Download Comparison of the Effects of Losartan and Captopril on Mortality in

Comparison of the Effects of Losartan and
Captopril on Mortality in Patients After
Acute Myocardial Infarction:
The OPTIMAAL Trial Design
Kenneth Dickstein, MD, PhD, and
Kjekshus, MD, PhD, for the OPTIMAAL Study Group
Patients with acute myocardial infarction and evidence
of heart failure or left ventricular dysfunction during the
acute phase have an excessive mortality risk. Therapy
with angiotensin-converting enzyme inhibitors attenuates the detrimental effects of angiotensin II and has
been shown to substantially reduce morbidity and mortality in this population. Selective, angiotensin type 1
receptor antagonism with losartan, which inhibits the
effects of angiotensin II regardless of its source at the
receptor level, may provide more complete blockade of
the renin-angiotensin system. The Optimal Therapy in
Myocardial Infarction with the Angiotensin II Antagonist
Losartan (OPTIMAAL) study is a multicenter, doubleblind, randomized, parallel, captopril-controlled trial.
The primary hypothesis is that, compared with captopril,
losartan will decrease the risk for all-cause mortality by
20% in high-risk patients after acute myocardial infarc-
enzyme (ACE) inhibitors
Angiotensin-converting
have been shown to reduce morbidity and mor-
tality both in patients with chronic heart failure1 and in
selected, high-risk patients after acute myocardial infarction (AMI).2 Table I provides an overview of the
large post-AMI trials with ACE inhibitors. In the
Acute Infarction Ramipril Efficacy (AIRE) study, the
ACE inhibitor, ramipril, improved survival in patients
with AMI who had clinical evidence of heart failure.3
Therapy with ACE inhibitors has also resulted in
significant improvement with regard to morbidity and
mortality in the post-AMI population with evidence of
left ventricular systolic dysfunction without clinical
heart failure; the Survival and Ventricular Enlargement (SAVE)4 and Trandolapril Cardiac Evaluation
(TRACE)5 studies evaluated patients with left ventricular dysfunction as evidenced by ejection fractions
<40%, and the Survival of Myocardial Infarction
Long-term Evaluation (SMILE)6 study evaluated patients with Q-wave anterior wall AMI only. Two
megatrials, the International Study of Infarct Survival
(ISIS-4)7 and the Gruppo Italiano per lo Studio dela
From the Cardiology Division, Central Hospital in Rogaland,
Stavanger, Norway; and the Department of Cardiology, Rikshospitalet, Oslo, Norway. This study is supported by a grant from Merck &
Co. Inc., Reseach Laboratories, West Point, Pennsylvania. Manuscript
received June 4, 1998; revised manuscript received and accepted
September. 29, 1998.
Address for reprints: Kenneth Dickstein MD, Cardiology Division,
Central Hospital in Rogaland, Stavanger, 4011, Norway. E -mail:
[email protected]
©1999 by Excerpta Medica, Inc.
All rights reserved.
John
tion. The study population will consist of 5,000 patients,
50 years of age, with heart failure during the acute
phase or with a new Q-wave anterior infarction or
reinfarction. Patients will be randomized to treatment
with either losartan or captopril. All patients will be
followed until 937 deaths occur (event-driven). The primary end point is total mortality (all-cause mortality).
The secondary and tertiary end points are sudden death
(and/or resuscitated cardiac death) and fatal/nonfatal
reinfarction. Based on the assumed event rate, treatment
effect and a 95% power to detect a 20% reduction in
all-cause mortality at the 4.3% significance level (2sided, adjusted for 2 interim analyses), the trial will
enroll at least 5,004 patients and continue until a total
number of 937 events has been reached (intention-totreat analysis). © 1999 by Excerpta Medica, Inc.
Am J Cardiol 1999;83:477-481)
Sopravvivenza nell'InfartoMiocardico (GISSI-3)8
included unselected patients with AMI and demonstrated a significant, but relatively small outcome benefit compared with that demonstrated in selected,
high-risk patients. The data provided in the Table
support 2 essential observations. The 4 trials that
demonstrated a substantial survival advantage with an
ACE inhibitor selected high-risk patients and had long
follow-up times.
ACE inhibitor therapy administered after AMI has
also been demonstrated to reduce the incidence of
heart failure, hospitalization for heart failure, and the
reinfarction rate, and is now considered conventional
therapy in selected patients.9 Therapy has been shown
to attenuate infarct expansion, favorably affect the
remodeling process with reductions in ventricular volumes, and improve exercise performance after AMI.
