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Kamilova Sokhiba Eldarovna, Republican Specialized Scientific and Practical Medical Center For Therapy and Medical Rehabilitation, cardiologist, Interventional Cardiology Department E-mail: sahibak@mail.ru
COMPARATIVE EFFICACY OF PRASUGREL AND CLOPIDOGREL ON PLATELET HEMOSTASIS IN PATIENTS WITH DIABETES MELLITUS SUFFERING FROM A CRITICAL LOWER LIMB ISCHEMIA
Astract: Comparison of prasugrel and Clopidogrel on inhibition of platelet aggregation in patients with diabetes mellitus, suffering from a critical lower limb ischemia is examined in the article.
Keywords: prasugrel, clopidogrel, platelet aggregation, peripheral arterial disease.
Diabetes mellitus is a growing problem worldwide, and in the United States it is associated with an obesity [1, 2]. Diabetes is a major risk factor for the development of atherosclerosis and diffuse calcification of peripheral arteries [3], leading ultimately to critical ischemia, and then to amputation of the lower limb [4]. The pathological process affects the entire vascular system, especially the shin and foot arteries. The incidence of chronic arterial insufficiency (CHA) is from 3 to 12% [5]. Depending on the severity of atherosclerotic lesions, clinical complaints vary greatly, from classical intermittent claudication and the restriction of walking to ulceration or gangrene of the foot.
Therapy of peripheral artery disease (PAD) includes both medicamentous and endovascular treatment. Antithrombotic therapy is the cornerstone in this issue, and is aimed at reducing thrombotic complications.
Dual antiplatelet therapy (DAT), including a combination of acetylsalicylic acid (ASA) and clopidogrel, is recommended for all patients undergoing revascularization of the lower extremity arteries [6].
Despite a wide choice of drugs aimed at the treatment and prevention of thrombotic complications, the frequency of amputation of the lower extremities in individuals with PAD is still at a high level. Thus, in one study, a comparison was made of the frequency of high amputations in patients with or without diabetes mellitus. A 12-month observation showed that in the group with diabetes, the percentage of amputations significantly prevailed (3.16% vs. 0.46% p < 0.001). In the subgroup of individuals with critical ischemia, the frequency of amputation significantly increased (6.30% vs. 2.47%, p = 0.003) compared to the subgroup, suffering only intermittent claudication [7, 8].
A significant breakthrough in the treatment and prevention of thrombotic complications was the development of an alternative blocker of P2Y12 receptor platelets - prasugrel. In
currently studied doses, prasugrel inhibits platelet aggregation, adenosine-induced diphosphate is faster, more stable (reproducible) and to a greater extent than standard and even higher doses of clopidogrel, in both healthy and patients with coronary heart disease, including those who is subjected to percutaneous coronary interventions. When prasugrel and clopidogrel were compared in a second phase trial, patients who underwent urgent or "scheduled" percutaneous coronary interventions (JUMBO) showed a tendency toward a lower incidence of ischemic events in prasugrel with an acceptable safety profile.
Pharmacodynamical studies have shown that the degree of platelet aggregation achieved within 30 min after taking prasugrel is close to the peak effect of clopidogrel 6 hours after its administration [7, 8].
Aim. To compare the effectiveness of prasugrel and clopidogrel on adenosine diphosphate (ADP) - induced platelet aggregation in patients with diabetes mellitus suffering from a critical lower limb ischemia.
