Randomized trials have established the efficacy of antianginal medications in the treatment of chronic stable coronary disease. Using data from the Global Registry of Acute Coronary Events (GRACE) and Canadian Registry of Acute Coronary Events (CANRACE), we examined the temporal trends in antianginal use (beta blockers, calcium antagonists, and nitrates) before non-ST-elevation acute coronary syndrome presentation from 1999 to 2008 in 10,019 patients. The relationships among previous antianginal use, clinical characteristics on presentation, and in-hospital management and outcomes were examined. Beta blockers were the most commonly used agents, and there was a significant decline in the use of nitrates over time. Compared with patients not on any antianginal therapy before presentation, those on treatment were more likely to be older, female, and have a history of hypertension, diabetes, previous angina, and myocardial infarction; they were less likely to present with positive biomarkers (all p <0.001). Patients not on antianginal therapy before presentation were more likely to undergo coronary angiography and percutaneous coronary intervention and less likely to have recurrent ischemia during hospitalization (all p <0.001). In multivariable analysis, previous antianginal use was independently associated with lower use of coronary angiography in hospital (p = 0.034) but not with in-hospital mortality. In conclusion, there has significant temporal decline in nitrate use before non-ST-elevation acute coronary syndrome. Patients receiving antianginal therapy before presentation more frequently had preexisting cardiovascular disease and previous revascularization and were less likely to present with non-ST-segment elevation MI compared with patients on no antianginal therapies. Previous antianginal use was independently associated with a lower use of coronary angiography in hospital.
Beta blockers (BB), calcium antagonists (CA), and nitrates have long been the mainstay of treatment for stable coronary artery disease because they improve exercise duration and reduce electrocardiographic evidence of ischemia during exercise and the frequency of anginal episodes. There has been clear evidence of improvement in mortality and morbidity when using BB in selected patient populations such as those with previous MI and ventricular dysfunction, and the most recent American College of Cardiology/American Heart Association guidelines for chronic stable angina recommend BB as first-line therapy for the treatment of angina. Despite this, in previous studies examining the treatment of chronic stable angina, CAs have been the most commonly prescribed agent. A large observational study using the Global Registry of Acute Coronary Events (GRACE) database examined chronic nitrate use and presentation of acute coronary syndrome (ACS) and reported that chronic nitrate use was associated with a shift from ST-segment elevation MI (STEMI) toward non-ST-elevation acute coronary syndrome (NSTE-ACS) and with less cardiac biomarker release. The primary goals of our study were to describe (1) the temporal changes in the chronic use of antianginal therapy among patients presenting to hospital with non-ST-segment elevation myocardial infarction (NSTEMI) or unstable angina (UA) and (2) whether pretreatment with antianginal therapy was associated with differences in the clinical presentation, management, and outcomes of NSTE-ACS.
Methods
The full details of the GRACE database design and methods have been previously published. Briefly, GRACE is a multinational, multicenter, prospective registry of a broad spectrum of patients with ACS that was expanded (GRACE 2 ) in 2003. The inclusion criteria were age >18 years, alive at hospital presentation, and ACS as the provisional diagnosis, with at lease one of the following: elevated cardiac biomarkers, electrocardiographic changes indicative of ischemia or infarction, or known history of coronary artery disease. Patients were excluded if the ACS was precipitated by surgery or other comorbidities. The final ACS diagnosis was classified as STEMI, NSTEMI, or UA. At each site, a trained coordinator collected data on standardized case report forms. Enrollment in GRACE/GRACE 2 was completed in December 2007, but Canadian enrollment was extended in 2008 in the Canadian Registry of Acute Coronary Events (CANRACE), which had identical inclusion and exclusion criteria.
We examined data on 10,019 Canadian patients in the GRACE/GRACE 2 /CANRACE database who had a final diagnosis of NSTE-ACS, and for whom information regarding previous treatment with antianginal therapy was available and complete. The study population was then stratified according to the use of antianginal therapy (none vs ≥1 agent). We examined the chronic use of BB, CA, and nitrates over a priori divided time periods within our study population to assess for potential changes in treatment over time.
