Ischemic and hemorrhagic strokes in the context of the ...Non valvular afib . CHADS. 2 > 1 Non...

Van Hellerslia, PharmD, BCPS, CACP Clinical Assistant Professor

Temple University School of Pharmacy

Ischemic and hemorrhagic strokes in the context of the direct acting oral anticoagulants

•Over 4 million Americans are on oral anticoagulant therapy

•Treatment of venous thromboembolic events

•Prevention of stroke in atrial fibrillation(AF) patients

•Number of AF patients expected to rise from 2.6-6.1 million to 5.6-12 million by 2050

Mozaffarian D et al Circulation. 2015;131:e29–e322. Heit JA Arterioscler Thromb Vasc Biol 2008;28:370-2. Statistical Brief #268: AHRQ, 2007

Presenter

Presentation Notes

Over 4 million Americans are on oral anticoagulant therapy. The leading indications for oral anticoagulant therapy are to treat venous thromboembolisms or to prevent strokes in the context of atrial fibrillation. In the next 30 years or so, the number of patients with atrial fibrillation is expected to double.

0%

10%

20%

30%

40%

50%

60%

Relative Risk Reduction

Warfarin vs placebo

Antiplatelet vsplacebo

Warfarin vsantiplatelet

Hart RG et al. Ann Intern Med. 2007;146(12):857-67.

Presenter

Presentation Notes

When we think about stroke prevention in patients with atrial fibrillation. Anticoagulation provides greater protection than antiplatets.

Factor VIIa

Factor Xa

THROMBIN

Factor IIa

Factor VIIIa

Factor IXa

Tissue factor

Factor XIa Factor

XIIa

Factor Va

WARFARIN

Dabigatran (Pradaxa®)

Rivaroxaban (Xarelto®) Apixaban (Eliquis®) Edoxaban (Savaysa®)

Activates Platelets

Presenter

Presentation Notes

As we will be speaking about anticoagulants, I wanted to provide some context in regards to where and how these agents work. Warfarin works to deplete vitamin K dependant coagulation factors such as Factor IX, VII, X and II. In order for warfarin to achieved its anticoagulant effect, the coagulation factors have to be sufficiently depleted. Which can take days as Factor X has a half life of about 24 hrs and thrombin or factor II has a half life of about 96 hours. In contrast the direct acting oral anticoagulants dont deplete but directly bind to and inhibit the anticoagulant activity of Factor Xa (in the case of Rivaroxaban and apixaban) or Factor IIa

Fixed dosing

Quick onset/offset

Less drug/diet interactions

Less lab monitoring

At least non-inferior to warfarin in reducing thrombotic outcomes

Comparable or less major bleeding relative to warfarin

Less intracranial bleeding

RE-LY (n=18,113)

ROCKET-AF (n=14,264)

ARISTOTLE (n=18,201)

ENGAGE AF (n=21,108)

Design Open label Non-inferiority

Double-blind Non-inferiority



Population Non valvular afib CHADS2 > 1

Non valvular afib CHADS2 > 2



Intervention Dabigatran (dose blinded) 110 mg BID vs 150 mg BID

Rivaroxaban (blinded) 20 mg daily

Apixaban (blinded) 5 mg BID

Edoxaban (blinded) 30 mg daily 60 mg daily

Control warfarin (open)

warfarin (blinded)

warfarin (blinded)

warfarin (blinded)

Outcomes Stroke/Systemic embolism

Major bleeding Major + non-major bleeding

Major bleeding Major bleeding

Connolly SJ et al. N Engl J Med 2010;363:1875-1876. Patel M et al N Engl J Med 2011;365:883-91 Granger CB et al N Engl J Med 2011; 365:981-992 Giugliano RP et al N Engl J Med 2013;369:2093-2104.

Presenter

Presentation Notes

So what’s the evidence that supports these claims. Each of the DOACs currently on the market have been rigorously studied in randomized controlled trials against warfarin. This table summarizes the DOAC trials in atrial fibrillation

0.5 1 1.5

RELY (dabigatran) 0.66 (0.53-0.82)

ROCKET-AF (rivaroxaban) 0.88 (0.75-1.03)

ARISTOTLE (apixaban) 0.79 (0.66-0.95)

ENGAGE AF (edoxaban) 0.87 (0.73-1.04)*

RR (95% CI)

Favors DOAC Favors warfarin

*97.5% CI

Presenter

Presentation Notes

This forest plot illustrates the overall favoring of the direct acting oral anticoagulants when compared to warfarin for the prevention of stroke or systemic embolism in atrial fibrillation.

