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Published on 16 October 2015

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Direct thrombin inhibitors and anticoagulation

 

 

Oral direct thrombin inhibitors, such as dabigatran etexilate, broaden the treatment options in patients with pulmonary embolism and deep vein thrombosis
Tobias Zeus
Department of Cardiology, Pneumology 
and Angiology
Thomas Hohlfeld 
Department of Pharmacology
Amin Polzin 
Malte Kelm
Department of Cardiology, Pneumology 
and Angiology,
University Hospital Düsseldorf, Germany
Email: Zeus@med.uni-duesseldorf.de
Outpatient anticoagulation therapy has traditionally been dominated by the use of vitamin K antagonists (VKA) for the last few decades. Therefore, much data and knowledge has been amassed concerning the indication, contraindication, dosage and co-medication. A major disadvantage of effective anticoagulation with VKA is the prolonged half-life, obligatory drug monitoring, small therapeutic range, genetic variability and a high potential for drug and food interactions.
Several favourable criteria have been defined for novel drugs in this field (Table 1). Many of these criteria have been met by the non-VKA oral anticoagulants (NOACs). Two different targets were investigated by the pharmaceutical industry: Factor Xa inhibition and direct thrombin inhibition. Rivaroxaban, a factor Xa inhibitor, the first NOAC approved in Europe, gained approval in 2008 for the prophylaxis of deep vein thrombosis (DVT) after orthopaedic surgery. Further approved indications followed and included thromboembolic prophylaxis in non-valvular atrial fibrillation (August 2011) and treatment and prophylaxis of DVT and pulmonary embolism (April 2014). This review focuses on dabigatran and its use in patients with DVT and PE.
Direct thrombin inhibitors
Direct thombin inhibitors (DTIs) act as anticoagulants by inhibiting factor II (thrombin). On the basis of the interaction with the thrombin molecule, three different types of DTIs can be distinguished:
1. Bivalent binding: hirudin; bivalirudin; desirudin; lepirudin
2. Univalent binding: argatroban; melagatran (prodrug ximelagatran); dabigatran
3. Allosteric inhibition: several substances under preclinical investigation.
The only DTI approved for the treatment of DVT and PE is dabigatran. Dabigatran etexilate is converted by esterase-catalysed hydrolysis into the active component, dabigatran. The absolute bioavailability after oral intake is approximately 6.5%. Excretion is mainly renal, effective plasmatic levels are reached within two hours; drug half-life is 13.4 hours in patients with normal renal function. In Europe, two dosages have been approved for patients with PE and/or DVT: 110mg twice-daily and 150mg twice-daily.
Characterisation of disease
DVT and PE are integrated under the definition of venous thromboembolism (VTE). VTE remains a major illness with regards to morbidity, mortality and hospitalisation in Europe, especially for elderly patients. In past years, the therapeutic and diagnostic actions have been shifted gradually from an in-hospital to an outpatient setting. Early mobilisation of patients is a major therapeutic and preventive focus to avert severe adverse events such as hospital-acquired pneumonias, chronic venous insufficiency, etc. The severity of VTE is illustrated by a 30-day all-cause mortality of ~10%.1 Patients on oral anticoagulation have a risk for recurrent VTE of 8% in the first six months, with the highest rates within the first two weeks.2 Looking at longer time intervals, risk of recurrence increases to almost 40% within a follow-up of 10 years.3 Factors such as active cancer or sub-therapeutic levels of anticoagulation have been identified as triggers. Therefore, the need for a fast-acting and reliable anticoagulant with predictable effect is obvious.
Anticoagulation in the acute phase
The objective of rapid onset anticoagulation is prevention of progression of disease, early death and recurrence of disease. Dependent on the underlying disease, the minimum duration of anticoagulation is three months. European Society of Cardiology (ESC) guidelines recommend immediate parenteral anticoagulation in the acute phase with either unfractionated heparin (UFH), low molecular weight heparin (LMWH) or fondaparinux for the first 5–10 days.4 This was followed by the initiation of oral VKA in the last few decades. The standard therapeutic sequence was the continuation of parenteral anticoagulation for five days, starting with VKA as early as possible. The therapeutic range is defined by an international normalised ratio (INR) of 2.0–3.0 and parenteral anticoagulation should be continued for two consecutive days after the INR range has been achieved. Since April 2014, dabigatran has been an alternative option for oral anticoagulation.
