Articles
Effect of ramipril on mortality and morbidity of survivors of
acute myocardial infarction with clinical evidence of
heart failure
The Acute Infarction Ramipril Efficacy (AIRE) Study Investigators
Summary
Survival after acute myocardial infarction has been enhanced
by treatment with thrombolytic agents, aspirin, and
&bgr;-adrenoceptor blockade. However, there remains a
substantial subgroup of patients who manifest clinical
evidence of heart failure despite the first two of these
treatments, and for whom &bgr;-adrenoceptor antagonists are
relatively or absolutely contraindicated. These patients have a
greatly increased risk of fatal and non-fatal ischaemic,
arrhythmic, and haemodynamic events. In this selected
high-risk subset of patients we investigated the effect of
therapy with the angiotensin converting enzyme (ACE) inhibitor
ramipril, postulating that it would lengthen survival.
2006 patients who had shown clinical evidence of heart
failure at any time after an acute myocardial infarction (AMI)
were recruited from 144 centres in 14 countries. Patients were
randomly allocated to double-blind treatment with either
placebo (992 patients) or ramipril (1014 patients) on day 3 to
day 10 after AMI (day 1). Patients with severe heart failure
resistant to conventional therapy, in whom the attending
physician considered the use of an ACE inhibitor to be
mandatory, were excluded. Follow-up was continued for a
minimum of 6 months and an average of 15 months.
On intention-to-treat analysis mortality from all causes was
significantly lower for patients randomised to receive ramipril
(170 deaths; 17%) than for those randomised to receive
placebo (222 deaths; 23%). The observed risk reduction was
27% (95% Cl 11% to 40%; p=0·002). Analysis of
prespecified secondary outcomes revealed a risk reduction of
19% for the first validated outcome (ie, first event in an
individual patient)—namely, death, severe/resistant heart
failure, myocardial infarction, or stroke (95% CI 5% to 31%;
p=0·008).
Oral administration of ramipril to patients with clinical
evidence of either transient or ongoing heart failure, initiated
between the second and ninth day after myocardial infarction,
resulted in a substantial reduction in premature death from all
causes. This benefit was apparent as early as 30 days and was
consistent across a range of subgroups.
Lancet 1993; 342: 821-28
Members of the AIRE Study Group and participants In the study are
listed at the end of the article
Correspondence to: Prof S G Ball, Academic Unit of Cardiovascular
Studies, University of Leeds, Leeds LS2 9JT, UK
Introduction
Patients with clinical evidence of heart failure after
myocardial infarction have a poor outcome even if the
manifestations of failure resolve within the first 24 hours. 1-3
The AIRE Study was designed to determine whether
administration of the angiotensin converting enzyme
(ACE) inhibitor, ramipril, to these patients would improve
survival. After acute myocardial infarction (AMI) the
degree of ventricular damage, the extent of myocardium at
further ischaemic risk, and an arrhythmic tendency
contribute substantially to the risk of subsequent fatal and
non-fatal cardiac events.5 Because of this heterogeneity,
therapy beneficial to one aspect may worsen another and
thereby produce a neutral or negative overall effect on
survival.6-8 The findings of the second CONSENSUS
Study,8 in which patients were given the ACE inhibitor
enalapril after acute myocardial infarction, are particularly
relevant in this regard and in the context of the AIRE
Study.
At present diuretics are used extensively in the treatment
of patients with cardiac failure after AMI and their efficacy
in acute heart failure is well established. However, in the
long-term there is a tendency for diuretics to increase
afterload and deplete electrolytes, and in many patients
ventricular function continues to deteriorate.9 After AMI,
particularly where thombolysis has failed and there has
been a full thickness infarction, the infarcted area thins and
elongates-the so-called infarct expansion.1O The
subsequent, and for many patients presumed adverse,
"remodelling" of the heart, in which the ventricle enlarges
and becomes distorted with hypertrophy of the remaining
viable myocardium, continues despite treatment with
diuretic therapy." ACE inhibitors reduce afterload,
preserve electrolytes, and reduce the ventricular
enlargement that ensues in some patients after
infarction.9,11 Several major trials indicate benefit from this
group of drugs in patients with symptomatic chronic heart
failure not adequately controlled with digoxin and diuretic,
and in those likely to develop infarct expansion and
ventricular dilation after AMI, but do not address the
patient population studied here.12-15
At the inception of the AIRE Study we postulated that,
after myocardial infarction, patients with a high risk of
premature death (denoted by clinically observed signs of
either transient or ongoing heart failure) would benefit
from receiving appropriately timed oral ramipril.4,16 There
was no restriction on the use of concomitant therapies, but
we expected most of the patients to have received diuretic or
a nitrate and few to be taking a P-adrenoceptor antagonist
821
 (though such treatment would not be absolutely
contraindicated). The first CONSENSUS trial had
demonstrated particular benefit from ACE inhibitor
therapy in patients with severe heart failure (New York
Heart Association classification grade IV).12 However,
those with recent myocardial infarction or unstable angina
were excluded. We too were concerned about potential
adverse effects of ACE inhibition, particularly when used
early after acute myocardial infarction.16 Therefore only
patients who were haemodynamically stable and without
overt evidence of ongoing ischaemia were randomised, and
not before the second day after myocardial infarction.
Patients with severe cardiac failure (NYHA classification
grade IV) were excluded from the study.
Ramipril has high affinity for, and binds tightly to,
converting enzyme in both circulation and tissuesp,18 It
also has strong bradykinin potentiating effects. 19 The AIRE
Study tests the hypothesis that patients with acute
myocardial infarction complicated by clinical evidence of
heart failure will live longer if they receive long-term
ramipril treatment, initiated between the second and ninth
days after infarction. Randomisation between ramipril and
matching placebo was arranged in blocks of 10 patients, and
was stratified by centre. The prespecified primary
statistical endpoint was all-case ("intention-to-treat"),
all-cause mortality.

