The Journal of International Medical Research 1991; 19: 202 - 209
Indobufen versus Placebo in the Prevention of Restenosis after Carotid Endarterectomy: a Double-blind Pilot Study C. Pratesi', R. PuIlP, G. MilanesF, M. Lavezzari", F. Pamparana' and D. Bertinl' 'Department a/Vascular Surgery, University 0/ Florence, Florence, Italy;2Medical Department, Farmitalia Carlo Erba, Milan, Italy
A randomized clinical trial was undertaken to assess the efficacy of indobufen in inhibiting platelet adhesiveness in carotid thromboendarterectomy. The patients were treated under double-blind conditions with indobufen and with placebo, and were then assessed by means of scintigraphy with labelled platelets, ultrasonic tomography and angiography for a minimum follow-up period of 6 months. Haematological and clinical assessments were also performed. The results ofthe study suggest that platelet accumulation in carotid endarterectomy may be an early sign of restenosis; anti-aggregant treatment with indobufen carried out at an early stage prior to surgery inhibited platelet accumulation. The tinal result showed that anti-aggregant treatment had a positive influence on the short- and medium-term outcome of carotid endarterectomy. KEY WORDS: lndobufen; anti-aggregant treatment; carotid stenosis; platelet adhesiveness; thrombo-endarterectomy; restenosis.
INTRODUCTION
n a varying number of cases the natural course of a cerebral ischaemic attack may be aggravated by the onset of a stroke, the pathogenesis of which may be either haemodynamic or embolic. More
I
Received for publication 22 October 1990; accepted 4 February 1991. Address for correspondence: Professor C. Pratesi, Cattedra di Chirurgia Vascolare, Policlinico Careggi, Viale Morgagni 85,50134 Firenze, Italy.
202
importance is attached nowadays to these factors than to the spasm, which was originally thought to play a decisive role. It should also be stressed that perhaps the most frequent cause of repeated ischaemic episodes leading to a stoke is an embolism, as demonstrated by studies into the relationship between the type of lesion at the carotid bifurcation and the clinical outcome. In this respect, it is also necessary to take into account the important role played by intra- and extracranial collateral vessels in compensating for possible stenotic le© Copyright 1991 by Cambridge Medical Publications Ltd
Indobufen after carotid endarterectomy
sions and, thus, reducing the number of lesions that are pathogenic. The various treatments for dealing with events that could lead to a stroke include the use of anticoagulants and anti-aggregants, as well as a surgical approach basically involving carotid endarterectomy. The decision to adopt anyone of these treatments in preference to the others will naturally depend on many factors: the clinical symptoms (since an episode of the vertebrobasilar type will require a different approach from that adopted, for example, for an ingravescent carotid type); the morphology of the lesion as revealed by ultrasonic tomography or angiography; the condition of the patient; and the existence of any associated risk factors. Account must also be taken of the possibility (usually quite remote) of a stroke occurring either immediately or soine time after carotid endarterectomy. A common cause of strokes immediately after carotid endarterectomy is an embolism caused by incorrect arterial preparation or by inappropriate insertion of a shunt during surgery. Another cause is an ischaemic mechanism linked either to a lack of interhemispherical compensation during the clamping of the carotid or to a thrombosis caused by surgery. When strokes occur some time after endarterectomy,the cause would appear to be restenosis with the many complex problems linked to the event: the true extent of its influence, which varies considerably according to the type of follow-up; the pathogenetic interpretation; and the ways of preventing, or at least reducing, the severity of the stroke. Once the possible causes of a serious cerebral ischaemic attack have been examined, it is necessary to evaluate the methods proposed for its prevention. In view of the ischaemic mechanism, an important factor appears to be correct use of the intraluminal shunt in order to avoid the above complications: the shunt should be inserted only after performing a rapid endarterectomy
