Cerebrovascular (CVD) disease is commonly associated with coronary artery disease and adversely affects outcome. The goal of the present study was to examine the temporal management patterns and outcomes in relation to previous CVD in a contemporary “real-world” spectrum of patients with acute coronary syndrome (ACS). From 1999 to 2008, 14,070 patients with non–ST-segment elevation ACS were recruited into the Canadian Acute Coronary Syndrome I (ACS I), ACS II, Global Registry of Acute Coronary Events (GRACE/GRACE 2 ), and Canadian Registry of Acute Coronary Events (CANRACE) prospective multicenter registries. We stratified the study patients according to a history of CVD and compared their treatment and outcomes. Patients with a history of CVD were older, more likely to have pre-existing coronary artery disease, elevated creatinine, higher Killip class, and ST-segment deviation on admission. Despite presenting with greater GRACE risk scores (137 vs 117, p <0.001), patients with previous CVD were less likely to receive evidence-based antiplatelet and antithrombin therapies during the initial 24 hours of hospital admission. They were also less likely to undergo in-hospital coronary angiography and revascularization. These disparities in medical and invasive management were preserved temporally across all 4 registries. Patients with concomitant CVD had worse in-hospital outcomes. Previous CVD remained an independent predictor of in-hospital mortality (adjusted odds ratio 1.43, 95% confidence interval 1.06 to 1.92, p = 0.019) after adjusting for other powerful prognosticators in the GRACE risk score. However, it was independently associated with a lower use of in-hospital coronary angiography (adjusted odds ratio 0.70, 95% confidence interval 0.60 to 0.83, p <0.001). Underestimation of patient risk was the most common reason for not pursuing an invasive strategy. Revascularization was independently associated with lower 1-year mortality (adjusted odds ratio 0.48, 95% confidence interval 0.33 to 0.71, p <0.001), irrespective of a history of CVD. In conclusion, for patients presenting with non–ST-segment elevation-ACS, a history of CVD was independently associated with worse outcomes, which might have been, in part, because of the underuse of evidence-based medical and invasive therapies.
Atherosclerosis is a systemic inflammatory disorder that often affects multiple vascular territories. Previous observational and retrospective cohort studies have documented a clear association between cerebrovascular (CVD) disease and the presence and severity of coronary artery disease (CAD). In addition, previous CVD has been shown to adversely affect the prognosis in patients with stable CAD and those presenting with acute coronary syndromes (ACS). The objectives of the present study were to examine: (1) the temporal trends in the management patterns and outcomes of patients with previous CVD presenting with non–ST-segment elevation (NSTE)-ACS across 4 registries in Canada (Canadian Acute Coronary Syndrome I [ACS I], ACS II, Global Registry of Acute Coronary Events [GRACE/GRACE 2 ] and Canadian Registry of Acute Coronary Events [CANRACE]) spanning 1999 through 2008; (2) the independent association between a history of CVD and in-hospital coronary angiography; (3) the independent relation between in-hospital revascularization and 1-year mortality; and (4) physician rationale for management decisions to explore the reasons for the treatment disparities in this high-risk population.
Methods
The Canadian ACS I, ACS II, GRACE/GRACE 2 and CANRACE registries were prospective, multicenter, observational studies of patients admitted with ACS. The full details of the registry designs have been previously published. In ACS I and ACS II, patients ≥18 years old presenting to hospital with suspected cardiac ischemia of onset of <24 hours were eligible for inclusion. In GRACE/GRACE 2 and CANRACE, patients ≥18 years old with a presumptive diagnosis of ACS and at least one of the following were eligible for inclusion: electrocardiographic changes consistent with ACS, serial increases in serum biochemical markers of cardiac necrosis, and/or documented history of CAD. The GRACE/GRACE 2 registry recruited patients until December 2007 and continued in Canada as CANRACE in 2008. The inclusion and exclusion criteria and patient case report forms remained the same. Patients presenting with ACS precipitated or accompanied by serious noncardiac co-morbidities, surgery, or trauma were excluded from the registries. To minimize selection bias, the study centers were instructed to enroll consecutive patients.