Methods
The rationale, design, organisation, and outcome definitions of the
AIRE Study were described prospectively.4 In brief it was a
multicentre, multinational, double-blind, randomised, placebo-
controlled study. 2006 patients with acute myocardial infarction
and clinical evidence of heart failure were recruited in 144 centres
in 14 countries.
All patients aged at least 18 years admitted to coronary care,
intensive care, or general medical units with a definite AMI and
clinical evidence of heart failure at any time after the index AMI
(usually sufficient to justify at least short-term diuretic or
vasodilator treatment), were eligible. AMI was defined as an
evolving electrocardiogram (ECG) diagnostic of myocardial
infarction (ie, progressive changes in the ST segment and T wave
compatible with AMI with or without the presence of pathological
Q waves) and abnormal cardiac enzymes (ie, elevation of creatine
phosphokinase and/or aspartate aminotransferase and/or lactic
dehydrogenase to greater than twice the upper limit of the
laboratory reference range or equivalent increases in their
isoenzymes). Clinical evidence of heart failure was defined as at Table 1: Patient characteristics, trial therapy, and concomitant
least one of the following: evidence of left ventricular failure medication at baseline
(pulmonary venous congestion with interstitial or alveolar oedema
on at least one chest radiograph); evidence of pulmonary oedema

(bilateral post-tussive crackles extending at least one-third of the

way up the lung fields in the absence of chronic pulmonary
disease); or auscultatory evidence of a third heart sound with
persistent tachycardia. Although clinical evidence of heart failure
following the index AMI was mandatory for trial entry, this could
be transient and not necessarily present at the time of
randomisation. Patients with severe heart failure (usually NYHA
grade IV), heart failure of primary valvular or congenital aetiology,
unstable angina, or any of the recognised contraindications to
clinicians would hesitate to prescribe a cardioprotective
p-adrenoceptor antagonist to patients in this group. However a
spectrum was envisaged. At one end would be patients with no
evidence of impaired ventricular function, who would receive a
p-adrenoceptor antagonist, and at the other those with severe
failure treated with diuretics and an open ACE inhibitor. Clinical
judgment would be used to select patients between these extremes
to be randomised to ACE inhibitor or placebo. Clinicians were

ACE inhibitor treatment were excluded from the study. All
participating centres were asked to complete a simple screening
form for each patient admitted with a suspected or definite AMI, to
describe the population from which the eventual study group was
selected.
The strategy was then to select a group of patients after
myocardial infarction thought to have a particularly poor prognosis
and in the majority of whom, because of evidence of left ventricular
dysfunction, treatment with a diuretic or vasodilator drug would
have been instituted though not necessarily continued. Most
encouraged at all times to continue their normal clinical practice in
terms of overall management and drug therapy.
Initiation of treatment
Treatment was initiated in hospital between day 3 and day 10 after
AMI (day 1 = day of index infarction). Patients initially received
2-5mg of ramipril or placebo twice daily. Those who tolerated this
dose received it for 2 days and then were given 5 mg of ramipril or
placebo twice daily thereafter. Patients who could not tolerate the

822

Figure 1: Mortality curves Illustrating the primary endpoint of
all-cause mortality analysed by intention-to-treat
Most patients were followed for less than 18 months, and the curves have
been terminated at 30 months because of the small numbers of patients
with prolonged follow-up.
higher 5 mg dose were discharged on 2mg or placebo twice daily.
Ramipril 1-25 mg or placebo was provided for those patients who
could not tolerate the initial 2-5 mg dose. These patients began
again on the lower dose 1-25 mg twice daily for 2 days before
increasing to 2-5 mg twice daily and then 5 mg twice daily. When
therapy was started or dosage was changed, blood pressure was
monitored before and at 2, 4, and 6 hours, all adverse events being
recorded. If a patient was unable to tolerate ramipril at least 2-5 mg
twice daily or matching placebo he or she was withdrawn from the
study treatment but followed at the prescribed visit intervals for
intention-to-treat analysis. The protocol did not allow discharge of
a patient on the low dose of 1-25 mg twice daily.
Follow-up
Patient follow-up was designed to minimise any interference with
usual clinical practice. All patients, including those withdrawn
from randomised treatment, were seen at 4 and 12 weeks after
randomisation and thereafter every 12 weeks until study close. At
each visit, the occurrence of a study outcome, other adverse events,
compliance, and concomitant therapy were recorded. Renal
function (serum electrolytes, creatinine, and urea) was reviewed in
accordance with the investigator’s normal clinical practice.
Patients could continue or begin any other necessary treatment
except an ACE inhibitor while on randomised treatment.
Monitoring of serum potassium was strongly advised, particularly
if potassium-sparing diuretics or potassium supplements were
judged necessary.
The last day in the analysis of the mortality data was Feb 28,
1993, six months after the 2000th patient had been recruited. As
soon as possible after this date, the final status of all patients was
assessed.
Sample size
On the following assumptions the trial was estimated to require
about 2000 patients: predicted average patient follow-up 15
months; predicted placebo mortality 20% at 15 months; a
"clinically relevant improvement" defined as a 25% reduction in
all-cause mortality, resulting in an expected mortality of 15 % in the
active treatment group at 15 months; and statistical power of at least
80% at a significance level of 5% (two-tailed test, log rank test).4
Study organisation
An independent adjudicating panel (IAP) acted as the overall
ethical supervisory body and had access to the randomisation code.
The IAP performed the interim analysis. The IAP was also
responsible for transmitting data on serious adverse events to the
relevant regulatory authorities. An international steering
Table 2: Summary of primary endpoints, validated secondary
events, and secondary endpoints
committee met regularly to review progress and was responsible,
inter alia, for the clinical definition of the secondary endpoints.
The executive committee, chaired by the principal investigator
(SGB) and including representatives of the sponsor, the study
managers, and the data manager, was responsible for the day-to-
day decisions on the conduct of the study and the operation of the
AIRE Study Co-ordinating Centre. All endpoints were validated
by a subcommittee of the international steering committee. An
independent group was responsible for conducting a series of
prospective audits of study procedures, to ensure that the study
conduct adhered closely to the European Guidelines for Good
Clinical Research Practice.
Statistical methods
The primary endpoint was all-cause mortality, analysed by
intention-to-treat. Survival curves were obtained by use of the
Kaplan-Meier estimate, and the log rank test was used for
comparison of the two groups (ramipril and placebo). The relative
hazard and corresponding 95% confidence interval (CI) was
obtained by fitting a Cox proportional hazards regression model
with a single covariate-namely, the allocated treatment.
Subgroup effects were examined by including interaction terms in
the Cox proportional hazards regression model.
The secondary endpoint was the time to the first validated
secondary event-namely, death, progression to severe resistant
heart failure, reinfarction, or stroke. These data were analysed in
the same way as those for the primary endpoint.
A planned interim analysis was performed after 175 deaths, half
way through the projected total of 350 deaths. A very stringent
stopping rule was specified in the protocol (p < 0-001 was the
guideline for early termination) so that no adjustment was required
to the final analysis to compensate for this interim analysis. In
addition, during the early stages, the independent adjudicating
panel requested a safety analysis after a total of 40 deaths had been
reported. This analysis could not have led to early termination of
the study with a claim of efficacy, and so again no adjustment was
made to the final analysis.
All statistical endpoints were reviewed and validated by a
subcommittee of the international steering committee and the
procedures used are being reported elsewhere .20
Patient population
The study began in Leeds, and in its first year (1989) two
amendments were made to produce the protocol under which the
vast majority of patients were randomised. The inclusion criteria
were extended to include patients with non-Q as well as Q-wave
infarction and the protocol was clarified to emphasise that patients
with transient cardiac failure after myocardial infarction were
eligible to be randomised. The study was extended to include
numerous other centres. Most of the patients were recruited
between April, 1991, and the close of recruitment on Aug 27, 1992.
A total of 52 019 patients had been reviewed. The main reason for
exclusion was no firm evidence of myocardial infarction in 21 302
823
 Figure 2: Curves illustrating proportion of surviving patients
who had withdrawn from study medication during follow-up
Patients withdrawn from study medication continued to be followed for
inclusion in the intention-to-treat analysis.

