Reintervention as a clinical trial endpoint after peripheral arterial bypass surgery.

BACKGROUND: Graft patency is usually the primary endpoint in studies of peripheral arterial bypass surgery, but gives only a limited indication of clinical outcome. The aim of this study was to evaluate reintervention as a study endpoint after femorodistal bypass surgery. METHODS: The database from a multicentre, prospectively planned study of 517 patients undergoing femorodistal bypass for severe ischaemia was used to investigate the predictive value of technical endpoints. Clinical symptoms, graft patency, vascular interventions and clinical outcomes were recorded for 12 months after operation. RESULTS: Complete follow-up data were obtained on 498 patients (96 per cent). Success in terms of patients' need for reintervention agreed with clinical outcome in 90 (95 per cent confidence interval (c.i.) 87-93) per cent of cases. Primary and secondary patency agreed with the clinical outcome in 80 (95 per cent c.i. 77-84) and 81 (95 per cent c.i. 78-85) per cent of patients respectively. However, the best agreement with clinical outcome was obtained from the composite endpoint of 'patient alive without reintervention': 92 (95 per cent c.i. 90-94) per cent. CONCLUSION: Recording the number of patients who did not need reintervention for 12 months after femorodistal bypass gave a more accurate assessment of the number with clinical improvement than was obtained by recording bypass graft patency. Inclusion of patient survival in a composite endpoint increased the clinical relevance of this endpoint in patients with severe ischaemia who had femorodistal bypass surgery.

Incidence of stenoses in femorodistal bypass vein grafts in a multicentre study.

OBJECTIVES: To establish the incidence of graft stenosis in a large population of patients undergoing femorodistal bypass procedures and to investigate the differences in incidence between individual surgical centres and other subpopulations. PATIENTS AND METHODS: A total of 277 patients with femorodistal bypasses underwent duplex scanning of vein grafts for 12 months for the detection of graft stenoses. A standard definition of a significant stenosis was used in all twenty participating centres. RESULTS: Overall stenosis rate was 27%. Stenoses were more common in composite vein grafts (43%) than in single segment vein grafts (25%) p=0.05. Stenoses were more common in female patients (38%) than males (22%) p=0.02. Stenosis rates in individual centres entering more than 20 patients varied from 9% to 56%. In a multiple regression analysis only aspirin use, sex and centre were significant factors predicting the likelihood of graft stenosis. CONCLUSION: Female patients, those taking aspirin and patients with composite vein grafts appear to be more at risk of graft stenosis, but this does not fully explain wide variations in the incidence of stenoses reported by individual centres.

Association of sex with patency of femorodistal bypass grafts.

OBJECTIVE: There is evidence for superior patency in infra-inguinal bypass procedures in men compared to women. A large, prospectively planned series was investigated in order to confirm this finding and to determine the origin of this difference in outcome. METHODS: Patients underwent femorodistal bypass surgery and a prospectively planned 12-month follow-up. Outcomes in male and female patients were compared and investigated for associations with characteristics of the patients and the surgical procedures. RESULTS: A total of 517 patients received femorodistal bypass grafts, including 424 vein grafts and 93 prosthetic and vein-prosthetic composite grafts. Patency was confirmed to be higher in male than in female patients (56% vs. 42%, p=0.005). Fewer male patients received prosthetic or composite grafts (21% vs. 33%, p=0.005), but the difference in patency was evident only in patients receiving vein grafts. Female patients were smaller, included fewer smokers (p<0.001) and had worse symptoms (p=0.03), but none of these characteristics explained the difference in outcome. Patency in vein grafts was associated with graft diameter (p=0.004), but graft diameter was not significantly associated with sex (p=0.09) or with body size. CONCLUSIONS: It was confirmed that patency of femorodistal bypasses is significantly higher in males than females. None of the factors investigated here explain this difference, but the greater use of prosthetic and composite grafts in female patients suggests that poorer vein quality should be investigated as a possible source of the inferior outcome in female patients.

Antithrombotic agents after peripheral transluminal angioplasty: a review of the studies, methods and evidence for their use.

