• No results found

Disclosure: Dr. Smith has no actual or potential conflict of interest associated with this presentation.

N/A
N/A
Protected

Academic year: 2021

Share "Disclosure: Dr. Smith has no actual or potential conflict of interest associated with this presentation."

Copied!
9
0
0

Loading.... (view fulltext now)

Full text

(1)

Michael Smith, Pharm. D., BCPS, CACP Pharmacy Clinical Manager William Backus Hospital

Disclosure:

Dr. Smith has no actual or potential conflict of 

interest associated with this presentation.

You were just diagnosed with atrial fibrillation.  

What drug are you going to use?

A. Dabigatran

B. Rivaroxaban

C. Warfarin

D. Um, no thanks, I don’t want to bleed to 

death!

“One snowy morning in February, 1933, Ed Carlson, a 

farmer from Deer Park, Wisconsin, came into Karl 

Paul Link's laboratory carrying a milk‐can full of blood 

that refused to coagulate. Outside he had a small 

heap of spoiled sweet clover hay and a dead heifer 

freezing in the back of his truck.”

(2)

Discuss the mechanism of action, indications, 

contraindications and adverse effects.

Discuss the available monitoring and 

reversibility of these agents. 

Identify patients that may benefit from the 

new agents and those that may not.

Ideal Anticoagulant

Oral and Injectable

Rapid onset/off

Effective on venous and arterial thrombosis

Rapidly reversible

No monitoring necessary, but possible

No drug interactions

No or predictable effects of renal/hepatic disease 

9

XIIa

IIa Tissue factor

1. Adapted from Petitou M et al. Nature. 1991;350(6319 suppl):30-33. 2. Hirsh J, Fuster V. Circulation. 1994;89:1449-1468. 3. Hirsh J et al.

Chest. 2001;119(1 suppl):64S-94S. 4. Nutescu EA et al. Pharmacotherapy. 2004;24(7 Pt 2):82S-87S. 5. Bauer KA. J Thromb Thrombolysis.

2006;21:67-72.

Xa

XII

XI XIa

IX IXa VIIa VII

VIII VIIIa X Xa V Va II Fibrinogen Fibrin (Thrombin) Factor Xa inhibitors4,5 Direct thrombin inhibitors4,5 Vitamin K antagonists4 Unfractionated heparin2,3 Intrinsic system (surface contact) Extrinsic system (tissue damage) Low–molecular-weight heparins2,3

Dabigatran Rivaroxaban Apixaban

Medical Prophylaxis

MAGELLAN ADOPT

THA RE‐NOVATE RECORD I

RECORD II ADVANCE‐3 TKA RE‐MOBILIZE RE‐MODEL RECORD III RECORD IV ADVANCE‐1 ADVANCE‐2 VTE  Treatment RE‐MEDY RE‐COVER RE‐SONATE EINSTEIN‐DVT  EINSTEIN‐PE EINSTEIN‐EXT AMPLIFY AMPLIFY‐EXT

Dabigatran Rivaroxaban Apixaban

Atrial Fibrillation RE‐LY ROCKET ARISTOTLE Acute  Coronary  Syndrome RE‐DEEM (phase II) ATLAS TIMI 46 ATLAS TIMI 51 APPRAISE (phase II) Heart Valve  replacement RE‐ALIGN (phase II)

Direct thrombin inhibitor (DTI)

Indication: Reduce the risk of stroke and 

systemic embolism in patients with non‐

valvular atrial fibrillation.

Dose 

For CrCl>30 ml/min: 150mg BID

For CrCl 15‐30ml/min: 75mg BID

80% renal elimination

(3)

RE‐LY trial

18,113 patients with atrial fibrilliation, 

unblinded warfarin use, 110mg or 150mg 

dabigatran, non‐inferiority, 

Outcome (%/yr)  Dabigatran Warfarin Relative Risk P value Stroke or systemic embolism  1.11 1.69 0.66 (0.53‐0.82) 0.01 Death from any cause 3.64 4.13 0.88 (0.77‐1.0) 0.051 Major Bleeding  3.11 3.36 0.93 (0.81‐1.07) 0.31 Anything bad  6.91 7.64 0.91 (0.82‐1.00) 0.04

TTR = 64%.

