Noacs

NOACS

NEWER ORAL ANTI COAGULANTSDr. k. nagendra prasadNEWER ORAL ANTICOAGULANTS

TOPIC OUTLINEIntroductionTypes of NOAC s and their propertiesAdvantages of NOAC s over VKAStart-up and follow-up scheme for patients on NOACSHow to measure the anticoagulant effect of NOACsHow to deal with dosing errors and management of bleeding complications when it occurs.How to switch between various anticoagulant regimens.

NEWER ORAL ANTICOAGULANTS

SPECIAL SITUATIONS

patients undergoing a planned surgical intervention or ablation.patients undergoing an urgent surgical intervention.patients with AF and coronary artery disease. NOACs vs. VKAs in AF patients with a malignancy.


Introduction

Vitamin K antagonists (VKAs) are the mainstay of management of thromboembolic events for > 5decades.

Despite its unquestionable impact to prevent strokes, they have significant limitations, such us common drug or food interactions, and the necessity of regular monitoring to adjust doses, inter personal variation in response.NEWER ORAL ANTICOAGULANTS










Indications for NOAC s Prevention of arterial thromboembolic events in non-valvular atrial fibrillation and VTE prophylaxis following hip and knee-replacement surgery DABIGATRAN ,RIVAROXABAN, APIXABAN.

Treatment of deep vein thrombosis - RIVAROXABANNEWER ORAL ANTICOAGULANTS

Dabigatran Etexilate

Dabigatran etexilate, a prodrug of dabigatran, which reversibly inhibits both free and clot bound thrombin, It has an oral bioavailability of 6%. After oral administration, dabigatran etexilate is rapidly and completely converted to dabigatran by esterases. Plasma levels of dabigatran peak 2 hours after drug administration. Dabigatran has a half-life of 14 to 17 hours, which permits once- or twice-daily administration, and 80% of the drug is excreted unchanged by the kidneys.NEWER ORAL ANTICOAGULANTS

Coadministration of dabigatran etexilate and amiodarone,verapamil, quinidine,dronedarone - strong P-gp inhibitors, increases dabigatran levels.

It shouls be taken with food or water to minimise dyspepsia.

If a dose is missed it should be taken within 6 hours.



DOSE REGIMENfor acute VTE: 150 mgBID; for VTE prevention after knee or hip replacement surgery (14 or 30 days, respectively): 110 mg (initial dose) then 220 mg daily. COMMON SIDE EFFECTS Indigestion, upset stomach, or burning ,stomach painAllergic reaction, including hives, rash, and itchingBleeding


The RE-LY (Randomized Evaluation of Long-term anticoagulant therapY with dabigatran etexilate) phase III trial was a prospective, randomized, open-label trial comparing two blinded doses of dabigatran etexilate (110 or 150 mg BID) with warfarin in 18,113 patients with AF and at least one additional risk factor (a mean CHADS score of 2.1).


RESULTS150 mg BID dose superior to warfarin for reduction of stroke and systemic embolism with similar major bleeding.

110 mg BID dose non inferior to warfarin for SSE but with significant lower bleeding rates.

ICH is significantly low with both doses .NEWER ORAL ANTICOAGULANTS

RELY-ABLEAssessed the Additional information on the long-term effects of the two doses of dabigatran in patients completing RE-LY by extending the follow-up of patients on dabigatran from a mean of 2 years at the end of RE-LY by an additional 2.3 years. RELY-ABLE confirmed the results reported in RE-LY.ConclusionsDuring 2.3 years of continued treatment with dabigatran after RE-LY, there was a higher rate of major bleeding with dabigatran 150 mg twice daily in comparison with 110 mg, and similar rates of stroke and death.NEWER ORAL ANTICOAGULANTS

VTE trialsRECOVER and REMEDY Non inferior to warfarin in VTE prevention (2.4% vs 2.1%) No diffrerences in major bleeding.NEWER ORAL ANTICOAGULANTS

RIVAROXABANIt has an oral bioavailability of 80%.Rivaroxaban has a rapid onset of action and a half-life of 7 to 11 hours.Rivaroxaban has a dual mode of elimination; one third is cleared as unchanged drug via the kidneys, one third is metabolized by the liver via CYP3A4-dependent and -independent pathways with the metabolites then excreted in the feces, and one third is metabolized in the liver with the inactive metabolites then eliminated via the kidneys.NEWER ORAL ANTICOAGULANTS

Rivaroxaban is a substrate for P-gp, and concomitant administration of potent inhibitors of both P-gp and CYP3A4, such as ketoconazole or ritonavir, is contraindicated because they increase plasma drug levels.

