DR. SASINTHAR RCARDIOLOGY,J IPMER

Newer oral anticoagulants

Problems with warfarin

Delayed onset & offsetNarrow therapeutic rangeUnpredictable dose responseDrug–drug, drug–food interactionsProblematic monitoringSlow reversibilityHemorrhagePregnancy

VKORC1 and CYP2C9

polymorphisms

Age

Body weight

4 weekly vs 12 weeklyVariability in INR results

IDEAL ANTICOAGULANT

EffectiveMinimal complications/side effectsFixed dosingConvenient administration Rapid absorption Good bioavailabilityFast on and offset actionPredictable pharmacokinetics No interactions with food or drugsNo HITNo coagulation monitoringReversibilityAntidote available

BetrixabanYM150TAK442

V,VII,XI,XIII

NOAC

DOAC

TSOACODISODA

Who is an appropriate candidate for the Novel OACs?

FDA approved indicationHistory of good medication complianceFrequent medication, diet, or health status changes

that make warfarin management difficultNot taking medication s known to interact with NOACBarriers to patient/family educationDifficulty or hardship with frequent INR monitoringUnstable INRsCrCl> 30 ml/minHigh risk of IC bleedDocumented warfarin failure

Who is NOT a good candidate for NOACs ?

Consistent INRRenal dysfunctionHepatic dysfunction Pregnant or breast feeding womenMedication non-adherenceUnable to payHistory of GI bleeding (dabigatran)History of coronary artery disease or

myocardial infarction (dabigatran)

FDA APPROVED INDICATIONS

1.Approved for VTE prophylaxis following knee or hip surgery only

2.After 5-10 days of parental anticoagulant treatment only

Dabigatran etexilate (Pradaxa)

The RE-LY (Randomized Evaluation of Long-term anticoagulant therapY with dabigatran etexilate)

RESULTS

150 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 .

RELY-ABLE Assessed the Additional information on the long-

term effects of the two doses of dabigatran in pts 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. Conclusions—During 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.

VTE TRIALSRECOVER and REMEDY –

RECOVER- Large randomized, double-blind trial comprised of 2,564 patients with confirmed DVT or PE

Non inferior to warfarin in VTE prevention (2.4% vs 2.1% After 6 months of treatment)

No differences in major bleeding. Discontinuation rate 9% vs 6.8%

RIVAROXABAN (Xarelto)

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.

VTE TRIALS

EINSTEIN DVT – 2,900 patients with acute DVT without PE15 mg twice-daily dose of rivaroxaban vs 20 mg

oncedaily dose versus enoxaparin followed by a VKA for 3,6, or 12 months

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.

Apixaban (Eliquis)

ARISTOTLE

Compared apixaban (5 mg BID) with dose-adjusted warfarin in 18,201 patients with non-valvular AF (a mean CHADS2 scoreof2.1).

After a mean f/u 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.

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.

APPRAISE

The 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 events

Edoxaban (Savaysa)

Recently approved by the FDA but not yet by the EMA.

ENGAGE AF-TIMI

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 2.8 years f/u, 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.

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.

OTHER fXa inhibitors

These 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.

CONCOMITANT USE OF NOAC and DIGOXIN

Digoxin is a P-glycoprotein inhibitor and commonly used drug in AF.

But there is clinically relavent interaction between digoxin and NOACS.

Comparison between NOACs

There no direct head-to-head comparisons between NOACs have been made in RCTs.

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.

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.

Which to choose ?

How to measure effect ?

Novel reversal agents in clinical developmentThere are currently 3 NOAC-specific reversal

agents in clinical development: (1) Andexanet alfa, (2) Idarucizumab, and (3) PER977

(Ciraparantag)

Managing NOACs in patients requiring long-term oral antiplatelets

Approximately 6 – 8% of patients undergoing PCI have an indication for long-term OAC with VKA or NOACs due to various conditions such as AF, mechanical heart valves or VTE.

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 PPI is recommended.

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)

Studies evaluating combinations of NOAC or VKA + antiplatelets post PCI & stenting

PIONEER AF PCI – Rivaroxaban; ongoing RE-DUAL PCI – Dabigatran ; ongoing AUGUSTUS - Apixaban ; ongoing EVOLVE-AF-PCI – Edoxaban; ongoing

Unknown whether SAPT/DAPT plus NOAC is safer than SAPT/DAPT plus VKA or vice versa

NOACs vs.vitamin K antagonists in AF pts with a malignancy

Active malignancy usually was an exclusion criterion in NOAC trials.

When anticoagulant therapy needs to be initiated in a patient with malignancy, therapy with VKAs or heparins should be considered over NOACs, because of the clinical experience with these substances, the possibility of close monitoring (for VKAs and unfractionated heparin, UFH), and reversal options (for VKAs and UFH).

NOACs and cardioversion

Electrical cardioversion in patients treated with NOACs has a similar (and very low) thrombo-embolic risk as under warfarin

Subgroup analyses from: RE-LY (dabigatran) ROCKET-AF (rivaroxaban), ARISTOTLE (apixaban)

The recently published X-VeRT trial confirmed the low pericardioversion stroke risk in patients treated with rivaroxaban compared with warfarin

Ongoing Clinical Studies: ENAMATE – Rivaroxaban ENSURE – Adoxaban NOACS & Cardioversion

H. Heidbuchel et al. Updated EHRA practical guide for use of the non-VKA oral anticoagulants. Europace 8/2015

IDEAL ANTICOAGULANT

EffectiveMinimal complications/side effectsFixed dosingConvenient administration Rapid absorption Good bioavailabilityFast on and offset actionPredictable pharmacokinetics No interactions with food or drugsNo coagulation monitoringReversibilityAntidote available1.Coadministration of dabigatran and amiodarone,verapamil, quinidine,dronedarone - strong P-gp inhibitors, increases dabigatran levels

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.

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 rivaroxaban.

Edoxaban also is a substrate for P-glycoprotein-concomitant administration with quinidine, amiodarone, and verapamil will result in a significant increase of plasma levels of edoxaban

CONCLUSION

NOACs have shown to have a favourable balance between efficacy and safety compared with VKA s.

Advantages Of NOACs include fewer interactions with medications and no interaction with food, rapid onset, fast clearance, and no need for laboratory monitoring.

Individualized anticoagulant treatment should be based on patients’ age, renal function, and concomitant treatments.

Further research is underway to develop reliable and accessible measures to monitor the anticoagulant effects of the new agents, as well as antidotes with the ability to effectively reverse anticoagulation effect.