- Email: [email protected]
Management and Outcomes of Non-ST Elevation Acute Coronary Syndromes in Relation to Previous Use of Antianginal Therapies (from the Canadian Global Registry of Acute Coronary Events [GRACE] and Canadian Registry of Acute Coronary Events [CANRACE])
Management and Outcomes of Non-ST Elevation Acute Coronary Syndromes in Relation to Previous Use of Antianginal Therapies (from the Canadian Global Registry of Acute Coronary Events [GRACE] and Canadian Registry of Acute Coronary Events [CANRACE]) Jaskaran S. Kang, MDa, Shaun G. Goodman, MD, MSca,b, Raymond T. Yan, MDa, Jose Lopez-Sendon, MDc, Yves Pesant, MDd, John J. Graham, MDa,b, David Fitchett, MDa,b, Graham C. Wong, MDe, Barry F. Rose, MDf, Frederick A. Spencer, MDg, and Andrew T. Yan, MDa,*, for the Canadian GRACE and CANRACE Investigators 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. Ó 2013 Elsevier Inc. All rights reserved. (Am J Cardiol 2013;112:51e56) 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
a Terrence Donnelly Heart Centre, St Michael’s Hospital, University of Toronto, Toronto, Ontario, Canada; bCanadian Heart Research Centre, Toronto, Ontario, Canada; cHospital Universitario La Paz, Madrid, Spain; d St-Jerome Hospital, Quebec City, Quebec, Canada; eVancouver General Hospital and University of British Columbia, Vancouver, British Columbia, Canada; fMemorial University, St John’s, Newfoundland, Canada; and g Thrombosis and Atherosclerosis Research Institute, McMaster University, Hamilton, Ontario, Canada. Manuscript received December 14, 2012; revised manuscript received and accepted February 19, 2013. Dr Andrew Yan is supported by a New Investigator Award from the Heart and Stroke Foundation of Canada. See page 55 for disclosure information. *Corresponding author: Tel: (416) 864-5465; fax: (416) 864-5159. E-mail address: [email protected] (A.T. Yan).
0002-9149/13/$ - see front matter Ó 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2013.02.053
episodes.1e4 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,5e7 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.8 Despite this, in previous studies examining the treatment of chronic stable angina, CAs have been the most commonly prescribed agent.9 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.10 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-STsegment elevation myocardial infarction (NSTEMI) or www.ajconline.org
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Figure 1. Temporal trends of antianginal medication use before presentation.
unstable angina (UA) and (2) whether pretreatment with antianginal therapy was associated with differences in the clinical presentation, management, and outcomes of NSTEACS. Methods The full details of the GRACE database design and methods have been previously published.11 Briefly, GRACE is a multinational, multicenter, prospective registry of a broad spectrum of patients with ACS that was expanded (GRACE2) in 2003.12 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/ GRACE2 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/GRACE2/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.13 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.14e19 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.20 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;
Coronary Artery Disease/Previous Anti-Anginal Therapies and Acute Coronary Syndrome Table 1 Baseline characteristics according to previous antianginal use Variable
Previous Antianginal Use
Table 3 In-hospital management and outcomes p Value
Variable
No (n ¼ 4,554) Yes (n ¼ 5,465) Age (yrs)* 63 (54e73) Men 68.8% Previous angina pectoris 27.3% Previous myocardial 16.7% infarction Previous PCI 8.5% Previous coronary bypass 5.9% Previous heart failure 5.0% Previous stroke/transient 5.6% ischemic attack Previous hypertension 46.4% 43.1% Dyslipidemia† Current smoker 31.2% Previous atrial fibrillation 5.5% Diabetes mellitus 20.7% Heart rate (beats/min)* 80 (69e94) Systolic blood pressure 146 (129e164) (mm Hg)* 88 (76e104) Creatinine (mmol/L)* Positive initial biomarkers 51.5% Positive biomarkers at 24 h 70.8% ST deviation 31.2% GRACE risk score* 114 (92e142) Final diagnosis NSTEMI 72.5% Unstable angina pectoris 27.5%
71 (61e79) 62.1% 69.5% 52.4%
<0.001 <0.001 <0.001 <0.001
29.8% 22.1% 16.5% 13.7%
<0.001 <0.001 <0.001 <0.001
78.7% 68.7% 17.4% 14.6% 36.5% 76 (64e91) 143 (125e162)
<0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001
96 (80e122) 36.6% 56.3% 32.6% 128 (103e157)
<0.001 <0.001 <0.001 0.073 <0.001
57.5% 42.5%
<0.001
* Presented as median values with interquartile range. † Defined as previously diagnosed hyperlipidemia or patient on lipidlowering agent.
Table 2 Medication use within the first 24 hours Medicine
Aspirin Clopidogrel Warfarin Unfractionated heparin Enoxaparin Any heparin Glycoprotein IIb/IIIa inhibitors Beta blocker Calcium antagonist Nitroglycerin ACE inhibitor Angiotensin receptor blocker Statin Inotrope
Prior Antianginal Use No (n ¼ 4,554)
Yes (n ¼ 5,465)
92.8% 67.3% 3.3% 29.8% 61% 88.2% 8.3% 73.8% 9.5% 63% 43.2% 7.8% 62.5% 1.9%
89.9% 60.3% 7.7% 29.6% 56.3% 83.7% 5.0% 80.2% 37.5% 74.7% 56.8% 15.9% 71.7% 1.5%
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p Value
<0.001 <0.001 <0.001 0.608 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 0.02
ACE ¼ angiotensin converting enzyme.
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.
Prior Antianginal Use
p Value
No Yes (n ¼ 4,554) (n ¼ 5,465) In-hospital cardiac procedures Coronary angiography Time to coronary angiography (d)* PCI Coronary bypass LVEF assessment In-hospital outcomes All-cause mortality Reinfarction Cardiogenic shock Heart failure Recurrent myocardial ischemia Sustained ventricular tachycardia
64.8% 3 (2,4) 33.4% 3.7% 63.5%
54.5% 3 (2,5) 25.3% 3.5% 59.5%
<0.001 <0.001 <0.001 0.20 <0.001
2.7% 4.5% 1.2% 6.3% 22.5% 1.7%
2.8% 3.4% 1.0% 9.6% 27.5% 1.5%
0.65 0.005 0.12 <0.001 <0.001 0.48
LVEF ¼ left ventricular ejection fraction. * Presented as median values with interquartile range.
