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Canadian Journal of Anaesthesia =... May 2015Heparin anticoagulation followed by protamine reversal is commonly used in cardiopulmonary bypass (CPB) cardiac procedures, but this strategy has some limitations. The... (Review)
Review
PURPOSE
Heparin anticoagulation followed by protamine reversal is commonly used in cardiopulmonary bypass (CPB) cardiac procedures, but this strategy has some limitations. The primary objective of this study was to determine the reliable alternatives for anticoagulation during CPB for cardiac surgery. For each drug proposed, the secondary objectives were to outline the main advantages and disadvantages, to propose a therapeutic protocol, and to provide a cost-benefit analysis.
SOURCE
A systematic review of the literature was performed between September 2012 and December 2013. It was based on the protocol established by the "Cochrane collaboration Handbook". Twenty articles were analyzed. The Thériaque database from the University Hospital of Grenoble made the economic analysis possible.
PRINCIPAL FINDINGS
Seven alternative anticoagulation strategies were considered: danaparoid sodium, lepirudin, argatroban, bivalirudin, ancrod, idraparinux, and EP217609. Danaparoid sodium has issues with individual variability. Several studies (EVOLUTION-ON, CHOOSE-ON) proposed a reliable therapeutic protocol for bivalirudin. Ancrod resulted in an increase in the transfusion of blood products. Direct thrombin inhibitors offer a promising alternative. EP217609 is a synthetic anticoagulant currently undergoing Phase IIa clinical trials. It is an indirect inhibitor of factor Xa, a direct inhibitor of free and bound thrombin, and can be neutralized by avidin.
CONCLUSIONS
The ideal anticoagulation strategy for cardiac surgery with CPB does not exist. Heparin and protamine remain the gold standard for anticoagulation therapy. To date, bivalirudin is the most promising molecule despite its high cost and lack of a readily available antagonist.
Topics: Anticoagulants; Cardiopulmonary Bypass; Cost-Benefit Analysis; Drug Costs; Heparin; Hirudins; Humans; Peptide Fragments; Protamines; Recombinant Proteins
PubMed: 25697279
DOI: 10.1007/s12630-015-0339-6 -
The Cochrane Database of Systematic... Mar 2012Fibrinogen depleting agents reduce fibrinogen in blood plasma, reduce blood viscosity and hence increase blood flow. This may help remove the blood clot blocking the... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Fibrinogen depleting agents reduce fibrinogen in blood plasma, reduce blood viscosity and hence increase blood flow. This may help remove the blood clot blocking the artery and re-establish blood flow to the affected area of the brain after an ischaemic stroke. The risk of haemorrhage may be less than with thrombolytic agents. This is an update of a Cochrane review first published in 1997 and last updated in 2003.
OBJECTIVES
To assess the effect of fibrinogen depleting agents in patients with acute ischaemic stroke.
SEARCH METHODS
We searched the Cochrane Stroke Group Trials Register (July 2011), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, Issue 7), the Chinese Stroke Trials Register (September 2011), MEDLINE (1950 to July 2011), EMBASE (1980 to July 2011) and Web of Science Conference Proceedings (1990 to July 2011). In addition, we searched six Chinese databases, four ongoing trials registers (July 2011) and relevant reference lists. For previous versions of the review, we handsearched journals and contacted researchers in China and Japan and relevant drug companies.
SELECTION CRITERIA
Randomised trials of fibrinogen depleting agents started within 14 days of stroke onset, compared with control in patients with definite or possible ischaemic stroke.
DATA COLLECTION AND ANALYSIS
Two review authors independently selected trials, assessed trial quality and extracted the data. We resolved disagreement by discussion.
MAIN RESULTS
We included eight trials involving 5701 patients. Six trials tested ancrod and two trials tested defibrase (patients were treated for less than three hours to less than 48 hours). Allocation concealment was adequate in seven trials. Fibrinogen depleting agents marginally reduced the proportion of patients who were dead or disabled at the end of follow-up (risk ratio (RR) 0.95, 95% confidence Interval (CI) 0.90 to 0.99, 2P = 0.02). There was no statistically significant difference in death from all causes during the scheduled treatment or follow-up period. There were fewer stroke recurrences in the treatment group than in the control group (RR 0.67, 95% CI 0.49 to 0.92, 2P = 0.01). However, symptomatic intracranial haemorrhage was about twice as common in the treatment group compared with the control group (RR 2.42, 95% CI 1.65 to 3.56, 2P < 0.00001).
AUTHORS' CONCLUSIONS
The current evidence is promising but not yet sufficiently robust to support the routine use of fibrinogen depleting agents for the treatment of acute ischaemic stroke. Further trials are needed to determine whether there is worthwhile benefit, and if so, which categories of patients are most likely to benefit.
