Effects of Picotamide, an Antithromboxane Agent, on Carotid Atherosclerotic Evolution
A Two-Year, Double-Blind, Placebo-Controlled Study in Diabetic Patients
Background and Purpose We assessed the effects of long-term treatment with picotamide, an antiplatelet agent with dual antithromboxane activity, on the evolution of early asymptomatic carotid atherosclerotic lesions in diabetic patients.
Methods In a double-blind, placebo-controlled, 2-year study, 50 type II normotensive diabetic patients (35 men; mean age, 66±5 years) with asymptomatic mild or moderate nonstenotic (<50%) carotid atherosclerotic lesions and negative history of cerebrovascular ischemic events were enrolled and randomly given picotamide (300 mg TID) or the corresponding placebo. A high-resolution, real-time B-scan echographic assessment of carotid arteries was performed at baseline and after 1, 3, 6, 12, 18, and 24 months of double-blind treatment. Prevalence and evolutionary trends of carotid atherosclerotic lesions (number per patient and mean stenosis expressed as percent) were considered as efficacy primary end points.
Results At baseline, mean±SD numbers of carotid atherosclerotic lesions per patient were 2.7±1.8 and 2.2±1.2 in the picotamide and placebo groups, respectively. Mean±SD percent stenosis was 25.3±7% in the picotamide group and 27.3±6% in the placebo group. Forty-nine patients completed the study. At month 24, the placebo group (n=24) showed a significant progression in number of carotid atherosclerotic lesions (3.04±1.8; P<.02 versus baseline) and in mean percent stenosis (35±17%; 95% confidence interval, 33% to 37%; P<.01 versus baseline). In the picotamide group (n=25), mean number of carotid atherosclerotic lesions (2.7±1.6) and percent stenosis (26±9%; 95% confidence interval, 24.8% to 27.2%) remained unchanged. At month 24, compared with randomized placebo, lesion numbers (P<.03) and percent stenosis (P<.01) in the picotamide group were significantly lower. During the study, 12 patients experienced major or minor ischemic vascular events (9 in the placebo group and 3 in the picotamide group; P=.07).
Conclusions In diabetic patients compared with patients receiving placebo, long-term treatment with picotamide can slow the evolution of early carotid atherosclerotic lesions, inhibiting progression of plaque number and growth.
Diabetic patients have a higher incidence of atherosclerosis involving coronary, carotid, and peripheral arteries.1 Both in nondiabetic as well in diabetic subjects, atherosclerotic lesions in the extracranial carotid artery constitute a major risk factor for cerebrovascular ischemic events.2 Framingham data have shown that the incidence of thrombotic stroke is doubled in diabetic patients.3
Platelets and platelet-derived products play a key role in the evolution, progression, and complication of atherosclerotic lesions.4 In non–insulin-dependent diabetes mellitus, a platelet hyperactivity and an enhanced thromboxane A2 (TXA2) production have been demonstrated.5 TXA2 is the major biologically active metabolite of arachidonic acid produced by platelets and is a powerful platelet-activating and smooth muscle–contracting substance.6
Picotamide (Plactidil, Sandoz Prodotti Farmaceutici SpA) is an antiplatelet drug with an original dual mechanism of action: it inhibits TXA2 synthase and antagonizes the TXA2 receptor at equivalent concentrations while enhancing endothelial formation of prostacyclin.7 8 This dual activity results in a more effective inhibition of TXA2-mediated actions.9 10
High-resolution, real-time echotomography is considered a reliable and accurate method to assess atherosclerotic carotid artery lesions and is particularly suitable for monitoring the evolution of extracranial carotid atherosclerosis in longitudinal studies.11
The aim of this double-blind, randomized, placebo-controlled, 2-year study was to assess the effect of picotamide on the progression and evolution of asymptomatic mild or moderate (≤50% stenosis) extracranial carotid stenotic lesions in diabetic patients. Secondary end points were the effects of treatment on the rate of major and minor vascular events (ie, acute myocardial infarction, stroke, transient ischemic attack).