OBJECTIVE: to review published studies and assess the strength of the evidence for the use of antithrombotic agents for the prevention of re-occlusion after peripheral angioplasty. METHODS: a literature search was performed. All randomised comparative studies with patency assessments or clinical endpoints were included. The methods and results of the studies were compared and evaluated. RESULTS: eleven randomised trials were identified, six of them were double blind. The majority of patients included were those with femoropopliteal lesions. A significant benefit of aspirin in one placebo-controlled study is balanced by no apparent benefit in another study. No dose-dependent effect of aspirin in the range 50-1000 mg/day has been shown in any of the four studies investigating such an effect. None of the three studies comparing platelet inhibitors and oral anticoagulants have shown any differences in outcome and no other well-designed studies of anticoagulants have been reported. CONCLUSIONS: evidence for a reduction in the likelihood of re-occlusion or restenosis after peripheral transluminal angioplasty with platelet inhibitors remains equivocal. Evidence for the efficacy of any other agent in this indication is also lacking.

Graft material and results of platelet inhibitor trials in peripheral arterial reconstructions: reappraisal of results from a meta-analysis.

AIMS: To investigate the characteristics of published trials in order to establish the origin of the differing results obtained in trials of platelet inhibitors after peripheral bypass procedures. METHODS: Analysis of the information from 11 randomised, controlled trials of platelet inhibitors after peripheral bypass procedures published up until 1999 and involving 2302 patients undergoing peripheral bypass operations, 1250 of whom were treated with platelet inhibitors. RESULTS: There is a significant treatment benefit of platelet inhibitors on meta-analysis of the trials, but a significant heterogeneity amongst the individual trial results. The proportion of patients in a trial with prosthetic grafts was a significant factor in explaining the heterogeneity. Proportion of prosthetic grafts was associated with sample size and with the proportion of grafts above the knee, but these were not found to make an independent contribution to the heterogeneity observed. The platelet inhibitor regimen used, the severity of ischaemic symptoms and the proportion of smokers included were also not found to be important. CONCLUSIONS: The improvement of graft patency by aspirin and related platelet inhibitors in clinical trials in peripheral bypass procedures can be attributed to an effect on patients with prosthetic grafts. There is little evidence that these agents prevent occlusion of vein grafts. The conclusion of an earlier meta-analysis that antiplatelet agents should be used for all bypasses is not supported.

Pharmacokinetics of oral iloprost in patients with Raynaud's phenomenon secondary to systemic sclerosis.

Iloprost is a chemically stable, pharmacologically highly potent prostacyclin-minietic. The therapeutic efficacy of the intravenous preparation was proven in patients with peripheral arterial occlusive disease or with Raynaud's phenomenon (RP). Recently, a sustained release oral preparation was developed for outpatient therapy. The purpose of the current study was to investigate whether the oral drug has a different pharmacokinetic profile in patients with RP secondary to systemic sclerosis (SSc) in comparison with healthy volunteers. Ten patients with RP secondary to SSc and 10 healthy volunteers (matched for age and sex) participated. Oral iloprost 50 microg was given twice daily for 8 days with dosing intervals of 5 h and plasma levels were taken over 10 h on Day 1 and 8. Plasma levels of iloprost were determined by a validated specific and sensitive radio-immunoassay. Compared with healthy volunteers, patients with SSc exhibited higher AUC values (by mean factors of 2. 1 and 2.0 on Day 1 and 8) and maximum plasma levels (by mean factors of 1.6 and 1.8 on Day 1 and 8). The increased systemic iloprost exposure was observed after both daily doses and on both monitored study days. Mean AUC values did not show accumulation over the 8 days. These findings are in agreement with a reduced total clearance of iloprost given by i.v. route in SSc patients compared to healthy volunteers, although no participant with severe renal impairment was included. A weak but significant correlation was found between individual creatinine clearance and AUC values. In conclusion, RP secondary to SSc is associated with an increased systemic iloprost exposure which is probably caused by changes of the metabolic clearance of iloprost. These effects cannot be explained by changes of renal function alone.

Adjuvant medical therapy in peripheral bypass surgery.

