Results of the randomized, placebo-controlled clopidogrel and acetylsalicylic acid in bypass surgery for peripheral arterial disease (CASPAR) trial.

OBJECTIVE: Dual antiplatelet therapy with clopidogrel plus acetylsalicylic acid (ASA) is superior to ASA alone in patients with acute coronary syndromes and in those undergoing percutaneous coronary intervention. We sought to determine whether clopidogrel plus ASA conferred benefit on limb outcomes over ASA alone in patients undergoing below-knee bypass grafting. METHODS: Patients undergoing unilateral, below-knee bypass graft for atherosclerotic peripheral arterial disease (PAD) were enrolled 2 to 4 days after surgery and were randomly assigned to clopidogrel 75 mg/day plus ASA 75 to 100 mg/day or placebo plus ASA 75 to 100 mg/day for 6 to 24 months. The primary efficacy endpoint was a composite of index-graft occlusion or revascularization, above-ankle amputation of the affected limb, or death. The primary safety endpoint was severe bleeding (Global Utilization of Streptokinase and Tissue plasminogen activator for Occluded coronary arteries [GUSTO] classification). RESULTS: In the overall population, the primary endpoint occurred in 149 of 425 patients in the clopidogrel group vs 151 of 426 patients in the placebo (plus ASA) group (hazard ratio [HR], 0.98; 95% confidence interval [CI], 0.78-1.23). In a prespecified subgroup analysis, the primary endpoint was significantly reduced by clopidogrel in prosthetic graft patients (HR, 0.65; 95% CI, 0.45-0.95; P = .025) but not in venous graft patients (HR, 1.25; 95% CI, 0.94-1.67, not significant [NS]). A significant statistical interaction between treatment effect and graft type was observed (P(interaction) = .008). Although total bleeds were more frequent with clopidogrel, there was no significant difference between the rates of severe bleeding in the clopidogrel and placebo (plus ASA) groups (2.1% vs 1.2%). CONCLUSION: The combination of clopidogrel plus ASA did not improve limb or systemic outcomes in the overall population of PAD patients requiring below-knee bypass grafting. Subgroup analysis suggests that clopidogrel plus ASA confers benefit in patients receiving prosthetic grafts without significantly increasing major bleeding risk.

Sustained bilateral hemodynamic benefit of contralateral carotid endarterectomy in patients with symptomatic internal carotid artery occlusion.

BACKGROUND AND PURPOSE: We sought to investigate whether in patients with a symptomatic internal carotid artery (ICA) occlusion, endarterectomy of a severe stenosis of the contralateral carotid artery can establish long-term cerebral hemodynamic improvement. METHODS: Nineteen patients were studied on average 1 month before and 6 months after contralateral carotid endarterectomy (CEA). Volume flow in the main extracranial and intracranial arteries was measured with MR angiography. Collateral flow via the circle of Willis and the ophthalmic arteries was studied with MR angiography and transcranial Doppler sonography, respectively. Cerebral metabolism and CO(2) vasoreactivity were investigated with MR spectroscopy and transcranial Doppler sonography, respectively. Twelve nonoperated patients with a symptomatic ICA occlusion and contralateral ICA stenosis, who were matched for age and sex, served as control patients. RESULTS: In patients who underwent surgery, flow in the operated ICA increased significantly (P:<0.05) and flow in the basilar artery decreased significantly (P:<0.01) after CEA. On the occlusion side, mean flow in the middle cerebral artery increased significantly from 71 to 85 mL/min (P:<0.05) after CEA. The prevalence of collateral flow via the anterior communicating artery to the occlusion side increased significantly (47% before and 84% after CEA; P:<0.05), while the prevalence of reversed ophthalmic artery flow on the operation side decreased significantly (42% before and 5% after CEA; P:<0.05). In the hemisphere on the side of the ICA occlusion, lactate was no longer detected after CEA in 80% of operated patients, whereas it was no longer detected over time in 14% of nonoperated patients (P:<0.05). CO(2) reactivity increased significantly in operated patients in both hemispheres (P:<0.01). CONCLUSIONS: Contralateral CEA in patients with a symptomatic ICA occlusion induces cerebral hemodynamic improvement not only on the side of surgery but also on the side of the ICA occlusion.

