Six-year follow-up of a cohort of 203 patients with diabetes after screening for silent

myocardial ischaemia

Abstract

Aims .To determine the prognosis of patients with Type 1 or Type 2 diabetes, 6 years after screening for
silent myocardial ischaemia (SMI).

Methods. Two hundred and three asymptomatic patients with diabetes underwent systematic SMI
screening. From the results of this screening, they were allocated to one of three groups: patients (n =
171) with negative screening; patients (n = 32) with positive screening; and patients (n = 21) with
positive screening and coronary stenosis. Six years after the initial assessment, all patients were
reassessed. All events [death, cardiac death, non-fatal major cardiac events (NFMCEs)—acute
myocardial infarction, ventricular rhythm disorders, heart failure, unstable angina] were recorded.

Results. Fifteen patients were lost to follow-up. Patients (n = 20) with positive SMI screening and
coronary stenosis had a higher risk of NFMCEs (35% vs. 7%, P < 0.001), and a higher mortality rate (35%
vs. 15%, P < 0.05) compared with patients (n = 157) with negative screening. SMI-positive patients (n =
31) had a higher NFMCE rate compared with negative SMI screening patients, although overall mortality
rate was no different. Cancer was the leading cause of death (36.4%). In multivariate analysis, major
cardiac events (cardiac death and NFMCE) were related to baseline age, body mass index and coronary
stenosis (P < 0.01).

Conclusions. Patients with diabetes and SMI have a very poor prognosis as assessed by cardiac events or
death, especially in the presence of coronary stenosis.

Diabet. Med. 23, 1186–1191 (2006)

Keywords. adult diabetes, cancer, cardiovascular disease, mortality, silent myocardial ischaemia

Abbreviations ACE, angiotensin-converting enzyme; ALFEDIAM, Association of French Language for the
Study of Diabetes and Metabolic Diseases; BMI, body mass index; NFMCE, non-fatal major cardiac
event; SMI, silent myocardial ischaemia

Introduction

The early detection of diabetes-related complications may be useful because specific treatments are
available. Screening for some complications, such as retinopathy or nephropathy, by dedicated
examination is easily justified. In contrast, myocardial ischaemia in patients with diabetes is often
unnoticed. The Association of French Language for the Study of Diabetes and Metabolic Diseases
(ALFEDIAM), and the American Diabetes Association in collaboration with the American Heart
Association have issued guidelines relating to silent myocardial ischaemia (SMI) screening [1–3]. The
French guidelines were updated in 2004 [4] and were based on several short-term studies of the
prevalence of SMI, and its prognosis, in patients with diabetes [5–9].

The aim of this study was to determine the long-term prognosis of cardiovascular morbidity and
mortality of patients with diabetes in a cohort which had undergone screening for SMI and who had
been treated accordingly, and to determine factors relating to prognosis.
Patients and methods

Between May 1996 and April 1997, all patients with Type 1 or Type 2 diabetes (diagnosed according to
ADA criteria [10]), who were admitted to our unit, were consecutively included in an SMI screening
study, according to the criteria defined by the first recommendations from the ALFEDIAM [1], i.e. age
between 20 and 75 years, absence of clinical or ECG symptoms of coronary heart disease; duration of
Type 1 diabetes > 10 years for patients > 40 years of age and > 15 years for patients < 40 years of age;
and duration of Type 2 diabetes > 10 years for patients with no major cardiovascular risk factors or > 5
years for patients with at least one major cardiovascular risk factor. In those patients, systematic
assessment of micro- and macrovascular complications was performed at inclusion in the study. The
main cardiovascular risk factors of smoking, hypertension as defined by the World Health Organization’s
criteria, dyslipidaemia (total plasma cholesterol > 6.0 mmol/l and/or triglyceridaemia > 2.5 mmol/l), and
a family history of coronary heart disease before the age of 65 years were systematically recorded. The
population and screening modalities have been previously described [9]. Briefly, SMI screening was
based on two tests: the exercise electrocardiography, performed with the patient off medication or,
when this was not possible, inconclusive or questionable, thallium myocardial scintigraphy with exercise
testing and/or dipyridamole injection was performed. If one of these two tests was positive, the patient
underwent coronary angiography for diagnosis and potential therapy. Angiography was considered
positive if coronary stenosis > 50% was identified in any of the major coronary arteries.

