Long-term Cardiovascular Outcomes after Acute Coronary Syndrome: Incidence and Predictors During Long-term Follow-up in a Population-based Cohort Study

Abstract

Introduction

There is limited data on long-term outcomes after hospitalization for ACS. We aimed to estimate the rate of recurrent cardiovascular events in the long-term, in a population-based, unselected cohort of ACS patients.

Methods and results

We included 1379 patients with ACS hospitalized at Östersund hospital 2010-2014 and followed them from the day after discharge to 31 December 2017. The primary endpoint was the unadjusted rate of the composite of CV death, AMI and ischemic stroke. Risk factors for the primary endpoint were assessed in a multivariable Cox proportional hazards regression model. During a median follow-up of 4.7 years, the unadjusted rate of the primary endpoint was 10.3% at 1 year and 28.6% at the end of follow-up. Predictors of increased risk for subsequent events were congestive heart failure, diabetes mellitus, angina pectoris, prior revascularization with PCI or CABG and treatment with diuretics at discharge. Lipid-lowering therapy at discharge and revascularization with PCI or CABG were associated with a lower risk of recurrent events.

Conclusion

The risk of recurrent cardiovascular was high at 1 year and continued to be so during the following almost three years of median follow-up. Established predictors of cardiovascular risk were confirmed.

Introduction

Incidence and mortality of cardiovascular (CV) disease have decreased during recent decades(1). Improved acute treatment as well as effective secondary prevention have contributed to this positive development(2). However, ischemic heart disease and stroke still constitute the two leading causes of death, both in Sweden and worldwide(3, 4). There is limited data on long-term outcome after an acute coronary syndrome (ACS) in recent years. Most of our current knowledge on long-term risk after ACS is based on clinical trials, generally not mirroring the general population and with relatively short follow-up periods. Register based studies have study samples more representative of the general population, but they have an inherent weakness in the lack of adjudication of outcome events, which can lead to both under- and overestimation of endpoints, and thereby false risk estimates. Both clinical trials and register-based studies point at a substantial risk elevation for recurrent events in both the short and long terms after ACS(5, 6). Moreover, improved survival after ACS in combination with a growing and ageing population will lead to an increased burden of coronary heart disease(7). These findings highlight the importance of optimized care, both in the acute phase and long term regarding secondary prevention of recurrent events. A reliable estimate of long-term risk in a contemporary post-ACS population is therefore important in order to be able to direct adequate secondary preventive measures. The aim of this study was to assess the risk for recurrent CV events in an unselected cohort of patients hospitalized for ACS, i.e. acute myocardial infarction (AMI) and unstable angina (UA), with the possibility of long-term follow-up.

Methods

Study population and data collection

We included all patients registered in the NAILED-ACS Risk Factor Trial, which is a randomized, controlled trial conducted at Östersund Hospital, designed to investigate if intervention by a telephone-based, nurse-led secondary prevention programme could improve CV outcomes after ACS, compared with usual care. The study protocol has been published elsewhere(8). In summary, the trial included all patients hospitalized for ACS at Östersund Hospital between 1 January 2010 and 31 December 2014. Suspected ACS patients were identified through review of patient records and included if they fulfilled the critiera for UA, defined as suspected ischemic chest pain and electrocardiogram changes suggestive of myocardial ischemia, such as ST-segment depression or T-wave alteration, or type 1 AMI according to the third universal definition of MI. A study flow chart is presented in Fig. 1.

Östersund Hospital is the only hospital in the county of Jämtland/Härjedalen, with a catchment area of about 126.000 people. During the inclusion period, the primary reperfusion treatment for ST-segment myocardial infarction was thrombolysis. In may 2015, Östersund hospital established a 24/7 primary percutaneous coronary intervention (PPCI) network in the county of Jämtland/Härjedalen, which resulted in a switch in reperfusion treatment for STEMI from thrombolysis to PPCI in the vast majority of cases.

Endpoints were identified and adjudicated by reviewing all study subjects discharge records from subsequent hospitalizations at the department of internal medicine and cardiology at Östersund Hospital. Cause of death was adjudicated by reviewing death certificates as well as patient records and classified according to prespecified criteria. To identify endpoints that took place in other departments, relevant International Statistical Classification of Diseases and Related Health Problems (ICD-10) diagnoses were extracted from the national patient register (NPR), which contains main and secondary diagnoses for all hospitalizations in Sweden. These were also adjudicated by review of patient records. The adjudication of events was performed by four experienced physicians (2 senior consultants and 2 senior residents) who were part of the study team. Each physician worked independently according to a standardized workflow algorithm and endpoints were adjudicated strictly according to a prespecified endpoint definition. Consecutive meetings were held where complicated cases were discussed and consensus reached.