Subjects and Methods
The study was conducted between October 1989 and December 1993 at our division. A total of 210 diabetic subjects were screened to find eligible patients.
Fifty (35 men; mean age, 66±5 years) diabetic patients were enrolled after giving their informed consent. Approval was given by the local ethics committee. Main inclusion criteria were non–insulin-dependent diabetes mellitus in good glycemic control (fasting plasma glucose ≤7.8 mmol/L) and at least one asymptomatic, nonstenotic (<50% lumen narrowing) extracranial carotid atherosclerotic plaque. Exclusion criteria were age above 75 years, history of hypertension (sitting diastolic blood pressure ≥95 mm Hg or antihypertensive treatment), and/or positive history at baseline of major or minor vascular events (ie, unstable angina, myocardial infarction, transient ischemic attack, stroke) necessitating antithrombotic treatment.
Randomization and Treatment
Blocked randomization was performed with a block size of 4. Blinded treatment allocation was obtained by central randomization. Picotamide tablets or the corresponding placebo were given at a dosage of 300 mg three times daily. Concomitant treatment at baseline with antiplatelet drugs other than the study picotamide was not permitted.
Accompanying medication (hypoglycemic treatment with oral antidiabetic agents) was left unchanged during the study duration.
Carotid sonography was performed at entry and after 1, 3, 6, 9, 12, 18, and 24 months of the double-blind treatment following a standardized protocol. We used a real-time, high-resolution echo color Doppler vascular system (APOGEE CX, Interspec Inc) equipped with a multifrequency 7.5-MHz probe. The ultrasonographic examination was performed at the same time by two trained physicians (M.C., T.P.). Both observers examined each subject at the initial and the final examination.
Ultrasonographic scanning was performed with the patient in a supine position, with a mild rotation of the extended neck as described.12 The probe was placed along the vessel axis. The carotid arteries were explored with longitudinal (anterior, lateral, posterior) and transverse scan. Multiple long-axis and short-axis sections were defined, paying attention to define the endothelial border from the origin of the common carotid artery to beyond the carotid artery bifurcation. To indicate the exact site of the lesions, the extracranial carotid tract was divided into three sites for the common carotid (lower third, middle third, upper third), the bifurcation was considered one site, and the internal carotid was divided into its lower and upper halves. The external carotid was considered a separate site. The vessel was also designated as anterior, posterior, lateral, or medial. Whenever indicated, the distance of the lesion from the bifurcation was determined in millimeters. A mechanical calibrator pinpointed the lesion on the video screen, and this was videotaped for later analysis together with the echographic images and the operator’s commentary. Measurements were reproduced on follow-up examination using the same procedure.
The examiners attempted to use the same technique every time, with low gain settings to eliminate reverberation artifacts. Carotid plaques were visualized in real time. Short- and long-axis views were obtained for measurements. When a plaque was detected, it was examined in a series of cross-sectional scans to evaluate the angle of interrogation that would lead to a perpendicular longitudinal view at the site of maximal plaque thickness. Degree of stenosis was then calculated by comparing the residual lumen at the maximal extrinsic point of the plaque with the distal arterial segment using the following formula: [(D−d)/D]×100, where D is the vessel diameter distal to the plaque and d is defined as the smallest lumen diameter on the image that demonstrated the most severe luminal narrowing (Fig 1⇓).
Color and pulsed-wave Doppler were used to assess flow characteristics in each vessel.13 Variance color Doppler images were obtained with the maximal frame rate. In all studies, the sound spectral analysis waveforms were recorded with beam angles of 30° to 60°. Maximum velocity was recorded distal to a plaque. Color and pulsed-wave Doppler data were used only to supplement echographic data to provide a comprehensive vascular estimate and not to calculate degree of stenosis. Lesion numbers, mean lesion numbers per patient, and extent of stenosis were calculated.