There is only a minor interaction between Rivaroxiban and verapamil unlike dabigatran and edoxaban.

Co adminstration of FLUVASTATIN or ROSUVASTATIN with this drug does not need dose reduction of rivaroxiban.NEWER ORAL ANTICOAGULANTS



DOSE REGIMEN- for acute VTE: 20 mg daily (15 mg twice daily for initial 21 days);

for VTE prevention after knee or hip replacement surgery (14 or 30 days, respectively): 10 mg dailyNEWER ORAL ANTICOAGULANTS

ROCKET AF

The ROCKET AF was a double-blinded study in which 14,264 patients with non-valvular AF and CHADS2 scores 2 (mean 3.5) were studied.

After a median follow-up of 1.93 years, rivaroxaban was noninferior to warfarin for the prevention of stroke or systemic embolism.

There were no differences in the risk of major bleeding, although intracranial and fatal bleeding occurred less frequently in the rivaroxaban group.

Gastrointestinal bleeding and transfusion requirements were greater with rivaroxaban.

Total mortality was not significantly different between groups.NEWER ORAL ANTICOAGULANTS

ATLAS : Background - 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.


ATLAS ACS 2-TIMI 51 trial 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 was 10.7% with placebo, 9.1% with rivaroxaban 2.5 mg and 8.8% with rivaroxaban 5mg with no interaction by ACS subtype.

Rates of definite, probable or possible stent thrombosis were 2.2% and 2.3% with 2.5 and 5 mg rivaroxaban, respectively, vs. 2.9% with placebo .

Rates of CV death were signifi cantly lower with rivaroxaban 2.5 mg compared with placebo but not with rivaroxaban 5 mg (4.0%). NEWER ORAL ANTICOAGULANTS

Non-CABG major bleeds occurred in 1.8% and 2.4% with 2.5 and 5 mg rivaroxaban, respectively, compared with 0.6% with placebo.

Intracranial haemorrhage rates were 0.4% with 2.5 mg and 0.7% with 5 mg rivaroxaban vs. 0.2% with placebo.

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 risksNEWER ORAL ANTICOAGULANTS

CONCLUSION -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.NEWER ORAL ANTICOAGULANTS

VTE trialsEINSTEIN DVT non inferior to warfarin for DVT(2.1% vs 3%) with similar bleeding risk.

EINSTEIN PE non inferior to warfarin for PE with loer bleeding risk than warfarin.

EINSTEIN EXTENSION similar results.NEWER ORAL ANTICOAGULANTS

ApixabanApixaban is a direct, reversible, competitive, and selective inhibitor of factor Xa and the last NOAC approved by the FDA and EMA for the prevention of stroke and embolism in non-valvular AF. It is well absorbed achieving peak plasma concentration in 14 h.It is predominantly metabolized in liver.It is a mild P- glycoprotein inhibitor.Compared to other NOACS it has least bleeding complications and greater efficacy.NEWER ORAL ANTICOAGULANTS



ARISTOTLEThe Apixaban for Reduction In STroke and Other ThromboemboLic Events in AF (ARISTOTLE) compared apixaban (5 mg BID) with dose-adjusted warfarin in 18,201 patients with non-valvular AF (a mean CHADS2 scoreof2.1).

After amean followup of 1.8 years, apixaban was significantly better than warfarin, with fewer primary outcomes (overall strokes and systemic emboli), but with no significant differences in rates of ischaemic strokes.

Patients treated with apixaban had significantly fewer intracranial bleeds, but GI bleedings were similar between both groups.

All-cause mortality was found to be significantly lower in the apixaban group.NEWER ORAL ANTICOAGULANTS

Apixaban was also compared with aspirin alone in the AVERROES study, a double-blinded study of 5599 patients who were not suitable candidates for VKA treatment (mean CHADS2 score of 2).

After a mean follow-up of 1.1 years, the study was prematurely stopped due to a clear benefit in favour of apixaban.

