Dipak Patade

NOACs Options for anticoagulation expanding steadily over the past few decades a greater number of agents for prevention and management of thromboembolic disease. In addition to heparins and vitamin K antagonists, anticoagulants that directly target the enzymatic activity of thrombin and factor Xa have been developed. Appropriate use of these agents requires knowledge of their individual characteristics, risks, and benefits.

Other acronyms orally acting direct thrombin inhibitors and direct factor Xa inhibitors also known as: direct oral anticoagulants (DOACs), target-specific oral anticoagulants (TSOACs), oral direct inhibitors (ODIs), and NOACs, which stands for "novel oral anticoagulants”

Clinical indications 1.Venous thromboembolism (VTE) prophylaxis (non-orthopedic) 2.VTE prophylaxis (orthopedic) 3.VTE treatment (individuals without cancer, initial anticoagulation) 4.VTE treatment (individuals without cancer, long-term anticoagulation) 5.VTE treatment (individuals with cancer) 6.Atrial fibrillation (AF) 7.Acute coronary syndromes (ACS) 8.Heparin-induced thrombocytopenia (HIT)

Risk groupDrug nameTrial name VTE prophylaxisDabigatranRE-NOVATE I and RE-NOVATE II. RE-MODEL, RE-MOBILIZE RiveroxabanRECORD-1 TO 4 ApixabanADVANCE -1 TO 3 VTE treatmentDabigatranRE-COVER I and RE-COVER II RiveroxabanEINSTEIN-DVT,EINSTEIN-PE ApixabanAMPLIFY VTE extensionDabigatranRE-MEDY, RE-SONATE RiveroxabanEINSTEIN-EXT ApixabanAMPLIFY-EXT VTE recurrenceAspirinINSPIRE,WARFASA RiveroxabanEINSTEIN-CHOICE CANCER VTENOACSMETANALYSIS RiveroxabanSELECT-D

Risk groupDrug nameTrial name CAD/PADRiveroxabanCOMPASS HEART FAILURERiveroxabanCOMMANDER-HF VTE PROPHYLAXIS IN MEDICAL PTSRiveroxabanMARINER ACSRiveroxabanATLAS ACS 2-TIMI 51 trial GEMINI-1 ApixabanAPPRAISE 2 Valvular HDDabigatranRE-ALIGN And yet many more to published soon ……………………………………

DABIGATRAN

Dabigatran for Prophylaxis of DVT, Pulmonary Embolism and After Hip Replacement Surgery prophylaxis of deep venous thrombosis (DVT) and pulmonary embolism (PE) in patients who have undergone hip replacement surgery. two randomized, double-blind, phase III trials :RE-NOVATE I and RE-NOVATE II. Endpoints: Primary efficacy endpoint: composite of total VTE and all-cause mortality during treatment Secondary efficacy endpoints: all-cause mortality, symptomatic DVT, distal DVT, composite of fatal/non-fatal DVT and PE during follow-up Primary safety endpoint: major bleeding Secondary safety endpoints: composite of major and clinically relevant non-major bleeding events, other bleeding events during treatment, liver enzyme elevation and acute coronary events Trial participants: 3494 patients aged ≥18 years, scheduled for elective total hip replacement IN RE- NOVATE I 2055 patients aged ≥18 years, scheduled for elective total hip arthroplasty IN RE NOVATE II

RE-NOVATE I Study design

RE-NOVATE I Results

RE-NOVATE II study design

RE-NOVATE II results

RE-NOVATE CONCLUSIONS Oral dabigatran showed statistical non-inferiority to subcutaneous enoxaparin for VTE and all-cause death. There was no significant difference between dabigatran and enoxaparin for major VTE and VTE-related death. Safety: The rates of minor and major bleeding were comparable in all 3 study groups.

VTE treatment and secondary prophylaxis Randomized, double-blind phase III non-inferiority studies In the treatment of acute VTE and further secondary prevention RE-COVER I and RE-COVER II

RE-COVER I Active treatment: dabigatran 150 mg p.o. twice daily for 6 months plus warfarin placebo after an initial treatment with a parenteral anticoagulant (low molecular weight or unfractionated heparin) plus warfarin placebo (sham INR) for at least 5 days (n=1274) Control treatment: dose-adjusted warfarin (INR 2.0–3.0) for 6 months, starting after randomization, plus dabigatran placebo, starting after at least 5 days parenteral anticoagulation (n=1265)

Efficacy: Dabigatran was non-inferior to warfarin in the the prevention of recurrent or fatal VTE in patients with acute VTE Safety: In the dabigatran group, the rate of major or clinically relevant nonmajor bleeding events was significantly lower as in the warfarin group. The difference in major bleeding was not significant

direct thrombin inhibitor dabigatran has similar effects on VTE recurrence and a lower risk of bleeding compared with well-controlled warfarin for the treatment of acute VTE. Pooled analysis of this study RE-COVER II and the RE-COVER I trial gave hazard ratios for recurrent VTE of 1.09, for major bleeding of 0.73, and for any bleeding of 0.70