Topics: Ancrod; Batroxobin; Brain Ischemia; Fibrinolytic Agents; Humans; Intracranial Hemorrhages; Randomized Controlled Trials as Topic; Stroke
PubMed: 22419274
DOI: 10.1002/14651858.CD000091.pub2 -
The Cochrane Database of Systematic... Jun 2011Peripheral arterial disease (PAD) is frequently treated by either an infrainguinal autologous (using the patient's own veins) or synthetic graft bypass. The rate of... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Peripheral arterial disease (PAD) is frequently treated by either an infrainguinal autologous (using the patient's own veins) or synthetic graft bypass. The rate of occlusion of the graft after one year is between 12% and 60%. To prevent occlusion, patients are treated with an antiplatelet or antithrombotic drug, or a combination of both. Little is known about which drug is optimal to prevent infrainguinal graft occlusion. This is an update of a Cochrane review first published in 2003.
OBJECTIVES
To evaluate whether antithrombotic treatment improves graft patency, limb salvage and survival in patients with chronic PAD undergoing infrainguinal bypass surgery.
SEARCH STRATEGY
The Cochrane Peripheral Vascular Diseases Group searched their Specialised Register (last searched August 2010) and the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2010, Issue 3).
SELECTION CRITERIA
Randomised, controlled trials; two review authors independently assessed the methodological quality of each trial using a standardised checklist.
DATA COLLECTION AND ANALYSIS
Data collected included patient details, inclusion and exclusion criteria, type of graft, antithrombotic therapy, outcomes, and side effects.
MAIN RESULTS
A total of 14 trials were included in this review; 4970 patient results were analysed. Four trials evaluating vitamin K antagonists (VKA) versus no VKA suggested that oral anticoagulation may favour autologous venous, but not artificial, graft patency as well as limb salvage and survival. Two other studies comparing VKA with aspirin (ASA) or aspirin and dipyridamole provided evidence to support a positive effect of VKA on the patency of venous but not artificial grafts. Three trials comparing low molecular weight heparin (LMWH) to unfractionated heparin (UFH) failed to demonstrate a significant difference on patency. One trial comparing LMWH with placebo found no significant improvement in graft patency over the first postoperative year in a population receiving aspirin. One trial showed an advantage for LMWH versus aspirin and dipyridamol at one year for patients undergoing limb salvage procedures. Perioperative administration of ancrod showed no greater benefit when compared to unfractionated heparin. Dextran 70 showed similar graft patency rates to LMWH but a significantly higher proportion of patients developed heart failure with dextran.
AUTHORS' CONCLUSIONS
Patients undergoing infrainguinal venous graft are more likely to benefit from treatment with VKA than platelet inhibitors. Patients receiving an artificial graft benefit from platelet inhibitors (aspirin). However, the evidence is not conclusive. Randomised controlled trials with larger patient numbers are needed in the future to compare antithrombotic therapies with either placebo or antiplatelet therapies.
Topics: Arteriosclerosis; Fibrinolytic Agents; Graft Occlusion, Vascular; Humans; Intermittent Claudication; Ischemia; Leg; Peripheral Vascular Diseases; Randomized Controlled Trials as Topic; Thrombosis; Vitamin K
PubMed: 21678330
DOI: 10.1002/14651858.CD000536.pub2 -
A systematic review of randomized evidence for fibrinogen-depleting agents in acute ischemic stroke.Journal of Stroke and Cerebrovascular... 1998To assess the efficacy and safety of fibrinogen-depleting agents (snake venom extracts) in the treatment of acute ischemic stroke.
OBJECTIVE
To assess the efficacy and safety of fibrinogen-depleting agents (snake venom extracts) in the treatment of acute ischemic stroke.
METHODS
A systematic review of all the relevant randomized controlled trials (RCTs) was performed. RCTs were identified from the Cochrane Stroke Group's Specialized Trial Register, additional electronic and hand searching, and personal contact with pharmaceutical companies. We included all completed and unconfounded truly or quasi-randomized trials in patients with ischemic stroke comparing fibrinogen depleting agents with control started within 14 days of the stroke onset. The Peto method was used for analysis.
RESULTS
Eight completed and two ongoing RCTs have been identified so far. Only three trials using ancrod (182 patients) met the inclusion criteria. Ancrod was associated with a significant reduction in early deaths (5.6% v 16%; odds ratio [OR], 0.33; 95% confidence interval [CI], 0.13 to 0.85; 2P=.02) suggesting that treatment of 100 patients would avoid about 10 early deaths. The frequency of asymptomatic intracranial hemorrhage shown by computed tomography was similar between ancrod-treated and control groups (7.6% v 9.6%; OR, 0.78; 95% CI, 0.26 to 2.33; 2P=.65). No major intracranial or extracranial hemorrhages or recurrent ischemic strokes occurred in the ancrod-allocated patients. There were nonsignificant trends in favor of ancrod in death from any cause (OR, 0.57; 95% CI, 0.27 to 1.23; 2P=.15) and death or disability (OR, 0.52; 95% CI, 0.26 to 1.03; 2P=.06) at the end of trial follow-up.