with continual control of its patency. As far as the prevention of restenosis is concerned, angioplasty would appear to be useful in either autologous or heterologous material, either as a routine measure for all patients or at least for high-risk patients, e.g. women, those with small carotid arteries, smokers and dyslipidaemics. It must be borne in mind, however, that the use of an intraluminal shunt or angioplasty may result in thrombosis in the area operated upon, I especially if there is a simultaneous drop in pressure, as often happens after surgery at the carotid bifurcation, or ifthere is a variation in the 'local haemostasis' resulting from the surgical operation itself. Lusby et al? reported their experiences with 17 patients who had been subjected to scintigraphic examination with Illindiumlabelled platelets 3, 24 and 48 h afterthromboendarterectomy. Regardless of whether or not they had been treated with anti-aggregants, all the patients were found to be positive in every scan, except for one who had received continous infusion of heparin sodium. Patients who had previously undergone operations on the contralateral carotid artery suffered no platelet aggregationduring thrombo-endarterectomy, apart from one case where the first operation had been carried out only 3 days before the second. After 3 days labelled platelet deposition was still reported but after 8 - 10days it was no longer present. The study by Lusby et al.,2 however, was not randomized and did not include details of patient follow-up; in some patients treated with acetylsalicylic acid no prevention of local aggregation was observed with respect to patients who had not been treated with anti-aggregants. Vitacchiano et at? evaluated platelet accumulation using III indium-labelledplatelets in 20 patients, 10 of whom had been treated with ticlopidine before and after surgery. They found large areas of hyperaccumulation in 40% of the untreated patients and small areas of slight accumulation in 30% of the treated patients. Monitoring 203
C. Pratesi, R. Pulli, G. Milanesi et at.
was performed 1 and 24 h after re-infusion of labelled platelets, which took place I h after thrombo-endarterectomy, i.e. at an early stage. The results of controls tested at 15 and 21 days were no longer positive. Of the patients in the untreated group with slight accumulation at the site of thromboendarterectomy, one suffered a transient ischaemic attack on the first day. Each of the groups included three cases of patch applicationbut no differenceswere recorded with regard to local platelet aggregation. Ehringer et al/: performed a randomized study of the effect of acetylsalicylic acid on a group of 30 patients subjected to thrombo-endarterectomy of the carotid bifurcation and compared the results with those from a homogeneous placebo group of 32 patients. The operations were performed without patches or shunts. The acetylsalicylic acid-treated group showed less platelet aggregation than the control group, as observed by ultrasonic tomography at various time intervals up to 8 weeks following surgery. There was a higher incidence of intra-operative bleeding in the acetylsalicylic acid-treated patients, necessitating more accurate haemostasis. In view of these findings it was decided to carry out a controlled study to examine platelet function and platelet deposition at the site of endarterectomy in two groups of patients: one group was treated with indobufen, a new anti-platelet drug;" and the other parallel group received placebo. PATIENTS AND METHODS
Patients A total of 20 patients between the ages of 50 and 70 years were admitted to the study. All patients displayed symptoms of stenosis and had been treated by means of endarterectomy followed by angioplasty, some receiving polytetrafluoroethylenegrafts and the remainder receiving autologous vein graft, and having had the same anaesthesia. The criteria for excluding patients from the study were: previous vascular surgery 204
other than endarterectomy; severe obesity or diabetes; expected survival of less than 12 months; intestinal malabsorption; hypertension with diastolic pressure > 115 mmHg; known or suspected allergic hypersensitivity to drugs in general and to salicylates, phenylpropionates and indoleacetates in particular; peptic ulcer; severe renal or hepatic insufficiency; chronic refractory anaemia or haemorrhagic diathesis; women being treated with oestrogens/progestogens; and treatment with drugs likely to influence platelet aggregation and/or coagulation. Study design The protocol involved the administration of 400 mg/day indobufen for the antiaggregant group of patients, starting 2 days prior to surgery (following a suitable washout