and no evidence of cardiac failure in 16 989. Of the remaining

13 728 screened patients, exclusions in order of number were: died
before possible inclusion 2784, unstable angina 2314, no consent or
follow-up impracticable 1962, on or about to start an ACE inhibitor
1404, severe heart failure 1329, renal failure 289, sustained
hypotension 279, and "other reasons" 1361. We estimate that
15-20% of the patients with definite myocardial infarction had
evidence of transient or ongoing cardiac failure and were eligible
for the trial, of whom one-half were randomised.

Exclusion of one centre

During the courseof the study it became apparent that data from
one inconsistent. After discussion with the members of
centre were
the independent adjucating panel it was agreed to remove the 20
patients apparently recruited and randomised at this centre. This
was done before study close. Analyses that included the Heiative hazara

information available on these patients had no important

Figure 3: Relative hazards with corresponding 95% Cis,
qualitative impact on the description of the patient population or illustrating consistent benefit with ramipril over a wide range of
outcome of the study. The data presented are those of the
1986
subgroups
remaining patients. In no case the test for interaction statistically
was significant at the 5%
level.
Results
Baseline demographic data
All-cause mortality
1004 patients were randomised to ramipril and 982 to
placebo; randomisation to drug or placebo was well Figure 1 shows the findings for all-cause mortality.
balanced within the 14 countries. Table 1 shows the Separation of the curves occurred early and they continued
to diverge throughout the study. There were 170 deaths
demographic data of the patients and the relevant
conditions for which they were receiving treatment before (17%) in the ramipril group and 222 (23%) in the placebo
the index infarction. Some 22-6% of patients had received group, with overall a 27% reduction in the risk of death
treatment for a previous myocardial infarction but only (95% CI 11% to 40%), which was highly significant
8-2% had a history of previous heart failure. The mean time statistically (p 0-002).
=

to randomisation was 54 (SD 2-1) days after AMI for

ramipril and 5-4 (SD 2-2) for placebo. The groups were well
matched in all aspects at baseline (table 1). Overall, 58% of
patients received thrombolytic treatment. Concomitant
medication was similar in the two groups.
Trial therapy
More than 90% of patients in each treatment group were
discharged from hospital on study medication. A greater
percentage of patients receiving placebo achieved the
Secondary endpoints
Table 2 shows all-cause mortality (primary endpoint) and
secondary events validated by the outcomes
subcommittee.2&deg; For the formal analysis we used only the
findings for the first validated event in any individual
patient-namely, death, reinfarction, stroke, or
development of severe/resistant heart failure (table 2).
Again the reduction, 19% (95% CI5% to 31 %), was highly
significant statistically (p 0-008). =

"higher dose level" (table 1). ,

Follow-up Withdrawal from study medication

The average time of follow-up was 15 months with a The withdrawal rates from study drug, excluding patients
minimum of 6 months. Only 1 patient was lost to who had died, are shown in figure 2. In total there were 352
follow-up-last seen 12 weeks after randomisation, at premature withdrawals from the ramipril group and 318
which time the data for this patient were censored. from the placebo group. Intolerance was given as the

