Low-dose iloprost infusions compared to the standard dose in patients with peripheral arterial occlusive disease Fontaine stage IV. DAWID Study Group.

BACKGROUND: Intravenous iloprost, titrated from 0.5 up to 2.0 ng/kg/min has been shown in patients with PAOD III/IV to significantly improve healing of trophic lesions, relief of rest pain, and reduce the rate of major amputation or death at 6 months as compared to placebo. The effect is considered related to improvement of the microcirculation. The aim of the present trial was to identify an optimum dose regarding treatment response and tolerability, by studying 4 doses of 25, 50, 75 and 100 micrograms iloprost daily. PATIENTS AND METHODS: 302 patients with PAOD IV were randomised via a double-blind fashion to one of the 4 doses. The primary endpoint was the responder rate at end of treatment. Responders were defined as patients with very good or good global efficacy, as judged by lesion healing and pain relief. Side effects were documented and a pre-defined benefit/risk index was calculated. RESULTS: No dose-dependency of iloprost regarding primary or secondary endpoints was observed. The rate of responders ranged between 48.7-53.5%. Side effects, mainly related to vasodilation, increased dose-dependently (p < 0.001, chi 2-test), with a significant decrease of the benefit/risk index from 2.19 +/- 1.19 to 1.64 +/- 0.97 (p = 0.012, ANOVA). Responders had a better outcome at 6 months than non-responders (2.6 fold higher rate of major amputation or death; life table analysis). CONCLUSIONS: It is concluded that iloprost should be titrated to the optimum rather than maximum tolerated dose, since a higher incidence of side effects not associated with an increased treatment response was observed at higher doses.

Peripheral arterial occlusions: local low-dose thrombolytic therapy with recombinant tissue-type plasminogen activator (rt-PA).

OBJECTIVE: To study the efficacy and risks of local thrombolytic therapy of peripheral arterial occlusions using rt-PA. DESIGN: This open study was performed in one clinic in Munich, Germany. METHODS: 288 patients suffering from occlusions of the lower limb arteries were subjected to 336 treatments performed with a permanently controlled technique. In a short pilot study 10mg rt-PA/h were administered for 5 h but in the majority of the cases only 2.5mg/h were administered for a maximum of 5 h. The average total dose of rt-PA was 2.97mg and the average time for lysis was 78 min. RESULTS: 43 (84.3%) out of 51 embolic occlusions and 168 (71.5%) out of 235 thrombotic occlusions were recanalised with a cumulative patency of 95% and 79.7% respectively after 2 years. One systemic bleeding occurred in the pilot study with 10mg rt-PA/h whereas with the 2.5mg/h dosage no systemic bleeding or embolism occurred in the 315 treatments. There were no deaths during hospitalisation. Six major and two forefoot amputations were necessary. Thirteen patients required a bypass operation and one an embolectomy. The advantages of our controlled technique are: short duration of treatment, small doses of activating agent, an accurately directed pathway with the possibility of dilating stenoses during the same session, no danger of systemic bleeding or embolism and, therefore, good prospects of success with minimal risk. CONCLUSION: The use of rt-PA for local lysis substitutes the inadequate tissue activator available for effective spontaneous lysis and is, therefore, almost physiological. The effect of a very low dose of rt-PA was as good as that of higher doses.

[Local low dosage thrombolysis with rt-PA. Systemic effects on the fibrinolytic system--data on the assessment of the value and risk of this method]. / Die lokale, niedrig dosierte Thrombolyse mit rt-PA. Systemische Auswirkungen auf das Fibrinolysesystem--Daten zur Einschätzung von Leistungsfähigkeit und Risiko der Methode.

We investigated 70 patients suffering from peripheral vascular disease for alterations in fibrinolytic parameters before, during and twice after local, low dose thrombolysis with rt-PA (1 - 7.5 mg). Recanalization was achieved in all 10 embolic occlusions and in 87% of 60 thrombotic occlusions. We found no alterations of fibrinogen and plasminogen plasma levels, but significant consumption of antiplasmin 5 min after the end of rt-PA application. Degradation products of fibrinogen and fibrin showed a parallel increase only during the therapy. PAI I concentrations significantly increased until the 2nd day after the therapy. Since we limited the maximum dose of rt-PA to 7.5 mg we never saw systemic bleeding or embolisation in more than 300 cases.

