Anticoagulation with vitamin K antagonists helps treat and prevent thromboembolic diseases and prevent strokes in atrial fibrillation. There is a a risk of bleeding due to a narrow therapeutic range, food and drug interactions and the need for regular monitoring renders treatment complicated. Target specific oral anticoagulants (TSOACs) allow for fixed dosing without the need for monitoring, few drug interactions and rapid onset of action. However, as of yet specific antidotes are not available to reverse the anticoagulant effects of TSOACs. Data from large-scale Phase III trials has shown that TSOACs are at least non-inferior to warfarin in the treatment and prevention of stroke or thromboembolic events. Trials have also shown that TSOACs are associated with a lower major bleeding risk and a significantly reduced risk of intracranial bleeding. TSOACs appear to be an effective, safer alternative to VKAs. However, there are still concerns about their efficacy and safety in subgroup populations.1. Introduction.
Warfarin, from a group of drugs known as vitamin K antagonists (VKA) has been used since the 1950s to prevent and treat thromboembolism. Although warfarin is effective it has interactions with food and drugs that can both potentiate and lessen anticoagulant effect. Warfarin requires frequent laboratory monitoring because of its narrow therapeutic range. Time spent with an international normalised ratio (INR) above the therapeutic range increases the risk of bleeding. Conversely time spent below the therapeutic range increases the risk of thromboembolism. As a result numerous patients on warfarin receive inadequate anticoagulation.
Target specific oral anticoagulants (TSOCAs) now provide an alternative for prevention and treatment of venous thromboembolism (VTE) and to avoid strokes resulting from atrial fibrillation (AF). TSOCAs have more predictable pharmacodynamics and pharmacokinetics. There are concerns about a lack of specific antidote for TSOCAs that could be used in major bleeding events. Warfarin and other VKAs are used in a number of clinical scenarios. In acute VTE warfarin is started along with parenteral anticoagulation, for example low molecular weight heparin (LMWH), this is continued until the INR is ‘2 for at least 24 hours. For a first episode of VTE the target INR should be 2.5. Risk factors which predict stroke should be assessed before commencing a patient of warfarin for AF. The optimal INR for stroke prevention in AF is 2.5. Warfarin may be used to prevent thrombotic formation resulting from structural heart abnormalities, including prosthetic valves. A study in 2006 showed that among 6454 patients treated with warfarin for AF almost 50% of the time, the INR was outside the target range. A raised INR increases a risk of bleeding, whereas a sub-therapeutic INR increases the risk of thromboembolic event.
2ii. Mechanism of action.
VKAs interfere with the post translational ??-carboxylation of glutamic acid residues in clotting factors II, VII, IX and X (Figure 2) by competitively inhibiting vitamin K epoxide reductase component 1 (VKORC1). This prevents the reduction of vitamin K epoxide to its active hydroquinone form. Warfarin takes effect after several days as it takes time for carboxylated clotting factors to degrade. The prothrombin time is the time taken for clotting of citrated plasma after the addition of calcium and thromboplastin. INR is the universal monitoring index based on the patient’s prothrombin time. Warfarin takes 12 to 16 hours to effect prothrombin time and lasts in the system 4 to 5 days. Warfarin dosing is based on the individuals INR. The precise target INR is dependent on the clinical situation. Duration of treatment may also vary. Induction or inhibition of the isoenzymes in warfarin’s metabolism may alter a patient’s INR, as can altered physiological and disease states.2ii. Reversal methods.
Two randomised controlled trials have shown that if a patient is over anti-coagulated and warfarin subsequently stopped, an INR between 6 and 10 will decline to ‘4 in around 2.5 days[8+9]. Warfarin can also be reversed using vitamin K via the enteral route or more rapidly via intravenous administration. Low doses of oral vitamin K with warfarin discontinuation, is appropriate treatment in correcting a high INR in non bleeding patients. In patients with non-life threatening bleeding a combination of oral and intravenous vitamin K can be used. Life threatening bleeding in warfarin patients can be reversed using prothrombin concentrates. Where not available fresh frozen plasma can be used instead. Plasma doesn’t normally correct the INR completely unless large volumes are given. Warfarin exacerbates bleeding therefore a cause for the bleed should be sought.
3. Direct thrombin inhibitors (DTI).
3i. Primary indication for DTI therapy.
