Journal of Pharmacy Practice

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Use of Antiplatelet Agents for Primary and Secondary Prevention of Cardiovascular Disease Amongst Type 2 Diabetic Patients Hasniza Zaman Huri, Lee Qiu Yi, Rokiah Pendek and Che Zuraini Sulaiman Journal of Pharmacy Practice 2008; 21; 287 DOI: 10.1177/0897190008318136 The online version of this article can be found at: http://jpp.sagepub.com/cgi/content/abstract/21/4/287

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On behalf of: New York State Council of Health-system Pharmacists

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Use of Antiplatelet Agents for Primary and Secondary Prevention of Cardiovascular Disease Amongst Type 2 Diabetic Patients

Journal of Pharmacy Practice Volume 21 Number 4 August 2008 287-301 # 2008 Sage Publications 10.1177/0897190008318136 http://jpp.sagepub.com hosted at http://online.sagepub.com

Hasniza Zaman Huri, BPharm, MClin Pharm, Lee Qiu Yi, BPharm, Rokiah Pendek, MBBCh, BAO, MRCP, and Che Zuraini Sulaiman, BPharm, MClin Pharm Background. A retrospective observational study was conducted to study the use of antiplatelet agents for primary and secondary prevention of cardiovascular disease among hospitalized type 2 diabetes mellitus patients. Method. A total of 355 patients were included in the study. The compliance with the American Diabetes Association recommendation on the use of antiplatelet therapy for prevention of cardiovascular disease was studied. Results. For the primary prevention group, type 2 diabetes mellitus, patients with known dyslipidemia were more likely to receive antiplatelet therapy than those without dyslipidemia (P ¼ 0.023). The rate of adherence

Introduction Diabetes is a growing concern in Malaysia because there is marked increase in prevalence of diabetes as observed in a few studies.1,2 Statistics show the number of admissions for diabetes in Malaysia increased from 21 872 in 1995 to 41 375 in 2005 From the Departments of Pharmacy (HZH, LQY) and Medicine (RP), Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia; and the Pharmacy Unit, University Malaya Medical Centre, Selangor, Malaysia (CZA). Address correspondence to: Hasniza Zaman Huri, BPharm (Hons), MClin Pharm, Department of Pharmacy, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia; ([email protected])

to the American Diabetes Association recommendations on the use of antiplatelet therapy for secondary prevention of cardiovascular disease was higher than for primary prevention of cardiovascular disease (P ¼ 0.001). Conclusion. In conclusion, many of the eligible patients still do not receive antiplatelet therapy, particularly in primary prevention of cardiovascular disease. Measures should be taken to ensure that type 2 diabetes mellitus patients receive the antiplatelet therapy and hence prevent macrovascular complications. Keywords: Type 2 diabetes; primary; secondary; prevention; cardiovascular disease; antiplatelet

and show an increase of 100% over a span of 10 years.3 According to the World Health Organization (WHO), the mortality rate due to diabetes mellitus in Malaysia was found to be 4% in 2002.4 This happened because diabetes can be associated with a wide range of complications if not adequately managed. Long-term complications can be divided into microvascular disease and macrovascular disease. These complications may develop in type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) although there are differences in the spectrum of incidence. Macrovascular disease is the most common cause of morbidity and mortality in type 2 diabetes.5 Macrovascular disease is defined as illnesses affecting the larger arteries supplying the heart, brain, and the legs, thereby causing ischemic

287 Downloaded from http://jpp.sagepub.com at UKM Medical Centre on December 29, 2009

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Journal of Pharmacy Practice / Vol. 21, No. 4, August 2008

heart disease, cerebrovascular disease, and peripheral vascular disease.6,7 The incidence of cardiovascular disease (CVD) is 2 to 3 times higher in patients with T2DM than in nondiabetic individuals.8 The Antithrombotic Trialists’ Collaboration meta-analysis found that antiplatelet therapy reduces the relative risk of any serious vascular event by 25% in patients at high risk for a cardiovascular (CV) event.9 Because antiplatelet agents have an established role in primary and secondary prevention of CV events, they become one of the highly recommended agents in the regimen for management of diabetes.10 Antiplatelet therapy is needed in the management of diabetes mellitus because there is an increase of platelet aggregability and adhesiveness due to platelet and endothelial dysfunction, impaired coagulation cascade, and fibrinolysis process among diabetic individuals compared to nondiabetic individuals.10 Consequently, the balance in normal hemostasis is shifted to favor thrombosis and accelerated atherosclerosis and results in increasing CVD.10 Therefore, based on the available evidence, current guidelines from American Diabetes Association (ADA), International Diabetes Federation, Canada Diabetes Association, and Malaysian Diabetes Association recommended that in the absence of specific contraindications, antiplatelet therapy should be used in primary and secondary prevention of CVD in diabetic patients.11-14 The primary prevention group consists of patients with at least one or more CV risk factors whereas the secondary prevention group consists of patients with a history of CVD. The most common antiplatelet agent recommended is aspirin, followed by clopidogrel and ticlopidine. Nevertheless, many studies have shown that antiplatelet therapy is underused in T2DM patients, especially for primary prevention. The adherence to ADA guideline recommendations for antiplatelet therapy use is less than optimal.8,15,16 Therefore, this research aims to identify the pattern of use of antiplatelet therapy as well as to study the use of antiplatelet therapy in primary and secondary prevention of CVD in T2DM based on recommendations from the ADA guidelines.

inpatients, to study the compliance with ADA recommendations on the use of antiplatelet agents for primary prevention among T2DM inpatients, and to also study the compliance with ADA recommendations on the use of antiplatelet agents in secondary prevention of CVD among T2DM inpatients.

