European Heart Journal (2004) 25, 2013–2018
Clinical research
Mortality following non-ST elevation acute
coronary syndrome: 4 years follow-up of the PRAIS
UK Registry (Prospective Registry of Acute
Ischaemic Syndromes in the UK)
Anil K. Tanejaa,b,*, Julian Collinsona, Marcus D. Flathera,b,*, Ameet Bakhaia,
Diego Perez de Arenazaa,c, Duolao Wangd, Jennifer Adgeye, Keith A.A. Foxf
a
Clinical Trials and Evaluation Unit, Royal Brompton and Harefield NHS Trust, Sydney Street, London SW3 6NP, UK
National Heart and Lung Institute, Imperial College School of Medicine, London, UK
c
Hospital Italiano, Buenos Aires, Argentina
d
Medical Statistics Unit, London School of Hygiene and Tropical Medicine, UK
e
Royal Victoria Hospital, Belfast, UK
f
The Royal Infirmary of Edinburgh, Edinburgh, UK
b
Received 4 February 2004; revised 31 July 2004; accepted 5 August 2004
KEYWORDS
Aim To present information on long-term prognosis and risk factors following an
admission with non-ST elevation acute coronary syndrome.
Methods A cohort of 653 patients was followed for mortality and causes of death using
data from the UK Office of National Statistics (ONS). Cox proportional hazards model
was used to identify the prognostic factors.
Results Overall survival at a maximum follow-up of 45 months was 77.8% (95% CI
74.1–81.1%). Seventy-three per cent of the deaths were clearly due to a cardiovascular cause. Age, male gender, heart failure, ST depression or bundle branch block were
all associated with higher short- and long-term risk. Taking aspirin or having a revascularization procedure, over the period of six months following initial hospitalisation
were both associated with a lower long-term risk.
Conclusion Non-ST elevation acute coronary syndromes carry a high risk of death over
a 4-year period. Conventional risk factors can predict both short- and long-term risk.
More invasive management and the use of evidence-based therapies appear to be
associated with a lower risk.
c 2004 Published by Elsevier Ltd on behalf of The European Society of Cardiology.
Long term follow up;
Non-ST acute coronary
syndrome;
Causes of mortality;
Risk factors and prognosis
Introduction
* Corresponding author. Tel.: +44 (0) 207 351 8827; fax: +44 (0) 207 351
8829.
E-mail addresses: [email protected] (A.K. Taneja),
[email protected] (M.D. Flather).
Coronary heart disease is the most common cause of death
in Europe. In the UK, it is estimated that there are about
120000 hospital admissions each year non-ST elevation
acute coronary syndromes (ACS).1 Early reperfusion with
thrombolysis or primary angioplasty are well established
0195-668X/$ - see front matter c 2004 Published by Elsevier Ltd on behalf of The European Society of Cardiology.
doi:10.1016/j.ehj.2004.08.009
2014
treatments for ST elevation ACS.2 For non-ST elevation
ACS, expert guidelines recommend early risk stratification, effective antithrombotic therapy and a low threshold
for angiography and revascularization, especially in higher
risk patients.3–6 A number of prospective observational
registries including OASIS,7 GRACE8–10 and CRUSADE,11
as well as the original PRAIS-UK12 study have provided
information on the outcomes, risk stratification and management of ACS. The OASIS Registry has reported a 2-year
follow-up,13 but otherwise most studies have only reported short-term data.
The Prospective Registry of Acute Ischaemic Syndrome in the UK (PRAIS UK)12 set out to determine characteristics, practice patterns, outcomes and important
markers of risk of patients admitted with ACS without
ST elevation admitted to UK hospitals. Six months follow-up of patients has been reported, and we now report
on longer-term follow-up of a subset of these patients.
A.K. Taneja et al.