Riveroxaban

RECORD 4

Efficacy: Oral rivaroxaban was significantly superior to subcutaneous enoxaparin for thromboprophylaxis after total knee arthroplasty. Safety: Although there were more major, major plus clinically relevant nonmajor, and any bleeding events with rivaroxaban, the differences compared with enoxaparin were not statistically significant

The EINSTEIN DVT Study Design Included an Initial Intensified Regimen of 'Xarelto'  A single-drug approach with 'Xarelto' was used in EINSTEIN DVT  An intensified dose of 'Xarelto' (15 mg bid) was given for the first 21 days to provide protection when patients are at highest risk of recurrence  After 21 days 'Xarelto' 20 mg od was given to provide continued protection against VTE recurrence  Primary efficacy outcome: symptomatic recurrent VTE (composite of recurrent DVT, non-fatal PE or fatal PE)  Principal safety outcome: composite of major or clinically relevant non-major bleeding The EINSTEIN Investigators, mg bid Objectively confirmed DVT without symptomatic PE N=3449 'Xarelto' Day 1 Day 21 Enoxaparin (1.0 mg/kg) bid for at least 5 days, plus VKA target INR 2.5 (INR range 2.0–3.0) Predefined treatment period of 3, 6 or 12 months 20 mg od 'Xarelto' R 30-day observation period

Effective DVT Treatment Matters Time to event (days) Cumulative event rate (%) 'Xarelto' (N=1731) Enoxaparin/VKA (N=1718) 4.0 HR=0.68 (95% CI 0.44–1.04) p<0.001 for non-inferiority p=0.08 for superiority The EINSTEIN Investigators, 2010 Intention-to-treat population 'Xarelto' and standard of care had similar efficacy in the reduction of symptomatic recurrent VTE

Safety Matters: Similar Rates of Clinically Relevant Bleeding Enoxaparin/VKA (N=1711) 'Xarelto' (N=1718) Time to event (days) Cumulative event rate (%) HR=0.97 (95% CI 0.76–1.22) p=0.77 The EINSTEIN Investigators, 2010 Safety population 'Xarelto' and standard of care had similar rates of major and clinically relevant non-major bleeding

Safety Matters: Similar Rates of Clinically Relevant Bleeding 32 'Xarelto'Enoxaparin/VKA n (%)n First major/clinically relevant non-major bleeding 139(8.1)138(8.1) Major bleeding14(0.8) 20(1.2) Contributing to death1(<0.1)5(0.3) In a critical site3(0.2)3

'Xarelto' (N=1731), % Enoxaparin/VKA (N=1718), % HR (95% CI)p-value Net clinical benefit* (0.47–0.95) 0.03 Favourable Benefit–Risk Balance Matters The EINSTEIN Investigators, 2010 *Defined as the composite of the primary efficacy outcome and major bleeding

'Xarelto' (N=1731) Enoxaparin/VKA (N=1718) Male patients (%) Age, mean (years) Weight (%) ≤50 kg >50–100 kg >100 kg Creatinine clearance (%) <30 ml/min –<50 ml/min –<80 ml/min ≥80 ml/min Patient Characteristics: Similar in Both Study Arms in EINSTEIN DVT The EINSTEIN Investigators, 2010 Intention-to-treat population

'Xarelto' (N=1731) Enoxaparin/VKA (N=1718) Intended treatment duration (%) 3 months months months Pretreatment with LMWH/heparin/fondaparinux ≤48 h (%) Active cancer (%) Unprovoked VTE (%) Patient and Treatment Characteristics: Similar in Both Study Arms in EINSTEIN DVT The EINSTEIN Investigators, 2010 Intention-to-treat population

The EINSTEIN PE Study Design Included an Initial Intensified Regimen of 'Xarelto'  A single-drug approach with 'Xarelto' was used in the pivotal EINSTEIN PE study - the largest ever conducted in the acute treatment of PE, involving haemodynamically stable patients  An intensified dose of 'Xarelto' (15 mg bid) was given for the first 21 days to provide protection when patients are at highest risk of recurrence  After 21 days, 'Xarelto' 20 mg od was given to provide continued protection against VTE recurrence  Primary efficacy outcome: symptomatic recurrent VTE (composite of recurrent DVT, non-fatal PE or fatal PE)  Principal safety outcome: composite of major or clinically relevant non-major bleeding The EINSTEIN–PE Investigators, mg bid Objectively confirmed PE with or without symptomatic DVT N=4832 'Xarelto' Day 1 Day 21 Enoxaparin (1.0 mg/kg) bid for at least 5 days, plus VKA target INR 2.5 (INR range 2.0–3.0) Predefined treatment period of 3, 6 or 12 months 20 mg od 'Xarelto' R 30-day observation period