Methodology Study Design A retrospective observational study was conducted in a teaching hospital, namely University of Malaya Medical Centre (UMMC). The UMMC’s main objectives are health services, learning, and research, and it has about 900 beds, with both acute and nonacute cases.

Inclusion Criteria All T2DM patients admitted to UMMC from January 2002 to December 2006 and fulfilled the requirements of the International Classification of Disease Tenth Revision (ICD-10) codes for T2DM, which were in the range of E11.0 to 11.9. T2DM inpatients aged between 30 and 80 years. T2DM inpatients with at least one or more CV risk factors (including a family history of CVD, hypertension, smoking, dyslipidemia, or albuminuria) and requiring antiplatelet agents as primary prevention of CVD based on recommendations from ADA guidelines.11 T2DM inpatients with a history of CVD (including a history of peripheral vascular disease, angina, stroke, myocardial infarction [MI], vascular bypass procedure, transient ischemic attack, or claudication) and requiring antiplatelet agents as secondary prevention of CVD based on recommendations from ADA guidelines.11

Exclusion Criteria

Objectives of the Study The purposes of this study were to identify the pattern of use of antiplatelet therapy for primary and secondary prevention of CVD among T2DM

All diabetes inpatients other than T2DM. T2DM inpatients who did not have any CV risk factors or any history of CVD based on recommendations from ADA guidelines and do not require antiplatelet therapy.11


Use of Antiplatelet Agents for Primary and Secondary Prevention of CVD Among T2DM / Huri et al

Study Procedures This study was started after approval by the Medical Ethics Committee of UMMC. Firstly, all patients who fulfilled the first and second inclusion criteria or ‘‘initial screening procedure’’ were identified from the patients’ reference number (R/N) lists generated from the hospital information system (HIS). The ICD-10 codes for T2DM ranged from E11.0 to 11.9. The total number of admissions that fulfilled the initial screening procedure was 7023. For these reasons, systematic sampling was carried out to scale down the study population, and hence, every 15th patient that fulfilled the initial screening procedures was selected. Secondly, the subsequent screening for inclusion criteria was done to include those with any CV risks (requiring antiplatelet for primary prevention) or those with a history of CV events (requiring antiplatelet for secondary prevention). Finally, patients’ medical records were reviewed and all the required data were collected and entered into the data collection form. Laboratory and drug information were retrieved via the laboratory information system (LIS) and pharmacy information system (PIS).

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further classified into two groups as shown below. The compliance with ADA recommendations on antiplatelet therapy was evaluated by considering the criteria as shown in Table 1.

Classification of Patients Group 1 (primary prevention of CVD) Patients with at least one or more CV risk factors (with a family history of CVD, hypertension, smoking, dyslipidemia, or albuminuria) and requiring antiplatelet agents as primary CVD prevention based on recommendations from ADA guidelines.11

Group 2 (secondary prevention of CVD) Patients who already had CVD (with a history of peripheral vascular disease, angina, stroke, MI, vascular bypass procedure, transient ischemic attack, or claudication) and required antiplatelet agents as secondary CVD prevention based on recommendations from ADA guidelines.10,11,17

Statistical Analysis

Data Collection Demographic data Age (nonelderly patients ¼ 30-64 years, while elderly patients ¼ 65-80 years), gender, ethnicity, height, weight, and body mass index.

Relevant clinical records History of CVD (referred to all CVDs suggested in ADA guidelines), presenting symptoms of CVD, presenting any risk factors of CVD (referred to all the risk factors listed in ADA guidelines), current medication records, and vital signs (blood pressure).

The collected data were transformed into an appropriate form for statistical analysis. The statistical package for social science (SPSS) statistical version 14.0 was used to analyze the data collected in this study. The data were analyzed using descriptive statistics to summarize the findings. Continuous data were expressed as mean + SD and categorical data were expressed as percentages. The chi-square test and Fisher exact test were used to compare categorical variable. A P value less than .05 was considered statistically significant. A total of 234 participants were needed to give a power of b ¼ 0.8 for this study with the confidence level of 95%. The results and findings are presented in tables and graphs to facilitate understanding.

Results

Antiplatelet therapy Choices and dosage regimen of antiplatelet therapy used. After the data collection process was completed, patients that fulfilled all the inclusion criteria were

Patient Disposition A total of 7023 patients with an age range of 30 to 80 years were admitted to UMMC, with diagnosis of T2DM (E11.0-11.9) from January 2002 to December


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Table 1. Criteria for Determining the Compliance and Noncompliance with ADA Recommendations on Antiplatelet Therapy Compliance

Noncompliance

1. T2DM inpatients that required antiplatelet therapy for primary prevention of CVD are receiving the therapy. According to ADA recommendations: Use of aspirin therapy (75-162 mg/day) as primary prevention strategy in those with T2DM at increased CV risk including those who are more than 40 years of age with at least one additional risk factor such as – family history of CVD – hypertension – smoking – dyslipidemia – albuminuria

1. T2DM inpatients that required antiplatelet therapy for primary prevention of CVD and are not receiving the therapy.11

2. T2DM inpatients that required antiplatelet therapy for secondary prevention of CVD are receiving the therapy. According to ADA recommendations: Use of aspirin therapy (75-162 mg/day) as secondary prevention strategy in those diabetic patients with a history of CVD due to atherosclerosis including those with a history of angina myocardial infarction transient ischemic attack stroke peripheral vascular disease vascular bypass procedure claudication

2. T2DM inpatients that required antiplatelet therapy for secondary prevention of CVD and are not receiving the therapy.11

3. Aspirin therapy should be considered in diabetic patients aged between 30 and 40 years, particularly in the presence of other CV risk factors.11