824
primary or a contributory factor in 126 of the ramipril
withdrawals and in 68 of the placebo withdrawals, whereas
progression to severe/resistant heart failure was the stated
reason for 58 ramipril withdrawals and 92 placebo
withdrawals.
Serious adverse events
There were fewer patients with reported serious adverse
events on ramipril, 581 (58%), than placebo, 625 (64%).
Serious adverse events included the endpoints of the trial
(death, progression to severe/resistant heart failure,
reinfarction, and stroke) as well as possible adverse effects
of treatment. Syncope was reported for 24 (2-4%) patients
on ramipril and 17 (1-7%) on placebo with a similarly
increased occurrence of hypotension in the ramipril treated
group-42 (4-2%) compared with placebo 23 (2-3%). Renal
failure occurred with a similar frequency in the two groups:
15 (15%) on the drug and 12 (1-2%) on placebo. Angina,
which it was thought might be worsened in some patients
prescribed an ACE inhibitor, was reported as a serious
adverse event in 181 patients (18%) taking ramipril and 171
(17%) taking the placebo.
Interactions-effect of age, sex, delay to treatment, and
adjuvant therapy
Several interactions were examined (figure 3). All the
estimated relative hazards were below 1 and in no case was
the test for interaction significant at the 5% level.
Discussion
Ramipril, administered to patients with clinical evidence of
heart failure on the second to ninth days after myocardial
infarction for an average of 15 months, caused a highly
significant and substantial reduction in all-cause mortality.
The mortality curves for ramipril and placebo were clearly
separating within weeks of starting treatment and
continued to diverge. There was a significant, though
smaller, benefit from drug on the secondary endpoint-
namely, time to occurrence of the first validated outcome of
death, progression to severe/resistant heart failure,
reinfarction, or stroke. These positive findings based on
intention-to-treat analysis are even more striking when we
note that by 18 months 40% of patients (excluding those
who had already died) were no longer taking randomised
medication and that most of the patients withdrawn from
placebo were taking open-label ACE inhibitor.
Ramipril was well tolerated and more than 90% of the
patients in the ACE-inhibitor group were taking it when
they left hospital. Importantly there was no pre-trial run-in
phase to exclude patients who could not tolerate the drug;
this strategy gives a simple appraisal of the benefit of
treatment with ramipril, increasing the relevance of the
findings to normal clinical practice. Subsequent
withdrawal rate over the first 2 years was only marginally
higher with ramipril than with placebo (withdrawals caused
by minor adverse effects of the active agent were offset by
the lower incidence of heart failure necessitating open label
treatment).
The findings of this study should be compared with those
of the two other published mortality trials undertaken with
ACE inhibitors in patients after myocardial infarction. In
the CONSENSUS II Study8 all patients with presumed
myocardial infarction were randomised within 24 hours to
treatment with intravenous enalaprilat or placebo followed
by oral treatment with enalapril or placebo. The study was
stopped by the ethical review committee after recruiting
just over 6000 of the intended 9000 patients. At this time
more patients had died on drug than on placebo though the
difference was not statistically significant. In contrast, the
SAVE Study15.21 included 2231 patients 3-16 days (average
11 days) after myocardial infarction. These patients were
carefully selected in that they were symptomless at
randomisation, had a radionuclide ejection fraction less
than or equal to 40%, and had undergone an exercise test to
exclude ischaemia. Only 33% had been given a
thrombolytic, but almost 60% had coronary angiography
and 25% had a revascularisation procedure before entry
into the study. All patients had a dose of captopril
prerandomisation and only those who tolerated this were
entered into the study. Follow-up was for an average of 42
months and mortality was reduced by 19%. However, no
effect on mortality was apparent until almost 1 year after the
start of treatment. This contrasts strikingly with the
observations reported here, with benefit apparent early and
after a much shorter follow-up.
ACE inhibitors have become established treatment,
when added to diuretic, in chronic congestive cardiac
failure. Two major trials, V-HeFT 11 and the treatment
and prevention arms of SOLVD,13,22 investigating the
effect of this group of drugs on mortality in patients with
chronic heart failure, were published during the course of
the AIRE Study. In both the entry criteria were based on a
measurement of ejection fraction and both excluded
patients with recent myocardial infarction (within the
previous one or three months and the great majority of
patients were entered much later). The V-HeFT IIStudy’4
required evidence that exercise capacity was limited by
fatigue/breathlessness but not by chest pain, again like
SAVE excluding overt ongoing ischaemic problems. In the
SOLVD treatment and prevention studies patients were
given enalapril for up to 1 week then placebo for 2 weeks and
only those patients tolerating the drug and its withdrawal
were randomised.13,22 V-HeFT 1114 and the SOLVD13
treatment arm showed that enalapril reduced mortality in
patients with symptomatic heart failure. The SOLVD
prevention arm did not reveal a statistically significant
reduction in mortality.22 Whilst ejection fractions in
patients entering the SOLVD treatment and prevention
arms differed by only 3%, mortality in the symptom-free
prevention group was less than half that of the symptomatic
patients in the placebo group of the treatment arm.13.22
AIRE Study investigators were informed of the findings of
the SOLVD treatment arm and those of the SAVE Study
since it was thought that patients selected on the criteria of
these trials would benefit from treatment with an ACE
inhibitor.
The AIRE Study was designed to take account of
changing clinical practice. Patients with severe heart failure
(NYHA grade IV) were known to have a particularly poor
prognosis at the beginning of the study and although the
first CONSENSUS Study had excluded patients less than
2 months post myocardial infarction (and for the majority
