. Patients previously receiving an ACE inhibitor were
switched to 12.5 or 15.0 mg of lisinopril. At the end of 4 weeks of open-label
lisinopril therapy, patients were randomized to a background open-label dose
of 2.5 or 5.0 mg of lisinopril plus 2 double-blind 10-mg tablets of lisinopril
or matching placebo. After 2 weeks, a third 10-mg tablet of lisinopril or
matching placebo was added, and these doses were maintained for up to 54 months.
Asterisk indicates that an additional 210 patients did not have a record of
previous ACE inhibitor use.
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After this 4-week, open-label tolerability phase, patients were randomized
equally to low- (LD) or high-dose (HD) groups. The 5.0- or 2.5-mg minimal
dose of open-label lisinopril was continued in all patients. The 10-mg open-label
lisinopril dose was discontinued and replaced with 2 double-blind 10-mg tablets
of active lisinopril or placebo. If tolerated, a third 10-mg tablet of active
drug or placebo was added after 2 weeks, providing a total active dose of
2.5 or 5.0 mg in the LD group and 32.5 or 35.0 mg in the HD group. These target
doses were continued for the remainder of the study, although doses of blinded
medication could be adjusted at the investigator's discretion. Blood pressure
and renal function were monitored after 2 and 4 weeks of this titration phase
and every 3 to 6 months during the maintenance phase.
END POINTS AND ANALYSES
The primary efficacy end point was all-cause mortality; the major secondary
end point was combined risk for death or hospitalization for any reason, both
analyzed as time to first event. These findings are described in detail elsewhere.20
The primary safety and tolerability analyses focused on changes in blood
pressure and related symptoms and on alterations in renal function and serum
potassium levels that are generally considered dose related. For this purpose,
in addition to hypotension and postural hypotension, the adverse events reported
as dizziness, vasodilatation, syncope, and shock were grouped together as
a single category, hypotension/dizziness. Adverse events considered probably
or possibly related to the renal effects of ACE inhibitors included kidney
function abnormality, kidney failure, uremia, increased creatinine level,
increased nonprotein nitrogen level, and hyperkalemia; these were grouped
together as renal dysfunction/hyperkalemia. In addition, complete information
was collected on other side effects and adverse events.
These safety data, as well as the primary efficacy end points, were
monitored periodically by an independent Data and Safety Monitoring Board,
but this board did not find it necessary to modify the conduct of the study,
and the protocol was completed as planned when the last patient randomized
into the study had been followed up for a minimum of 36 months.
RESULTS
PATIENT DISPOSITION
A total of 3793 patients signed consent forms and entered the trial,
and their disposition is shown in Figure 2. Of these, 3178 were receiving an ACE inhibitor at baseline, 405
were not, and previous ACE inhibitor treatment was not recorded in the remaining
210 (who were not randomized and therefore did not have complete baseline
information). Of the 3793 patients who entered, 3164 eventually underwent
randomization and 629 did not. The largest subgroup of nonrandomized patients
(209) were individuals who signed consent to have an EF determination but
did not have a qualifying EF measurement. These patients also constituted
most of the subjects in whom previous ACE inhibitor treatment status was not
known. The remainder were not randomized for a variety of administrative reasons
(62 protocol deviations; 55 with <80% medication compliance during the
tolerability phase; 43 with consent withdrawn; and 29 others) or because of
adverse events (231 patients) that will be discussed below.
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Figure 2. Schematic diagram of the disposition
of the 3793 patients who entered the trial and received lisinopril during
the open-label tolerability period. ACE indicates angiotensin-converting enzyme;
EF, ejection fraction.
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PATIENT CHARACTERISTICS
Table 1 presents the baseline
characteristics of the 3164 patients who entered the trial and underwent randomization
and the 420 patients with qualifying EF values who received lisinopril during
the open-label tolerability phase but did not undergo randomization. The randomized
and nonrandomized patients were similar in most of their baseline characteristics,
with the exception that a higher proportion of the nonrandomized group were
in New York Heart Association class IV (14.0% vs 7.1%). Patients randomized
to HD and LD groups did not differ in any baseline characteristic.
