tion of cardiovascular (CV) events in patients with diabetes mellitus (DM). In 1997, the American Diabetes Diabetes Care Team consists of a multidisciplinary team …
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Clinical Research and Methods
Aspirin for Primary Prevention in Patients With Diabetes Mellitus
Kenneth X Nguyen; Jacqueline S Marinac, PharmD; Chao Sun, MD, MPH
Background and Objectives: Evidence supports the routine use of low-dose aspirin ASA in the prevention of cardiovascular CV events in patients with diabetes mellitus DM In 1997, the American Diabetes Association ADA recommended ASA prophylaxis for all diabetic patients over the age of 30 with one additional risk factor for cardiovascular disease CVD Our objective was to determine the adherence to the ADA guidelines for ASA therapy in DM using a national database Methods: Data from the 1997 2000 National Ambulatory Medical Care Survey NAMCS was used to determine the usage rates of ASA in patients with DM over age 30 years with one or more CV risk factors Multiple logistic regression methods were used to determine what factors were related to ASA prophylaxis Results: During 19972000, more than one third of all diabetic patients should have been considered for ASA prophylaxis because they had one or more CV risk factors Yet, from 19972000, the percentage of these patients given ASA for
primary prevention was 28 in 1997, 29 in 1998, 21 in 1999, and 57 in 2000 Factors associated with increased ASA prophylaxis were non-white ethnicity, male gender, older age more than 44 years old, rural clinic setting, preventative counseling given during visit, being prescribed more than two medications, having cardiovascular risk factors, and being seen by a cardiologist Conclusions: Adherence rates to the ADA standard of care guideline regarding routine ASA prophylaxis in adults with DM and at least one CV risk factor are extremely low National efforts directed at increasing these rates of ASA prophylaxis are indicated to meet the Healthy People 2010 goal of 30 Fam Med 2005;372:112-7 Diabetes mellitus DM affects an estimated 17 million Americans or 62 of the US population 1 The economic burden of DM in the United States is also considerable and growing The annual cost in medical expenditures and lost productivity climbed from 98 billion in 1997 to 132 billion in 20022 Estimates show that more than 20 of all patients who have coronary artery disease CAD also have DM3 Cardiovascular events are at least two to four times more likely in patients with DM, with men and women equally
at risk for developing cardiovascular disease CVD4 In 1999 alone, around 450,000 people with DM died in the United States, mostly from cardiovascular complications5 In an effort to lessen the rate of CAD in patients with DM, the American Diabetes Association ADA in 1997 recommended aspirin ASA therapy for the primary and secondary prevention of cardiovascular events in patients with DM This recommendation is partially based on the results of four major clinical trials showing that ASA prophylaxis reduced the risk of major CV events in patients with DM6-10 Table 1 The 1997 guidelines advised the use of ASA therapy for secondary prevention in all diabetic men and women with macrovascular complications, such as a history of myocardial infarction or stroke The ADA has since extended its 1997 recommendation of ASA to all individuals with DM over age 30 years and with one or more of the following classic cardiovascular risk factors: hypertension, dyslipidemia, family history of CAD, smoking, obesity, microalbuminuria, or macroalbuminuria Limited information is available regarding the adherence to the ADA ASA guidelines A study published in 2001 analyzed a national telephone survey that
captured the self-reported use of ASA in diabetics over 21 years during the years 1988199411 At that time, only 20 of the total diabetic population was on ASA prophylaxis–37 for secondary prevention and only 13 for primary prevention A second paper surveyed ASA
From the Kansas City University of Medicine and Biosciences all; and Pfizer Inc, Shawnee, Kan Dr Marinac
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Table 1 Summary of Four Major Clinical Trials Using Routine Aspirin to Prevent Major Cardiovascular Events
of Patients Enrolled in Study 22,071 of Patients With DM 533 Mean Followup Time 602 months
Study Name Physicians Health Study7
Dosage 325 mg qod
