2. Approach to Anticoagulation
1937: First use of heparin for treatment of venous
thrombosis:
– Murray, D. et al (1937) Surgery, 2, 163.
– Crafoord, C. (1937) Acta Chir. Scand. 79, 407.
1947: First description of heparin followed by Vitamin K
Antagonist (warfarin, dicoumarol) for pulmonary embolism
.
– 329 patients with pulmonary embolism treated, with
only one death.
– Allen, EV et al. (1947) Ann Intern Med 27:371.
3. Heparin: “An Indirect Anticoagulant”
Dependent of Antithrombin III
• Katzung BG et al. Basic & Clinical Pharmacology, 11th
Edition, McGraw-Hill, 2009.
4. • Randomized, controlled study of anticoagulation versus no
treatment.
• Med/Surg. patients with PE (based on history, physical exam,
pulmonary infarction on CXR, and right heart strain on EKG.
• Treatment:
– Heparin 10,000 units q 6 hours, for 6 doses without laboratory control.
– Acenocoumarol (Nicoumalone) adjusted for Prothrombin Time
• Barritt, D. W. and S. C. Jordan. Lancet 1(7138): 1309-1312,
1960.
6. Results
Group Total Deaths Non-Fatal Other
From PE recurrences Deaths
Untreated 19 5 5 0
Treated 54 0 1 2
Interim analysis resulted in early termination of untreated
group.
Deaths in Treatment Arm:
1 death from aspiration pneumonia
1 death related to medication error. Patient received
phenindione instead of Acenocoumarol and developed renal
failure.
Barritt, D. W. and S. C. Jordan (1960). Lancet 1(7138): 1309-1312.
7. Warfarin
Why We Hate It! Maybe not so bad!
Narrow Therapeutic Window Tremendously large experience
Sensitive to changes in diet We know everything about it (Vitamin K-
Dependent Factors: II, VII, IX, X, C, S)
Slow to act, very long half-life Simple, standardized test for functional
level (INR).
Numerous drug interactions Reversal agents highly effective and readily
available.
Wide range in therapeutic doses, Virtually no side effects except for bleeding.
difficult to predict.
Treacherous to use in cancer Cheap!
patients!
8. Ximelagatran:
Caution Needed For New Drug Development!
• A “new” oral direct thrombin inhibitor.
ASH Section devoted to it in 2005!
• After marketing in Europe and other
countries, severe hepatic dysfunction
observed in 5-6%, including cases of
fatal liver failure.
• Withdrawn in 2006.
10. Parameter Dabigaran Rivaroxaban Apixaban
Target Thrombin Factor Xa Factor Xa
Oral bioavailability 6.5% 80% 66%
Dosing Fixed, once or twice daily Fixed, once or twice Fixed, twice daily
daily
Pro-Drug Yes No No
Half-life (h) 12–14 7–13 8–13
Routine coagulation No No No
monitoring
Renal clearance 80% 66%; half as inactive ∼25%
drug
Potential drug P-gp inhibitors, Inhibitors of CYP3A4 CYP3A4 inhibitors
interactions (Rifampicin, quinidine, and P-gp
amiodarone)
Involvement of CYP No CYP3A4 CYP3A4
Clinical status FDA Approved FDA Approved Phase III
• Cytochrome P450 3A4 P-gp: P-glycoprotein
• Excerpt from Eriksson et al, 2011
11. Drug Trade Name Manufacturer
Apixaban Eliquis ® Pfizer/Bristol-Myers
Squibb
Rivaroxaban Xarelto ® Bayer/Johnson &
Johnson (Janssen)
Dabigatran Pradaxa ® Boehringer
Ingelheim
12. Development Strategies
Clinical Trial Development
– Prophylaxis in high risk orthopedic patients
– Atrial fibrillation
– Treatment of venous thrombosis
– Acute Coronary Syndrome
Fixed dose
No monitoring
Statistics: non-inferiority versus superiority
13. ISTH Bleeding Definitions
• Major Bleeding – Bleeding …
– with a fall in hemoglobin of ≥2 g/dL, or
– with transfusion of ≥2 units of PRBC or whole blood, or
– that occurs in a critical location, i.e., intracranial, intraspinal,
intraocular, retroperitoneal, intraarticular or pericardial, or
– that causes death
• Clinically Relevant Non-Major Bleeding – Bleeding
– that does not meet criteria for major bleeding, and
– that requires any medical or surgical intervention to treat the
bleeding
14. • “Indications and Usage: PRADAXA (dabigatran
etexilate mesylate) capsules is indicated to reduce
the risk of stroke and systemic embolism in patients
with non-valvular atrial fibrillation.”
