High clopidogrel maintenance dosage in patients with diabetes mellitus and coronary artery disease

The clinical benefits of clopidogrel (Plavix), a potent platelet P2Y₁₂ receptor blocker, are well established.^1-3 There is, however, significant interindividual variability in platelet response to clopidogrel.^4,5 Individuals with inadequate response to clopidogrel are at increased risk for cardiovascular ischemic events.⁵ Numerous clinical, cellular, and genetic factors have been identified with clopidogrel response variability.⁵ Among these, inadequate dosing appears to play a pivotal role.^5-7 Recent studies have confirmed that higher than standard clopidogrel loading doses enhance platelet inhibition and improve clinical outcomes.^5-9 Despite this initial improvement in platelet response, patients may demonstrate suboptimal platelet inhibition during the maintenance phase of clopidogrel treatment.^5,10-14 Because patients with type 2 diabetes mellitus have increased platelet reactivity and decreased in vitro responsiveness to clopidogrel compared with patients without diabetes,^5,13,14 we conducted a study to determine whether an increased maintenance dosage of clopidogrel of 150 mg/day would lead to increased platelet inhibition compared with the usual dosage of 75 mg/day in these high-risk patients.

Subjects and methods

The Optimizing Antiplatelet Therapy in Diabetes Mellitus (OPTIMUS) study was a randomized, single-center, prospective, parallel-group platelet function study that included subjects between 25 and 80 years of age with type 2 diabetes and a known history of coronary artery disease; these subjects were in a chronic steady-state phase (> 1 month) of standard clopidogrel treatment (75 mg/daily). Low-dose aspirin (81 mg/day) was also given to all subjects. Study participants underwent assessment for a suboptimal clopidogrel response, which was considered study time point 1. Those identified as sub-optimal responders were randomly assigned to receive a daily maintenance dose of either 75 or 150 mg of clopidogrel. After 30 days (study time point 2), platelet function was reevaluated, and all patients were returned to the standard dosage of 75 mg/day. After another 30 days (study time point 3), platelet function was measured for the final time.

Figure 1. Maximal platelet aggregation following 20 ìmol/L adenosine

diphosphate (ADP) stimuli assessed at study time points 1 (T1; blue bars) and

2 (T2; yellow bars). Values are expressed as percentage of maximum platelet

aggregation. Error bars indicate standard deviations of the mean.

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Blood samples obtained at each study point were used to assess platelet aggregation using light transmittance aggregometry following stimulus with adenosine diphosphate (ADP; 5 or 20 mol/L) and the P2Y₁₂ reactivity ratio using flow cytometry, according to standard procedures.⁵ Measurements of aggregation were performed at peak aggregation (Agg_max) and at 5 minutes (Agg_late). Suboptimal responders were defined as those with a 20 mol/L ADP-induced Agg_max of > 50%. The percent decrease in aggregation values obtained at baseline and after treatment (Agg_max and Agg_late) was used to determine the inhibition of platelet aggregation (IPA). The following equation was used: IPA (%) = (intensity of aggregation at baseline) — (intensity of aggregation at 30 days)/(intensity of aggregation at baseline).

To evaluate adherence and responsiveness to aspirin, which was defined as Agg_max < 20% following 0.5 mg/mL arachidonic acid stimuli, arachidonic acid-induced platelet aggregation was also assessed.

Results

A total of 64 subjects underwent platelet function assessment. Forty subjects had a suboptimal response to clopidogrel and were randomly assigned to either 75 or 150 mg/day of clopidogrel. The mean Agg_max was 66.2% ± 8% in the 40 subjects with suboptimal clopidogrel response at time point 1, compared with the mean Agg_max of 39.9% ± 8% in the remaining 24 subjects not eligible for randomization. Except for a slightly older age in subjects randomly assigned to receive the 150-mg/day dosage, subjects assigned to the 75-mg/day dosage (n = 20) and those assigned to the 150-mg/day dosage (n = 20) were similar with regard to baseline demographic characteristics. There were no changes in medical therapy, bleeding complications, or interruptions in clopidogrel or aspirin therapy because of side effects. All subjects were adherent and responsive to aspirin therapy.

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After the 20 mol/L ADP stimuli, Agg_max at study point 1 was similar between the 2 groups. As shown in Figure 1, subjects receiving the 150-mg/day dosage of clopidogrel had a marked decrease in Agg_max at study time point 2, compared with their baseline values and with subjects receiving 75 mg/day of clopidogrel. Among subjects receiving the 75-mg/day dosage, Agg_max values stayed the same between study time points 1 and 2. At study time point 2, the Agg_max decreased to < 50% in 8 subjects (40%) in the 150-mg group, whereas it remained unchanged in the 75-mg group.