Patients with severe renal impairment (serum creatinine.2.5 mg/dL or CrCl ,25 mL/min) were excluded from the ARISTOTLE and AVERROES trials.NEWER ORAL ANTICOAGULANTS

APPRAISEThe Apixaban for Prevention of Acute Ischaemic Events (APPRAISE) 2 study 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 eventsNEWER ORAL ANTICOAGULANTS

Edoxaban

Edoxaban is another reversible factorXainhibitor, recently approved by theFDA but not yet by the EMA. It is rapidly absorbed and reaches peak plasma concentration within 12 h. Up to 50% of edoxaban is eliminated by the kidneys and rest through multiple pathways. It is also a substrate for P-glycoprotein-concomitant administration with quinidine, amiodarone, and verapamil will result in a significant increase of plasma levels of edoxaban.Therefore, in patients under concomitant use of potent glycoprotein inhibitors , body weight < 60 kg, or moderatesevere renal impairment (CrCl < 50 mL/min), edoxaban dose should be reduced by 50%.NEWER ORAL ANTICOAGULANTS



ENGAGE AF-TIMI

The Effective Anticoagulation with Factor Xa Next Generation in Atrial FibrillationThrombolysis in Myocardial Infarction (ENGAGE AF-TIMI 48) compared the two dose regimens of edoxaban (30 and 60 mg once daily) with warfarin in a total of 21,026 patients with non-valvular AF. After a follow-up of 2.8 years, both regimens of edoxaban were non-inferior to warfarin with respect to the prevention of stroke or systemic embolism.


Edoxaban was associated with lower, dose-related rates of bleeding, including major bleeding, intracranial bleeding, and life-threatening bleeding.

GI bleeding - occurred more frequently with high-dose edoxaban but less frequently with low-dose edoxaban compared with warfarin. NEWER ORAL ANTICOAGULANTS

Finally, the incidence rate of haemorrhagic stroke and the rate of death from cardiovascular causes were significantly lower with both edoxaban regimens.

Patients with severe renal dysfunction (CrCl < 30 mL/min), high risk of bleeding, use of dual antiplatelet, acute coronary syndromes or coronary revascularization, and strokes within 30 days were excluded.


HOKUSAI VTE in DVT it is non inferior to warfarin and in PE it is superior to warfarin with similar bleeding risk in both conditions.NEWER ORAL ANTICOAGULANTS

OTHER fXa inhibitorsThese are betrixaban, YM150, and TAK442. Betrixaban has the unique features of a 15-hour half-life and extrarenal clearance. Betrixaban and YM150 are undergoing phase II evaluation for stroke prevention in AF, whereas TAK442 is undergoing phase II evaluation for prevention of recurrent ischemia in ACS patients.NEWER ORAL ANTICOAGULANTS

CONCOMITANT USE OF NOAC and DIGOXINDigoxin is a P-glycoprotein inhibitor and commonly used drug in AF.But there is clinically relavent interaction between digoxin and NOACS.NEWER ORAL ANTICOAGULANTS

Comparison between new oralanticoagulantsThere no direct head-to-head comparisons between these drugs.NOACs have been made in randomized, controlled trials, and extrapolation from primary trial data is the best available strategy for medical prescription. However, due to differences in trial design, in the estimated risk for stroke in the study population, comparator uniformity, and definitions of efficacy and safety endpoints make complex direct comparisons.NEWER ORAL ANTICOAGULANTS

Comparative analysis of the four NOACs confirmed that NOACs significantly reduced the composite of stroke or systemic embolic events by 19% compared with warfarin, which very much depended on large reduction in haemorrhagic strokes. Data for all four NOACS showed that they were associated with a 14% non-significant reduction in major bleedings.NEWER ORAL ANTICOAGULANTS


General recommendations


How to measure effect


The activated partial thromboplastin time (aPTT) may provide a qualitative assessment of the presence of dabigatran.The prothrombin time (PT) may provide a qualitative assessment of the presence of factor Xa inhibitors.Quantitative tests for DTI and FXa inhibitors - diluted thrombin-time and chromogenic assays, respectively,But they may not (yet) be routinely available in most hospitals.Moreover, there are no data on a cut-off of these specific tests below which elective or urgent surgery is safe, and therefore their use in this respect cannot be recommended at this time.NEWER ORAL ANTICOAGULANTS

When interpreting these results, considerwhen the last dose of NOAC was administeredpatient characteristics, and renal function determinants of elimination half-life NEWER ORAL ANTICOAGULANTS

DABIGATRAN

aPTT level (i.e. 1224 h after ingestion) of 2 the upper limit of normal or ECT 3 times and a dTT(Hemoclot) - .200 ng/mL after 12 h of the last dose is associated with a higher risk of bleeding.


What if scenarios


Patient has a bleeding complication

Specific antidotes for NOACs are still lacking and the strategies to reverse anticoagulant effect are limited.Time is the best advantage of NOACs, in view of their relatively short elimination half-lives. If a major bleeding complication occurs, standard supportive measurements must be started. These include mechanical compression, surgical haemostasis, fluid replacement, and additional haemodynamic support.NEWER ORAL ANTICOAGULANTS

Haemodialysis can accelerate drug removal in those patients receiving dabigatran; however, its benefit in life-threatening bleeding has not been established.