probably much longer), this group with severe heart failure
was specifically excluded since it was felt that most
physicians would wish to consider prescribing ACE
inhibitors to these patients.4.12 However, the difficulty of
defining different grades of heart failure was recognised and
clinicians were able to decide individually what they
regarded as sufficiently severe heart failure unresponsive to
conventional therapy to justify open prescription of this
group of drugs rather than to enter such patients into the
825
 trial. Similarly, the subsequent progression to severe/
resistant heart failure, usually NYHA grade IV, but again at
the discretion of the physician, necessitating prescription of
open ACE inhibitor, was used as a secondary endpoint in
this study. During the course of the study, increasing
numbers of patients with moderate heart failure were
treated with open label ACE inhibitor in preference to
continuing study drug.
The early effect within weeks was very similar to that
observed in the first CONSENSUS Study of patients with
severe failure. An analysis at 30 days, prespecified before
the randomisation code was broken, showed that the
difference between drug and placebo was close to
significance (p=0-053). Furthermore when a second
analysis was done on mortality only between 30 days and
study close, thus biasing the findings considerably against
the drug, a further substantial benefit was apparent
(p=0016).
In a recent further analysis of the SOLVD data23 and in
the SAVE Study15 administration of ACE inhibitor was
claimed to reduced myocardial infarction rates. Whilst
there was a trend to fewer such events on ramipril than on
placebo in the AIRE Study no clear reduction was
apparent. However, the number of validated reinfarctions
was small, largely because of the much shorter average
follow-up period than those in SOLVD and SAVE. The
favourable trend observed here would be in keeping with
the observations made after a similar period of follow-up in
these studies. The incidence of stroke was higher in the
active drug group but the numbers were small and an
adverse effect of the drug can be neither supported nor
refuted. Fewer patients progressed to severe/resistant heart
failure in the active drug group and there were fewer
admissions to hospital (data not shown), as would be
expected from the mode of action of ramipril and the
findings of other trials; but hospital admission was not
specified as part of the primary or secondary analyses. Both
sudden death, presumed arrhythmic, and progression to
severe failure were reduced by administration of ramipril.
The classification of death in heart failure is complex and
the approach used in the AIRE Study will be detailed
elsewhere.2O The findings on mode of death and adverse
events including stroke and myocardial infarction will also
be described in further publications.
40% of patients were not taking diuretic therapy at
randomisation, indicating only short lived evidence of heart
failure in a substantial proportion. Whilst the subgroup
analysis (figure 3) showed remarkable consistency with all
relative hazards below 1, patients not taking diuretics at
randomisation may have derived less benefit, though it
must be emphasised that the difference was not statistically
significant. A similar trend was seen for patients under 65
years of age. Benefit accrued irrespective of administration
of a thrombolytic agent. The proportion of patients
receiving such treatment was similar to that in the
CONSENSUS II Study8 and in excess of that in the SAVE
tria1.15 It is likely, however, that the inclusion criteria for
both the AIRE and SAVE studies will have produced a bias
towards the selection of patients in whom attempts at
reperfusion were unsuccessful. Almost 80% of patients
were taking aspirin at the time of randomisation.
Experimental evidence indicates that ACE inhibitors and
aspirin alter prostaglandin metabolism. Interaction
between the effects of the two agents has been reported in
severe heart failure.24 In AIRE we saw a clear benefit with
ramipril in aspirin-treated patients; but there was a trend
826
towards an even greater benefit in those not receiving
aspirin.
The action ramipril was additive to that of
of
P-adrenoceptor antagonists. Most studies with (3-blockers,
which in general reduce morbidity and mortality after
myocardial infarction, have specifically excluded patients
with clinical evidence of left ventricular failure.25 One
notable exception was the Beta-blocker Heart Attack Trial,
which included patients with either mild or transient
clinical signs and symptoms of heart failure.26 A
retrospective analysis of this subgroup of patients
indicated that propranolol had a beneficial effect on
survival, though mortality rates remained high.26 Ramipril
offers clear benefit complementary to current conventional
treatment.
Patient screening data and extrapolation from many
other studies both before1 and after the widespread use of
thrombolytic agents27-29 indicate that as many as 20% of
patients with myocardial infarction might fall into this
group. Ramipril brought about a striking reduction in
mortality and this seemed independent of treatment
with thrombolysis, 0-adrenoceptor antagonists, and
oral nitrates. Furthermore and importantly, women3o
benefited equally to men. Clinicians were able to identify by
simple everyday measures a group who can expect
substantial benefit from treatment with the ACE inhibitor
ramipril.
The AIRE Study group thank Hoechst for their support. Prof S G Ball is
a British Heart Foundation Chairholder and thanks colleagues in Leeds
(Dr A S Hall, Dr A F Mackintosh, Dr C Winter, Dr L B Tan, Dr J C
Cowan, Dr G W Reynolds) and representatives of the sponsor (Dr M A
Akbary, Dr N Bender, Dr B Rangoonwala, and Prof P Stonier) for
support throughout the study.
AIRE Study administration
Independent adjudicating panel D G Julian (UK, chairman); A J Moss
(USA); G D Murray (UK); P A Poole-Wilson (UK); M L Simoons
(Netherlands).
International steering committee S G Ball (chairman, principal investigator);
N Bender (sponsor); J G F Cleland (UK); D L Clement (Belgium); P J
Commerford (South Africa); S Dalla Volta (Italy); C Delagardelle,
(Luxembourg); L Erhardt (Sweden); W Fennell (Ireland); A S Hall
(advisor to principal investigator); R Hopf (Germany); S Jagerholm
(Finland); M Jolly (coordinating centre); W Klein (Austria); G D Murray