Table 4 Independent predictors of cardiac catheterization during index hospitalization Independent predictors GRACE risk score (per 10 higher) Female gender Previous myocardial infarction Previous congestive heart failure Previous transient ischemic attack Previous major bleeding Previous atrial fibrillation Previous PCI Previous coronary bypass surgery On-site cardiac catheterization availability Antianginal use (none) Antianginal use (1 agent) Antianginal use (2 agents)
Adjusted OR (95% CI)
p Value
0.93 (0.91e0.96) 0.78 (0.69e0.87) 0.62 (0.50e0.75) 0.51 (0.43e0.61) 0.67 (0.55e0.80) 0.59 (0.42e0.82) 0.76 (0.66e0.88) 1.38 (1.18e1.61) 0.82 (0.71e0.94) 2.89 (1.78e4.69) Referent group 0.83 (0.73e0.95) 0.82 (0.63e1.07)
<0.001 <0.001 <0.001 <0.001 <0.001 0.002 <0.001 <0.001 0.006 <0.001 0.006 0.14
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). 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).
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Table 5 Independent predictors of all-cause mortality during index hospitalization Independent Predictor Age (per 10 yrs higher) Heart rate (per 10 beats/min higher) Systolic blood pressure (per 10 mm Hg higher) Killip Class I Killip Class II Killip Class III Killip Class IV Creatinine (per 10 mmol/L higher) Cardiac arrest ST deviation Initial positive biomarker Antianginal use (none) Antianginal use (1 agent) Antianginal use (2 agents)
Adjusted OR (95% CI)
p Value
2.22 (1.93e2.55) 1.09 (1.03e1.15) 0.84 (0.81e0.88)
<0.001 0.005 <0.001
Referent group 2.64 (1.39e5.03) 3.32 (2.32e4.78) 3.00 (0.70e12.92) 1.04 (1.03e1.05) 5.34 (2.10e13.63) 1.48 (0.97e2.27) 1.11 (0.73e1.70) Referent group 0.70 (0.35e1.37) 0.60 (0.29e1.25)
0.003 <0.001 0.14 <0.001 <0.001 0.069 0.62 0.30 0.17
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] ¼ 0.83, 95% confidence interval [CI] 0.70e0.98, p ¼ 0.03). The rates of cardiogenic shock and sustained ventricular tachycardia were not significantly different between groups (Table 3). Compared with patients who did not receive chronic antianginal therapy, those who received chronic antianginal therapy had a significantly lower unadjusted rate of in-hospital reinfarction but higher rates of heart failure and recurrent ischemia (Table 3). The unadjusted in-hospital mortality rate was 2.7% for patients not treated with chronic antianginals and 2.8% in chronic antianginal users (p ¼ 0.65; Table 3). In multivariable analysis, higher age, Killip class, heart rate and creatinine, cardiac arrest, and lower systolic blood pressure were independent predictors of in-hospital mortality (Table 5). Chronic antianginal use with a single agent or multiple agents was not a significant predictor for inhospital mortality (adjusted OR ¼ 0.70, 95% CI 0.35e1.37, p ¼ 0.30 for use of 1 antianginal agent and adjusted OR ¼ 0.60, 95% CI 0.29e1.25, p ¼ 0.17 for 2 antianginal agents). Discussion In this large observational study, we found that BBs remained the most commonly used agents among patients on antianginal therapy before ACS presentation. ACS patients on chronic antianginal therapy were less likely to have NSTEMI and reinfarction in hospital and were less likely to undergo in-hospital coronary angiography. There
was no independent association between previous use of antianginal therapy and in-hospital mortality. The cardioprotective effects of antianginal therapies have been the focus of previous studies.21,22 Recently, a retrospective analysis involving >50,000 patients examined chronic nitrate use and ACS presentation.10 Those presenting with ACS and with a history of chronic nitrate use (defined as treatment being started 7 days before the index event) were more likely to receive an admission diagnosis of NSTEMI or UA, as opposed to STEMI. This association remained even after adjustment for age, gender, medical history, previous therapy, previous angina, and revascularization. Moreover, regardless of ACS presentation type, patients with previous nitrate use were less likely to have positive biomarkers. Yet to the best of our knowledge, no studies to date have specifically evaluated whether this association is unique to nitrates and antianginal medications as a class. The present study imparts new insights in several regards. In our study, patients who were on chronic antianginal therapy were older and more likely to be female. These patients were less likely to receive therapies such as antiplatelet agents or anticoagulants. These findings in elderly and female patients are similar to those from other studies investigating the use of evidence-based therapies in patients with ACS.23e27 This observation could be in part attributable to age, bleeding risk, and the fact that these patients were more likely to have atrial fibrillation and already be on oral anticoagulant. Moreover, the difference in presentation and the fact that they less frequently presented with positive biomarkers may have influenced the decision to start antiplatelet or anticoagulation agents. However, patients who were already on chronic antianginal therapy were more likely to receive statins, antianginals, and angiotensin receptor blockers. This may be because physicians were inclined to continue therapies used before admission or because of a higher prevalence of risk factors such as hypertension and dyslipidemia. The group on chronic antianginals also had higher prevalence of cardiovascular risk factors except smoking. Smoking rates were probably lower in these patients because there had likely been considerable effort toward counseling for smoking cessation for preventative health measures in patients with preexisting disease. Alternatively, those individuals currently smoking at the time of presentation might have been less likely to adopt a drug prevention strategy.28 We found that patients on chronic antianginal therapy before admission had lower rates of assessment of LV function and cardiac catheterization during hospitalization. This latter observation was observed even after adjustment for the presence of on-site cardiac catheterization facilities. This may be related to the fact that this group had significantly more comorbidities, as well as a higher burden of coronary disease at baseline that had been previously delineated and might not be amenable to revascularization. Finally, it is possible that a lower rate of abnormal biomarker might have favored medical management rather than an early invasive approach. Finally, we observed higher rates of recurrent ischemia and heart failure in the group treated with chronic antianginals. This might be due to the differences in medical