Conelly, SJ. N Engl J Med 2009;361:1139-51.

Efficacy and safety of dabigatran compared with warfarin at different levels of international normalized ratio control for stroke prevention in atrial fibrillation: an analysis of the RE-LY trail.

Lancet. 2010 Sep 18;376(9745):975-83

Wallentin L. Lancet. 2010 Sep 18;376(9745):975-83

Warnings and Precautions 

 Dabigatran therapy should be temporarily discontinued before invasive or surgical 

procedures to decrease bleeding risk. 

 Dabigatran should be discontinued 1 to 2 days (if CrCl is 50 mL/min or greater) or 3 to 5 days 

(if CrCl is less than 50 mL/min) before invasive or surgical procedures. 

 Consider a longer period without the drug in patients undergoing major surgery, spinal 

puncture, or placement of a spinal or epidural catheter or port. 

 P‐glycoprotein (PgP) inducers and inhibitors may affect dabigatran pharmacokinetics. 

Coadministration of rifampin, a PgP inducer, should be avoided because it reduces 

dabigatran exposure.  AUC increase with amiodarone (12%), quinidine (53%), verapamil

(23%), ketoconazole (150%).

Adverse Drug Reactions 

 The most common adverse reactions, occurring in at least 15% of patients receiving 

dabigatran to reduce the risk of stroke in atrial fibrillation, are gastritis‐like symptoms (35% 

with dabigatran and 24% with warfarin) and bleeding.  In the RE‐LY study, major bleeding 

occurred in 3.3% of patients treated with dabigatran and 3.6% of patients treated with 

warfarin. Bleeding of any kind occurred in 16.6% of patients treated with dabigatran and 

18.4% of patients treated with warfarin.

Prescribing information, Boehringer Ingelheim Pharmaceuticals, 2012

FDA Drug Safety Communication:  Safety review of post‐market  reports of serious bleeding events  with the anticoagulant Pradaxa (dabigatran etexilate mesylate) 12‐7‐2011: “The U.S. Food and Drug 

Administration (FDA) is evaluating 

post‐marketing reports of serious 

bleeding events in patients taking 

Pradaxa (dabigatran etexilate mesylate).  Pradaxa is a blood 

thinning (anticoagulant) medication 

used to reduce the risk of stroke in 

patients with non‐valvular atrial fibrillation (AF), the most common 

type of heart rhythm abnormality.”

Is renal function to blame?

 “Patients with severe renal impairment were not studied in RE‐LY. Dosing  recommendations in subjects with severe renal impairment are based on  pharmacokinetic modeling”

75 mg dose was never clinically studied! Renal  Function CrCl (mL/min) Increase  in AUC Increase  in C max T1/2 (h) Normal ≥ 80 1 X 1 X 13 Mild 50‐80 1.5 X 1.1 X 15 Moderate 30‐50 3.2 X 1.7 X 18 Severe* 15‐30 6.3 X 2.1 X 27

(4)

Never mind...

FDA Drug Safety Communication: Update on the risk for serious bleeding  events with the anticoagulant Pradaxa

11‐02‐2012The U.S. Food and Drug Administration (FDA) has evaluated new information  about the risk of serious bleeding associated with use of the anticoagulants (blood thinners)  dabigatran (Pradaxa) and warfarin (Coumadin, Jantoven, and generics). Following the  approval of Pradaxa, FDA received a large number of post‐marketing reports of bleeding  among Pradaxa users. As a result, FDA investigated the actual rates of gastrointestinal  bleeding (occurring in the stomach and intestines) and intracranial hemorrhage (a type of  bleeding in the brain) for new users of Pradaxa compared to new users of warfarin. The results  of this Mini‐Sentinel assessment indicate that bleeding rates associated with new use of  Pradaxa do not appear to be higher than bleeding rates associated with new use of  warfarin, which is consistent with observations from the large clinical trial used to  approve Pradaxa (the RE‐LY trial)  Healthcare professionals who prescribe Pradaxa should carefully follow the dosing  recommendations in the drug label, especially for patients with renal impairment (when  kidneys don’t function normally) to reduce the risk of bleeding. 