period), with a follow-up of at least 6 months. In addition to the normal laboratory examinations, the following studies were also performed: a scintigraphic map using III indium (according to the method of Heaton et al. 6 ) after thrombo-endarterectomy; platelet aggregation both in vivo according to the method of Born 7 (collagen and adenosine diphosphate inducers) and with radioimmunological doses of platelet factor 4 and ~-thromboglobulin; bleeding time; platelet kinetics;" and serum fibrinogen concentrations. In order to evaluate local morphological modifications,real-time ultrasonic tomography was performed 1, 3 and 6 months after the operation. Angiography was performed intra-operatively in all cases, as is the normal practice at the end of surgery, in order to ensure removal of carotid obstructions. The protocol also included venous angiography to be performed as a control at the end of the study and in the event of neurological symptoms or on the basis of the results of the ultrasonic tomography. Scintigraphic analysis with Illindiumlabelled platelets was carried out 7 days after operation - the results were always
Indobufen after carotidendarterectomy positive during the first few days but any aggregation remaining after 7 days was indicative of enhanced interaction between platelets and the vessel wall following thrombo-endarterectomy. Statistical analysis Data were analysed by Student's t-test for paired data. RESULTS
A comparison of the two treatment groups of patients showed equal distribution with regard to sex (nine men and one women in each group), age (average 63.3 years in the group treated with indobufen and 63.0 years in the placebo treatment group) and atherosclerotic risk factors such as smoking, diabetes, hypertension and dyslipidaemia. The need for surgery was indicated by neurological disorders, i.e. transitory ischaemic attacks, occurring in the carotid region. On average the amount of time
between the last neurological episode and surgery was basically the same in both treatment groups. The morphological features of the carotid lesion as observed by angiography were: in the indobufen-treated group seven cases of serrated stenosis and three of ulcerated plaques, and in the placebo-treated group four cases of serrated stenosis and six of ulcerated plaques. During the operation no complications due to technical problems arose in any of the patients and the nature of the anaesthesia was the same in all cases. Angiographic analysis at the end of the operation showed no endarterectomy-related effects and none of the patients showed neurological disturbances when they recovered from the anaesthetic. Reduction in bleeding time, as observed after 8 days and 6 months in the placebotreated group and the increase recorded after the same periods in the indobufen-
•
Indobufen
D
Placebo
** P
Indobufen versus Placebo in the Prevention of Restenosis after Carotid Endarterectomy: a Double-blind Pilot Study C. Pratesi', R. PuIlP, G. MilanesF, M. Lavezzari", F. Pamparana' and D. Bertinl' 'Department a/Vascular Surgery, University 0/ Florence, Florence, Italy;2Medical Department, Farmitalia Carlo Erba, Milan, Italy
A randomized clinical trial was undertaken to assess the efficacy of indobufen in inhibiting platelet adhesiveness in carotid thromboendarterectomy. The patients were treated under double-blind conditions with indobufen and with placebo, and were then assessed by means of scintigraphy with labelled platelets, ultrasonic tomography and angiography for a minimum follow-up period of 6 months. Haematological and clinical assessments were also performed. The results ofthe study suggest that platelet accumulation in carotid endarterectomy may be an early sign of restenosis; anti-aggregant treatment with indobufen carried out at an early stage prior to surgery inhibited platelet accumulation. The tinal result showed that anti-aggregant treatment had a positive influence on the short- and medium-term outcome of carotid endarterectomy. KEY WORDS: lndobufen; anti-aggregant treatment; carotid stenosis; platelet adhesiveness; thrombo-endarterectomy; restenosis.
INTRODUCTION
n a varying number of cases the natural course of a cerebral ischaemic attack may be aggravated by the onset of a stroke, the pathogenesis of which may be either haemodynamic or embolic. More
I
Received for publication 22 October 1990; accepted 4 February 1991. Address for correspondence: Professor C. Pratesi, Cattedra di Chirurgia Vascolare, Policlinico Careggi, Viale Morgagni 85,50134 Firenze, Italy.