Femoro-popliteal artery thrombolysis with intra-arterial infusion of recombinant tissue-type plasminogen activator--report of a pilot trial.

Recombinant tissue-type plasminogen activator (rt-PA) was infused at a rate of 10 mg/h into 50 thrombosed femoral and popliteal arteries. Patency was restored in 43 but a secondary angioplasty led to 2 reocclusions and in 3 patients early rethrombosis occurred. A favourable clinical result was thus obtained in 38 patients (76%). Thirteen bleeding complications occurred in 10 patients, mainly haematomas at puncture sites. One patient required blood transfusion for gastro-intestinal bleeding from a previously unknown ulcer. The angiographic recanalisation rate in 16 patients who received a slower infusion of rt-PA (5 or 3 mg/h) was 94% and the clinical success rate in this series was 81%. However, the incidence of bleeding complications was not decreased by the slower infusion rate. The data obtained confirm the feasibility of rt-PA thrombolysis in peripheral arterial thrombosis and warrant a comparative study with streptokinase.

[Fibrinolysis with rt-PA in peripheral arterial occlusions]. / Fibrinolyse mit rt-PA bei peripheren arteriellen Verschlüssen.

First experiences using rt-PA for the local lysis of peripheral arterial occlusions have shown that it is a potent activator of the fibrinolytic system. 2 to 5 mg of rt-PA administered for 1 to 1 1/2 hours are sufficient to completely dissolve even long occlusions. With doses up to 20 mg over 2 hours no systemic bleeding was observed. With 50 mg given within 5 hours and with an infusion of 2.5 mg per hour for 48 hours there were two cases of systemic haemorrhaging entirely due to the fibrinolysis. No appreciable defects in the coagulation system and no other side effects were observed.

Peripheral arterial occlusions: a 6-year experience with local low-dose thrombolytic therapy.

Early and long-term results of treatment with local low-dose thrombolysis in 554 patients with 564 peripheral arterial occlusions are reported. Of 92 embolic occlusions present for 2 months or more, 59 (64.1%) were recanalized with a cumulative patency of 89.5% after 5 years. Of 472 thrombotic occlusions present for up to 6 months and more, 254 (53.8%) were successfully treated with a cumulative patency of 58.8% after 5 years. The hospital mortality and amputation rate were 1.6% and 1.95%, respectively. The average age of the patients was 69.1 years and more than half of those treated had stage III or IV disease. A 6-year experience with local low-dose thrombolytic therapy has completely confirmed its efficacy and has led to improvements in technique, which are described. The doses of streptokinase and urokinase needed for a successful result have been substantially reduced and the duration of treatment shortened. The number of complications has also been reduced. Differential therapeutic considerations compared to vascular surgery are mentioned. The results should motivate a reconsideration of the diagnostic and therapeutic measures to be used in the treatment of peripheral arterial occlusions.

Drug-induced inhibition of platelet function delays progression of peripheral occlusive arterial disease. A prospective double-blind arteriographically controlled trial.

240 patients were admitted to a double-blind study to determine the effect of long-term treatment with platelet-function inhibiting agents on occlusive arterial disease in the lower extremities. Patients were randomised into 1 of 3 treatment groups: aspirin 330 mg; dipyridamole 75 mg and aspirin 330 mg; or matching placebo 3 times daily. The duration of treatment was 2 years. Arteriography was carried out at the beginning of the study and 2 years later or before if deterioration was observed. 199 patients completed the study according to the trial protocol. The serial arteriograms were assessed in pairs qualitatively, by means of simple comparative viewing, and semiquantitatively with Bollinger's score system. Progression of the disease was most pronounced in the placebo-treated group, less so in the aspirin-treated group, and least of all in the dipyridamole-and-aspirin group. Patients who smoke and those with hypertension may benefit most from treatment with the 2 preparations under investigation.