3. Aspirin therapy is not considered in diabetic patients aged between 30 and 40 years, particularly in the presence of other CV risk factors.11

4. Aspirin therapy should not be recommended for patients under the age of 21 years.11

4. Aspirin therapy is given to patients under the age of 21 years.11

5. Other antiplatelet agents are recommended as alternatives for high-risk patients with aspirin allergy bleeding tendency (peptic ulcer, duodenal ulcer or gastro ulcer, etc) receiving anticoagulant therapy recent gastrointestinal bleeding clinically active hepatic disease who are not candidates for aspirin therapy.11

5. Other antiplatelet agents are not recommended as alternatives for high-risk patients with aspirin allergy bleeding tendency (peptic ulcer, duodenal ulcer or gastro ulcer, etc) receiving anticoagulant therapy recent gastrointestinal bleeding clinically active hepatic disease who are not candidates for aspirin therapy.11

6. Combination therapy using other antiplatelet agents such as clopidogrel in addition to aspirin should be used in patients with severe and progressive CVD such as those stated in ADA guidelines.11 ADA = American Diabetes Association; CV = cardiovascular; CVD = cardiovascular disease; T2DM = type 2 diabetes mellitus.



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Table 2. Patients’ Demographic Characteristics Approval from the UMMC ethics committee Initial screening for inclusion criteria from patients’ R/N list generated from hospital information system (HIS) T2DM inpatients with diagnosis of E11.0-11.9 admitted between Jan 2002 and Dec 2006 aged between 30 and 80 years (7023 admissions)

Demographic Characteristics Excluded (626 patients) 189 repeated admissions 437 patients aged below 30 or above 80 years

Total patient fulfilled initial screening (6397 patients) Systematic sampling of every 15th patient (427 patients) Second screening for inclusion criteria with at least one CV risk factor already had CVD required antiplatelet therapy as primary or secondary prevention

Excluded (72 patients) without any CV risk factor or CVD and did not require antiplatelet therapy

Eligible participants completed the study (355 patients)

Participants eligible to be considered for primary prevention of CVD with antiplatelet therapy (140 patients)

Participants eligible to be considered for secondary prevention of CVD with antiplatelet therapy (215 patients)

Figure 1. Flow chart of patient disposition. CV = cardiovascular; CVD = cardiovascular disease; T2DM = type 2 diabetes mellitus; UMMC = University Malaya Medical Centre; R/N = registration number.

2006. The initial screening process for inclusion criteria from the patients’ R/N list led to an exclusion of 626 patients from the study, bringing the total to 6397 patients. Systematic sampling was carried out for every 15th patient in the R/N list that had fulfilled the initial screening. In the second screening of inclusion criteria, a total of 427 patients’ medical records were reviewed, but only 355 patients (83.1%) were included in the study. The distribution of patients is summarized in Figure 1.

Patients’ Demographics Patients’ demographic characteristics are presented in the Table 2. Patients were divided into two groups. Group 1 consists of T2DM patients who have been identified with at least one or more CV risk factors. Group 2 consists of T2DM patients who had a history of CV events. The majority of patients in this study were men, which made up 55.8% of the sample. The ratio of men to women was 1:0.79. The majority of

Gender Men Women Age Nonelderly Elderly Race Malay Chinese Indian Others Total

Group 1 Number (%)

Group 2 Number (%)

Total Number (%)

74 (52.9) 66 (47.1)

124 (57.7) 91 (42.3)

198 (55.8) 157 (44.2)

99 (70.7) 41 (29.3)

110 (51.2) 105 (48.8)

209 (58.9) 146 (41.1)

(40.0) (27.9) (31.4) (0.7)

64 (29.8) 64 (29.8) 82 (38.1) 5 (2.3)

120 (33.8) 103 (29.0) 126 (35.5) 6 (1.7)

140 (39.4)

215 (60.6)

355 (100.0)

56 39 44 1

Group 1 = primary prevention of cardiovascular disease; Group 2 = secondary prevention of cardiovascular disease.

the patients were nonelderly and were mainly Indians. However, the Malays were the commonest race in the primary prevention group who accounted for 40% of total patients in the group. The age of patients was normally distributed when tested using the Kolmogorov-Smirnov test and the mean + SD age of patients was 61.1 + 11.6 years. The minimum and maximum age of patients were 32 and 80 years, respectively. The median age of patients was 62 years.

CV Risk Factors that Required Antiplatelet for Primary Prevention From this study, the most commonly reported CV risk factor among all the T2DM inpatients was hypertension. This was followed by dyslipidemia, smoking habits, and a family history of CVD. The least reported CV risk factor was albuminuria. The details of the CV risk factors are shown in Table 3.

CV Events that Required Antiplatelet for Secondary Prevention The most common CV event reported among Group 2 patients was MI with angina as the second most common reported among the study population. Nonetheless, the least common history of CV events was claudication. The frequency of the CV events reported by Group 2 patients is shown in Table 4.

Pattern of Use of Antiplatelet Therapy Overall use of antiplatelet agents. The overall use of antiplatelet therapy in primary and secondary CVD



Table 3. Frequency of Cardiovascular Risk Factors Reported by Group 1 Patients (N ¼ 140)

The number of cardiovascular risk factors reported was not added up to the total number of patients in Group 2 as patients usually presented with more than one risk factor. CVD = cardiovascular disease.

Table 4. Frequency of History of Cardiovascular Events Reported by Group 2 Patients (N ¼ 215) History of Cardiovascular Events

Number of Patients (%)

Myocardial infarction Angina Vascular bypass procedures Stroke Peripheral vascular disease Transient ischemic attack Claudication

150 (69.8) 134 (62.3) 74 (34.4) 71 (33.0) 53 (24.7) 12 (5.6) 6 (2.8)

The number of cardiovascular disease/events reported was not added up to the total number of patients in Group 2 as patients usually presented with more than one event.