Cerebral metabolism of patients with stenosis of the internal carotid artery before and after endarterectomy.

Occlusion or severe stenosis, with a reduction in the diameter of more than 70% of the extracranial arteries may lead to hpoperfusion of the brain with an increased risk of cerebral infarction. The aim of this study was to investigate whether endarterectomy of stenosed internal carotid arteries leads to alternations in cerebral metabolism in regions in which no infarcts were visible with magnetic resonance imaging (MRI). We studied 10 healthy control subjects and 20 patients with transient or nondisabling cerebral ischemia with MRI and 1H magnetic resonance spectroscopic imaging. All patients underwent carotid endarterectomy. Patients were examined 1 week before and 3-6 months after carotid endarterectomy. The N-acetyl aspartate (NAA)/choline ratio in the symptomatic hemisphere before endarterectomy (2.29 +/- 0.42) was significantly (p < 0.001) lower than for control subjects (3.18 +/- 0.32). In five of the patients lactate was detected preoperatively in regions that were not infarcted. The NAA/choline ratio in the symptomatic hemisphere of these five patients did not increase significantly after endarterectomy (1.99 +/- 0.22 vs. 2.23 +/- 0.48). The NAA/choline ratio in patients without lactate preoperatively increased significantly (p < 0.01) after endarterectomy to a normal level (from 2.39 +/- 0.42 to 2.92 +/- 0.52). These results indicate that the presence of cerebral lactate may predict whether the NAA/choline ratio increases after carotid endarterectomy.

Cerebral metabolic differences between the severe and critical hypoperfused brain.

Occlusion or severe stenosis, with a reduction in the diameter of the extracranial arteries of more than 70%, may lead to hypoperfusion of the brain with an increased risk of cerebral infarction. The aim of this study was to investigate whether a decrease in metabolism in noninfarcted hypoperfused cerebral areas is correlated with the level of hypoperfusion. Fifty-one patients without infarcts, with borderzone infarcts, with territory infarcts, and fourteen healthy control subjects were investigated with MRI and MR spectroscopic imaging. The NAA/choline ratio in the symptomatic hermisphere was significantly decreased in patients with borderzone infarcts compared with patients without infarcts, with patients with territory infarcts, and with control subjects. Furthermore, patients with borderzone infarcts had a relatively high frequency of cerebral lactate. These results indicate that there might be a lower limit of hypoperfusion that can be measured indirectly with MR spectroscopic imaging, below which irreversible cerebral damage occurs.

Tissue factor expression on mesothelial cells is induced during in vitro culture--manipulation of culture conditions creates perspectives for mesothelial cells as a source for cell seeding procedures on vascular grafts.

Lining the luminal surface of prosthetic small diameter bypasses with endothelial cells (EC) will lower its thrombogenicity. Unfortunately, human EC are only scarcely available. Mesothelial cells (MC) have antithrombotic properties in vivo and can be harvested in large numbers, from the omentum. Recent work demonstrated that the expression of tissue factor (TF) is induced in MC after isolation and culture. Different culture conditions were studied to suppress TF-expression. MC grown in pooled human serum (HS) are procoagulant (717 +/- 119 pM factor Xa/min.10(5) cells). Replacing HS for fetal calf serum, precoating the surface with extracellular matrix and the addition of the xanthine-oxidase inhibitor allopurinol, inhibited TF expression by 90% (p < 0.001). Allopurinol clearly reduced TF-mRNA levels. TF expression on cultured MC is an in-vitro effect due to culture conditions and the formation of oxygen free radicals. By reducing TF expression by 90%, we have established conditions in which MC are a good alternative for EC for seeding on synthetic grafts.

Photoplethysmography reexamined: lack of correlation with duplex scanning.