Soft plaques were defined as homogenous echo structures of low intensity. Hard plaques were defined as homogenous echo structures of high intensity and echo shadows.
Mixed plaques were defined as lesions with echo reflections of both high and low intensity with or without echo shadows.
Laboratory tests (blood cell and platelet count and levels of hematocrit, hemoglobin, glucose, total cholesterol, triglycerides, fibrinogen, and fibrinogen degradation products) were carried out at each visit.
Blood samples were drawn by clean venipuncture from the antecubital vein after a 12-hour overnight fast period. Serum total cholesterol and triglyceride levels were determined by enzymatic methods (Boehringer AG). Plasma fibrinogen was measured by the thrombin method of Clauss. Plasma fibrinogen/fibrin degradation products were measured using a latex agglutination assay (Hemodiagnostica Stago).
To assess patient compliance with the treatment, ex vivo platelet aggregation tests were performed at baseline and at 6, 12, 18, and 24 months. Platelet aggregation was studied in platelet-rich plasma using an Elvi 840 dual-channel aggregometer (Elvi Logos). Aggregating stimulus used was collagen (Diagnostica Stago) with a final concentration of 2 μg/mL. Platelet aggregation studies were performed exclusively by laboratory staff. Data regarding platelet aggregation were pooled and analyzed only at the end of the trial.
Main parameters were analyzed on an intention-to-treat basis. A mixed ANOVA model and a Wilcoxon score rank test were used for analysis of evolution and progression of plaque number and stenosis. For binary variables, modified χ2 tests were used. Student’s t test was used for the analysis of biochemical parameters. Values of P<.05 were considered significant. Results are reported as mean±1 SD.
Clinical baseline characteristics of the patients are shown in Table 1⇓. The two groups were well matched regarding the main variables considered (ie, age, smoking habits, lipid levels). Type, localization, and mean percent stenosis are shown in Table 2⇓.
At baseline, mean±SD number of carotid atherosclerotic lesions and percent stenosis of all lesions per patient were 2.2±1.2 (range, 1 to 4) and 27.3±6.4% in the placebo group and 2.7±1.8 (range, 1 to 5) and 25.3±7.2% in the picotamide group, respectively.
Forty-nine patients completed the 24-month study period. Because of ethical reasons, at month 24, 10 of 50 patients (8 in the placebo group and 2 in the picotamide group) were being treated with antiplatelet agents (acetylsalicylic acid or ticlopidine). One patient in the placebo group died because of malignant disease.
At month 24, the placebo group (n=24) showed a significant progression in mean carotid atherosclerotic lesion number (3.04±1.8; P<.02, Wilcoxon rank test versus baseline) and in mean percent stenosis (35±17%; P<.04, ANOVA). In the picotamide group (n=25), mean number of carotid atherosclerotic lesions and percent stenosis remained unchanged (Table 3⇓). At month 24, compared with the randomized placebo group, lesion number (P<.003) and percent stenosis (P<.001) in the picotamide group were significantly lower.
During the study, 21 new lesions appeared in the placebo group and 6 appeared in the picotamide group (P=.04; Mantel-Haenszel χ2 test). No significant modifications of plaque types were observed during the study in both groups. At month 24, the percentages of soft, hard, and mixed plaques were 16%, 42%, and 42% in the picotamide group and 14%, 65%, and 21% in the placebo group, respectively. In the placebo group, mixed plaques showed a more pronounced percent stenosis progression over time (from 24.4±15% at baseline to 40.5±17% at month 24; P<.005) compared with hard and soft plaque types (from 23.5±8% and 26.6±12% at baseline to 25.7±8% and 45.8±25%, respectively; P=NS).
In the picotamide group, no significant changes were observed in mean percent stenosis over time in each plaque-type group (from 29.1±9%, 30.1±17%, and 21.0±9% at baseline to 26.1±10%, 30.7±16%, and 21.4±15% at month 24 in mixed, hard, and soft plaques, respectively; P=NS) (Table 4⇓).
