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The effect of desmopressin on reducing blood loss in cardiac surgery: a meta-analysis of double-blind, placebo-controlled trials
Cattaneo M, Harris AS, Stromberg U, Mannucci PM
Thrombosis and Haemostasis. 1995;74((4):):1064-1070.
Abstract
The effect of desmopressin (DDAVP) on reducing postoperative blood loss after cardiac surgery has been studied in several randomized clinical trials with conflicting outcomes. Since most trials had insufficient statistical power to detect true differences in blood loss, we performed a meta-analysis of data from relevant studies. Seventeen randomized, double-blind, placebo-controlled trials were analyzed, which included 1171 patients undergoing cardiac surgery for various indications; 579 of them were treated with desmopressin and 592 with placebo. Efficacy parameters were blood loss volumes and transfusion requirements. Desmopressin significantly reduced postoperative blood loss by 9%, but had no statistically significant effect on transfusion requirements. A subanalysis revealed that desmopressin had no protective effects in trials in which the mean blood loss in placebo-treated patients fell in the lower and middle thirds of distribution of blood losses (687-1108 ml/24 h). In contrast, in trials in which the mean blood loss in placebo-treated patients fell in the upper third of distribution (> 1109 ml/24 h), desmopressin significantly decreased postoperative blood loss by 34%. Insufficient data were available to perform a sub-analysis on transfusion requirements. Therefore, desmopressin significantly reduces blood loss only in cardiac operations which induce excessive blood loss. Further studies are called to validate the results of this meta-analysis and to identify predictors of excessive blood loss after cardiac surgery.
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2.
Randomized controlled trial of desmopressin plus terlipressin vs. terlipressin alone for the treatment of acute variceal hemorrhage in cirrhotic patients: a multicenter, double-blind study. New Italian Endoscopic Club
de Franchis R, Arcidiacono PG, Carpinelli L, Andreoni B, Cestari L, Brunati S, Zambelli A, Battaglia G, Mannucci PM
Hepatology. 1993;18((5):):1102-7.
Abstract
1-Deamino-8-D-arginine vasopressin (DDAVP, desmopressin), a synthetic analog of the antidiuretic hormone L-arginine vasopressin, improves hemostasis parameters in cirrhotic patients. Hence its use in combination with a vasoactive drug such as terlipressin might improve the performance of this drug in controlling variceal bleeding. The aim of this trial was to compare the efficacy of desmopressin plus terlipressin with that of terlipressin alone in controlling acute variceal hemorrhage. Cirrhotic patients with active variceal hemorrhage diagnosed endoscopically were randomized within 2 hr of admission to receive desmopressin plus terlipressin or placebo plus terlipressin. Terlipressin (2 mg, intravenous bolus) was given at time 0 and every 4 hr thereafter for 24 hr. Desmopressin (0.3 microgram/kg, intravenously) or placebo was given in saline solution over 30 min at time 0 and at 26 hr. Patients were monitored for 24 hr after cessation of treatment. Treatment failure was defined as recurrence of active bleeding during treatment or within the 24 hr after treatment. After enrolling 51 of the planned 84 patients, we carried out an interim analysis. Treatment failure occurred in 13 of 24 patients randomized to receive desmopressin plus terlipressin (54.2%) and in 6 of 22 patients randomized to receive terlipressin (27.3%) (p = 0.06, Fisher's exact test). The trial was interrupted at this stage because patients treated with the "new" therapy fared worse than those treated with the standard therapy, and the possibility of reversing this trend by completing the trial was deemed remote. The addition of desmopressin does not improve and may worsen the efficacy of terlipressin in controlling acute variceal bleeding in cirrhotic patients.
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3.
DDAVP shortens the prolonged bleeding times of patients with severe von Willebrand disease treated with cryoprecipitate. Evidence for a mechanism of action independent of released von Willebrand factor
Cattaneo M, Moia M, Delle Valle P, Castellana P, Mannucci PM
Blood. 1989;74((6):):1972-5.
Abstract
After infusion of cryoprecipitate, the very prolonged bleeding time of patients with severe von Willebrand disease (vWD) is shortened but not always normalized in spite of normalization of plasma von Willebrand factor (vWF) levels. Therefore treatments that further improve primary hemostasis in severe vWD patients are needed. Since DDAVP shortens the bleeding time in a variety of bleeding disorders, we investigated in a double-blind, placebo-controlled crossover study the effects of the intravenous (IV) infusion of DDAVP (0.3 microgram/kg) on the bleeding times of 10 patients with severe vWD treated with cryoprecipitate. Their very prolonged bleeding times (greater than 30 minutes), partially corrected by the infusion of cryoprecipitate (14 +/- 2 minutes, mean +/- SEM), were further shortened by the administration of DDAVP (9 +/- 2 minutes, P less than .01) but not of saline (15 +/- 3 minutes, ns). Plasma vWF levels, raised from unmeasurable to normal values by cryoprecipitate, were not changed after DDAVP or saline. The defective deposition of platelets from eight patients onto human umbilical artery subendothelium was increased but not normalized by cryoprecipitate and was not significantly affected by DDAVP or saline. Therefore the infusion of DDAVP after cryoprecipitate may be of clinical benefit for management of bleeding episodes in severe vWD patients. Since severe vWD patients do not have releasable tissue stores of vWF, DDAVP must shorten their prolonged bleeding times independently of released vWF.