CONCLUSIONS
There were too few patients and outcome events to draw reliable conclusions from the present data. Although ancrod-like agents appeared promising, their routine use cannot be recommended at the moment. Two ongoing trials (including about 1,000 patients in total) will provide more data. Future trials should test simpler fixed-dose regimens to allow better generalizability.
PubMed: 17895058
DOI: 10.1016/s1052-3057(98)80023-2 -
The Cochrane Database of Systematic... 2003Chronic peripheral arterial disease (PAD) is frequently treated by implantation of either an infrainguinal autologous venous or artificial graft. One-year occlusion... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Chronic peripheral arterial disease (PAD) is frequently treated by implantation of either an infrainguinal autologous venous or artificial graft. One-year occlusion rates for infrainguinal bypasses vary between 15 and 75%, depending on the site of distal anastomosis, length, quality, and material of the graft, but also on other factors such as proximal inflow and distal outflow conditions. To prevent graft occlusion, patients are usually treated with either an antiplatelet or antithrombotic drug, or a combination of both. Little is known about which drug is optimal to prevent infrainguinal graft occlusion.
OBJECTIVES
To evaluate whether antithrombotic treatment in patients with chronic PAD undergoing infrainguinal bypass surgery improves graft patency, limb salvage and survival by performing a meta-analysis of performed RCTs.
SEARCH STRATEGY
The search strategy was that adopted by the Cochrane Review Group on Peripheral Vascular Diseases. Additional data bases were reviewed (Reference lists of papers resulting from this search, MEDLINE from 1966-onwards and EMBASE from 1980-onwards using the terms 'anticoagulant' and 'arterial surgery'.
SELECTION CRITERIA
The methodological quality of each trial was assessed independently by at least two reviewers using the checklist provided by the Peripheral Vascular Diseases Collaborative Review Group, with emphasis on concealment of randomisation. Each trial was given an allocation score of A (clearly concealed), B (unclear if concealed), or C (clearly not concealed) and a summary score of A (low risk of bias), B (moderate risk), or C (high risk). Trials scoring A were included and those scoring C were excluded. For a trial scoring B, an attempt was made to obtain more information by contacting the author.
DATA COLLECTION AND ANALYSIS
For each trial, the number of patients originally allocated to each treatment group was extracted from the data and an 'intention to treat' analysis performed. Data collection on each trial included inclusion and exclusion criteria, patient details, type of graft, type and dose of antithrombotic therapy used, outcome, and side effects. The treatment and control groups were compared for important prognostic factors and differences described. If any of the above data was not available, further information was sought from the author. However, the heterogeneity between trials could not be tested due to inaccessible data. Data were synthesized by comparing group results.
MAIN RESULTS
The analysis including four trials which evaluated vitamin K antagonists (VKA) versus no VKA indicate, that oral anticoagulation tendentially favours venous but not artificial graft patency as well as limb salvage and survival. Two other studies comparing VKA with aspirin or aspirin/dipyridamole supported evidence for a positive effect of VKA on the patency of venous but not artificial grafts. Subgroup analysis for artificial grafts as performed in one trial showed a favourable effect of antiplatelet agents on synthetic bypasses. In two trials with a relatively small number of patients low molecular weight heparin treatment was associated with a lower incidence of early postoperative graft thrombosis compared to treatment with unfractionated heparin. In one trial infusion of antithrombin concentrate was reported to have a negative effect on intraoperative graft thrombosis necessitating the study to be stopped before termination. Perioperative administration of ancrod was compared to unfractionated heparin showing no benefit of one drug compared to the other.
REVIEWER'S CONCLUSIONS
Patients operated for an infrainguinal venous graft might benefit from treatment with VKA, whereas patients receiving an artificial graft might profit more from platelet inhibitors (aspirin). However, the evidence is not conclusive. Randomised controlled trials with larger patient numbers comparing antithrombotic therapies with either placebo or antiplatelet therapies are called for in the future.
Topics: Arteriosclerosis; Fibrinolytic Agents; Graft Occlusion, Vascular; Humans; Intermittent Claudication; Ischemia; Leg; Peripheral Vascular Diseases; Postoperative Complications; Randomized Controlled Trials as Topic; Thrombosis; Vitamin K
PubMed: 14583924
DOI: 10.1002/14651858.CD000536 -
The Cochrane Database of Systematic... 2003Fibrinogen depleting agents reduce fibrinogen in blood plasma, reduce blood viscosity and hence increase blood flow. This may help remove the blood clot blocking the... (Review)
Review
BACKGROUND
Fibrinogen depleting agents reduce fibrinogen in blood plasma, reduce blood viscosity and hence increase blood flow. This may help remove the blood clot blocking the artery and re-establish blood flow to the affected area of the brain after an ischaemic stroke. The risk of haemorrhage may be less than with thrombolytic agents.