Direct factor Xa inhibitor

Half life 5‐9hrs

Dose 10mg, 15mg, 20mg depending on 

indication, point in therapy, and renal 

function.

65% renal elimination

Prescribing information, Janssen Pharmaceuticals, 2011

Indication Dosage

To reduce the risk of stroke and systemic 

embolism in patients with nonvalvular atrial fibrillation 

For patients with CrCl >50 mL/min: 20 mg 

orally, once daily with the evening meal 

For patients with CrCl 15 ‐50 mL/min: 15 

mg orally, once daily with the evening 

meal For the prophylaxis of DVT, which may 

lead to PE in patients undergoing knee or 

hip replacement surgery.

Hip: 10 mg orally, once daily for 35 days

Knee: 10 mg orally, once daily for 12 days For the treatment of deep vein 

thrombosis (DVT), pulmonary embolism 

(PE), and for the reduction in the risk of 

recurrence of DVT and of PE 

15 mg orally twice daily with food for the 

first 21 days for the initial treatment. 

After the initial treatment period, 20 mg 

orally once daily for the remaining 

treatment period.

Prescribing information, Janssen Pharmaceuticals, 2011

ROCKET‐AF trial

14,264 patients, double‐blind, Rivaroxaban

20mg daily vs warfarin, non‐inferiority, 55% 

TTR

Outcome (%/yr) Rivaroxaban Warfarin Hazard ratio P value Stroke or systemic 

embolism

2.1 2.1 0.88 (0.75‐1.03) <0.00

Death from any cause 4.5 4.9 0.92 (0.82‐1.03) 0.15 Major Bleeding 3.6 3.4 1.04 (0.90‐1.20) 0.58

Anything bad ? ?

Patel MR. N Engl J Med 2009;361:1139-51.

Eriksson NEJM. 2008;358:2765-277 KakkarLancet. 2008;372:31-39 LassanNEJM. 2008;358:2776-2786 TurpieLancet. 2009;373(9676):1673-80

RECORD-1 RECORD-2 RECORD-3 RECORD-4

Population THR n=4541 THR n=2509 TKA n=2531 TKA n=3148 Comparator Enoxaparin 40mg Daily Enoxaparin 40mg Daily Enoxaparin 40mg Daily Enoxaparin 30mg BID Duration 35 days Riva- 35 days

Enox- 10 days

14 days 14 days VTE events 1.1% Rivarox

3.7% Enox 2% Rivarox 9.3% Enox 9.6% Rivarox 18.9% Enox 6.9% Rivarox 10.1% Enox Major Bleeding 0.3% Rivarox

0.1% Enox <0.1% 0.6% Rivarox 0.5% Enox 0.7% Rivarox 0.3% Enox RECORD trials

• Randomized, double blind, thromboprophylaxis of orthopedic surgery

• Rivaroxaban 10mg PO Daily vs Enoxaparin; rivaroxaban started 6‐8hrs  after surgery

EINSTEIN‐DVT and EINSTEIN‐PE trials  Treatment of VTE and the long‐term prevention of VTE. 

 Open‐label, non‐inferiority study.

 Patients received rivaroxaban 15 mg twice daily for 3 weeks followed by 20 mg 

once daily for 3, 6, or 12 months, 

or 

 Enoxaparin 1 mg/kg twice daily followed by warfarin or an acenocoumarol dose 

adjusted to an international normalized ratio (INR) of 2 to 3 for 3, 6, or 12 months.  DVT TTR 57.7%; PE TTR 62.7% 

Outcome % Rivaroxaban Warfarin Hazard Ratio P value DVT‐Recurrent VTE 2.1 3.0 0.68 (0.44‐1.04) <0.001 DVT‐Bleeding 8.1 8.1 PE‐Recurrent VTE 2.1 1.8 1.12 (0.75‐1.68) 0.003 PE‐Bleeding 10.3 11.4 0.90 (0.76–1.07) 0.23 N Engl J Med 2010;363:2499-510. N Engl J Med 2012;366:1287-97.