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4.
Intravenous and subcutaneous administration of desmopressin (DDAVP) to hemophiliacs: pharmacokinetics and factor VIII responses
Mannucci PM, Vicente V, Alberca I, Sacchi E, Longo G, Harris AS, Lindquist A
Thrombosis & Haemostasis. 1987;58((4):):1037-9.
Abstract
When desmopressin (DDAVP) is given to mild and moderate hemophiliacs intravenously (i.v.) or subcutaneously (s.c.), there is a very large between-patient variability for peak levels of factor VIII coagulant activity (VIII:C). To evaluate whether or not between-patient variability is related to DDAVP levels achieved in plasma, we measured drug levels in 14 hemophilic volunteers (VIII:C 2 to 31 U/dL) who were randomly given 0.3 micrograms/Kg of i.v. or s.c. DDAVP and crossed-over to the other treatment after an interval of 15-30 days. Peak DDAVP levels (Cmax) were higher for i.v. DDAVP (p less than 0.02), times to peak levels (tmax) were shorter for i.v. DDAVP (p less than 0.001). There was no difference between the i.v. and s.c. routes for plasma DDAVP time curve (AUC) and half-life (t 1/2), but there was much larger variability for pharmacokinetic parameters with i.v. than with s.c. DDAVP. Post-DDAVP VIIIC increased 3.4 +/- 1.6 fold (i.v.) and 3.3 +/- 1.3 fold (s.c.) over baseline levels, with no significant correlation between peak VIIIC and DDAVP levels for either route of administration. These findings establish the s.c. route of DDAVP administration to be bioequivalent in effect to the i.v. route, albeit with less variability. At the DDAVP dosage used in this study and currently recommended for therapy, the VIIIC response is neither a function of the rate of absorption of the compound nor of the magnitude of its plasma concentration.
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5.
Controlled trial of desmopressin in liver cirrhosis and other conditions associated with a prolonged bleeding time
Mannucci PM, Vicente V, Vianello L, Cattaneo M, Alberca I, Coccato MP, Faioni E, Mari D
Blood. 1986;67((4):):1148-53.
Abstract
The synthetic vasopressin derivative desmopressin (DDAVP) shortens a prolonged bleeding time (BT) in patients with uremia, congenital platelet dysfunction, and von Willebrand disease. To establish the limits of the clinical usefulness of DDAVP, a controlled randomized study was carried out in 53 patients and ten volunteers with different conditions that have in common a prolonged BT. DDAVP significantly shortened the BT in 21 cirrhotics (P less than .01), in eight patients with unclassified prolonged BT (P less than .05) and in ten volunteers taking the antiplatelet drugs aspirin (P less than .05) and ticlopidine. The BT changes were not statistically significant in 15 patients with severe thrombocytopenia nor in nine with congenital platelet dysfunction, even though a few patients with storage pool deficiency responded with a marked BT shortening. Our findings indicate that DDAVP might be given when biopsies or other surgical procedures must be carried out in patients with prolonged BT. However, the compound is often ineffective in patients with thrombocytopenia or congenital platelet dysfunction.
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6.
Deamino-8-D-arginine vasopressin shortens the bleeding time in uremia
Mannucci PM, Remuzzi G, Pusineri F, Lombardi R, Valsecchi C, Mecca G, Zimmerman TS
New England Journal of Medicine. 1983;308((1):):8-12.
Abstract
In a randomized double-blind cross-over trial we gave either 1-deamino-8-D-arginine vasopressin or placebo to 12 patients with uremia, hemorrhagic tendencies, and prolonged bleeding times. After vasopressin infusion, all patients had shortened bleeding times, with the effect lasting for at least four hours in most cases. Platelet count, platelet cyclic AMP levels, platelet retention on glass beads, plasma fibronectin, serum thromboxane B2 and residual prothrombin, hematocrit, and plasma osmolarity were unchanged after vasopressin. A consistent post-infusion increase in factor VIII coagulant activity and, to a lesser extent, in factor VIII-related antigen and ristocetin cofactor accompanied the shortening of bleeding time. In addition, vasopressin induced the appearance in plasma of larger von Willebrand-factor multimers than those present in the resting state. The compound was given to nine additional patients with acute or chronic renal failure and prolonged bleeding times, before major surgery or renal biopsy. In these patients, shortening of the bleeding time was associated with normal hemostasis. Our findings indicate that 1-deamino-8-D-arginine vasopressin can be used for temporary correction of bleeding time and may prevent surgical bleeding in patients with uremia.
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7.
Response of factor VIII/von Willebrand factor to DDAVP in healthy subjects and patients with haemophilia A and von Willebrand's disease
Mannucci PM, Canciani MT, Rota L, Donovan BS
British Journal of Haematology. 1981;47((2):):283-293.