Blockade of the production of angiotensin II is
incomplete during ACE inhibition.10 There is considerable escape, especially after low-dose and chronic
therapy. Importantly, alternative pathways for the generation of angiotensin II from angiotensin I exist
within the myocardium via enzymes such as human
heart chymase, cathepsin G, and chymostatin-sensitive AII-generating enzyme (CAGE).11 This permits
occupation and stimulation of angiotensin II receptors,
even in the presence of apparently adequate ACE
inhibition. In addition, ACE cleaves not only angiotensin I to form angiotensin II, but also inhibits the
degredation of bradykinin. Some important adverse
effects of ACE inhibition (cough and angioedema) are
0002-9149/99/$-see front matter
Pll 50002-9149(98)00898-4
477
TABLE 1 Mortality Studies— Angiotensin-Converting Enzyme Inhibition After AMI
Trial
ISIS-4
GISS1-3
CONSENSUS II
SAVE
TRACE
AIRE
SMILE
No.
58,050
19,394
6,090
2,231
1,749
2,006
1,556
Population
All AMI patients
All AMI patients
All AMI patients
LV dysfunction
LV dysfunction
Clinical failure
Anterior AMI
Time
5 wks
6 wks
6 mo
3 yrs
2 yrs
1 .4 yrs
1 yr
Risk Ratio
0.93 (0.87-0.99)
0.88 (0.79-0.99)
1.10 (0.93-1.29)
0.81 (0.68-0.97)
0.78 (0.67-0.91)
0.73 (0.60-0.89)
0.71 (0.49-0.94)
Absolute Risk
Reduction
0.5%
0.8%
5.0%
7.6%
6.0%
4.0%
p Value
0.02
0.02
0.26
0.02
0.01
0.002
0.01
CONSENSUS = Cooperative North Scandinavian ENalapril SUrvival Study; see text for explanation of other trials.
most likely due to these nonspecific actions.12 It is
therefore pharmacologically attractive to antagonize
the effects of angiotensin II at the receptor level.
Losartan is a potent, orally active and highly specific,
nonpeptide, angiotensin II type-1 (AT1) receptor antagonist devoid of intrinsic agonist activity.
The safety and efficacy of losartan in the treatment
of hypertension have been established in studies involving >7,000 patients.13 In 2 invasive, placebocontrolled studies in patients with symptomatic heart
failure, oral losartan produced beneficial hemodynamic effects both acutely14 and after chronic treatment.15 A trial performed to compare the short-term
efficacy of losartan with enalapril in patients with
moderate or severe heart failure symptoms revealed
no evidence of deterioration when patients were
switched from chronic enalapril therapy to losartan.16
Two trials evaluated the effect of losartan versus placebo on exercise performance (n = 724).17 Although
losartan treatment did not demonstrate improved exercise performance, pooled results demonstrated significant reductions with regard to hospitalization and
survival on chronic losartan therapy.
The Evaluation of Losartan in the Elderly (ELITE)
trial evaluated the effects of losartan versus captopril
added to digitalis and diuretics for 1 year in elderly
patients (age  65 years, n = 722) with symptomatic
heart failure and an ejection fraction <40%. 18 Although there was no difference between the treatments
with regard to the primary end point (incidence of
mild renal dysfunction), significant differences were
observed with regard to both morbidity and mortality.
All-cause hospitalization occurred more frequently
with captopril (p = 0.014), and losartan was associated with improved survival compared with captopril,
with a risk reduction of 46% (p = 0.035) by intentionto-treat analysis.
Unexpectedly, almost the entire mortality benefit
appeared to be related to a reduction in the incidence
of sudden death in the losartan group (64%). This
finding should be viewed with some caution in that
there were relatively few deaths overall, and rigorous
adjudication of the mode of death was not incorporated into the protocol. Although the dominant category of death in patients with clinical heart failure or
left ventricular dysfunction is sudden cardiac death,
the mortality benefits demonstrated with ACE inhibition have been limited to death due to progressive
478
THE AMERICAN JOURNAL OF CARDIOLOGY®
VOL. 83
heart failure.1 Only -blocker therapy has been shown
to reduce sudden death in post-AMI patients. These
trials largely excluded patients with moderate to severe heart failure.19 It would represent major progress
if selective AT1 receptor antagonism could improve
survival through reduction in the incidence of sudden
death.