73.2%

Without Antiplatelet Therapy With Antiplatelet Therapy

Figure 2. Overall use of antiplatelet therapy for primary and secondary prevention of cardiovascular disease.

Table 5. Use of Antiplatelet Therapy in Group 1 and Group 2 Patients Use of Antiplatelet Therapy, Number (%) Type of CVD Prevention Group 1 (primary CVD prevention) Group 2 (secondary CVD prevention) Total

140

Yes

No

70 (50.0)

70 (50.0)

215 190 (88.4)

25 (11.6)

355 260 (73.2)

95 (26.8)

CVD = cardiovascular disease.

prevention group was 73.2%. Antiplatelet therapy use was mainly encountered in the secondary CVD prevention group (Figure 2). The details are shown in Table 5.

180

177

160 140 Number of Patients

Types and dosage regimen of antiplatelet agents. Antiplatelet therapy was given to patients as monotherapy or in combination. There were a few types of antiplatelet therapy used as shown in Figure 3. The most common antiplatelet used among T2DM patients for primary and secondary CVD prevention was aspirin alone therapy (68%), followed by a combination of aspirin and clopidogrel (18.5%), ticlopidine alone therapy (8.1%), and clopidogrel alone therapy (4.5%). The least popular antiplatelet therapy used was the combination of three antiplatelet agents (0.8%) where only 2 patients in Group 2 received this type of therapy as shown in Table 6. Antiplatelet therapy was prescribed to the patients in different dosage regimens depending on patients’ medical condition and suitability. Aspirin 100 mg/day was the

N

120 100 80 60

48

40 21 20

12 2

0

Clopidogrel Alone

121 (86.4) 63 (45) 61 (43.5) 33 (23.6) 22 (15.7)

Ticlopidine Alone

Hypertension Dyslipidemia Smoking habit Family history of CVD Albuminuria

Aspirin plus Clopidogrel

Number of Patients (%)

Aspirin Alone

Cardiovascular Risk Factors

26.8%

Combination of 3 Antiplatelet Agents

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Figure 3. Types of antiplatelet agents used for primary and secondary prevention of cardiovascular disease among hospitalized type 2 diabetes mellitus patients.



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Table 6. Dosage Regimen of Antiplatelet Therapy Used for Primary and Secondary Prevention of CVD Among Hospitalized T2DM Patients Number of Patients (percentages, %) Dosage Regimen Aspirin alone (N ¼ 177) 75 mg/day 100 mg/day 150 mg/day Combination of two antiplatelet agents (N ¼ 48) Aspirin 100 mg plus 75 mg clopidogrel daily Ticlopidine alone (N ¼ 21) 250 mg bd Clopidogrel alone (N ¼ 12) 75 mg/day 250 mg/day Combination of three antiplatelet agents (N ¼ 2) Aspirin 100 mg, clopidogrel 75 mg plus ticlopidine 250 mg bd Clopidogrel 75 mg, ticlopidine 250 mg bd plus dipyridamole 75 mg daily Total

Group 1

Group 2

Total

4 (5.7) 50 (71.4) 6 (8.6)

1 (0.5) 98 (51.6) 18 (9.5)

5 (1.9) 148 (56.9) 24 (9.2)

4 (5.7)

44 (23.2)

48 (18.5)

4 (5.7)

17 (8.9)

21 (8.1)

2 (2.9) 0 (0.0)

8 (4.2) 2 (1.1)

10 (3.8) 2 (0.8)

0 (0.0) 0 (0.0) 70 (26.9)

1 (0.5) 1 (0.5) 190 (73.7)

1 (0.4) 1 (0.4) 260 (100.0)

CVD = cardiovascular disease; T2DM = type 2 diabetes mellitus.

most popular dosage regimen encountered among T2DM inpatients at UMMC, which made up to more than 50%, followed by a combination of 100 mg aspirin and 75 mg clopidogrel daily (18.5%). Next, ticlopidine 250 mg/bd was the preferred agent. Meanwhile, for clopidogrel, the dose of 75 mg/day was more commonly prescribed to the patients than the dosage of 250 mg/day. Dipyridamole 75 mg/day was the least popular antiplatelet agent used among T2DM patients, and it was only used as a combination therapy. The findings are summarized in Table 6.

Group 1: Primary Prevention of CVD Patients’ Demographics Table 7 shows that the use of antiplatelet therapy for primary prevention of CVD among T2DM patients did not influence the patients’ demographic characteristics such as gender, age, and race. Men, Malays, and nonelderly inpatients were more likely to receive antiplatelet therapy. However, this finding was not statistically significant.

CV Risk Factors In this study, it was noted that T2DM patients that had been diagnosed with albuminuria were more likely to receive antiplatelet therapy for primary

Table 7. Demographic Characteristics Among T2DM Inpatients for Primary Prevention of CVD Use of Antiplatelet Therapy, N (%) Characteristics Gender Men Women Age Nonelderly Elderly Race Malay Chinese Indian Other Total

N

Yes (N ¼ 70)

No (N ¼ 70)

74 66

36 (51.4) 34 (48.6)

37 (52.9) 33 (47.1)

99 41

47 (67.1) 23 (32.9)

52 (74.3) 18 (25.7)

P Value .866

.353 .467a 54 41 42 3 140

30 21 17 2 70

(42.9) (30.0) (24.3) (2.8) (50.0)

24 (34.3) 20 (28.6) 25 (35.7) 1 (1.4) 70 (50.0)

P value derived from chi-square test. CVD = cardiovascular disease; T2DM = type 2 diabetes mellitus. a. Data may not be reliable as two cells (25%) have expected count of less than 5.

prevention of CVD followed by dyslipidemia, hypertension, a family history of CVD, and smoking habit. However, these findings were not statistically significant except for patients with dyslipidemia. Patients with dyslipidemia were more likely to receive antiplatelet therapy than patients without dyslipidemia (2 ¼ 5.154; N ¼ 63, P ¼ .023). These findings are summarized in Table 8.