Endpoints

The primary endpoint was major adverse cardiovascular events (MACE) defined as the composite of CV death, type 1 AMI and ischemic stroke, whichever happened first. The follow-up period was from the day after discharge from the index event hospitalization until 31 dec 2017. All diagnoses were classified according to ICD-10 codes. Death was classified as CV, non-CV or unknown cause of death. CV death was defined as death from CV causes within 30 days after an AMI, sudden cardiac death (SCD), congestive heart failure, stroke, CV procedures, CV bleeding and other CV causes such as pulmonary embolism and peripheral artery disease(9). AMI was defined according to the third universal definition of myocardial infarction. Only type 1 AMIs were included, where type 1 AMI is defined as an AMI classically caused by plaque rupture, erosion, ulceration or dissection followed by thrombosis at the lesion or distal embolization causing myocardial ischemia and necrosis(10). Ischemic stroke was defined as an acute episode of focal or global cerebral, spinal or retinal dysfunction caused by infarction of central nervous system (CNS) tissue.

Results

Baseline characteristics

1379 ACS-patients were included (64.9% men and 36.1% women) and followed from the day after discharge from the index event hospitalization for ACS until 31 dec 2017. The median age was 71 years, with a considerably higher median age in the female population. Index ACS-type were NSTEMI in 62.9%, STEMI in 29.5% and UA in 7.6% of cases. 58.5% had hypertension, 22.1% diabetes and 8.6% atrial fibrillation. 21.4% had previously had an MI and 5.9% an ischemic stroke. 53.8% were revascularized during index hospitalization (43.8% PCI and 10% CABG). Baseline characteristics are presented in Table 1. Generally, patients were pharmacologically well treated at discharge. 92.7% had aspirin, 78.5% a P2Y12-inhibitor, 8.2% oral anticoagulation (OAC), 88% betablocker, 87% lipid lowering therapy and 77.3% RAAS-blockade. Medication on admission and at discharge is presented in Tables 2 and 3 respectively.

Primary endpoint

In total, there were 327 events meeting the criteria for the primary endpoint during the entire study period, with a median follow-up time of 4.7 years, K-M cumulative incidence 28.6% (95% confidence interval(CI): 26.2–31.0) (Fig. 2). At 1 year, K-M cumulative incidence was 10.3% (95% CI: 8.7–12.1). The K-M incidence of the individual components of the primary endpoint are presented in Figs. 3, 4 and 5 respectively.

Risk according to age

KM estimates for the primary end-point according to age stratification were analyzed at 3 years, due to few events in two youngest age strata towards the end of the studied time period. At 3 years, there were 19 events, KM estimate 8.1% (95% CI: 5.1–12.5) among patients < 60 years (n = 237), 40 events, KM estimate 10.2% (95% CI: 7.4–15.7) among patients 60–69 years (n = 396), 60 events, KM estimate 16% (95% CI: 12.5–20.1) among patients 70–79 years (n = 377) and 126 events, KM estimate 34.2% (95% CI: 29.4–39.3) among patients ≥ 80 years (n = 396), see Fig. 6.

Predictors of the primary endpoint

Baseline characteristics according to the occurrence of the primary endpoint are displayed in Table 4. Patients suffering a primary endpoint event were significantly older and more likely female. Index ACS-type was predominantly NSTEMI among patients reaching an endpoint, who also had significantly more comorbidities such as hypertension, diabetes mellitus and atrial fibrillation. There was also a clear overrepresentation of prior AMI, congestive heart failure (CHF), ischemic stroke and peripheral artery disease among patients experiencing an event. Event-free patients were also revascularized to a far greater extent.

Variables tested in a univariable cox regression model are presented in Table 6. In a multivariable model, presented in Table 7, age HR 1.03 (95% CI: 1.02–1.05), prior CHF HR 1.56 (95% CI: 1.11–2.21), prior diabetes mellitus HR 1.74 (95% CI: 1.36–2.22), prior angina HR 1.41 (95% CI: 1.08–1.85), prior PCI HR 1.41 (95% CI: 1.00–2.00), prior CABG HR 1.82 (95% CI: 1.36–2.49) and treatment with diuretics at discharge HR 1.32 (95% CI: 1.04–1.68) were independently associated with an increased risk of the primary endpoint during the study period. Revascularization during index event hospitalization with PCI HR 0.58 (95% CI: 0.44–0.77) and CABG HR 0.51 (95% CI: 0.31–0.85) as well as lipid lowering therapy at discharge HR 0.69 (95% CI: 0.51–0.94) were associated with a reduced risk for the occurrence of the primary endpoint.