Data from experimental ischemia-reperfusion
models demonstrates the role of AT1 receptor stimulation in the genesis of ventricular dysrrhythmia and
confirms that both losartan20 and another selective,
AT1 receptor antagonist, CV-11974,21 successfully
prevent sustained ventricular tachycardia. Experimental evidence demonstrating substantially reduced
local norepinephrine release in human atrial tissue
with losartan versus captopril has recently been reported.22 The data suggest that the ACE inhibitor
potentiation of bradykinin's effect on myocardial norepinephrine release may be the operative mechanism.
A large trial is currently underway that is powered to
prospectively compare the effect of losartan with captopril on mortality as the primary end point in patients
aged >60 years with symptomatic heart failure and an
ejection fraction <40% (ELITE II). 23
Selective AT1 receptor antagonism contrasts with
ACE inhibition in that levels of circulating angiotensin II rise. This leads to unopposed stimulation of the
AT2 receptor. Research suggests that AT2 receptor
agonism may provide potential benefits by attenuating
the pathologic trophic response in hypertension and
the noninfarcted myocardium. 24 Stimulation of cardiac AT2 receptors also exerts an antipressor effect by
inhibiting AT1-mediated chronotropic and pressor effects.25 AT2 receptor agonism may also maintain endothelial responsiveness via nitric oxide production
and antagonize the vasoconstrictor effect of angiotensin II.26 The marked changes in the relative receptorbinding densities in the failing myocardium, with reduction in messenger ribonucleic acid expression for
the AT1 receptor closely paralleling the down-regulation of -1 receptor transduction, together with preservation or increase in AT2 receptor-binding density,
is suggestive of a compensatory mechanism.27 Recent
data demonstrate reductions in ventricular dimensions
and collagen deposition in an infarction model with
rats treated with losartan. 28 Interestingly, concurrent
therapy with a selective AT2 receptor antagonist resulted in the loss of this effect, suggesting a role for
FEBRUARY 15, 1999
FIGURE 1. Study flow chart.
stimulation of the AT2 receptor in the remodeling
process after AMI. Chronic therapy with losartan versus captopril in rats after left coronary artery ligation
demonstrated superior survival in the losartan group.29
It may be postulated that selective AT1 receptor antagonism has potential cardioprotective advantages in
the treatment of patients after AMI.
The extensive documentation demonstrating the
favorable effects of ACE inhibitor therapy after AMI
in high-risk patients precludes placebo treatment in
future clinical trials.30 However, it is appropriate to
evaluate whether a selective, angiotensin II antagonist
could provide equal or superior protection as an ACE
inhibitor. Captopril was chosen because the agent's
efficacy and dosage is well documented. Captopril is
indicated for the treatment of patients after AMI in
most countries and is off-license and available. Comparing losartan with captopril as an active control
ensures that no patient would be denied the clinical
benefit of inhibition of the renin-angiotensin system.
Hypotheses: The primary hypothesis is that treatment with losartan in selected, high-risk patients after
AMI will reduce all-cause mortality compared with
captopril. The secondary and tertiary hypotheses are
that the patients treated with losartan will have a
reduced incidence of sudden cardiac death (and/or
resuscitated cardiac arrest) and fatal/nonfatal reinfarction. Other specified objectives include comparison of
the effects of losartan with captopril on cardiovascular
death, death from progressive heart failure, fatal/nonfatal stroke, heart failure requiring hospitalization, and
coronary revascularization procedures, in addition to
safety and tolerability based on incidence of discontinuations due to adverse events. The definitions of the
major end points to be adjudicated by the Endpoint
Committee are provided in Appendix 1.
Patient population: Clinically stable patients with
definite AMI that satisfy the inclusion criteria are
eligible for participation. Timing for initiation of therapy wilLbe decided by the investigator based on
clinical practice. If randomization is planned within
24 hours of the onset of symptoms, patients must
demonstrate at least 12 hours of observed clinical
stability. If randomization is planned >24 hours after
the onset of symptoms, patients must demonstrate at
least 2 hours of observed clinical stability. Patients
must be randomized into the trial within 10 days after
the onset of symptoms. Inclusion criteria:
1. Patients may be men or women and must be
 50 years of age.
2. Patients with an AMI who have signs or symp
toms of heart failure during the acute phase as sug
gested by 1 of the following: treatment with diuretic
or vasodilator therapy for heart failure, pulmonary
rales, third heart sound, persistent (2 hours) sinus
tachycardia ( 100 beats/min), radiographic evidence
of pulmonary congestion, ejection fraction <35% or
end-diastolic dimension >65 mm; and/or new Q-wave
anterior wall AMI, new left bundle branch block, or
any reinfarction (regardless of location) with previous
pathologic Q waves in the anterior wall, even without
signs of heart failure.
