EP Special Topics 2016 Anticoagulation Defibrillator Therapy CRT - - PowerPoint PPT Presentation

EP Special Topics

2016

Anticoagulation Defibrillator Therapy CRT

NOACs, OACs, NVKD-ACs, DACs, DTIs

Disclosures

No disclosures Will not discuss off-label uses Will refer to some drugs by both trade and generic names due to their novelty

Clearing Up the Confusion

OAC: Oral Anticoagulant NOAC: Novel Oral AntiCoagulant NVKD-OAC: Non-Vitamin K-Dependent Oral Anticoagulant DAC: Direct Anticoagulant DTI: Direct Thrombin Inhibitor XaI: Factor Xa Inhibitor

Scope of the Problem

1 in 4 will develop atrial fibrillation AF causes 5x greater stroke risk Valvular AF 17x greater risk 15-20% of strokes due to AF AF strokes are particularly bad

Mechanisms of Action

Warfarin

Limitations of Warfarin

Vitamin K antagonists appears to inhibit production of vitamin K– dependent proteins found in bone (osteocalcin synthesized by

• steoblasts, matrix Gla protein found in bone, cartilage and

soft tissue, and protein S synthesized by osteoblasts).

Limitation Clinical Implications

Slow onset and ofgset of action Need for bridging with a rapidly acting anticoagulant Interindividual variability in anticoagulant efgect Variability in dosing requirements Narrow therapeutic index Need for routine coagulation monitoring Food and drug interactions Dietary precautions; need for routine coagulation monitoring Reduced synthesis of all vitamin K–dependent proteins Risk of skin necrosis in patients with protein C or S deficiency; potential for osteoporosis*

Circulation: April 5, 2011 vol. 123 no. 13 1436-1450

Food Vitamin K Content

Vegetables

Green beans Asparagus Broccoli Carrots Avocado Brussels sprouts Cauliflower Red Cabbage Cabbage Celery Green peas Collard greens Corn Endive (raw) Cucumber Kale (raw leaf) Egg plant Lettuce (iceberg) Lettuce (bibb, red leaf) Mushrooms Mustard greens (raw) Onions Parsley Green pepper Spinach Potato Turnip greens (raw) Pumpkin Watercress (raw) Sauerkraut (canned) Swiss chard Tomato

Low Medium High

Fats & Oils

Food Vitamin K Content

Corn oil Margarine Mayonnaise Peanut oil Olive oil Canola oil Safflower oil Soybean oil Sesame oil Sunflower oil

Low Medium High

Coffee Cola Fruit juices Milk Tea, black Tea, green Water

Beverages

Low Medium High

Limitations of Warfarin

55% of warfarin-eligible patients receive it Elderly even less likely Other high-risk patients even less likely 28% discontinue warfarin by 1 year

Limitations of Warfarin

High major-bleeding rates 20% in first year for CHADS-VASc ≥ 4 50-60% in target range (INR 2.0 to 3.0) In trials and registries - general population? Worse in elderly!

Limitations of Warfarin

Vitamin K antagonists appears to inhibit production of vitamin K– dependent proteins found in bone (osteocalcin synthesized by

• steoblasts, matrix Gla protein found in bone, cartilage and

soft tissue, and protein S synthesized by osteoblasts).

Limitation Clinical Implications

Slow onset and ofgset of action Need for bridging with a rapidly acting anticoagulant Interindividual variability in anticoagulant efgect Variability in dosing requirements Narrow therapeutic index Need for routine coagulation monitoring Food and drug interactions Dietary precautions; need for routine coagulation monitoring Reduced synthesis of all vitamin K–dependent proteins Risk of skin necrosis in patients with protein C or S deficiency; potential for osteoporosis*

Circulation: April 5, 2011 vol. 123 no. 13 1436-1450

Warfarin Limitations

Room for Improvement!

Mechanisms of Action

Warfarin

Mechanisms of Action

Novel Anticoagulants

Ximelagatran

First NOAC Showed reduced risk of stroke No increased bleeding risk Abandoned due to liver toxicity

Dabigatran

(Pradaxa)

Administered as Dabigatran Etexilate Zero pharmacologic effect Converted to Dabigatran within 1 hr T1/2 = 12 - 17 hours Thrombin Inhibitor (Factor II) 10% bioavailability 80% renal clearance

Dabigatran

RE-LY Trial


(Randomized Evaluation of Long-Term Anticoagulant Therapy Trial)