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Table 8. Cardiovascular Risks Among T2DM Inpatients That Require Antiplatelet Therapy for Primary Prevention of CVD Use of Antiplatelet Therapy, Number (%) Cardiovascular Risks

N

Yes

Albuminuria 22 14 (63.6) Dyslipidemia 63 36 (57.1) Hypertension 121 59 (48.8) Family history of CVD 33 14 (42.4) Smoking habit 61 25 (41.0)

No 8 (36.4) 27 (42.9) 62 (51.2) 19 (57.6) 36 (59.0)

Table 9. Number of Cases That Complied With the ADA Recommendations on the Use of Antiplatelet Therapy for Primary Prevention of CVD Among Hospitalized T2DM Patients From January 2002 to December 2006 Number of Cases That Complied with ADA Guidelines (%)

P Value .407 .023a .591 .285 .072

CV = cardiovascular; CVD = cardiovascular disease; T2DM = type 2 diabetes mellitus. The number of patients was not added up to the total number of patients that had a history of CV risk as patients usually reported with more than one CV risk. P value derived from chi-square test. a. Statistically significant.

Year

N

2002 2003 2004 2005 2006 Total

24 34 41 9 32 140

7 (29.2) 15 (22.7) 21 (51.2) 6 (66.7) 18 (56.3) 67 (47.9)

ADA = American Diabetes Association; CVD = cardiovascular disease; T2DM = type 2 diabetes mellitus.

Table 10. Demographic Characteristics Among T2DM Inpatients for Secondary Prevention of CVD

Compliance With the ADA Recommendations on the Use of Antiplatelet Therapy Table 9 summarizes the percentage of cases that were found to be compliant with the ADA guidelines on the use of antiplatelet therapy for primary prevention of CVD. The trend was found to increase tremendously from 2004 to 2005. However, it showed a slight decrease in 2006 as compared to the year before. The reason for this is unknown. Of the 140 cases, only 47.9% of cases were found to be compliant with the ADA recommendations.

Group 2: Secondary Prevention of CVD Patients’ Demographics Table 10 shows that the patients’ demographic characteristics did not influence the use of antiplatelet therapy for secondary prevention of CVD in hospitalized T2DM patients. Men, Indians, and nonelderly inpatients were more likely to receive antiplatelet therapy for secondary prevention of CVD. However, this finding was not statistically significant.

CV Events Table 11 shows that T2DM patients with a history of bypass vascular procedure (2 ¼ 4.252; N ¼ 74, P ¼ .039) and MI (2 ¼ 4.234; N ¼ 150,

Use of Antiplatelet Therapy, N (%) Characteristics Gender Men Women Age Nonelderly Elderly Race Malay Chinese Indian Other Total

N

Yes (N ¼ 190) No (N ¼ 25)

P Value .266

124 107 (56.3) 91 83 (43.7)

17 (68.0) 8 (32.0)

110 100 (52.6) 105 90 (47.4)

10 (40.0) 15 (60.0)

.235 .325a 66 62 62 53 84 72 3 3 215 190

(32.6) (27.9) (37.9) (1.6) (88.4)

4 (16.0) 9 (36.0) 12 (48.0) 0 (0.0) 25 (11.6)

CV = cardiovascular; CVD = cardiovascular disease; T2DM = type 2 diabetes mellitus. P value derived from chi-square test. a. Data may not be reliable as 2 cells (25%) have expected counts less than 5.

P ¼ 0.040) were more likely to receive antiplatelet therapy for secondary prevention of CVD.

Compliance With the ADA Recommendations on the Use of Antiplatelet Therapy Table 12 summarizes the percentage of cases that complied with the ADA guidelines on the use of antiplatelet therapy for secondary prevention of CVD. The percentage was found to be higher (85.6%) when compared to the previous group that used antiplatelet for primary prevention of CVD (47.9%).



Table 11.

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CV Events Among T2DM Inpatients That Require Antiplatelet Therapy for Secondary Prevention of CVD Use of Antiplatelet Therapy, Number (%)

CV Events

N

Bypass vascular procedure Myocardial infarction Angina Peripheral vascular disease Transient ischemic attack Claudication Stroke

74 150 134 53 12 6 71

Yes

P Value

No

70 (94.6) 137 (91.3) 120 (89.6) 47 (88.7) 10 (83.3) 5 (83.3) 59 (83.1)

.039a,c .040a,c .487a .936a 1.000b .528b .090a

4 (5.4) 13 (8.7) 14 (10.4) 6 (11.3) 1 (8.3) 1 (16.7) 12 (16.9)

CV = cardiovascular; CVD = cardiovascular disease; T2DM = type 2 diabetes mellitus. The number of patients was not added up to the total number of patients that had a history of CV events as patients usually reported with more than one CV event. a. P value derived from chi-square test. b. P value derived from Fisher exact test. c. Statistically significant.