Important exclusion criteria include patients with
supine systolic arterial pressure <100 mm Hg at the
time of randomization, patients currently receiving an
ACE inhibitor or angiotensin II antagonist, and patients with unstable angina, hemodynamically significant stenotic valvular heart disease, and hemodynamically significant dysrhythmia.
Study design: Patients will receive all standard therapy throughout the trial ( blockers, thrombolytics,
aspirin, nitrates, and so forth). Treatment will be initiated during the initial hospitalization phase and continue for a minimum of 6 months of active therapy.
Patients will be randomized to a single dose of captopril 6.25 mg followed by captopril 12.5 mg titrated
as tolerated to 25 and then 50 mg 3 times daily or to
losartan 12.5 mg titrated to 25 and then 50 mg once
daily as tolerated (Figure 1). Placebo tablets to assure
adequate blinding will be provided.
The study will be conducted under the scientific
direction of the Steering Committee. The independent
Data and Safety Monitoring Board will be responsible
for identifying safety issues and interpreting emerging
study data at the interim analyses and making any
recommendations regarding modifications or termination to the Steering Committee. An independent,
CORONARY ARTERY DISEASE/THE OPTIMAAL TRIAL DESIGN 479
blinded Endpoint Classification Committee will re- APPENDIX 1
CLASSIFICATIONS/DESCRIPTIONS
OF ADJUDICATED
END
view all major morbidity and mortality events to determine if the event is to be considered a primary, POINTS:
PRIMARY END POINT:
secondary, or tertiary study end point (Appendix 2).
Total mortality irrespective of cause. Death will be subclassified as:
I. CARDIOVASCULAR DEATH
Data analysis: The primary hypothesis is that treatA. CARDIAC
ment with losartan compared with captopril in patients
1. Death due to AMI (fatal AMI). If the clinical history (including cardiac
with AMI will increase the time to event and decrease markers and electrocardiography), autopsy results, and circumstances of death
the incidence of death due to any cause. At the end of suggest this was the definite or probable underlying cause of death within 7 days
the study, a reduction of 20% in total mortality in the after 2.AMI.
Death due to progressive heart failure. When preceded by New York Heart
losartan group compared with the captopril group is Association class IV heart failure symptoms or circulatory collapse in the absence
considered an important difference to detect. The vari- of acute AMI within the preceding 7 days.
3. Death due to other cardiac causes. Includes acute pericarditis, myocarditis
able that will be used to assess the primary hypothesis and endocarditis.
during the follow-up period is the end point (time to
4. Sudden cardiac death. Witnessed instantaneous or near-instantaneous
event) of death due to any cause. The time to first death that occurs without warning or within 1 hour of nondiagnostic symptoms or
subsequent to resuscitation, or nonwitnessed, unexpected death in patients with
event of the end points of sudden cardiac death (and/or out known terminal noncardiovascular disease (includes cardiac deaths not due to
resuscitated cardiac death) and fatal/nonfatal reinfarc- an identifiable cause such as AMI or progressive heart failure, presumed or
to be arrhythmic in etiology, that occur with a sudden mode).
tion will be used to address the secondary and tertiary documented
B. NONCARDIAC
hypotheses. All efficacy and safety analyses will be
1. Death due to stroke (fatal stroke). If the clinical history, autopsy results,
and circumstances of death suggest this was the definite or probable underlying
based on the intention-to-treat approach.
mode of death.
Statistical methods: Adjudicated end points will be cause2.and
Other cardiovascular causes (includes death primarily due to pulmonary
used for all analyses related to deaths and hospitaliza- embolism, ruptured aortic aneurysm, and aortic dissection).
C. DEATH RELATED TO CARDIOVASCULAR PROCEDURES
tions. Hypotheses will be tested at a 2-sided signifiDeath within 7 days of an invasive procedure including coronary artery
cance level of 5%. For time-to-event variables, the bypass
graft surgery, percutaneous transluminal coronary angioplasty, and carrelative risk for each event, its confidence interval, and diac transplantation.
