Direct thrombin inhibitors

This review deals with a newly-developed category of antithrombotic drugs – the direct thrombin inhibitors. These agents interact with thrombin and block its catalytic activity on fibrinogen, platelets and other substrates. Heparin and its derivatives (low molecular weight heparins and the active pentasaccharide) inhibit thrombin and/or other coagulation serine proteases indirectly via antithrombin, and the warfarin-type drugs interfere with the synthesis of the precursors of the coagulation serine proteases. The direct thrombin inhibitors approved for clinical use at present (lepirudin, desirudin, bivalirudin, argatroban) and another in the advanced clinical testing stage (melagatran/ximelagatran), are the subject of this review. The chemical structure; kinetics of thrombin inhibition; pharmacokinetics and clinical use of each of these is discussed.     

Bivalirudin versus heparin and provisional GP IIb/IIIa inhibitors in patients treated for ST‐segment elevation myocardial infarctions: Comparison of outcomes in a “real‐world” setting

Introduction

The beneficial effects of bivalirudin during primary PCIs are controversially discussed, data on unselected patients are rare. It was the aim of the study to compare bivalirudin versus heparin and provisional glycoprotein IIb/IIIa inhibitors (GPIs) in a “real‐world” study.

Methods

From 05/2013 until 11/2014, the STEMI‐patients in the Bremen STEMI registry were treated with periinterventional bivalirudin; before and after this period the standard anticoagulative treatment was heparin and provisional GPIs.

Results

In 714 patients bivalirudin was used for PCI, this cohort was compared to 683 patients with heparin and provisional GPIs. In patients with bivalirudin a significantly lower rate of hospital bleedings was observed compared to patients with heparin (4.6% vs 8.1%, P < 0.01, multivariate HR 0.57, 95%CI 0.35‐0.93), in an exclusive analysis of severe bleedings a trend toward less bleedings was found in patients with bivalirudin (2.0% vs 3.5%, P = 0.07, multivariate HR 0.66, 95%CI 0.30‐1.42). The rate of stent thromboses reinfarctions and mortality was not different between the bivalirudin and the heparin group. During 1‐year follow‐up bivalirudin was associated with a lower rate of bleedings and no significant differences in stent thromboses, reinfarctions, and mortality. Bivalirudin was not associated with an excess of bleedings or stent thromboses in subgroups that are regularly underrepresented in randomized trials (older patients, women, cardiogenic shock).

Conclusions

In this “real‐world” cohort of patients with STEMI bivalirudin compared to heparin and GPIs was associated with less bleedings and no significant differences in stent thromboses, reinfarctions, and mortality during hospital and long‐term course.

     

Management of heparin-induced thrombocytopenia

Background: Heparin-induced thrombocytopenia (HIT) is a rare but severe prothrombotic adverse effect of heparin treatment. The underlying cause is the formation of highly immunogenic complexes between negatively charged heparin and positively charged platelet factor 4 (PF4). Resulting antibodies against these PF4/heparin complexes can activate platelets via the platelet FcγIIa receptor, leading to thrombin generation and thus to the paradox of a prothrombotic state despite thrombocytopenia and application of heparin. Prompt diagnosis of HIT is important in order to change treatment to prevent severe thromboembolic complications. However, this is often difficult as thrombocytopenia is frequent in hospitalized patients and the commercially available laboratory tests for HIT antibodies have a high negative predictive value but only a poor positive predictive value. This leads to overdiagnosis and overtreatment of HIT, which also bear the risk for adverse outcomes.

Areas covered: This review aims at resuming recent data on HIT, thereby focusing on the role of new anticoagulants and providing a framework for diagnosis and treatment. Furthermore, it provides some insights into the pathogenesis of this peculiar adverse drug reaction and ventures a guess at its future relevance in clinical practice.

Expert opinion: New drugs which are strongly negatively charged should be assessed for their capacity to form complexes with PF4. If they do so, they bear the risk of inducing a HIT-like immune response. The immunology of HIT is still largely unresolved. Understanding HIT might provide insights into other immune and autoimmune response mechanisms.     

Optimal anticoagulation prior to cath: Bivalirudin vs. Heparin the saga continues…

• During the pre‐procedural (medication) phase, the use of bivalirudin monotherapy is associated with the lowest rate of bleeding in patients with Non‐ST elevation myocardial infarction (Non‐STEMI) undergoing an early invasive strategy.
• Monotherapy with either bivalirudin or unfractionated heparin (UFH) appear interchangeable in this setting.
• The use of GPI upstream with either drug should be discouraged due to an increased risk of bleeding and net adverse events.
• The use of low dose aspirin plus potent P2Y12 inhibitors followed by a transradial approach with implantation of drug‐eluting coronary stents with fluorinated polymers represents an strategy that may help limit perioperative ischemic and hemorrhagic complications in these individuals.