BACKGROUND: A review was conducted of published clinical trials of adjuvant medical therapy in infrainguinal bypass procedures to evaluate the strength of the evidence for the use of various agents. METHODS: Trials were identified by literature search. The methods used were reviewed and the results with each agent tested were assessed taking into account the soundness of the study design. RESULTS: Thirty-three studies were identified; fewer than half had a randomized and double-blind design. Most were single-centre studies including a mixture of different surgical procedures and patients with varying degrees of lower limb ischaemia. Clinical outcomes were seldom reported. The median sample size was 61. The median follow-up duration was 12 months, but was often not standardized for all patients in a trial. Only aspirin in prosthetic grafts and ticlopidine in vein grafts have been shown in well designed, double-blind, randomized, controlled trials to reduce the likelihood of occlusion in infrainguinal bypass grafts. CONCLUSION: The majority of the trials reviewed had significant deficiencies in their design, reducing the reliance that can be placed on their results. Further studies are required to investigate adequately the effectiveness of existing medical therapies for the maintenance of infrainguinal bypass grafts.

Seasonal variation of Raynaud's phenomenon secondary to systemic sclerosis.

OBJECTIVE: Patients with systemic sclerosis (SSc) were assessed for 12 months to quantify the seasonal variation in Raynaud's phenomenon (RP) in patients with an underlying connective tissue disease. METHODS: Eighteen patients with SSc (17 limited, 1 diffuse type) were studied. Raynaud's attacks were recorded in a daily diary for four 2-week periods at 3 month intervals. Daily number and duration of attacks and overall severity of RP were calculated for each 2-week period. Mean daily temperatures, measured and perceived, were obtained for each period. RESULTS: In winter, patients had a mean of 2.9 attacks/day (SD +/-1.1), daily duration 70 minutes (SD +/-48) and a severity of score of 4.1 (SD +/-2.0) out of 10. All 3 variables correlated with ambient outdoor temperature and varied significantly over the 12 months (p<0.001) with mean reductions of 48, 50, and 56% respectively from winter to summer. Only 3 of 18 patients reported no attacks during the summer period. The mean measured and perceived outdoor temperatures increased from winter to summer by 10.6 and 14.3 degrees C, respectively. CONCLUSION: For patients with SSc, RP is a problem throughout the year. Symptoms may be reduced by about 50% in the summer months, but few patients experience complete relief.

Relationship of femorodistal bypass patency to clinical outcome. Iloprost Bypass International Study Group.

OBJECTIVE: To investigate the relationship between bypass patency, limb survival and clinical symptoms after femorodistal bypass procedures. DESIGN: Multicentre, prospectively planned 12-month postoperative follow-up. PATIENTS AND METHODS: Five hundred and seventeen patients undergoing femorodistal bypass surgery for severe ischaemia. Clinical symptoms, bypass patency were recorded at regular intervals up to 12 months postoperatively. RESULTS: Complete follow-up data was obtained on 498 patients (96%). Fifty-six (17%) of the 341 patients with patent bypasses had either rest pain or ulcers or had undergone major amputation at 12 months. Of the 167 patients with an occluded bypass, 22 patients (13%) had improved clinical symptoms and a total of 59 patients (35%) had avoided major amputation at 12 months. The clinical outcome for patients classified preoperatively as Fontaine stage IV was significantly worse than for those in stage III preoperatively despite similar bypass patency rates. CONCLUSIONS: There is a fair correlation between technical and clinical outcome after femorodistal bypass surgery at 12 months, but there are significant numbers of patients with occluded bypasses who have a good clinical outcome and of patients with patent bypasses who have a poor clinical outcome. The reporting of symptoms in addition to bypass patency would aid the interpretation of surgical results.

Oral iloprost in Raynaud's phenomenon secondary to systemic sclerosis: a multicentre, placebo-controlled, dose-comparison study.