(independent statistician); M G Niemeyer (Netherlands); S Rasmussen
(Denmark); M A Riccitelli (Argentina); L Richardson (coordinating
centre); P D Stonier (sponsor); H-P Vogelin (Switzerland); C Winter
(independent safety coordinator).
Outcome subcommittee J G F Cleland (UK), L Erhardt (Sweden).
Authorship subcommittee S G Ball, D G Julian, G D Murray.
Coordinating personnel M A Akbary (sponsor), J Clinch, M Jolly, N Raw,
L Richardson, H Twigg, P J Williamson.
Data centre G D Murray, A Lawrence, J Love, T Welby, C A Woods.
Parttapants
Countries and centres listed in order of number of patients recruited; principal
investigators denoted by *.
UK: General Infirmary at Leeds (S G Ball*, J C Cowan, C Winter); St James’s
University Hospital, Leeds (A F MacKintosh*, L B Tan); Royal Hallamshire Hospital,
Sheffield (L Caldicott, K Channer*, S K Hawley, A Wilson); Oldchurch Hospital,
Romford (I Dews, H Kadr, J Stanton, C Statuch, J D Stephens*); Wharfedale General
Hospital, Otley (K E Berkin*); Good Hope District General Hospital, Sutton
Coldfield (S Davies, M V J Raj*); Stracathro Hospital, Brechin (T S Callaghan*);
Mayday Hospital, Croydon (S Joseph*, A C Rao); Walton Hospital, Liverpool (D
Hambleton, R S Hornung*, E Rodrigues*); Royal South Hants Hospital,
Southampton, and Southampton General Hospital (H Roberts, D Waller*, N Warner);
Sunderland District Hospital (S E Pugh*, N Ramaknshnan, M Sekar); Wexham Park
Hospital, Slough (R A Blackwood*, P Robinson); Cumberland Infirmary, Carlisle (M
Clark, R H Robson*); General Hospital, Hartlepool (P T Pickens, G Tildesley*, R W
B White); Pinderfields General Hospital, Wakefield (P Kelly, J I Wilson*);
Whittington Hospital, London (S Jones, C Kingdom, D L H Patterson*); Wycombe
General Hospital, High Wycombe (A Bentley, S. Gupta, W G Hendry*); Royal Sussex
County Hospital, Brighton (C Davidson*, P Glennon); Ashford Hospital (A Bishop, D
Kluth, A Mooney, P Wilkinson*); Pontefract General Infirmary (T P Anthony, A K
Ghosh*); Greenwich District Hospital (D Robson*); Erne Hospital, Enniskillen (B
McAleer, M P S Varma*); Harrogate District Hospital (H Larkin*); Hillingdon
Hospital (S Kaddoura, C Knight, G Sutton*); Scarborough Hospital (R S Clark*);
Walsgrave Hospital, Coventry (M Been*, A Raman); Royal Lancaster Infirmary (A K
Brown*); St Mary’s Hospital, London (R Foale*, J Shahi); Hinchingbrooke Hospital,
Huntingdon (C Borland*); Friarage Hospital, Northallerton (T G Jayasuriya, U
Somasundram*).
Sweden: Hoglandssjukhuset, Eksj&ouml; (S Ekdahl*, S Hansen); UniversitetssJukhuset,
Lmkoping (M Broqvist, U Dahlstrom*, 0 Kongstad); Allmanna Sjukhuset, Malmo (C
Cline, L Erhardt*, R Willenheimer); Huddinge Sjukhus (H Berglund, 0 Nyquist*);
Sjukhuset, Angelholm (P Nyman, D Ursing*); Lanslasarettet, Karlshamn (S Jensen*);
Landskrona Lasarett (F Gyland, R Linne, T Ragnartz*); Sjukhuset, Kristinehamn (R
Watz*); Centrallasarettet, Karlskrona (M Freitag, L Olsson*); Simrishamns Sjukhus (J
Hallgren*, P Lindvall).
Ireland: St James’ Hospttal, Dublin (C Bergin, P Crean*, N El-Guylam, B McAdams,
D Morais, R Sheahan); Sligo General Hospital (J McKenna, D Murray*); Mallow
General Hospital (P Sullivan*); Cork Regional Hospital (W Fennell*, P Kearney, C
Vaughan); Mater Misericordiae Hospital, Dublin (J Galvin, D Sugrue*); Limerick
Regional Hospital (T Peirce*); Louth County Hospital, Dundalk (N Ghaisas, E
Harkin, T O’Callaghan*); County Hospital, Roscommon (P McHugh*, S Nisar);
University College Hospital, Galway (K Daly*, F Lavin, P Shah); Our Lady’s
Hospital, Navan (R Juneja, K McGarry*); Monaghan General Hospital (S Junejo, B
MacMahon*, N P Pillay*); Our Lady of Lourdes Hospital, Drogheda (D Long, C
Maguire, B C Muldoon*, P Shiels); Letterkenny General Hospital (L Bannan*, E
Connelly); Portiuncula Hospital, Ballinasloe (J Barton*); St Vincents, Dublin (C
McCreery, P Quigley*).
South 4/nca; Addington Hospital, Durban (S Cassim, D P Naidoo*); H F Verwoerd
Hospital, Pretoria (D P Myburgh*); Universitas Hospital, Bloemfontein (J D Marx*);
Groote Schuur Hospital, Cape Town (P J Commerford*, J Lawrenson); Hydromed
Hospital, Bloemfontein (H Du T Theron*); R K Khan Hospital, Chatsworth (M C
Rajput*); Umtas Hospital, Verwoerdburg (J M Bennett*); Baragwanath Hospital,
Soweto (P Sareli*).
Argentina: Hospital Argerich, Buenos Aires (P Arce, M A Riccitelli*); Hospital
Santojanni, Buenos Aires (D Ryba*); Hospital Carlos Durand, Buenos Aires (E Beck,
A Demartini*); Hospital Pirovano, Buenos Aires (N Goncalves Borrega,J Lazzari*);
Sanatorio Mitre, Buenos Aires (M Gonzalez, A Sosa Liprandi*); Hospital de Clinicas
Jose de San Martin, Buenos Aires (J Martinez Martinez, E A Sampo*); Hospital
Espaflol, Buenos Aires (G Bortman*, H Grancelli); Hospital Ramos Mejia, Buenos
Aires (J Carbajales, A Girotti*); Hospital Juan A Fernandez, Buenos Aires (B
Maumer*, 0 Gabrielli); Hospital Italiano, Buenos Aires (A Cagide*); Hospital
Interzonal de Agudos Eva Peron, Buenos Aires (A Lapuente*); Policlinico Bancario,
Buenos Aires (R Esper*).
Netherlands: Martini Ziekenhuis, Gromngen (L J Takens*, M Y van der Heijden); De
Wever Ziekenhuis, Heerlen (J A Kragten*, R Renkens); Het Nieuwe Spittaal, Zutphen
(A C Tans*); Spaarne Ziekenhuis, Heemstede (MJ W Grosfeld, H H Kruyswijk*); St
Streekziekenhuis Hilversum (A de Groot, K L Liem*); Elkerliek Ziekenhuis, Helmond
(H Olthofk); Canisius-Wilhelmina Ziekenhuis, Nijmegen (H E Haerkens-Arends, T E
H Hooghoudt*); Merwede Ziekenhuis, Sliedrecht en Dordrecht (A Kuypers, M G
Niemeyer*); St Ziekenhuis Amstelveen (J P van Mantgem*); St Sint Joseph
Ziekenhuis, Veldhoven (E Aelfers, L C Slegers*); St Clara Ziekenhuis, Rotterdam (M
G Scheffer*); Martini Ziekenhuis, Groningen (B Oedit Doebe, L E J M Schrijvers*);
St Sint Joseph Ziekenhuis, Veghel (L Relik van Wely*); Drechtsteden Ziekenhuis,
Zwijndrecht (A H Herweijer*).
Belgium: Hopital Braine-I’Alleud (M DeMyttenaere*); Sint-Annaziekenhuis, Sint-
Truiden (P Peerenboom*); A Z Sint-Jozef, Turnhout (I Bekaert*); Onze Lieve Vrouw
Middelares Ziekenhuis, Deume (P Surmont*); Heilig Hartziekenhuis, Neerpelt (A
Van Dorpe*); Onze Lieve Vrouwziekenhuis, Mechelen (J Beys*); Heilig
Hartziekenhuis, Roeselare (D Clement*); Clinique des Deux Alice, Brussels (E Benit*,
M Beyloos, C Durieux); Kliniek Zwarte Zusters, leper (M Bayart*); Sint-Jozefkliniek,
Bornem (M Herssens*); Hopital de Samte Therese, Bastogne (S Cremers*); A Z