• Dabigatran etexilate is the prodrug of dabigatran,
which reversibly inhibits the active site of thrombin.
• Oral bioavailability is ∼6%.
• DE is rapidly converted to dabigatran by esterases in
the blood and liver with peak plasma concentrations
achieved 2–3 h after oral administration.
15. Dabigatran versus Warfarin in Patients
with Atrial Fibrillation:
Randomized Evaluation of Long-Term Anticoagulation
Therapy (RE-LY)
• Atrial fibrillation and a risk of stroke
• Noninferiority trial, Randomized
• Dabigatran: 110 mg or 150 mg twice daily (blinded to which
dose)
(Orthopedic studies were once daily!)
• Warfarin (unblinded) adjusted-dose.
• Median follow-up period was 2.0 years.
• The primary outcome was stroke or systemic embolism.
• No mention of numbers of cancer patients in cohorts.
– Connolly S, et al, NEJM 2009; 361:1139-1151
16. Cumulative Hazard Rates for the Primary
Outcome of Stroke or Systemic Embolism.
Months
Connolly SJ et al. N Engl J Med 2009;361:1139-1151.
17. Efficacy Outcomes, According to
Treatment Group
Event Dabigatran Dabigatran Warfarin Relative Relative Relative
110 mg bid 150 mg bid (n=6022) Risk Risk Risk
(n=6015) (n=6076) DE 110 vs W DE 150 vs DE 150 vs
W DE 110
Stroke or 1.53 1.11 1.69 0.91 0.66 0.73
Systemic ( p<0.001 for (p<0.001) (p=0.005)
Embolism Non-inferior)
MI 0.72 0.74 0.53 1.35 1.38 1.02
(p 0.07) (p 0.048) (p 0.88)
Death from 2.43 2.28 2.69 0.90 0.85 0.94
Vascular (p 0.21) (p 0.04) (p 0.44)
Causes
Death from 3.75 3.64 4.13 0.91 0.88 0.97
any cause (p 0.13) (p 0.051) (0.66)
Events are %/yr Connolly SJ et al.
NEJM 2009;361:1139-1151.
p are superiority unless noted as non-
inferiority
18. Safety Outcomes, According to
Treatment Group
Event Dabigatran Dabigatran Warfarin Relative Risk Relative Risk Relative Risk
110 mg bid 150 mg bid (n=6022) DE 110 vs W DE 150 vs W DE 150 vs
(n=6015) (n=6076) D110
Major 2.71 3.11 3.36 0.80 0.93 1.16
Bleeding (p 0.003) (p 0.31) (p 0.052)
Minor 13.16 14.84 16.37 0.79 0.91 1.16
Bleeding (p<0.001) (p 0.005) (p<0.001)
All 14.62 16.42 18.15 0.78 0.91 1.16
Bleeding (p<0.001) (p 0.002) (p<0.001)
Events are %/yr
p are superiority unless noted as non-
inferiority
Connolly SJ et al. NEJM 2009;
19. RE-LY: Dabigatran versus Warfarin in
Patients with Atrial Fibrillation:
• Dabigatran 150 mg bid: As safe as warfarin, more effective.
• Dabigatran 110 mg bid: Safer than warfarin, as effective.
– Connolly SJ et al. NEJM 2009;361:1139-1151.
• FDA Approved 150 mg and 75 mg doses for non-valvular
atrial fibrillation?
• “Ultimately, the FDA's decision to approve only the 150-mg
strength was based on our inability to identify any subgroup
in which use of the lower dose would not represent a
substantial disadvantage”
– Beasley et al. NEJM 364:1788-1790, 2011
20. Dabigatran For Prevention Of VTE After
Major Orthopaedic Surgery: Phase III Studies
Study Comparator Time to 1st Treatment
administration of duration
dabigatran
RE-NOVATE Enoxaparin 1–4 hours 28–35 days
(THR) 40 mg qd, starting post-surgery
evening before surgery
RE- Enoxaparin 6–12 hours post- 12–15 days
MOBILIZE 30 mg bid, starting 12– surgery
(TKR) 24 hours post-surgery
RE-MODEL Enoxaparin 1–4 hours 6–10 days
(TKR) 40 mg qd, starting post-surgery
evening before surgery
Dabigatran 150 and 220 mg daily were investigated in
all three studies.