Coronary Artery Disease/Previous Anti-Anginal Therapies and Acute Coronary Syndrome
management and care that they received in hospital or to confounding by indication. In addition, patients with chronic antianginal use were not managed as aggressively with lower rates of coronary angiography and revascularization, and may have had more residual flow-limiting coronary disease causing symptoms. Alternatively, this may simply reflect the inherent differences between groups—that is, patients on chronic antianginal therapy were older and more likely to have previous hypertension, myocardial infarction, and heart failure. The present study is limited by its retrospective and nonrandomized nature. However, it does allow for accurate assessment of real-world practice patterns. We did not collect data on the specific antianginal agent, dose, or duration of therapy. Furthermore, we do not know the reason a particular agent was selected or the severity of anginal symptoms before admission. Although ACS patients on chronic antianginal therapies more frequently had a history of angina, some of these medications might have been prescribed for other indications. The purpose of this observational study was not to establish the efficacy of chronic antianginal therapy or any cause-and-effect relationships because there were likely unmeasured or unknown confounders. Randomized controlled trials would be best suited to establish treatment efficacy, but it would be infeasible to randomize patients to antianginal therapies before ACS. Finally, there is an apparent underutilization of secondary prevention therapies after ACS, which warrants further assessment of the long-term prescription and adherence to such treatments.29 Acknowledgment: We thank Sue Francis, BA, for her assistance in the preparation of this manuscript. We are grateful to all the study coordinators, investigators, and patients who participated in GRACE/GRACE2 and CANRACE. Disclosures Dr. Jose Lopez-Sendon has received speaker/consulting honoraria and/or research grant support from Sanofi, Servier, Menarini, Merk, and Pfizer. Dr. John J. Graham has received speaker/consulting honoraria and/or research grant support from Astra Zeneca, Eli Lilly, and Bristol Myers Squibb. Dr. David Fitchett, Dr. Graham C. Wong, Dr. Barry F. Rose, Dr. Frederick A. Spencer, Dr. Andrew T. Yan, Dr. Shaun G. Goodman, and Dr. Yves Pesant have received speaker/consulting honoraria and/or research grant support from Sanofi Aventis and Bristol Myers Squibb. The other authors report no conflicts of interest. 1. Parker JO, Amies MH, Hawkinson RW, Heilman JM, Hougham AJ, Vollmer MC, Wilson RR. Intermittent transdermal nitroglycerin therapy in angina pectoris. Clinically effective without tolerance or rebound. Minitran Efficacy Study Group. Circulation 1995;91: 1368e1374. 2. Savonitto S, Ardissiono D, Egstrup K, Rasmussen K, Bae EA, Omland T, Schjelderup-Mathiesan PM, Marraccini P, Wahlqvist I, Merlini PA, Rehnqvist N. Combination therapy with metoprolol and nifedipine versus monotherapy in patients with stable angina pectoris. Results of the International Multicenter Angina Exercise (IMAGE) Study. J Am Coll Cardiol 1996;27:311e316.
55
3. Smith NL, Reiber GE, Psaty BM, Heckbert SR, Siscovick DS, Ritchie JL, Every NR, Koepsell TD. Health outcomes associated with betablocker and diltiazem treatment of unstable angina. J Am Coll Cardiol 1998;32:1305e1311. 4. Taylor SH. Usefulness of amlodipine for angina pectoris. Am J Cardiol 1994;73:28Ae33A. 5. Colucci WS. Landmark study: the Carvedilol Post-Infarct Survival Control in Left Ventricular Dysfunction Study (CAPRICORN). Am J Cardiol 2004;93:13Be16B. 6. Doughty RN, Whalley GA, Walsh HA, Gamble GD, López-Sendón J, Sharpe N. Effects of carvedilol on left ventricular remodeling after acute myocardial infarction: the CAPRICORN Echo Substudy. Circulation 2004;109:201e206. 7. Hjalmarson A, Goldstein S, Fagerberg B, Wedel H, Waagstein F, Kjekshus J, Wikstrand J, El Allaf D, Vítovec J, Aldershvile J, Halinen M, Dietz R, Neuhaus KL, Jánosi A, Thorgeirsson G, Dunselman PH, Gullestad L, Kuch J, Herlitz J, Rickenbacher P, Ball S, Gottlieb S, Deedwania P. Effects of controlled-release metoprolol on total mortality, hospitalizations, and well-being in patients with heart failure: the Metoprolol CR/XL Randomized Intervention Trial in congestive heart failure (MERIT-HF). MERIT-HF Study Group. JAMA 2000;283: 1295e1302. 8. Fraker TD Jr, Fihn SD, Gibbons RJ, Abrams J, Chatterjee K, Daley J, Deedwania PC, Douglas JS, Ferguson TB Jr, Fihn SD, Fraker TD Jr, Gardin JM, O’Rourke RA, Williams SV, Smith SC Jr, Jacobs AK, Adams CD, Anderson JL, Buller CE, Creager MA, Ettinger SM, Halperin JL, Hunt SA, Krumholz HM, Kushner FG, Lytle BW, Nishimura R, Page RL, Riegel B, Tarkington LG, Yancy CW. 2007 chronic angina focused update of the ACC/AHA 2002 Guidelines for the management of patients with chronic stable angina: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines Writing Group to develop the focused update of the 2002 Guidelines for the management of patients with chronic stable angina. Circulation 2007;116:2762e2772. 