Table 12. Number of Cases That Complied With the ADA Recommendations on the Use of Antiplatelet Therapy for Secondary Prevention of CVD Among T2DM Inpatients From January 2002 to December 2006

Year

N

2002 2003 2004 2005 2006 Total

41 48 56 33 37 215

Table 13. The Rate of Compliance With the ADA Recommendations on the Use of Antiplatelet Therapy in Primary and Secondary Prevention of CVD Among T2DM Inpatients From January 2002 to December 2006

Number of Cases That Complied with ADA Guidelines (%) 32 (78.0) 44 (91.7) 49 (87.5) 25 (75.8) 34 (91.9) 184 (85.6)

ADA = American Diabetes Association; CVD = cardiovascular disease; T2DM = type 2 diabetes mellitus.

Compliance with ADA Recommendations, Number (%) Types of CVD Prevention

N

Yes

Primary CVD prevention 140 67 (47.9) Secondary CVD prevention 215 184 (85.6) Total

355 251 (70.7)

No 73 (52.1) 31 (14.4) 104 (29.3)

CVD = cardiovascular disease; T2DM = type 2 diabetes mellitus. Chi-square ¼ 60.51; df ¼ 1; P value ¼ .001.

Discussion Recommendations on the Use of Antiplatelet Therapy for Primary and Secondary Prevention of CVD This study shows that overall, 70.7% of cases were compliant with ADA recommendations on the use of antiplatelet therapy for primary and secondary prevention of CVD. The rate was higher in secondary prevention of CVD. This finding was found to be statistically significant when tested using the 2 test. Hence, this illustrated that T2DM patients who had a history of CV events were more likely to receive antiplatelet therapy than patients who had CV risks. The findings are summarized in Table 13.

Patients’ Demographics From this study, it was found that the majority of patients were men. This finding concurred with a study conducted by Wild et al18 where they reported that diabetes prevalence is higher in men. In this study, it was found that the Malays were the commonest race in the primary CVD prevention group. This might be because the Malays have the poorest glycemic control compared with the Chinese and Indians.19 According to a study conducted by Ng et al, Malay patients had significantly higher HbA1c compared with the Chinese and Indians. Because uncontrolled diabetes is usually associated with hyperlipidemia, this will increase the risk of CVD


296


among Malays.20 Hence, primary prevention of CVD therapy is highly recommended to them. Wild et al18 noted that the majority of diabetic patients in developing countries were in the range of 45 to 64 years of age. The finding is consistent with this study as the mean + SD age of patients in this study was 61.1 +11.6 years. This is because most of the T2DM patients developed diabetes at over 40 years of age.18

Risk Factors for CVD Hypertension is a common comorbidity among diabetic patients, and up to 60% of T2DM patients have concomitant hypertension.21 In Malaysia, the estimated prevalence of hypertension in diabetic patients was 20.6% compared to 14% in the general population.20 From this study, it was found that 86.4% of the study’s participants reported with hypertension, which concurred with previous findings. Dyslipidemia was the second common CV risk factor followed by smoking habit. This happens because patients with T2DM have an increased prevalence of lipid abnormalities.11

as outpatients in their study. Conversely, this study was conducted in tertiary hospital and mainly focused on the use of antiplatelet therapy among T2DM inpatients. Hospitalized patients receive more medical attention when compared to the patients in the outpatient setting. Nonetheless, no previous study that focused on the utilization of antiplatelet therapy among T2DM inpatients was found. From this study, the use of antiplatelet therapy was higher in the secondary CVD prevention group than in the primary prevention group in which only 50% of patients with at least one CV risk factor were reported to be on antiplatelet therapy. This finding concurred with many previous studies.16,23,24,25 This may relate to the lack of convincing evidence of the role of antiplatelet agents for primary CVD prevention. The role of aspirin in reducing the risk of CVD in patients without known CVD is controversial. Patients with low risk for coronary heart disease (0 or 1 CV risk) may not benefit from aspirin therapy but can be harmed by its adverse events, which include hemorrhagic stroke and gastrointestinal bleeding.26,27

Types of Antiplatelet Therapy

CV Events From this study, the most commonly reported CV event among T2DM patients was MI, followed by angina, vascular bypass events, and stroke. This finding mirrored a previous study, which reported that T2DM is considered to be a coronary disease equivalent.22 Thus vascular bypass procedures such as coronary artery bypass graft (CABG) and percutaneous transluminal coronary angioplasty (PTCA) were commonly reported by this group of patients.

Pattern of Use of Antiplatelet Therapy Overall Use of Antiplatelet Agents Despite increasing evidence to support the effectiveness of antiplatelet therapy among diabetic patients, antiplatelet use has been underused as reported in many studies.8,16,23,24 A study conducted by Miller et al25 reported that the overall prevalence of antiplatelet use among adults with diabetes was 53.6%. Nonetheless, this study showed that the overall use of antiplatelet therapy among T2DM patients was 73.2% for primary and secondary prevention of CVD. This inconsistent finding can be explained by the different settings of the study. Miller et al25 included all the T1DM and T2DM inpatients as well

From this study, it was discovered that aspirin alone therapy was the most common antiplatelet therapy used among T2DM patients followed by a combination of aspirin and clopidogrel and ticlopidine alone therapy. This finding was in line with previous studies conducted by Bruno et al16 and Miller et al.25 Aspirin was the commonest antiplatelet used in primary and secondary CVD prevention because a lot of clinical trials have shown the efficacy of aspirin in both the primary and secondary prevention of CVD especially in MI, stroke, and CV death compared to other antiplatelet agents.9,10,26,28,29 Additionally, most of the established guidelines recommended that aspirin was the superior antiplatelet agent in primary and secondary prevention of CVD in the absence of any contraindication.11-14