18,113 patients, open label AF + 1 risk factor (CHADS2 ≥ 1) Non-inferiority trial Compared Dabigatran to warfarin INR goal 2.0-3.0 achieved 64% of the time 2 Dabigatran doses (110 mg BID & 150 mg BID)

Dabigatran

RE-LY Trial Results Dabigatran 110 mg BID Non-inferior to warfarin in stroke reduction 20% reduction in major bleeding (p=0.003) Increased risk of GI bleeding (11.3 vs 5.8% p<0.001)

Dabigatran

RE-LY Trial Results Dabigatran 150 mg BID 34% reduction in stroke and embolization No overall increase in major bleeding Increased risk of GI bleeding (11.8 vs 5.8% p<0.001)

Dabigatran

Dosing Recommendations Recommended Dose is 150 mg BID CrCl 15-30: 75 mg BID CrCl < 15: Not recommended Dialysis: Not recommended Different doses/adjustments for DVT/PE prophylaxis

Rivaroxaban

(Xarelto) Small molecule active drug Direct Factor Xa Inhibitor T1/2 = 9-12 hours Peak plasma concentration 2.5-4 hrs (elderly 11-13 hrs) 50% bioavailability 66% urine excretion (36% unchanged)

Rivaroxaban

ROCKET-AF Trial


Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation

14,264 patients Double Blinded, randomized Rivaroxaban 20 mg Warfarin (INR 2.0 - 3.0 - achieved 58% of the time) CHADS2 Score ≥ 2.0 Half of patients had prior stroke - high-risk patient group

Rivaroxaban

ROCKET-AF Results 12% relative reduction in stroke or embolization NOT statistically significant Non-inferior to warfarin Statistically significant reduction intracranial hemorrhage and bleeding death

Apixaban

(Eliquis)

Small molecule active drug Direct Factor Xa Inhibitor (like Rivaroxaban) Peak plasma concentrations at 2 hrs T1/2 ≈ 12 hours 50% bioavailability 25% urine excretion Strong CyP-450 3A4 Inhibitors increase levels

Apixaban

AVERROES Trial


Apixaban Versus Acetylsalicylic Acid to Prevent Strokes Trial

5599 patients Apixaban 5 mg vs. ASA 81-325 mg Unsuitable for warfarin Stopped early due to clear Apixaban superiority Bleeding rates similar to ASA Apxiaban better tolerated than ASA (less discontinuations)

Apixaban

ARISTOTLE Trial


Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation Trial

18,201 patients Apixaban 5 mg Warfarin (INR 2.0 - 3.0 - achieved 58% of the time) AF + at least one risk factor (CHADS2 ≥ 1) Lower risk patients than ROCKET-AF

Apixaban

ARISTOTLE Trial Results 21% relative reduction in stroke or embolization 31% relative reduction in overall bleeding 11% relative reduction in mortality Better tolerated than warfarin

Edoxaban

(Savaysa)

Small molecule active drug Direct Factor Xa Inhibitor (like Rivaroxaban/Apixaban) Peak plasma concentration at 1 - 1.5 hrs T1/2 ≈ 8-10 hours 40% urine excretion 50% Bioavailability Strong CyP-450 3A4 Inhibitors increase levels

Edoxaban

ENGAGE-AF - TIMI 48


Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation

>20,000 patients Double Blind CHADS2 ≥ 2 (high risk) Warfarin (INR 2.0 - 3.0 - achieved 68.4% of the time)

Bioprosthetic valves and repaired valves included

Edoxaban

ENGAGE-AF Trial Results Edoxaban 30 mg daily 53% relative reduction in major bleeding 15% relative reduction in mortality 7% relative increase in stroke or embolization

Edoxaban

ENGAGE-AF Trial Results Edoxaban 60 mg daily 20% relative reduction in major bleeding 14% relative reduction in mortality 21% relative reduction in stroke or embolization

Comparison of Anticoagulants

Warfarin Dabigatran Rivaroxaban Apixaban Edoxaban Administration

Once a day Twice a day Once a day Twice a day Once a day

Target

Vit K–dependent factors Thrombin (Factor II) Factor Xa Factor Xa Factor Xa

Time to Peak Efgect

3–5 d 1 h 2.5–4 h 3 h 1–2 h

Dose

Variable 150 mg BID 110 mg BID 20 mg QD 15 mg (renal) 5 mg BID 2.5 mg (CRI+risk) 60 mg QD 30 mg QD

Half-Life

40 h 12–14 h 7–11 h 12 h 9–11 h

Interactions

Many

P-Gp Transporter CYP 3A4 Inhibitors P-Gp Transporter CYP 3A4 Inhibitors P-Gp Transporter CYP 3A4 Inhibitors P-Gp Transporter

