We sought to evaluate the rates, time course, and causes of death in the long-term follow-up of unselected patients with acute coronary syndromes (ACS). We enrolled 2046 consecutive patients hospitalized from January 2004 to December 2005 with an audited final diagnosis of ACS. The primary study end point was 5-year all-cause mortality. In our series, 896 patients had ST-segment elevation (STE) and 1,150 non–ST-segment elevation (NSTE). Mean age of the study population was 71.6 years. Primary percutaneous coronary intervention was performed in 86% of STE-ACS, and 70% of NSTE-ACS was managed invasively. The 5-year all-cause mortality was 36.4% for STE-ACS and 42.0% for NSTE-ACS, with patients with STE-ACS showing a trend boarding statistical significance toward a lower risk of mortality (hazard ratio [HR] = 0.88, 95% confidence interval [CI] 0.76 to 1.02, p = 0.08). Landmark analysis demonstrated that patients with STE-ACS had a higher risk of 30-day mortality (STE-ACS vs NSTE-ACS HR = 1.53, 95% CI 1.16 to 2.06, p = 0.003) whereas the risk of NSTE-ACS increased markedly after 1 year (STE-ACS vs NSTE-ACS HR = 0.67, 95% CI 0.53 to 0.84, p = 0.001). The contribution of noncardiovascular (CV) causes to overall mortality increased from 3% at 30 days to 34% at 5 years, with cancer and infections being the most common causes of non-CV death both in STE-ACS and NSTE-ACS. In conclusion, long-term mortality after ACS is still too high both for STE-ACS and NSTE-ACS. Although patients with STE-ACS have a higher mortality during the first year, the mortality of patients with NSTE-ACS increases later, when non-CV co-morbidities gain greater importance.
Until now, data on late consequences of acute coronary syndromes (ACS) have been mainly derived from clinical trials. These may be hampered by selection bias, thereby excluding older and sicker patients. Furthermore, in daily clinical practice, ACS are not seen in isolation but rather in connection with a series of additional medical co-morbidities. These factors, whereby patients are often excluded from clinical trials, are among the main determinants of prognosis. In contrast, observational studies addressing long-term follow-up of unselected cohorts of patients hospitalized for ACS are few, limited, and with conflicting results in terms of mortality rates. Moreover, few data are available regarding the time course and specific causes of death in the long-term follow-up of patients with ACS, also they are limited to patients with non–ST-segment elevation (NSTE) ACS. The aim of this study was to compare 5-year outcomes of unselected patients with ST-segment elevation (STE) versus NSTE ACS in a real-world context of contemporary acute treatment and secondary prevention, focusing specifically on the time course of events and the causes of death.
Methods
The S. Orsola-Malpighi Hospital is a tertiary care center located in Bologna, Northern-Italy (approximately 1 million people catchment area) with a high-volume catheterization laboratory, available on a 7 days × 24 hours basis. The “S. Orsola-Malpighi ACS database” contains comprehensive demographical, clinical, procedural, laboratory, and outcome information of patients with ACS hospitalized at our institution and was approved by the local ethics committee. All consecutive patients hospitalized from January 1, 2004, to December 31, 2005, with an audited final diagnosis of ACS were enrolled.
Patients were identified in 2 complementary ways to include all relevant cases, thus avoiding selection bias:
- (1)
Patients prospectively screened and enrolled by a trained physician working at the emergency department or the coronary care unit during index hospitalization for ACS.
- (2)
Patients identified through a systematic review (clinical audit) of all medical records of patients discharged from January 1, 2004, to December 31, 2005, with the following International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis codes: 410.X1 or 4111. The audit was performed by an end point adjudication committee (GM, FV, and LC) and patients fulfilling the diagnostic criteria of ACS (mentioned in the following) were included in the database.
