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 and
Keith A.A. Foxf
a Clinical Trials and Evaluation Unit, Royal Brompton and Harefield NHS Trust, Sydney Street, London SW3 6NP, UK
b 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
Received February 4, 2004;
revised July 31, 2004;
accepted August 5, 2004
* Corresponding author. Tel.: +44 (0) 207 351 8827; fax: +44 (0) 207 351 8829 (E-mail: m.flather{at}rbh.nthames.nhs.uk).
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Abstract
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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 74.181.1%). 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.
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Introduction
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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 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.36 A number of prospective observational registries including OASIS,7 GRACE810 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.
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Methods
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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.
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Statistics
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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 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. KaplanMeier 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.
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Results
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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.
Rate and causes of mortality (Figs. 1 and 2)
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: 88.292.8%]) and at 45 months 77.8% (95% CI: 74.181.1%).
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 645 months it was 67% (Fig. 2). Deaths over time are shown in Fig. 3.

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Fig. 3 KaplanMeier survival curve showing proportion of survivors over time following hospital admission in 653 patients with non-ST elevation acute coronary syndromes.
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Effects of baseline characteristics and treatment modalities on death during long-term follow-up based on 653 patients
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, the hazard ratio (HR) of death for patients aged 6070 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: 1.67.3), P=0.001] and for T inversion or other ECG changes was 1.9 (95% CI 0.94.1, 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 an HR of 1.78 (95% CI 1.222.59, P=0.003) compared to female patients.
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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
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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.
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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 0.110.85, P=0.02) and use of aspirin in-hospital was associated with an almost 50% reduction (HR 0.51, CI 0.320.82, P=0.005).
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Discussion
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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 follow-up 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 with our findings. Significant predictors of risk at follow-up 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 0.772.62) 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 non-ST 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 guidelines36 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, β-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 further 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 β-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.
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Acknowledgments
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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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