ANTIDOTE FOR NOACsVISHAL VANANIMumbai 2015

NOACS ARE GOOD

• Predictable effect without need for laboratory monitoring• Fewer food and drug interactions• More predictable half-life/elimination• Improved efficacy/safety ratio• Non inferior bleeding risk than VKAs.

BLEEDING RISK

• Risks of bleeding from NOACs are generally lower or similar to other agents, with some limited exceptions.

• The overall risk of bleeding with NOACs versus vitamin K antagonists was reviewed in a meta-analysis of 12 randomized trials that included 102,607 patients with atrial fibrillation or venous thromboembolism.

• Compared with vitamin K antagonists, NOACs were associated with lower risks of• major bleeding (relative risk [RR] 0.72; 95% CI 0.62-0.85),• fatal bleeding (RR 0.53; 95% CI 0.43-0.64), and• intracranial bleeding (0.43; 95% CI 0.370.50);

• Major gastrointestinal bleeding was not increased (RR 0.94; 95% CI 0.75-1.99)

• Routine monitoring of coagulation not required, but quantitative assessment of drug exposure may be needed in emergency situations:• Serious bleeding events• Urgent surgery• renal or hepatic insufficiency• Thrombotic events• potential DDI• suspected overdosing

MEASURING THE ANTICOAGULANT EFFECT OF NOACS

MEASURING THE ANTICOAGULANT EFFECT OF NOACS

• Important to know exactly when NOAC was administered relative to time of blood sampling. Maximum effect at maximum plasma concentration (~3h after administration).

• Activated thromboplastin time (aPTT): qualitative assessment of dabigatran, but sensitivity varies.

• Diluted thrombin time (DTT): Hemoclot® suitable for quantitative assessment of dabigatran but no data on cut off below which surgery is safe.

• Anti-FXa chromogenic assays: commercially available for quantitative assessment, but no data to associate level with bleeding or thrombo-embolism risk.

MEASURING THE ANTICOAGULANT EFFECT OF NOACS

Dabigatran Apixaban Edoxaban RivaroxabanPlasma peak 2h after ingestion 1-4h post ingestion 1-2h after ingestion 2-4h after ingestion

Plasma trough 12-24h after ingestion 12-24h after ingestion

12-24h after ingestion 16-24h after ingestion

PT cannot be used cannot be used prolonged but no known relation with bleeding risk

prolonged: may indicate excess bleeding risk but local calibration required

INR cannot be used cannot be used cannot be used cannot be used

aPTT at trough >2x ULN suggests excess bleeding risk

cannot be used prolonged but no known relation with bleeding risk

cannot be used

dTT At trough >200ng/ml ≥ 65s: excess bleeding risk

cannot be used cannot be used cannot be used

Anti-FXa assays n/a no data yet quantitative; no data on threshold values for bleeding or thrombosis

quantitative; no data on threshold values for bleeding or thrombosis

Ecarin clotting time

at trough >2x ULN: excess bleeding risk

not affected; cannot be used

not affected; cannot be used

not affected; cannot be used

WHAT TO DO IF THERE IS A (SUSPECTED) OVERDOSE WITHOUT BLEEDING

ORA CLOTTING TEST IS INDICATING A RISK OF

BLEEDING

• Acute recent ingestion of overdose: activated charcoal to reduce absorption (standard dosing scheme for adults of 30 to 50 g).

• Consider coagulation tests to assess possible bleeding risk.

• In absence of bleeding, wait-and see approach.

NON LIFE THREATENING BLEEDINGDABIGATRAN FXa INHIBITORS

Inquire last intake + dosing regimenEstimate normalization of haemostasis

Normal renal function: ±24h• CrCl 50-80 ml/min: 24-36h• CrCl 30-50 ml/min: 36-48h • CrCl <30 ml/min: ≥48hMaintain diuresis

Normalisation of haemostasis: ±24h

Local haemostatic measuresFluid replacement (colloids if needed)

• RBC substitution if necessary• Platelet substitution (in case of thrombocytopenia ≤ 60 x 109 /L or thrombopathy)

• Fresh frozen plasma as plasma expander (not as reversal agent)• Tranexamic acid can be considered as adjuvans

• Desmopressin can be considered in special cases (coagulopathy or thrombopathy)