Patients with symptoms suggestive of myocardial ischemia were classified as having STE-ACS if the 12-lead electrocardiogram disclosed a persistent (>20 minutes) STE occurring in 2 contiguous leads (>0.2 mV in V1-V3, >0.1 mV in other leads) or a new (or presumably new) left-bundle-branch block.
A diagnosis of NSTE-ACS was made in case of symptoms suggestive of myocardial ischemia plus 1 of the following: (1) ST-segment depression >0.05 mV in any lead, (2) transient (<20 minutes) STE in 2 contiguous lead, (3) inverted T waves >1 mm in 2 contiguous lead, (4) positive cardiac biomarkers, and (5) documentation of coronary artery disease. Patients presenting with pacemaker rhythm and preexisting left-bundle-branch block were categorized as having NSTE-ACS.
The final diagnosis was adjudicated by the end point adjudication committee that systematically reviewed all cases; disagreements were solved by consensus.
The primary study end point was 5-year mortality. The main secondary end point was cardiovascular (CV) death. Other secondary end points included recurrence of myocardial infarction (re-MI), stroke, major bleeding, and rehospitalization for any cause and/or unstable angina and/or heart failure at 5-year follow-up. CV death was defined as composite of death from cardiac cause, sudden death, any death without other known cause, and fatal stroke. In patients presenting without an MI on hospital admission, in-hospital MI was defined by the occurrence of symptoms of ischemia, along with a typical troponin or creatine kinase-MB increase above the upper limit of normal or new significant Q waves in at least 2 contiguous electrocardiographic leads. In-hospital re-MI was defined as the recurrence of typical clinical symptoms and new electrocardiographic changes with an increase of creatine kinase-MB above ≥50% of the previous level. Stroke was defined as sudden onset of a focal neurologic deficit lasting >24 hours, confirmed by a CT scan. In-hospital bleeding was classified as major or minor according to the Thrombolysis In Myocardial Infarction classification.
Major bleeding occurring after discharge was defined as follows: intracranial hemorrhage, bleeding requiring transfusion or surgery or hospitalization, and hemoglobin reduction >5 g/dl when available.
Thirty-day, 1-year, and 5-year follow-up was complete for 2040 of 2046 (99.7%), 1985 of 2046 (97.1%), and 1703 of 2046 (83.2%) patients, respectively. As reference cohort for 5-year mortality, we used residents of the Emilia Romagna region aged from 70 to 79 years, with no history of hospitalization for CV, oncologic, pneumologic, or nephrologic causes, based on regional administrative data.
Categorical data are expressed as proportions and continuous variables reported as mean ± SD or medians and interquartile range (Twenty-fifth to seventy-fifth percentiles), as appropriate. The study population was divided into 2 groups according to the final confirmed diagnosis: STE-ACS or NSTE-ACS. For comparisons between groups, the chi-square test for categorical variables was used. The 2-tailed Student t test was used to compare normally distributed continuous variables. Comparison of nonnormally distributed variables was conducted using the Mann-Whitney U test.
The Kaplan-Meier method was used to analyze the occurrence of death and CV death during follow-up and comparison between groups was conducted using the log-rank test. To better define the temporal distribution of events during follow-up among the 2 groups, a landmark analysis was performed from 0 (admission) to 30 days, from 30 days to 1 year, and from 1 year to 5 years. These time periods were predefined to describe the early acute and postdischarge phase (0 to 30 days), as well as the medium and long-term outcome.
Multivariable Cox regression analysis was performed to identify predictors of 5-year death. The following variables were chosen on the basis of clinical judgment and included in the model: age, gender, diabetes, hypertension, dyslipidemia, smoking status, previous stroke, previous MI, previous coronary revascularization (percutaneous coronary intervention or coronary artery bypass graft), peripheral arterial disease, systolic blood pressure and heart rate on admission, Killip class on admission, atrial fibrillation on admission, estimated glomerular filtration rate calculated by the Modification of Diet in Renal Disease equation, hemoglobin level on admission, troponin T positivity, STE-ACS versus NSTE-ACS, ST-segment deviation, left ventricular ejection fraction measured by echocardiography, and percutaneous coronary intervention or coronary artery bypass grafting performed during index hospitalization.