9. Beaulieu MD, Blais R, Jacques A, Battista RN, Lebeau R, Brophy J. Are patients suffering from stable angina receiving optimal medical treatment? QJM 2001;94:301e308. 10. Ambrosio G, Del Pinto M, Tritto I, Agnelli G, Bentivoglio M, Zuchi C, Anderson FA, Gore JM, López-Sendón J, Wyman A, Kennelly BM, Fox KA. Chronic nitrate therapy is associated with different presentation and evolution of acute coronary syndromes: insights from 52 693 patients in the Global Registry of Acute Coronary Events. Eur Heart J 2009;31:430e438. 11. GRACE investigators. Rationale and design of the GRACE (Global Registry of Acute Coronary Events) Project: a multinational registry of patients hospitalized with acute coronary syndromes. Am Heart J 2001;141:190e199. 12. Goodman SG, Huang W, Yan AT, Budaj A, Kennelly BM, Gore JM, Fox KA, Goldberg RJ, Anderson FA Jr. The expanded Global Registry of Acute Coronary Events: baseline characteristics, management practices, and hospital outcomes of patients with acute coronary syndromes. Am Heart J 2009;158:193e201; e1e5. 13. Yan AT, Steg PG, Fitzgerald G, Feldman LJ, Eagle KA, Gore JM, Anderson FA, López-Sendón J, Gurfinkel EP, Brieger D, Goodman SG. Recurrent ischemia across the spectrum of acute coronary syndromes: prevalence and prognostic significance of (re-)infarction and ST-segment changes in a large contemporary registry. Int J Cardiol 2010;145:15e20. 14. Every NR, Larson EB, Litwin PE, Maynard C, Fihn SD, Eisenberg MS, Hallstrom AP, Martin JS, Weaver WD. The association between on-site cardiac catherterization facilities and the use of coronary angiography after acute myocardial infarction. Myocardial Infarction Triage and Intervention Project Investigators. N Engl J Med 1993;329: 546e551. 15. Krumholz HM, Chen J, Murillo JE, Cohen DJ, Radford MJ. Admission to hospitals with on-site cardiac catheterization facilities; impact on long-term cost and outcomes. Circulation 1998;98: 2010e2016. 16. Bhatt DL, Roe MT, Peterson ED, Li Y, Chen AY, Harrington RA, Greenbaum AB, Berger PB, Cannon CP, Cohen DJ, Gibson CM, Saucedo JF, Kleiman NS, Hochman JS, Boden WE, Brindis RG, Peacock WF, Smith SC Jr, Pollack CV Jr, Gibler WB, Ohman EM. Utilization of early invasive management strategies for high-risk patients with non-ST elevation acute coronary syndromes; results from
56
17.
18.
19.
20.
21. 22.
23.
The American Journal of Cardiology (www.ajconline.org) the CRUSADE Quality Improvement Initiative. JAMA 2004;292: 2096e2104. Van de Werf F, Gore JM, Avezum A, Gulba DC, Goodman SG, Budaj A, Brieger D, White K, Fox KA, Eagle KA, Kennelly BM. Access to catheterization facilities in patients admitted with acute coronary syndrome: multinational registry study. BMJ 2005;330:441. Roe MT, Peterson ED, Newby LK, Chen AY, Pollack CV Jr, Brindis RG, Harrington RA, Christenson RH, Smith SC Jr, Califf RM, Braunwald E, Gibler WB, Ohman EM. The influence of risk status on guideline adherence for patients with non-ST-segment elevation acute coronary syndromes. Am Heart J 2006;151:1205e1213. Fox KA, Anderson FA Jr, Dabbous OH, Steg PG, López-Sendón J, Van de Werf F, Budaj A, Gurfinkel EP, Goodman SG, Brieger D. Intervention in acute coronary syndromes: do patients undergo intervention on the basis of their risk characteristics? The Global Registry of Acute Coronary Events (GRACE). Heart 2007;93:177e182. Granger CB, Goldberg RJ, Dabbous O, Pieper KS, Eagle KA, Cannon CP, Van de Werf F, Avezum Á, Goodman SG, Flather MD, Fox KAA, for the Global Registry of Acute Coronary Events Investigators. Predictors of hospital mortality in the Global Registry of Acute Coronary Events. Arch Intern Med 2003;163:2345e2353. Kurosawa S, Kanaya N, Niiyama Y, Nakayama M, Fujita S, Namiki A. Landiolol, esmolol and propranolol protect from ischemia/reperfusion injury in isolated guinea pig hearts. Can J Anaesth 2003;50:489e494. Hill M, Takano H, Tang X, Kodani E, Shirk G, Boli R. Nitroglycerin induces late preconditioning against myocardial infarction in conscious rabbits despite development of nitrate tolerance. Circulation 1991;104: 694e699. Emery M, Lopez-Sendon J, Steg PG, Anderson FA Jr, Dabbous OH, Scheuble A, Eagle KA. Patterns of use and potential impact of early
24.
25.
26.
27. 28. 29.
beta-blocker therapy in non-ST-elevation myocardial infarction with and without heart failure: the Global Registry of Acute Coronary Events. Am Heart J 2006;152:1015e1021. Yan AT, Yan RT, Tan M, Fung A, Cohen EA, Fitchett DH, Langer A, Goodman SG. Management patterns in relation to risk stratification among patients with non-ST elevation acute coronary syndromes. Arch Intern Med 2007;167:1009e1016. Mehta RH, Roe MT, Chen AY, Lytle BL, Pollack CV Jr, Brindis RG, Smith SC Jr, Harrington RA, Fintel D, Fraulo ES, Califf RM, Gibler WB, Ohman EM, Peterson ED. Recent trends in the care of patients with non-ST-segment elevation acute coronary syndromes: insights from the CRUSADE initiative. Arch Intern Med 2006;166: 2027e2034. Spencer F, Scleparis G, Goldberg RJ, Yarzebski J, Lessard D, Gore JM. Decade-long trends (1986 to 1997) in the medical treatment of patients with acute myocardial infarction: a community-wide perspective. Am Heart J 2001;142:594e603. Rathore SS, Mehta RH, Wang Y, Radford MJ, Krumholz HM. Effects of age on the quality of care provided to older patients with acute myocardial infarction. Am J Med 2003;114:307e315. John RM. Crowding out effect of tobacco expenditure and its implications on household resource allocation in India. Soc Sci Med 2008;66:1356e1367. Yusuf S, Islam S, Chow C, Rangarajan S, Dagenais G, Diaz R, Gupta R, Kelishadi R, Iqbal R, Avezum A, Kruger A, Kutty R, Lanas F, Lisheng L, Wei L, Lopez-Jaramillo P, Oguz A, Rahman O, Swidan H, Yusoff K, Zatonski W, Rosengren A, Teo KK. Use of secondary prevention drugs for cardiovascular disease in the community in highincome, middle-income, and low-income countries (the PURE Study): a prospective epidemiological survey. Lancet 2011;378:1231e1243.