Competing risk analysis according to Fine and Gray did not alter the result of the multivariable analysis.

Discussion

This was a retrospective observational study in a contemporary, population-based and unselected cohort of ACS-patients, with a long follow-up period, reporting long-term cardiovascular outcomes after ACS. To our knowledge, there are no comparable studies reporting outcomes in absolute numbers. Almost one out three patients died for cardiovascular reasons or had a recurrent ischemic event during the study period. Over 40% of all events and more than half of all MI´s occurred during the first year. IS events were more evenly distributed, with nearly 1/3 occurring during the first year.

Compared with the Cardiovascular risk in post-myocardial infarction patients: nationwide real-world data demonstrate the importance of a long-term perspective study (6), which was a Swedish nationwide register based study (n = 97254) to assess the incidence and risk factors of subsequent cardiovascular events in the Swedish post MI population, we found a lower event rate both short and long term. That study included AMI-patients surviving the first week after discharge, with a total follow-up of 4 years and a mean follow-up time of 2.5 years. The 1-year rate of the composite of cardiovascular (CV) death, recurrent MI and stroke was estimated to 18.3%, and the risk remained high in patients without an event during the first year, in the subsequent 2 years at about 20%, which is almost twice as high as in our material. The patient data upon which these results are based is comparable with ours in terms of a high median age and a relatively low frequency of revascularization during hospitalization. On the other hand, preexisting heart failure was clearly more prevalent (26.3%) compared with our cohort (5.3%) which might contribute to a higher event rate in general and CV mortality in particular. Moreover, in our study all end-points were adjudicated and we only included type-1 MI´s, which likely contributes to the observed lower event rate. Type-2 MI has been associated with a clearly higher mortality in previous reports and the proportion of type-2 MI in SWEDEHEART has been estimated to 7.1%(11).

In a large study comparing long-term outcomes after MI (3 years) 2002–2011 in nationwide registers from England, France, Sweden and USA in more than 100000 patients > 65 years, the cumulative incidence of the composite of all-cause death, MI and stroke varied between 26% (France) and 36.2% (USA)(12). These numbers are more at level with our results when taking into account that the end-point included all-cause death and that the studied populations had a high burden of comorbidities and a very high mean age of 77.5–78.6 years.

These results indicate that the risk is high during the first year, and remains high also in a longer time perspective, which highlights the importance of adequate secondary prevention and revascularization procedures.

Older age, diabetes mellitus, prior ischemic stroke, heart failure (treatment with diuretics at discharge), established coronary heart disease (prior PCI, CABG or angina) independently predicted increased risk for the primary endpoint in our material, whereas revascularization during index hospitalization and lipid-lowering therapy were associated with favorable outcome.

In accordance with previous publications, older age conferred increased risk for recurrent cardiovascular events in this study(13). An ageing population and increasing proportion of survivors of ACS should urge health care systems to direct their attention regarding secondary prevention not only to younger patients. Diabetes Mellitus has repeatedly been shown to forcefully increase the risk for cardiovascular disease(14). It has also been linked to excess mortality after MI compared with patients without diabetes(15), and ESC guidelines for non-ST-segment elevation acute coronary syndromes (NSTE-ACS) recommend that a multifactorial approach, with treatment targets should be considered in this subset of ACS-patients (grade of recommendation IIa)(16). In our material, diabetes was the comorbidity with the strongest association of elevated long term ischemic risk after ACS, which in conjunction with previous evidence points at the importance of good metabolic control and intensive lipid lowering therapy(17). There is vast evidence from clinical trials that lipid-lowering statin therapy reduces cardiovascular morbidity and mortality in both chronic and acute coronary syndromes(18, 19). In our study, lipid-lowering therapy was strongly associated with a reduced risk for recurrent events in the long term, which confirm the results from clinical trials and contribute to generalizability to a real-world ACS-population.

Ischemic stroke and heart failure have, as in this study, been identified previously as markers of elevated risk for recurrent ischemic events and death(6, 13, 20, 21).