From the initial 203-patient cohort, which included 75 (36.9%) patients with Type 1 diabetes, 128
(63.1%) patients with Type 2 diabetes, 114 (56.2%) men and 89 (43.8%) women, the screening strategy
defined the three following groups: SMI negative patients, i.e. with a negative exercise test and/or
negative myocardial scintigraphy (n = 171, 84.2%); SMI-positive patients, with at least one of the two
tests being positive [whatever the coronary angiography result, n = 32 (15.8%)]. A subgroup (n = 21) of
these SMI-positive subjects also had positive coronary angiography. The other patients (n = 11) either
refused the angiogram (n = 5) or had negative angiography (n = 6).

Six years after initial screening, all patients were invited for a clinical examination, resting
electrocardiogram and functional tests (exercise test and/or myocardial scintigraphy) if needed. For
some patients, the collection of the data was obtained via the general practitioner, the diabetologist or
the cardiologist. All the events which had occurred during follow-up were recorded. Information from
death certificates, history reported by the cardiologist, ECG and notes review was obtained. Deaths,
whether cardiac or not, and non-fatal major cardiac events (NFMCEs; myocardial infarction, heart
failure, unstable angina and ventricular rhythm disorders) were recorded.

Statistical analysis

The results are given as mean and standard deviation or as percentages. The mean values were
compared using Student’s t-test and the paired t-test; percentages were compared using the chi-
squared test and the MacNemar’s test. Uni- and multivariate analyses were performed using forward
stepwise logistic regression with a variable inlet and outlet threshold at 0.10. Differences with P-values
<0.05 are considered statistically significant.

This study was approved by the local ethics committee.

Results

Table 1 shows the baseline clinical characteristics, cardiovascular risk factors and complications for the
three groups according to the outcome of the SMI screening.

Events—overall population

After 6 years, 15 (7.4%) patients were lost to follow-up. Of the 188 remaining patients, 33 had died
(17.6%). Cancers were the most common cause of death (12 patients, 36.4%), followed by cardiac
deaths (six patients, 18.2%). Eleven deaths were attributed to the following causes: traffic accident (n =
1), bedridden state (n = 1), cirrhosis (n = 1), pneumonia (n = 1), septic shock (n = 3), and stroke (n = 4). In
four patients, the cause of death was unknown. Among these 33 deaths, 28 (85%) occurred in patients
with Type 2 diabetes, as compared with only five (15%) in patients with Type 1 diabetes. Twenty
NFMCEs occurred in 20 patients (10.6%).

SMI-negative and SMI-positive groups

Results concerning deaths, cardiac death and NFMCEs are summarized in Table 2. The overall mortality
or mortality from a cardiac origin in the SMI-positive group was not significantly different from that of
the SMI-negative group (respectively 29 vs. 15.3% and 6.5 vs. 2.5%). In contrast, NFMCE was more
common in the SMI-positive group as compared with the SMI-negative group (29 vs. 7.1%, P < 0.001).

SMI-positive group with coronary stenosis

The overall mortality rate in this group was higher compared with the SMI-negative group (35 vs. 15.3%,
P < 0.05); however, there was no significant increase in cardiac mortality compared with the SMI-
negative group (10 vs. 2.5%, P > 0.05). NFMCE was more frequent in this group compared with the SMI-
negative group (35 vs. 7.1%, P < 0.001). These results are summarized in Table 2.

In univariate analysis, the appearance of major cardiovascular events (cardiac death and NFMCE) was
correlated with age, type of diabetes (Type 2 diabetes/Type 1 diabetes; P < 0.001), body mass index
(BMI), hypertension, carotid artery disease, dyslipidaemia (P < 0.05) and with SMI-positive testing and
coronary stenosis (P < 0.001). In multivariate analysis, only age (OR 1.09; 95% CI 1.03–1.15; P < 0.05),
BMI (OR 1.1; 95% CI 0.99–1.23; P < 0.05) and coronary stenosis (OR 3.18; 95% CI 1.03–9.84; P < 0.01)
remained significant.

Events—patients with Type 2 diabetes

At inclusion, patients with Type 2 diabetes (n = 128, 63.1%), compared with patients with Type 1
diabetes (n = 75, 36.9%), were older (60.7 ± 8.8 vs. 41.8 ± 11.4 years; P < 0.001), had higher BMI (27.6 ±
4.6 vs. 23.7 ± 2.4 kg/m2; P < 0.001), similar sex-ratio (M : F 1.4 vs. 1.2, P = 0.66), shorter diabetes
duration (16.6 ± 7.1 vs. 20.4 ± 8 years; P < 0.001), and were more likely to have SMI and SMI with
coronary stenosis (respectively 20.3 vs. 9.3%, P < 0.01; 14.1 vs. 4%, P < 0.01).Eleven patients with Type 2
diabetes were lost to follow-up.

