Compliance to ACC-AHA clinical practice guidelines in acute coronary syndrome in a developing country

Bernadette A. Tumanan-Mendoza, MD, MScCE, MscHE*, Dante D. Morales, MD*, Agnes M. Baston, MD, Daniel Francisco T. Morales, MD, Vim I. Samonte, MD, Mary Cheryl N. Larona, MD Word Count: 3869 Brief Title: Compliance to ACC-AHA CPGs in ACS
*

Consultant, Department of Internal Medicine, Manila Doctors Hospital United Nations Ave., Manila 1000 Philippines

Senior Lecturer, Department of Clinical Epidemiology University of the Philippines College of Medicine Pedro Gil, Manila 1000 Philippines

Medical Director Manila Doctors Hospital United Nations Ave., Manila, Philippines

Clinical Associate Professor University of the Philippines-Philippine General Hospital Taft Avenue, Manila 1000 Philippines

Resident trainee, Department of Internal Medicine Manila Doctors Hospital United Nations Ave., Manila 1000 Philippines Address for Correspondence Bernadette A. Tumanan-Mendoza, MD, MScCE, MScHE Department of Internal Medicine United Nations Ave., Manila 1000 Philippines Telephone Number: +635211704; fax number +635211704 Email address: bernadette.tumanan@gmail.com

Funding Sources: Clinical Practice Guideline Project, Medical Directorate Office, Manila Doctors Hospital and Pfizer Philippines

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Abstract
Objectives To determine 1) practice patterns and 2) mortality rates, duration of ICU and hospital stay of ACS patients before and after dissemination of the ACC-AHA CPGs in a tertiary hospital in the Philippines. Background Adoption of clinical practice guidelines developed in western countries is problematic in a developing country setting. This is particularly true in acute coronary syndrome where several level I recommendations may not be feasible. Methods This was a quasi-experimental study composed of pre and postdissemination phases. Dissemination methods included both passive and active strategies. Results During the pre-dissemination phase, 124 consecutive charts of ACS patients were reviewed. The post-dissemination phases included 120 and 115 consecutive patients for the passive dissemination and active dissemination strategies, respectively. Percentage of usage of specific diagnostic and therapeutic interventions, mortality rates, length of hospital and ICU stay were analyzed. There were high compliance rates to many diagnostic examinations with level I recommendations. Usage rates for nitrates, beta-blockers, ACE-I, statins, and anti-thrombotic agents ranged from 70 - 100% before and after dissemination. Fibrinolytics, GPIIbIIIa and invasive procedures were infrequently used, either due to unavailability or non-affordability. The mortality rate was 12.1% in the pre-dissemination phase, while in the post-dissemination phases, they were 2.5 - 2.6%. However, the average duration of hospitalization (7 days) and ICU stay (1-1.7 days), were not significantly different. Conclusions The compliance rates to several Class I recommendations of the ACS guidelines were relatively high. Increased survival was noted in the postdissemination phases; however, average ICU and hospital stay were similar in all phases. Key words: clinical practice guidelines, acute coronary syndrome,

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List of Abbreviations: ACC = American College of Cardiology AHA = American Heart Association ACE-inhibitor = angiotensin converting enzyme inhibitor ACS = Acute Coronary Syndrome AMI = acute myocardial infarction CPGs = clinical practice guidelines CK-MB = creatine kinase-muscle brain isoenzyme ECG = electrocardiogram ICU = intensive care unit

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Introduction Cardiovascular diseases, particularly, acute myocardial infarction and unstable angina (acute coronary syndrome) rank high in the list of causes of mortality in many developed countries. With the socio-economic, cultural and demographic transitions taking place in many less developed countries, acute coronary syndrome has become an important contributor to the total burden of disease and death in many countries of the developing world. In the Philippines, cardiovascular diseases accounted for 16.5% and 13.2% of the total deaths in the year 2000 which by 2004 became 17.6% and 12.8% [1]. Significant variations in the management of myocardial infarction have been observed within and across countries. Regional variation in the pharmacological treatment and utilization of cardiac procedures, have raised concerns about the appropriateness of care in some settings [2]. In 1995, a small pilot study performed by centers in the International Clinical Epidemiology Network showed that there were major differences in practice patterns with regard therapeutic interventions for this condition in developed and developing countries. These variations were seen in the proportions of patients receiving thrombolytic therapy (0-40%), beta-blockers (077%), anticoagulants (0-98%), ACE-inhibitors (5-50%), and calcium channel blockers (5-50%). There were also variations in the length of hospital stay (7-20 days), referral to rehabilitation program (0-60%), and utilization of coronary angiography (019%) [Heller, 1995, unpublished data].