1046 patients form 56 centres
(Hospital admission with Non-ST elevation ACS)
34 centres approval
for long-term follow-up
393 patients not
followed for long-term
653 patients available
for long-term follow-up
6 months follow-up of 653 patients
Methods
PRAIS UK was carried out as a prospective, observational, cohort
registry of patients admitted to 56 UK hospitals with acute coronary syndromes without ST elevation. Between May 1998 and
February 1999, 1046 patients with non-ST elevation ACS were
enrolled.12 Each participating hospital was requested to enrol
20 consecutive eligible patients and provide follow-up for 6
months. Eligible patients had to have a clinical history of ACS
with either ECG changes consistent with acute myocardial ischaemia, or with prior evidence of coronary artery disease (e.g.,
prior myocardial infarction, prior revascularization). Patients
with persistent ST elevation or those receiving thrombolysis
were excluded. The study was carried out with 6 months follow-up after index hospital admission. The study received national and local ethical approvals, and each patient provided
informed consent.
The decision to perform long-term follow-up was taken 3
months after starting enrolment in PRAIS-UK. Although approval
from the Multicentre Research Ethics Committee for long-term
follow-up was obtained for all centres, local approvals could
only be requested from hospitals that were still enrolling patients, or those that had not yet started enrolment. Local ethical approvals were eventually obtained in 34 out of the 56
hospitals that enrolled a total of 653 patients with 100% mortality follow-up at 6 months. Of these, 490 patients gave consent
for long-term mortality follow-up. A flow diagram of patients
and deaths is shown in Fig. 1.
The Office of National Statistics (ONS) for England, Wales and
Northern Ireland, and the General Register Office (GRO) of Scotland provided vital status as of 15th November 2002. Dates of
death and copies of death certificates were also provided.
Two experienced clinicians independently classified the causes
of death into cardiovascular (including myocardial infarction,
stroke, and thrombo-embolism), cancer, and ‘‘other’’ (mostly
respiratory causes). Five disagreements were resolved after
discussion.
Statistics
Analysis was performed using the STATA software. Continuous
risk factors were described by mean and standard deviation,
whereas categorical variables were summarized by number of
479 patients followed-up
to 45 months (84 deaths)
60 deaths at 6 months
114 no consent
for long- term follow-up
Fig. 1 Flow diagram of the rate and causes of deaths.
patients and percentage. The Cox proportional hazards model
was used to assess the impact of the selected risk factors on
the survival of patients based on all 653 patients. Assessment
of the assumption of proportionality for a significant predictor
was visually checked to see whether survival curves tended to
be parallel. In the Cox model analysis, P-values less than 0.05
were considered significant. Kaplan–Meier plots have been used
to display the survival rates over the study period by some selected categorical risk factors. To further investigate the impact
on long-term survival of whether the aspirin was used at 6
months and whether there was a PTCA/CABG procedure during
the first 6 months after hospital admission, a subgroup analysis
was performed on 490 patients who survived 6 months by Cox
model with the risk factors in Table 1 as controlling co-variates.
Troponin was only available in 4% of the population and was not
included in this analysis. Likewise, Glycoprotein (GP) IIb/IIIa
antagonists were being introduced at the time and were used
very little at any of the centres involved.
Results
Follow-up for 6 months was complete for 653 patients;
beyond this we had complete follow-up to 45 months
for 490 patients. Thus the mean follow-up period for
the overall cohort was 2.4 years.
Baseline characteristics (Table 1)
Baseline characteristics are shown in Table 1. There were
no significant differences in baseline characteristics between the original PRAIS-UK cohorts, the subset of 653
patients enrolled in hospitals with long-term follow-up
and the 490 patients that had follow-up beyond 6
months.