OBJECTIVES
The objective of this review was to assess the effect of fibrinogen depleting agents in patients with acute ischaemic stroke.
SEARCH STRATEGY
We searched the Cochrane Stroke Group Trials Register (last searched May 2003). In addition we searched the following electronic databases: EMBASE (1980-October 2001), China Biological Medicine Database (CBM-disc 1981- December 2002), Chinese Stroke Trials Register (1996 - December 2002) and Index of Scientific and Technical Proceedings (Web of Science Proceedings [1990-October 2001]). We handsearched relevant journals and contacted Chinese and Japanese researchers and drug companies.
SELECTION CRITERIA
Randomised and quasi-randomised trials of fibrinogen depleting agents started within 14 days of stroke onset, compared with control in patients with definite or possible ischaemic stroke.
DATA COLLECTION AND ANALYSIS
Two reviewers independently applied the inclusion criteria, assessed trial quality and extracted the data.
MAIN RESULTS
Five trials involving 2926 patients were included. A further trial (ESTAT) has not yet been published in full. Four trials tested ancrod and one trial tested defibrase. Allocation concealment was adequate in four trials. Fibrinogen depleting agents moderately reduced the proportion of patients who were dead or disabled at the end of follow up (Relative risk [RR] 0.90, 95% Confidence Interval [CI] 0.82 to 0.98, 2P=0.02). There was no statistically significant difference in death from all causes during the scheduled treatment period (RR 0.71, 95% CI 0.44 to 1.13) and at the end of follow-up (RR 0.98, 95% CI 0.78 to 1.24). There was a non-significant excess of symptomatic intracranial haemorrhages with treatment (RR 2.64, 95%CI 0.96 to 7.30, 2P=0.06).
REVIEWER'S CONCLUSIONS
Fibrinogen depleting agents are promising. However more data, particularly ESTAT data, are needed before more reliable conclusions can be drawn.
Topics: Ancrod; Brain Ischemia; Fibrinolytic Agents; Humans; Randomized Controlled Trials as Topic; Stroke
PubMed: 12917882
DOI: 10.1002/14651858.CD000091 -
The Cochrane Database of Systematic... 2000Fibrinogen depleting agents reduce fibrinogen in blood plasma, reduce blood viscosity and hence increase blood flow. This may help remove the blood clot blocking the... (Review)
Review
BACKGROUND
Fibrinogen depleting agents reduce fibrinogen in blood plasma, reduce blood viscosity and hence increase blood flow. This may help remove the blood clot blocking the artery and re-establish blood flow to the affected area of the brain after an ischaemic stroke. The risk of haemorrhage may be less than with thrombolytic agents.
OBJECTIVES
The objective of this review was to assess the effect of fibrinogen depleting agents in people with acute ischaemic stroke.
SEARCH STRATEGY
We searched the Cochrane Stroke Group trials register, Embase (to January 1996) and the Index of scientific and technical proceedings (1982 to 1996). We handsearched 10 Chinese journals and the proceedings of the 4th Chinese Stroke Conference (1995). We contacted Chinese and Japanese researchers, and drug companies.
SELECTION CRITERIA
Randomised and quasi-randomised trials of fibrinogen depleting agents started within 14 days of stroke onset, compared with control in patients with definite or possible ischaemic stroke.
DATA COLLECTION AND ANALYSIS
Two reviewers independently applied the inclusion criteria, assessed trial quality and extracted the data.
MAIN RESULTS
Three trials involving 182 patients were included. All trials tested ancrod. Allocation concealment was adequate in two trials. Fibrinolytic therapy appeared to reduce the number of deaths during the scheduled treatment period (odds ratio 0.33, 95% confidence interval 0.13 to 0.85). There was no difference in death from all causes at the end of follow-up (odds ratio 0.57, 95% confidence interval 0.27 to 1.23). The risk of haemorrhage appeared to be small, but there were too few data to be conclusive. One trial in 132 people showed a statistically non-significant decrease in the odds of being dead or disabled at the end of follow-up (odds ratio 0.52, 95% confidence interval 0.26 to 1.03).
REVIEWER'S CONCLUSIONS
Although ancrod appears to be promising, it is not possible to draw reliable conclusions from the available data.
Topics: Ancrod; Brain Ischemia; Fibrinolytic Agents; Humans; Stroke
PubMed: 10796295
DOI: 10.1002/14651858.CD000091