Microcirculation and tolerability following i.v. infusion of PGE1 and iloprost: a randomized cross-over study in patients with critical limb ischemia.

In a randomized cross-over study, the effect of PGE(1) and iloprost on microcirculation as well as the tolerability was investigated in 36 patients with peripheral arterial occlusive disease stage III and IV according to Fontaine. Patients received PGE(1) and iloprost by single 3-h i.v. infusions on two different days at doses recommended by the manufacturers or in previous studies (PGE(1): first hour 20 microg, next 2h 30 microg each. Iloprost: first hour 0.5 ng/kg/min, next 2h 1.0 ng/kg/min). Transcutaneous oxygen pressure (tcPO(2)) values increased much more with PGE(1). Median tcPO(2) increase over baseline 30 min after the end of infusion was 9 and 2 mmHg for PGE(1) and iloprost, respectively, corresponding to median AUC differences from baseline of 1050 and 210 min mmHg. Because of its exploratory character, the study was not powered to test for significance. Adverse effects occurred in 19.4% (PGE(1)) and 30.6% (iloprost) of patients. Dose reduction was required in 3 patients receiving iloprost (hypotension, nausea, irritation of the infused vein), and in none receiving PGE(1).

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.