Mortality following non-ST elevation acute coronary syndrome
2015
Table 1 Baseline characteristics of patients
Variables
Mean (SD) or No (%)
Overall PRAIS (N = 1046)
Long-term PRAIS (N = 653)
Age(years)
Age <60
Age 60-70
Age >70
65.8 (11.9)
343 (32.8%)
283 (27.1%)
420 (40.1%)
66 (12)
206 (31.6%)
183 (28.0%)
264 (40.4%)
ECG
1. Normal
2. ST dep/BBB
3. Other changes*
166 (15.9%)
304 (29.1%)
576 (55.06%)
109 (16.7%)
182 (27.9%)
362 (55.4%)
Systolic BP (mm Hg)
Diastolic BP (mm of Hg)
Heart rate (beats/min)
Gender (%male)
Diabetes
Treated hypertension at baseline
Prior stroke
Heart failure at baseline
Smokers at baseline
Prior angina
Prior MI
Prior PTCA/stent
Prior CABG
146.5 (28.7)
81.5 (16.2)
77.5 (19.11)
635 (60.7%)
170 (16.3%)
388 (37.1%)
81 (7.7%)
139 (13.3%)
239 (22.9%)
778 (74.4%)
504 (48.2%)
140 (13.4%)
142 (13.6%)
147.4 (29.2
82.1 (16.1)
77.2 (18.8)
395 (60.5%)
101 (15.5%)
247 (37.8%)
47 (7.2%)
85 (13.0%)
147 (22.5%)
505 (77.3%)
316 (48.4%)
96 (14.7%)
79 (12.1%)
0.80
0.70
Proportion of patients surviving
Year
0.5
1
2
3
4
Survival
0.925
0.908
0.856
0.809
0.774
95% CI
0.902-0.943
0.882-0.928
0.824-0.882
0.774-0.839
0.737-0.807
0.50
In the first 6 months, there were a total of 48 deaths
(7.3%). Of these, 12 (1.8%) occurred in-hospital and 36
(5.5%) in the period from discharge up to 6 months.
There were a further 84 deaths at final follow-up. The
survival rate at one year was 90.8% (95% confidence
interval [CI: 88.2–92.8%]) and at 45 months 77.8% (95%
CI: 74.1–81.1%).
By classifying the deaths, we found 69 [73%] were due
to cardiovascular causes. In the first six months the proportion of cardiovascular deaths was 92% and from 6–45
months it was 67% (Fig. 2). Deaths over time are shown in
Fig. 3.
0.60
Rate and causes of mortality (Figs. 1 and 2)
0.90
1.00
ECG = Electrocardiogam, ST dep = ST depression, BBB = Bundle branch block, MI = Myocardial infarction, PTCA = percutaneous transluminal
coronary angioplasty, CABG = coronary artery bypass grafting.
* Other changes includes T-wave inversion, Q-waves, and other ST- and T-wave changes.
0
1
2
3
4
5
Time of follow -up (years)
Time (year)
No of
Patients
0
0.5
1
2
3
4
653
594
469
442
418
396
Fig. 3 Kaplan–Meier survival curve showing proportion of survivors over
time following hospital admission in 653 patients with non-ST elevation
acute coronary syndromes.
Effects of baseline characteristics and treatment
modalities on death during long-term follow-up
based on 653 patients
MI 50%
Other cardiovascular 19%
Cancer 15%
Other non-cardiovascular 16%
Fig. 2 Causes of death in patients with long-term follow-up.
Results from the Cox regression analysis are shown in Table 2. Age, gender, systolic blood pressure (SBP), heart
rate, prior heart failure, prior stroke and ECG changes
were found to be significantly associated with the risk
of death in the long-term follow-up period. For example,
2016
A.K. Taneja et al.
Table 2 Hazard ratios and 95% confidence interval for the
effects of baseline characteristics on mortality in long-term
PRAIS follow-up study (653 patients): Cox regression analysis
Variables
Hazard ratio
95% CI
P
45
Age
<60 years
60–70 years
>70 years
1.00
2.29
4.88
ECG changes
Normal
ST dep or BBB
Other changes*
1.00
3.44
1.94
1.62
0.92
7.29
4.07
<0.001
0.081
1.78
1.18
1.43
0.94
1.06
2.41
1.41
0.83
0.69
1.22
0.74
0.77
0.88
1.01
1.60
0.95
0.52
0.43
2.59
1.87
2.62
1.00
1.10
3.63
2.08
1.33
1.11
0.003
0.480
0.26
0.048
0.008
<0.001
0.088
0.444
0.123
2.39
1.44
3.97
<0.001
Male
Smoker
Diabetes
SBP (10 mmHg)
Hear Rate (5bpm)
Prior heart failure
Prior MI
Prior angina
Prior PCI/Stent
or CABG
Prior stroke
40
1.18
2.62
4.44
9.06
0.014
<0.001
35
30
25
20
15
10
5
>70
1.00
0.90
0.70
0.80
60-70 yrs
0.60
>70 yrs
0.50
Proportion of patients surviving
<60 yrs
2
3
4
60-70
<60
Normal
Fig. 5 Long-term risk of death stratified by age and ECG-changes at
baseline. ST dep = ST depression; BBB = Bundle branch block. \Other
changes include T-wave inversion, Q-waves, and other ST- and T-wave
changes.