Sint-Norbertus, Duffel (F De Keyser, U Van Walleghem*).
Germany: Krankenhaus Sachsenhausen, Frankfurt (R Hopf*, A Moller); Klinik am
Eichert, Goppingen (J Hauber, F Hofgartner, H A Sigel*); Dreieich-Krankenhaus,
Langen (M Grieshaber, M Neubauer*, K Rudolph); Evangelisches Krankenhaus,
Herne (W Sehnert*); Albert Schweitzer Krankenhaus, Northeim (R Cartsburg, P
Kleine*); Kreiskrankenhaus, Wurselen (T H Hennecke,J Kindler*, P Ramme); St
Josefs Hospital, Cloppenburg (D Hellmann, D A Hemmen-Funk*); Kreiskrankenhaus
Gunzenhausen (F Freytag*); Stadtkrankenhaus, Hanau (H J Becker*, A Eisenmenger,
W A Fach); Evangelisches Krankenhaus, Essen (P Bernhardt*); B K H Ernst
Scheffler, Aue (H Jacob, K Malinowski*); Stadtisches Krankenhaus, Duren (H Roth,
H Simon*); Kreiskrankenhaus, Waldbrol (H J Bias, K 0 Bischoff*); Stadtische
Kliniken, Chemnitz (U Gerner*); Stadtische Kliniken, Oldburg (P Tomow*).
Denmark: F A C Hillerod (S Galatius Jensen, K Mellemgaard*); Braedstrup Sygehus
(A Amtoft*, A Axelsen, C Christensen); Rigshospitalet, Copenhagen (S Haunso, P
Jorgensen, S Rasmussen*); Horsens Sygehus (P Strunge*); Naestved Centralsygehus
(T Lysbo Svendsen*, H Madsen, W Nielsen); Svendborg Sygehus (F Egede*,J
Rasmussen,J Markenvard); Centralsygehuset I Nyk&oslash;bing F (H Mollerup, B Sigurd*);
Frederikssund Sygehus (M Kirchhoff, A McNair, P E Nielsen*) ; K A S Glostrup,
Copenhagen (J E Rokkedal Nielsen*); Sundby Hospital, Copenhagen (M P
Andersen*).
Austria: Krankenanstalt Rudolfstiftung, Vienna (E Bucher, P Elliott, J Slany*);
Medizinische Universitatsklimk Graz (M Grisold, W Klein*); Hanusch-Krankenhaus,
Vienna (E Aldor*, C Domaus, W Kainz); Krankenhaus Lainz, Vienna (J Mlczoch, H
Nobis*, S Trinks).
Fmland. Helsinki University Central Hospital (S Pohjola-Sintonen*); Jorvi Hospital,
Espoo (V Naukkarinen*, R Siplla); Malmi District Hospital, Pietarsaari (K Nikus*, P
E Wingren); Porvoo District Hospital (M Harkbnen*, S Jagerholm*); Lappi Central
Hospital, Rovaniemi (M Eloranta*,J Isojarvi); Lohja District Hospital (0 Suhonen*);
Lounais-Hame District Hospital, Forsa (J Koskelainen*).
Italy’Polichnico Umversilano, Padova (F De Cian, S Dalla Volta*); Ospedale
Generale, Bassano del Grappa (G Berton, F Cucchini*); Ospedale Civile, Piacenza (I
Abelli, U Gazzola*, G Q Villani); Ospedale Generale Regionale, Vicenza (P
Centofante, G M Mosele, M Vincenzi*); Ospedale Generale Provinciale, Conegliano
(F Accorsi*, G A Deitos).
Luxembourg: Centre Hospitalier De Luxembourg (C Delagardelle*).
mtMernd; Kreisspital, Bulach (U Munch, H-P Vogelin*).
References
1 Gottlieb S, Moss AJ, McDermott M, Eberly S. Interrelation of left
ventricular ejection fraction, pulmonary congestion and outcome in
acute myocardial infarction. Am J Cardiol 1992; 69: 977-84.
2 Killip T, Kimball JT. Treatment of myocardial infarction in a
coronary care unit: a two year experience in 250 patients. Am J Cardiol
1967; 20: 457-64.
3 Bigger JT, Coromilas J, Weld FM, Reiffel JA, Rolmitzkey LM.
Prognosis after recovery from acute myocardial infarction. Annu Rev
Med 1984; 35: 127-47.
4 Hall AS, Winter C, Bogle SM, Mackintosh AF, Murray GD, Ball SG.
The Acute Infarction Ramipril Efficacy (AIRE) Study: rationale,
design, organization, and outcome definitions. J Cardiovasc Pharmacol
1991; 18 (suppl 2): S105-S109.
5 The Multicenter Postinfarction Research Group. Risk stratification
and survival after acute myocardial infarction. N Engl J Med 1983; 309:
331-36.
6 The CAST Investigators. Preliminary report: effect of encainide and
flecainide on mortality in a randomized trial of arrhythmia suppression
after myocardial infarction. N Engl J Med 1989; 321: 406-12.
7 The MDPIT research group. The effect of diltiazem on mortality and
reinfarction after myocardial infarction. N Engl J Med 1988; 319:
385-92.
8 Swedburg K, Held P, Kjekshus J, et al. On behalf of the
CONSENSUS II Study Group. Effects of early administration of
enalapril on mortality in patients with acute myocardial infarction.
Results of the Cooperative North Scandinavian Enalapril Survival
Study II (CONSENSUS II). N Engl J Med 1992; 327: 678-84.
9 Sharpe N, Murphy J, Smith H, Hannan S. Treatment of patients with
symptomless left ventricular dysfunction after myocardial infarction.
Lancet 1988; 334: 255-59.
10 Hutchins GM, Bulkley BH. Infarct expansion versus extension: two
different complications of acute myocardial infarction. Am J Cardiol
1978; 41: 1127-32.
11 Pfeffer MA, Braunwald E. Ventricular remodeling after myocardial
infarction. Circulation 1990; 81: 1161-72.
12 The CONSENSUS trial study group. Effects of enalapril on mortality
in severe congestive heart failure; results of the Cooperative North
Scandinavian Enalapril Survival Study (CONSENSUS). N Engl J
Med 1987; 316: 1429-35.
13 The SOLVD Investigators. Effect of enalapril on survival in patients
with reduced ejection fractions and congestive heart failure. N Engl J
Med 1991; 325: 293-302.
14 Cohn JN, Johnson G, Ziesche S, et al. A comparison of enalapril with
hydralazine-isosorbide dinitrate in the treatment of chronic congestive
heart failure. N Engl J Med 1991; 325: 303-10.
15 Pfeffer MA, Braunwald E, Moye LA, et al. Effect of captopril on
mortality and morbidity in patients with left ventricular dysfunction
after myocardial infarction. N Engl J Med 1992; 327: 669-77.
16 Hall AS, Ball SG. ACE inhibitors after AMI. Lancet 1989; 337:
1527.
17 Bunning P. Kinetic properties of the angiotensin converting enzyme
inhibitor ramiprilat. J Cardiovasc Pharmacol 1987; 10 (suppl 7):
S31-S35.
18 Erman A, Winkler J, Chen-Gal B, Rabinov M, Zelykovski A, Tadjer
S, Shmueli J, Levi E, Akbary A, Rosenfeld B. Inhibition of
angiotensin converting enzyme by ramipril in serum and tissue of man.
J Hypertens 1991; 9: 1057-62.
19 Linz W, Wiemer G, Scholkens BA. ACE-inhibition induces NO-
formation in cultured bovine endothelial cells and protects isolated
ischaemic rat hearts. J Mol Cell Cardiol 1992; 24: 909-10.
20 Cleland JGF, Erhardt L, Hall AS, Winter C, Ball SG. Validation of
primary and secondary outcomes and classification of mode of death
among patients with clinical evidence of heart failure after myocardial
infarction. A report from the Acute Infarction Ramipril Efficacy
(AIRE) Study Investigators. J Cardiovasc Pharmacol (in press).
21 Moye LA, Pfeffer MA, Braunwald E, for the SAVE Investigators.
Rationale, design and baseline characteristics of the survival and