We compared patients who did and did not receive chronic antianginal therapy before hospitalization with respect to the following outcomes: in-hospital mortality, reinfarction, cardiogenic shock, cardiac biomarker status on presentation and at 24 hours, pulmonary edema and/or acute congestive heart failure, and sustained ventricular tachycardia or fibrillation. The definition of reinfarction was restricted to a re-elevation in cardiac biomarkers ≥24 hours after presentation. In regard to in-hospital management, we examined for possible differences in medical therapy within the first 24 hours of hospitalization as well as the rates of left ventricular function assessment, coronary angiography, percutaneous coronary intervention (PCI), and coronary bypass graft surgery.
Discrete variables are presented as frequencies or percentages. Continuous variables are presented as medians with interquartile ranges. We compared group differences in discrete and continuous variables using chi-squared and Mann-Whitney U tests, respectively. We developed a multivariable model to examine factors associated with coronary angiography and in-hospital mortality, based on clinical considerations and previous studies. Generalized estimating equations were used to control for the clustering of patients within hospitals. The variables considered in the multivariable model for coronary angiography were gender, previous myocardial infarction, previous heart failure, previous cerebrovascular disease, history of atrial fibrillation, history of PCI or coronary bypass graft surgery, availability of cardiac catheterization facilities, and GRACE risk score. The GRACE risk score is based on age, heart rate, systolic blood pressure, serum creatinine, Killip class, cardiac arrest at presentation, the presence of ST-segment deviation, and elevated cardiac biomarkers. Statistical analysis was performed using SPSS v. 15.0 (SPSS Inc., Chicago, Illinois), and 2-sided p <0.05 was considered to be significant.
Results
Between 1999 and 2008, there were 10,019 Canadian patients with a final diagnosis of NSTE-ACS with complete data on previous chronic antianginal use. Overall, 54.5% of patients were being treated with ≥1 antianginal medication; 28.4%, 19.7% and 6.5% were on 1, 2, and 3 antianginal agents, respectively. The rates of BB use were 39.3%, nitrate use 24.4%, and CA use 23.6%. Figure 1 shows rates of previous use of the 3 antianginal agents. There was a significant decline in the chronic use of nitrates over time.
Table 1 summarizes the relevant demographics and clinical features of the study population. NSTEMI and UA were the final diagnosis in 72.5% and 27.5%, respectively, of patients not treated with chronic antianginal agents; of those on chronic antianginal therapy, 57.5% presented with NSTEMI and 42.5% with UA (p <0.001; Table 1 ).
| Variable | Previous Antianginal Use | p Value | |
|---|---|---|---|
| No (n = 4,554) | Yes (n = 5,465) | ||
| Age (yrs) ∗ | 63 (54–73) | 71 (61–79) | <0.001 |
| Men | 68.8% | 62.1% | <0.001 |
| Previous angina pectoris | 27.3% | 69.5% | <0.001 |
| Previous myocardial infarction | 16.7% | 52.4% | <0.001 |
| Previous PCI | 8.5% | 29.8% | <0.001 |
| Previous coronary bypass | 5.9% | 22.1% | <0.001 |
| Previous heart failure | 5.0% | 16.5% | <0.001 |
| Previous stroke/transient ischemic attack | 5.6% | 13.7% | <0.001 |
| Previous hypertension | 46.4% | 78.7% | <0.001 |
| Dyslipidemia † | 43.1% | 68.7% | <0.001 |
| Current smoker | 31.2% | 17.4% | <0.001 |
| Previous atrial fibrillation | 5.5% | 14.6% | <0.001 |
| Diabetes mellitus | 20.7% | 36.5% | <0.001 |
| Heart rate (beats/min) ∗ | 80 (69–94) | 76 (64–91) | <0.001 |
| Systolic blood pressure (mm Hg) ∗ | 146 (129–164) | 143 (125–162) | <0.001 |
| Creatinine (μmol/L) ∗ | 88 (76–104) | 96 (80–122) | <0.001 |
| Positive initial biomarkers | 51.5% | 36.6% | <0.001 |
| Positive biomarkers at 24 h | 70.8% | 56.3% | <0.001 |
| ST deviation | 31.2% | 32.6% | 0.073 |
| GRACE risk score ∗ | 114 (92–142) | 128 (103–157) | <0.001 |
| Final diagnosis | |||
| NSTEMI | 72.5% | 57.5% | <0.001 |
| Unstable angina pectoris | 27.5% | 42.5% | |
∗ Presented as median values with interquartile range.
† Defined as previously diagnosed hyperlipidemia or patient on lipid-lowering agent.