a Terrence Donnelly Heart Centre, St Michael’s Hospital, University of Toronto, Toronto, Ontario, Canada; bCanadian Heart Research Centre, Toronto, Ontario, Canada; cHospital Universitario La Paz, Madrid, Spain; d St-Jerome Hospital, Quebec City, Quebec, Canada; eVancouver General Hospital and University of British Columbia, Vancouver, British Columbia, Canada; fMemorial University, St John’s, Newfoundland, Canada; and g Thrombosis and Atherosclerosis Research Institute, McMaster University, Hamilton, Ontario, Canada. Manuscript received December 14, 2012; revised manuscript received and accepted February 19, 2013. Dr Andrew Yan is supported by a New Investigator Award from the Heart and Stroke Foundation of Canada. See page 55 for disclosure information. *Corresponding author: Tel: (416) 864-5465; fax: (416) 864-5159. E-mail address: [email protected] (A.T. Yan).
0002-9149/13/$ - see front matter Ó 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2013.02.053
episodes.1e4 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,5e7 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.8 Despite this, in previous studies examining the treatment of chronic stable angina, CAs have been the most commonly prescribed agent.9 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.10 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-STsegment elevation myocardial infarction (NSTEMI) or www.ajconline.org
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Figure 1. Temporal trends of antianginal medication use before presentation.
unstable angina (UA) and (2) whether pretreatment with antianginal therapy was associated with differences in the clinical presentation, management, and outcomes of NSTEACS. Methods The full details of the GRACE database design and methods have been previously published.11 Briefly, GRACE is a multinational, multicenter, prospective registry of a broad spectrum of patients with ACS that was expanded (GRACE2) in 2003.12 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/ GRACE2 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/GRACE2/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.13 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.14e19 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.20 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;
Coronary Artery Disease/Previous Anti-Anginal Therapies and Acute Coronary Syndrome Table 1 Baseline characteristics according to previous antianginal use Variable
Previous Antianginal Use
Table 3 In-hospital management and outcomes p Value
Variable
No (n ¼ 4,554) Yes (n ¼ 5,465) Age (yrs)* 63 (54e73) Men 68.8% Previous angina pectoris 27.3% Previous myocardial 16.7% infarction Previous PCI 8.5% Previous coronary bypass 5.9% Previous heart failure 5.0% Previous stroke/transient 5.6% ischemic attack Previous hypertension 46.4% 43.1% Dyslipidemia† Current smoker 31.2% Previous atrial fibrillation 5.5% Diabetes mellitus 20.7% Heart rate (beats/min)* 80 (69e94) Systolic blood pressure 146 (129e164) (mm Hg)* 88 (76e104) Creatinine (mmol/L)* Positive initial biomarkers 51.5% Positive biomarkers at 24 h 70.8% ST deviation 31.2% GRACE risk score* 114 (92e142) Final diagnosis NSTEMI 72.5% Unstable angina pectoris 27.5%
71 (61e79) 62.1% 69.5% 52.4%
<0.001 <0.001 <0.001 <0.001
29.8% 22.1% 16.5% 13.7%
<0.001 <0.001 <0.001 <0.001
78.7% 68.7% 17.4% 14.6% 36.5% 76 (64e91) 143 (125e162)
<0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001
96 (80e122) 36.6% 56.3% 32.6% 128 (103e157)
<0.001 <0.001 <0.001 0.073 <0.001
57.5% 42.5%
<0.001
* Presented as median values with interquartile range. † Defined as previously diagnosed hyperlipidemia or patient on lipidlowering agent.
Table 2 Medication use within the first 24 hours Medicine
Aspirin Clopidogrel Warfarin Unfractionated heparin Enoxaparin Any heparin Glycoprotein IIb/IIIa inhibitors Beta blocker Calcium antagonist Nitroglycerin ACE inhibitor Angiotensin receptor blocker Statin Inotrope
Prior Antianginal Use No (n ¼ 4,554)
Yes (n ¼ 5,465)
92.8% 67.3% 3.3% 29.8% 61% 88.2% 8.3% 73.8% 9.5% 63% 43.2% 7.8% 62.5% 1.9%
89.9% 60.3% 7.7% 29.6% 56.3% 83.7% 5.0% 80.2% 37.5% 74.7% 56.8% 15.9% 71.7% 1.5%
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p Value
<0.001 <0.001 <0.001 0.608 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 0.02
ACE ¼ angiotensin converting enzyme.
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.
Prior Antianginal Use
p Value
No Yes (n ¼ 4,554) (n ¼ 5,465) In-hospital cardiac procedures Coronary angiography Time to coronary angiography (d)* PCI Coronary bypass LVEF assessment In-hospital outcomes All-cause mortality Reinfarction Cardiogenic shock Heart failure Recurrent myocardial ischemia Sustained ventricular tachycardia
64.8% 3 (2,4) 33.4% 3.7% 63.5%
54.5% 3 (2,5) 25.3% 3.5% 59.5%
<0.001 <0.001 <0.001 0.20 <0.001
2.7% 4.5% 1.2% 6.3% 22.5% 1.7%
2.8% 3.4% 1.0% 9.6% 27.5% 1.5%
0.65 0.005 0.12 <0.001 <0.001 0.48
LVEF ¼ left ventricular ejection fraction. * Presented as median values with interquartile range.