the hazard ratio (HR) of death for patients aged 60–70
years and over 70 years was 2.29 (CI: 1.18,4.44;
P = 0.014) and 4.88 (CI: 2.62,9.06; P < 0.001), respectively compared to that for patients aged less than 60
(see Fig. 4). HR for death for ST depression or bundle
branch block was 3.4 [(95% CI: 1.6–7.3), P = 0.001] and
for T inversion or other ECG changes was 1.9 (95% CI
0.9–4.1, P = 0.08) compared with normal baseline ECG.
The interaction between age and ECG in the long-term
risk of death is shown in Fig. 5. A patient with a prior
heart failure has 2.41 times the risk of death compared
to a patient without history of heart failure. Males had
1
Other
0
SBP = systolic blood pressure; MI = myocardial infarction;
PCI = Percutaneous coronary intervention; CABG = coronary artery
bypass grafting; BBB = bundle branch block. ST dep = ST depression,
BBB = Bundle branch block.
*
Other changes includes T-wave inversion, Q-waves, and other STand T-wave changes.
0
ST dep/
BBB
5
Time of follow-up (years)
Fig. 4 Survival curves for long-term follow-up (653 patients) by age
group.
an HR of 1.78 (95% CI 1.22–2.59, P = 0.003) compared
to female patients.
Effects of PTCA/CABG and aspirin on death
The effects of revascularization and aspirin use in-hospital on death during long-term follow-up was based on 479
patients who survived to 6 months. The results show
that, after controlling for the baseline characteristics
listed in Table 1, a revascularization procedure during
the first 6 months was associated with 70% lower risk of
death (HR 0.3, CI 0.11–0.85, P = 0.02) and use of aspirin
in-hospital was associated with an almost 50% reduction
(HR 0.51, CI 0.32–0.82, P = 0.005).
Discussion
Our findings show that there is a substantial continuing
risk beyond the first 6 months after presentation with
non-ST elevation ACS with an estimated annual death
rate of about 6%. The majority of these deaths are cardiovascular in nature. Easily identified baseline characteristics including age, baseline ECG, and a prior history of
heart failure that predict early risk are also useful in predicting long-term risk. In the long-term, baseline factors
such as male gender, and a prior history of stroke also appear to be important. It is likely that the risk of non-fatal
acute coronary syndromes, heart failure and other vascular events will also be high in this population, based on
previous studies.2,10
There are few registry studies with long-term followup of patients similar to those in PRAIS-UK. Most
registries follow-up patients for 6 months. The OASIS registry13 has reported follow-up to 2 years. Overall mortality was about 12% (18% for those with diabetes, 10%
without; adjusted HR 1.57, P < 0.001) which is consistent
Mortality following non-ST elevation acute coronary syndrome
with our findings. Significant predictors of risk at followup included age, diabetes and a prior history of heart
failure, MI, PTCA, stroke or CABG. Although OASIS was
a large registry, the follow-up in PRAIS-UK is substantially
longer. Our data are highly consistent with the OASIS
observations for diabetes (PRAIS-UK HR 1.43, CI 0.77–
2.62) and the wider confidence intervals are due to our
smaller sample. Both ST, and non-ST, elevation acute
coronary syndromes appear to have a similar risk after
6 months.14 The ISIS-2 long-term follow-up (mainly ST
elevation patients) showed a 4-year risk of death of
about 25%,15 which is the same as in our study of nonST elevation acute coronary syndromes.