All data were recorded on standardized patient case report forms by the local study coordinator or the most responsible physician. In ACS I and ACS II, the patients were interviewed by the designated study coordinator at the admitting hospital or centrally by the Canadian Heart Research Centre by telephone to ascertain their 1-year outcome. In ACS II, the most responsible physician was asked to indicate the reason(s) (not mutually exclusive) for not referring the patient for coronary angiography if a noninvasive treatment approach had been undertaken. The local institutional review boards approved the study protocols, and all patients provided informed consent.
In the present study, only patients with NSTE-ACS were included as there are significant differences in the appropriate early management of patients presenting with ST-elevation ACS. Therefore, patients with ≥0.1 mV of ST-segment elevation in ≥2 contiguous leads and those with a final diagnosis other than ACS were excluded from the present analysis. In Canada, from 1999 to 2008, a total of 14,070 patients with NSTE-ACS were recruited from 51 centers in ACS I (n = 3,257; 1999 to 2001), 36 centers in ACS II (n = 1,956; 2002 to 2003), 48 centers in GRACE/GRACE 2 (n = 7,535; 2004 to 2007), and 35 centers in CANRACE (n = 1,322; 2008). The patients were stratified according to a history of CVD (stroke or transient ischemic attack). On-site coronary angiography was available in 29.4%, 33.3%, 38.3% and 42.8% of the participating hospitals in ACS I, ACS II, GRACE/GRACE 2 and CANRACE, respectively.
We stratified the study patients according to a history of CVD and compared their baseline demographic characteristics, treatments, and outcomes. Continuous data are reported as the median and interquartile range, and categorical data are reported as percentages. The Mann-Whitney U test was used for comparison of continuous variables, and Pearson’s chi-square test for categorical variables. Trends were examined using the Kendall τ-b test for continuous variables and the chi-square test (for trend) for categorical variables.
To evaluate the independent association between a history of CVD and use of coronary angiography, we adjusted for potential confounders in a multivariable logistic regression model. Similar methods were used to assess the independent association between history of CVD and in-hospital mortality. We considered all components of the GRACE risk score (a validated predictor of in-hospital mortality) as candidate predictor variables. To explore the differential effect of revascularization on 1-year mortality, we tested for an interaction between a history of CVD and in-hospital revascularization. Generalized estimating equations were used to control for the clustering of patients within hospitals. Model discrimination and calibration were assessed by the c-statistic and Hosmer-Lemeshow goodness-of-fit test, respectively. A sensitivity analysis was performed to exclude patients who died within 48 hours after admission, as they might not have had a chance to undergo coronary angiography. All analyses were performed using Statistical Package for Social Sciences, version 15.0 (SPSS, Chicago, Illinois). A 2-sided p value of <0.05 was considered statistically significant.
Results
Table 1 lists the baseline demographic and clinical characteristics of the patients stratified by a history of CVD. A total of 14,070 patients with NSTE-ACS were recruited from 1999 to 2008, of whom 1,377 (9.8%) had a history of CVD. Patients with CVD were older and were more likely to have pre-existing CAD, diabetes, elevated creatinine, higher Killip class, and ST-segment deviation on admission. They also presented with greater GRACE risk scores.
