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.”
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
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
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.
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
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 todeath!
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
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
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?
You were just diagnosed with atrial fibrillation.
What drug are you going to use?
A. Dabigatran
B. Rivaroxaban
C. Apixaban
D. Warfarin