Dosage Regimen of Antiplatelet Agents From this study, aspirin 100 mg/day was the most common dosage regimen used among T2DM patients. The dosage regimen of aspirin that was used at UMMC was appropriate because the dosage regimen recommended by ADA is in the range of 75 to 162 mg/day. This range (75-150 mg/day) of dosage regimen was being used among the patients



because it has been found that the proportion reduction in vascular events was 19% with aspirin 500 to 1000 mg/day, 26% with aspirin 160 to 325 mg/day, and 32% with aspirin 75 to 150 mg/day.9 According to the Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial’s finding, an 8.7% relative risk reduction was seen in vascular death, MI, or ischemic stroke with the use of 75 mg/day of clopidogrel. Therefore, clopidogrel 75 mg/day was found to be prescribed to T2DM patients who underwent percutaneous coronary intervention as secondary prevention of CVD, and normally it was given up to 5 days prior to the intervention and 4 weeks after the intervention. In contrast, no study was conducted to evaluate the effect and the dosage regimen of ticlopidine. However, 250 mg twice daily of ticlopidine was found to significantly reduce the annual microaneurysm progression by 67%.30 At UMMC, ticlopidine 250 mg twice daily is prescribed.31 On the other hand, the recommended dosage regimen of dipyridamole for secondary prevention of ischemic stroke and transient ischemic attacks was in range of 300 to 600 mg/day.32 However, the dose of dipyridamole used in this study was smaller (75 mg/day) because it was used in the combination of three antiplatelet agents.

Primary Prevention of CVD With Antiplatelet Therapy Diabetes mellitus increases the risk of CVD about 2-fold to 3-fold in men and postmenopausal women and around 5-fold in premenopausal women.33 This illustrated that the risk of CVD is known to be particularly high in women with diabetes than in men. Antiplatelet therapy, especially aspirin, has shown to significantly reduce the rate of CV events in women.16,34,35 Nevertheless, previous studies reported that men were more likely to receive antiplatelet therapy for primary CVD prevention as compared to women.8,16,23,25,36,37 Those studies concluded that this happened because only 2 of 5 primary prevention trials of antiplatelet therapy included women, thus some physicians may be less enthusiastic about the evidence base supporting the use of antiplatelet therapy in women (Hypertension Optimal Treatment Trial [HOT]34 and Primary Prevention Project [PPP]).38 However, this study showed no apparent relationship of antiplatelet use with gender. This might be because physicians prescribe the antiplatelet therapy merely based on patients’ medical condition and CV risks.

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The Physician’s Health Study (PHS) found that aspirin reduced the relative risk for MI for elderly patients more than it did for younger patients, thus antiplatelet therapy is highly recommended to those elderly patients with a high risk of developing MI. Nguyen et al36 reported that diabetic patients aged above 75 years were more likely to receive aspirin for primary CVD prevention than those aged 30 to 44 years. Klinke et al8 and Miller et al25 also supported this finding in their studies. They suggested that greater attention paid by physicians to elderly patients might lead to the increased use of aspirin among the elderly patients, and they tend to underestimate the CV risk in younger T2DM patients. Nonetheless, this study illustrated that age did not influence the use of antiplatelet therapy. This may be because physicians did not underestimate the CV risk in younger T2DM patients, hence similar hospital care and treatment patterns were provided to all patients. The presence of multiple comorbidities and polypharmacy in the elderly patients that could lead to potential adverse effects and drug interactions would probably be another reason why this finding was not significant. In other words, physicians tend to be more careful when prescribing to elderly patients. Therefore, it can be assumed that age is not a factor to be considered before aspirin could be prescribed to a potential patient. Among all the CV risk factors, only dyslipidemia was significantly associated with the use of antiplatelet therapy. This finding was in line with the study conducted by Nguyen et al.36 Because dyslipidemia was known to be one of the most important risk factors for the development of CV complications in T2DM, this might be the reason why antiplatelet therapy was more likely to be prescribed to this group of patients.39 From this study, it was found that only 47.9% of the total cases (67 out of 140 cases) were compliant with ADA recommendations on the use of antiplatelet therapy for primary prevention of CVD among T2DM patients. Only half of the total number of patients eligible to be considered for primary CVD prevention was found to be on antiplatelet therapy. These findings suggest that antiplatelet therapy was underprescribed among the patients in the primary CVD prevention group. This finding concurred with the previous studies conducted by Nguyen et al,36 Bruno et al,16 Miller et al,25 and Klinke et al.8 This is mainly because there is still some ambiguity regarding the role of antiplatelet therapy in primary


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prevention of CVD, and thus physicians hesitate to prescribe antiplatelet therapy to the patients. A study reported that those 55-year-old patients with low CV risk factors (0 risk factors in men; 0 or 1 risk factor in women) were harmed by aspirin whereas only those with moderate to high risk (more than 2 risk factors) seemed to benefit.40 Hayden et al26 also concluded that the net effect of aspirin improves with increasing risk for coronary heart disease. Furthermore, regular use of aspirin is associated with about 2-fold increased risk of upper gastrointestinal bleeding or perforation. Most of the physicians might then ponder several points: a. For whom do the benefits of daily aspirin outweigh the hazards, b. Will the daily aspirin be appropriate for those whom the risk of a vascular disease is likely much less than 1% a year, and c. Is a patient contraindicated to antiplatelet therapy (Antithrombotic Trialists’ Collaboration 2002).9 Some of the physicians may not be able to identify the CV risk factors of the patients, especially regarding the family history of CVD and smoking habit. For instance, they may be uncertain whether patients have a family history of CVD or smoking habit. This is because patients might lie that they are nonsmokers and some of the patients may not know whether they had any family history of CVD. Prioritization of other medical problems might be another reason that leads to noncompliance with the ADA guidelines on the use of antiplatelet therapy for primary prevention of CVD in UMMC. This is because some of the cases that were found not adhering to the guidelines were mainly those T2DM patients concurrent with other medical conditions such as sepsis, septic shock, rectum or thyroid cancer or admitted to the hospital because of hypoglycemia or for ophthalmopathy surgery or amputation. Apart from that, 2 cases were found to be noncompliant because an alternative antiplatelet agent was not prescribed to the patients once they were noted to be contraindicated and allergic to aspirin. In contrast, 1 case was found to be noncompliant because the patient was prescribed aspirin despite having gastric ulcer and no alternative antiplatelet therapy was given after the patient recovered from gastric ulcer.