OBJECTIVE: To identify the optimal dose of oral iloprost on the basis of efficacy and tolerability in patients with Raynaud's phenomenon secondary to systemic sclerosis. DESIGN: Multicentre, randomized, parallel-group comparison of two different doses of oral iloprost and placebo. SETTING: European university hospitals. PATIENTS: A total of 103 patients with Raynaud's phenomenon secondary to systemic sclerosis. INTERVENTION: Patients received one of three treatments for 6 weeks: placebo, oral iloprost 50 microg or oral iloprost 100 microg. Each treatment was taken twice daily, giving total daily doses of iloprost of 100 and 200 microg. MEASUREMENTS: The frequency, total daily duration and severity of Raynaud's attacks were recorded in a specially designed patient diary; physician's global assessment and adverse events were recorded at visits to the clinic. Analysis was performed on an intention-to-treat population. RESULTS: A total of 103 patients were recruited, 89 completed the assessments throughout the treatment period and 82 completed an additional 6 weeks of follow-up after treatment. Thirty-five patients received placebo, 33 received iloprost 50 microg and 35 received iloprost 100 microg. The mean percentage reductions in the frequency, total daily duration and severity of Raynaud's attacks were numerically greater in the iloprost groups at the end of treatment and at the end of follow-up. At the end of treatment (6 weeks), there were significant treatment differences in the total daily duration of attacks (P = 0.03), but not in the severity (P = 0.07) or the frequency of attacks (P = 0.37). At the end of follow-up (12 weeks), there were significant treatment differences in the total daily duration of attacks (P = 0.001) and in the severity of attacks (P = 0.007), but not in the frequency of attacks (P = 0.07). Percentages of patients improved at the end of treatment as assessed by the physician were 44% placebo, 57% iloprost 50 microg and 64% iloprost 100 microg (not significant). Side-effects were reported by 80% of patients on placebo, 85% on oral iloprost 50 microg and 97% on oral iloprost 100 microg. Premature discontinuations of treatment in each group were 9, 30 and 51%, respectively, with 6, 27 and 51% being due to adverse events. CONCLUSION: The results on the daily duration of Raynaud's attacks suggest that both 50 and 100 microg oral iloprost twice daily may be effective in the treatment of Raynaud's phenomenon secondary to systemic sclerosis. The 50 microg iloprost dose was better tolerated in this patient group.

The effects of platelet inhibitors on platelet uptake and restenosis after femoral angioplasty.

OBJECTIVE: To investigate the effects of two platelet inhibitors, aspirin and iloprost, on platelet uptake and restenosis at the site of angioplasty in patients undergoing femoral or popliteal angioplasty. EXPERIMENTAL DESIGN: Prospective, open, randomised group comparison. SETTING: Two university hospitals. PATIENTS: 43 patients undergoing femoral or popliteal angioplasty were randomised. INTERVENTIONS: Patients received either aspirin (300 mg/day), iloprost (8 hours/day i.v. infusion) or no antiplatelet medication during angioplasty and on the subsequent two days. MEASURES: Platelet uptake was measured using 111Indium-labelled platelets. Restenosis was assessed by repeat angiography at 3 months and clinical symptoms up to 12 months. RESULTS: Median changes in platelet uptake were similar in the three treatment groups, but all platelet radioactivity ratios > 2.0 occurred in the control group. Restenosis at 3 months was observed in 3 control, 5 aspirin and 1 iloprost patient. Further surgical intervention was performed in 3 control and 3 aspirin patients, but in none of the iloprost patients up to 12 months after angioplasty. CONCLUSIONS: Antiplatelet therapy may prevent large increases in platelet deposition at the angioplasty site, but the link between platelet deposition and restenosis was not substantiated in this study.

Pharmacokinetics and pharmacodynamics of intra-graft iloprost in femorodistal bypass surgery.

Intra-graft injection of the prostacyclin analogue, iloprost, was performed at the end of femorodistal bypass procedures in 12 patients with severe peripheral arterial occlusive disease. Iloprost plasma levels were measured and compared with changes in haemodynamics. There was a high initial iloprost plasma level (mean 625 pg/ml) which dropped to a mean of 50 pg/ml after 15 min. This correlated with an immediate reduction in systolic blood pressure which had returned to pretreatment levels after 15 min. In contrast, the vascular resistance distal to the graft showed a reduction after 5 min which was maintained for at least 20 min after iloprost injection and the mean blood flow through the graft increased steadily throughout the same period of measurement. The study showed an effect of iloprost on blood pressure which correlated with plasma levels, but the time course of the changes in distal vascular resistance and graft blood flow demonstrated an effect more prolonged than the half-life of iloprost.

Iloprost reduces peripheral resistance during femoro-distal reconstruction.