Results and Patient Characteristics 44 risk reduction of myocardial infarction MI and 18 reduction in important vascular events Similar benefit in patients with DM Men ages between 4084 36 risk reduction in MI and 15 reduction in major cardiovascular CV events Similar benefit in patients with DM Men and women ages 50 80, mean age 615 Reductions in vascular events MI, stroke, etc were about 25 in high-risk patients Similar benefit in patients with DM One-year benefit 20/ 1,000 P00001 Men and women of variable age 18
risk reduction in fatal and non-fatal MI and no increased risk of hemorrhagic stroke, gastrointestinal, retinal, or vitreous bleeding Men and women between the ages of 1870
HOT trials8
18,700
1,501
75 mg qd
38 years
APT trials9
110,000
Variable
75325 mg qd
Variable
ETDRS10
3,711
3,711
325 mg qd
5 years
Important cardiovascular events include non-fatal MI, non-fatal stroke, and death from cardiovascular event Anti-platelet trials APT was a meta-analysis of 145 randomized clinical trials, consisting mostly of secondary prevention trials DM–diabetes mellitus qod–every other day qd–every day HOT–Hypertention Optimal Treatment ETDRS–Early Treatment Diabetic Retinopathy Study Report
prophylaxis among diabetic patients receiving care in the Department of Veterans Affairs VA Health Care System in 200012 In that study, 45 reported taking daily ASA for primary prevention of CVD Current data, however, regarding the use of ASA are lacking The former study evaluated data from 19881994, prior to the 1997 ADA recommendation of ASA prophylaxis In the latter study, the population consisted exclusively of individuals receiving care in the VA hospital system This is not
representative of the total US diabetic population, since the mean age of the group was 67 years and virtually all male Our goal, therefore, was to examine the adherence to the 1997 ADA position statement regarding ASA prophylaxis using a more current national database We used the public database provided by the National Center for Health Statistics NCHS called the National Ambulatory Medical Care Survey NAMCS to examine the trends and factors related to ASA prophylaxis by persons with DM from 19972000 Methods This study is a retrospective analysis of data obtained from the NAMCS for the 4-year period between 1997 2000 Data captured in this database are based on a
random sample of visits to non-federally employed office-based physicians who are primarily engaged in direct patient care Specially trained interviewers visit the physicians prior to their participation in the survey to provide them with survey materials and instruct them on how to complete the forms Each physician is randomly assigned to a 1-week reporting period Data are obtained on patients symptoms, diagnosis, and all medications ordered or provided The survey also provides statistics on the demographic
characteristics of patients and services provided, including information on diagnostic procedures, patient management, and planned future treatment The NAMCS has a three-stage probability sampling design that randomly collects data from different geographic areas, medical specialties, and patient visits A more detailed description of the survey is described on the CDC Web site1 The Ambulatory Care Drug Database System ACDDS is a system designed by the NCHS to assign pharmaceutical agents a unique numerical code1 Using the ACDDS codes for ASA or ASA-containing products, we estimated the frequency in which ASA was reported on the NACMS as either ordered, supplied, administered, or continuing medication It is
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metropolitan locations Stepwise selection procedure was used for entering independent variables into the model, and only those variables that met the 005 significance entry level were reported We used patient visit weight provided by the NAMCS in every statistical procedure to reflect the national estimates Results Patient Demographics According to the NAMCS, from 19972000, there were 134,940,000 outpatient visits related to DM in ambulatory care practice sites in the United States Most patients were Caucasian 779 and lived in an urban setting 785, and more than half were female 53 Only patients over the age of 30 were included in the analysis Of those, 97 were between the ages of 30 44, 298 between 4559, 395 between 6074, and 174 were over the age of 75 The vast majority of those patients were seen by either a family physician or an internist 883 Most had been to the clinic at least twice 930, and almost half had received some form of preventive counseling during the visit 499 We excluded 99 of the patients from analysis because they had a history of a CVD ASA Prophylaxis Rates The percentage of patients with DM and at least one additional CVD risk factor was 349 in 1997, 363 in