[Effect of ticlopidine on peripheral obliterating arteriopathy]. / Einfluss von Ticlopidin auf die periphere obliterierende Arteriopathie.

The efficacy of and tolerance to ticlopidine, a platelet inhibitor, in preventing progression of obliterative arterial disease was compared with that of a placebo in a double-blind and randomized trial in 43 patients (22 on placebo, 21 on ticlopidine) over a period of one year. The course of the disease in both groups was assessed by serial angiography of the lower limbs, both at the beginning and at the end of the study. There was a significantly reduced progression in the ticlopidine group (P less than 0.01). The results support the hypothesis that platelets are of great importance in the progression of arteriosclerosis and that inhibition of platelet function is an effective principle of prevention. Ticlopidine in this respect is an alternative to the use of acetylsalicylic acid.

[Transluminal dilatation of the distal abdominal aorta and of the common and external iliac arteries (author's transl)]. / Transluminale Gefässdilatation der distalen Bauchaorta, der Arteria iliaca communis und externa.

Percutaneous transluminal angioplasty (PTA), a radiological procedure for dilating stenosed or occluded vessels, was carried out for 67 stenoses and three occlusions of the abdominal aorta or of the common or external iliac arteries. Seventy procedures were carried out; of these, 65 showed satisfactory primary results (observation period 15 days) ie, the clinical situation was improved. On four occasions the procedure had to be abandoned for technical reasons and, in one case, there was an early recurrence. Subsequently there were two late recurrences (after six and 24 months) during an observation period of three to 24 months. In the successfully dilated stenoses or occlusions there was a highly significant increase in the vessel diameter, with a highly significant reduction in the pressure gradient across the stenosis. The results are discussed. The authors conclude that in the presence of stenoses of the distal aorta or common or external iliac arteries PTA, which carries little risk and can be repeated, should be considered and attempted before surgical intervention.

Semiquantitative assessment of lower limb atherosclerosis from routine angiographic images.

In the present report a score system is introduced with the aim of analysing routine angiographic images. The system consists of a vectorial score, which codes the pattern of occlusions, stenoses and plaques, and of an additive score describing the severity of the lesions visualised. The technique is suitable for computerised data analysis.

[Low dose thrombolytic treatment for revascularisation in arterial occlusion (author's transl)]. / Niedrig dosierte thrombolytische Therapie zur Wiederherstellung der Strombahn bei arteriellen Verschlüssen.

Acute and subacute arterial occlusions of between 4.5 and 29 cm long could be dissolved in 11 patients by infiltration of small amounts (4000 to 110 000 U) of streptokinase or urokinase directly into the thrombus using a catheter. Use of a Grüntzig catheter enabled dilatation of possible stenoses during the same session. In 3 femoro-popliteal obliterations where lysis and catheter dilatation did not lead to sufficiently patent lumina occlusion recurred. In 3 patients with wide-ranging obliteration of the femoral, popliteal and almost all the arteries of the calf almost complete revascularisation could be achieved. Only transient slight side effects of lysis and coagulation disturbances were observed systemically. For prophylaxis of reobliteration platelet aggregation inhibitors are given for pre- and long-term aftercare.

[Prevention of re-occlusion after recanalisation of occluded arteries by the catheter method (author's transl)]. / Verhütung von Wiederverschlüssen nach Rekanalisation obliterierter Arterien mit der Kathetermethode.

In a double-blind study, prevention of re-thrombosis was tested on 101 patients in whom stenosis or segmental occlusion of a large artery of the lower limbs had been successfully removed by the intraluminal catheter method. The combination of 75 mg dipyridamol and 330 mg acetylsalicylic acid, three times daily by mouth, proved to be slightly more effective than acetylsalicylic acid alone at the same dosage. In the group with the combined treatment 84% of the arteries remained open, compared with 70% on acetylsalicylic acid alone.