(5)

Contraindications:Rivaroxaban therapy is contraindicated in patients with  known allergy to rivaroxaban or any of the product ingredients, and in  patients with active major bleeding.

Warnings and Precautions:  Avoid the use of  in patients with CrCl <15  mL/min since drug exposure is increased.

 Treatment of Deep Vein Thrombosis (DVT), Pulmonary Embolism (PE),  and Reduction in the Risk of Recurrence of DVT and of PE and  Prophylaxis of Deep Vein Thrombosis Following Hip or Knee  Replacement Surgery:

 Avoid the use in patients with CrCl <30 mL/min due to an expected  increase in rivaroxaban exposure and pharmacodynamic effects in this  patient Population.

Prescribing information, Janssen Pharmaceuticals, 2011

Drug Interactions: Rivaroxaban is a substrate of CYP3A4/5, P‐glycoprotein  (P‐gp); concomitant use of rivaroxaban with combined P‐gp and strong  CYP3A4 inhibitors (eg, ketoconazole, itraconazole, lopinavir/ritonavir,  ritonavir, indinavir/ritonavir, conivaptan) should be avoided.   Concomitant use of rivaroxaban with combined P‐gp and weak or 

moderate CYP3A4 inhibitors (eg, erythromycin, azithromycin, diltiazem,  verapamil, quinidine, ranolazine, dronedarone, amiodarone, felodipine)  should be avoided in patients with renal impairment, unless the benefit  outweighs the bleeding risk.

 Concomitant use of rivaroxaban with combined P‐gp and strong CYP3A4  inducers (eg, carbamazepine, phenytoin, rifampin, St. John’s wort)  should be avoided, or consideration given to use of an increased  rivaroxaban dose. Administration with rifampicin resulted in a 50%  reduction in rivaroxaban AUC and a 22% reduction in the rivaroxaban Cmax, with accompanying reductions in rivaroxaban effects.

Prescribing information, Janssen Pharmaceuticals, 2011

ROCKET AF Discussion…

 “Event rates were similar at 30 days and 1 year after 

withdrawal, suggesting that the mechanism of events did 

not involve hypercoagulability early after withdrawal of 

rivaroxaban. Events occurring at the end of the study were 

probably related to increased difficulty in achieving the 

transition from blinded trial therapy to the open‐label use of 

a vitamin K antagonist when the patient had previously been 

assigned to the rivaroxaban group, since presumably many 

patients who had previously been assigned to the warfarin group would have already had a therapeutic INR.”

Patel MR. N Engl J Med 2009;361:1139-51.

 “Rivaroxaban is rapidly replacing warfarin and enoxaparin to  reduce the risk of pulmonary and venous thromboembolism after  hip and knee surgery. When we examined the reports, we found  that the primary event was not hemorrhage, as with other  anticoagulants. Instead, the largest category of events (158 cases,  44.4% of the total) was serious thrombus, most often pulmonary  embolism—the very event rivaroxaban is intended to prevent. As  might be expected, there were also numerous reports of  hemorrhage (121 cases, 34% of the total).”

Direct factor Xa inhibitor

Indication: To reduce the risk of stroke and 

systemic embolism in patients with 

nonvlvular atrial fibrillation.*

Dose: 5mg BID

Renal elimination 25%

* Proposed indication

(6)

FDA decision due on 3/28/12, 3/17/13

Originally granted a priority review by the 

FDA

A priority review designation is given to drugs 

that offer major advances in treatment, or 

provide a treatment where no adequate 

therapy exists.

Press release, Bristol-Myers Squibb, 9/26/2012

 ARISTOTLE Trial

 18,201 patients, double‐blind, apixaban 5mg BID 

vs warfarin, non‐inferiority, 62.2% TTR

*p value for superiority!

Outcome (%/yr) Apixaban Warfarin Hazard ratio P value Stroke or systemic embolism 1.27 1.60 0.79 (0.66‐0.45) 0.01* Death from any cause 3.52 3.94 0.89 (0.80‐0.998) .047 Major Bleeding 2.13 3.09 0.69 (0.60‐.80) <0.001 Anything bad 6.13 7.2 0.85 (0.78‐0.92) <0.001

Granger CB. N Engl J Med. 2011;365(11):981-92

Warnings, precautions, side effects.