Revascularization during index-hospitalization for ACS, both CABG and PCI, were strongly associated with better outcome in this study. Jernberg et al reported that absence of revascularization was associated with increased cardiovascular risk (6). An early invasive strategy, with coronary angiography followed by PCI if appropriate, has been shown to reduce cardiovascular events long-term after NSTE-ACS, compared with an initial conservative strategy (22, 23). In ST-segment myocardial infarction (STEMI), there is solid evidence that prompt revascularization reduces mortality and subsequent ischemic events (24, 25). Elderly patients are generally considered to have a greater burden of coronary disease and thereby more myocardial ischemia and seem to derive a relatively greater benefit from revascularization (26, 27). Given the high median age in this cohort, this seems to hold true for our patient population and has important implications for the often difficult clinical decision-making regarding revascularization in the care of elderly patients with ACS.

Strengths and limitations

This unselected, single-center cohort, with the aim to study the long-term cardiovascular outcome after hospitalization for ACS, was relatively small, which is a limitation. However, the data collected can be considered to be of high quality as well as the adjudication of clinical endpoints. The outcome measures cardiovascular death, myocardial infarction and ischemic are fairly standardized. We chose to only include type 1 MI´s, because we had the opportunity to evaluate every clinical event, and since a type 1 MI has a different prognostic impact than for example a type 2 MI. This might lead to lower event rates compared with register-based studies, in which it is hard to discriminate between infarction types. Due to the establishment of a PPCI-network in the region, patients received a different reperfusion treatment, with a clear dominance of PPCI from May 2015 until the end of follow-up, compared with a fibrinolysis dominated reperfusion treatment before May 2015, which might has affected outcomes.

Conclusion

In an unselected cohort of ACS-patients, with a median follow-up time of 4.7 years, the risk for the composite of CV-death, MI and IS was 10.3% at 1 year and 28.6% during the entire study period.

Risk factors associated with an increased risk of the primary end-point were Diabetes Mellitus, prior revascularization, heart failure at discharge and prior IS. Associated protective factors were revascularization during index hospitalization and lipid lowering therapy at discharge.

Declarations

Data availability

The datasets used and analysed in this study are available from the corresponding author on reasonable request.

Acknowledgements

This study was supported by the unit of research, education and development of region Jämtland/Härjedalen.

Author contributions

A.U., A.G., A.L.I. and T.M. were involved in study design, data collection, adjudication of events, analysis and revision of the manuscript. L.S. supervised statistical analysis and performed more complex statistical tasks. T.M. is the main supervisor.