1998, 405 in 1999, and 397 in 2000 All of these patients, however, should have received ASA prophylaxis according to the guidelines mentioned previously Yet, the percentage of high-risk diabetic patients who received ASA prophylaxis was 28 in 1997, 29 in 1998, 21 in 1999, and 57 in 2000 Figure 1 Patient Predictors of ASA Prophylaxis The greatest patient predictor of ASA prophylaxis was age Table 2 Those over age 75 years were 42 times more likely to receive ASA prophylaxis than were individuals in the ages 3044 years group Men were 39 more likely than women to be given ASA, and whites were 25 less likely than non-whites to receive ASA Those with dyslipidemia or hypertension were 55 and 34 more likely to be prescribed ASA prophylaxis Similarly, obese and tobacco-using diabetic patients were 35 and 24 more likely to be given ASA prophylaxis By contrast, two variables decreased the likelihood of being on ASA prophylaxis New patients were 41
important to note that all prescription and over-thecounter medications should be listed on the NAMCS The usage of two newer anti-platelet agents, clopidogrel and ticlodipine, was also determined since both are considered by the ADA to be an
acceptable substitute for ASA therapy6 Inclusion Criteria The patients included in our study were identified though the presence of International Classification of Diseases, Ninth Revision, Clinical Modification diagnostic codes ICD-9 for diabetes mellitus: 250, 3572, 3620, or 3664113 Patients with cardiovascular risk factors, as defined by the ADA, were identified with these ICD-9 codes: hypertension 401, 402, 403, 404, 405, obesity 2780, 27800, 27801, and dyslipidemia 272 Cigarette smoking could also be identified in the NAMCS survey if the physician recorded that counseling for tobacco use was performed Using logistic regression techniques, we determined if the presence of one of these risk fa 
ctors was related to ASA prophylaxis in patients with DM, ages 30 years or older Exclusion Criteria Patients who had specific contraindications to ASA therapy were excluded These included patients who had active gastrointestinal bleeds, hemophilia, ASA hypersensitivity, active hepatic disease, and/or concomitant use of an anticoagulant therapy such as warfarin or heparin We also excluded patients who were less than age 30 years or pregnant Since our study evaluated the use of ASA as primary
prevention of cardiovascular events, we excluded all patients who had certain preexisting cardiovascular diseases These included history of myocardial infarction 410, 411, and 412, angina 413, coronary artery disease 414, 4294292, 42944297, stroke 433, 434, 435, 436, 437, 438, transient ischemic attacks 7802, intermittent claudication 4439, or peripheral vascular disease 440 Statistical Analysis All statistical analyses were performed with Statistical Analysis Software Version 80 SAS Institute, Cary, NC We used bivariate statistics to describe the frequency of the diagnosis of diabetes in all patient visits, to determine the trends of aspirin use in patients with and without cardiovascular risk factors, and to determine the use of ASA among diabetic patients based on the categories of patient and physician demographic factors from 19972000 The patient and physician demographic factors we considered in our study were gender, race, age, new patient status, CV risk factors, office location, number of drugs prescribed, use of preventive counseling, and physician specialty Multiple logistic regression analysis was used to assess the independent contribution of patient and
physi-
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Figure 1 Aspirin ASA Prophylaxis Use Among Diabetic Adults to Prevent Cardiovascular Disease
