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(Stroke. 1995;26:597-601.)
© 1995 American Heart Association, Inc.

Articles

Effects of Picotamide, an Antithromboxane Agent, on Carotid Atherosclerotic Evolution

A Two-Year, Double-Blind, Placebo-Controlled Study in Diabetic Patients

Manlio Cocozza, MD; Tommaso Picano, MD; Ugo Oliviero, MD; Nicola Russo, MD; Vincenzo Coto, MD Massimo Milani, MD

From the IV Division of Internal Medicine, University of Naples; and the Cardiovascular Department, Sandoz Prodotti Farmaceutici SpA (M.M.), Milan, Italy.

Correspondence to Massimo Milani, MD, Cardiovascular Medical Department, Sandoz Prodotti Farmaceutici SpA, Via Arconati 1, 10135 Milano, Italy.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
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.

Key Words: thromboxane antagonist • antiplatelet agents • carotid artery disease • diabetes mellitus • ultrasonics

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
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

Top Abstract Introduction Subjects and Methods Results Discussion References

 
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.

Ultrasound Examination
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]x100, 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).

View larger version (7K): [in this window] [in a new window]   Figure 1. Diagram showing methods used for estimating plaque stenosis on echo Doppler evaluation. The linear formula is [(D-d)/D]x100 where d is the diameter of residual lumen at the plaque site and D is the diameter distal to the lesion. ICA, ECA, and CCA indicate internal, external, and common carotid artery, respectively.

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.

Blood Analysis
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).

Platelet Aggregation
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.

Statistical Analysis
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 ² 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.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
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.

View this table: [in this window] [in a new window]   Table 1. Baseline Clinical Characteristics of the Treatment Groups

View this table: [in this window] [in a new window]   Table 2. B-Mode Ultrasonographic Baseline Characteristics of the Treatment Groups

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.

View this table: [in this window] [in a new window]   Table 3. Mean Number of Lesions and Percent Stenosis Per Patient at Baseline and After 24 Months of Treatment

During the study, 21 new lesions appeared in the placebo group and 6 appeared in the picotamide group (P=.04; Mantel-Haenszel ² 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).

View this table: [in this window] [in a new window]   Table 4. Evolution of Percent Stenosis Over Time According to Plaque Type

Figs 2 and 3 show the evolution of carotid plaques in two patients (placebo, Fig 2; picotamide, Fig 3) at baseline and after 24 months of double-blind treatment.

View larger version (113K): [in this window] [in a new window]   Figure 2. Doppler sonographic scans of a placebo-treated patient (60 years old): top, baseline scan shows atherosclerotic soft plaque at the origin of internal carotid artery (stenosis of 40%); bottom, scan at month 24 shows mixed plaque with estimated 80% stenosis of the internal carotid artery.

View larger version (115K): [in this window] [in a new window]   Figure 3. Doppler sonographic scans of a picotamide-treated patient (67 years old): top, baseline scan shows mixed atherosclerotic plaque at bifurcation (stenosis of 30%); bottom, scan at month 24 shows no modification in the morphology and extent of stenosis.

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; ² test) (Table 5).

View this table: [in this window] [in a new window]   Table 5. Major Events in Patients Treated With Picotamide or Placebo

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
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.

	Acknowledgments

 
This study was supported by Sandoz Prodotti Farmaceutici SpA.

Received July 21, 1994; revision received December 26, 1994; accepted December 26, 1994.

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Top Abstract Introduction Subjects and Methods Results Discussion References

 

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This Article Abstract Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Cocozza, M. Articles by Milani, M. Search for Related Content PubMed PubMed Citation Articles by Cocozza, M. Articles by Milani, M. Pubmed/NCBI databases Compound via MeSH Substance via MeSH