| Variable | History of CVD | p Value | |
|---|---|---|---|
| No (n = 12,693) | Yes (n = 1,377) | ||
| Age | 66 (57–76) | 75 (67–81) | <0.001 |
| Men | 66.4% | 58.5% | <0.001 |
| Current smoker | 23.3% | 14.5% | <0.001 |
| Hypertension | 59.2% | 78.7% | <0.001 |
| Diabetes | 27.3% | 39.0% | <0.001 |
| Dyslipidemia | 54.1% | 63.9% | <0.001 |
| Previous angina pectoris | 50.5% | 64.5% | <0.001 |
| Previous myocardial infarction | 33.8% | 51.9% | <0.001 |
| Previous coronary artery bypass surgery | 13.9% | 20.4% | <0.001 |
| Previous percutaneous coronary intervention | 19.3% | 22.0% | 0.018 |
| Previous heart failure | 9.9% | 21.2% | <0.001 |
| Systolic blood pressure (mm Hg) | 146 (128–165) | 145 (125–166) | 0.44 |
| Diastolic blood pressure (mm Hg) | 80 (70–91) | 77 (66–89) | <0.001 |
| Heart rate (beats/min) | 76 (65–90) | 78 (67–94) | <0.001 |
| Killip class | <0.001 | ||
| I | 85.1% | 74.0% | |
| II | 10.5% | 17.7% | |
| III/IV | 4.4% | 8.3% | |
| Cardiac arrest | 0.6% | 1.4% | 0.002 |
| ST-segment deviation | 27.5% | 32.5% | <0.001 |
| Abnormal initial biomarker | 44.6% | 46.3% | 0.23 |
| Abnormal biomarker within 24 hours | 64.4% | 65.9% | 0.26 |
| Initial creatinine (μmol/L) | 91 (77–109) | 102 (83–132) | <0.001 |
| GRACE risk score | 117 (95–145) | 137 (114–166) | <0.001 |
Table 2 lists the use of antiplatelet and antithrombin medications within the first 24 hours of admission stratified by a history of CVD. Overall, the use of aspirin, glycoprotein IIb/IIIa inhibitors, and heparin (unfractionated heparin or low-molecular-weight heparin) was lower for patients with a history of CVD. These trends were consistent temporally across all 4 registries. Overall, the use of thienopyridines increased across registries but remained lower in patients with previous CVD in the GRACE/GRACE 2 and CANRACE registries.
| Variable | ACS I | ACS II | GRACE/GRACE 2 | CANRACE | All Patients | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| No CVD (n = 2,965) | CVD (n = 292) | p Value | No CVD (n = 1,765) | CVD (n = 191) | p Value | No CVD (n = 6,782) | CVD (n = 753) | p Value | No CVD (n = 1,181) | CVD (n = 141) | p Value | No CVD (n = 12,693) | CVD (n = 1,377) | p Value | |
| Medication use within first 24 hours | |||||||||||||||
| Aspirin | 91.7% | 80.8% | <0.001 | 93.2% | 91.1% | 0.28 | 92.5% | 86.7% | <0.001 | 92.9% | 87.8% | 0.029 | 2.5% | 86.2% | <0.001 |
| Thienopyridine | 8.0% | 16.2% | <0.001 | 56.2% | 55.5% | 0.85 | 66.1% | 62.3% | 0.039 | 78.0% | 62.0% | <0.001 | 52.2% | 51.5% | 0.60 |
| Glycoprotein IIb/IIIa inhibitor | 5.5% | 3.4% | 0.14 | 12.1% | 6.8% | 0.029 | 6.7% | 2.6% | <0.001 | 6.2% | 0% | 0.003 | 7.1% | 3.1% | <0.001 |
| Heparin ⁎ | 90.3% | 82.8% | <0.001 | 90.5% | 88.5% | 0.36 | 87.2% | 81.1% | <0.001 | 84.7% | 78.5% | 0.065 | 88.2% | 82.2% | <0.001 |
| In-hospital procedures | |||||||||||||||
| Coronary angiography | 40.6% | 27.3% | <0.001 | 66.1% | 49.7% | <0.001 | 60.2% | 42.4% | <0.001 | 68.6% | 53.6% | <0.001 | 57.2% | 41.4% | <0.001 |
| Percutaneous coronary intervention | 15.3% | 7.3% | <0.001 | 31.7% | 23.6% | 0.021 | 31.4% | 21.4% | <0.001 | 39.4% | 21.6% | <0.001 | 28.4% | 18.7% | <0.001 |
| Coronary artery bypass surgery | 4.6% | 4.8% | 0.85 | 11.1% | 7.3% | 0.11 | 3.6% | 2.3% | 0.062 | 4.5% | 2.2% | 0.21 | 5.0% | 3.6% | 0.020 |
| Percutaneous coronary intervention/coronary artery bypass surgery | 19.9% | 12.1% | 0.001 | 42.4% | 30.9% | 0.002 | 34.4% | 23.7% | <0.001 | 43.7% | 23.9% | <0.001 | 33.0% | 22.2% | <0.001 |
Table 2 also shows the use of diagnostic coronary angiography and the rates of revascularization stratified by a history of CVD. Overall, the use of coronary angiography was lower in patients with CVD. The rates of percutaneous coronary intervention, coronary artery bypass grafting, and percutaneous coronary intervention/coronary artery bypass grafting were also lower in patients with a history of CVD. These differences in the use of diagnostic coronary angiography and revascularization rates between patients with and without previous CVD were maintained across all 4 registries, despite the overall increasing rates of diagnostic coronary angiography and revascularization with time. In multivariable logistic regression analysis, previous CVD was independently associated with lower in-hospital use of coronary angiography (adjusted odds ratio [OR] 0.69, 95% confidence interval [CI] 0.58 to 0.82, p <0.001) after adjusting for potential confounders ( Table 3 ). The model c-statistic was 0.74, and the Hosmer-Lemeshow p value was 0.65, suggesting adequate model discrimination and fit, respectively.