Conflicts of interest

Nothing to declare

References

1. Yeh RW, Sidney S, Chandra M, Sorel M, Selby JV, Go AS. Population trends in the incidence and outcomes of acute myocardial infarction. N Engl J Med. 2010;362(23):2155–65.
2. Wallentin L, Becker RC, Budaj A, Cannon CP, Emanuelsson H, Held C, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361(11):1045–57.
3. Khan S, De Munter J. The National Board of Welfare, Statistics on Causes of Death 2019. 2020(ISSN 1400–3511):1–3.
4. Collaborators GBDCoD. Global, regional, and national age-sex-specific mortality for 282 causes of death in 195 countries and territories, 1980–2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2018;392(10159):1736–88.
5. Abtan J, Bhatt DL, Elbez Y, Sorbets E, Eagle K, Ikeda Y, et al. Residual Ischemic Risk and Its Determinants in Patients With Previous Myocardial Infarction and Without Prior Stroke or TIA: Insights From the REACH Registry. Clin Cardiol. 2016;39(11):670–7.
6. Jernberg T, Hasvold P, Henriksson M, Hjelm H, Thuresson M, Janzon M. Cardiovascular risk in post-myocardial infarction patients: nationwide real world data demonstrate the importance of a long-term perspective. European Heart Journal. 2015;36(19):1163–70.
7. Moran AE, Forouzanfar MH, Roth GA, Mensah GA, Ezzati M, Flaxman A, et al. The global burden of ischemic heart disease in 1990 and 2010: the Global Burden of Disease 2010 study. Circulation. 2014;129(14):1493–501.
8. Mooe T, Björklund F, Graipe A, Huber D, Jakobsson S, Kajermo U, et al. The Nurse-Based Age Independent Intervention to Limit Evolution of Disease After Acute Coronary Syndrome (NAILED ACS) Risk Factor Trial: Protocol for a Randomized Controlled Trial. JMIR Research Protocols. 2014;3(3):e42.
9. Hicks KA, Mahaffey KW, Mehran R, Nissen SE, Wiviott SD, Dunn B, et al. 2017 Cardiovascular and Stroke Endpoint Definitions for Clinical Trials. J Am Coll Cardiol. 2018;71(9):1021–34.
10. Thygesen K, Alpert JS, Jaffe AS, Simoons ML, Chaitman BR, White HD, et al. Third universal definition of myocardial infarction. Eur Heart J. 2012;33(20):2551–67.
11. Baron T, Hambraeus K, Sundstrom J, Erlinge D, Jernberg T, Lindahl B, et al. Type 2 myocardial infarction in clinical practice. Heart. 2015;101(2):101–6.
12. Rapsomaniki E, Thuresson M, Yang E, Blin P, Hunt P, Chung SC, et al. Using big data from health records from four countries to evaluate chronic disease outcomes: a study in 114 364 survivors of myocardial infarction. Eur Heart J Qual Care Clin Outcomes. 2016;2(3):172–83.
13. Johansson S, Rosengren A, Young K, Jennings E. Mortality and morbidity trends after the first year in survivors of acute myocardial infarction: a systematic review. BMC Cardiovasc Disord. 2017;17(1):53.
14. Emerging Risk Factors C, Sarwar N, Gao P, Seshasai SR, Gobin R, Kaptoge S, et al. Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies. Lancet. 2010;375(9733):2215–22.
15. Alabas OA, Hall M, Dondo TB, Rutherford MJ, Timmis AD, Batin PD, et al. Long-term excess mortality associated with diabetes following acute myocardial infarction: a population-based cohort study. J Epidemiol Community Health. 2017;71(1):25–32.
16. Collet JP, Thiele H, Barbato E, Barthelemy O, Bauersachs J, Bhatt DL, et al. 2020 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation. Eur Heart J. 2020.
17. Ahmed S, Cannon CP, Murphy SA, Braunwald E. Acute coronary syndromes and diabetes: Is intensive lipid lowering beneficial? Results of the PROVE IT-TIMI 22 trial. Eur Heart J. 2006;27(19):2323–9.
18. Pedersen TR, Kjekshus J, Berg K, Haghfelt T, Faergeman O, Faergeman G, et al. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). 1994. Atheroscler Suppl. 2004;5(3):81 – 7.
19. Cannon CP, Braunwald E, McCabe CH, Rader DJ, Rouleau JL, Belder R, et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med. 2004;350(15):1495–504.
20. Ulvenstam A, Kajermo U, Modica A, Jernberg T, Soderstrom L, Mooe T. Incidence, trends, and predictors of ischemic stroke 1 year after an acute myocardial infarction. Stroke. 2014;45(11):3263–8.
21. Brammas A, Jakobsson S, Ulvenstam A, Mooe T. Mortality after ischemic stroke in patients with acute myocardial infarction: predictors and trends over time in Sweden. Stroke. 2013;44(11):3050–5.
22. Fox KA, Clayton TC, Damman P, Pocock SJ, de Winter RJ, Tijssen JG, et al. Long-term outcome of a routine versus selective invasive strategy in patients with non-ST-segment elevation acute coronary syndrome a meta-analysis of individual patient data. J Am Coll Cardiol. 2010;55(22):2435–45.
23. Elgendy IY, Kumbhani DJ, Mahmoud AN, Wen X, Bhatt DL, Bavry AA. Routine invasive versus selective invasive strategies for Non-ST-elevation acute coronary syndromes: An Updated meta-analysis of randomized trials. Catheter Cardiovasc Interv. 2016;88(5):765–74.
24. investigators G. An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction. N Engl J Med. 1993;329(10):673–82.
25. Keeley EC, Boura JA, Grines CL. Primary angioplasty versus intravenous thrombolytic therapy for acute myocardial infarction: a quantitative review of 23 randomised trials. Lancet. 2003;361(9351):13–20.
26. Spoon DB, Psaltis PJ, Singh M, Holmes DR, Jr., Gersh BJ, Rihal CS, et al. Trends in cause of death after percutaneous coronary intervention. Circulation. 2014;129(12):1286–94.
27. Singh M, Peterson ED, Roe MT, Ou FS, Spertus JA, Rumsfeld JS, et al. Trends in the association between age and in-hospital mortality after percutaneous coronary intervention: National Cardiovascular Data Registry experience. Circ Cardiovasc Interv. 2009;2(1):20–6.