In the OASIS Registry4 investigators reported that
higher rates of revascularization procedures were associated with lower rates of refractory angina or readmission
for unstable angina, but with no detectable impact on
cardiovascular death or MI and with a higher rate of
stroke. In our exploratory analysis, patients who underwent a revascularization procedure in the first 6 months
after an acute coronary syndrome had a lower long-term
risk of death. This observation is consistent with the
GRACE risk model.16 Similarly, the use of evidence-based
treatments like aspirin were also associated with a lower
long-term risk. These observations point to the importance of ensuring these high-risk patients receive high
quality, evidence-based care.
The major accepted international and national guidelines3–6 for the management of acute coronary syndromes
stress the importance of risk stratification so that more
aggressive, invasive and possibly expensive management
strategies are targeted towards high risk patients. These
risk stratification algorithms have been derived from
randomized controlled trials or registry studies. The TIMI
risk score stratifies those with unstable angina or non-ST
elevation MI17 and an absolute risk is given depending on
the number of risk factors. The GRACE study16 gives a
combined score for ST elevation and non-ST elevation
acute coronary syndromes that allows the calculation of
an individual’s mortality risk from discharge to 6 months.
These scores use simple clinical data and are easily calculated. The advantage of the GRACE risk score is that it is
derived from a large registry dataset rather than a more
selected randomized controlled trial population. Most of
the variables included are not dichotomous, which may allow a more sensitive assessment of risk. There is evidence
that patients are managed according to availability of resources rather than the true risk or characteristics of the
patient and that lower risk patients are referred for PCI.18
In terms of allocation of resources and transferring patients for invasive management, these scores have important roles in triaging patients.
Registry projects have demonstrated an increase in
the use of evidence-based therapies over time, starting
from relatively low levels.19,20 Recent studies, such as
GRACE8 and the EURO Heart Survey,21 have confirmed
improved uptake, although basic therapies such as aspirin, b-blockers and statins remain underused. Methods
for tackling this include educational programmes for
the staff caring for these patients; the efficacy of such
programmes were demonstrated a decade ago22 and fur-
2017
ther similar projects are underway, such as GAP (Guidelines Application in Practice).23 This initiative aims to
measure the effects of quality improvement project on
adherence to evidence-based therapies for patients with
AMI. This has improved the treatment of post-myocardial
infarction patients in-hospital and at discharge. The GAP
investigators concluded that implementation of guideline-based tools for AMI may facilitate quality improvement among a variety of institutions, patients, and
caregivers. The CRUSADE (Can Rapid risk stratification
of Unstable angina patients Suppress ADverse outcomes
with Early implementation of the ACC/AHA guidelines?)
project is also underway in the USA and aims to improve
the management of non-ST elevation MI by focussing on
the strategies and treatments recommended in the
ACC/AHA guidelines by the use of hospital protocols
and educational programmes.11 Similar programmes are
being planned in Europe.
Our study is limited by including only 653 of the original patients. This subset seems to be representative of
the original cohort of 1046, but the results still may be
subject to selection bias. At the time of enrolment, troponin was under-used in our cohort, with only 4% of the
patients enrolled having this test performed. We also
do not have information on concomitant treatments such
as b-blockers, statins or clopidogrel during the long-term
follow-up. A more modern approach of risk stratification,
revascularization and the use of effective therapies is
likely to alter our findings of long-term risk. There is a
potential for under-diagnosis of diabetes since this was
based on a clinical history rather than glucose levels or
HbA1c. More sensitive tests for diabetes may alter the
long-term hazard ratios.
The analysis of long-term follow-up of PRAIS UK patients shows that non-ST elevation acute coronary syndrome patients carry a high risk of death and need
better treatment strategies to reduce risk. Increased
use of existing evidence-based treatments, greater use
of revascularization and the introduction of new effective therapies, are likely to reduce this risk. More prospective studies with longer follow-up are needed to
understand the long-term outlook of patients with ACS,
and to develop reliable strategies to reduce the high burden of illness.
Acknowledgements
We are grateful to all investigators and research co-ordinators and acknowledge Merck Sharp and Dohme for their
original support of the PRAIS UK Registry. We are also
grateful to the Office of National Statistics of England
and Wales, and General Registry Office (GRO) for Scotland for providing us with data on vital status and causes
of death.
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