Table 4 Independent predictors of cardiac catheterization during index hospitalization Independent predictors GRACE risk score (per 10 higher) Female gender Previous myocardial infarction Previous congestive heart failure Previous transient ischemic attack Previous major bleeding Previous atrial fibrillation Previous PCI Previous coronary bypass surgery On-site cardiac catheterization availability Antianginal use (none) Antianginal use (1 agent) Antianginal use (2 agents)
Adjusted OR (95% CI)
p Value
0.93 (0.91e0.96) 0.78 (0.69e0.87) 0.62 (0.50e0.75) 0.51 (0.43e0.61) 0.67 (0.55e0.80) 0.59 (0.42e0.82) 0.76 (0.66e0.88) 1.38 (1.18e1.61) 0.82 (0.71e0.94) 2.89 (1.78e4.69) Referent group 0.83 (0.73e0.95) 0.82 (0.63e1.07)
<0.001 <0.001 <0.001 <0.001 <0.001 0.002 <0.001 <0.001 0.006 <0.001 0.006 0.14
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). 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).
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Table 5 Independent predictors of all-cause mortality during index hospitalization Independent Predictor Age (per 10 yrs higher) Heart rate (per 10 beats/min higher) Systolic blood pressure (per 10 mm Hg higher) Killip Class I Killip Class II Killip Class III Killip Class IV Creatinine (per 10 mmol/L higher) Cardiac arrest ST deviation Initial positive biomarker Antianginal use (none) Antianginal use (1 agent) Antianginal use (2 agents)
Adjusted OR (95% CI)
p Value
2.22 (1.93e2.55) 1.09 (1.03e1.15) 0.84 (0.81e0.88)
<0.001 0.005 <0.001
Referent group 2.64 (1.39e5.03) 3.32 (2.32e4.78) 3.00 (0.70e12.92) 1.04 (1.03e1.05) 5.34 (2.10e13.63) 1.48 (0.97e2.27) 1.11 (0.73e1.70) Referent group 0.70 (0.35e1.37) 0.60 (0.29e1.25)
0.003 <0.001 0.14 <0.001 <0.001 0.069 0.62 0.30 0.17
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] ¼ 0.83, 95% confidence interval [CI] 0.70e0.98, p ¼ 0.03). The rates of cardiogenic shock and sustained ventricular tachycardia were not significantly different between groups (Table 3). Compared with patients who did not receive chronic antianginal therapy, those who received chronic antianginal therapy had a significantly lower unadjusted rate of in-hospital reinfarction but higher rates of heart failure and recurrent ischemia (Table 3). The unadjusted in-hospital mortality rate was 2.7% for patients not treated with chronic antianginals and 2.8% in chronic antianginal users (p ¼ 0.65; Table 3). In multivariable analysis, higher age, Killip class, heart rate and creatinine, cardiac arrest, and lower systolic blood pressure were independent predictors of in-hospital mortality (Table 5). Chronic antianginal use with a single agent or multiple agents was not a significant predictor for inhospital mortality (adjusted OR ¼ 0.70, 95% CI 0.35e1.37, p ¼ 0.30 for use of 1 antianginal agent and adjusted OR ¼ 0.60, 95% CI 0.29e1.25, p ¼ 0.17 for 2 antianginal agents). Discussion In this large observational study, we found that BBs remained the most commonly used agents among patients on antianginal therapy before ACS presentation. ACS patients on chronic antianginal therapy were less likely to have NSTEMI and reinfarction in hospital and were less likely to undergo in-hospital coronary angiography. There
was no independent association between previous use of antianginal therapy and in-hospital mortality. The cardioprotective effects of antianginal therapies have been the focus of previous studies.21,22 Recently, a retrospective analysis involving >50,000 patients examined chronic nitrate use and ACS presentation.10 Those presenting with ACS and with a history of chronic nitrate use (defined as treatment being started 7 days before the index event) were more likely to receive an admission diagnosis of NSTEMI or UA, as opposed to STEMI. This association remained even after adjustment for age, gender, medical history, previous therapy, previous angina, and revascularization. Moreover, regardless of ACS presentation type, patients with previous nitrate use were less likely to have positive biomarkers. Yet to the best of our knowledge, no studies to date have specifically evaluated whether this association is unique to nitrates and antianginal medications as a class. The present study imparts new insights in several regards. In our study, patients who were on chronic antianginal therapy were older and more likely to be female. These patients were less likely to receive therapies such as antiplatelet agents or anticoagulants. These findings in elderly and female patients are similar to those from other studies investigating the use of evidence-based therapies in patients with ACS.23e27 This observation could be in part attributable to age, bleeding risk, and the fact that these patients were more likely to have atrial fibrillation and already be on oral anticoagulant. Moreover, the difference in presentation and the fact that they less frequently presented with positive biomarkers may have influenced the decision to start antiplatelet or anticoagulation agents. However, patients who were already on chronic antianginal therapy were more likely to receive statins, antianginals, and angiotensin receptor blockers. This may be because physicians were inclined to continue therapies used before admission or because of a higher prevalence of risk factors such as hypertension and dyslipidemia. The group on chronic antianginals also had higher prevalence of cardiovascular risk factors except smoking. Smoking rates were probably lower in these patients because there had likely been considerable effort toward counseling for smoking cessation for preventative health measures in patients with preexisting disease. Alternatively, those individuals currently smoking at the time of presentation might have been less likely to adopt a drug prevention strategy.28 We found that patients on chronic antianginal therapy before admission had lower rates of assessment of LV function and cardiac catheterization during hospitalization. This latter observation was observed even after adjustment for the presence of on-site cardiac catheterization facilities. This may be related to the fact that this group had significantly more comorbidities, as well as a higher burden of coronary disease at baseline that had been previously delineated and might not be amenable to revascularization. Finally, it is possible that a lower rate of abnormal biomarker might have favored medical management rather than an early invasive approach. Finally, we observed higher rates of recurrent ischemia and heart failure in the group treated with chronic antianginals. This might be due to the differences in medical
Coronary Artery Disease/Previous Anti-Anginal Therapies and Acute Coronary Syndrome
