Efficacy and Safety of Heparinase I  versus Protamine in Patients Undergoing Coronary Artery Bypass Grafting with and without Cardiopulmonary Bypass

Stafford‐Smith, Mark; Lefrak, Edward A.; Qazi, Anjum; Welsby, Ian J.; Barber, Linda D.; Hoeft, Andreas; Dorenbaum, Alejandro; Mathias, Jasmine; Rochon, James J.; Newman, Mark F.

doi:10.1097/00000542-200508000-00005

Cited by 52 publications

(30 citation statements)

References 49 publications

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“…However, the study by Stafford-Smith et al . [6] identified many adverse reactions compared to the other studies, and when excluded, the incidence was 0.69% (8 out of 1165) (range 0-27%).…”

Section: Surrogate Marker Studiesmentioning

confidence: 78%

“…The only credible alternative to protamine reversal of heparin today is heparinase I as described by Stafford-Smith et al . [6]: this was, however, found inferior to protamine sulfate and could not be recommended as an alternative drug in general. Of note, alternatives do exist that can replace the use of heparin and protamine sulfate (e.g.…”

Section: Discussionmentioning

confidence: 94%

“…[6] compared the efficacy and safety of protamine sulfate with heparinase I in order to evaluate whether the latter favourably could replace protamine sulfate. One hundred and sixty-seven patients were randomized to either protamine sulfate or heparinase I, and with a very profound clinical scoring 40 versus 44 patients were found to have increased morbidity.…”

Section: Prospective Studiesmentioning

confidence: 99%

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Serious Anaphylactic Reactions due to Protamine Sulfate: A Systematic Literature Review

Nybo

Madsen

2008

Basic Clin Pharma Tox

136

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Anaphylactic reactions caused by injection of protamine sulfate during cardiac surgery are a well-known complication. A systematic literature review was therefore conducted to gather evidence of the knowledge concerning these side effects, and to see if any prospective randomized studies supported this. Studies investigating the effect of protamine sulfate in human beings were extracted from MEDLINE, Embase and the Cochrane Library, retrieving 487 articles. Abstracts were evaluated by both authors, and referred articles not found in the primary search were furthermore extracted from reviews and case reports, resulting in a total of 272 relevant articles. Of these, 9 retrospective studies and 16 prospective studies were performed in an evidence-based manner. However, only 3 of the 16 prospective articles had an optimal design as far as inclusion criteria, randomization, and description of symptoms were concerned. Incidence of anaphylactic reactions in the prospective studies was 0.69% compared to 0.19% in the retrospective studies, but caution should be taken due to a pronounced heterogeneity of those studies. One study found heparinase I unsuitable as replacement for protamine sulfate. Overall, our findings support the low incidence of anaphylactic reactions reported in previous studies, but of note only few prospective investigations was conducted on the subject. Our study also emphasizes the need for critical appraisal of many routine procedures: in all aspects of medical care, systematic literature review conducted in a well-structured, repeated manner should be given high priority.Protamine sulfate is a strongly alkaline polypeptide, mainly used to reverse anticoagulant effects of heparin. When injected intravenously, the alkaline protamine combines with the acidic heparin to form a neutral salt, thereby eliminating the anticoagulating properties of heparin. Another major use of protamine sulfate occurs in neutral protamine Hagedorn (NPH ) insulin, where complexion with insulin delay absorption and prolong the duration of action. Although being a relatively safe drug, it can cause severe systemic reactions with pronounced morbidity and mortality [1], and protamine sulfate is reported as one of the most common causes of life-threatening adverse reactions during cardiac surgery when used for rapid neutralization of heparin. Anaphylactic reactions to protamine sulfate have been known for many years, but the incidence reported varies from 0.06% to 10.6% [2] and range from minor haemodynamic instability to fatal cardiovascular collapse. The incidence of catastrophic reactions to protamine sulfate during cardiovascular surgery is reported to be 0.13% [3], and a recent study has confirmed the relation between protamine sulfate reactions and mortality risk [4]. The protamine-heparin complexes are thought to be responsible for the adverse effects observed, including allergic reactions, systemic hypotension and increased pulmonary arterial pressure, but most articles gathering this knowledge have been either...