In a prospective study a comparison was made between the results of photoplethysmography and ultrasonic duplex scanning in 151 consecutive legs with swelling, aching, and suspected venous insufficiency. Thirty-four percent of the legs had a history of previous deep venous thrombosis, 26% had undergone previous superficial vein surgery, and 11% had active or healed ulceration. Photoplethysmographic findings were normal in 86 (57%) of these legs and indicated deep venous disease in 33 (22%). With duplex scanning, incompetent vein segments were found in 140 legs (93%). The kappa coefficient of agreement between the result, classified as either normal, superficial disease only, or deep incompetence, was 0.12 +/- 0.06. In legs with superficial disease, the number of incompetent levels was no greater in legs with abnormal results of photoplethysmography than in legs with normal results of photoplethysmography. In general, an abnormal photoplethysmographic result is related to multilevel reflux and the presence of visible skin changes. Photoplethysmography had the same value, in these patients, to predict the presence of multilevel reflux as had inspection of the skin of the goiter area. These results do not warrant the continued use of photoplethysmography for surgical decision making in patients with suspected venous insufficiency.

Digital video subtraction angiography and duplex scanning in assessment of carotid artery disease: comparison with conventional angiography.

Digital video subtraction angiography (DVSA) and duplex scanning were compared to conventional angiography with regard to their accuracy in quantifying internal carotid artery disease. A classification of 108 carotid arteries available for comparison was made into five groups: normal (14), stenosis to 20% (15), stenosis from 20% to 49% (19), stenosis from 50% to 99% (44), and occlusion (16). The overall agreement corrected for chance (K) for DVSA was 0.738 +/- (SE) 0.049, which was better than for duplex scanning (K = 0.610 +/- 0.055). For hemodynamically significant disease (greater than or equal to 50% diameter reduction), both techniques were highly accurate: DVSA had a sensitivity of 95% (57/60) and a specificity of 92% (44/48); the sensitivity of duplex scanning was also 95% (57/60) and the specificity 85% (41/48). The accuracy in differentiating between high-grade stenosis and occlusion was 98% (59/60) for duplex scanning and 100% (60/60) for DVSA. The most prominent limitation of duplex scanning was its overestimation of disease in normal and minimally diseased arteries. Its specificity for ruling out any degree of disease was only 21% (3/14). DVSA had a poor predictive value of a normal test, 55% (12/22), and was more than one category wrong seven times, while this occurred only three times for duplex scanning. At the present time carotid endarterectomy without conventional angiography is only advocated when there is complete agreement between DVSA and duplex scanning.

Criteria for interpretation of ocular pneumoplethysmography (Gee).

Ocular pneumoplethysmography (OPG) (Gee) is one of the most widely used tests for evaluation of carotid artery disease. Its usefulness depends on its diagnostic accuracy, which depends on the criteria used for interpretation of OPG tracings. Application of different criteria as suggested in the literature by Gee et al, McDonald et al, Baker et al, Eikelboom, and O'Hara et al on 200 OPG tests compared with angiography resulted in variations of sensitivity from 70% to 95%, specificity from 70% to 94%, and overall accuracy from 75% to 90%. In validating OPG, one has to be aware of these substantial differences. We found the criteria of McDonald et al the most suitable for clinical use.

Increase in alpha rhythm frequency after carotid endarterectomy.

OBJECTIVES: Besides preventing stroke, carotid endarterectomy (CEA) is reported to improve cerebral circulation and brain function. We tested whether this improvement is reflected by changes in the qEEG. METHODS: qEEG changes in 166 patients with a >70% stenosis of the internal carotid artery (ICA) were assessed after subtraction of the preoperative and postoperative spectra (eyes closed condition) before and 3 months after CEA. The mean frequency of the alpha band (MFA), the peak frequency of the alpha band (F alpha), and bands with limits relative to each patient's F alpha were studied in relation to neurological symptoms, patency or occlusion of the contralateral ICA, shunt requirement, and side of surgery. RESULTS: MFA and F alpha significantly increased over both hemispheres. After alignment on F alpha, a decrease of spectral band power was seen below F alpha, and a band power increase above F alpha. The group of patients with a contralateral ICA occlusion showed significantly more improvement than the group without. The group of patients with neurological deficits showed a tendency for improvement. No differences were found concerning shunt requirement or the side of surgery. CONCLUSIONS: After CEA the alpha rhythm frequency increases. In general, patients with a contralateral ICA occlusion improve more than other patients, in agreement with data from the literature on cerebral circulation and brain function.

Axilloaxillary bypass for symptomatic stenosis of the subclavian artery.