| Independent Predictors | Adjusted Odds Ratio | 95% Confidence Interval | p Value |
|---|---|---|---|
| Registry | |||
| Acute Coronary Syndrome I | Reference | — | — |
| Acute Coronary Syndrome II | 2.72 | 1.70–4.36 | <0.001 |
| GRACE | 2.55 | 1.61–4.09 | <0.001 |
| CANRACE | 3.01 | 1.51–6.00 | 0.002 |
| Age (years) | |||
| <65 | Reference | — | — |
| 65–74 | 0.92 | 0.80–1.06 | 0.23 |
| ≥75 | 0.47 | 0.38–0.58 | <0.001 |
| Heart rate (per 10-beats/min increase) | 0.95 | 0.93–0.98 | <0.001 |
| Systolic blood pressure (per 10-mm Hg increase) | 1.02 | 1.00–1.05 | 0.035 |
| Killip class | |||
| I | Reference | — | — |
| II | 0.63 | 0.53–0.74 | <0.001 |
| III/IV | 0.78 | 0.64–0.95 | 0.012 |
| Female gender | 0.75 | 0.68–0.83 | <0.001 |
| Previous myocardial infarction | 0.72 | 0.62–0.84 | <0.001 |
| Previous coronary artery bypass surgery | 0.82 | 0.73–0.92 | 0.001 |
| Previous percutaneous coronary intervention | 1.16 | 1.02–1.31 | 0.021 |
| Previous heart failure | 0.59 | 0.51–0.69 | <0.001 |
| On-site coronary angiography | 3.69 | 2.35–5.79 | <0.001 |
| Creatinine (per 10 μmol/L) | 0.98 | 0.97–0.99 | <0.001 |
| Previous cerebrovascular disease | 0.69 | 0.58–0.82 | <0.001 |
In ACS II, the physicians were asked to indicate the reason(s) they had decided to pursue a noninvasive approach ( Table 4 ). Of 1,954 patients, 693 (35%) were not referred for in-hospital coronary angiography. The most commonly cited reason for not pursuing an invasive approach was insufficient patient risk in both the CVD and non-CVD patients. Significant co-morbidity and renal insufficiency were more commonly cited reasons in patients with previous CVD. Bleeding or other safety concerns were reported for 6.3% of cases, with no significant difference between the groups with and without previous CVD. The median GRACE risk score of the patients who did not undergo coronary angiography and were considered not at great enough risk was significantly higher among the patients with CVD than those without CVD.
| Variable | History of CVD | p Value | |
|---|---|---|---|
| No (n = 597) | Yes (n = 96) | ||
| Patient not at high enough risk | 42.5% | 39.6% | 0.59 |
| Not supported by evidence | 7.0% | 8.3% | 0.65 |
| Not high-enough risk/not supported by evidence | 49.2% | 47.9% | 0.81 |
| Significant co-morbidity | 7.4% | 15.6% | 0.007 |
| Renal insufficiency | 1.5% | 5.2% | 0.017 |
| Bleeding or other safety concerns | 4.0% | 6.3% | 0.32 |
| Patient/family refused | 6.9% | 5.2% | 0.54 |
| Previously defined anatomy unsuitable | 12.7% | 15.6% | 0.44 |
| Previously defined anatomy and revascularization already planned | 5.7% | 4.2% | 0.54 |
| No reason given | 15.9% | 5.2% | 0.006 |
| GRACE risk score of patients not considered high risk who did not undergo coronary angiography | 123 (101–146) | 142 (112–178) | 0.019 |
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