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On the other hand, a prospective cohort in 1992-1994 involving nine tertiary centers in the Philippines reported the low usage of effective therapies such as thrombolytics (0-15%), angiography (0-6%), angioplasty (0-2%), and bypass surgery (0-2%). Furthermore, this study found that during that time, beta-blockers and aspirin, despite the evidence supporting their effectiveness, were prescribed in only 39% and 71% of patients respectively [3]. In addition about 33% of patients in the study received expensive medications lacking proven efficacy such as the oxygen radical scavenger, trimetazidine, and the "metabolic enhancers", coenzyme Q10 and Lcarnitine [3]. One of the solutions offered as a response to the problem of practice variations is the development of clinical practice guidelines, defined by the Institute of Medicine as systematically developed statements to assist practitioner and patient decisions about appropriate health care for specific clinical circumstances [4]. Guidelines on myocardial infarction and unstable angina have been developed internationally and were based on the wealth of literature on proven therapies and trials which ascertained the non-effectiveness of some therapies [5]. However, several studies in the United States and Europe found that these evidence-based guidelines were under-utilized [6 8]. There are many possible reasons for variations in practice within countries and across regions, including differences between settings in the speed and degree of adoption as well as lack of physician awareness of the most recent evidence on the efficacy and safety of available treatments. Moreover, among physicians in the U.S., knowledge has been shown to vary across different specialist groups [9] while in other countries/clinical settings, differences in the delay in access to knowledge exist. Although literature has shown that increased adherence to guidelines yielded better clinical outcomes [10], it is not sufficient to examine clinical policies and practices solely based on clinical evidence of efficacy and safety. Guidelines must also be evaluated in terms of available local resources and priorities. Developing an

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institutionalized clinical policy based on clinical practice guidelines aligned with the local setting is a step in improving quality of care and optimizing the use of available resources. It is in these contexts that this study was undertaken. General Objective: To determine the impact on clinical outcomes ICU and hospital stay, and mortality rates of patients with acute coronary syndrome before and after the dissemination of a guideline based on an international but locally accepted clinical practice guidelines on acute coronary syndrome (the American College of Cardiology-American Heart Association, ACC-AHA guidelines) at Manila Doctors Hospital. This hospital is a tertiary hospital located in the capital of the Philippines, a developing country presently classified by World Bank as one of the lower middle income countries [11]. Specific Objectives: 1. To determine the practice patterns on the diagnosis and management of acute coronary syndrome before and after dissemination of the guidelines; 2. To determine the clinical outcomes ICU and total hospital stay, and mortality rates of patients before and after dissemination of the guidelines. Methods A. Design, Study Setting, Participants and Intervention The study design was quasi-experimental (before and after study). It was comprised of several phases, the pre-dissemination, dissemination and postdissemination phases (use of passive dissemination strategies) of the clinical practice guidelines for acute coronary syndrome at the Manila Doctors Hospital. During the pre-dissemination phase, consecutive charts of patients aged 19 years and above, diagnosed to have acute coronary syndrome from July 31, 2004 to September, 2005 were reviewed. The definition of acute coronary syndrome cases was based on those described by Interheart, an international case-control study on the risk factors for acute myocardial

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infarction and the ACC- AHA guidelines on ST elevation myocardial infarction and unstable angina and non-ST segment elevation myocardial infarction [1-2,13]. On the other hand, eligibility criteria for beta-blocker, thrombolytic or aspirin therapies were based on the 1st and second Infarct Survival Studies [14-15]. A data collection form was used to record pertinent data on subject identifiers, hospital entry, course of hospitalization and discharge. The dissemination phase was conducted from September 23, 2005 - September 30, 2005. This involved the dissemination of an in-hospital guideline based on the ACCAHA 2002 Guidelines on the Management of Unstable Angina and Non-ST Elevation Myocardial Infarction [1] and the ACC-AHA 2004 Guidelines on the Management of ST Elevation Myocardial Infarction [2]. The guideline formulated was reviewed and approved by members of the Section of Cardiology of the Department of Internal Medicine of the Manila Doctors Hospital. Dissemination strategies (considered passive dissemination strategies) included holding hospital conferences, printing of laminated copies and reminders. The laminated copies of the guideline summaries were distributed to each hospital floor, emergency room and specialty units (e.g., ICU, hemodialysis unit). Reminders in the form of checklists were given out to residents of the Department of Internal Medicine. The phase of the study using passive dissemination strategies was from October 1, 2005 to November, 2006. The data collected from these patients were the same as in the pre-dissemination phase. The results were analyzed after the above phases were concluded. However, continuation of the study was also planned using active dissemination strategies and data regarding practice patterns and clinical outcomes were also collected. This

part of the study was implemented from January to August, 2007. During this time, a simple 2-page clinical practice guideline checklist was incorporated in the charts of all newly diagnosed patients with acute coronary syndrome. The admitting internal medicine residents or two of the study investigators filled up the checklist after

