International variation in the use of evidence-based medicines for acute coronary syndromes

Judith M Kramera,*, L.Kristin Newbya, Wei-Ching Changb, R.John Simesc, Frans Van de Werfd, Christopher B Grangera, Kerry L Leee, Harvey D Whitef, Leopoldo S Piegasg, Eric J Topolh, Robert M Califfa and Paul W Armstrongb for the SYMPHONY and 2nd SYMPHONY Investigators1

a Duke University Medical Center, Duke Center for Education and Research on Therapeutics, and Duke Clinical Research Institute, Durham, NC, USA
b Canadian Vigour Centre, University of Alberta, Edmonton, Alberta, Canada
c National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Sydney, Australia
d Department of Cardiology, University Hospital Gasthuisberg and Director, Leuven Coordinating Center, Leuven, Belgium
e Biostatistics and Bioinformatics, Duke University Medical Center and Duke Clinical Research Institute, Durham, NC, USA
f Green Lane Coordinating Center, Green Lane Hospital, Auckland, New Zealand
g Universidade de Sâo Paulo, Instituto Dante Pazzanese de Cardiologica, Sâo Paulo, Brazil
h Cleveland Clinic Foundation, Cleveland, OH, USA

* Corresponding author. Dr J. M. Kramer, Duke University Medical Center, 2400 Pratt Street, Room 0311 Terrace Level, Durham, NC 27705, USA. Tel.: +1-919-668-8501; Fax: +1-919-668-7059
E-mail address: krame009{at}mc.duke.edu

Received 15 May 2003; accepted 19 September 2003 This paper was guest edited by Christopher P. Cannon, Brigham and Women’s Hospital, Boston, USA

Abstract

Aims We sought to evaluate international patterns of use and factors influencing use of evidence-based medications early after ACS.

Methods and results Using a database of 15 904 ACS patients enrolled in the SYMPHONY and 2nd SYMPHONY trials in 37 countries, we performed descriptive and logistic regression analyses. After controlling for other factors, region was significantly associated with the use of every class of evidence-based medication, most pronounced for intravenous unfractionated heparin (IV UFH), low-molecular-weight heparin (LMWH), angiotensin II converting enzyme inhibitors (ACEI) and discharge use of lipid-lowering agents. Latin America and Eastern Europe were among the highest users of early ACEI, yet the lowest users of discharge lipid-lowering therapy. Relative to the United States, all regions except Canada had greater use of LMWH and lower use of IV UFH. Compared with patients with acute myocardial infarction, those with unstable angina less often received aspirin, beta-blockers, ACEI, or IV UFH. Older age was associated with lower use of aspirin, beta-blockers, IV UFH, and lipid-lowering agents.

Conclusion Use of evidence-based therapies for management of ACS patients is strongly associated with region. To improve patient outcomes, more research is needed to understand this variation, and to institute appropriate solutions.

Key Words: Acute coronary syndromes • Evidence-based medicine • Drug therapy • Cross-cultural comparisons • International differences • Guidelines

1. Introduction

In published practice guidelines, there is growing international consensus on which life-saving therapies should be administered to patients with acute coronary syndromes (ACS).1–6Further, recent analyses have emphasized the importance of guideline adherence to clinical outcomes.7However, there is a recognized gap between published guidelines derived from clinical trials and actual use of evidence-based medications in clinical practice.8Underuse of life-saving therapies for secondary prevention of coronary heart disease (CHD) is particularly troublesome since CHD is a major worldwide cause of premature death and disability. The World Health Organization estimates that by the year 2020 there will be 11.1 million deaths per year from CHD worldwide.9Failing primary prevention, patients having an acute coronary event present an important opportunity to commence life-saving therapies both to improve immediate outcomes and for secondary prevention.

For logistical reasons most detailed studies evaluating adherence to practice guidelines have been conducted at a regional or national level.10–12Much could be learned by a more detailed examination of broad international practice patterns in evidence-based therapy for CHD. The combined database from two large-scale international clinical trials, Sibrafiban vs aspirin to Yield Maximum Protection from ischemic Heart events post-acute cOroNary sYndromes (SYMPHONY) and 2nd SYMPHONY trials,13–15provided a unique opportunity to evaluate international patterns of care for ACS patients. Using the extensive information collected on concomitant medications administered in the period immediately following the diagnosis of ACS, we evaluated contemporarypatterns of use of evidence-based medications in the context of existing practice guidelines and examined factors that influence their use.