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“…However, the study by Stafford-Smith et al . [6] identified many adverse reactions compared to the other studies, and when excluded, the incidence was 0.69% (8 out of 1165) (range 0-27%).…”

Section: Surrogate Marker Studiesmentioning

confidence: 78%

Section: Discussionmentioning

confidence: 94%

Section: Prospective Studiesmentioning

confidence: 99%

See 1 more Smart Citation

Serious Anaphylactic Reactions due to Protamine Sulfate: A Systematic Literature Review

Nybo

Madsen

2008

Basic Clin Pharma Tox

136

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“…Its activity decayed accordingly, so that after approximately 36 min, little activity remained. However, another study examining the efficacy and safety of heparinase I as an alternative to protamine in patients undergoing aortocoronary bypass graft surgery found that though heparinase I reversed heparin anticoagulation but is not equivalent to protamine because of its inferior safety profile (Stafford-Smith et al 2005). Further studies are required to compare heparinase I and protamine for clinically relevant outcome variables.…”

Section: Heparin Antagonistmentioning

confidence: 99%

Microbial heparin/heparan sulphate lyases: potential and applications

Tripathi

Banga

Mishra

2012

Appl Microbiol Biotechnol

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Heparin/heparan sulphate glycosaminoglycans (HSGAGs) are composed of linear chains of 20-100 disaccharide units of N-acetylated D: -glucosamine α (1-4) linked to glucuronic acid. HSGAGs are widely distributed on the cell surface and extracellular cell matrix of virtually every mammalian cell type and play critical role in regulating numerous functions of blood vessel wall, blood coagulation, inflammation response and cell differentiation. These glycosaminoglycans present in this extracellular environment very significantly influence the blood coagulation system and cardiovascular functions. Recent studies have investigated the mechanism by which cancer causes thrombosis and emphasizes the importance of the coagulation system in angiogenesis and tumour metastasis. Heparan sulphate/heparin lyases or heparinases are a class of enzymes that are capable of specifically cleaving the (1-4) glycosidic linkages in heparin and heparan sulphate to generate biologically active oligosaccharides with substantially significant and distinct clinical, pharmaceutical and prophylactic/therapeutic applications. Bioavailability and pharmacokinetic behaviour and characteristics of these oligosaccharides vary significantly depending on the origin/nature of the substrate (heparin or heparan sulphate-like glycosaminoglycans), the source of enzyme and method of preparation. Various microorganisms are reported/patented to produce these enzymes with different properties. Heparinases are commercially used for the depolymerization of unfractionated heparin to produce low molecular weight heparins (LMWHs), an effective anticoagulant. Individual LMWHs are chemically different and unique and thus cannot be interchanged therapeutically. Heparinases and LMWHs are reported to control angiogenesis and metastasis also. This review catalogues the degradation of HSGAGs by microbial heparin/heparan sulphate lyases and their potential either specific to the enzymes or with the dual role for generation of oligosaccharides for a new generation of compounds, as shown by various laboratory or clinical studies.

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“…A trend towards a shorter length of stay in the ICU and reduced mortality was observed in the iPGI 2 group, but the numbers were too small to achieve statistical significance. In order to avoid protamine reaction, heparinase I, a heparin degrading enzyme, was compared to protamine in a multicenter randomized controlled trial (Stafford-Smith et al, 2005). The prevention of protamine-induced PH was also explored as a secondary endpoint.…”

Section: Protaminementioning

confidence: 99%

A Pathophysiological Approach to Understanding Pulmonary Hypertension in Cardiac Surgery

Nguyen¹,

Deschamps²,

Perrault³

et al. 2012

Perioperative Considerations in Cardiac Surgery

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Efficacy and Safety of Heparinase I versus Protamine in Patients Undergoing Coronary Artery Bypass Grafting with and without Cardiopulmonary Bypass

Abstract: Heparinase I reverses heparin anticoagulation after aortocoronary bypass graft surgery but is not equivalent to protamine because of its inferior safety profile.

Cited by 52 publications

References 49 publications

Serious Anaphylactic Reactions due to Protamine Sulfate: A Systematic Literature Review

Serious Anaphylactic Reactions due to Protamine Sulfate: A Systematic Literature Review

Microbial heparin/heparan sulphate lyases: potential and applications

A Pathophysiological Approach to Understanding Pulmonary Hypertension in Cardiac Surgery

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