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discussion with the attending physician/consultant regarding diagnostic and management strategies based on the clinical practice guideline checklist. The patient's hospital course was followed-up and the corresponding completely filled-up checklist which includes the patient's clinical outcome was collected upon discharge.

B. Statistical Analysis The estimated sample size, 288, was arrived at, using the equation N = (Z/2)2 x p x (1-p) 2 where: N = sample size Z = constant equivalent to 1.96 P = estimated proportion of compliance set at 75% = 0.05 at 95% CI Descriptive statistics were used for the demographics and adherence to the disseminated guideline was determined by computing for percentage of usage of a particular diagnostic or therapeutic modality. The differences in the percentages during the pre- and postdissemination phases were determined using z-test test or, if the sample size requirement was not met, Fisher's exact test was used. T-test was used for testing significant change in means between the two phases. For all tests, the level of significance was set at 0.05. All statistical computations were done using Stata version 9.0. Results A. Demographics A total of 124 patients were included in the pre-dissemination phase while 120 and 115 patients in the post-dissemination phases, the first one using passive strategies

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and the latter using active dissemination strategies. The patients' characteristics were almost similar in all phases of the study with the males comprising 75% or more of the population (Tables 1A and 1B). However, there was a significant increase (from 12-14.5% to 31%) in the proportion of patients with ST segment elevation myocardial infarction compared to those with unstable or non-ST segment elevation myocardial infarction in the phase using active dissemination strategies in contrast to the pre- and post-dissemination phases using passive dissemination strategies. Moreover, there were more patients with diabetes in the post-dissemination phases (passive dissemination = 47%; active dissemination = 39%) compared to the predissemination phase (34%). B. Diagnostics Tables 2A and 2B give a summary of the frequency of the diagnostics designated with level 1 recommendation on the ACC-AHA guidelines were carried out. These ACC-AHA guidelines refer to the clinical practice guidelines on unstable angina and acute myocardial infarction [1-2]. High compliance rates with regard the use of ECG, cardiac biomarkers, lipid levels and 2D-Echocardiography were seen. On the other hand, very low compliance rates were seen in the use of stress testing and coronary angiography as diagnostic and prognostic tools both in the pre- and post-dissemination phases. On the other hand, the compliance rate for the determination of lipid levels decreased in the post-dissemination phases as compared to the pre-dissemination phase (96% to 86% in both post-dissemination phases). Likewise, there was also a decrease in the use of the 2D-echocardiogram, from 91% to 86-89% in the post-dissemination phases. These tests might have been done post-discharge to save on costs of hospitalization but these were not ascertained. C. Therapeutics The compliance rates to therapeutics with Level 1 recommendation are listed in Tables 3A and 3B. High compliance rates (85% and above) in either pre-or post-

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dissemination phases were seen for the use of nitrates, statins, and any of the antithrombotic agents, aspirin, clopidogrel or heparin. Among these anti-thrombotics, there was a significant increase in aspirin usage in the active dissemination phase compared to the passive dissemination phase (60% to 72%). Moreover, there was an increase in the usage of beta-blockers in the post-dissemination phases (85% and 87% in the passive and active dissemination phases, respectively) compared to the pre-dissemination phase (81%). On the other hand, angiotensin converting enzyme (ACE) inhibitors were given to about 70% of the patients while 26-32% received angiotensin receptor blockers. However, low compliance rates were seen for GPIIbIIIa antagonists, percutaneous coronary intervention and coronary artery bypass graft. Tables 4A and 4B show the frequency of usage of other medications which might have been given due to concomitant conditions, e.g., diuretics for congestive heart failure, amiodarone for arrhythmias, etc. However, noteworthy was the usage of

medications which are not included in the recommendations, like trimetazidine, coenzyme Q10, L-carnitine, and omega-3 fatty acids. Seventeen percent of the patients in the pre-dissemination phase received at least one of these medications compared to 15% in the passive dissemination phase. Usage of any of these medications, however, markedly dropped in the active dissemination phase to 8.7% (largely due to about 6.5% decrease in the usage of trimetazidine, i.e., from 10% to 3.5%). Morphine was not routinely given to all patients. It was instead administered to patients with continuing ischemic pain even after the administration of the recommended dose of nitrates. This was also true for non-dihydropyridines which are recommended as alternative drugs for rate control for those in whom beta-blockers are contraindicated. D. Clinical Outcomes

