**5. Types of antiplatelet**

#### **5.1 Aspirin**

Aspirin selectively and irreversibly acetylates the COX-1 enzyme, thereby blocking the formation of thromboxane A2 in platelets and leads to inability of platelet to resynthesize COX-1 (Patrono et al., 2005). Aspirin has been used as a primary strategy to prevent CVD in type 2 diabetes due to its effectiveness in atherosclerosis prevention is well established. Various meta-analyses studies and large scale randomized controlled trials in T2DM support that low-dose aspirin therapy should be prescribed as prevention strategy in T2DM, if the contraindication is not exist (Colwell, 2004). Low dose of aspirin inhibits thromboxane production by platelets but has little or no effects on other sites of platelet activity (Colwell & Nesto, 2003). Several randomized controlled trials had been designed to assess the

TXA2 synthesis, decreased prostacyclin production, decreased NO production, decreased antioxidant levels and increased expression of activation-dependent adhesion molecules (Halushka et al., 1981; Mayfield et al., 1985; Watala et al., 1998; Martina et al., 1998; Trovati et al., 1997; Sarji et al., 1979; Tschoepe, et al., 1997; Leet et al., 1981). For patients with T2DM, the presence of dyslipidemia and platelet hyperactivity justifies the use of antiplatelet agents

Increased physical activity, dietary modifications and pharmacologic interventions are the key methods in management of dyslipidemia in type 2 diabetes mellitus (Mooradian, 2008). 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 (Antithrombotic Trialist' Collaboration, 2002). Antiplatelet agents are used for primary and secondary prevention of CVD in type 2 diabetes mellitus patients. 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 (Colwell & Nesto, 2003). Consequently, the balance in normal hemostasis is shifted to favor thrombosis and accelerated atherosclerosis and results in increasing CVD (Colwell & Nesto, 2003). For primary prevention of cardiovascular diseases, type 2 diabetes mellitus patients with high risk acquiring cardiovascular events such as those with family history of cardiovascular disease, hypertension, obesity (BMI > 30 kg/m2), smoking, dyslipidemia and albuminuria (Colwell, 2004). Several types of antiplatelet agents is being utilized for prevention of CVD which including aspirin, ticlopidine, clopidogrel and glycoprotein (Gp) IIb-IIIa antagonist such as abciximab, eptifibatide and tirofiban (Patrono et al., 2004; American Diabetes Association, 2006; Colwell & Nesto, 2003). Aspirin is one of the most common antiplatelet that been suggested in prevention of CVD in diabetes. Clopidogrel and ticlopidine are theinopyridine antiplatelet agents that generally suggested if patients are contraindicated to aspirin (American Diabetes Association, 2006). In contrast, Gp IIb-IIIa antagonist is usually given to diabetes patients who undergo precutaneous coronary intervention in order to intensify the antiplatelet therapy and to reduce the risk of procedure related thrombotic complication and

Aspirin selectively and irreversibly acetylates the COX-1 enzyme, thereby blocking the formation of thromboxane A2 in platelets and leads to inability of platelet to resynthesize COX-1 (Patrono et al., 2005). Aspirin has been used as a primary strategy to prevent CVD in type 2 diabetes due to its effectiveness in atherosclerosis prevention is well established. Various meta-analyses studies and large scale randomized controlled trials in T2DM support that low-dose aspirin therapy should be prescribed as prevention strategy in T2DM, if the contraindication is not exist (Colwell, 2004). Low dose of aspirin inhibits thromboxane production by platelets but has little or no effects on other sites of platelet activity (Colwell & Nesto, 2003). Several randomized controlled trials had been designed to assess the

**4. Role of antiplatelet agents in primary prevention of CVD** 

as primary prevention strategy of CVD.

reoccurrence of CV event (Patrono et al., 2004).

