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Engineered heparins as new anticoagulant drugs.

ABSTRACT: Heparin is an anionic polysaccharide that is widely used as a clinical anticoagulant. This glycosaminoglycan is prepared from animal tissues in metric ton quantities. Animal-sourced heparin is also widely used in the preparation of low molecular weight heparins that are gaining in popularity as a result of their improved pharmacological properties. The recent contamination of pharmaceutical heparin together with concerns about increasing demand for this life saving drug and the fragility of the heparin supply chain has led the scientific community to consider other potential sources for heparin. This review examines progress toward the preparation of engineered heparins through chemical synthesis, chemoenzymatic synthesis, and metabolic engineering.

SUBMITTER: Vaidyanathan D

PROVIDER: S-EPMC5412866 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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Engineered heparins as new anticoagulant drugs.

Vaidyanathan Deepika D Williams Asher A Dordick Jonathan S JS Koffas Mattheos A G MAG Linhardt Robert J RJ

Bioengineering & translational medicine 20161121 1

Heparin is an anionic polysaccharide that is widely used as a clinical anticoagulant. This glycosaminoglycan is prepared from animal tissues in metric ton quantities. Animal-sourced heparin is also widely used in the preparation of low molecular weight heparins that are gaining in popularity as a result of their improved pharmacological properties. The recent contamination of pharmaceutical heparin together with concerns about increasing demand for this life saving drug and the fragility of the ...[more]

PMID: 28516163

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Project description:ObjectiveTo do an indirect comparison analysis of apixaban against dabigatran etexilate (2 doses) and rivaroxaban (1 dose), as well as of rivaroxaban against dabigatranetexilate (2 doses), for their relative efficacy and safety against each other, with particular focus on the secondary prevention population for stroke prevention in atrial fibrillation. A secondary objective was to do the same analysis in the primary prevention cohort.DesignIndirect treatment comparisons of phase III clinical trials of stroke prevention in atrial fibrillation, with a focus on the secondary prevention cohorts. A secondary analysis was done on the primary prevention cohort.Data sourcesMedline and Central (up to June 2012), clinical trials registers, conference proceedings, and websites of regulatory agencies.Study selectionRandomised controlled trials of rivaroxaban, dabigatran, or apixaban compared with warfarin for stroke prevention in atrial fibrillation.ResultsIn the secondary prevention (previous stroke) subgroup, when apixaban was compared with dabigatran (110 mg and 150 mg twice daily) for efficacy and safety endpoints, the only significant difference seen was less myocardial infarction (hazard ratio 0.39, 95% confidence interval 0.16 to 0.95) with apixaban compared with dabigatran 150 mg twice daily. No significant differences were seen in efficacy and most safety endpoints between apixaban or dabigatran 150 mg twice daily versus rivaroxaban. Less haemorrhagic stroke (hazard ratio 0.15, 0.03 to 0.66), vascular death (0.64, 0.42 to 0.99), major bleeding (0.68, 0.47 to 0.99), and intracranial bleeding (0.27, 0.10 to 0.73) were seen with dabigatran 110 mg twice daily versus rivaroxaban. In the primary prevention (no previous stroke) subgroup, apixaban was superior to dabigatran 110 mg twice daily for disabling or fatal stroke (hazard ratio 0.59, 0.36 to 0.97). Compared with dabigatran 150 mg twice daily, apixaban was associated with more stroke (hazard ratio 1.45, 1.01 to 2.08) and with less major bleeding (0.75, 0.60 to 0.94), gastrointestinal bleeding (0.61, 0.42 to 0.89), and other location bleeding (0.74, 0.58 to 0.94). Compared with rivaroxaban, dabigatran 110 mg twice daily was associated with more myocardial infarction events. No significant differences were seen for the main efficacy and safety endpoints between dabigatran 150 mg twice daily and rivaroxaban, or in efficacy endpoints between apixaban and rivaroxaban. Apixaban was associated with less major bleeding (hazard ratio 0.61, 0.48 to 0.78) than rivaroxaban.ConclusionsFor secondary prevention, apixaban, rivaroxaban, and dabigatran had broadly similar efficacy for the main endpoints, although the endpoints of haemorrhagic stroke, vascular death, major bleeding, and intracranial bleeding were less common with dabigatran 110 mg twice daily than with rivaroxaban. For primary prevention, the three drugs showed some differences in relation to efficacy and bleeding. These results are hypothesis generating and should be confirmed in a head to head randomised trial.

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Engineered heparins as new anticoagulant drugs.

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Engineered heparins as new anticoagulant drugs.

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