Material and methods. Subjects of the study were patients (n = 50) with diabetes mellitus (DM) having signs of chronic arterial insufficiency of the lower limbs. To achieve the goal of the study, a choice was made (50 patients suffering from PAD) with separation into two groups of 25 people (in group C was used clopidogrel and in group P - prasugrel as part of DAT). Both groups were comparable in age, severity of peripheral arterial lesions (according to the Fontaine-Pokrovsky classification) and the lesion segment (according to the dopplerography of the arteries of the lower extremities). Exclusion criteria (acute myocardial infarction, acute disturbance of cerebral circulation, ketoacidosis, terminal stage of renal failure, erosive diseases of the gastrointestinal tract). The diagnosis of the main nosological forms and their treatment were established on the basis of the generally accepted criteria set forth in the relevant recommendations for
Section 11. Medicine
the diagnosis and treatment of hypertension (AH) and coronary heart disease (CHD): ESC2017 and AHA / ACC2016 (diet, ACE inhibitors / ARB, beta -blockers, statins, preparations of acetylsalicylic acid, etc.). The average age of the patients was 65 years. In 86% of patients, dyslipidemia was detected. AH was diagnosed in 76%, and 22% of patients had a history of myocardial infarction. In the overwhelming majority of cases (n = 30), the severity of the lesions of the arteries of the lower extremities corresponded to the 3rd stage of the Fontaine-Pokrovsky classification (Table 1). In group C, a loading dose (LD) of clopidogrel 600 mg / single was applied with the transition to a maintenance dose (MD) of 75 mg / day. In group P, the LD of prasugrel was 60 mg / single with the transition to a maintenance dose of 10 mg / day. The observation period was 7 days. Aggregation activity of thrombocytes was evaluated 0, 4, 24 hours and after 7 days on the platelet aggregation analyzer LA 230 (Biola LLC, Russia). Blood sampling was collected from an antecubital vein into citrated tubes.
The statistical processing of the material was carried out using the "Statistics 6.0" software package. When creating the database, the Microsoft Excel 2016 editor was used. The results are expressed as the mean (M) and its standard deviation (g) for continuous values, the reliability factor (p) and as the percentage (percentage) for categorical variables (ie, describing qualitative features). Differences were considered significant at p < 0.05.
Results. 4 hours after taking the LD in group P, there was a significant decrease in platelet aggregation activity in comparison with that of group C (86.7% vs 29.5%, p < 0.0001). After 24 hours of taking MD of clopidogrel and prasugrel, the aggregation ability in group C decreased to 58.6%, and in group P, the degree of aggregation inhibition reached 89.8% (p < 0.0001). Seven days later, in the presence of MD of thi-enopyridine in both groups, there was some leveling of the
inhibition of aggregation, but with a significantly more significant effect in group P (72.6% vs. 60.4%, p < 0.0001) (Fig. 1). When 5.0 ^M of ADP was added to blood samples (before taking thienopyridines), the platelet aggregation activity in both groups did not differ significantly. However, after taking the LD (after 4 hours), the degree of maximal aggregation (MA) in group P was significantly lower, compared with the group C (25.7% vs 62.4%, p < 0.0001). After 24 hours MA in group C continued to prevail over that in the group P. 7 days later, the degree of MA in group C remained significantly higher (44.8% vs. 32.1%, p < 0.0001) (Fig. 2).
Table 1. - Baseline characteristics
Age (years), mean ± SD 65.3 ± 4.2
Body mass index (kg/m2), mean ± SD 30.7 ± 4.8
Current smoker 15(30.0)
Cardiovascular history, n (%)
Congestive heart failure 9(18)
Hypertension 38(76)
Hypercholesterolemia 43(86)
Prior myocardial infarction 11(22)
Duration of type 2 DM (years), mean ± SD 9.3 ± 4.5
Antihyperglycaemic medication, n (%)
Insulin 13(26.0)
Non-insulin 37(74)
Stage of the Fontaine Classification, n (%)
IIB 10(20)
III 30(60)
IV 10(20)
Arterial lesion by segment, n (%)
Femoral-popliteal segment 18(36)
Tibial segment 32(64)
Figure 1. Degree of suppression of platelet aggregation in both groups
Figure 2. The degree of maximum (ADP induced) platelet aggregation in both groups
Conclusions. The admission of prasugrel in DAT with acetylsalicylic acid in patients with DM suffering from lower limb ischemia led to a more rapid and pronounced inhibition of platelet activity. These findings may explain the clinical benefit observed with the appointment of prasugrel in patients
with critical ischemia of the lower extremities. The more rapid and persistent disaggregation effect of prasugrel allows to reduce preoperative preparation period (for endovascular treatment) and to "prevent" various thrombogenic complications that quite often occur in patients with DM.
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