management and care that they received in hospital or to confounding by indication. In addition, patients with chronic antianginal use were not managed as aggressively with lower rates of coronary angiography and revascularization, and may have had more residual flow-limiting coronary disease causing symptoms. Alternatively, this may simply reflect the inherent differences between groups—that is, patients on chronic antianginal therapy were older and more likely to have previous hypertension, myocardial infarction, and heart failure. The present study is limited by its retrospective and nonrandomized nature. However, it does allow for accurate assessment of real-world practice patterns. We did not collect data on the specific antianginal agent, dose, or duration of therapy. Furthermore, we do not know the reason a particular agent was selected or the severity of anginal symptoms before admission. Although ACS patients on chronic antianginal therapies more frequently had a history of angina, some of these medications might have been prescribed for other indications. The purpose of this observational study was not to establish the efficacy of chronic antianginal therapy or any cause-and-effect relationships because there were likely unmeasured or unknown confounders. Randomized controlled trials would be best suited to establish treatment efficacy, but it would be infeasible to randomize patients to antianginal therapies before ACS. Finally, there is an apparent underutilization of secondary prevention therapies after ACS, which warrants further assessment of the long-term prescription and adherence to such treatments.29 Acknowledgment: We thank Sue Francis, BA, for her assistance in the preparation of this manuscript. We are grateful to all the study coordinators, investigators, and patients who participated in GRACE/GRACE2 and CANRACE. Disclosures Dr. Jose Lopez-Sendon has received speaker/consulting honoraria and/or research grant support from Sanofi, Servier, Menarini, Merk, and Pfizer. Dr. John J. Graham has received speaker/consulting honoraria and/or research grant support from Astra Zeneca, Eli Lilly, and Bristol Myers Squibb. Dr. David Fitchett, Dr. Graham C. Wong, Dr. Barry F. Rose, Dr. Frederick A. Spencer, Dr. Andrew T. Yan, Dr. Shaun G. Goodman, and Dr. Yves Pesant have received speaker/consulting honoraria and/or research grant support from Sanofi Aventis and Bristol Myers Squibb. The other authors report no conflicts of interest. 1. Parker JO, Amies MH, Hawkinson RW, Heilman JM, Hougham AJ, Vollmer MC, Wilson RR. Intermittent transdermal nitroglycerin therapy in angina pectoris. Clinically effective without tolerance or rebound. Minitran Efficacy Study Group. Circulation 1995;91: 1368e1374. 2. Savonitto S, Ardissiono D, Egstrup K, Rasmussen K, Bae EA, Omland T, Schjelderup-Mathiesan PM, Marraccini P, Wahlqvist I, Merlini PA, Rehnqvist N. Combination therapy with metoprolol and nifedipine versus monotherapy in patients with stable angina pectoris. Results of the International Multicenter Angina Exercise (IMAGE) Study. J Am Coll Cardiol 1996;27:311e316.
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3. Smith NL, Reiber GE, Psaty BM, Heckbert SR, Siscovick DS, Ritchie JL, Every NR, Koepsell TD. Health outcomes associated with betablocker and diltiazem treatment of unstable angina. J Am Coll Cardiol 1998;32:1305e1311. 4. Taylor SH. Usefulness of amlodipine for angina pectoris. Am J Cardiol 1994;73:28Ae33A. 5. Colucci WS. Landmark study: the Carvedilol Post-Infarct Survival Control in Left Ventricular Dysfunction Study (CAPRICORN). Am J Cardiol 2004;93:13Be16B. 6. Doughty RN, Whalley GA, Walsh HA, Gamble GD, López-Sendón J, Sharpe N. Effects of carvedilol on left ventricular remodeling after acute myocardial infarction: the CAPRICORN Echo Substudy. Circulation 2004;109:201e206. 7. Hjalmarson A, Goldstein S, Fagerberg B, Wedel H, Waagstein F, Kjekshus J, Wikstrand J, El Allaf D, Vítovec J, Aldershvile J, Halinen M, Dietz R, Neuhaus KL, Jánosi A, Thorgeirsson G, Dunselman PH, Gullestad L, Kuch J, Herlitz J, Rickenbacher P, Ball S, Gottlieb S, Deedwania P. Effects of controlled-release metoprolol on total mortality, hospitalizations, and well-being in patients with heart failure: the Metoprolol CR/XL Randomized Intervention Trial in congestive heart failure (MERIT-HF). MERIT-HF Study Group. JAMA 2000;283: 1295e1302. 8. Fraker TD Jr, Fihn SD, Gibbons RJ, Abrams J, Chatterjee K, Daley J, Deedwania PC, Douglas JS, Ferguson TB Jr, Fihn SD, Fraker TD Jr, Gardin JM, O’Rourke RA, Williams SV, Smith SC Jr, Jacobs AK, Adams CD, Anderson JL, Buller CE, Creager MA, Ettinger SM, Halperin JL, Hunt SA, Krumholz HM, Kushner FG, Lytle BW, Nishimura R, Page RL, Riegel B, Tarkington LG, Yancy CW. 2007 chronic angina focused update of the ACC/AHA 2002 Guidelines for the management of patients with chronic stable angina: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines Writing Group to develop the focused update of the 2002 Guidelines for the management of patients with chronic stable angina. Circulation 2007;116:2762e2772. 9. Beaulieu MD, Blais R, Jacques A, Battista RN, Lebeau R, Brophy J. Are patients suffering from stable angina receiving optimal medical treatment? QJM 2001;94:301e308. 10. Ambrosio G, Del Pinto M, Tritto I, Agnelli G, Bentivoglio M, Zuchi C, Anderson FA, Gore JM, López-Sendón J, Wyman A, Kennelly BM, Fox KA. Chronic nitrate therapy is associated with different presentation and evolution of acute coronary syndromes: insights from 52 693 patients in the Global Registry of Acute Coronary Events. Eur Heart J 2009;31:430e438. 11. GRACE investigators. Rationale and design of the GRACE (Global Registry of Acute Coronary Events) Project: a multinational registry of patients hospitalized with acute coronary syndromes. Am Heart J 2001;141:190e199. 12. Goodman SG, Huang W, Yan AT, Budaj A, Kennelly BM, Gore JM, Fox KA, Goldberg RJ, Anderson FA Jr. The expanded Global Registry of Acute Coronary Events: baseline characteristics, management practices, and hospital outcomes of patients with acute coronary syndromes. Am Heart J 2009;158:193e201; e1e5. 13. Yan AT, Steg PG, Fitzgerald G, Feldman LJ, Eagle KA, Gore JM, Anderson FA, López-Sendón J, Gurfinkel EP, Brieger D, Goodman SG. Recurrent ischemia across the spectrum of acute coronary syndromes: prevalence and prognostic significance of (re-)infarction and ST-segment changes in a large contemporary registry. Int J Cardiol 2010;145:15e20. 14. Every NR, Larson EB, Litwin PE, Maynard C, Fihn SD, Eisenberg MS, Hallstrom AP, Martin JS, Weaver WD. The association between on-site cardiac catherterization facilities and the use of coronary angiography after acute myocardial infarction. Myocardial Infarction Triage and Intervention Project Investigators. N Engl J Med 1993;329: 546e551. 15. Krumholz HM, Chen J, Murillo JE, Cohen DJ, Radford MJ. Admission to hospitals with on-site cardiac catheterization facilities; impact on long-term cost and outcomes. Circulation 1998;98: 2010e2016. 16. Bhatt DL, Roe MT, Peterson ED, Li Y, Chen AY, Harrington RA, Greenbaum AB, Berger PB, Cannon CP, Cohen DJ, Gibson CM, Saucedo JF, Kleiman NS, Hochman JS, Boden WE, Brindis RG, Peacock WF, Smith SC Jr, Pollack CV Jr, Gibler WB, Ohman EM. Utilization of early invasive management strategies for high-risk patients with non-ST elevation acute coronary syndromes; results from
56
17.
