DIRECT ORAL ANTICOAGULANT(DOACS) DRUGSInhibiting thrombosis without inducing bleed-ing is the holy grail of anticoagulant therapy.Dr Sandeep KumarPG Department of Internal MedicineSKIMS

INTRODUCTION New oral anticoagulants (NOACs) are an alternative for vitamin K antagonists (VKAs) to prevent stroke in patients with non-valvular atrial fibrillation (AF). Both physicians and patients will have to learn how to use these drugs effectively and safely in specific clinical situations.

NOACs offer advantages of predictable effect without need for monitoring, fewer food and drug interactions, shorter plasma half- life, and an improved efficacy/safety ratio), the proper use of

NOACs will require new approaches in many aspects.

Whereas the 2010 ESC Guidelines (and the 2012 Update) mainly discuss the indications for anticoagulation in general (e.g. based on the CHA2DS2-VASc score) and of NOAC in particular , they guide less on how to deal with NOAC in specific clinical situations.

The EHRA set out to coordinate a unified way of informing physicians on the practical use of the different NOACs, in a text that supplements the AF Guidelines as a guidance tool for safe and effective use of NOACs when prescribed.

ANTI THROMBOTIC DRUGS

ROLE OF PLATELETS IN ARTERIAL THROMBOSIS

SITE OF ACTION OF ANTI PLATELET DRUGS

ANTICOAGULANT DRUGS Parental anticoagulant drugsHeparin Fondaparinaux

MECHANISM OF ACTION OF HEPARIN, LOW-MOLECULAR-WEIGHT HEPARIN (LMWH), AND FONDAPARINUX, A SYNTHETIC PENTASACCHARIDE. A.

PARENTERAL DIRECT THROMBIN INHIBITORSBevalirudin – active site & exosite 1Argatroban – active site (Hepatic metabolism)Lepirudin – active site & exosite 1 (Renal clearance)

INDIRECT THROMBIN INHIBITORS & XA INHIBITORS Fondaparinaux – catalyses Factor Xa inhibition (not thrombin) Danaparoid – treatment of HIT Idrapavinum

VKAs(Vitamin K Antagonists) Warfarin Acenocaumerol

ORAL ANTICOAGULANT DRUGS

NEW ORAL ANTICOAGULANT DRUGSFactor Xa inhibitors Apixaban EdoxabanRivaroxaban Factor 2a inhibitors & Factors Xa inhibitors

Dabigatran etixilate

Feature Rivaroxaban Apixaban Dabigatran

Target Xa Xa 2a + Xa

Mol Wt 436 460 628

Prodrug No No Yes

Bioavailability (80%)

80 50 6

Time to peak (Hr) 3 3 2

Half life (Hr) 9 9-14 12-17

Renal excretion(%) 65 25 80

Antidote None None None

COMPARISON OF FEATURES OF NOAC DRUGS

SITE OF ACTION OF OAC AGENTS

NEW ORAL ANTICOAGULANTS: COMPARATIVE PHARMACOLOGY WITH VITAMIN K ANTAGONISTS.

In the last 4 years, 6 phase 3 trials including a total of 27 023 patients with venous thromboembolism (VTE) compared a direct oral anticoagulant (DOAC) with vitamin K antagonists (VKAs). To aid the clinician in assessing the amount of information, we address frequently raised clinical questions in a review of combined trial results. We included the phase 3 trials that compared dabigatran etexilate, rivaroxaban, apixaban, or edoxaban with VKA therapy in patients with acute symptomatic VTE. Recurrent VTE occurred in 2.0% of DOAC recipients compared with 2.2% in VKA recipients (relative risk [RR] 0.90, 95% confidence interval [CI] 0.77-1.06). Treatment with a DOAC significantly reduced the risk of major bleeding (RR 0.61, 95% CI 0.45-0.83). In parallel, intracranial bleeding, fatal bleeding, and clinically relevant nonmajor bleeding occurred significantly less in DOAC recipients. The efficacy and safety of DOACs were consistent in patients with pulmonary embolism, deep venous thrombosis, a body weight ‡100 kg, moderate renal insufficiency, an age ‡75 years, and cancer. In conclusion, DOACs and VKAs have similar efficacy in the treatment of acute symptomatic VTE, a finding that is consistent in key clinical subgroups. Treatment with a DOAC significantly reduces the risks of major bleeding. (Blood. 2014;124(12):1968-1975)

TO AID THE CLINICIAN IN DEALING WITH THE OVERWHELMING AMOUNT OF INFORMATION, WE PRESENT A REVIEW OF THE COMBINED RESULTS OF THE PHASE 3 TRIALS AND ADDRESS VARIOUS FREQUENTLY RAISED CLINICAL QUESTIONS: 1- What is overall efficacy of DOACs compared with VKAs on recurrent VTE? 2 – What is the safety profile of DOACs compared with VKAs in terms of

major bleeding, intracranial bleeding, major gastrointestinal bleeding, and clinically relevant non-major (CRNM) bleeding?