Effective PE Treatment Matters Time to event (days) 'Xarelto' (N=2419) Enoxaparin/VKA (N=2413) HR=1.12 (95% CI 0.75–1.68) p=0.003 (non-inferiority) p=0.57 (superiority) Cumulative event rate (%) 'Xarelto' also showed consistent efficacy across subgroups The EINSTEIN–PE Investigators, 2012 Intention-to-treat population 'Xarelto' and standard of care had similar efficacy in the reduction of symptomatic recurrent VTE

Effective PE Treatment Matters 38

Safety Matters: Similar Rates of Clinically Relevant Bleeding 'Xarelto' n/N (%) Enoxaparin/VKA n/N (%) HR (95% CI) p-value 249/2412 (10.3) 274/2405 (11.4) 0.90 (0.76–1.07) p= Time to event (days) 'Xarelto' (N=2412) Enoxaparin/VKA (N=2405) Cumulative event rate (%) 'Xarelto' also showed consistent safety across subgroups The EINSTEIN–PE Investigators, 2012 Safety population Major or clinically relevant non-major bleeding

Cumulative event rate (%) Time to event (days) 'Xarelto' (N=2412) Enoxaparin/VKA (N=2405) Significant Reduction: Halving the Risk of Major Bleeding The EINSTEIN–PE Investigators, 2012 Safety population 'Xarelto' reduced major bleeding by 51% compared with standard of care, with large reductions in critical site bleeding

Significant Reduction: Halving the Risk of Major Bleeding 41 'Xarelto'Enoxaparin/VKA HR (95% CI) p-value n (%)n Major bleeding26(1.1)52(2.2) 0.49 (0.31–0.79) p=0.003 Fatal2(<0.1)3(0.1) Non-fatal critical site7(0.3)26(1.1) Intracranial1(<0.1)10(0.4) Retroperitoneal1(<0.1)7(0.3)

'Xarelto' can be Used in a Wide Range of Haemodynamically Stable PE Patients  Efficacy and safety outcomes were consistent across key patient subgroups, including elderly patients and those with renal impairment  'Xarelto' was effective regardless of the severity of PE, whether it was anatomically limited (≤25% of vasculature of a single lobe) or extensive (multiple lobes and >25% of entire pulmonary vasculature)  'Xarelto' was associated with a similar rate of adverse events compared with standard of care  This included serious adverse events and treatment-emergent adverse events  There was no evidence of liver toxicity in patients who received 'Xarelto' The EINSTEIN–PE Investigators, 2012

APIXABAN

Efficacy: Apixaban was similarly effective in preventing VTE after total knee arthroplasty. Safety: Apixaban was superior to enoxaparin for major and clinically relevant bleeding episodes

Apixaban after the initial Management of PuLmonary embolIsm and deep vein thrombosis with First-line therapY (2013)

Efficacy: For the treatment of acute VTE, a fixed-dose regimen of apixaban alone was non-inferior to conventional treatment consisting of enoxaparin followed by warfarin Safety: Treatment with apixaban was associated with significantly less major and clinically relevant non-major bleeding

Extension VTE trials

Efficacy: Dabigatran was as effective as well-controlled warfarin in the extended treatment of VTE and secondary prevention of symptomatic VTE. Safety outcome: Treatment with the direct thrombin inhibitor was associated with a reduced risk for bleeding but an increased incidence of acute coronary events.

Efficacy: Extended treatment with rivaroxaban was superior to placebo in preventing symptomatic recurrent VTE. A prespecified indicator of net clinical benefit (symptomatic recurrent VTE plus major bleeding) favored rivaroxaban Safety: The incidence of major bleeding was similar in both groups. However, the rate of clinically relevant non-major bleeding was higher in the patients assigned to rivaroxaban

Efficacy: Extended anticoagulation with apixaban at either a treatment dose (5 mg) or a thromboprophylactic dose (2.5 mg) resulted in a large and significant reduction in the risk of recurrent fatal or non-fatal VTE. Safety: Both of the regimen of apixaban were safe. The rates of major bleeding in the apixaban groups were low and similar to those in the placebo group.

VTE recurrence trials

ASPIRE and WARFASA studies(INSPIRE project) 2014 The ASPIRE and WARFASA studies were independent, investigator- initiated, randomized, double-blind, placebo-controlled, clinical trials designed to examine the efficacy and safety of low-dose aspirin100mg in the extended treatment of VTE. Eligible patients were those with a first episode of unprovoked VTE, defined as proximal deep-vein thrombosis (DVT) or pulmonary embolism (PE), who had completed initial treatment with heparin and warfarin or an equivalent anticoagulant regimen. Venous thromboembolism was considered as unprovoked when it occurred in the absence of any known specific permanent or temporary clinical risk factor.