2. Methods

2.1. Patient population
The methods and results of the SYMPHONY and 2nd SYMPHONY trials have been previously published.13–15Between August 1997 and August 1999 at 931 clinical centers in 37 countries, these two trials enrolled 15 904 patients with a diagnosis of ACS (ST-segment elevation or non-ST-segment elevation myocardial infarction [MI] or unstable angina) to test the effectiveness of sibrafiban, an oral glycoprotein IIb/IIIa inhibitor, vs aspirin for secondary prevention of CHD. Patients enrolled in these studies must have had their qualifying ACS event within the prior 7 days and have been clinically stable for 12h. These studies complied fully with the Declaration of Helsinki. Locally appointed ethics committees approved the research protocol; informed consent was obtained from all subjects.

2.2. Assessment of regional variation in use of evidence-based medications
Countries participating in SYMPHONY and 2nd SYMPHONY were grouped into six regions (Table 1). Due to established differences in treatment patterns between the United States (US) and Canada,16and the much larger enrollment in the US, these North American data are reported separately. We assessed regional variation in the overall rates of use of medications that had been recommended prior to the start of the SYMPHONY trials by the US Agency for Health Care Policy and Research’s Unstable Angina Guidelines,1the American College of Cardiology/American Heart Association’s guidelines for the management of patients with acute myocardial infarction,2and by the European Society of Cardiology’s guidelines for the treatment of acute myocardial infarction3(Table 2). Thus, we assessed early administration of aspirin, beta-blockers, intravenous unfractionated heparin (IV UFH), and angiotensin converting enzyme inhibitors (ACEI) between the qualifying ACS event and start of study treatment (median 91h [inter-quartile range 61–131]). Since guidelines do not recommend very early treatment with lipid-lowering therapy,17for this class of drugs only, we analyzed medication use at discharge. Although not recommended in US or European guidelines before the start of the SYMPHONY trials, low-molecular-weight heparin (LMWH) use was also evaluated.


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Table 1 Enrollment by region

 

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Table 2 Acute coronary syndrome guidelines before the start of SYMPHONY

 
Use of concomitant medications in the SYMPHONY trials was at the discretion of the treating physician. All patients had to be eligible for aspirin use, but its administration prior to randomization was determined by the treating physician. Since the SYMPHONY trials were not acute treatment trials, specific reperfusion strategies used for the qualifying event were not captured. For the purposes of this analysis, we characterized the qualifying event as acute myocardial infarction (MI) with or without thrombolysis or as unstable angina. Since the first intravenous glycoprotein IIb/IIIa receptor antagonist was not approved by US regulatory authorities for treatment of ACSuntil May of 1998, or by many European authorities until the third-quarter of 1999, we did not analyze use of these drugs.

2.3. Statistical analysis
Descriptive analyses were prepared by region for baseline characteristics, clinical outcomes, and medication use. Clinical outcomes included 90-day death, death or MI, overall revascularization, coronary artery bypass graft surgery (CABG), percutaneous coronary intervention (PCI), total bleeds, major bleeds, stroke, and rehospitalization. These end-points were used as determined for the main SYMPHONY trials. Data are presented as percentages for categorical variables with group comparisons made using the chi-square test, and as medians and interquartile ranges for continuous variables with group comparisons performed using Kruskal–Wallis non-parametric analysis of variance. A P-value of <0.05 was considered statistically significant. No adjustment was made for multiple comparisons.

Association of baseline factors with medication use was examined for each drug by multivariable logistic regression analysis using a backward, stepwise procedure. The following variables were considered: age, sex, region, race, height, weight, body mass index, MI as qualifying event (unstable angina as reference), MI location (anterior or inferior), systolic and diastolic blood pressure at qualifying event, elevated creatine kinase (CK) and elevated CK-MB level at qualifying event, Killip class at qualifying event, PCI between qualifying event and start of study treatment, and history of diabetes, hypertension, hypercholesterolemia, heart failure, MI, or revascularization. Results are presented as odds ratios (OR) with 95% confidence intervals. For region, the US was the reference, as it was the highest enrolling region, and therefore provided the most stable estimate. All analyses were performed using SPSS Version 11.0.