In contrast, dialysis is not effective for factor Xa inhibitors due to their high plasma binding and lower renal clearance.

The administration of prothrombin complex concentrate (PCC) or activated prothrombin complex (aPCC) concentrates can be considered in life-threatening bleeding, despite the scarce evidence.

Administration of PCC could start at a dose of 25 U/kg and can be repeated if clinically indicated.NEWER ORAL ANTICOAGULANTS


Novel reversal agents in clinical developmentThere are currently 3 NOAC-specific reversal agents in clinical development: (1) andexanet alfa, (2) idarucizumab, and (3) PER977NEWER ORAL ANTICOAGULANTS

Andexanet alfa is a recombinant, modified human factor Xa that is being developed as a direct factor Xa reversal agent.

It has been shown to rapidly attenuate the anti-FXa activity of apixaban, rivaroxaban, edoxaban, and enoxaparin and to restore thrombin generation in phase 2 studies in healthy human volunteers.

Andexanet alfa has been generally well tolerated and is currently in phase 3 clinical trials (ANNEXA-A [apixaban] and ANNEXA-R [rivaroxaban]).NEWER ORAL ANTICOAGULANTS

Idarucizumab is a fully humanized antibody fragment (Fab) that binds dabigatran with high affinity and specificity.

Idarucizumab rapidly reverses the anticoagulant effect of a 220 mg twice daily dose of dabigatran in healthy human volunteers and is currently being evaluated in phase 3 trials.

Idarucizumab has been generally well tolerated in healthy human volunteers and is currently in clinical trials in the RE-VERSE AD study.NEWER ORAL ANTICOAGULANTS

PER977 (ciraparantag) is a water-soluble small-molecule nonspecific reversal agent.

In preclinical testing and during testing with edoxaban in healthy male volunteers, it rapidly reversed the effect of multiple anticoagulants, purportedly via hydrogen bonding.

It is currently in phase 1 to 2 clinical testing in healthy human volunteers.NEWER ORAL ANTICOAGULANTS

Patient undergoes intervention

The most appropriate management should be individualized depending on the NOAC used, the type of surgery, the required anaesthetic regimen, and the patients characteristics, particularly, on their renal function.

For patients undergoing minor interventions,NOACs can be continued around the time of the procedure, similar to VKA-treated patients.

Some examples include skin cancer removal, joint injection, cataract removal, or tooth extraction in which an adequate local haemostasis is commonly possible. Intervention should not be performed at peak concentrations but 12 or 24 h after the last intake, depending on their specific regimen dosing.NEWER ORAL ANTICOAGULANTS


Managing oral antiplatelet agents in patients requiring long-term oral anticoagulantsApproximately 6 8% of patients undergoing PCI have an indication for long-term OAC with VKA or NOACs due to various conditions such as atrial fibrillation, mechanical heart valves or venous thromboembolism.

In the absence of safety and efficacy data, the use of prasugrel or ticagrelor as part of triple therapy should be avoided.

Gastric protection with a proton pump inhibitor is recommended.

The dose intensity of OAC should be carefully monitored with a target INR of 2.0 2.5 in patients treated with VKA & in patients treated with NOACs, the lowest tested dose for stroke prevention should be applied (i.e. dabigatran 110 mg twice a day, rivaroxaban 15 mg once a day, apixaban 2.5 mg twice a day)NEWER ORAL ANTICOAGULANTS

new-generation DESs are recommended over BMSs in patients requiring OAC at low bleeding risk (HAS-BLED 2). For patients at high bleeding risk (HAS-BLED 3) undergoing PCI who require OAC, the choice between a BMS and a new-generation DES needs to be individualised.

it is not known whether there are differences according to the type of OAC (NOACs versus VKA) or stent platform.NEWER ORAL ANTICOAGULANTS


Evaluation of Dual Therapy With Dabigatran vs. Triple Therapy With Warfarin in Patients With AF That Undergo a PCI With Stenting (REDUAL-PCI)

The main objective of this study is to compare a Dual Antithrombotic Therapy (DAT) regimen of 110mg dabigatran etexilate b.i.d. plus clopidogrel or ticagrelor (110mg DE DAT) and 150mg dabigatran etexilate b.i.d. plus clopidogrel or ticagrelor (150mg DE-DAT) with a Triple Antithrombotic Therapy (TAT) combination of warfarin plus clopidogrel or ticagrelor plus ASA

Noacs

Health & Medicine

Transcript of Noacs