• Consider dialysis (primary evidence: - 65% after 4h)

• Charcoal haemoperfusion not recommended (no data)

DABIGATRAN FXa INHIBITORS

• All of the above

• Prothrombin complex concentrate (PCC)• 25 U/kg (may be repeated once or twice but no clinical evidence)

• Activated PCC• 50IE/kg; max 200 IE/day: no strong data about additional benefit over PCC. Can be considered before PCC if available

• Activated factor VII• (rFVIIa; 90g/kg); no data about additional benefit + expensive (only animal evidence)

LIFE THREATENING BLEEDING

PATIENTS UNDERGOING AN URGENT SURGICAL INTERVENTION

• Discontinue NOAC.• Try to defer surgery at least 12 h and ideally 24 h after last dose.• Urgent surgery associated with much higher rates of bleeding than

elective procedures, but lower than VKA-treated patients. 1

• Coagulation tests can be considered (classical test or specific tests) but strategy based on these results has never been evaluated. Therefore such strategy cannot be recommended and should not be used routinely.

1. Healey et al, Circulation 2012:126;343-8

Reversal of warfarin and the VKAs: Time of Effect

FIRST ANTIDOTE FOR NOACS

REVERSE-AD TRIAL

• Reversal Effects of Idarucizumab on Active Dabigatran

REVERSE-AD TRIAL• RE-VERSE AD : Multicenter, Open label, Single arm, Phase 3

Study• Target is to complete 300 patients• The interim analysis from RE-VERSE AD included data from

90 patients in the emergency setting who were taking dabigatran and required reversal.

REVERSE-AD TRIAL• Group A (Bleeding patients) – 51• Patients with uncontrolled or life-threatening bleeding complications,

e.g. intracranial haemorrhage or severe trauma after a car accident who are on Dabigatran

• Group B – 39• Patients who are taking dabigatran who may not be bleeding, but do

require an emergency surgery or invasive procedure as within following 8 hours for a condition other than bleeding.

Idarucizumab: A Specific Reversal Agent for

Anticoagulant Activity of Dabigatran

RE-VERSE AD

Allows severely ill patients, adequately reflecting the target population

RE-VERSE AD: Demographics

RE-VERSE AD: Primary Endpoints

• Time to cessation of bleeding in Group A• Hemostasis during procedure in Group B, assessed as normal, mildly,

moderately or severely abnormal• Reversal of aPTT and TT, Duration of reversal• Occurrence of major bleeding (for group B only) intraoperatively and

up to 24 hours post-surgery• Minimum unbound sum (free) dabigatran level• Reversal of anticoagulation as measured by diluted Thrombin Time

(dTT) or Ecarin Clotting Time (ECT) after the first infusion and before the start of the second

RE-VERSE AD: Secondary Endpoints

RESULTS

• Of the 81 patients that presented with elevated anticoagulation levels at baseline as measured with ecarin clotting time (ECT), results showed:1

• The study met its primary endpoint, achieving 100 per cent maximum reversal as median value across all patients

• Reversal was evident immediately after administration of the first vial of idarucizumab, and was complete in all but 1 patient

• After 4 and 12 hours, laboratory tests showed normal coagulation levels in almost 90 per cent of patients

RESULTS

• Normal blood clotting (haemostasis) during surgery was reported in 92 per cent of the patients that required surgery or invasive procedures

• There was no signal of a pro-coagulant effect following administration of idarucizumab

• Thrombotic events occurred in five patients, none of whom was receiving antithrombotic therapy at the time of the event

• There were 18 deaths overall. Mortality within 96 hours of study enrolment appeared to be related to the original reason for emergency admission to the hospital, while all later events appeared to be related to co-morbidities

CONCLUSIONS

• The data on these first 90 patients was sufficient for the FDA to review the new drug, as the drug has been given “accelerated approval status” and “priority review” by the FDA.• May get approval and be available in market by the year end.

ANDEXANET• As this drug also has FDA “accelerated approval status” and

“priority review”, the drug will be considered for FDA approval after the first few of the overall anticipated 270 patients in the trial have been enrolled.

• Andexanet is expected to have enough data from this study to get FDA approval by the middle of 2016 or earlier, if the clinical trial data look good.

…THANK YOU…