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The patient outcomes measured in terms of mortality and duration of ICU stay and total hospital days are shown in Tables 5A and 5B. Mortality decreased significantly by 9.6% (12.1% to 2.5%, p value = 0.006) from the pre-dissemination phase to the passive dissemination phase. Furthermore, the low mortality rate was maintained in the active dissemination phase. However, there was no change in the mean number of days that patients stayed in the ICU (1 1.7 days) as well as the average duration of hospital confinement (7 7.5 days). Discussion A. Practice Patterns (Compliance to Guidelines) 1. Diagnostics The high compliance rates with regard ECG and cardiac markers shown in Table 2 were expected as these examinations apart from the clinical history of anginal chest pain remain the cornerstone of the diagnosis of myocardial infarction. Furthermore, elevation of the cardiac biomarkers constitutes the diagnostic procedure that differentiates acute myocardial infarction from unstable angina. Indeed, it came as a surprise that there was a less than 100% usage of ECG in the post-dissemination phase. In reality however, the three patients on whom these procedures were not done upon admission to Manila Doctors Hospital, came in as referrals from other hospitals where the required ECGs were performed. On the other hand, it may seem ironic that the rates for the determination of troponin and CK-MB decreased in the post-dissemination phae (passive dissemination) compared to the pre-dissemination phase (99 to 94% for troponin and 84 to 75% for CK-MB). However, analysis of compliance with the recommendation of using either of these two biomarkers was maintained at 100%. Moreover, variations in the individual rates of either of the two biomarkers were affected by their availability in the study center during the study period.

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Very low rates for coronary angiography (2.4 7.8%) were reported and this could readily be explained by the fact that this was not available in the study setting. The low rates reflected only those patients who were transported temporarily or transferred to other institutions for the said procedure. Furthermore, the number of patients who underwent angiography after discharge was not ascertained. However, majority of the patients opted not to have angiography due to financial constraint. Similarly, although the treadmill exercise test was available in the study setting, very low rates were also seen. Economic reasons also seem to be the cause for these low rates. It was observed that many of the treadmill tests were done after discharge either in the study setting or in other health care facilities to decrease the costs of hospitalization. 2. Therapeutics There was high usage of nitrates (87-97.5%) since these were the initial agents utilized for the control of pain. Compliance rates of 80% - 87% for pre-and postdissemination phases, respectively, were seen for beta-blockers. This is a marked increase in the usage of this relatively cheap and proven anti-anginal agent with a level I recommendation compared to 39% usage as reported in the local study conducted in 1992-1994 [3]. A lower compliance of 70% with regards ACE-inhibitors, another drug with level I recommendation, may be explained by the intolerance to ACE-inhibitors of some patients and the usage of angiotensin receptor blocker (especially among diabetics) prior to the occurrence of the acute coronary syndrome. The unavailability of a GPIIbIIIa inhibitor in the study setting has limited its use, especially in high risk patients with persistent ischemic pain. (This medication had to be procured from another hospital for those few patients who received it.) The absence of a cardiac catheterization unit may also have on effect on the use of this class of antiplatelets since it is also recommended in patients about to undergo more invasive procedures such as percutaneous coronary interventions.

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The use of unconventional agents (agents not included in the recommendations, e.g., carnitine, coenzyme Q10) may be disconcerting considering that economic constraint was a common reason for the non-usage of expensive interventions like thrombolytics and invasive procedures. This is especially true in a setting where majority of access to health care is through out-of-pocket payments, estimated to be 61% (nationwide average) in 2002 (17). However, the utilization of these medications decreased compared to more than 10 years ago when they were given to 33.8% of patients with myocardial infarction (3). Moreover, although the usage rate of dipyridamole was 10.8% in the earlier study (3), none received it in the present study. 3. Clinical Outcomes As seen in Tables 5A and 5B, a significant decrease (12% to 2.5-2.6%) was seen in mortality rates. Many factors could have contributed to this finding which could possibly include the observation of high compliance rates to many diagnostic and therapeutic strategies with level I recommendations (although no significant change was demonstrated in most of the interventions in the pre-and post-dissemination phases, probably due to the non-achievement of the desired sample size). On the other hand, the pre-dissemination mortality rates was comparable with the average mortality rates in the earlier local study as well with foreign cohort studies on myocardial infarction in the thrombolytic era (3). However, the post-dissemination mortality rates were significantly lower compared to these early reports. Although the desired sample size of 288 was not achieved, the study sample size was adequate for some variables whereby the compliance rates were greater or less than the estimated compliance rate of 75% used in the sample size computation. B. Clinical and Health Policy Implications The Philippine Health Insurance (PhilHealth) supports guideline use as manifested in its PhilHealth Benchbook which was released in 2005 and implemented in 2007. As stated in this Benchbook, Standard 2.4.1 requires that "clinical pathways derived

