Managing PAD with multiple platelet inhibitors: The effect of combination therapy on bleeding time

Purpose: Patients with lower-extremity peripheral arterial disease (PAD) face a high risk of cardiovascular morbidity and mortality. Platelet inhibition (PI) significantly reduces this risk. Combination PI is common and increasingly indicated in patients with PAD; however, the effect on platelet function has not been objectively evaluated. Aspirin (ASA), clopidogrel (Clop), and cilostazol (Cilo) are the three most commonly used PI drugs in patients with PAD. A prospective, sequential evaluation of platelet function using the template bleeding time (BT) was performed for PAD patients taking these medications singly and in combination. Methods: Twenty-one patients with PAD, averaging 65.9 years of age, were studied. Patients were placed on sequential two-week regimens of the following therapies: washout (no PI), ASA (325 mg daily), ASA + Cilo (100 mg twice daily), washout, Cilo, Cilo + Clop (75 mg each day), washout, Clop, Clop + ASA, and Clop + ASA + Cilo. At the end of each phase, trained personnel measured the BT. Results: Baseline bleeding time for the group was 4.29 +/- 1.69 minutes. ASA (BT = 6.64 +/- 3.52) and Clop (BT = 10.17 +/- 5.4) significantly prolonged bleeding time (P < 0.01); however, no significant effect was observed with Cilo alone (BT = 5.41 +/- 2.69). Combined treatment with ASA + Clop (BT = 17.39 +/- 4.59) had a more pronounced effect on BT compared with either agent alone (P < 0.01). The addition of Cilo to either ASA (BT = 8.3 +/- 4.27) or Clop (BT = 12.7 +/- 7.46) or the combination of ASA + Clop (BT = 17.92 +/- 4.69) did not prolong BT. Conclusion: All patients with PAD require platelet inhibition, and many require pharmacotherapy for intermittent claudication. The platelet inhibitors aspirin and clopidogrel are used for the reduction of ischemic events. They significantly prolong bleeding time individually and to a greater extent in combination. Cilo is used to improve walking distance in patients with intermittent claudication. When Cilo is added to ASA, Clop, or the combination of the two, there is no additional increase in bleeding time. Therefore, Cilo can be used in combination with other platelet inhibitors without an additional effect on platelet function as reflected by the bleeding time.