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As shown in Figure 2, the 150-mg group had a higher IPA than the 75-mg group at study time point 2. An increase in IPA and a decrease in post-treatment platelet reactivity were shown for all subjects in the 150-mg group. Subjects in this group also returned to their baseline Agg_max values at study time point 3. There were no major differences in platelet aggregation in the 75-mg dosage group at all 3 study time points, indicating a suboptimal response with the standard dosing. Similar profiles were observed when platelet function assessments were evaluated considering Agg_max after 5 mol/L ADP stimuli and Agg_late after 5 and 20 mol/L ADP stimuli (data not shown).

Figure 2. Inhibition of maximal platelet aggregation between baseline (study

time point 1) and 30 days (study time point 2) assessed using 20 ìmol/L

adenosine diphosphate (ADP) stimuli in patients randomly assigned to 75-mg

(green bar) and 150-mg (blue bar) clopidogrel maintenance doses. Values are

expressed as percentage of platelet aggregation. Error bars indicate standard

deviations of the mean.

The P2Y₁₂ reactivity ratio was not significantly different between the 75mm and 150-mg dosage groups at baseline, but it was markedly decreased in the 150-mg group, at study time point 2. For subjects in the 75-mg group, the P2Y₁₂ reactivity ratio was relatively unchanged (Figure 3).

Discussion

The results of our study showed that platelet inhibition was increased with a 150-mg/day maintenance dosage of clopidogrel compared with the standard dosage of 75 mg/day. Discontinuation of the 150 mg/day dosage and a return to the 75 mg/day maintenance regimen resulted in a return to baseline values of all platelet function measures, indicating a dose-dependent effect of clopidogrel. The response to treatment with antiplatelet therapy varied, however, even though there was a general improvement in platelet function profiles in the higher maintenance dosage group, and a large percentage of subjects had persistent increased platelet reactivity.

Improved clinical outcomes are correlated with the addition of clopidogrel to aspirin therapy compared with aspirin treatment alone in high-risk patients.^1-3 Even with these improvements, patients with diabetes remain at high risk for ischemic events, possibly because of a suboptimal response to antiplatelet therapy.^13,14 A recurrence of ischemic events, including stent thrombosis, is associated with suboptimal clopidogrel-induced antiplatelet effects.⁵

The current recommended maintenance dosage of clopidogrel therapy is based on achieving a level of platelet inhibition similar to a dosage of 250 mg of ticlopidine (Ticlid) twice a day.⁵ This level, however, was not adjusted to take into account the pro-thrombotic setting of high-risk patients, such as those with type 2 diabetes. Compared with the usual loading dose of 300 mg of clopidogrel, higher loading doses (≥ 600 mg) have been shown to hasten and increase platelet inhibition and to improve short-term clinical end points.^5-7 These effects do not play a role in the long-term deterrence of ischemic events, however, as they are limited to the initial period of treatment. Findings of the current study show that the enhanced platelet inhibition is temporary, occurring only during administration of the higher dose of clopidogrel and confirm previous studies showing that the usual maintenance treatment regimen is suboptimal in many patients with type 2 diabetes.^13,14

Figure 3. P2Y₁₂ reactivity index at study time points 1 (T1) and 2 (T2) in

subjects randomly assigned to 75-mg (green bars) and 150-mg (blue bars)

clopidogrel maintenance doses. Values are expressed as percentages. Error

bars indicate standard deviations of the mean.

In patients with type 2 diabetes, platelet dysfunction may be the result of several mechanisms.¹⁵ The platelets of patients with type 2 diabetes are targets of the insulin-resistance phenomenon.^13-15 Upregulation of the P2Y₁₂ pathway, the target of the active metabolite of clopidogrel, and increased platelet reactivity may result from a diminished sensitivity to insulin. Additional mechanisms of platelet dysfunction include increased exposure to ADP, cytosolic levels of calcium, and platelet dysfunction.^13-15

According to current guidelines (class IIb indication, level of evidence C), the maintenance dosage of clopidogrel may be increased to 150 mg/day for patients in whom stent thrombosis may be disastrous or fatal if < 50% inhibition of platelet aggregation is shown.¹⁶ A comparable strategy may be used in clinical practice, although no data on the clinical or biological effectiveness of this treatment regimen exist. Despite our study showing improved platelet inhibition with the 150-mg clopidogrel maintenance dosage, 60% of subjects continued to have post-treatment platelet aggregation > 50%, which has been regarded as a therapeutic threshold for P2Y₁₂ inhibition.¹⁷ Our results emphasize the need for more successful antithrombotic approaches and possibly more individualized treatment.¹⁷ More studies are required to confirm the benefits of higher doses of maintenance therapy, stronger antiplatelet drugs, and individualized treatment.

Conclusions

Our study demonstrated that the standard maintenance dosage of 75 mg/day of clopidogrel resulted in a suboptimal response in subjects with type 2 diabetes. A 150-mg/day dosage of clopidogrel was shown to enhance platelet inhibition in this high-risk group; however, even with the higher maintenance dose of clopidogrel, many subjects continued to have high platelet aggregation levels. These findings indicate a need for more clinical studies examining the benefits of higher-dose maintenance regimens.