Eriksson et al. Blood 2006; Friedman et al. J Thromb
Haemost 2007; Eriksson et al. J Thromb Haemost 2007.
21. Dabigatran For Prevention of VTE
After Major Orthopaedic Surgery
DVT, PE and all-cause Enoxaparin Dabigatran Dabigatran
mortality (%) (150 mg qd) (220 mg qd)
RE-NOVATE (THR) 6.7% 8.6% 6.0%
(Enox 40 mg qd) p<0.0001* p<0.0001*
RE-MOBILIZE (TKR) 25.3% 33.7% 31.1% p=0.02†
(Enox 30 mg bid) p=0.0009†
RE-MODEL (TKR) 37.7% 40.5% 36.4%
(Enox 40 mg qd) p=0.0005* p=0.0345*
Major bleeding (%)
RE-NOVATE 1.6% 1.3% 2.0%
RE-MOBILIZE 1.4% 0.6% 0.6%
RE-MODEL 1.3% 1.3% 1.5%
*Non-inferior to enoxaparin; †Inferior to enoxaparin
Eriksson et al. Blood 2006; Friedman et al. J Thromb Haemost 2007;
Eriksson et al. JTH, 2007
22. The RECOVER Study:
Dabigatran versus Warfarin in the Treatment
of Acute Venous Thromboembolism
• Randomized, double blind study
• Initial treatment:
– “Approved parenteral anticoagulant (generally unfractionated
heparin administered intravenously or low-molecular-weight
heparin administered subcutaneously).”
– Given for at least 5 days.
• Dabigatran 150 bid (n=1273) or warfarin (n=1266)
• Analysis at 6 months.
• Cancer:
– Dabigatran: n=64 (5.0%), warfarin: n=57 (4.5%)
• Schulman S et al, NEJM 2009; 361:2342-2352
23. RECOVER Study: Cumulative Risk of
Recurrent VTE or Related Death
Schulman S et al. NEJM 2009;361:2342-2352.
24. Cumulative Risks of a First Event of Major
Bleeding and of Any Bleeding
Major Bleed: Hazard Ratio: 0.82 (95% CI, 0.45 to 1.48; P=0.38)
Any Bleeding: Hazard Ratio: 0.71 (95% CI, 0.59 to 0.85, p<0.001)
Schulman S et al. NEJM 2009;361:2342-2352.
25. Dabigatran For VTE Treatment
• “For the treatment of acute venous
thromboembolism, a fixed dose of dabigatran is as
effective as warfarin, has a safety profile that is
similar to that of warfarin, and does not require
laboratory monitoring.”
– Schulman S et al. NEJM 2009;361:2342-2352.
• Not yet FDA approved for VTE treatment!
• Study did not evaluate/validate its use for initial
anticoagulation treatment.
26. Dabigatran Etexilate: PRADAXA ®
• “Indicated to reduce the risk of stroke and systemic embolism
in patients with non-valvular atrial fibrillation.”
• Dosing: The recommended dose: PRADAXA 150 mg twice
daily.
• For patients with low creatinine clearance
– CrCl 15-30 mL/min, dose is PRADAXA 75mg twice daily
– CrCl <15 mL/min or on dialysis, dose cannot be provided
• “Effect of P-gp Inducers and Inhibitors on PRADAXA
Exposure”
– P-gp inducers (e.g., rifampin) reduces dabigatran exposure
and should generally be avoided.
– P-gp inhibitors ketoconazole, verapamil, amiodarone,
quinidine, and clarithromycin, do not require dose
adjustments.
27. Dabigatran Etexilate: PRADAXA ®
1. Atrial Fibrillation:
– 150 mg bid: more effective than warfarin
– 75 mg bid for CrCl 15-30 mL/min
2. VTE Treatment: (Not approved)
– Dabigatran 150 bid as effective as warfarin, and trend
towards reduced bleeding
3. High Risk Orthopedic Surgery: : (Not
approved)
– Dabigatran 150 and 220 mg daily not safer and trend
towards higher thrombosis rates.