**5. Types of antiplatelet** 

**5.1 Aspirin** 

efficacy of aspirin in primary prevention of CVD which included Primary Prevention Project (PPP), US physicians' Health Study (USPHS), Early Treatment of Diabetes Retinopathy Study (ETDRS), Hypertension Optimal Treatment Trial (HOT), British Male Doctors' Trial (BMD) and the Thrombosis Prevention Trial (TPT) (Colwell & Nesto, 2003; Hayden et al., 2002). In Primary Prevention Project (PPP), a low dose aspirin (100 mg/day) was evaluated for the prevention of cardiovascular events in individuals with one or more of the following conditions such as hypertension, hypercholesterolemia, diabetes, obese, family history of premature myocardial infarction or being elderly. After a mean of 3.6 years follow-up, aspirin was found to significantly lower the frequency of cardiovascular death (from 1.4 % to 0.8 %); relative risk (RR) 0.56 [confidence interval (CI) 0.31-.99] and total cardiovascular events (from 8.2 to 6.3% ; RR 0.77 [ 0.62-0.95] ). This trial involved large sample size (n = 4495) with the largest proportion of patients with diabetes mellitus (17%) (Collaborative Group of the Primary Prevention Project, 2001). Overall, PPP provides evidence to prove the efficacy of aspirin in diabetes; though participants were not blinded and were not given placebo pills. Additionally, a meta-analysis done by Hayden et al., (2002) also rated the quality of PPP as "fair" if compared to the rest of studies. In addition to PPP, a 5 years primary prevention trial in 22 701 healthy men; included 533 men with diabetes was conducted in US Physicians' Health Study (USPHS) in which a low-dose aspirin regimen (325 mg every other day) was given to treated group compared with placebo. A total of 44% significant risk reduction in CVD treated group was noted and the subgroup analyses in the diabetes reveals a reduction in myocardial infarction from 10.1 % (placebo) to 4.0 % (aspirin), yield a relative risk reduction of 0.39 for the diabetes men on aspirin therapy (Steering Committee of the Physicians' Health Study Research Group, 1989). Researcher and participants were blinded in this trial. In contrast with PPP, women were included in the study populations (2583 out of 4495 sample sizes). Hence, this study was more reliable compared to previous ones even though only 2% of the study population was diagnosed with diabetes. The Hypertension Optimal Treatment Trial (HOT) also examined the effects of low dose of aspirin (75 mg/day) versus placebo in 18 790 hypertension patients and 8% of them had diabetes. Results showed that aspirin significantly reduce cardiovascular event by 15% and myocardial infarction by 36% (Hansson et al., 1998). The HOT trial was another primary prevention study that included women, which was 46.6 % from total study population. Colwell (2004) commended that this study provided further evidence for the efficacy and safety of aspirin therapy in diabetes with systolic blood pressure less than 160 mmHg. Hayden et al., (2002) was in agreement with Colwell (2004) and concluded that HOT was a "good" quality of trial in their meta-analysis. Despite that, these findings were mirrored by Early Treatment of Diabetes Retinopathy Study (ETDRS) where they reported that although aspirin did not prevent progression of retinopathy but it did produce a significant reduction in risk for myocardial infarction (28%) over 5 years (P=0.038). This study may viewed as mixed primary and secondary prevention trials since those enrolled had a history of myocardial infarction and less than 50% had elevated blood pressure and history of CVD (ETDRS Investigators 1992). Conversely, the British Male Doctors' Trial (BMD) had conflicting results regarding aspirin effects in reducing the risk for myocardial infarction and adverse effects such as gastrointestinal bleeding and hemorrhagic stroke to diabetes patients. A total of 39 % of participants were discontinued therapy during the study due to adverse effect of aspirin (Hayden et al., 2002). Similar to PPP trial, participants in this study were not blinded thus results may be varies. Following this, a meta-analysis of these

Dyslipidemia and Type 2 Diabetes Mellitus:

measure the outcome for this purpose.

of CVD in type 2 diabetes patients have not been established.

prevention of CVD amongst T2DM patients.