Metabolized by CYP 3A4

TBD

You were just diagnosed with atrial fibrillation.  

What drug are you going to use?

A. Dabigatran

B. Rivaroxaban

C. Apixaban

D. Warfarin

. Um, no thanks, I don’t want to bleed to 

death!

You feel that…

A. The ability to monitor a drug is important

B. Warfarin monitoring is too troublesome

C. They didn’t monitor in the trials, it’s not 

necessary, so what’s the big deal?

D. Hey, we’re past the halfway point!

May be important for:

Compliance determination

Determining why treatment fails

Drug interactions/hepatic/renal issues

Hemorrhagic events

(7)

 PT and aPTT do not respond in a linear or 

predictable fashion.

 They are useful for testing for the presence of 

the drug in the plasma.

 Not for determination of the extent of 

anticoagulation.

 Caution when trying to test INR with concurrent 

warfarin use.

 Other tests are being developed

Assay Dabigatran Rivaroxaban Apixaban

PT Not really Sensitive Sensitive

aPTT Sensitive Not really Not really

Miyares MA. AJHP 2012;69:1473-84-356

Warfarin

Decreases production of factors II, VII, IX, X

To reverse…

Vitamin K to overcome competitive inhibition

▪~ 4 hours

Fresh frozen plasma (FFP)‐contains all 

coagulation factors in dilute amounts.

Complex concentrates (PCC)‐contain various 

coagulation factors.

39

XIIa

IIa Tissue factor

1. Adapted from Petitou M et al. Nature. 1991;350(6319 suppl):30-33. 2. Hirsh J, Fuster V. Circulation. 1994;89:1449-1468. 3. Hirsh J et al.

Chest. 2001;119(1 suppl):64S-94S. 4. Nutescu EA et al. Pharmacotherapy. 2004;24(7 Pt 2):82S-87S. 5. Bauer KA. J Thromb Thrombolysis.

2006;21:67-72.

Xa

XII

XI XIa

IX IXa VIIa VII

VIII VIIIa X Xa V Va II Fibrinogen Fibrin (Thrombin) Factor Xa inhibitors4,5 Direct thrombin inhibitors4,5 Vitamin K antagonists4 Unfractionated heparin2,3 Intrinsic system (surface contact) Extrinsic system (tissue damage) Low–molecular-weight heparins2,3

Prothrombin Complex Concentrates

3 Factor PCC (Bebulin VH, Profilnine SD)

Contain factors II, IX, X

4 Factor PCC

Available as Feiba NF in the US

II, IX, X and activated VII

These products are all unique with respect to 

concentrations of factors and considered not 

interchangeable. 

Consider “external validity”

Clinical trials have been done either in animal 

models or healthy human volunteers.

Mixed results with end points. Normalization of coagulation markers

Normalization of bleeding time

Human trials of PCCs have used agents not 

available in the US.

Apixaban Dabigatran Rivaroxaban Oral activated 

Charcoal

No data In vitro No data

Hemodialysis No data Human volunteers No data Hemoperfusion

w/charcoal

No data In vitro No data

Fresh frozen plasma No data Mouse No data Activated factor VIIa No data Rat Rat and Baboon 3‐factor PCC No data No data No data 4‐factor PCC No data Human volunteers 

and rats

Human volunteers

(8)

Apixaban Dabigatran Rivaroxaban Oral activated 

Charcoal

Yes Yes Yes

Hemodialysis No Yes No

Hemoperfusion w/charcoal

Possible Yes Possible

Fresh frozen plasma No No No

Activated factor VIIa Unclear Unclear Unclear

3‐factor PCC Unclear Unclear Unclear

4‐factor PCC Possible Possible Possible

Katz S, Kouides PA, Garcia DA, et al. Am J Hematol. 2012;87:S141-s145.

Panel’s conclusions…

 PCC: The use of either 3‐factor or 4‐factor PCCs have the potential to  increase the risk of thrombosis .  