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Table 1. Baseline Characteristics*
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PRERANDOMIZATION TITRATION AND STABILIZATION PHASE
The prerandomization titration and stabilization period provides information
about the tolerability of low- to medium-dose lisinopril in the 405 previously
ACE-naive subjects and in the 3178 patients who had received previous ACE
inhibitor treatment, most of whom (approximately 75%) received relatively
low doses (eg, total daily doses of lisinopril,  10 mg; of enalapril maleate, 10
mg; of captopril, 75 mg; or the equivalent). A total of 5 patients (all
previously received an ACE inhibitor) discontinued due to rash, angioedema,
or unspecified allergic reactions. Ten (5 who had and 5 who had not previously
used ACE inhibitors) discontinued due to cough. A total of 111 patients (3.1%)
discontinued due to adverse reactions in the categories of hypotension/dizziness
and renal dysfunction/hyperkalemia that were considered possibly related to
ACE inhibitor therapy (Table 2).
For the patients who did not receive an ACE inhibitor before entry, these
adverse reactions are subdivided into whether they occurred at the first or
second open-label dose. For either class of adverse effects, 4.2% of patients
who did not receive a previous ACE inhibitor (1.2% at the 2.5- or 5.0-mg dose
level and 3.1% at the 12.5- or 15.0-mg dose level) and 3.0% of patients who
did withdrew because of such events. The reasons were divided approximately
equally between effects possibly related to both categories of adverse effects.
These figures provide a maximum estimate of drug-related discontinuations
in these categories, since there was no concomitant placebo-treated control
group to provide an indication of the frequency of discontinuations for these
reasons unrelated to ACE inhibitor therapy.
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Table 2. Discontinuations Due to Possibly Dose-Related Adverse Events
During Open-Label Tolerability Phase*
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POSTRANDOMIZATION TOLERABILITY
Table 3 presents information
on the mean dose of randomized blinded medication taken by patients in the
LD and HD groups and the proportions of patients in each group who continued
to receive the target dose and who discontinued the study drug. Lisinopril
or placebo doses in more than 90% of patients in both groups were titrated
to the target of 35.0 or 32.5 mg. Thereafter, although the mean dose of study
medication (blinded lisinopril or blinded placebo) declined gradually in both
groups, the mean dose of blinded medication and the proportion of patients
receiving the target dose remained essentially identical in both groups throughout
the study. Indeed, the proportion of patients not taking randomized drug tended
to be lower in the HD group. Over time, a growing number of patients in both
groups received open-label ACE inhibitors instead of or in addition to the
blinded drug. This in large part was the result of hospitalizations for worsening
CHF, and occurred somewhat more frequently in patients randomized to the LD
lisinopril group (35.2% vs 29.7% in the HD group; P
= .002).
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Table 3. Use of Blinded Study Drug Postrandomization*
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Figure 3 illustrates the mean
values for blood pressure and serum creatinine level in the 3164 randomized
patients from the time of study entry (prebaseline) to the 4-year follow-up
point. The mean difference in systolic and diastolic blood pressure between
the LD and HD lisinopril groups was 3 to 4 mm Hg. Serum creatinine levels
differed by approximately 8.8 µmol/L (0.1 mg/dL) between the groups.
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Figure 3. Blood pressure (A) and serum creatinine
(B) measurements during the course of the study. Entry values (solid bars)
were obtained at the onset of the open-label tolerability phase. The second
set of bars represent the measurements obtained at the time of randomization,
with patients receiving 12.5 or 15.0 mg of lisinopril. The differences in
systolic and diastolic blood pressure between the high- and low-dose groups
were approximately 3 to 4 mm Hg and 2 to 3 mm Hg, respectively. The intergroup
differences in serum creatinine level averaged less than 8.8 µmol/L
(0.1 mg/dL).
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Adverse events reported as serious occurred in 83.3% of the LD and 79.0%
of the HD groups. Most of these were in the category of worsening heart failure,
coronary ischemia, sudden death, or arrhythmias, rather than known adverse
effects of ACE inhibitors. Withdrawals due to adverse events occurred in 17.0%
of the HD and 18.0% of the LD groups. Table
4 lists the most frequent adverse events that were classified by
the investigator as serious or that led to withdrawal of blinded study medication.