Since the association has been made between stenosis of the subclavian artery and neurologic symptoms, controversy has existed over the preferred surgical procedure for bypass. In addition, concern has been raised regarding the long-term patency and effectiveness of this extraanatomic procedure in relieving neurologic symptoms. Twenty-seven patients underwent this operation for posterior cerebral symptoms between 1973 and 1982; 25 were followed for up to 77 months (mean 26 months). Twenty-two patients had complete relief of symptoms, although 3 of them required a subsequent carotid endarterectomy. Two other patients had partial relief, and one patient's symptoms remained unchanged. Upper extremity symptoms, present in nine patients, were relieved by the operation. All grafts remained patent during follow-up. Axilloaxillary bypass is a durable procedure for symptomatic stenosis of the subclavian artery. It is a low-risk procedure and is therefore particularly suited for older patients with associated carotid artery disease.

Chronic cerebral hypotension induces a downward shift of the cerebral autoregulation: a hypothesis based on TCD and OPG-GEE studies in ambulatory patients with occlusive cerebrovascular disease.

In order to establish whether or not the cerebral autoregulation is still effective at blood pressure rates in those who experience a chronic cerebral hypotension 37 patients were subjected to noninvasive CO2 enhanced transcranial Doppler (TCD) and ocular pneumoplethysmographic (OPG-GEE) studies of the middle cerebral and ophthalmic arteries. The patients demonstrating a combination of a unilateral patent internal carotid artery (ICA diameter reduction less than 49%) and a contra-lateral ICA occlusion based on duplex scan examinations were examined. The cerebral blood flow velocities at normocapnia (BFV) and pulsatility indices (PI) were measured by TCD. An equivalent of the reserve capacity of the cerebral autoregulation was estimated by quantification of the CO2 enhanced cerebral vasomotor reactivity (VMR). Cerebral blood pressure equivalents such as the OSP/BSP ratio and the ophthalmo-brachial systolic pressure (OBSP) index were estimated by measuring the ocular systolic blood pressure (OSP) and the systemic systolic blood pressure (BSP). The TCD and OPG-GEE data are both in the normal range distally to a patent ICA (n = 22). If the ICA is occluded the OPG-GEE data show a significant reduction in both OSP/BSP ratio's and OBSP indices. If the VMR was in the normal range, distally to an occluded ICA (n = 25), the pressure drop was mild and the BFV at rest was in the normal range. Nevertheless, the waveforms were more damped as seen from the reduction in pulsatility indices but the reduction did not reach statistical significance when compared to the PI values distally to a patent ICA.(ABSTRACT TRUNCATED AT 250 WORDS)

Near-infrared reflected spectroscopy and electroencephalography during carotid endarterectomy--in search of a new shunt criterion.

The aim of this clinical study was to evaluate cerebral oximetry with near-infrared reflected spectroscopy (NIRS) as a monitoring system during carotid endarterectomy. The cross-clamping changes of cerebrovascular hemoglobin oxygen saturation (cereb. O2 satn.) were compared with data from a processed EEG analysis. Using the EEG as the gold standard we try to define a new shunt criterion based on near-infrared spectroscopy. 102 patients were studied. During cross-clamping the percentual decrease of cereb. O2 satn. was calculated. The relation between EEG and cereb. O2 satn. is described in terms of sensitivity and specificity, and is graphically shown in a Receiver Operator Characteristic (ROC) curve. At a cut-off value of 5% decrease or more for the cereb. O2 satn., a sensitivity of 100% was found. However, the specificity was only 44%. Higher cut-off values resulted in a gradual increase of the specificity at the expense of a significant decrease of the sensitivity. In conclusion, improved validation and calibration techniques are necessary before this technique may be used for relevant assessment of cerebral oxygenation during carotid surgery. In particular, in order to define a new shunt criterion, the focal aspect of this new technique is probably one of the limitations.

Simultaneous extensive extracranial and coronary revascularization. Long-term follow-up up to 13 years.