DTI as novel therapeutic option
There are three major disadvantages of oral anticoagulation with VKA:
1. The need for regular drug monitoring
2. The small therapeutic window, with time in therapeutic range of ~60%
3. The high rate of severe adverse drug related events.5
New drugs need to meet the clinical efficacy of VKA, show at least comparable rates of adverse events and offer comfortable handling.
Key trials
In the RE-COVER (2539 patients) and RE-COVER II (2589 patients) trials, dabigatran was tested against warfarin for the treatment of VTE.6,7 Both trial designs were double-blind, double-dummy. Enoxaparin/dabigatran and enoxaparin/warfarin were compared over a follow-up period of six months. Because the studies were planned as a twin study, the efficacy endpoint was defined as recurrent VTE or fatal PE in both studies. The safety outcome was defined as major bleeding. The results showed comparable efficacy of dabigatran with fewer episodes of major bleeding (Table 2). The analysis of pooled data of both studies showed a hazard ratio for efficacy of 1.09 and 0.73 for major bleeding. Compliance is important because of the twice-daily administration. Drug monitoring is not required. Compared to more than 50 years’ experience with VKA, the knowledge concerning NOACs is limited but it is developing fast. The recommendation level in the ESC guidelines is IB for the treatment of VTE with dabigatran as an alternative to VKA. Dosage recommendation is 150mg twice-daily or 110mg twice-daily for patients ≥80 years of age or those under concomitant verapamil treatment.
Extended treatment with DTI has been investigated in two further trials. Extension of anticoagulation over three  months should be considered for patients with first episode of unprovoked PE and low bleeding risk (IIa, B). Anticoagulation for indefinite duration is recommended for patients with a second episode of unprovoked PE (I, B). For patients with PE and cancer, extended anticoagulation should be considered for an indefinite period, or until cure of cancer (IIa, C).
RE-SONATE compared dabigatran with placebo for an additional 6 months with a superiority design. A total of 1343 patients were enrolled; VTE rate was 5.6% in the control group. Dabigatran-induced risk reduction for recurrent VTE was 92%. Bleeding occurred in 5.3% of the dabigatran group and in 1.8% of the placebo group.8
RE-MEDY compared dabigatran with warfarin for 18–36 months with a non-inferiority design. A total of 2856 patients were enrolled. VTE rate was 1.3% in the control group; hazard ratio (HR) was 1.44 with p=0.01 for non-inferiority. The rate of major bleeding was 0.9% for dabigatran versus 1.8% for warfarin (HR 0.52).8
These results underline that dabigatran is both effective and safe in extended treatment. However, for safe usage we have to focus on contraindications, drug–drug interactions and management of complications.
Contraindications and drug–drug interactions
As the excretion is mainly renal, renal impairment with creatinine clearance (CrCl) <30ml/min is a contraindication. Dose reduction to 110mg twice-daily should be considered in patients with CrCl 30–50ml/min, age ≥75 years, weight <50kg, known gastritis, oesophagitis or gastroesophageal reflux. Renal function has to be measured before initiation of dabigatran medication and thereafter once a year (every six months in patients with CrCl 30–50ml/min and/or age ≥75 years).
Further contraindications are acute, clinically relevant bleeding, intolerance of the drug or of components of the drug carrier and high bleeding risk. The latter comprises of, for example, former gastrointestinal bleeding, malignant disease with high bleeding risk, former intracranial haemorrhage, vascular aneurysm, etc. No other anticoagulants should be combined with dabigatran with the exception of the time period when conversion from parenteral anticoagulants to dabigatran is performed.
Severely impaired liver function or severe liver disease is another contraindication. Dabigatran is not suitable for anticoagulation of patients with mechanical heart valves. No combination with ketoconazole, ciclosporin, itraconazole or dronedarone is possible. Furthermore, it should be kept in mind that there are almost no data regarding concomitant use of dabigatran and inhibitors of platelet aggregation. Platelet aggregation inhibitors increase bleeding risk, therefore a combination with dabigatran seems hazardous.
Simultaneous treatment with P-glycoprotein inhibitors increases the active drug plasma concentration. Table 3 shows the most relevant P-glycoprotein inhibitors in daily clinical practice.