18.
19.
20.
21. 22.
23.
The American Journal of Cardiology (www.ajconline.org) the CRUSADE Quality Improvement Initiative. JAMA 2004;292: 2096e2104. Van de Werf F, Gore JM, Avezum A, Gulba DC, Goodman SG, Budaj A, Brieger D, White K, Fox KA, Eagle KA, Kennelly BM. Access to catheterization facilities in patients admitted with acute coronary syndrome: multinational registry study. BMJ 2005;330:441. Roe MT, Peterson ED, Newby LK, Chen AY, Pollack CV Jr, Brindis RG, Harrington RA, Christenson RH, Smith SC Jr, Califf RM, Braunwald E, Gibler WB, Ohman EM. The influence of risk status on guideline adherence for patients with non-ST-segment elevation acute coronary syndromes. Am Heart J 2006;151:1205e1213. Fox KA, Anderson FA Jr, Dabbous OH, Steg PG, López-Sendón J, Van de Werf F, Budaj A, Gurfinkel EP, Goodman SG, Brieger D. Intervention in acute coronary syndromes: do patients undergo intervention on the basis of their risk characteristics? The Global Registry of Acute Coronary Events (GRACE). Heart 2007;93:177e182. Granger CB, Goldberg RJ, Dabbous O, Pieper KS, Eagle KA, Cannon CP, Van de Werf F, Avezum Á, Goodman SG, Flather MD, Fox KAA, for the Global Registry of Acute Coronary Events Investigators. Predictors of hospital mortality in the Global Registry of Acute Coronary Events. Arch Intern Med 2003;163:2345e2353. Kurosawa S, Kanaya N, Niiyama Y, Nakayama M, Fujita S, Namiki A. Landiolol, esmolol and propranolol protect from ischemia/reperfusion injury in isolated guinea pig hearts. Can J Anaesth 2003;50:489e494. Hill M, Takano H, Tang X, Kodani E, Shirk G, Boli R. Nitroglycerin induces late preconditioning against myocardial infarction in conscious rabbits despite development of nitrate tolerance. Circulation 1991;104: 694e699. Emery M, Lopez-Sendon J, Steg PG, Anderson FA Jr, Dabbous OH, Scheuble A, Eagle KA. Patterns of use and potential impact of early
24.
25.
26.
27. 28. 29.
beta-blocker therapy in non-ST-elevation myocardial infarction with and without heart failure: the Global Registry of Acute Coronary Events. Am Heart J 2006;152:1015e1021. Yan AT, Yan RT, Tan M, Fung A, Cohen EA, Fitchett DH, Langer A, Goodman SG. Management patterns in relation to risk stratification among patients with non-ST elevation acute coronary syndromes. Arch Intern Med 2007;167:1009e1016. Mehta RH, Roe MT, Chen AY, Lytle BL, Pollack CV Jr, Brindis RG, Smith SC Jr, Harrington RA, Fintel D, Fraulo ES, Califf RM, Gibler WB, Ohman EM, Peterson ED. Recent trends in the care of patients with non-ST-segment elevation acute coronary syndromes: insights from the CRUSADE initiative. Arch Intern Med 2006;166: 2027e2034. Spencer F, Scleparis G, Goldberg RJ, Yarzebski J, Lessard D, Gore JM. Decade-long trends (1986 to 1997) in the medical treatment of patients with acute myocardial infarction: a community-wide perspective. Am Heart J 2001;142:594e603. Rathore SS, Mehta RH, Wang Y, Radford MJ, Krumholz HM. Effects of age on the quality of care provided to older patients with acute myocardial infarction. Am J Med 2003;114:307e315. John RM. Crowding out effect of tobacco expenditure and its implications on household resource allocation in India. Soc Sci Med 2008;66:1356e1367. Yusuf S, Islam S, Chow C, Rangarajan S, Dagenais G, Diaz R, Gupta R, Kelishadi R, Iqbal R, Avezum A, Kruger A, Kutty R, Lanas F, Lisheng L, Wei L, Lopez-Jaramillo P, Oguz A, Rahman O, Swidan H, Yusoff K, Zatonski W, Rosengren A, Teo KK. Use of secondary prevention drugs for cardiovascular disease in the community in highincome, middle-income, and low-income countries (the PURE Study): a prospective epidemiological survey. Lancet 2011;378:1231e1243.