There have been no studies evaluating the effect of PCCs on bleeding 

in humans receiving the new oral anticoagulants. Whether use of PCCs  will be effective to stop critical bleeding or reverse the anticoagulant  effects of the new agents enough to safely proceed with emergent  surgery is not established but seems, given the current state of  information, to be a reasonable approach in dire clinical situations in the  opinion of several of the authors.

Importantly, however, consensus was not reached regarding PCC, as 

two authors felt that PCC cannot be recommended at this time due to 

absence of data

Katz S, Kouides PA, Garcia DA, et al. Am J Hematol. 2012;87:S141-s145.

With respect to reversibility, you feel…

A. Keep those drugs away from me until a 

reversal agent is available.

B. Risk of severe hemorrhage is low (and 

possibly lower than warfarin), I’m 

comfortable with the new agents.

Things to consider: Efficacy/Safety Compliance Cost Management NEWER ORAL ANTICOAGULANTS SHOULD BE  USED AS FIRST‐LINE AGENTS TO PREVENT  THROMBOEMBOLISM IN PATIENTS WITH  ATRIAL FIBRILLATION AND RISK FACTORS FOR  STROKE OR THROMBOEMBOLISM

 Warfarin monitoring and  adverse reactions are an  enormous burden to the  healthcare system.  Convenience may lead to 

improved adherence and  persistence.

 Decreased hemorrhagic  stroke and intracranial  bleeding.

 Trend towards improved  mortality.

NEWER ORAL ANTICOAGULANTS SHOULD NOT  BE USED AS FIRST‐LINE AGENTS TO PREVENT  THROMBOEMBOLISM IN PATIENTS WITH  ATRIAL FIBRILLATION.

 RE‐LY trial was open label  with a 21% dropout rate for  dabigatran and increased  major GI bleeding and MI.  “Vanishing” difference in  relative efficacy as warfarin management improved.  ROCKET‐AF trial had only a 

57.8% TTR.

 Increased risk with poor  adherence and no consistent  follow‐up.

 Drug interactions? Granger CB, Armaganijan LV. Circulation. 2012;125:159-164.

Ansell, J. Circulation. 2012;125:165-170.

 Many patient factors to consider to determine which is most  appropriate.

 Anticoagulation management service available

▪Efficacy likely equal

 Poor compliance

▪Warfarin likely better

 Economic issues

▪Rx cost least with warfarin, but what about monitoring?

 Monitoring beneficial 

▪renal/hepatic disease, many medications/interactions

▪Possible with warfarin

 High risk of bleeding events

▪reversibility vs decreased bleeding risk

 What about those having poor response to warfarin?

(9)

You were just diagnosed with atrial fibrillation.  

What drug are you going to use?

A. Dabigatran

B. Rivaroxaban

C. Apixaban

D. Warfarin

References

Related documents

Creative production activities occur in partly interlocking segments of the economy that are focused on extending and exploiting symbolic cultural products such as

Integrated Twin-lens 3D Camera Recorder DVI-D (Line-by-line/ Side-by-side) HD SDI (Left) HD SDI (Right) simultaneous system Projector BT-3DL2550 BT-3DL2550 AG-3DP1 AG-3DP1

On the other hand, to understand the improvements obtained by the distance-aware round-robin mapping policy, we study the average distance to the home cache bank and the number

Managing cloud &amp; virtual environments Exploiting unified communications TRANSFORMING INFRASTRUCTURE &amp; NETWORKS ENABLING THE MOBILE-FIRST ENTERPRISE Intelligence in

Figure 9 compares the numerical solution obtained for detrended consumption in both models, the dashed line corresponds to the optimal growth solution and the solid line to the

Anxiety disorders are separated into multiple subcategories including generalized anxiety, panic, post-traumatic stress, social anxiety, and obsessive-compulsive disorder

Bair Chase Prop. denied), where the appellate court remanded the attorney’s fee issue to the trial court with instructions to separate the fees incurred in correcting usury

• Recommended to back up transaction logs to an Advanced Disk storage unit (copy #1) for faster backups and restores without having to rehydrate the data from a