3. Results

3.1. Patient population
The regional distribution of patients in the SYMPHONY trials is shown in Table 1.Although most patients were from North America and Western Europe, 17% were from Eastern Europe, 4% from Latin America, 4% from Australia/New Zealand, and 3% from Asia. Twenty-seven percent were women; 36% were >65 years old.

3.2. Regional variation in baseline characteristics and outcomes
Compared with patients from other regions, patients from the US had higher rates of prior percutaneous coronary intervention (PCI), prior coronary artery bypass surgery, and PCI between qualifying event and study start (Table 3). Current smoking varied significantly across regions (range 32–43%). Acute MI was the qualifying event in 55–84% of patients across the regions; 22–36% of these received thrombolysis for presumed ST-segment elevation MI.


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Table 3 Baseline characteristics by regiona

 
With the exception of a lower rate in Eastern Europe, rates of revascularization in the first 90 days after randomization were similar across the regions (Table 4). Ninety-day rates of total bleeding (range 14–22%) and major bleeding (range 2.1–6.8%) varied significantly, but stroke rates did not. There was also significant variability across regions in the rates of rehospitalization by 90 days (range 19–34%). Ninety-day mortality was highest in Asia and Latin America; the composite of death or MI within 90 days after randomization was highest in Asia (Table 4).


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Table 4 90-Day clinical outcomes by regiona

 
3.3. Variation in use of evidence-based medications
Use of evidence-based medications for ACS is shown by region in Table 5. Rates of use of aspirin (range 75–91%) and beta-blockers (range 68–78%) varied by region, but overall was higher and varied less across regions than early use of ACEI and discharge use of lipid-lowering agents. Latin American and Eastern Europe, who were among the highest users of ACEI, were the lowest users of lipid-lowering therapy. The extent to which LMWH was used also varied significantly by region. LMWH use was greatest in Western and Eastern Europe, Australia/New Zealand, and Asia. Overall use of anti-thrombin therapy (heparin or LMWH) was lower in Asia than all other regions.


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Table 5 Evidence-based medication use by regiona

 
In addition to regional variation, there were significant differences in the rates of medication use according to the type of qualifying event (Table 6). Patients with unstable angina less often received aspirin, beta-blockers, ACEI, IV UFH, and lipid-lowering agents than either MI cohort.


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Table 6 Evidence-based medication use by type of qualifying eventa

 
3.4. Adjusted analyses
After adjustment for differences in baseline characteristics, there was a statistically significant association between region and use of all classes of evidence-based medications (Figs. 1a, 1b and 1c). This variation was most pronounced for IV UFH, LMWH, ACEI and lipid-lowering agents (Figs. 1b and 1c). Relative to the US, all regions except Canada had significantly more use of LMWH and lower use of IV UFH. Even after adjusting for a history of hypertension, hypercholesterolemia, and heart failure, Latin America and Eastern Europe remained among the highest users of ACEI, yet were the lowest users of lipid-lowering therapy.



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Fig. 1(a) Factors Associated with the Use of Evidence-Based Medications: Aspirin (boxes) and Beta-blockers (circles). Odds ratio plot with 95% confidence intervals. 1Reference: United States; 2Reference: <65; 3Reference: Caucasian race; 4Reference: Killip Class I. (QE=qualifying event; PCI=percutaneous coronary intervention; rand=randomization). (b) Factors Associated with the Use of Evidence-Based Medications: Intravenous Unfractionated Heparin (boxes) and Low Molecular Weight Heparin (circles). Odds ratio plot with 95% confidence intervals. 1Reference: United States; 2Reference: <65; 3Reference: Caucasian race. (QE=qualifying event; PCI=percutaneous coronary intervention; rand=randomization). (c) Factors Associated with the Use of Evidence-Based Medications: Angiotensin-converting enzyme (ACE) Inhibitors (boxes) and Lipid-lowering agents at discharge (circles). Odds ratio plot with 95% confidence intervals. 1Reference: United States; 2Reference: <65; 3Reference: Caucasian race; 4Reference: Killip Class I. (QE=qualifying event).