29. RECORD Trials
(REgulation of Coagulation in ORthopaedic
surgery to prevent Deep vein thrombosis and
pulmonary embolism)
30. Xarelto®/Rivaroxaban
Trial Information
Drug Intervention
Elective
Trial Rivaroxaba Enoxapari Duration of Treatment
Surgery OR
n n
RECORD 1 THA 10mg PO QD 40mg SQ QD Both: 35 ± 4 days
Rivaroxaban: 35 ± 4
10mg PO QD
RECORD 2 THA 40mg SQ QD days
Enoxaparin: 13 ± 2 days
Rivaroxaban: 12 ±2
RECORD 3 TKA 10mg PO QD 40mg SQ QD days
Enoxaparin: 13 ± 2 days
10mg PO QD 30mg SQ
RECORD 4 TKA Both: 12 ± 2 days
q12h
Turpie AG, et al. Thrombo Haemost. 2011;105(3):444-
53.
31. Xarelto®/Rivaroxaban
RECORD Trial Efficacy Results
Composite of symptomatic VTE and all-cause mortality
Rivaro. Enoxaparin Odds ratio vs
(%) (%) Enox. (95% CL)
Pooled Data 0.5 1.0 0.48 (0.30-0.76) *
RECORD 1 0.3 0.4 0.88 (0.27-2.78)
RECORD 2 0.2 0.4 0.40 (0.04-2.45)
RECORD 3 0.7 2.1 0.31 (0.12-0.70)
RECORD 4 0.8 1.4 0.56 (0.25-1.2)
* p=0.001
Turpie AG, et al. Thrombo Haemost. 2011;105(3):444-53.
32. Xarelto®/Rivaroxaban:
RECORD Safety Outcomes
Rivarox. Enoxaparin Odds Ratio vs P value
(%) (%) Enox. (95% CL)
Day 12 +/- 2
Major Bleeding 0.3 0.2 1.62 (0.77-3.53) 0.23
Major + non- 2.8 2.5 1.17 (0.93-1.46) 0.19
major clinically
relevant
Any 6.6 6.2 1.07 (0.92-1.24) 0.38
Turpie AG, et al. Thrombo Haemost. 2011;105(3):444-
53.
33. Xarelto®/Rivaroxaban
RECORD Trials
• Rivaroxaban 10 mg daily:
• Consistently more effective than
Enoxaparin (40 mg daily or 30 mg bid)
for high risk orthopedic patients.
• Safety comparable with Enoxaparin.
34. ROCKET AF: Stroke Prevention in
Atrial Fibrillation
• “Rivaroxaban Once-daily oral direct
Factor Xa inhibition Compared with
vitamin K antagonism for prevention of
stroke and Embolism Trial in Atrial
Fibrillation.”
– Patel MR, et al. Rivaroxaban versus warfarin in
nonvalvular atrial fibrillation. N Engl J Med
2011;365:883-91.
35. ROCKET AF: Study Design
• Atrial Fibrillation With:
– At least 2 Risk Factors: CHF , Hypertension, Age 75,
Diabetes
– OR Stroke, TIA or Systemic embolus
• Treatment Arms:
– Rivroxaban: 20 mg daily
• (15 mg for Cr Cl 30-49 ml/min)
– Warfarin: INR target (2 – 3)
• Primary Endpoint: Stroke or non-CNS Systemic Embolism.
• Note! Rivaroxaban dose higher than Orthopedic prophylaxis
studies (20 mg vs 10 mg).
Patel MR, et al NEJM 365:883-91, 2011.
36. ROCKET-AF: Primary Efficacy
Outcome Rivaroxaban Warfari Hazard ratio p value
(n=7081) n (95% CI)
(n=7090)
Primary end point, 1.70 2.15 0.79 0.015
(superiority) (0.65-0.95)
Vascular death, 3.11 3.63 0.86 0.034
stroke, embolism (0.74-0.99)
Hemorrhagic stroke 0.26 0.44 0.59 0.024
(0.37-0.93)
Ischemic stroke 1.34 1.42 0.94 0.581
(0.75-1.17)
Unknown stroke 0.06 0.10 0.65 0.366
(0.25-1.67)
Primary Endpoint: Stroke or non-CNS Systemic Embolism.
Event Rates are per 100 patient-years.
Patel MR, et al NEJM 365:883-91, 2011.