A p value <0.05 in the 2-tailed tests was considered significant. All analyses were performed with SPSS 15.0 software (SPSS Inc., Chicago, Illinois) and Stata 11.0 software (StataCorp LP, College Station, Texas)
Results
From January 1, 2004, to December 31, 2005, 2,046 patients with confirmed final diagnosis of ACS were hospitalized and enrolled in the study. Baseline clinical, electrocardiographic, and laboratory findings of the study population are listed in Table 1 . The mean age was 71.6 years and 1,319 patients (64.5%) were men. Overall, 896 (44%) patients had STE-ACS and 1,150 (66%) NSTE-ACS. The 2 groups differed significantly in terms of baseline characteristic. Patients with NSTE-ACS had a greater burden of CV conditions and non-CV co-morbidities.
| Characteristics | All patients (n = 2046) | Acute Coronary Syndromes | P value | |
|---|---|---|---|---|
| STE | NSTE | |||
| (n = 896) | (n = 1150) | |||
| Age (years) | 71.6 ± 13.0 | 69.8 ± 13.8 | 73.1 ± 12.1 | <.001 |
| Men | 1319 (64.5%) | 609 (68.0%) | 710 (61.7%) | .003 |
| Previous MI | 652 (31.9%) | 167 (18.6%) | 485 (42.2%) | <.001 |
| Previous PCI/CABG | 436 (21.3%) | 103 (11.5%) | 333 (29.0%) | <.001 |
| Chronic heart failure | 215 (10.5%) | 38 (4.4%) | 177 (15.4%) | <.001 |
| Previous stroke | 128 (6.3%) | 53 (5.9%) | 75 (6.5%) | .57 |
| Peripheral artery disease | 312 (15.3%) | 67 (7.5%) | 245 (21.3%) | <.001 |
| Severe renal insufficiency | 209 (10.2%) | 44 (4.9%) | 165 (14.3%) | <.001 |
| COPD | 217 (10.6%) | 70 (8.1%) | 147 (12.7%) | <.001 |
| Diabetes mellitus | 492 (24.1%) | 174 (19.4%) | 318 (27.7%) | <.001 |
| Hypercholesterolemia | 913 (44.6%) | 356 (39.7%) | 557 (48.5%) | <.001 |
| Hypertension | 1407 (68.8%) | 538 (60.0%) | 869 (75.6%) | <.001 |
| Smokers | 637 (31.1%) | 362 (40.4%) | 275 (23.9%) | <.001 |
| Family-history of CAD | 363 (17.8%) | 182 (20.3%) | 181 (15.8%) | .007 |
| Home medications | ||||
| Aspirin | 737 (36.0%) | 229 (25.5%) | 508 (44.0%) | <.001 |
| Thienopyridine | 292 (14.3%) | 62 (6.9%) | 230 (20.0%) | <.001 |
| Warfarin | 145 (7.1%) | 30 (3.2%) | 115 (10.0%) | <.001 |
| B-Blockers | 765 (37.4%) | 203 (22.7%) | 562 (48.8%) | <.001 |
| ACE-I/ARBs | 880 (43.0%) | 280 (31.2%) | 600 (52.0%) | <.001 |
| Statin | 483 (23.6%) | 134 (14.8%) | 349 (30.3%) | <.001 |
| Systolic BP (mmHg) | 135 ± 36 | 127 ± 32 | 141 ± 38 | <.001 |
| Heart rate (beats/minute) | 83 ± 25 | 80 ± 22 | 87 ± 26 | <.001 |
| Killip class | ||||
| 1 | 1577 (77.1%) | 721 (80.5%) | 856 (74.5%) | |