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from clinical practice guidelines and other types of clinical evidence should be developed or implemented for the top 10 cases of admissions and/or consultations" (18). Standard 7.2 meanwhile requires that "resources for developing or adopting clinical practice guidelines are provided" by the hospital (18). Moreover, PhilHealth has an ongoing initiative whereby claims for reimbursement would be based on compliance to guideline recommendations. In view of this, medical review criteria and policy statements (which form bases for approving payments for claims) are promulgated based on key guideline recommendations. Presently, PhilHealth has identified ten guidelines for the ten commonly claimed illnesses (18). Unfortunately, this list does not include the guidelines on unstable angina and myocardial infarction. Lastly, the study signifies the support of a private tertiary hospital towards the utilization of evidence-based guidelines. In fact, the study even preceded the implementation of the PhilHealth Benchbook. C. Conclusions This study has shown the following: 1) There were high compliance rates to many diagnostic examinations with level I recommendation before and after dissemination except for stress test and invasive procedures. For invasive procedures, the low compliance rates may be attributed to the unavailability of the procedures in the study setting or financial constraints. 2) There were also high compliance rates (85% and above) to the use of nitrates, beta-blockers, statins and anti-thrombotic agents. Usage of angiotensin converting enzyme inhibitors were relatively lower (70%) due to intolerance to these agents and the prior use of angiotensin receptor blockers of some patients. On the other hand, fibrinolytics, GPIIbIIIa and invasive

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procedures were infrequently used, again, because they were not available or affordable.

3) In contrast to those interventions which were not available, several agents not
recommended in the guidelines such as L-carnitine, co-enzyme Q10, trimetazidine and omega3 fatty acids were given to about 17% of patients in the pre-dissemination phase but this decreased to 15% in the passive dissemination phase and was much lower in the active dissemination phase at 8.7%.

4) There was a statistically significant decrease in mortality rates in the postdissemination phases compared to the pre-dissemination phase (12.1 to 2.5 2.6%). 5) ICU and total hospital stay did not differ in the pre and post-dissemination phases. Competing interests The medical directorate office of MDH and its committee on research through its chair conceived, designed, and coordinated the study. In addition, the medical directorate office and Pfizer, Philippines provided the funds for conducting the study. However, Pfizer, Philippines did not in any way interfere with the design of the study, collection, analysis and interpretation of the data which were pursued according to the protocol set before the conduct of the study. Finally, the authors of the study maintained publication rights. The authors are connected to the setting of the study as follows: Dr. Bernadette Tumanan-Mendoza was the chair of the committee on research during the conduct of the study while Dr. Dante Morales is the present medical director, (both are consultants in the Department of Internal Medicine). On the other hand, Drs. Agnes Baston, Daniel Francisco Morales, Vim Samonte and Mary Cheryl Larona, were resident trainees in the Department of Internal Medicine during the time that the

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study was conducted. However, the above designations did not in any way provide conflicts of interest in the conduct of the study. Acknowledgements Victor L. Mendoza, MD, Flordeliza Tan, RN, Mark Javellosa, Melvin Sanicas, MD

References

1. Health Indicators, Department of Health Republic of the Philippines website. Available at: http://www.doh.gov.ph/kp/statistics/leading_mortality. Accessed June 22, 2008. 2. Pilote CL, et al. Regional variations across the United States in the management of acute myocardial infarction. N Eng J Med 1995; 333:565-572. 3. ISIP Study Group. Acute myocardial infarction in tertiary centers in Metro Manila: In-hospital survival and physicians practices. Asean Heart J 1999; 7:1-7. 4. Hayward RSA, Laupacis A. Initiating, conducting and maintaining guidelines development programs. Can Med Assoc J 1993;148:507-512. 5. ISIS-4 Collaborative Group. A randomized factorial trial assessing early oral captopril, oral mononitrate, and intravenous magnesium sulphate in 58,050 patients with suspected acute myocardial infarction. Lancet 1995; 435:669685. Mehta, RH, et al. Recent trends in the care of patients with non-ST-segment elevation acute coronary syndromes: insights from the CRUSADE initiative. Archives of Internal Medicine 2006; 166:2027-34. 7. Steg, PG, et al. Baseline characteristics, management practices, and in-hospital outcomes of patients hospitalized with acute coronary syndromes in the Global Registry of Acute Coronary Events (GRACE). American Journal of Cardiology 2002; 90:358-63. Collinson, J, et al, Clinical outcomes, risk stratification and practice patterns of unstable angina and myocardial infarction without ST elevation: Prospective Registry of Acute Ischaemic Syndromes in the UK (PRAIS-UK). European Heart Journal 2000; 21:1450-7. 9. Lomas J, et al. Do practice guidelines guide practice? The effect of a consensus statement on the practice of physicians. N Eng J Med 1989; - 16 -