 
After controlling for other factors, across all regions and for all medications except ACEI and LMWH, older age was associated with lower use of evidence-based medication. Female sex predicted lower use of aspirin, beta-blockers, and IV UFH. Non-Caucasians were less likely to receive ACEI or lipid-lowering agents, but were more likely to receive aspirin or LMWH. A higher Killip class was associated with lower early use of beta-blockers and higher early use of ACEI. Even after controlling for region, compared with patients presenting with MI, patients with unstable angina were significantly less likely to receive early aspirin, beta-blockers, ACEI, or IV UFH (Figs. 1a, 1b and 1c). There also was an association between having a history of MI and lower use of aspirin and beta-blockers (acutely), and lower use of lipid-lowering agents at discharge (Figs. 1a and 1c).

4. Discussion

The principal finding from this study of a broad spectrum of ACS patients is the prominent association between the use of evidence-based medication and region. This finding persisted even after careful consideration of baseline characteristics in multivariable analysis. These results extend the findings from recent regional10,11,16and international18–20studies by inclusion of a new territory, Asia, and highlight the existing opportunities for improving the use of evidence-based therapy worldwide.

4.1. Opportunities for improvement in use of evidence-based therapy
Although aspirin and beta-blocker use was fairly high across regions, there is still substantial room to improve. Considering that in the SYMPHONY trials all patients were selected as ideal candidates for long-term aspirin use, the range of 75–91% for early in-hospital use of aspirin is unacceptably low for a medication that reduces mortality by 18% in patients with an ACS.21

Beta-blocker use in our study (68–78%) was somewhat higher than observed in ENACT,10a recent European survey of acute management of ACS. However, it has been estimated that only about 15% of patients have absolute contraindications or intolerance to beta-blockers.22Thus, there is still considerable room to improve on the early use of beta-blockers.

We cannot explain the wide variation across regions in use of lipid-lowering agents at discharge, even after controlling for documented hypercholesterolemia at baseline. Given the high rate of baseline hypercholesterolemia (48% overall, range 31–58%), the absolute rates of lipid-lowering therapy at discharge (15–44%) were inappropriately low in all regions. These results are of particular concern since recent research has documented a significant association between prescribing lipid-lowering therapy at hospital discharge and higher long-term compliance, which was associated with lower mortality.23

4.2. Use of evidence-based medications in important subgroups
There are several findings that are independent of region and that raise concern as we try to optimize patient outcomes after ACS. The variation of medication use according to the type of qualifying event suggests under-treatment of patients with unstable angina compared with patients with MI. The Global Registry of Acute Coronary Events (GRACE)18also found this same relationship for beta-blockers and IV UFH. Although one might attribute some of this difference to more uncertain diagnosis of significant coronary artery disease in unstable angina compared with MI, the patients in the SYMPHONY trials had their qualifying coronary event an average of 3–4 days before entry into the study. Thus, patients without significant disease would more likely have been identified and excluded from the SYMPHONY studies than in an acute study. The relative under-treatment in unstable angina compared with MI may reflect a lower level of recognition by treating physicians that these evidence-based therapies are indicated in unstable angina just as they are in MI.

Also of concern in our study is a confirmation of previous findings associating older age with lower use of evidence-based medications,12,24,25despite greater absolute benefit conferred by these therapies in the elderly.26Our results may underestimate the problem of under-treatment in the elderly since one might expect patients in clinical trials to be better attended to than non-trial patients and because only the most ideal elderly are likely enrolled in clinical trials.27

4.3. Complexity of understanding regional variation in use of evidence-based medications
Understanding regional variation in use of evidence-based medication is complex. For example, the widest regional variation in our study was in both the overall use of anti-thrombin therapy and the proportions of IV UFH vs LMWH used across regions. In part, this may be due to the striking difference across the regions in use of early angiography and PCI. The analysis of the use of IV UFH and LMWH is further complicated by the mix of ST-segment elevation MI vs unstable angina/non-ST-segment elevation MI and by our inability to directly assess the choice of thrombolytic agent or concomitant anti-thrombin therapy for ST-segment elevation MI. However, even after controlling for qualifying event diagnosis and the use of early PCI, significant regional variation persisted in both the proportions of IV UFH vs LMWH used and overall use of anti-thrombin therapy across regions.