| 2 | 208 (10.2%) | 46 (5.1%) | 162 (14.1%) | <.001 |
| 3 | 162 (7.9%) | 46 (5.1%) | 116 (10.1%) | |
| 4 | 98 (4.8%) | 83 (9.3%) | 15 (1.3%) | |
| Persistent STE | 847 (41.4%) | 847 (94.5%) | ||
| New LBBB | 49 (2.4%) | 49 (5.5%) | ||
| Normal/No significant ST-T changes | 429 (21.0%) | 429 (37.3%) | ||
| Inverted T wave | 183 (8.9%) | 183 (15.9%) | ||
| STD | 478 (23.4%) | 478 (41.5%) | ||
| Pacing | 17 (0.8%) | 17 (1.5%) | ||
| Atrial fibrillation | 190 (9.3%) | 44 (4.9%) | 146 (12.7%) | <.001 |
| LVEF (%) | 47.1 ± 13.0 | 44.1 ± 11.8 | 49.6 ± 13.3 | <.001 |
| eGFR < 60 (ml/min/1.73 m 2 ) | 877 (42.9%) | 312 (34.8%) | 565 (49.1%) | <.001 |
| Hemoglobin (g/dl) | 13.7 ± 1.6 | 14.0 ± 1.6 | 13.5 ± 1.7 | .53 |
The use of in-hospital medications and interventions is listed in Table 2 . Primary percutaneous coronary intervention was performed in 82.4% of patients with STE-ACS, and most of patients with NSTE-ACS (69.2%) were managed invasively.
| Variable | All patients (n = 2046) | Acute Coronary Syndromes | P value | |
|---|---|---|---|---|
| STE | NSTE | |||
| (n = 896) | (n = 1150) | |||
| Medical treatment within 24h | ||||
| Aspirin | 1849 (90.4%) | 865 (96.5%) | 984 (85.6%) | <.001 |
| Thienopyridine | 1403 (68.5%) | 733 (81.8%) | 670 (58.3%) | <.001 |
| B-Blockers | 1613 (78.8%) | 692 (77.2%) | 921 (80.1%) | .18 |
| ACE-I/ARB | 1475 (72.1%) | 624 (69.6%) | 851 (74.0%) | .06 |
| UFH | 906 (44.3%) | 709 (79.1%) | 197 (17.1%) | <.001 |
| LMWH | 994 (48.6%) | 169 (18.9%) | 825 (71.7%) | <.001 |
| GP IIb-IIIa inhibitors | 943 (46.1%) | 604 (67.4%) | 339 (29.4%) | <.001 |
| Warfarin | 130 (6.4%) | 25 (2.8%) | 105 (9.1%) | <.001 |
| Statin | 914 (44.7%) | 385 (43.0%) | 529 (46.0%) | .19 |
| Coronary angiography | 1619 (79.1%) | 824 (91.9%) | 795 (69.2%) | <.001 |
| Coronary revascularization | ||||
| PCI | 1362 (66.6%) | 769 (85.8%) | 593 (51.6%) | <.001 |
| CABG | 48 (2.3%) | 2 (0.2%) | 46 (4.0%) | <.001 |
| Reperfusion therapy (STE-ACS) | ||||
| Primary PCI | 738 (82.4%) | |||
| Door to balloon < 90 min | 434 (62.9%) | |||
| Medical treatment at discharge | ||||
| Aspirin | 1818 (88.9%) | 831 (92.7%) | 987 (85.8%) | <.001 |
| Tienopiridine | 1465 (71.6%) | 721 (80.5%) | 744 (64.7%) | <.001 |
| Warfarin | 168 (8.2%) | 35 (3.9%) | 133 (11.6%) | <.001 |
| B-Blockers | 1757 (85.9%) | 754 (84.2%) | 1103 (87.2%) | .09 |
| ACE-I/ARB | 1588 (77.6%) | 714 (79.7%) | 874 (76.0%) | .10 |
| Statin | 1613 (78.8%) | 693 (77.3%) | 920 (80.0%) | .24 |
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