Renal Clearance

80 35 25 40

Anticoagulant Monitoring

Required Not required Not required Not required Not required

Antidote

Vitamin K Praxabind None None None

Notes

Contraindicated for CrCl > 95

NOAC Clinical Trials

Stroke or Systemic Embolism /yr Hemorrhagic Stroke /yr Major Bleeding /yr

Novel Agent Warfarin HR p Novel Agent Warfarin HR p Novel Agent Warfarin HR p

RE-LY

Dabigatran 110 mg twice a day 1.53 1.69 0.91 0.34 0.12 0.38 0.31 <0.001 2.71 3.36 0.80 0.003 Dabigatran 150 mg twice a day 1.11 1.69 0.66 <0.001 0.10 0.3 0.26 <0.001 3.11 3.36 0.93 0.31

ROCKET-AF

Rivaroxaban 20 mg every day 2.12 2.42 0.88 0.12 0.26 0.44 0.59 0.02 3.60 3.45 1.04 0.58

ARISTOTLE

Apixaban 5 mg twice a day 1.27 1.60 0.79 0.01 0.24 0.4 0.51 <0.001 2.13 3.09 0.69 <0.001

ENGAGE-AF

Edoxaban 30 mg daily 1.61 1.50 1.07 0.005 0.16 0.47 0.33 <0.001 1.61 3.43 0.47 <0.001 Edoxaban 60 mg daily 1.18 1.50 0.79 <0.001 0.26 0.47 0.38 <0.001 2.75 3.43 0.8 <0.001

NOAC Clinical Trials

Ischemic or Uncertain Stroke /yr Death /yr

Novel Agent Warfarin HR p Novel Agent Warfarin HR p

RE-LY

Dabigatran 110 mg twice a day 1.34 1.20 1.11 0.35 3.75 4.13 0.91 0.13 Dabigatran 150 mg twice a day 0.92 1.20 0.76 0.03 3.64 4.13 0.88 0.051

ROCKET-AF

Rivaroxaban 20 mg every day 1.34 1.42 0.94 0.58 4.5 4.9 0.92 0.15

ARISTOTLE

Apixaban 5 mg twice a day 0.97 1.05 0.92 0.42 3.52 3.94 0.89 0.047

ENGAGE-AF

Edoxaban 30 mg daily 1.7 1.25 1.41 <0.001 2.71 3.17 0.85 0.008 Edoxaban 60 mg daily 1.25 1.25 1.00 0.97 2.74 3.17 0.86 0.013

Warfarin’s Effects

ENGAGE-AF same 21% reduction for Edoxaban

Valvular AF

What is it? Mitral stenosis Hemodynamically significant valve lesions Prosthetic valves Repaired valves Prosthetic valves requiring anticoagulation ENGAGE-AF allowed bioprosthetic and repaired valves

Valvular AF

RE-ALIGN Dabigatran 150, 220, 300 mg vs. Warfarin Mechanical Valves (AVR or MVR) 252 patients (target of approximately 450 patients)

Valvular AF

RE-ALIGN Halted early 9 CVAs in Dabigatran arm vs. 0 in Warfarin arm 5 subclinical thromboses of valve vs. 0 Composite of stroke, transient ischemic attack, systemic embolism, myocardial infarction, or death 9% in Dabigatran arm vs. 5% in Warfarin arm Increased bleeding in Dabigatran arm

Valvular AF

What did we learn? Most events occurred in de-novo valve replacements With increased bleeding, increasing the dose of Dabigatran no an options For now, don’t use Dabigatran with mechanical valves

Advantages of Warfarin

Widespread use, familiarity Inexpensive Complications add to cost Effective when used with great care Anticoagulation clinics improve adherence to guidelines/nomograms and time at target Familiar antidotes

Advantages of NOACs

Convenience Fixed dose Rapid onset and offset of action Relatively short half-lives No need for bridging!