Simultaneous surgery for extensive extracranial and coronary revascularization was performed in 168 patients (mean age 61 years), from 1974 up to June 1987; 116 patients (69%) were in NYHA class III or IV, 133 (79%) had triple vessel disease and 51 (30%) had left main stem lesions. One or more previous myocardial infarctions were present in 96 patients (57%); normal preoperative left ventricular function was present in only 35%. In 22 cases, additional cardiac procedures were performed. Symptomatic extracranial disease was present in 76 patients (45%), arch vessel surgery was performed in 29 (17%) and bilateral haemodynamically significant carotid disease was present in 58 (35%). Operative mortality (3%) was mainly cardiac and operative morbidity mainly neurological (7%). Actuarial survival at 5 years (75%) and 10 years (57%) was mainly determined by the cardiac survival (87% at 5 years and 70% at 10 years), while neurological follow-up deaths were rare (neurological survival 97% at 5 years and 91% at 10 years). Late morbidity was more cardiac than neurologically determined; actuarial curves showed 72% to be free of all serious events or death at 5 years, and 47% at 10 years.

Spectral analysis criteria in duplex scanning of aortoiliac and femoropopliteal arterial disease.

To validate the use of duplex scanning in the detection of lesions in the aortoiliac and femoropopliteal arteries, duplex scanning was prospectively compared to intra-arterial digital subtraction angiography in 61 patients with peripheral atherosclerotic disease. Based on a peak systolic velocity ratio greater than or equal to 2.5 or the absence of a Doppler signal, the overall sensitivity and specificity to detect lesions of greater than or equal to 50% diameter reduction was 84% and 96%, although some segments in the femoropopliteal arteries showed a sensitivity of only 60%-70%. Occlusions were detected with an overall sensitivity of 92% and specificity of 99%. The existence of a bi/triphasic Doppler signal, a window in the systolic spectral waveform and an end diastolic velocity greater than or equal to 60 cm/s has additional value in further grading of stenoses. This study shows that duplex scanning is highly comparable to angiography in the detection greater than or equal to 50% diameter reducing lesions in the aortoiliac arteries. Further evaluation is needed for the femoropopliteal arteries.

Ultrasonic duplex scanning in atherosclerotic disease of the innominate, subclavian and vertebral arteries. A comparative study with angiography.

Ultrasonic duplex scanning of the vertebral artery has a sensitivity of 0.80 and a specificity of 0.83 for the detection of an obstructive lesion of 50% or more at the site of the ostium. For the subclavian arteries these values are respectively 0.73 and 0.91. For both vessels the test has a very high negative predictive value of respectively 0.96 and 0.97. Therefore duplex ultrasound scanning is a reliable test in screening patients suspected of multi-level atherosclerotic disease of the extracranial cerebral vessels. The problem remains in classifying the degree of stenosis. In the case of the vertebral artery the sample volume of the pulsed Doppler is usually too large in relation to the vessel diameter. In the case of the subclavian and innominate artery one of the main problems is the range of the pulsed Doppler system. A subclavian steal syndrome is easily diagnosed without any special test.

Clinically unsuspected complications of arterial surgery shown by post-operative digital subtraction angiography.

Intravenous digital subtraction angiography was performed within 20 days of 678 vascular reconstructions as a routine post-operative evaluation. After 339 carotid endarterectomies, 34 patients showed a stenosis of greater than 30% and six occlusions were seen. In 157 patients after aortic aneurysm repair, we found five anastomotic aneurysms and seven stenoses of greater than 30%. After aortic bypass surgery, 77 patients were evaluated and nine stenoses were found; no anastomotic aneurysms were seen. In 105 patients with femoro-distal bypass procedures, occlusion was reported in 11 cases and stenosis in 13 cases. One patient had two anastomotic aneurysms. To summarize, major abnormalities were present in 81 cases (12.7%) and consisted of 59 stenoses of greater than 30%, 17 occlusions and six patients with anastomotic aneurysms. Most of these were unexpected and were reason for more critical follow-up or re-operation.

Contrast venography: from gold standard to 'golden backup' in clinically suspected deep vein thrombosis.