37. ROCKET-AF: Safety Outcomes
Rivaroxaban Warfarin Hazard ratio P
Event Rate Event Rate (95% CI) value
All Clinically 1.03
Relevant 14.91 14.52 0.442
Bleeds (0.96, 1.11)
1.04
Major Bleeds 3.60 3.45 0.576
(0.90, 1.20)
Non-major 1.04
Clinically 11.80 11.37 0.345
Relevant (0.96, 1.13)
Bleeding 0.24 0.48 0.50 0.003
causing death (0.31-0.79)
Intracranial 0.49 0.74 0.67 0.019
hemorrhage (0.47-0.94)
38. EINSTEIN: Rivaroxaban For
Venous Thrombosis Treatment
• EINSTEIN-DVT and EINSTEIN-PE:
– Rivaroxaban 15 mg bid for 3 weeks followed by 20 mg once-daily
– Enoxaparin 1 mg/kg twice-daily (> 5 days), plus vitamin K antagonist (INR
2.0-3.0)
– (Allowed up to 48 hours of IV heparin, LMWH, Fondaparinux before
enrollment.)
• EINSTEIN Extension:
– Rivaroxaban 20 mg once-daily versus placebo in patients who have
already completed 6 or 12 months of Rivaroxaban or a vitamin K
antagonist.
• Primary Endpoint: Symptomatic, recurrent VTE
• Principle Safety Endpoint: Major bleeding and clinically relevant non-major
bleeding.
– Active cancer: Rivaroxaban, n=118 (6.8%), Control, n=89 (5.2%)
39. Cumulative Event Rates for the Primary
Efficacy Outcome in the DVT and PE Studies.
P<0.001 for
Acute noninferiorit
Treatmen y
t
Extended P<0.001
Treatment for
superiorit
y
The EINSTEIN Investigators. NEJM 2010;363:2499-2510.
40. Cumulative Event Rates for the Principal Safety
Outcome in the Acute DVT Study.
The EINSTEIN Investigators. NEJM 2010;363:2499-2510.
41. EINSTEIN: Rivaroxaban For Venous
Blood Clot Treatment
• Trend towards more effective than
heparin:warfarin, but statistically noninferior.
• As safe as heparin:warfarin.
• “A unique aspect of the Acute DVT Study is the
use of rivaroxaban as a single agent, replacing
both low-molecular-weight heparin and a vitamin
K antagonist in the treatment of DVT.”
– The EINSTEIN Investigators. N Engl J Med
2010;363:2499-2510.
42. EINSTEIN: Rivaroxaban For Venous
Blood Clot Treatment
• “The reversibility of the drugs’ (warfarin) effects and the
ability to measure the anticoagulant effect in specific
situations will continue to be highly desirable features and
will help to allay physicians' concerns.”
• “If these novel, breakthrough, oral anticoagulant drugs
prove to be effective across the broad spectrum of patients
in routine care and are conscientiously priced, the
worldwide impact will be huge.”
– Edtorial accompanying The Einstein Report.
– Elaine M. Hylek, N Engl J Med 2010; 363:2559-2561
43. MAGELLAN:
Prophylaxis in High Risk Medical Patients
• Is 10 days of anticoagulation with rivaroxaban non-inferior to
enoxaparin?
• Is 35 days of anticoagulation with rivaroxaban superior to
enoxaparin followed by placebo?
• Rivaroxaban compared with enoxaparin for the prevention of
venous thromboembolism in acutely ill medical patients.
• Rivaroxaban 10 mg po qd compared with Enoxaparin 40 mg
qd X 10 +/-4 days.
• Rivaroxaban 10 mg po qd compared with placebo X 35 +/- 4
days.
44. MAGELLAN:
Primary VTE efficacy endpoints:
– Day 10: Rivaroxaban vs Enoxaparin: (2.7% vs 2.7%)
– Day 35: extended thromboprophylaxis
– Rivaroxaban vs Enoxaparin (4.4% vs 5.7%).
Overall bleeding rates:
– Rivaroxaban higher:
– Day 10: Rivaroxaban (2.8%) vs Enoxaparin (1.2%)
– Day 35, Rivaroxaban (4.1%) vs Enoxaparin (1.7%)
p<0.0001.
– Rates of other adverse events, including liver and
cardiovascular events, were similar in both arms
45. ATLAS ACS 2 TIMI 51:
Rivaroxaban vs Placebo
• Tested 2.5 mg bid and 5 mg bid vs placebo
• Patients were on ASA and 93% also on clopidogrel
End point Riva 2.5 mg Placebo HR (95% CI) p
bid (%) (%)
CV
0.84 (0.72-0.97
death/MI/strok 9.1 10.7 0.02
)
e
0. 66 (0.51-
CV death 2.7 4.1 0.002
0.86)
All-cause 0.68 (0.53-0.