No differences were observed in blood cell count and levels of total cholesterol, triglycerides, plasma glucose, and fibrinogen. The number of smokers was slightly higher in the placebo group (n=12) compared with the picotamide group (n=8). This difference was not statistically significant. A similar extent of progression in lesion number and percent stenosis over time was observed in the placebo group, both in smokers as well as in nonsmoking subjects.
Collagen-induced platelet aggregation was significantly inhibited in more than 90% of the patients allocated to picotamide treatment at each time assessed (months 6, 12, 18, and 24). Compared with placebo, picotamide treatment significantly (P<.001, Student’s t test) enhanced levels of fibrinogen degradation product from the first month (placebo, 5±1 μg/mL; picotamide, 16±3 μg/mL).
During the study, 12 patients experienced major or minor ischemic vascular events or death (9 in the placebo and 3 in the picotamide group; P=.07; χ2 test) (Table 5⇓).
Non–insulin-dependent diabetic patients present a high prevalence of ultrasonographically assessed atherosclerosis compared with the nondiabetic population.1 Patients with extracranial carotid disease have a higher incidence of both cerebrovascular and coronary events.14 Framingham data have shown that the incidence of thrombotic stroke is doubled in diabetic subjects.3
Platelets play a key role in the genesis, evolution, and complications of atherosclerosis.15 Platelet hyperaggregability and high blood leukocyte count have been shown as strong predictors of carotid atherosclerosis progression.16 Platelet and monocyte involvement in the development of atherosclerosis is well established.4 15 The association of increased platelet aggregability with accelerated atherosclerosis supports their role in the early phase of plaque lesion progression also. TXA2, a platelet-derived eicosanoid, is a potent proaggregatory and vasoconstricting substance, and it is also involved in cell proliferation.6 It has been implicated as an important mediator of cardiovascular diseases.17 Enhanced production of TXA2 of platelet or monocyte/macrophage origin was demonstrated in patients with diffuse atherosclerosis,18 hypercholesterolemia,19 homocystinuria,20 and diabetes mellitus.5
In 27 atherosclerotic patients with small carotid lesions, 12-month treatment with 900 mg/d acetylsalicylic acid but not 50 mg/d seemed to slow carotid plaque growth.21
Picotamide is a new antiplatelet drug that both antagonizes TXA2 receptors and inhibits TXA2 synthase at equivalent concentrations. Picotamide reduces platelet and monocyte TXA2 production by 80% and 50%, respectively.10 Unlike aspirin, picotamide also exerts an antithromboxane action at extravascular sites such as the artery wall.10
In patients with peripheral atherosclerosis, picotamide significantly increased the walking distance and the ankle-arm pressure index.22 In a double-blind, randomized, multicenter, long-term study, picotamide significantly reduced the rate of vascular events in patients with peripheral occlusive arteriopathy.23
This is the first prospective, randomized, double-blind, placebo-controlled, long-term study assessing the effect of picotamide treatment on progression and evolution of nonstenotic carotid plaques in diabetic patients. Compared with placebo, long-term picotamide treatment can slow the evolution of early carotid atherosclerotic lesions in diabetic subjects, inhibiting progression and plaque growth and reducing the appearance of new lesions. Interestingly, in agreement with Hennerici et al,24 we observed that in patients receiving placebo mixed plaques showed a greater stenosis progression over time compared with hard and soft types. The inhibiting effects of picotamide on plaque progression were observed mainly in the mixed plaques.
Some study limitations have to be taken into account in evaluating these results. The relatively small sample size and the problems concerning sensitivity and reproducibility of ultrasound examination of atherosclerosis are the most relevant. However, we standardized the echo assessment procedures and used a double-blind, randomized, placebo-controlled study design.