ventricular enlargement trial. Am J Cardiol 1991; 68: 70D-
79D.
22 The SOLVD Investigators. Effect of enalapril on mortality and the
development of heart failure in asymptomatic patients with reduced
left ventricular ejection fractions. N Engl J Med 1992; 327:
685-91.
23 Yusuf S, Pepine CJ, Garces C, et al. Effect of enalapril on myocardial
infarction and unstable angina in patients with low ejection fractions.
Lancet 1992; 340: 1173-78.
24 Hall D, Zeitler H, Rudolph W. Counteraction of the vasodilator effects
of enalapril by aspirin in severe heart failure. J Am Coll Cardiol 1992;
20: 1549-55.
25 Yusuf S, Peto R, Lewis J, Collins R, Sleight P. Beta-blockade during
and after myocardial infarction: an overview of the randomized trials.
Prog Cardiovasc Dis 1985; 27 (5): 335-71.
827
26 Furberg CD, Hawkins CM, Lichstein E. Effect of propranolol in
postinfarction patients with mechanical or electrical complications.
Circulation 1984; 69 (4): 761-65.
27 The GISSI-2 Investigators. GISSIS-2: a factorial randomised trial of
alteplase versus streptokinase and heparin versus no heparin among
12 490 patients with acute myocardial infarction. Lancet 1990; 336:
65-71.
28 The International Study Group. In-hospital mortality and clinical
Aminoacid polymorphisms of insulin receptor substrate-1
in non-insulin-dependent diabetes mellitus
Summary
Since relative orabsolute insulin deficiency and insulin
insensitivity areinvolved in the aetiology of non-insulin-
dependent diabetes mellitus (NIDDM), we examined whether
patients with NIDDM exhibit genetic variability in the coding
region of insulin receptor substrate-1 (IRS-1), a candidate
gene that is ubiquitous in insulin-sensitive and insulin-like
growth factor 1 (IGF1) sensitive tissues, including those that
determine glucose production and clearance and those with
regulatory effects on pancreatic &bgr;-cell function. IRS-1 has a
central role as an adaptor molecule that links the insulin-
receptor and IGF1-receptor kinases with enzymes that regulate
cellular metabolism and growth.
Single-stranded conformation polymorphism analysis and
direct nucleotide sequencing were applied to genomic DNA
from 86 unrelated patients with NIDDM and 76
normoglycaemic controls. 10 of the patients with NIDDM and 3
of the controls were heterozygous at codon 972 for a
polymorphism in which glycine was substituted with arginine.
Moreover, at codon 513, 6 patients with NIDDM and 2 controls
had a heterozygous polymorphism with a transition from
alanine to proline. None of the polymorphism carriers had both
aminoacid variants and the total allelic frequency of IRS-1
polymorphisms was about three times higher in patients with
NIDDM than in controls (p=0&middot;02). Both aminoacid
substitutions were located close to tyrosine phosphorylation
motifs that are putative recognition sites for insulin and IGF1
signal transmission proteins. Analysis of the phenotypes
showed that patients with NIDDM who had IRS-1 variants did
not differ in their degree of insulin resistance compared with
patients without known IRS-1 polymorphisms. However,
carriers of the codon 972 variant had significantly lower
plasma levels of fasting insulin and C-peptide.
Our results suggest that aminoacid polymorphisms in IRS-1
may be involved in the aetiology of a subset of late-onset
NIDDM.
Lancet 1993; 342: 828-32
Steno Diabetes Center and Hagedorn Research Institute (K Almind,
C Bj&oslash;rbaek PhD, H Vestergaard MD, T Hansen MD, S Echwald PhD,
O Pedersen DMSc), Copenhagen, DK-2820 Gentofte, Denmark
Correspondence to: Dr Oluf Pedersen
828
course of 20 891 patients with suspected acute myocardial infarction
randomised between alteplase and streptokinase with or without
heparin. Lancet 1990; 336: 71-75.
29 Stevenson R, Ranjadaylan K, Wilkinson P, Roberts R, Timmis AD.
Short and long term prognosis of acute myocardial infarction since
introduction of thrombolysis. BMJ 1993; 307: 349-53.
30 Lorell BH. ACE inhibitors after myocardial infarcton. N Engl J Med
1993; 328: 966-67.
Introduction
A considerable body of evidence suggests that genetic
factors contribute to the pathogenesis of non-insulin-
dependent diabetes mellitus (NIDDM).1 Studies of
patients with overt NIDDM and of individuals at high risk
of NIDDM reveal abnormalities of insulin secretion and
insulin action.2 However, a genetic defect at one or more
steps in the cellular action of insulin and insulin-like growth
factor 1 (IGF1) might well involve the biochemical
pathways of tissues that regulate insulin secretion and
insulin-sensitive hepatic and extrahepatic tissues that
produce or extract glucose.
Insulin initiates its cellular effects by binding to the
a-subunit of its tetrameric plasma membrane receptor.3
The kinase in the P-subunit is thereby activated, which in
turn catalyses the intramolecular autophosphorylation of
specific tyrosine residues on the 0-subunit, which further
stimulates the tyrosine kinase activity of the receptor
towards other protein substrates in the cascade of insulin
action. Recently, the first endogenous substrate for the
insulin receptor kinase, insulin receptor substrate-1
(IRS-1) was cloned and sequenced .1-6 The complementary
DNA sequence encodes a hydrophilic protein that contains
multiple phosphorylation sites. During insulin exposure,
this protein undergoes rapid tyrosine phosphorylation and
the phosphorylated sites of IRS-1 associate with high
affinity to cellular proteins that contain SH2 domains
(src-homology-2 domains). Several SH2 domain-
containing proteins that are activated by IRS-1 have
recently been identified which suggests that IRS-1acts as a
multisite "docking" protein to bind signal proteins thereby
linking the receptor kinase to the variety of cellular
functions that are regulated by insulin.7 Besides being a
substrate for the insulin receptor kinase, IRS-1 is
phosphorylated after activation of the IGF1 receptor
kinase.8
Although more than twenty different mutations of the
insulin receptor gene have been reported in syndromes of
severe insulin resistance frequently associated with
acanthosis nigricans or ovarian hyperandrogenism,9
mutations in the insulin receptor molecule do not explain
the genetic basis of the common form of NIDDM. Because
of the key function of IRS-1 in mediating the early steps in
the action of insulin and IGF1, we addressed whether
patients with late-onset NIDDM exhibit variability in the
coding region of the IRS-1gene.