DTIs namely dabigatran is indicated for prevention of VTE in adult patients following elective total hip or total knee replacement. Dabigatran is also used to prevent stroke and systemic embolisation in non valvular AF with one or more risk factors and in the treatment of VTE. The first DTI, ximelagatran, is no longer available as it was associated with reports of liver toxicity.
Endorsement of dabigatran was based on the ‘Randomised evaluation of long term anticoagulation therapy trial (RE-LY)’. This looked at patients with AF and randomly assigned those at risk of stroke, in a blinded fashion into two dabigatran groups of varying doses (110mg and 150mg twice daily), or in an unblinded fashion to an adjusted dose warfarin group. Dabigatran at 110mg resulted in stroke and systemic embolism rates similar to the warfarin group. The 150mg dabigatran group was associated with lower rates of stroke and systemic embolism. The ‘Dabigatran versus Warfarin in the Treatment of Acute Venous Thromboembolism (RE-COVER)’ trial showed that dabigatran was as effective as warfarin at reducing the risk of VTE recurrence. It should be noted that this trial was funded, designed and carried out by Boehinger Ingelheim, who are the makers of dabigatran.
3ii. Mechanism of action.
Dabigatran etexilate is a prodrug hydrolysed by carboxylesterases to the active compound dabigatran after absorption.Dabigatran binds to the active site of free and fibrin bound thrombin (Figure3). Plasma levels of dabigatran peak 2 hours after ingestion. The half-life of dabigatran is 12 to 14 hours (Table 1) which is prolonged with renal impairment. In these cases a lower dose can be used. Drugs that interact with dabigatran are inhibitors or inducers of P-glycoprotein (P-gp) (Table1).
3iii. Reversal methods.
Presently there is no specific antidote in case of major bleeding. Minor bleeding is normally managed conservatively. Each case of bleeding should be judged individually. With moderate to severe bleeding, activated charcoal can be used to prevent further absorption if dabigatran was given within 2 hours. This is based on limited non clinical data. The use of unactivated or activated prothrombin complex concentrate (uPCC/ aPCC) should be considered in serious or life threatening bleeding. Use is based on limited evidence that they may attenuate bleeding. Other antidotes are still in development, for example aDabi-Fab. This consists of humanised dabigatran specific antibody fragment which binds dabigatran in a similar way to thrombin. aDabi-Fab is yet to undergo clinical trials.4. Direct factor Xa inhibitors.
4i. Primary indications for direct factor Xa inhibitor therapy.
Factor Xa inhibitors include rivaroxaban, apixaban, edoxaban and betrixaban. Rivaroxaban is approved for use in the prevention of VTE in adults who have undergone elective hip or knee replacement. It is licensed for prevention of stroke and systemic emboli in AF, treatment of VTE in adults and secondary prevention of acute coronary syndrome (ACS).
The ‘Randomised Evaluation of Long-Term Anticoagulation Therapy (ROCKET-AF)’ found amongst patients with AF, rivaroxaban was non-inferior in preventing stroke and systemic thromboembolism. In this trial the warfarin comparison group had an INR which was therapeutic for only 55% of the time. The ‘Oral rivaroxaban for the treatment of symptomatic pulmonary embolism’ (EINSTEIN-PE) trial found that rivaroxaban was non-inferior to warfarin in preventing recurrence of VTE. The comparison warfarin group had an INR that was within therapeutic range fore only 62.7% of the time. The average age of participants was relatively young at 58 when compared to similar trials and may have had fewer co-morbidities and take fewer medications.
4ii. Mechanism of action.
Factor Xa inhibitors limit the generation of thrombin (Figure 4). They bind to the active site of factor Xa. Rivaroxaban has been shown to inhibit prothrombinase associated and clot associated factor Xa. It does not have a direct effect on platelet aggregation. One-third is excreted unchanged by the kidney and 67% is converted by the liver (CYP3A4) to inactive metabolites. It has the potential to interact with CYP3A4 and P-gp inhibitors/ inducers4iii. Reversal methods.
There is no specific antidote for direct factor Xa inhibitors. For those at risk of imminent death uPCC can be used. Importantly administration of PCCs carries a substantial prothrombotic risk. The use of uPCC is based on limited clinical data. Administration of oral activated charcoal may be used to prevent further absorption. Minor bleeding is usually managed conservatively. Antidotes are in development, for example the recombinant protein (r-Antidote, PRT064445) is a catalytically inactive form of factor Xa. It has been shown to reverse the anticoagulant effect of
factor Xa inhibitors in animal models. Clinical trials are underway.5. Monitoring anticoagulation assays.