321:1306-1311. 10. Vikman, S, et al. Improved adherence to practice guidelines yields better outcome in high-risk patients with acute coronary syndrome without ST elevation: findings from nationwide FINACS studies. Journal of Internal Medicine 2004; 256:316-23. 11. The World Bank Data and Statistics. Country Classification. http://web.worldbank.org/WBSITE/EXTERNAL/DATASTATISTICS/0,,cont entMDK:20420458~menuPK:64133156~pagePK:64133150~piPK:64133175~ theSitePK:239419,00.html. Accessed January 26, 2010. 12. Ounpuu S, et al. INTERHEART: A global study of risk factors for acute myocardial infarction. American Heart Journal 2001;141:711-21. 13. Braunwald E, et al. ACC/AHA Guideline Update for the management of patients with unstable angina and non-ST segment elevation myocardial infarction. J Am Coll Cardiol 2002; 40:366-374. 14. Antman, EM, et al. ACC/AHA guidelines for the management of patients with acute ST-elevation myocardial infarction: executive summary: a report of the ACC/AHA Task Force on Practice Guidelines (Committee to Revise the 1999 Guideline for the Management of Patients with Acute Myocardial Infarction). Circulation 2004;110:588-636. 15. ISIS-1 Collaborative Group. Randomized trial of intravenous atenolol among 16,072 cases of suspected acute myocardial infarction. Lancet 1986; 2:57-65. 16. ISIS-2 Collaborative Group. Randomized trial of intravenous streptokinase, oral aspirin, both, or neither, among 17,187 cases suspected of acute myocardial infarction. Lancet 1988; 2:349-360. 17. Dror DM, Koren R, Steinberg DM. The impact of Filipino micro healthinsurance units on income-related equality of access to healthcare. Health Policy 2006; 77:304-317. 18. Performance Report on PhilHealth Use of CPGs for Quality Assurance and Accreditation. Health Technology Assessment Unit Quality Assurance Research and Policy Development Group, PhilHealth. The HTA Forum 2006; 4:1-3

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Table 1A Patient Characteristics in Pre-dissemination and Passive Dissemination Phases Pre-Dissemination Passive N = 124 Age range (years) Age (mean + SD) in years Gender: Male F emale Unstable Angina/NSTEM I STEMI Diabetes Mellitus Hypertension COPD Asthma CKD without HD CKD with HD Severe Infection Cardiac Dysrhythmia Previous CV 106 (85.5) 18 (14.5) 42 (33.9) 100 8 6 16 (80.6) (6.4) (4.8) (12.9) 106 (88.3) 14 (11.7) 56 (46.7) 95 7 7 5 (79.2) (5.8) (5.8) (4.2) 25 91 63.4 + 13.5 75 49 Dissemination N= 120 34 86 62.8 + 12.2 78 42

p Value* N/A 0.756 0.466

0.572 0.572 0.042 0.873 1.000 0.782 0.021 0.465 0.147 0.867 0.173

11 (8.9) 17 (13.7) 21 (16.9) 35 (28.2)

7 (5.8) 9 (7.5) 22 (18.3) 44 (36.7)

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Event
*: 5% level of significance : CKD chronic kidney disease : HD hemodialysis : CV cardiovascular events including previous ACS, stroke or history of peripheral vascular disease STEMI ST segment elevation myocardial infarction NSTEMI Non-ST segment elevation myocardial infarction COPD Chronic Obstructive Pulmonary Disease N/A Not applicable Number in parentheses represents percent.