II. NONCARDIOVASCULAR DEATH
the test for differences between treatments will be,
death from malignant disease, accident, suicide, respiratory, renal,
based on the Cox regression model. Two interim anal- liver,Includes
infectious disease, or bleeding.
yses for the primary efficacy end point (all-cause
SECONDARY END POINT:
SUDDEN CARDIAC DEATH OR RESUSCITATED CARDIAC ARREST
mortality) will be performed during the course of the
Resuscitated cardiac arrest is a verified hemodynamic collapse of cardiac
trial when approximately one half and three fourths of origin, with cardiopulmonary resuscitation resulting in survival for at least 24
the 937 total events (i.e., 422 and 703 deaths, respec- hours. Discharge of an implanted cardiac defibrillator will be coded only if
tachycardia/ventricular fibrillation is documented.
tively) have been observed. A 2-sided, symmetric ventricular
TERTIARY END POINT:
O'Brien-Fleming stopping boundary will be used as a
FATAL OR NONFATAL REINFARCTION
Requires at least 2 of the following criteria: (1) typical cardiac chest pain; (2)
guideline for any recommendation by the Data Safety
of new pathologic Q waves or new sustained electrocardiographic
Monitoring Board for early termination (i.e., the treat- development
changes consistent with ischemia; (3) abnormal peak values of cardiac markers;
ment groups are handled identically, and the same (4) autopsy confirmed recent AMI.
OTHER ADJUDICATED END POINTS:
evidence is required to stop the trial prematurely for
1. CARDIOVASCULAR DEATH
harm as for benefit). According to this boundary, the
Described under primary end point.
critical p values at the first and second interim analyses
2. DEATH FROM PROGRESSIVE HEART FAILURE
Described under primary end point.
are 0.0035 and 0.019, respectively. To maintain the
3. FATAL/NONFATAL STROKE
overall significance level at 5%, the critical p value at
Requires evidence of a focal, neurologic deficit, lasting 24 hours, or until
the final analysis is 0.043.
death. Neurologic deficit <24 hours is classified as a transient ischemic attack.
The sample size calculation for this trial is based on Stroke will be classified into the following 3 categories: atherothrombotic/
embolic cerebral infarction, hemorrhagic stroke, and other.
the assumption that the annual mortality rate in the
4. ANY HOSPITALIZATION FOR CARDIOVASCULAR REASONS
captopril group will be 17% and that this rate will be
Includes all hospitalization for AMI or coronary artery disease, heart failure,
reduced by 20% (absolute reduction 3.4%) in the cerebrovascular disease or stroke, coronary artery bypass graft surgery, percutaneous transluminal coronary angioplasty or other cardiac interventions, and
losartan group. Based on the assumed event rate and venous or arterial disease including pulmonary embolism. Hospitalization is
treatment effect, the trial should enroll at least 5,004 defined as any in-patient admission to an acute care hospital or health care facility
or elective treatment which requires an overnight stay.
patients and continue until a total number of 937 for acute
MODE AND PLACE OF DEATH:
events have been reached in order to have approxiDeaths are classified as in-hospital or out-of-hospital. Witnessed deaths are
mately 95% power at the 4.3% significance level (2- classified as sudden or nonsudden based on time of death with respect to onset of
of the fatal event; mode of death is sudden if death occurred within 1
sided, adjusted for interim analyses). The method used symptoms
hour from the onset of symptoms.
to calculate sample size is based on the log-rank test.
Time line: The following countries are participating
with approximately 300 centers: Denmark, Eire, Fin- APPENDIX 2
land, Germany, Norway, Sweden, and the United
Steering Committee: John Kjekshus (Chairman); Sweden: Karl Swedberg,
Kingdom. The first patient was enrolled on February 25, Ronnie Willenheimer; Norway: Kenneth Dickstein (Coordinator); Eivind S..
Denmark : Kristian Thygesen, Knud Skagen; Finland: Markku S. Niemi 1998. According to the study design and projected Myhre;
nen, Antero Kesaniemi; UK: Steven G. Ball, Andrew JS. Coats; Germany: Rainer
inclusion rate, enrollment should be completed by Dietz, Andreas Zeiher; Statistician : Hans Wedel; Merck Research Laboratories:
June 1999. According to the estimated event rate, the Krister Kristianson, Allan I. Goldberg.
Data and Safety Monitoring Board: Desmond Julian (Chairman); Curt D.
trial should be completed during the first quarter, Furberg;
William W. Parmley; Lars Rydén; David L. De Mets; Antonio Bayes de
2000.
Luna.
Endpoint Committee: John G.F.Cleland; Matti Romo.
480
THE AMERICAN JOURNAL OF CARDIOLOGY ®
VOL 83
FEBRUARY 15, 1999
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