Overall, these occurred in similar proportions of both groups and were dominated
by events that appear to be more closely related to the patients' underlying
cardiac conditions than to ACE inhibitor therapy. The low incidence of cough,
which probably reflected most patients having been exposed previously to ACE
inhibitors or at least tolerating doses of up to 12.5 or 15.0 mg of lisinopril,
did not appear to be increased at higher dosages.
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Table 4. Frequent Adverse Events*
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The potentially dose-related adverse effects of hypotension/dizziness
and renal dysfunction/hyperkalemia occurred somewhat more frequently in the
HD group, but the number of patients in whom study drug was withdrawn for
these adverse effects was small and quite similar in both groups. Furthermore,
many of these adverse effects did not lead to a change in the dose of the
study medication. Thus, for dizziness, 32.3% and 26.1% of the HD and LD groups,
respectively, had dose adjustments; after hypotension, these figures were
56.7% and 46.3%; for rising creatinine levels, they were 49.2% and 43.2%;
and for hyperkalemia, they were 44.3% and 33.3%.
ADVERSE EVENTS IN HIGH-RISK SUBGROUPS
Table 5 presents data on
the number of patients in several subgroups often thought to be at higher
risk for dose-related adverse effects of ACE inhibitors, including patients
with prerandomization systolic blood pressure of less than 120 mm Hg, patients
with prerandomization serum creatinine level of at least 132.6 µmol/L
(1.5 mg/dL), patients aged at least 70 years at randomization, and patients
with diabetes requiring hypoglycemic therapy. These high-risk subgroups tended
to have a higher frequency of hypotension/dizziness in the HD and LD groups,
but the relative increase in serious events appeared to be greater in the
HD group. Nonetheless, even in these 4 high-risk groups, the absolute increase
in the number of events classified as serious was generally less than 5% in
the HD compared with the LD group, and the absolute increase in the frequency
of withdrawal was not more than 2.5% in the HD compared with the LD group.
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Table 5. Incidence of Possible Dose-Related Side Effects in High-Risk
Subgroups*
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The incidence of renal dysfunction/hyperkalemia was also somewhat higher
in patients in these high-risk subgroups in both treatment groups, but the
occurrence of adverse effects that were classified as serious or requiring
withdrawal were not consistently higher in the HD lisinopril group compared
with the LD group, suggesting that ACE inhibitor–induced renal dysfunction
may be more related to patient factors than ACE inhibitor dose.
COMMENT
Although more than a decade has passed since the first trials demonstrating
that ACE inhibitors prolong survival1 and improve
symptoms in patients with CHF,22 physicians
continue to underuse these agents.11, 12, 13, 14, 15, 16
In some studies, up to 50% of patients considered appropriate for ACE inhibitor
therapy are not receiving these drugs, and most of those receiving ACE inhibitors
are receiving doses that have never been shown to be effective in clinical
trials. The most frequently cited reasons for these practices are concern
about the possibility of adverse effects related to hypotension and renal
dysfunction.12, 13, 15, 16, 17
To our knowledge, the ATLAS trial provides the first large experience
that addresses these concerns directly. The ATLAS trial showed that patients
whose lisinopril dose was titrated to a daily target of 32.5 or 35.0 mg exhibited
a trend toward improved survival and highly significant reductions in the
end point of death or hospitalization due to any cause and in hospitalizations
for heart failure. The results of the present safety and tolerability analyses
should serve to reassure physicians that even the high doses of lisinopril
used in this trial are generally well tolerated.
This conclusion is supported by a number of findings. First, there was
no between-group difference in the proportion of patients in whom, once having
demonstrated tolerability of medium doses of lisinopril, the study drug doses
could be titrated and maintained on the target. Mean doses of the blinded
study drugs were nearly identical throughout the trial, indicating that dose
reductions were not deemed more necessary by the investigators for patients
receiving the HD than in those given the LD therapy. The proportion of patients
withdrawing from therapy was, in fact, higher in the LD than in the HD group
(27.1% vs 30.7%, respectively). Second, for the group as a whole, the mean
differences in blood pressure and renal function between patients randomized
to the HD and LD groups were quite small. Third, although the occurrence of
adverse events possibly related to hypotension or renal dysfunction (as defined
previously) was greater in the HD group, these differences were relatively
small for events classified as serious or those that led to withdrawal. Last,
even when patients usually considered to be at particularly high risk for
these complications (eg, older patients or those with lower pretreatment blood
pressures, elevated serum creatinine levels, or diabetes) were examined, the
occurrence of serious events was relatively low. Indeed, serious renal dysfunction
did not appear to be dose related, and hypotension rarely required withdrawal
of lisinopril therapy, although dose reductions were frequent.