Results concerning deaths, cardiac deaths and NFMCEs for the SMI-negative group, the SMI-positive
group and the SMIpositive group with coronary stenosis are shown in Table 2.

Comparing SMI-positive and SMI-negative groups, there was no significant difference in overall or
cardiac mortality, although NFMCE was more common in the SMI-positive group (39.1 vs. 9.5%, P <
0.001).
Comparing the SMI positive with coronary stenoses group with the SMI-negative group, there was no
significant increase in mortality (either overall or from cardiac causes). NFMCE was, however, more
frequent in the SMI-positive group with coronary stenosis (41.2 vs. 9.5%, P < 0.01; Table 2).

Overall, prognosis was poorer in patients with Type 2 diabetes than patients with Type 1 diabetes, with
higher overall and cardiac mortality, respectively, 28 (23.9%) vs. 5 (7%), P < 0.001 and 5 (4.3%) vs. 1
(1.4%), P < 0.001 and a higher incidence of NFMCE, 18 (15.4%) vs. 2 (2.8%).

Therapeutic management

The assessment performed 6 years after the initial screening documented the patients’ therapeutic
management in the intervening period. After screening, all patients with coronary stenosis were treated
with specific cardiac drugs [calciumchannel blockers with or without angiotensin-converting enzyme
(ACE) inhibitors or aspirin]. Of these patients, five (23.8%) underwent transluminal coronary angioplasty
(TCA) with or without stenting. Coronary artery bypass surgery (CABG) was not performed on any
patient immediately after the initial screening. During the 6 years following the SMI screening, patients
who sustained NFMCEs were treated with a specific drug (calcium-channel blockers), two required
coronary artery bypass surgery and six transluminal coronary angioplasty. All of these patients were in
the SMI-positive group with coronary stenosis.

Table 3 shows therapeutic management at baseline and 6 years after the initial screening. At 6 years,
diabetes therapy had been intensified, with a decrease in the proportion of patients taking oral glucose-
lowering agents alone and an increase in the number of patients taking a combination of oral agents
with insulin; these data mostly concern patients with Type 2 diabetes. In addition, an increase in the
number of patients treated with ACE inhibitors, angiotensin II receptor antagonists and statins was
observed in the SMI-positive group and in the SMI-positive group with coronary stenosis groups.
Approximately one-third of SMI-negative and SMIpositive patients, and more than 50% of the SMI
positive patients with coronary stenosis, stopped smoking during follow-up; in statistical analysis,
smoking cessation was only significant in the SMI-positive group. The number of patients treated with
aspirin increased 6 years after the initial screening in the three groups, but reached statistical
significance only in the SMI-negative and SMI-positive groups.

Discussion

In a cohort of patients with Type 1 and Type 2 diabetes who were asymptomatic and recruited according
to ALFEDIAM guidelines [1] as high-risk patients, our study confirms the poor long-term prognosis
associated with the presence of SMI. The recruitment criteria for screening were very similar to those
recommended by American Heart Association guidelines [3]. NFMCE occurs more frequently when SMI
screening is positive (4.8%/year vs. 1%/year, P < 0.001), whatever the coronary angiography result.
Similarly, Faglia et al. reported a rate of 3.9%/year of developing a cardiac event in patients who screen
positive [11]. Such results are comparable with those observed in short-term studies [12–14], even if the
numbers are a little different as a result of differences in screening methodologies, initial populations
and duration of follow-up.

However, in our study, less than 20% of deaths are from cardiac causes. Cardiovascular diseases,
particularly cardiac, have been said to be the major cause of mortality in patients with diabetes [15,16],
accounting for between one-quarter [11] and two-thirds of the deaths [17]. The SMI-positive group with
coronary stenosis showed a higher all-cause mortality, but no significant increase in deaths from cardiac
causes. A type-2 statistical error, as a result of the small number of patients with coronary stenosis and
the low rate of cardiac death, could explain this somewhat surprising finding. Most studies of SMI
screening in patients with diabetes confirm that the presence of coronary stenosis is associated with an
increase in cardiovascular risk and in particular to a higher mortality from cardiac causes [12–14].
However, in these studies, the mortality from non-cardiac causes, and its relationship to the outcome of
the screening studies, is not reported. However, our results are comparable with those of the Milan
Study [11].