A randomised placebo-controlled trial was conducted to investigate the effect of iloprost, a stable prostacyclin mimetic, on peripheral resistance during femoro-distal bypass. Patients undergoing femoro-distal long saphenous vein bypass for critical ischaemia received 3000 ng of iloprost or placebo infused into the graft via an unligated side branch over 2 min. Graft blood flow and peripheral resistance were measured for 20 min, using an operative Doppler flowmeter (OpDop 130, SciMed, U.K.) and a pressure transducer to record graft pressure. Postoperatively, graft blood flow was assessed by daily duplex ultrasound for 7 days. Iloprost produced an immediate drop in peripheral resistance in all cases (n = 18) by a mean (range) of 40% (4-80%) compared with controls (n = 15) in whom there was a 5.3% (-8 to +36%) increase in resistance (p less than 0.01, Wilcoxon test). Decreased peripheral resistance in iloprost-treated patients persisted to 20 min. The largest decreases in peripheral resistance occurred in patients with the highest initial resistances (r = 0.56, p less than 0.02). Graft flow during the same period increased by 52% (-7 to 294%) compared with controls in whom there was a 6% (-17 to 26%) increase in flow, (p less than 0.01). Flow remained elevated by 53% over baseline values at 1 week post-infusion in the iloprost-treated group but this did not achieve statistical significance compared to controls in whom flow also increased by 13%. Iloprost produces an immediate decrease in peripheral resistance associated with a prolonged increase in graft blood flow. This may reduce graft failure in the early postoperative period.

Iloprost in cardiopulmonary bypass procedures.

The inhibition of platelet aggregation during cardiopulmonary bypass and effects on post-operative placebo-controlled study of 145 patients. Significant preservation of platelet numbers and function were shown without significant haemodynamic problems, but no effect on cerebral deficits could be found. The use of iloprost in patients with severe thrombocytopenia seems justified, but the clinical benefits from its use in routine cardiopulmonary bypass remain to be shown.

Pharmacokinetics of intragraft iloprost infusion during femoro-crural reconstruction.

Pharmacokinetics of a single intra-graft infusion of 3000ng iloprost during femoro-crural bypass surgery have been investigated. Plasma iloprost concentrations, biphasic half-lives, and total drug clearances were found to occur within ranges demonstrated for IV infusion dose regimens.

A double blind, randomised, multicentre comparison of two doses of intravenous iloprost in the treatment of Raynaud's phenomenon secondary to connective tissue diseases.

OBJECTIVE: To compare low (0.5 ng/kg/min) and standard dose (2 ng/kg/min) iloprost (a stable carbacyclin analogue of prostacyclin) in patients with Raynaud's phenomenon secondary to connective tissue disorders. DESIGN: Double blind, random allocation, three six hour infusions on consecutive days. Follow up period eight weeks. SETTING: Rheumatology units, five teaching hospitals. PATIENTS: 55 Patients with Raynaud's phenomenon (greater than seven attacks per week), 32 secondary to well documented classical progressive systemic sclerosis (American Rheumatism Association criteria), 11 CREST syndrome, 5 mixed connective tissue disease, 1 rheumatoid arthritis, 1 Sjögren's syndrome, 1 childhood dermatomyositis, and 4 abnormal nailfold capillaroscopy and antibody profiles but no definite diagnosis. INTERVENTIONS: All other treatment for Raynaud's phenomenon was discontinued two weeks before entry. 28 Patients were randomly allocated to receive the low dose, 27 the standard dose. Differing dilutions allowed infusion rates to be started at 10 ml/h with increments of 10 ml/h every 15 minutes until infusion rates reached 0.5 ng/kg/min and 2 ng/kg/min respectively. MAIN OUTCOME MEASURE(s)--Reduction in frequency, duration, and severity of attacks of Raynaud's phenomenon. Assessment of ulcer and ischaemic lesion healing. RESULTS: Both dosage regimens were equally effective in reducing severity, frequency, and duration of Raynaud's attacks. Ulcer healing occurred to similar degree in both treatment groups (standard dose 44%, low dose 39%). Low dose was associated with significantly fewer side effects. CONCLUSIONS: Both dosage regimens reduce severity of Raynaud's phenomenon and encourage ulcer healing. Low dose was associated with fewer side effects and was better tolerated by the patients.

Retrospective comparison of iloprost with other treatments for secondary Raynaud's phenomenon.