0.5 1 1.5

RELY (dabigatran) 0.93 (0.81-1.07)

ROCKET-AF (rivaroxaban) 1.03 (0.96-1.11)

ARISTOTLE (apixaban) 0.69 (0.60-0.80)

ENGAGE AF (edoxaban) 0.80 (0.71-0.90)

Favors DOAC Favors warfarin

Connolly SJ et al. N Engl J Med 2010;363:1875-1876. Patel M et al N Engl J Med 2011;365:883-91 Granger CB et al N Engl J Med 2011; 365:981-992

Presenter

Presentation Notes

Rates expected to be higher in clinical practice due to “imperfect use”

Barreto AD et al Stroke 2012;43:770-5 Tabata E et al Inter Med 2014;53:1515-1517

dabigatran rivaroxaban apixaban

Protime --- + Reagent specific

--

aPTT + -- --

Thrombin time ++ --- --

Anti-xa level n/a ++ calibrated

++ calibrated

Van Ryn J, J Throm Haemost 2010; Rogers R et al. Br J Hemae 2013; Ogata K et a lJ Clin Pharmacol 2010; www.dcri.org/education-training/meetings/meeting-presentations/acc-2011-presentations/ACC2011-Apixaban-Poster.pdf accessed 9/25/2013

https://www.dcri.org/education-training/meetings/meeting-presentations/acc-2011-presentations/ACC2011-Apixaban-Poster.pdf

https://www.dcri.org/education-training/meetings/meeting-presentations/acc-2011-presentations/ACC2011-Apixaban-Poster.pdf

Demaerschalk BM et al Stroke 2016;47

Gawehn A et al Journal of Medical Case reports 2016;10:269 Berrouschot J et al Stroke 2016;47:1936 Schafter N et al J Stroke Cerebrovas Dis 2016;25:126-127 Kafke W and Kraft W Case Rep Neurol 2016;8:140-144

Dabigatran not taken in last 48 hrs and

normal renal function?

No

Check thrombin time. Is TT normal?

No Consider **

idarucizumab 5 g then give TPA?

YES

OK to give TPA

YES

OK to give TPA

** Risk vs Benefit: BP, size of infarct, stroke severity, age of patient, time of presentation

Rivaroxaban not taken in last 48 hrs and normal

renal function?

No

Check Anti-Xa level (preferred) or Prothrombin Time*

Result normal?

No

Avoid TPA

YES

OK to give TPA

YES

OK to give TPA

* Sensitive Reagent: Neoplastin Plus, HemosIL RecombiPlasTin 2G ** Risk vs Benefit: BP, size of infarct, stroke severity, age of patient, time of presentation

Samama MM et al. Thrombosis Journal 2013;11:11

Apixaban not taken in last 48 hrs and normal renal

function?

No

Check Anti-Xa level Result normal?

No

Avoid TPA

YES

OK to give TPA

YES

OK to give TPA

** Risk vs Benefit: BP, size of infarct, stroke severity, age of patient, time of presentation

Samama MM et al. Thrombosis Journal 2013;11:11

Typical Afib Dosing Pearls

Dabigatran 150 mg po BID • Keep capsules in bottle (close tightly) • Expires after 4 months once bottle open • CAUTION in Gastric Bypass patients • CAUTION with enzyme inducers • CANNOT be given via enteral tube

Rivaroxaban 20 mg po daily • Take with food • CAUTION enteral tube administration (must be

gastric tube and with enteral feed)

Apixaban 5 mg po BID • Must be given BID • Reduced dose 2.5BID only provides net benefit in

specific conditions

Edoxaban 60 mg po daily • AVOID use in patients with CrCl>80 ml/min

Standard Risk of Bleeding

High Risk of Bleeding

Normal Renal function

Dabigatran: 24-48 hrs Factor Xa: 24hrs

Dabigatran: 48 hrs Factor Xa: 48 hrs

Impaired Renal function (crcl<50)

Dabigatran: 48 – 96hrs Factor Xa: 48 hrs

Dabigatran: 48 hrs - ?days Factor Xa: 48 hrs - ?days

No bridging is necessary Pre-operatively, evaluate renal function and determine number

of days to hold anticoagulant Balance bleeding/spinal hematoma risk of procedure with stroke

risk of withholding anticoagulation Avoid spinal anesthesia if possible

RELY Dabigatran (Pradaxa®)

ROCKET-AF Rivaroxaban (Xarelto®)

ARISTOTLE Apixaban (Eliquis®)

Ischemic stroke

0.92% per yr 1.37% per yr 0.97% per yr

ICH 0.30 % per yr 0.5% per yr 0.33% per yr

Connolly SJ et al. N Engl J Med 2010;363:1875-1876. Patel M et al N Engl J Med 2011;365:883-91 Granger CB et al N Engl J Med 2011; 365:981-992

Presenter

Presentation Notes

Note that the proportion of patients with a history of stroke was highest in the ROCKET –AF trial evaluating the use of rivaroxaban. Also note, the timing of initiation of therapy in patients with a stroke history. So that anticoagulation was delayed anywhere from 7 days to 30 days from the onset of a recent stroke in these DOAC trials