202
importance is attached nowadays to these factors than to the spasm, which was originally thought to play a decisive role. It should also be stressed that perhaps the most frequent cause of repeated ischaemic episodes leading to a stoke is an embolism, as demonstrated by studies into the relationship between the type of lesion at the carotid bifurcation and the clinical outcome. In this respect, it is also necessary to take into account the important role played by intra- and extracranial collateral vessels in compensating for possible stenotic le© Copyright 1991 by Cambridge Medical Publications Ltd
Indobufen after carotid endarterectomy
sions and, thus, reducing the number of lesions that are pathogenic. The various treatments for dealing with events that could lead to a stroke include the use of anticoagulants and anti-aggregants, as well as a surgical approach basically involving carotid endarterectomy. The decision to adopt anyone of these treatments in preference to the others will naturally depend on many factors: the clinical symptoms (since an episode of the vertebrobasilar type will require a different approach from that adopted, for example, for an ingravescent carotid type); the morphology of the lesion as revealed by ultrasonic tomography or angiography; the condition of the patient; and the existence of any associated risk factors. Account must also be taken of the possibility (usually quite remote) of a stroke occurring either immediately or soine time after carotid endarterectomy. A common cause of strokes immediately after carotid endarterectomy is an embolism caused by incorrect arterial preparation or by inappropriate insertion of a shunt during surgery. Another cause is an ischaemic mechanism linked either to a lack of interhemispherical compensation during the clamping of the carotid or to a thrombosis caused by surgery. When strokes occur some time after endarterectomy,the cause would appear to be restenosis with the many complex problems linked to the event: the true extent of its influence, which varies considerably according to the type of follow-up; the pathogenetic interpretation; and the ways of preventing, or at least reducing, the severity of the stroke. Once the possible causes of a serious cerebral ischaemic attack have been examined, it is necessary to evaluate the methods proposed for its prevention. In view of the ischaemic mechanism, an important factor appears to be correct use of the intraluminal shunt in order to avoid the above complications: the shunt should be inserted only after performing a rapid endarterectomy
with continual control of its patency. As far as the prevention of restenosis is concerned, angioplasty would appear to be useful in either autologous or heterologous material, either as a routine measure for all patients or at least for high-risk patients, e.g. women, those with small carotid arteries, smokers and dyslipidaemics. It must be borne in mind, however, that the use of an intraluminal shunt or angioplasty may result in thrombosis in the area operated upon, I especially if there is a simultaneous drop in pressure, as often happens after surgery at the carotid bifurcation, or ifthere is a variation in the 'local haemostasis' resulting from the surgical operation itself. Lusby et al? reported their experiences with 17 patients who had been subjected to scintigraphic examination with Illindiumlabelled platelets 3, 24 and 48 h afterthromboendarterectomy. Regardless of whether or not they had been treated with anti-aggregants, all the patients were found to be positive in every scan, except for one who had received continous infusion of heparin sodium. Patients who had previously undergone operations on the contralateral carotid artery suffered no platelet aggregationduring thrombo-endarterectomy, apart from one case where the first operation had been carried out only 3 days before the second. After 3 days labelled platelet deposition was still reported but after 8 - 10days it was no longer present. The study by Lusby et al.,2 however, was not randomized and did not include details of patient follow-up; in some patients treated with acetylsalicylic acid no prevention of local aggregation was observed with respect to patients who had not been treated with anti-aggregants. Vitacchiano et at? evaluated platelet accumulation using III indium-labelledplatelets in 20 patients, 10 of whom had been treated with ticlopidine before and after surgery. They found large areas of hyperaccumulation in 40% of the untreated patients and small areas of slight accumulation in 30% of the treated patients. Monitoring 203