Table 1B Patient Characteristics for Post-Dissemination Phases

Passive Dissemination Age range (years) Age (mean + SD) in years Gender: Male Female Unstable Angina/NSTEMI STEMI DM HPN COPD Asthma CKDb without HDc CKD with HD Severe Infection Cardiac Dysrhythmia Previous CVd Event N = 120 34-86 62.8 + 12.2 78 42 106(88.3) 14(11.7) 56(46.7) 95(79.2) 7(5.8) 7(5.8) 5(4.2) 7(5.8) 9(7.5) 22(18.3) 44(36.7)

Active Dissemination N = 115 32-88 61.8 + 11.64 83 32 84(73.04) 31(26.03) 45(39.13) 82(71.31) 3(5.76) 5(9.6) 5(9.6) 2(3.84) 3(5.76) 11(9.56) 11(9.56)

P Valuea

N/A 0.521 0.263 0.004 0.005 0.292 0.176 0.334 0.769 1.000 0.172 0.137 0.061 0.00

*: 5% level of significance : CKD chronic kidney disease : HD hemodialysis : CV cardiovascular events including previous ACS, stroke or history of peripheral vascular disease

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STEMI ST segment elevation myocardial infarction NSTEMI Non-ST segment elevation myocardial infarction COPD Chronic Obstructive Pulmonary Disease N/A Not applicable Number in parentheses represents percent.

Table 2A Percentages of Compliance for Diagnostics or Interventions with Level I Recommendation in Pre-dissemination and Passive Dissemination Phases

DIAGNOSTICS ECG Troponin CKMB Stress Test Cor Angio Lipid 2 D Echo

Pre-Dissemination Frequency(n) 124 (100) 123 (99.2) 104 (83.9) 2 (1.6) 3 (2.4) 119 (96) 113 (91.1)

Passive Dissemination 117 (97.5) 113 (94.2) 90 (75.0) 1 (0.8) 7 (5.8) 103 (85.8) 103 (85.8)

p Value 0.117 0.034 0.112 1.000 0.211 0.007 0.230

*: N total population of 124 : N total population of 120 : Coronary Angiography Number in parentheses represents percent.

Table 2B Percentages of Compliance for Diagnostics or Interventions with Level I Recommendation in Post-Dissemination Phases

DIAGNOSTICS ECG Troponin CKMB Stress Test Cor Angio Lipid 2 D Echo

Passive Dissemination 117 (97.5) 113 (94.2) 90 (75.0) 1 (0.8) 7 (5.8) 103 (85.8) 103 (85.8)

Active Dissemination 115 (100) 115 (100) 115 (100) 1 (0.88) 9 (7.83) 99 (86.09) 102 (88.6)

p Value 0.247 0.014 0.000 1.000 0.611 1.000 0.561

*: N total population of 120 : N total population of 115 : Coronary Angiography Number in parentheses represents percent. Table 3A Percentages of Compliance to Therapeutic Interventions with Level I Recommendation in Pre-dissemination and Passive Dissemination Phases

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THERAPEUTICS

Nitrates Morphine Beta blocker ACE-I Nondihydropyridin e Aspirin Clopidogrel Heparin

Any anti-thrombotic

PreDissemination Frequency (n) Percentage 116 (93.6) 9 (7.3) 92 (80.7) 87 (70.2) 8 (6.4) 85 (68.6) 54 (43.6) 117 (94.4) 121 (100) 116 (93.6) 2 (20.0) 0 (0) 0/3# (0) 0 (0)

Passive Dissemination Frequency (n) Percentage 117 (97.5) 9 (7.5) 95 (84.8) 84 (70) 14 (11.7) 72 (60.0) 60 (50.0) 108 (90.0) 119 (100) 107 (89.2) 7(58.3) 3 (2.5) 2/7# (28.6) 0 (0)

p Value

0.217 1.000 0.369 1.000 0.183 0.182 0.369 0.238 N/D 0.258 0.099 N/D N/D N/D

Statins Fibrinolytic GPIIbIIIa PCI CABG**

*: N total population of 124 except in fibrinolytics & PCI : N total population of 120 except in fibrinolytics & PCI : N total population less those with contraindications to betablocker : N total population of 10 patients with STEMI : N total population of 12 patients with STEMI : PCI Percutaneous Coronary Intervention; #: denominator denotes those who underwent coronary angiography **: CABG Coronary Artery Bypass Graft N/D Not determined; Number in parentheses represents percent.