**5.3 Ticlopidine** 

**5.4 Dipyridamole** 

Implications and Role of Antiplatelet Agents in Primary Prevention of Cardiovascular Disease 85

outcomes with clopidogrel plus aspirin versus aspirin alone in patients with acute ischemic heart disease (IHD) (CURE Steering Committee, 2001). These findings demonstrated that clopidogrel has beneficial effects in patients with acute coronary syndromes without STsegment elevation thus can be generalized as the study sample size (n =12,562) was large and patients were recruited from 482 centers in 28 countries. This trial also showed that 3.7% of patients in this combination therapy group had major bleeding and it was significant more compared with those solely on aspirin but there was no increase in lifethreatening bleeds (CURE Steering Committee, 2001). Hence, a loading dose of 300mg clopidogrel should be used in this setting followed by 75 mg daily (Patrono et al., 2004). Bhatt et al., (2002) concluded that clopidogrel is an effective drug for secondary prevention in diabetes. Therefore, previous studies clearly justified the use of dual anti platelet therapy with aspirin and clopidogrel for secondary prevention of CVD in diabetes patients. Its role in primary prevention of CVD in diabetes patients is vague since no study has directly

Ticlopidine also inhibit ADP-induced platelet aggregation with no direct effects on the metabolism of arachidonic acid (Patrono, 1998). It has slower antiplatelet effect compared with clopidogrel (Patrono et al., 2004). Ticlopidine in Microangiopathy of Diabetes (TIMAD) study was conducted by involving 435 patients with nonproliferative diabetes retinopathy to evaluate for its effects on macrovascular disease in diabetes patients. Patients were randomized to receive ticlopidine, 250 mg twice daily and were followed up to 3 years. Ticlopidine was found significantly reduced annual microaneurysm progression by 67% and overall progression of retinopathy was significantly less severe with ticlopidine (TIMAD Study Group, 1990). However, this study was not designed to evaluate effect of ticlopidine on cardiovascular events. There are limited studies done on effect of ticlopidine in prevention of CVD in diabetes. In contrast to clopidogrel, ticlopidine does not have an approved indication for patients with a recent myocardial infarction (Patrono et al., 2004). Even though ticlopidine has lower cost compared to clopidogrel, (Drug Formulary University Malaya Medical Centre, 2005; Patrono et al., 2004), its role in primary prevention

Dipyridamole inhibits platelet cyclic-3',5'-adenosine monophosphate and cyclic-3', 5' guanosine monophosphate phosphodiesterase (Natarajan et al. 2008). Overview of 25 trials among approximately 10000 high risks of CVD patients with the use of dipyridamole and aspirin, it was found that the addition of dipyridamole to aspirin has not been shown clearly to produce additional reductions in serious vascular events (Patrono et al., 2004). However, one of 25 trials suggested that there may be a worthwhile further reduction in stroke (Patrono *et al.* 2004). Patrono et al.*,* (2004) also suggested that the combination of low dose aspirin and extended release dipyridamole (200 mg twice daily) is considered an acceptable option for initial therapy of patients with non-cardioembolic cerebral ischemic events and not in patients with ischemic heart attack. The benefits of dipyridamole in patients with diabetes have not been reported (Natarajan et al., 2008). Specifically, there are limited studies or trials conducted to examine the role of dipyridamole for primary and secondary