C. Pratesi, R. Pulli, G. Milanesi et at.
was performed 1 and 24 h after re-infusion of labelled platelets, which took place I h after thrombo-endarterectomy, i.e. at an early stage. The results of controls tested at 15 and 21 days were no longer positive. Of the patients in the untreated group with slight accumulation at the site of thromboendarterectomy, one suffered a transient ischaemic attack on the first day. Each of the groups included three cases of patch applicationbut no differenceswere recorded with regard to local platelet aggregation. Ehringer et al/: performed a randomized study of the effect of acetylsalicylic acid on a group of 30 patients subjected to thrombo-endarterectomy of the carotid bifurcation and compared the results with those from a homogeneous placebo group of 32 patients. The operations were performed without patches or shunts. The acetylsalicylic acid-treated group showed less platelet aggregation than the control group, as observed by ultrasonic tomography at various time intervals up to 8 weeks following surgery. There was a higher incidence of intra-operative bleeding in the acetylsalicylic acid-treated patients, necessitating more accurate haemostasis. In view of these findings it was decided to carry out a controlled study to examine platelet function and platelet deposition at the site of endarterectomy in two groups of patients: one group was treated with indobufen, a new anti-platelet drug;" and the other parallel group received placebo. PATIENTS AND METHODS
Patients A total of 20 patients between the ages of 50 and 70 years were admitted to the study. All patients displayed symptoms of stenosis and had been treated by means of endarterectomy followed by angioplasty, some receiving polytetrafluoroethylenegrafts and the remainder receiving autologous vein graft, and having had the same anaesthesia. The criteria for excluding patients from the study were: previous vascular surgery 204
other than endarterectomy; severe obesity or diabetes; expected survival of less than 12 months; intestinal malabsorption; hypertension with diastolic pressure > 115 mmHg; known or suspected allergic hypersensitivity to drugs in general and to salicylates, phenylpropionates and indoleacetates in particular; peptic ulcer; severe renal or hepatic insufficiency; chronic refractory anaemia or haemorrhagic diathesis; women being treated with oestrogens/progestogens; and treatment with drugs likely to influence platelet aggregation and/or coagulation. Study design The protocol involved the administration of 400 mg/day indobufen for the antiaggregant group of patients, starting 2 days prior to surgery (following a suitable washout period), with a follow-up of at least 6 months. In addition to the normal laboratory examinations, the following studies were also performed: a scintigraphic map using III indium (according to the method of Heaton et al. 6 ) after thrombo-endarterectomy; platelet aggregation both in vivo according to the method of Born 7 (collagen and adenosine diphosphate inducers) and with radioimmunological doses of platelet factor 4 and ~-thromboglobulin; bleeding time; platelet kinetics;" and serum fibrinogen concentrations. In order to evaluate local morphological modifications,real-time ultrasonic tomography was performed 1, 3 and 6 months after the operation. Angiography was performed intra-operatively in all cases, as is the normal practice at the end of surgery, in order to ensure removal of carotid obstructions. The protocol also included venous angiography to be performed as a control at the end of the study and in the event of neurological symptoms or on the basis of the results of the ultrasonic tomography. Scintigraphic analysis with Illindiumlabelled platelets was carried out 7 days after operation - the results were always
Indobufen after carotidendarterectomy positive during the first few days but any aggregation remaining after 7 days was indicative of enhanced interaction between platelets and the vessel wall following thrombo-endarterectomy. Statistical analysis Data were analysed by Student's t-test for paired data. RESULTS
A comparison of the two treatment groups of patients showed equal distribution with regard to sex (nine men and one women in each group), age (average 63.3 years in the group treated with indobufen and 63.0 years in the placebo treatment group) and atherosclerotic risk factors such as smoking, diabetes, hypertension and dyslipidaemia. The need for surgery was indicated by neurological disorders, i.e. transitory ischaemic attacks, occurring in the carotid region. On average the amount of time
between the last neurological episode and surgery was basically the same in both treatment groups. The morphological features of the carotid lesion as observed by angiography were: in the indobufen-treated group seven cases of serrated stenosis and three of ulcerated plaques, and in the placebo-treated group four cases of serrated stenosis and six of ulcerated plaques. During the operation no complications due to technical problems arose in any of the patients and the nature of the anaesthesia was the same in all cases. Angiographic analysis at the end of the operation showed no endarterectomy-related effects and none of the patients showed neurological disturbances when they recovered from the anaesthetic. Reduction in bleeding time, as observed after 8 days and 6 months in the placebotreated group and the increase recorded after the same periods in the indobufen-
•
Indobufen
D
Placebo
** P