At month 24, 10 patients (8 in the placebo and 2 in the picotamide group) were under treatment with open-label antiplatelet drugs (acetylsalicylic acid or ticlopidine). These treatments could have interfered with the progression of atherosclerotic lesions, which were the end points of the study. However, the open-label antiplatelet regimen was introduced after a mean of 18±2 months of double-blind treatment; furthermore, the number of patients treated with open-label antiplatelet regimen was higher in the placebo than in the picotamide group.
Therefore, any confounding effects could have reduced, instead of increased, the observed differences between the picotamide and placebo groups.
This study was supported by Sandoz Prodotti Farmaceutici SpA.
- Received July 21, 1994.
- Revision received December 26, 1994.
- Accepted December 26, 1994.
- Copyright © 1995 by American Heart Association
Chan A, Beach KW, Martin DC, Strandness DE. Carotid artery disease in NIDDM diabetes. Diabetes Care. 1983;6:562-569.
Garcia ML, McNamara PM, Gordon T, Kannel WB. Morbidity and mortality in diabetics in the Framingham population: sixteen year follow-up study. Diabetes. 1974;23:105-111.
Davı̀ G, Catalano I, Averna M. Thromboxane biosynthesis and platelet function in type II diabetes mellitus. N Engl J Med. 1990; 322:1769-1774.
Gresele P, Deckmyn H, Arnout J, Nenci GG, Vermylen J. Characterization of N,N′-bis(3-picolyl)-4-methoxy-isophtalamide (picotamide) as a dual thromboxane synthase inhibitor/thromboxane A2 receptor antagonist in human platelets. Thromb Haemost. 1989; 61:479-484.
Giustina A, Bossoni S, Cimino A, Comini MT, Gazzoli N, Leproux GB, Wehrenberg WB, Romanelli G, Giustina G. Picotamide, a dual Txb synthetase inhibitor and Txb receptor antagonist, reduces exercise-induced albuminuria in microalbuminuric patients with NIDDM. Diabetes. 1993;42:178-182.
Neri Serneri GG, Gensini GF, Poggesi L, Modesti PA, Rostagno GF, Boddi M, Gori AM, Martini F, Ieri A, Margheri M, Abbate R. The role of extraplatelet thromboxane A2 in unstable angina investigated with a dual thromboxane A2 inhibitor: importance of activated monocytes. Coron Artery Dis. 1994;5:137-145.
Zwiebel WJ. Introduction to Vascular Ultrasonography. Orlando, Fla: Grune & Stratton; 1986:171-216.
Norris JW, Zhu CZ, Bornstein NM, Chambers BR. Vascular risks of asymptomatic carotid stenosis. Stroke. 1991;22:1485-1490.
Davı̀ G, Violi F, Gresele P. Thromboxane biosynthesis and platelet function in patients with peripheral arterial disease. Thromb Res. 1992;65:144. Abstract.
Davı̀ G, Averna M, Catalano I, Barbagallo C, Ganci A, Notarbartolo A, Ciabattroni G, Patrono C. Increased thromboxane biosynthesis in type IIa hypercholesterolemia. Circulation. 1992; 85:1792-1798.
Di Minno G, Davı̀ G, Margaglione M, Cirillo F, Grandone E, Ciabattoni G, Catalano I, Strisciuglio P, Andria G, Patrono C, Mancini M. Abnormally high thromboxane biosynthesis in homozygous homocystinuria: evidence for platelet involvement and probucol-sensitive mechanism. J Clin Invest. 1993;92:1400-1406.
Ranke C, Hecker H, Creutzig A, Alexander K. Dose-dependent effect of aspirin on carotid atherosclerosis. Circulation. 1993; 87:1873-1879.
Coto V, Cocozza M, Oliviero U, Lucariello A, Picano T, Coto F, Cacciatore L. Clinical efficacy of picotamide in long-term treatment of intermittent claudication. Angiology. 1989;40:880-885.
Balsano F, Violi F, the ADEP Group. Effect of picotamide on the clinical progression of peripheral vascular disease: a double-blind placebo-controlled study. Circulation. 1993;87:1563-1569.