A decrease in cardiac mortality similar to that seen in the general population [18] could have several
possible explanations. Even if all patients with diabetes are considered as highrisk patients for
cardiovascular disease, and if systematic screening of SMI is still controversial [3,19,20], we believe,
firstly, that SMI screening may have facilitated the identification of those patients who are at greatest
risk, thereby making it possible to offer them specific treatment. Secondly, we believe that such
screening may also have allowed for more global and intensive management of the patients as
recommended by American Heart Association guidelines [3] and, in particular, of their risk factors, and
indeed the proportion of patients treated with ACE inhibitors, angiotensin II receptor antagonists,
statins, and aspirin increased. These treatments have proven efficacy in primary or secondary
prevention [21–23]. Our patients fell into an intermediate group. Because they had no symptoms of
coronary heart disease, intervention could be regarded as primary prevention yet, as they had
demonstrable vascular abnormalities, it could equally be regarded as secondary prevention. Moreover,
in a recent study focusing on patients with SMI, the cardiovascular event rate was lower on statin
therapy [24]. In addition, patients with SMI were less likely to smoke. The contrast between the absence
of higher cardiac mortality despite an increased frequency of NFMCE in our study could suggest better
cardiological management of such events or decreased severity of these events because of treatment
strategies. Finally, differences in ethnic origin and hence in the genetics as well as the heterogeneity of
the different cohorts could contribute to discrepancies in prognosis.

Patients with Type 2 diabetes clearly constitute a high-risk group as 28% died during the follow-up, and
in the whole cohort 15.3% experienced NFMCEs, this latter proportion rising to 39.1% in the SMI-
positive group. Such a poor prognosis in a patient with Type 2 diabetes is well recognized [25,26], and
may be explained by many factors such as age, BMI, and the presence of other cardiovascular risk
factors.

Age alone is a recognized serious risk factor for major cardiac events and for death both in the general
population [27] and in patients with diabetes [17,28]. Thus, age is an important factor in the screening
strategy for SMI suggested in the most recent guidelines [4]. Although the effect of BMI has not been
studied frequently, BMI influences the development of major cardiac events: 47% of the coronary
disease risk is because of BMI [29]; similarly, in a proteinuric population with Type 2 diabetes, BMI is a
predictive factor for a major event [30]. In our whole study population, in addition to age and BMI, the
only other factor which is predictive of the appearance of major cardiac events is the presence of
coronary stenosis. This latter factor has also been observed by Cosson [28]. In contrast, we were unable
to confirm the predictive value of other risk factors such as microalbuminuria [14,30,31], sex,
hypertension or autonomic neuropathy [5,8,11,12].

The annual death rate in our study was 2.9%, confirming the poor prognosis of patients with diabetes in
terms of overall mortality, as reported by two other studies [17,32]. However, in other reports, lower
annual death rates were found: 0.3% [11], 0.6% [26], 1.8% [33], possibly in part as a result of differences
in underlying cardiovascular risk in the populations studied.
The primary cause of death in our study was cáncer (36.4%). This may be because of the age of our
patients. In some cohorts (general population or patients with diabetes), the major cause of death is
cardiovascular [34,35]. However, other studies have also reported high death rates from cancers, as in
the Norfolk cohort [36], the Milan Study [11] or in a Chinese series [37], where they, respectively,
accounted for 44, 60 and 29.5% of all-cause mortality. However, our population size is relatively small,
some patients were lost to follow-up, and we were unable to identify the cause of death in four
patients. However, the anticipated poor cardiovascular prognosis of our patients with diabetes provided
the justification to screen systematically for SMI and then aggressively manage both the vascular disease
and its risk factors. This probably prevented fatal cardiac events, as shown by some studies [38,39], and
one could argue that it was the resultant increase in lifespan which resulted in the observed increase in
cancer risk.

Limitations of our study include a rather low cardiac event rate although the population was deemed to
be at high risk. These results are comparable with those observed in the Milan Study, and may be
because of similar genetic backgrounds, Mediterranean lifestyle or a potential effect of treatments
implemented after the screening. In our study, the role of treatments is difficult to ascertain because
the choice of drugs and their doses and duration were left to the general practitioner’s discretion and
were not recorded prospectively. Another limitation relates to the screening tests, which do not have
100% sensitivity [5,40]. False-negative patients may have been included in the SMI-negative group, as
not all patients underwent coronary angiography. This latter point also represents a limitation of our
work as we were unable to compare patients with SMI and positive or negative coronary angiography.
However, as a result of the small number of patients with SMI and negative coronary angiography, such
a study would probably need to be multicentre.

In conclusion, this study demonstrates the severity of SMI in patients with diabetes, both in terms of all-
cause mortality and NFMCE. In patients with diabetes, treating all cardiovascular risk factors as
intensively and as early as possible is mandatory for these high-risk patients in order to prevent the
occurrence of cardiac events.

Competing interests

None declared.

Acknowledgements

The authors wish to thank Dr Martin Press (Royal Free Hospital, London) for his advice and contribution
to this article.