2.9 4.5 0.002
death 87)
Major non-
CABG 1.8 0.6 3.46 (2.08-5.77) 0.001
bleeding
ICH 0.4 0.2 2.83 (1.02-7.86) 0.04
Fatal bleeding 0.1 0.2 0.67 (0.24-1.89) 0.45
46. Rivaroxaban: Xarelto®
• 1. Nonvalvular Atrial Fibrillation:
– CrCl >50 mL/min: XARELTO® 20 mg PO daily with the evening meal.
– CrCl 15 to 50 mL/min: 15 mg PO daily with the evening meal.
• 2. Prophylaxis of Deep Vein Thrombosis:
– 10 mg PO daily with or without food.
– Initial dose > 6 to 10 hours after surgery once hemostasis has been
established.
– THR: 35 days is recommended.
– TKR: 12 days is recommended.
• 3. VTE Treatment (Not Approved)
– Rivaroxaban 15 mg bid for 3 weeks followed by 20 mg once-daily
• 4. Acute Coronary Syndrome (Not Approved)
– Rivaroxaban 2.5 mg bid with antiplatelet agents.
47. Rivaroxaban: Xarelto®
• Drugs That Inhibit CYP3A4 Enzymes and Drug Transport
Systems:
– Avoid concomitant administration with combined P-gp and strong CYP3A4
inhibitors, which cause significant increases in rivaroxaban exposure.
• Drug-Disease Interactions With Drugs That Inhibit
CYP3A4 Enzymes and Drug Transport Systems:
– Use only if benefit justifies risk in patients with renal impairment with concomitant
use of P-gp and weak or moderate CYP3A4 inhibitors due to potentially significant
increase in rivaroxaban exposure.
• Drugs That Induce CYP3A4 Enzymes and Drug Transport
Systems:
– Avoid P-gp and strong CYP3A4 inducers due to decreases in rivaroxaban
exposure.
49. ADVANCE:
Apixaban versus Enoxaparin In High-Risk
Orthopedic Patients
ADVANCE-3: THR
– Apixaban 2.5 mg orally bid
– Initiated 12 to 24 hours after wound closure.
– Enoxaparin at a dose of 40 mg q 24 hours.
– Initiated 12 hours before surgery.
– Prophylaxis was continued for 35 days after surgery,
Primary efficacy outcome:
Composite of All DVT, PE, or death from any cause during the
treatment period.
50. APIXABAN: ADVANCE-3 (THR)
Apixaban versus Enoxaparin In High-Risk
Orthopedic Patients
Apixaban Enoxaparin Relative
(2.5 mg bid) (40 mg qd) Risk
Primary Endpoint 1.4% (n=27) 3.9% (n=74) 0.36,
P<0.001
Symptomatic deep- <0.1% (n=1) 0.2% (n=5)
vein thrombosis
All Bleeding 4.8% (n=129) 5.0% (n=134)
(Major and Minor)
Major Bleeding 0.8% 0.7%
(95% CI: 0.5 to 1.3) (95% CI: 0.4 to 1.1)
Treatment was for 35 days
The primary Endpoint: Composite of asymptomatic or symptomatic DVT, PE,
or death from any cause during the treatment period.
Lassen et al, NEJM, 363;26, 2010.
51. ARISTOTLE: Phase III trial or
Apixaban vs Warfarin in Atrial
Fibrillation
Apixaban 5 mg twice daily
Warfarin (target INR 2.0 to 3.0)
Atrial fibrillation and at least one additional risk
factor for stroke. (n=18,201 patients).
Primary outcome: Ischemic or hemorrhagic
stroke or systemic embolism.
Designed to test for noninferiority.
– Granger et al. N Engl J Med 2011;365:981-
92.
52. ARISTOTLE: Phase III trial or Apixaban
vs Warfarin in Atrial Fibrillation
End point Apixaban Warfarin HR (95% CI) p
(%/year) (%/year)
Stroke or 1.27 1.60 0.79 (0.66-0.95) 0.01
systemic
embolism*
Major bleeding 2.13 3.09 0.69 (0.60-0.80) <0.001
All-cause 3.52 3.94 0.89 (0.80-0.99) 0.047
mortality
Hemorrhagic 0.24 0.47 0.51 (0.35-0.75) <0.001
stroke
Ischemic/uncer 0.97 1.05 0.92 (0.74-1.13) 0.42
tain stroke
Apixaban 5 mg twice daily
Granger et al. N Engl J Med 2011;365:981-92.