ASPIRE and WARFASA studies(INSPIRE project) 2014 prospective, combined analysis of the WARFASA and ASPIRE trials provides clear evidence that – aspirin reduces the risk of recurrent VTE events by ≈40% and is a very safe and effective therapy. Although it does not reduce the rate of VTE by as much as vitamin K antagonists or newer oral anticoagulants (direct thrombin inhibitors or factor Xa inhibitors), among patients for whom such therapies are not considered appropriate or are discontinued, aspirin should be strongly considered. Aspirin for the Prevention of Recurrent Venous Thromboembolism.The INSPIRE Collaboration,circulation September 23, 2014 Vol 130, Issue 13

NOAC in CANCER-VTE

SELECT-D study Pilot study 406 patients Riveroxaban 15 mg BID x 21 days f/b 20 mg OD vs LMWH dalteparin 200U/kg x 1 month f/b 150 U/kg for 12 months Reduced VTE recurrence ( 4 % vs 11 %) Rate of major bleeding almost same( 6% vs 5.5 % ) Similar results have been shown by Edoxaban in similar pilot studies Studies favors Edoxaban over Riveroxaban for Cancer related VTE Study with Apixaban is ongoing.

NOAC in CAD and HF patients

ATLAS ACS 2-TIMI 51 trial Anti-Xa Therapy to Lower cardiovascular events in addition to Aspirin with or without thienopyridine therapy in Subjects with Acute Coronary Syndrome 2 – Thrombolysis in Myocardial Infarction 51 Trial (2011) Acute coronary syndromes arise from coronary atherosclerosis with superimposed thrombosis. Since factor Xa plays a central role in thrombosis, the inhibition of factor Xa with low-dose rivaroxaban might improve cardiovascular outcomes in patients with a recent acute coronary syndrome. compared rivaroxaban 2.5 mg or 5 mg twice daily (unlike the 20 mg once-daily dose for atrial fibrillation) with placebo in 15,526 patients following ACS. At a mean follow-up of 13 months, the primary efficacy endpoint of CV death, MI or stroke,Rates of definite, probable or possible stent thrombosis were analysed

The use of rivaroxaban 2.5 mg twice daily, might be considered in combination with aspirin and clopidogrel if ticagrelor and prasugrel are not available for NSTEMI patients who have high ischaemic and low bleeding risks. In patients with a recent acute coronary syndrome, rivaroxaban reduced the risk of the composite end point of death from cardiovascular causes, myocardial infarction, or stroke. Rivaroxaban increased the risk of major bleeding and intracranial hemorrhage but not the risk of fatal bleeding.

Low-dose 2.5-mg rivaroxaban demonstrated reduced risk of death from cardiovascular (CV) causes, myocardial infarction (MI), or stroke Increased risk of major bleeding and intracranial hemorrhage, but not fatal bleeding

APPRAISE 2 assessed the effects of the oral factor Xa inhibitor apixaban 5 mg twice daily compared with placebo, in addition to standard-of-care antiplatelet therapy following ACS. It was terminated early (median 8 months) due to a markedly increased risk of severe bleeds, including intracranial haemorrhage, without any apparent benefit in terms of ischaemic events.

Low dose NOAC Riveroxaban 2.5 mg with SAPT after dropping aspirin Possible less repeat ACS vents with less bleeding.

COMPASS trial In stable CAD/PAD patient Adding low dose Riveroxaban 2.5 BID with SAPT (Apsirin) increases bleeding but reduces secondary event rates.

COMMANDER HF trial Heart failure is associated with activation of thrombin-related pathways, which predicts a poor prognosis. Hypothesis: treatment with rivaroxaban, a factor Xa inhibitor, could reduce thrombin generation and improve outcomes for patients with worsening chronic heart failure and underlying coronary artery disease.

NOAC and Valvular HD

NOAC for thromboprophylaxis of general medical patients

MARINER trial

Ongoing trials

Modified Caprini risk assessment model for VTE in general surgical patients Cardiac surgery (moderate to high Caprini score) –rates of VTE up to 1 percent in this population (prophylaxis unknown) but older studies suggest higher rates (up to 25 percent) in the absence of prophylaxis. Noncardiac thoracic surgery (moderate to high Caprini score) – symptomatic VTE ranges from 0.18 to 7.4 percent (highest in pneumonectomy, esophagectomy, extended resection) Neurosurgery (moderate to high Caprini score) – Meta-analyses report a pooled incidence of VTE in untreated patients between 16 and 29 percent, highest in those undergoing craniotomy Major trauma (moderate to high Caprini score) – While studies report an incidence of DVT as high as 58 percent among those not receiving prophylaxis these rates may reflect the most seriously ill patients with multiple other injuries (eg, traumatic brain and spinal injury)