One important limitation to these safety and tolerability analyses should
be emphasized. Of the 3584 patients who entered the baseline phase with qualifying
EF values, 88.8% were already taking ACE inhibitors, although most, around
75%, were receiving relatively low total daily doses. The proportions of patients
in the participating institutions in whom ACE inhibitor therapy previously
had been initiated and subsequently withdrawn because of adverse effects is
unknown, but generally only a small percentage of patients with CHF do not
tolerate some dose of an ACE inhibitor. More helpful is the experience of
the 405 patients who had not previously received ACE inhibitors and who were
entered in the ATLAS trial. Only 4.2% of these did not enter the trial because
of hypotension or renal dysfunction, and this figure may be an overestimate
of the number attributable to the effects of the drug, since there was no
corresponding control group to provide an estimate of the spontaneous occurrence
of these adverse events. These observations should reassure physicians who
are concerned about hypotension-related and renal adverse events with ACE
inhibitors.
Patients entering clinical trials often differ from the overall patient
population in being more compliant and motivated and in having fewer serious
comorbid conditions. In addition, supervision during the trial may be closer
than that in ordinary practice, although in this study visits occurred only
at 3-month intervals after titration upward, and laboratory tests were mandated
after 3 months and then yearly—an intensity of follow-up quite consistent
with usual practice. Therefore, it is possible that similar degrees of tolerability
may not be achieved in the nontrial setting.
These findings should not be interpreted as indicating that all patients
with CHF will tolerate high doses of ACE inhibitors. Rather, ATLAS results
demonstrate that a strategy of titrating to and maintaining higher ACE inhibitor
doses than are used currently in clinical practice will be successful in most
patients and certainly in most of those who tolerate low doses. This is the
case even in patients with lower blood pressure, baseline increases in serum
creatinine levels, and diabetes and who are aged at least 70 years, each of
which is associated with less use of ACE inhibitors in clinical practice.
Although hypotension will occur in some patients, this is usually not serious
and generally does not require withdrawal of the ACE inhibitor therapy. This
new information on ACE inhibitor tolerability, coupled with the lack of evidence
that low doses of ACE inhibitors improve morbidity and mortality and with
the additional reduction in the composite of death and hospitalizations at
the high doses used in ATLAS, provide a clear message that higher ACE inhibitor
doses can and should be used in most patients.
AUTHOR INFORMATION
Accepted for publication July 20, 2000.
The ATLAS trial study was supported by a grant from Zeneca Pharmaceuticals,
Macclesfield, England.
From the Departments of Medicine, University of California–San
Francisco and the Department of Veterans Affairs Medical Center, San Francisco
(Dr Massie), University of Alberta, Edmonton (Dr Armstrong), and University
of Hull, Kingston upon Hull, England (Dr Cleland); Cardiac Unit, University
of Adelaide, Adelaide, South Australia (Dr Horowitz); Department of Circulatory
Physiology, College of Physicians and Surgeons, Columbia University, New York,
NY (Dr Packer); Department of Cardiology, Imperial College School of Medicine,
University of London, London, England (Dr Poole-Wilson); and Department of
Medicine, the Karolinska Institutet, Stockholm, Sweden (Dr Rydén).
A complete listing of the participants in the Assessment of Lisinopril and
Survival (ATLAS) trial was published previously (Circulation.
1999;100:2317).
Corresponding author: Barry M. Massie, MD, Cardiology Division (111C),
Veterans Affairs Hospital, 4150 Clement St, San Francisco, CA 94121 (e-mail: Barry.Massie{at}med.va.gov). Reprints are not available from the authors.
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