In a series of 180 patients, clinically suspected of having deep venous thrombosis (DVT), contrast venography was compared with radionuclide phlebography, duplex ultrasonography and strain gauge plethysmography. In most patients lung scintigraphy was also performed to detect pulmonary embolism (PE). Venography was performed on a routine basis. All venograms were read by at least two observers (radiologists or radiologist/resident) and an inter-observer agreement was reached of 96% with a kappa value of 0.935. In six patients venography was technically impossible or inadequate, 58% of the patients actually had DVT and 26% developed pulmonary embolism (PE). Of the patients with proven DVT, 43% developed PE. Of the three other methods duplex scanning scored the best for the detection of proximal thrombosis, with 92%, 90% and 9.2, and strain gauge plethysmography the worst, with values of 72%, 78% and 3.2 for, respectively, sensitivity, specificity and positive likelihood ratio's. On the basis of the presented material and the current literature it is concluded that the choice for a screening test for proximal thrombosis could best be made on the basis of (local) availability, cost-effectiveness and patient comfort. Duplex ultra-sonography is tipped as the most promising method, accepting that distal thrombosis (calf veins) does not play an important role in PE. Contrast venography should be used as a 'golden backup' in any case of doubt.

Ophthalmopneumoplethysmography (OPG-Gee) without and with bypass-compression for quantification of hemodynamic significance of superficial temporal artery-middle cerebral artery (STA-MCA) anastomosis.

The Extracranial-Intracranial (EC/IC) Bypass Procedure is a new method in order to try to increase the Intracranial Perfusion Pressure (ICPP). Postoperative patency of the bypass can be shown by means of Seldinger angiography. By this method no information however is obtained on the hemodynamic function of the bypass. OPG-Gee measures the Ophthalmic Artery Pressure (OAP) which is related to the ICPP. In this study OPG-Gee is performed without and subsequently with compression of the bypass. Quantification of the hemodynamic significance of the bypass is obtained by measuring the pressure decay in the ophthalmic arteries during this procedure. The Rest Pressure Difference (RPD), i.e. the pressure difference between the two ophthalmic arteries without bypass compression is measured. By subtracting the RPD from the BCD the remaining pressure is called the Net Bypass Pressure (NBP), i.e. the pressure difference, which the EC/IC bypass contributes to the ICPP. If, however, at constant systemic arterial blood pressure (SABP) the OAP drops during bypass compression on both sides, we hypothesize that the NBP is the sum of both drops, because, as a result of the interhemispheric steal mechanism, the less perfused hemisphere steals from the better perfused hemisphere. In a group of 40 patients OPG-Gee without and subsequently with bypass compression was applied. Twenty two of 40 OPG-Gee's showed NBP's of 4 mm of mercury or more (55%). In the group of 29 patients with unilateral internal carotid artery occlusion in 21 patients (72%) an NBP of 4 mm of mercury or more was found (mean of 13 mm of mercury).(ABSTRACT TRUNCATED AT 250 WORDS)

The accuracy of ultrasonic duplex scanning in carotid artery disease.

Ultrasonic duplex scanning of the internal carotid artery is highly accurate in the detection of disease as expressed in its sensitivity of 0.97 and specificity of 0.82 for haemodynamic significant lesions. For the detection of obstructions of 20% or over, these parameters are 0.94 and 0.77 respectively. The most striking problem is the poor classification of normal vessels and those with minor lesions. The duplex scanning overestimates the degree of disease in these cases. For the external carotid artery the method differentiates reasonably well between non-haemodynamic and haemodynamic significant lesions.

The hemodynamic significance of carotid coiling.

The cerebral perfusion pressure, as measured by ocular pneumoplethysmography (OPG-Gee), was used to evaluate the hemodynamic significance of carotid coiling in 25 patients, eight of whom had bilateral coiling. Positional studies were done with the head in the normal position and turned to the right and left. Seven of the 33 coilings (21%) were hemodynamically significant with the head in the normal position. A change in perfusion pressure when the head was turned was seen in 16 of 50 rotation studies (32%). There was a reduction in pressure in 11 instances and increase in five. In a control group of 24 subjects with normal angiograms, 18 of 48 studies (37%) showed a change in perfusion pressure with the head turned. Carotid coiling can be hemodynamically significant. Rotation of the head can compromise the carotid circulation whether coiling is present or not. OPG proved to be a simple means of evaluating the hemodynamic significance of carotid coiling and the effects of head rotation on the carotid circulation.