Secondary Prevention of CVD With Use of Antiplatelet Therapy Similar to the primary prevention group, none of the demographic characteristics of patients were found

to be significantly associated with the use of antiplatelet therapy for secondary prevention of CVD. However, fewer elderly patients were noted to be on antiplatelet therapy than nonelderly patients for secondary prevention of CVD. It was found that a number of elderly patients in this group had been diagnosed with renal insufficiency, end-stage renal failure, and stroke and thus an antiplatelet agent such as aspirin was not being prescribed to them as they may be more susceptible to adverse effects of aspirin. This was supported by the findings from a large stroke prevention in Atrial Fibrillation II trial where researchers concluded that advanced age was associated with an increased incidence of bleeding during aspirin therapy.26 Aspirin inhibits biosynthesis of prostaglandin that is involved in the maintenance of renal blood dynamics and compensatory vasodilatation.41 Thus the therapeutic dose of aspirin may pose threat to kidney function especially in the susceptible ones such as elderly patients or those with known renal insufficiency.41 Besides, polypharmacy is commonly seen in some elderly diabetic patients with known CVD. Consequently, concurrent medications become an issue to be considered when starting an antiplatelet therapy for an elderly T2DM patient. From this study, it was demonstrated that T2DM patients with a history of vascular bypass procedure (94.6%) were more likely to receive antiplatelet therapy. This was followed by patients with MI (91.3%). Most of the previous studies did not include patients with a history of vascular bypass into their study population.8,24,25,42 Antiplatelet therapy has been shown to reduce CV events significantly by 4% among patients who had recently had CABG as it can produce a massively significant reduction in thrombotic occlusion of bypass grafts.9 This might be the reason why T2DM patients with a history of bypass vascular procedures were more likely to receive antiplatelet therapy at UMMC. Antiplatelet therapy was also more frequently prescribed to T2DM patients with known MI for prevention of death. This finding concurred with studies conducted by Miller et al25 and Brown et al.42 Peripheral vascular disease had not significantly been associated with antiplatelet use among this group of patients. This finding was in parallel with the study conducted by Bruno et al.16 From this study, the rate of adherence to the ADA recommendations on the use of antiplatelet therapy for secondary CVD prevention was found to be significantly higher than



primary CVD prevention. A total of 85.6% patients (184 of 215 patients) who were eligible to receive antiplatelet therapy were reported to receive it. It was found that a majority of cases (25 cases of 31 cases) that were noted to be noncompliant with the ADA recommendations were patients with stroke, renal insufficiency, gastritis, duodenitis, or gastrointestinal problems and also those eligible for other alternative antiplatelet therapy despite aspirin, but they were not given any antiplatelet therapy. Similar to the primary CVD prevention group, prioritization of the other more serious medical problems is another reason that leads to noncompliance with the ADA guidelines on the use of antiplatelet therapy for secondary prevention of CVD. Patients who were not given antiplatelet therapy as recommended in the ADA guidelines were mainly those who were concurrent with sepsis, septic shock, amputation, infection, or cancer of breast, rectum, or thyroid. The remaining 6 cases were found to be noncompliant with the ADA recommendations because patients were prescribed aspirin despite having peptic ulcer and with recent gastrointestinal bleeding. Thus, aspirin was being withheld but no alternative antiplatelet therapy was given to these patients. According to the ADA guidelines, other more suitable antiplatelet agents should be used as an alternative for this group of patients.11

Compliance With ADA Recommendations in General for Both Primary and Secondary Prevention of CVD Groups From this study, it was found that the dosage regimen that was used in UMMC was appropriate and within the recommended dosage range. Besides, it was noted that overall 75.2% of cases were compliant with ADA recommendations for the use of antiplatelet therapy in primary and secondary prevention of CVD among T2DM patients. When analyzed individually, the compliance of the use of antiplatelet therapy to ADA recommendations among the primary prevention group for CVD prevention was found to be lower. However, Morimoto et al43 found that the thresholds of antiplatelet therapy for Asian populations should be 2 to 4 times higher than those for the US population because of higher risk of hemorrhagic complications. They concluded that the implications of foreign guidelines should be evaluated before they are used in other countries and antiplatelet therapy should not be

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used without careful consideration.43 Hence, there is a need for caution when implementing ADA guidelines on the use of antiplatelet agents for primary and secondary prevention of CVD among T2DM patients. The benefits and harms of antiplatelet therapy to a particular patient should be interpreted and compared cautiously before the start of the therapy.

Limitations Since this was a retrospective study, the data collected were based on secondary reporting. In addition, this study is focused mostly in the study population, and hence it might not be possible to extrapolate these results to other races or countries.

Conclusion In conclusion, many of the eligible patients still do not receive antiplatelet therapy, particularly in primary prevention of CVD. Therefore, measures should be taken to ensure that T2DM patients receive the antiplatelet therapy. This is important to ensure that T2DM patients benefit from the use of antiplatelet therapy and hence prevent macrovascular complications. In T2DM patients who are at increased CV risk, the use of antiplatelet therapy could reduce the onset of CV events whereas in patients with a history of CVD, the use of antiplatelet therapy could reduce the subsequent CV events.

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