One hundred and twenty seven patients who had Raynaud's attacks secondary to connective tissue disease received intravenous infusions of iloprost in controlled clinical trials. Results of previous treatments for Raynaud's attacks had been recorded by clinicians in 84 of these cases, allowing a comparison to be made with the response to iloprost treatment. Iloprost was reported by the patients as beneficial in 49 (58%) of 84 cases, whereas only 36 (43%) of the 84 patients had previously found any other treatment to be useful. Twenty four of 48 (50%) patients who had not responded to any previous treatment found iloprost to be of benefit. Success or failure of treatment with iloprost was not accurately predicted by the result of treatment with any other drug, except prostacyclin. This survey suggests that iloprost is a useful treatment for patients with severe secondary Raynaud's phenomenon and can be effective in patients unresponsive to other treatments.

Iloprost improves femoro-distal graft flow after a single bolus injection.

A double-blind, randomised, placebo-controlled trial was conducted to study the effect of the stable prostacyclin analogue iloprost on femoro-distal graft blood flow. After completing femoro-distal reconstruction, 3000 ng of iloprost or placebo was injected into the graft over 2 min. Graft blood flow, measured by electromagnetic flowmetry, increased by a mean (range) of 94% (12 to 192%) in patients receiving iloprost (n = 15) compared to 6% (-34 to 53%) in controls (n = 16; p less than 0.0001, t-test). Increased graft flow, measured by duplex ultrasound, was maintained in the iloprost group over a 7 day period postoperatively (F = 5.2, p = 0.03; analysis of variance) and remained higher at 7 days (p = 0.007, t-test). Iloprost produces an immediate, sustained increase in graft blood flow after femoro-distal reconstruction and may therefore be of benefit in reducing the incidence of early graft failure.

Metabolic investigations with Femodene--an oral contraceptive containing gestodene and ethinyloestradiol.

The metabolic effects of a new oral contraceptive Femodene (SHD 356C) containing 75 micrograms gestodene (delta-15-levonorgestrel) and 30 micrograms ethinyloestradiol were studied in two groups of women. Group 1 consisted of women not currently using oral contraceptives; Group 2 consisted of women switching to Femodene from their current oral contraceptive. Changes in lipid metabolism were assessed by measuring serum levels of cholesterol, triglycerides, LDL-C, VLDL-C, HDL-C, HDL2-C and HDL3-C. Minimal changes occurred in lipid metabolism apart from increases in triglyceride concentrations. Women in Group 1 showed a 105% increase in SHBG levels and a 51% increase in caeruloplasmin levels compared to increases of 33% and 2% in women in Group 2. A comparison of the two groups of women suggested that the gestagen in Femodene exerted a less anti-oestrogenic effect than most of the gestagens currently used in oral contraceptives. No significant changes occurred in liver function (assessed by estimation of gamma-glutamyl transferase) or in the coagulation factors, Factor X and antithrombin III. Minor effects on glucose tolerance as assessed by blood glucose and plasma insulin levels were noted. These minimal effects on metabolism, combined with its high efficacy and acceptability shown in clinical trials, makes Femodene an ideal alternative to currently used oral contraceptives.

3-hydroxybutyrate dehydrogenase in tissues from normal and ketonaemic sheep.

1. In liver, rumen epithelium and kidney cortex of the sheep, a dehydrogenase active against dl-3-hydroxybutyrate occurred in both the cytosol and particulate fractions of the tissues. In brain, heart, skeletal and smooth muscles, the enzyme occurred only in the particulate fraction. 2. Enzyme activity in the cytoplasmic fraction of liver and rumen epithelium was similar with either d(-)-3-hydroxybutyrate or dl-3-hydroxbutyrate, but was less with acetoacetate as the substrate. The cytosol fraction of kidney cortex showed very little activity with d(-)-3-hydroxybutyrate, confirming that most of the activity with dl-3-hydroxybutyrate was with the l(+) isomer in this tissue. 3. 3-Hydroxybutyrate dehydrogenase activities in the cytosol and particulate fractions of liver, rumen epithelium and kidney cortex and in the particulate fraction of brain tissue were not stimulated by phosphatidylcholine, unlike the enzyme in sheep muscle and in tissues of other species. 4. The activity of 3-hydroxybutyrate dehydrogenase was not increased significantly in any of the tissues of ketonaemic sheep. 5. Comparison of rates of 3-hydroxybutyrate production in vivo with the enzyme activity in ketogenic tissue suggested that in sheep the maximum rate of production might be limited by this activity.