5. Monitoring anticoagulation assays.
Warfarin therapy depends on adjusting dosage to keep INR in the target range. INR allows values of the prothrombin time from various locations to be directly compared. There are many variables associated with the pharmacokinetics of warfarin, as well as a narrow therapeutic range, anticoagulation monitoring and dosage adjustment are required. Under anticoagulation is associated with risk of VTE and stroke. Over anticoagulation is associated with increased risk of bleeding. Trials have shown improved anticoagulation control could reduce the likelihood of anticoagulant associated adverse events.
TSOACs have predictable pharmacodynamic and pharmacokinetic profiles which means that coagulation monitoring is not normally required. Articles point to the need for anticoagulation assessment in emergency situations. Table 2 shows the preferred assays that can be used in monitoring TSOACs. 6i. Major bleeding.
Table 4 shows bleeding complications of TSOACs versus warfarin in 4 studies involving 39,705 patients. In terms of treatment for AF, the RE-LY trial showed major bleeding was lower with dabigatran 110mg BD compared with warfarin. There was no major difference in those treated with dabigatran 150mg BD and warfarin. Table 3 shows that INR reached therapeutic levels in only 64% of cases. Therefore dabigatran may only be superior to poorly controlled anticoagulation with warfarin and bleeding rates on warfarin may not be representative. The New England Journal of Medicine published a follow up article to the RE-LY trial in April 2013. This stated that there had been reports of serious and fatal bleeding associated with the use of dabigatran. On examination of data it was found that bleeding rates associated with dabigatran use between October 2010 and December 2011 was not higher than with warfarin. The ROCKET-AF trialshowed similar rates of major bleeding in rivaroxaban and warfarin groups. In this study warfarin only had therapeutic INR for 55% of the time and may not represent real life.
In VTE rates of bleeding associated with dabigatran (1.57%) were similar to warfarin (1.90%) in the RE-COVER study. The EINSTEIN-PE trial showed rivaroxaban (1.07%) had a lower risk of major bleeding when compared to warfarin (2.16%). This trial did have a lower average age of the participant and therefore may have fewer co-morbidities and an inherent lower bleeding risk.ii. Sites of major bleeding.
Gastrointestinal bleeding was increased in patients with NOACs versus warfarin as shown in table 4. The efflux of dabigatran by P-glycoprotein transporters into the gastrointestinal tract may be a mechanism for this. Table 4 shows that NOACs have a lower occurrence of intracranial bleeding when compared to warfarin. Interestingly although TSOACs have no antidotes available, they were associated with a lower risk of major bleeding and mortality.
iii. Major bleeding in subgroups.Graph 1 shows that in patients ’75 treated with VKA were less safe, TSOACs were associated with a lower risk of bleeding than VKA. Elderly patients are more likely to experience, falls, hospitalisation and display cognitive impairment. In the VKA treatment these could contribute to under or over anticoagulation. TSOACs are associated with more stable pharmacokinetics.
Clinical trials select a proportion of a selected population with optimal compliance, this could prove to be problematic in a real world scenario. When looking at an elderly subgroup, few 80-90 year olds are included in trials. As a result the frailest population may not be represented.
Elderly patient are also more likely to have impairment in their renal function. Dabigatran is around 80% renally cleared. As Graph 2 shows the RECOVER I-II trial showed an increased bleeding risk in those with renal impairment on dabigatran versus warfarin. Although reduced doses of dabigatran and rivaroxaban are available for elderly patients and those with a reduced creatinine clearance. Those with advanced renal impairment were excluded from major 7. Discussion.
DTI and direct factor Xa inhibitors are approved in the treatment and prevention of thromboembolic events, and stroke associated with AF. These agents have a rapid onset and a predictable clearance and fewer drug interactions than VKA. They have been shown to be effective in treating and preventing VTE.
At present there is no approved antidotes for TSOACs. Despite this they are associated with a lower risk of intracranial bleeding. In terms of major bleeding events they have been found to be non-inferior or superior in safety to standard VKA treatment. Conversely they have been found to have an increased risk of gastrointestinal bleeding. Patients with renal insufficiency have delayed clearance and hence may have elevated levels of drug leading to an increase risk of bleeding.
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