five randomized clinical trials (except ETDRS) was performed by Hayden et al., (2002) and systematic reviews on nine articles about the effect of aspirin on gastrointestinal bleeding and hemorrhagic stroke were conducted. They concluded that the net benefit of aspirin increase with CV risk. Nonetheless, this meta-analysis was found to have selection bias due to exclusion of 2 large trials that examined the effects of aspirin in patients with diabetes or stable angina. Sanmuganathan et al., (2001) also reached similar estimates of the beneficial effects of aspirin in primary prevention of CVD. The Japanese Primary Prevention of Atherosclerosis With Aspirin for Diabetes (JPAD) trial was the first prospectively designed trial to evaluate the use of aspirin (81 mg or 100 mg) in the primary prevention of cardiovascular events in patients with type 2 diabetes (*n* = 2539) aged 30–85 years in Japan (Ogawa et al., 2008). Among patients aged > 65 years (*n* =1363), aspirin was associated with a 32% reduction in the risk of the primary end point (6.3 vs. 9.2%; *P* = 0.047). Furthermore, in aspirin-treated patients, the incidence of fatal coronary and cerebrovascular events was significantly lower by 90% (0.08 vs. 0.8%; *P* = 0.0037). Paradoxically, there were no differences in nonfatal coronary and cerebrovascular events. Aspirin was well tolerated, with no significant increase in the composite of hemorrhagic stroke and severe gastrointestinal bleeding (Angiolillo, 2009). The outcome of this study was in opposite with the current recommendations on aspirin usage in primary prevention of CVD in diabetes patients (Angiolillo, 2009). However, the ASCEND and ACCEPT-D study are two ongoing trials will provide further insights to the appropriateness of aspirin usage in primary prevention of CVD in patients with diabetes. Another recent trial (POPADAD), failed to show any benefit with aspirin or antioxidants in primary prevention of cardiovascular events (Belch, 2008). The outcome of the study could be due to small number of patients with low event rates. A study on the utilization of antiplatelet therapy in type 2 diabetes patients revealed that many of the eligible patients did not receive the drugs as primary prevention strategy for CVD (Huri et al., 2008). Therefore, the recommendations on aspirin usage in primary prevention of CVD in type 2 diabetes patients must be fully justified after taking consideration against the benefit versus risk of its use. In another words, the recommendations should be base on individual patients' assessment and clinical judgment. Proper use of aspirin in primary prevention of CVD in type 2 diabetes patients may result in long-term benefits.

#### **5.2 Clopidogrel**

Clopidogrel is another type of antiplatelet agents used in primary prevention of CVD in type 2 diabetes when patients are intolerant to aspirin. It inhibits ADP-induced platelet aggregation by blocking the purinergic receptors and therefore prevents the activation of the GpIIb-IIIa receptor and subsequent binding to fibrinogen (Colwell & Nesto, 2003). Clopidogrel is preferable compared to ticlopidine because of its safety profile (Savi & Herbert, 2005; Bertrand et al., 2000). Nevertheless, the information regarding the usage of clopidogrel in primary prevention of CVD is limited than for secondary prevention of CVD in diabetes patients. Even though clopidogrel may be slightly more effective than aspirin, the size of any additional benefits is statistically uncertain and it has not been granted a claim of superiority against aspirin (Patrono et al., 2004). However, the publication of the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) recently had led to FDA approval of a new indication for clopidogrel in patients with acute coronary syndromes without ST-segment elevation (Patrono et al., 2004).The CURE trial examined CV

outcomes with clopidogrel plus aspirin versus aspirin alone in patients with acute ischemic heart disease (IHD) (CURE Steering Committee, 2001). These findings demonstrated that clopidogrel has beneficial effects in patients with acute coronary syndromes without STsegment elevation thus can be generalized as the study sample size (n =12,562) was large and patients were recruited from 482 centers in 28 countries. This trial also showed that 3.7% of patients in this combination therapy group had major bleeding and it was significant more compared with those solely on aspirin but there was no increase in lifethreatening bleeds (CURE Steering Committee, 2001). Hence, a loading dose of 300mg clopidogrel should be used in this setting followed by 75 mg daily (Patrono et al., 2004). Bhatt et al., (2002) concluded that clopidogrel is an effective drug for secondary prevention in diabetes. Therefore, previous studies clearly justified the use of dual anti platelet therapy with aspirin and clopidogrel for secondary prevention of CVD in diabetes patients. Its role in primary prevention of CVD in diabetes patients is vague since no study has directly measure the outcome for this purpose.