Advantages of NOACs

Improved or equal efficacy Dabigatran 150 and Apixaban 5 better than warfarin Decreased (Apixaban) or similar mortality (all others) Differences in outcomes were small and likely due to differences in study design, sample size, intrinsic risk,

• etc. rather than differences in the drugs themselves

Advantages of NOACs

Safety Hemorrhagic Stroke reduced 40 to 70% All Reduced Intracranial Hemorrhage by 50% Similar or reduced (Dabigatran and Apixaban) major bleeding

Disadvantages of NOACs

Safety Increased GI bleeding Cost Unknown valvular AF* Dabigatran cannot be used with mechanical prosthetic valves

Questions with NOACs

What about patients on warfarin, doing well Improved INRs didn’t reduce the benefit of NOACs Rivaroxaban, Apixaban, and Dabigatran all showed improved safety regardless of how well INR was controlled

Reversal Agents

Warfarin Vitamin K and FFP Duration of effect of FFP: 6-8 hours Onset of action of IV Vitamin K: Onset 2 hrs, Peak 6-24 hrs

Reversal Agents

Dabigatran / Idarucizumab (Praxabind) 90% of patients showed complete reversal in 4 hours Reversal effect lasts 24 hours Approved under accelerated protocol based on reversal in healthy volunteers Ongoing trial of reversal for emergency surgery

Reversal Agents

Xa Inhibitors aPCC (Activated Prothrombin Complex Concentrate

4-factor aPCC Increased Thrombosis Activates the clotting cascade

Advantages of NOACs

Should I wait for antidotes to be available to use Xa Inhibitors? Major bleeding and intracranial hemorrhage lower No bleed is better than reversed bleed AACP

Advantages of NOACs

Are they cost effective? Nobody knows… many people are looking at this Dabigatran seems to be cost effective when “quality” of warfarin therapy considered based

• n time outside therapeutic range

In the US, patients often make this decision!

Special Situations

Switching from Warfarin to Dabigatran Stop warfarin Start Dabigatran when INR < 2.0

Special Situations

Switching from Dabigatran to Warfarin Start Warfarin based on CrCl CrCl > 50: 3 days before stopping Dabigatran CrCl 30-50: 2 days before stopping Dabigatran CrCl 15-30: 1 day before stopping Dabigatran CrCl < 15: Don’t do this!

Special Situations

Switching from Warfarin to Rivaroxaban Stop warfarin Start Dabigatran when INR < 3.0

Special Situations

Switching from Rivaroxaban to Warfarin Stop Rivaroxaban Start heparin and warfarin at time of next dose (24 hours) Stop heparin when warfarin therapeutic

Special Situations

Switching from Warfarin to Apixaban Stop warfarin Start Apixaban when INR < 2.0

Special Situations

Switching from Edoxaban to Warfarin Start warfarin and reduce Edoxaban to ½ dose Stop Edoxaban when INR ≥ 2.0 Or Stop Edoxaban Start warfarin and heparin in 24 hrs Stop heparin when INR ≥ 2.0

Special Situations

Switching from Warfarin to Edoxaban Stop warfarin Start Apixaban when INR < 2.5

Special Situations

Surgical Interventions

Does anticoagulation need to be stopped at all? If yes then… Dabigatran: (longer if higher bleeding risk) 2-3 days before procedure 3-4 if CrCl < 50 Rivaroxaban, Apixaban, Edoxaban: 2-3 days before procedure

Summary

Dabigatran, Rivaroxaban, Apixaban, Edoxaban More expensive More convenient Safer (less major and intracranial hemorrhage) Less safe (GI bleeding) Equal or improved efficacy Not reversible (except dabigatran)

Summary

Dabigatran, Rivaroxaban, Apixaban, Edoxaban No bridging necessary Stop 2-3 days before surgery (except Dabigatran and renal dysfunction) Transitioning to/from Warfarin complex

Recommendations

Base anticoagulation decision on CHADS-VASc Score Warfarin recommended for mechanical heart valves Prior stroke/TIA, CHADS-VASc ≥ 2 anticoagulate Use NOAC if unable to obtain stable INRs Bridge warfarin with UFH or LMWH with mechanical valves Evaluate renal function before starting NOACs

Recommendations

May omit anticoagulation for CHADS-VASc = 0 Use warfarin for CHADS-VASc ≥ 2 and CrCl<15 If CHADS-VASc =1 may anticoagulate or not If CHADS-VASc ≥ 2 and moderate CKD, low-dose NOAC or warfarin Do NOT use NOAC with mechanical heart valves

Summary

Should all patients be switched to NOACs? NO!

AICD Update

Defibrillators are expensive New outcomes data help determine who will benefit Used to be easy Prior cardiac arrest

AICD Update

Then it got complicated Prior cardiac arrest or EF ≤ 30% with Prior MI EF ≤ 35% with CAD, NYHA Class I-III, NSVT, Inducible VT EF ≤ 40% with CAD & NSVT and inducible sustained VT Then added to make it more complex EF ≤ 35%, NYHA Class II-III ± CAD

AICD Update

That wasn’t complex enough so now…

CRT Update