3. What is the efficacy and safety of DOACs compared with VKAs in specific subgroups (ie, patients with pulmonary embolism [PE], patients with deep venous thrombosis [DVT], patients with cancer, elderly patients, obese patients, and patients with impaired renal function)?

4. What is the net clinical benefit in terms of patient-relevant outcomes (ie, prevention of recurrence with minimal risk of major bleeding) of DOACs compared with VKAs?

TRIAL SUMMARIES1

CONCLUSIONIn conclusion, DOACs and VKAs have similar efficacy in the treatment of acute symptomatic deep venous thrombosis and pulmonary embolism, a finding that is consistent in key clinical subgroups. Treatment with a DOAC is associated with a significant reduction in the risk of major bleeding, intracranial bleeding, and fatal and clinically relevant non-major bleeding.

The most striking finding is the significant almost 40% relative reduction in major bleeding. Consistent with this observation are the reductions in important components of major bleeding, such as fatal bleeding (64% relative reduction) and intracranial bleeding (63% relative reduction). Although rare, they are the most feared complications of anticoagulant treatment. In line with these reductions,DOAC recipients have significantly less CRNM bleeding, and there are no indications that the risk of major gastrointestinal bleeding is increased in this setting of VTE. The benefit of DOACs with respect to major bleeding was maintained in patients with moderate renal insufficiency and elderly patients, whereas in cancer patients the risk of major bleeding was at least comparable with that in the standard treatment group, and possibly better. Taken together, our results in- dicate that DOACs can be prescribed safely for patients with VTE.

Our findings with respect to major bleeding are very similar to the results seen in the atrial fibrillation (AF) trials, where DOACs reduced intracranial hemorrhage by a significant 52% compared with VKAs.10 In contrast, DOACs were associated with a significant 25% relative increase in major gastrointestinal bleeding in the AF trials, whereas in the treatment of VTE, no difference in major gastrointestinal bleeding rates was seen.10 The reasons for this discrepancy are at present unclear but may include differences in patient characteristics (eg, use of concomitant antiplatelet drugs) and treatment duration.

Rivaroxaban represents a clinical and cost- effective option for treatment of DVT or PE for all treatment durations, and even dominates LMWH and VKA therapy in the 3-month treatment group.

INITIATING ANTICOAGULANT THERAPY

MEASURES IN CASE OF BLEEDING

DABIGATRAN REVERSAL - IDARUCIZUMAB Specific reversal agents for non–vitamin K antagonist oral anticoagulants

are lacking. Idarucizumab, an antibody fragment, was developed to reverse the anticoagulant effects of dabigatran.

Among 68 patients with an elevated dilute thrombin time and 81 with an elevated ecarin clotting time at baseline, the median maximum percentage reversal was 100% (95% confidence interval, 100 to 100). Idarucizumab normalized the test results in 88 to 98% of the patients, an effect that was evident within minutes.

Charles V. Pollack, Jr., M.D., Paul A. Reilly, Ph.D., Idarucizumab for Dabigatran Reversal, N Engl J Med 2015; 373:511-520August 6, 2015 DOI: 10.1056/NEJMoa1502000

LAST INTAKE OF DRUG BEFORE ELECTIVE SURGICAL INTERVENTION

RECENT ADVANCES IN ANTICOAGULATION

Anti-sense of factor 11a in thrombosis Genetically engineered antisense codon of factor 11a gene is used to inhibit the factor 11a production and hence effecting coagulation cascade.

MECHANISM

STUDY DESIGN

EFFICACY AND SAFETY OUTCOMES

REFERENCES 1 - Direct oral anticoagulants compared with vitamin K antagonists for

acute venous thromboembolism: evidence from phase 3 trialsNick van Es,1 Michiel Coppens,1 Sam Schulman,2 Saskia Middeldorp,1 and Harry R. Bu ̈ller11Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands; and 2Department of Medicine, McMaster University and Thrombosis and Atherosclerosis Research Institute, Hamilton, ON, Canada(DOI 10.1182/blood-2014-04- 571232.)

2- Making (Anti)Sense of Factor XI in Thrombosis, Robert Flaumenhaft, M.D., Ph.D NEJM .December 2014

3 -.Harrison's principles of internal medicine

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