Kuramatsu JB et al JAMA 2015;313:828-836

Presenter

Presentation Notes

There was a retrospective cohor study from 19 German tertiary care centers that evaluated over 1100 cases of OAC related ICH. They wanted what impact if any dose reversal of anticoagulation during the acute phase, as well as blood pressure control at 4 hours have on hemtoma enlargement. They found that for those patients who did not have hematoma enlargement, they were more like to have their INR reversed within 4 hours (INR<1.3); SBP<160 mmHg at 4 hours

Monoclonal antibody fragment with 350x affinity for dabigatran vs thrombin

Neutralizes unbound and bound dabigatran

Schiele F et al Blood 2013;121:3554-62 Glund S et al Lancet 2015; 386: 680–90 Glund S et al Thromb Haemost 2015;113:943-51

Group A Group B

N=51 N=39

Description Serious Bleeding ICH n=18(35%) Trauma related n=9 (18%) Gastrointestinal n=20 (39%) Other n= 11 (22%)

Indication for surgery Bone fractures n= 8 Acute cholecystitis n=5 ARI, cath placement n=4 Acute appendicitis n=3 Joint/wound infection n=3 Abscess n=2 Acute mesenteric ischemia n=2

Pollack CV et al N Engl J Med 2015;373:511-20

Pollack CV et al N Engl J Med 2015;373:511-20

• Onset of activity: within 10 minutes • Half-life: 47 minutes, terminal half life: 10.3 hours • Elimination: Approximately 30% in urine in 6

hours • Metabolism: protein catabolism

P’ kinetics:

• 2.5 gm x 2 iv bolus or 1 hour infusion Dose:

• aPTT and CBC 4hr, 12hr, 24hr • Signs and symptoms of bleeding Monitoring:

Schiele F et al Blood 2013;121:3554-62 Pollack CV et al N Engl J Med 2015;373:511-20

In absence of antidote, national guidelines for life threatening bleeding suggest:

•Supportive care (includes mechanical hemostasis) •Dialysis NOT helpful

Prohemostatic agents: Prothrombin complex concentrate (PCC) or Factor VII

• No clinical trials on use of PCC or Factor VIIa for Xa inhibitor reversal • Data based on healthy volunteers, animal studies or ex-vivo studies

Holbrook A et al. Chest. 2012;141(2_suppl):e152S-e184S Hemphill JC et al. Stroke 2015; 46:2032-2060 EerenbergES et al. Circulation 2011; 124

Time (min)

PT

(se

cond

s±S

D)

0 20 40 600

5

10

15

20

25

Rivaroxaban administration4F-PCC administration

Liver laceration injury

Rivaroxaban vehicle +Saline vehicleSaline vehicle4F-PCC 25 IU/kg4F-PCC 50 IU/kg4F-PCC 100 IU/kg

Pine P et al, NCS 14th Annual Meeting 2016 Poster

Lu G et al Nat Med 2013;19:446-451 Portola Pharmaceuticals

Presenter

Presentation Notes

Serine replaced with alanine to eliminate catalytic activity and prevent prothombin cleavage γ- carboxyglutamic acid (Gla) domain removed; lacks membrane binding

Leeds JM et al, NCS 14th Annual Meeting 2016 Poster

Can be potentially be used to reverse all factor Xa inhibitors (LMWH, fondaparinux, rivaroxabain, apixaban, edoxaban etc)

Primary Endpoint: 94±2% vs. 21±9%; P<0.001 92±11% vs. 18±15%, P<0.001

Siegal DM et al N Engl J Med 2015;373:2413-24

Primary Endpoint: 92±3% vs. 33±6%, P<0.001 97±2% vs. 45±12%, P<0.001


UFH: unfractionated heparin Aronis KN and Hylek EM J Thromb Thrombolysis 2016;41:253–272 LMWH: low molecular weight heparin Ansel J et al N Engl J Med 2014; 371:2141-2142

Supportive care (charcoal, transfusion, mechanical hemostasis)

Manage Blood Pressure

Dialysis not helpful

Prothrombin Complex Concentrate???

Aronis KN and Hylek EM J Thromb Thrombolysis 2016;41:253–272

Half-life Normal renal function

CrCl 15-50 CrCl <15 Dialysis

Severe Hepatic

Dabigatran 12-17 hrs √ # X X

Rivaroxaban 5-10 hrs √ # X X

Apixaban 12 hrs √ # # or X X

Edoxaban 5-10 hrs X # X X

√ OK to use X Consider avoiding use # Needs dose adjustment

• Patients with CrCl <30 ml/min were excluded from clinical trials for dabigatran, rivaroxaban, and edoxaban.

• Patients with CrCl <25 ml/min or Scr >/=2.5 excluded from apixaban trial

Ischemic and hemorrhagic strokes in the context of the ...Non valvular afib . CHADS. 2 > 1 Non...

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