Management of complications
For surgery, there are three factors which have to be taken under consideration:
1. Is there high or low surgical bleeding risk?
2. Is the renal function defined by CrCl?
3. Is there time to delay surgery or is there an acute indication?
Table 4 gives an overview of when to stop dabigatran ahead of elective surgery. Because of the short half-life, bridging with UFH or LMWH is not recommended before or after surgery. After surgery, dabigatran treatment should be initiated as soon as possible.9
Measurement of the anticoagulatory effect of dabigatran is difficult. Quantitative and qualitative assessment could be obtained by the activated partial thromboplastin time (aPTT), which shows a curvilinear relationship.10 If the aPTT level exceeds twice the upper limit of the hospital-specific assay, a higher bleeding risk could be assumed. As there is little effect of dabigatran on INR, this parameter does not help to assess bleeding risk. The ecarin clotting time (ECT) assay provides a direct measure of the DTI activity. Elevated bleeding risk is resembled by threefold-elevated ECT 12 hours after the last dabigatran intake. Thrombin time is highly sensitive and may be used to exclude residual anticoagulation. In addition, a calibrated assay for anticoagulation is available (Hemoclot).
Bleeding is a serious challenge as no antidote exists. In an acute setting, the bleeding has to be controlled by all means through compression, endoscopic, interventional or surgical actions. Fresh frozen plasma, prothrombin complex concentrate or activated Factor VII could be administered but no reliable data concerning efficacy exists. Haemodialysis is able to withdraw dabigatran (62% after two hours and 68% after four hours) but is a complex procedure in acute bleeding.11
Conclusions
Oral DTIs, such as dabigatran, broaden the treatment options in patients with PE and DVT. Dabigatran shows comparable efficacy to VKA in the first three months and also in extended usage. The safety profile of dabigatran seems to be superior to VKA. Deliberate use demands continuous monitoring of renal function and knowledge of drug kinetics and interactions. Careful monitoring of real world data will help to define its potential benefit in routine patient care.
Key points
  • Deep vein thrombosis (DVT) and pulmonary embolism (PE) show significant morbidity and mortality.
  • Direct thrombin inhibitors offer a new and convincing therapeutic option.
  • Oral intake without the need of drug monitoring and short half-life characterise daily use.
  • Contraindications and drug–drug interactions with direct thrombin inhibitors have to be considered.
  • Reasonable application of direct thrombin inhibitors offer effective and safe secondary prophylaxis after DVT or PE.
References
  1. Goldhaber et al. Acute pulmonary embolism: clinical outcomes in the International Cooperative Pulmonary Embolism Registry (ICOPER). Lancet 1999;353(9162):1386–9.
  2. Heit JA et al. Heparin and warfarin anticoagulation intensity as predictors of recurrence after deep vein thrombosis or pulmonary embolism: a population based cohort study. Blood 2011;118(18):4992–9.
  3. Prandoni P et al. The risk of recurrent venous thromboembolism after discontinuing anticoagulation in patients with acute proximal deep vein thrombosis or pulmonary embolism. A prospective cohort study in 1,626 patients. Haematologica 2007;92(02):199–205.
  4. Konstantinides SV et al. 2014 ESC Guidelines on the diagnosis and management of acute pulmonary embolism. Eur Heart J 2014;doi:10.1093/eurheart/ehu283.
  5. Lenzer J. Anticoagulants cause the most serious adverse events, finds US analysis. BMJ 2012;344:e3989.
  6. Schulman S et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med 2009;361(24):2342–52.
  7. Schulman S et al. Treatment of acute venous thromboembolism wirh dabigatran or warfarin and pooled analysis. Circulation 2014;129(7):764–72.
  8. Schulman S et al. Extended use of dabigatran, warfarin, or placebo in venous thromboembolism. N Engl J Med 2013;368(8):709–18.
  9. Heidbuchel H et al. EHRA practical guide on the use of new oral anticoagulants in patients with non-valvular fibrillation: executive summary. Eur Heart J 2013;34(27):2094–106.
  10. van Ryn J et al. Dabigatran etexilate — a novel, reversible, oral direct thrombin inhibitor: interpretation of coagulation assays and reversal of anticoagulant activity. Thromb Haemost 2010;103:1116–27.
  11. Stangier J et al. Influence of renal impairment on the pharmacokinetics and pharmacodynamics of oral dabigatran etexilate: an open label, parallel-group, single-centre study. Clin Pharmacokinet 2010;49:259–68.


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