less likely to be prescribed ASA than returning patients Lastly, patients with DM who attended an urban clinic were 19 less likely to be given ASA prophylaxis than patients attending a rural clinic Physician Predictors of ASA Prophylaxis Prescribing Physicians who gave preventive counseling were 78 more likely to give ASA than those who did not Those who prescribed three to four medications were 94 times more likely to include ASA in their regimen If five or more medications were ordered, ASA was 228 times more likely to be used Cardiologists saw 36 of the DM population, and cardiologists prescribed ASA prophylaxis three times more frequently than primary care physicians Yet, overall, only 84 of patients with DM who visited a cardiologist received ASA prophylaxis Discussion Aspirin Prophylaxis in Diabetes Mellitus We estimated that a significant proportion 38 of the diabetic population in our sample would have been candidates for ASA prophylaxis based on ADA guidelines Our estimated prevalence of ASA usage for primary prevention in
these high-risk patients was, however, only 28 in 1997, 29 in 1998, 21 in 1999, and 57 in 2000 Our findings, which parallel those of other studies, indicate that ASA prophylaxis is underused11,12 Improving Awareness of CVD and Diabetes Due to the rising medical and economic burden of DM and its subsequent CV complications, there have
been several initiatives directed at increasing the use of ASA in patients with DM The US Department of Health and Human Services HHS published Healthy People 2010, an initiative that targets national health care goals One goal of Healthy People 2010 is to increase the proportion of adults with DM who use ASA routinely to 3014 Further, the Veterans Health Administration VHA initiated in 2000 a project called the Quality Enhancement Research Initiative for Diabetes Mellitus QUERI-DM15 Following that initiative, 45 of the diabetic patients in the VA Health System had reported ASA use for the primary prevention of CVD in 200212 Kaiser Permanente KP, the largest health care organization in the United States, designed The Diabetes Care Prevention Care Program16 Kaisers Diabetes Care Team consists of a multidisciplinary team of case managers, primary care
physicians, and pharmacists The program, which began in North Carolina in 1996, reported in 1997 that 78 of their patients with DM with coronary artery disease were using ASA16 We were, unfortunately, unable to identify an effort by KP to promote ASA as a method of primary prevention Lastly, in a recent study, researchers initiated a project to improve ASA prophylaxis in patients attending a rural primary care clinic Using pharmacydirected interventions and phone interviews, the program improved prophylactic ASA therapy in diabetic adults from 33 to 8217 Potential Study Design Errors and Concerns There are several limitations to our work A major limitation of our study is that ASA could have been underreported since it is an over-the-counter OTC drug ASA could have been recommended to adults with DM but not formally documented on the survey despite the physicians training to report OTC medications It is, however, unlikely to change our results significantly Similar studies, using the NAMCS and similar methodology, have shown that the documentation of ASA and other OTC medications like multivitamins in NAMCS is reasonable and accurate3 Further, the estimates using the NAMCS are
based on nationwide results of surveys completed by physicians and/or trained medical personnel Other studies like the Third National Health and Nutrition Examination Survey NHANES III or the VHA rely on self-reported ASA use and, therefore, may have inflated the results This may partially explain why our frequency of ASA prophylaxis appears low A second issue is that the NAMCS cannot identify ASA dosage or duration of therapy Further, the NAMCS is unable to detect the major cardiovascular risk factor of a positive family history of CAD Lastly, the NAMCS is designed to capture sequential patient visits, and it is unable to distinguish between individual patients The survey could have included patients who
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Table 2 Independent Factors Related to Aspirin Use for Primary Prevention of Cardiovascular Events Among Diabetic Patients Who Visited a Doctors Office in the United States
Factors in All Diabetic Visits of Aspirin Use Adjusted OR 95 CI Gender Female 5303 226 100 reference Male 4697 295 139 130149 Race Non-white 2207 296 100 reference White 7793 247 075 070082 Age years 3044 972 124 100 reference 4559 2983 210 173 147204 6074 3954 288