Overall, initial medical therapies within the first 24 hours of hospitalization differed significantly between the 2 groups. The results are summarized in Table 2 . Patients receiving chronic antianginals were less likely to receive therapies such as antiplatelet agents and anticoagulant and more likely to receive statins, angiotensin receptor blockers, and antianginal agents in the first 24 hours than patients not on previous antianginal therapy. Patients who received chronic antianginal therapy were less likely to undergo cardiac catheterization and PCI during index hospitalization than their counterparts who were not on chronic antianginal therapy ( Table 3 ).
| Medicine | Prior Antianginal Use | p Value | |
|---|---|---|---|
| No (n = 4,554) | Yes (n = 5,465) | ||
| Aspirin | 92.8% | 89.9% | <0.001 |
| Clopidogrel | 67.3% | 60.3% | <0.001 |
| Warfarin | 3.3% | 7.7% | <0.001 |
| Unfractionated heparin | 29.8% | 29.6% | 0.608 |
| Enoxaparin | 61% | 56.3% | <0.001 |
| Any heparin | 88.2% | 83.7% | <0.001 |
| Glycoprotein IIb/IIIa inhibitors | 8.3% | 5.0% | <0.001 |
| Beta blocker | 73.8% | 80.2% | <0.001 |
| Calcium antagonist | 9.5% | 37.5% | <0.001 |
| Nitroglycerin | 63% | 74.7% | <0.001 |
| ACE inhibitor | 43.2% | 56.8% | <0.001 |
| Angiotensin receptor blocker | 7.8% | 15.9% | <0.001 |
| Statin | 62.5% | 71.7% | <0.001 |
| Inotrope | 1.9% | 1.5% | 0.02 |
| Variable | Prior Antianginal Use | p Value | |
|---|---|---|---|
| No (n = 4,554) | Yes (n = 5,465) | ||
| In-hospital cardiac procedures | |||
| Coronary angiography | 64.8% | 54.5% | <0.001 |
| Time to coronary angiography (d) ∗ | 3 (2,4) | 3 (2,5) | <0.001 |
| PCI | 33.4% | 25.3% | <0.001 |
| Coronary bypass | 3.7% | 3.5% | 0.20 |
| LVEF assessment | 63.5% | 59.5% | <0.001 |
| In-hospital outcomes | |||
| All-cause mortality | 2.7% | 2.8% | 0.65 |
| Reinfarction | 4.5% | 3.4% | 0.005 |
| Cardiogenic shock | 1.2% | 1.0% | 0.12 |
| Heart failure | 6.3% | 9.6% | <0.001 |
| Recurrent myocardial ischemia | 22.5% | 27.5% | <0.001 |
| Sustained ventricular tachycardia | 1.7% | 1.5% | 0.48 |
In multivariable analysis, previous PCI and the presence of on-site catheterization facilities were independent predictors of cardiac catheterization during index hospitalization. Conversely, higher GRACE risk score, female gender, previous history of myocardial infarction, previous heart failure, and previous cerebrovascular disease or atrial fibrillation were independent negative predictors of cardiac catheterization ( Table 4 ). In addition, any previous antianginal use was a negative predictor of cardiac catheterization (adjusted odds ratio [OR] = 0.83, 95% confidence interval [CI] 0.70–0.98, p = 0.03).
| Independent predictors | Adjusted OR (95% CI) | p Value |
|---|---|---|
| GRACE risk score (per 10 higher) | 0.93 (0.91–0.96) | <0.001 |
| Female gender | 0.78 (0.69–0.87) | <0.001 |
| Previous myocardial infarction | 0.62 (0.50–0.75) | <0.001 |
| Previous congestive heart failure | 0.51 (0.43–0.61) | <0.001 |
| Previous transient ischemic attack | 0.67 (0.55–0.80) | <0.001 |
| Previous major bleeding | 0.59 (0.42–0.82) | 0.002 |
| Previous atrial fibrillation | 0.76 (0.66–0.88) | <0.001 |
| Previous PCI | 1.38 (1.18–1.61) | <0.001 |
| Previous coronary bypass surgery | 0.82 (0.71–0.94) | 0.006 |
| On-site cardiac catheterization availability | 2.89 (1.78–4.69) | <0.001 |
| Antianginal use (none) | Referent group | |
| Antianginal use (1 agent) | 0.83 (0.73–0.95) | 0.006 |
| Antianginal use (≥2 agents) | 0.82 (0.63–1.07) | 0.14 |
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