53. APPRAISE-1: Apixaban, in
combination with antiplatelet therapy
after acute coronary syndromes
• Alexander J et al. N Engl J Med. 2011 Aug 25;365(8):699-
708
• Apixaban tested at 2.5 mg bid and 10 mg qd.
• Acute coronary syndrome (myocardial infarction, with or
without ST-segment elevation, or unstable angina) within the
previous 7 days
• Apixaban or placebo in addition to mono or dual antiplatelet
therapy.
54. Kaplan–Meier Curves for the Primary Efficacy Outcome.
Alexander JH et al. N Engl J Med 2011;365:699-708.
55. Kaplan–Meier Curves for the Primary Safety Outcome.
Alexander JH et al. N Engl J Med 2011;365:699-708.
56. Monitoring of Dabigatran:
Drug added to normal plasma
EC PT
T
TT aPT
T
• Peak plasma level is ~180 ng/ml.
– van Ryn et al. Thromb Haemost 2010; 103: 1116–1127
57. Barriers To Broader Use Of New
Oral Anticoagulants:
• “Fixed Dose,” but it is not yet known which dose we should be using.
– And like LMWH, it is highly unlikely that doses will not need to be
titrated in select high-risk populations, such as cancer, moderate
liver/renal dysfunction, thrombocytopenia, chemotherapy, etc.
• No established assay for plasma levels.
– Assay will be essential for cancer patients, who are at risk for organ
dysfunction, thrombocytopenia, as well as drug interactions.
• Limited data on drug interactions.
• Limited knowledge about dosing in mild-moderate organ dysfunction,
obesity, thrombocytopenia, etc.
• No reversal agent!
58. New Agents For DVT Treatment In
Cancer?
Both Dabigatran and Rivaroxaban VTE Treatment studies showed
non-inferiority to warfarin.
In cancer, warfarin is known not to be optimal (Lee et al. CLOT Study,
NEJM, 2003).
Need to demonstrate non-inferiority to LMWH in cancer population.
Studies included only 4-6% cancer patients and no subgroup analysis
was provided.
Patients with liver disease, or renal insufficiency, or life-expectancy
<6 months were excluded.
NO MONITORING, NO REVERSAL AGENTS!
59. Correspondences on major bleeding
in community setting/trauma on
Dabigatran
• “Lack of a readily available method to determine the
degree of anticoagulation”
• “Currently, the only reversal option for dabigatran is
emergency dialysis (as suggested in a single line in the
package insert)”.
• “Recently, we have cared for several injured patients
receiving dabigatran, all of whom had poor outcomes.
Although the results of conventional coagulation studies
were normal, the values obtained on rapid
thromboelastography (rTEG) at the time of admission were
grossly abnormal.”
• Cotton BA et al., N Engl J Med 2011; 365:2039-2040
(Letter)
61. • Reduction of Risk of Stroke and Systemic Embolism in Nonvalvular Atrial
Fibrillation:
– XARELTO® is indicated to reduce the risk of stroke and systemic
embolism in patients with nonvalvular atrial fibrillation.
– There are limited data on the relative effectiveness of XARELTO® and
warfarin in reducing the risk of stroke and systemic embolism when
warfarin therapy is well controlled.
• Prophylaxis of Deep Vein Thrombosis:
– XARELTO® is indicated for the prophylaxis of deep vein thrombosis
(DVT), which may lead to pulmonary embolism (PE) in patients
undergoing knee or hip replacement surgery.
62. RECORD4: Rivaroxaban For Thrombosis
Prophylaxis in THR Patients
12 Total VTE
Enoxaparin 30 mg q12h, 10-14 days
10.1%
10 Rivaroxaban 10 mg qd 10-14 days
Incidence (%)
8 6.9% Efficacy: Non-inferiority of rivaroxaban
6
4 Major VTE Symptomatic Major
2.0% VTE bleeding
2 1.2% 1.2% 0.7% 0.7% 0.3%
0
RRR 31% p=0.124 p=0.187 p=0.124
p=0.012
Redrawn from Turpie AG et al. Lancet 373, 1673-80, 2009.