238 203279 742090 377 420 356495 New patient status No 9302 268 100 reference Yes 698 129 059 049070 Cardiovascular risk factor None6204 203 100 reference Smoking691 276 124 104150 Hypertension2971 340 134 125144 Dyslipidemia/albuminuria 943 397 155 141171 Obesity293 267 135 111164 Office location Nonmetropolitan area 2150 304 100 reference Metropolitan area7850 246 081 075087 Drugs prescribed two4935 029 100 reference Threefour 2441 274 941 8081096 five2624 674 2275 19702628 Preventive counseling No 5011 197 100 reference Yes 4989 320 178 166191 Physician specialty Primary care internal medicine or family medicine8817 275 100 reference Endocrinology 827 347 163 144184 Cardiology 356 844 314 278354 OR–odds ratio CI–confidence interval OR and 95 CI are adjusted for age, gender, race, and office location based on multiple logistic regression analysis
may have been seen more than once at the same site However, given the robust nature of the database, we were able to evaluate more than 134 million patient visits for DM during that 4-year period Therefore, it is unlikely that the limitations mentioned above are of great significance Conclusions According to ADA
Clinical Practice Guidelines regarding ASA, we estimated that approximately 35 40 of the DM population would have been considered appropriate candidates for ASA prophylaxis Based on national estimates, however, we found that only 35 of all patients with DM, ages 30 years or more, with at least one CV risk factor received ASA primary prevention therapy in the United States from 19972000 A
significant amount of work needs to be done to improve the adherence of the ADA guidelines in the general DM population One possible method to increase the use of ASA prophylaxis is pharmacy-directed interventions since it was effective in both a rural community setting and a large health care organization Further, considering that the majority of patients with DM are cared for by primary care physicians, initiatives directed toward primary care physicians are likely to be of value
Corresponding Author: Address correspondence to Dr Marinac, Pfizer Inc, 14615 West 50th Street, Shawnee, KS 66216 Phone/fax: 913-268-7329 jacquelinesmarinac@pfizercom
Clinical Research and Methods
REFERENCES 1 Centers for Disease Control home page wwwcdcgov Accessed June 10, 2003 2 National Institutes of Health home
page wwwniddknihgov Accessed June 10, 2003 3 Stafford RS Aspirin use is low among United States outpatients with coronary artery disease Circulation 2000;101:1097-101 4 Feskens EJ, Kromhout D Glucose tolerance and the risk of cardiovascular disease: the Zutphen Study J Clin Epidemiol 1992;45:1327-34 5 American Diabetes Association home page wwwdiabetesorg Accessed June 10, 2003 6 American Diabetes Association Aspirin therapy in diabetes position statement Diabetes Care 1997;20:1772-3 7 Steering Committee of the Physicians Health Study Research Group Final report on the aspirin component of the ongoing Physicians Health Study N Engl J Med 1989;3213:129-35 8 Hansson L, Zanchetti A, Carruthers SG, et al Effects of intensive bloodpressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment HOT randomized trial Lancet 1998;351:1755-62 9 Antiplatelet Trialists Collaboration Collaborative overview of randomized trials of antiplatelet therapy: prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients BMJ 1994;308:81-106
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Aspirin effects on mortality and morbidity in patients with diabetes mellitus JAMA 1992;26810:1292-9 11 Rolka DB, Fagot-Campagna A, Narayan KMV Aspirin use among adults with diabetes Diabetes Care 2001;24:197- 201 12 Krein SL, Vijan S, Pogach LM, Hogan MM, Kerr EA Aspirin use and counseling about aspirin among patients with diabetes Diabetes Care 2002;25:965-70 13 National Center for Health Statistics International classification of diseases, ninth revision, clinical modication, third edition, volume 1 DHHS publication no PHS 89-1260 Washington, DC: US Public Health Service, 1989 14 Healthy People 2010 homepage wwwhealthypeoplegov Accessed June 29, 2003 15 Krein SL, Hayward RA, Pogach L, Boots-Miller BB Department of Veterans Affairs Quality Enhancement Research Initiative for diabetes mellitus Med Care 2000;38suppl1:I38-I48 16 Kaiser Permanente home page wwwkaiserpermanentecom Accessed June 29, 2003 17 Faragon JJ, Waite NM, Hobson EH, Seoldo N, VanAmburrgh JA, Midgen H Improving aspirin prophylaxis in a primary care diabetic population Pharmacotherapy 2003;231:73-9 18 American Diabetes Association Aspirin therapy in diabetes position statement Diabetes Care 2000;23suppl 1:S61-S62
19 American Diabetes Association Aspirin therapy in diabetes position statement Diabetes Care 2003;26:S87-S88
Source:cfri.org