Regional variation in use of evidence-based medications could also be related to differences in economic resources. These differences may affect the ability to provide patients with all evidence-based medications recommended in practice guidelines. In the World Health Organization database there was observed an inverse linear relationship between a country’s gross national product and its overall mortality rate, a relationship also found in analyses of international clinical trial data.28Beyond a country’s absolute wealth, other factors may lead to international variation in use of evidence-based medications including variation in the cost of medications across regions and a region’s social and political commitment to and tolerance for expending resources for healthcare.

Evidence for wide variation in prices of medications between countries can be seen in a comparison of costs of the same drugs in US and Canada. Consumer’s Pharmacy Guide29reveals that most drugs in the US cost at least twice that in Canada. Yet, the higher use of expensive drugs such as lipid-lowering agents in the US suggests more price tolerance in this region. Finally, while economic issues likely contribute, economics alone could not explain how a region such as Eastern Europe had both the lowest use of lipid-lowering agents, yet one of the highest rates of ACEI use, or why Eastern Europe had by far the lowest use of the least expensive drug, aspirin.

Another possible explanation for the observedregional variation could be differences in baseline characteristics not accounted for by covariates used in the logistic regression analyses. There are both known confounders not available for our analysis (e.g. type of thrombolytic, type of hospital, and specialty of treating physician) and unmeasured potential confounders such as social and cultural factors that affect treatment pattern but that cannot be easily captured in the course of clinical trials. Other interregional factors potentially unaccounted for include differences in marketing forces, in the availability of generic drug products, and in healthcare systems and their reimbursement schemes.

4.4. Limitations
Practice guidelines for the treatment of ACS are continually evolving as exemplified by broadening recommendations for ACEI,6,30LMWH,5,6,31and lipid-lowering therapy.32The dissemination of new information and its adoption into practice may differ by country and region, which coupled with the rapid accrual of new trial data and flux in the guidelines themselves, may create regional heterogeneity. In support of this hypothesis, convincing evidence supporting use of aspirin and beta-blockers has been available since the 1980s,33,34and the highest and most consistent use of evidence-based medications was observed for these agents in all regions. However, there was still substantial variation in their use, suggesting that factors other than dissemination and incorporation of evidence are likely at play.

Due to the observational nature of our analyses and the multiple comparisons, even statistically significant results should be viewed as hypothesis-generating rather than definitive. Since the study data were derived from clinical trials, they may not accurately reflect clinical practice in the broader population of ACS patients treated within each region. For example, since participation in the SYMPHONY trials varied widely by region, differential selection itself could be one factor affecting regional variation. However, one might expect that a population of patients enrolled in clinical trials would, if anything, be biased toward higher use of concomitant medications,27reflecting the best effort of a region.

The regions themselves are likely heterogeneous with regard to practice patterns, healthcare systems and socioeconomics. Such regional variation has been carefully documented between Canada and the US.16Regional heterogeneity in use of evidence-based medication also has been demonstrated in two European surveys, the ENACT10study looking at early treatment of ACS and the EUROASPIRE II11study assessing secondary prevention strategies for CHD. Despite these limitations, the persistence in our study of striking regional variation after multivariable analysis demands further study to identify the factors responsible for the variance.

5. Conclusions

The use of evidence-based medications for early treatment of ACS varies widely by geographic region. These results indicate substantial global opportunities for improving quality of care in ACS and ultimately for secondary prevention of CHD. Next steps include further investigation into the social and economic determinants of regional use, as well as development and testing of appropriate interventions to increase adherence to evidence-based guidelines.

Acknowledgments

The authors wish to thank Manjushri V. Bhapkar, MS for her expert statistical support and contributions to this manuscript and Rhonda Bartley for her administrative support.

Footnotes

1 The SYMPHONY trials were funded by research grants from F. Hoffmann-La Roche, Ltd., Basel, Switzerland. The analyses for this manuscript were funded by the investigators. Back

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