Table 3B Percentages of Compliance to Therapeutic Interventions with Level I Recommendation in Post-Dissemination Phases

THERAPEUTICS

Nitrates Morphine Beta blocker ACE-I Nondihydropyrid ine Aspirin

Passive Dissemination Frequency (n) Percentage 117 (97.5) 9 (7.5) 95 (84.8) 84 (70) 14 (11.7) 72 (60.0) - 21 -

Active Dissemination Frequency (n) Percentage 100 (86.9) 11 (9.6) 100 (86.9) 81 (70.4) 16 (13.9) 83 (72.1)

p Value

0.208 0.644 0.125 1.000 0.697 0.055

Clopidogrel Heparin
Any antithrombotic

60 (50.0) 108 (90.0) 119 (100) 107 (89.2) 7 (58.3) 3 (2.5) 2/7# (28.6) 0/7# (0)

46 (40.0) 106 (92.2) 115 (100) 108 (93.9) 8(25.8) 1 (0.86) 4/9# (44.4) 2/9#(22.2)

0.149 0.650 1.000 0.244 0.074 0.622 0.633 0.475

Statins Fibrinolytic GPIIbIIIa PCI CABG**

*: N total population of 120 except in fibrinolytics & PCI : N total population of 115 except in fibrinolytics & PCI : N total population less those with contraindications to betablocker : N total population of 12 patients with STEMI : N total population of 31 patients with STEMI : PCI Percutaneous Coronary Intervention; #: denominator denotes those who underwent coronary angiography **: CABG Coronary Artery Bypass Graft Number in parentheses represents percent.

Table 4A Frequency of Use of other Medications in Pre-dissemination and Passive Dissemination Phases

THERAPEUTICS

Pre-Dissemination Frequency (n) Percentage (n/N*) 32 (25.8) 20 (16.1) 11 (8.9) 42 (33.9) 2 (1.6) 30 (24.2) 10 (8.1) 1 (0.8) 6 (4.8) 4 (3.2) 15 (12.1) 10 (8.1) 10 (8.1)

Passive Dissemination Frequency (n) Percentage (n/N) 38 (31.7) 20 (16.7) 20 (14.3) 38 (31.7) 5 (4.1) 10 (8.3) 12 (10.0) 0 (0) 2 (1.7) 4 (3.3) 17 (14.2) 10 (8.3) 14 (11.7)

p Value

ARB Long-acting DHP Aldactone Furosemide Thiazide Digoxin Trimetazidine Omega3 Fatty Acid Coenzyme Q10 L-Carnitine Dopamine Dobutamine Amiodarone

0.325 1.000 0.084 0.785 0.275 0.001 0.659 1.000 0.281 1.000 0.706 1.000 0.394

*: N total population of 124 : N total population of 120

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ARB Angiotensin Receptor Blocker DHP - Dihydropyridine Number in parentheses represents percent.

Table 4B Frequency of Use of other Medications in Post-Dissemination Phases

THERAPEUTICS

Passive Dissemination Frequency (n) Percentage (n/N*) 38 (31.7) 20 (16.7) 20 (14.3) 38 (31.7) 5 (4.1) 10 (8.3) 12 (10.0) 0 (0) 2 (1.7) 4 (3.3) 17 (14.2) 10 (8.3) 14 (11.7)

Active Dissemination Frequency (n) Percentage (n/N) 35 (30.4) 11 (9.56) 11 (9.56) 26 (25.9) 2 (1.73) 13 (11.3) 4 (3.5) 0 (0) 6 (5.2) 0 (0) 13 (11.3) 9 (7.8) 11 (9.6)

p Value

ARB Long-acting DHP Aldactone Furosemide Thiazide Digoxin Trimetazidine Omega3 Fatty Acid Coenzyme Q10 L-Carnitine Dopamine Dobutamine Amiodarone

0.88 0.124 0.125 0.143 0.447 0.513 0.068 N/D 0.164 0.122 0.561 1.000 0.675

*: N total population of 120 : N total population of 115 ARB Angiotensin Receptor Blocker DHP Dihydropyridine N/D Not Applicable Number in parentheses represents percent.

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Table 5A Patient Outcomes in Pre-dissemination and Passive Dissemination Phases

PATIENT OUTCOMES Mortality Frequency Percentage Days of Hospitalization Mean

PREDISSEMINATION

PASSIVE DISSEMINATION

p VALUE

15 12.1 7.0 5.2

3 2.5 6.9 3.8

0.006

0.919

SD Days of ICU Stay Mean 1.2 3.0 SD 1.0 2.2 0.4308

Table 5B Patient Outcomes in Post-Dissemination Phases

PATIENT OUTCOMES Mortality Frequency Percentage Days of Hospitalization

Passive Dissemination 3 2.5 6.9

Active Dissemination 3 2.6 7.5

p VALUE 1.000

0.224

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Mean

3.8

5.2

SD Days of ICU Stay Mean 1.0 2.2 SD 1.7 2.3 0.136

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