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New Oral Anticoagulants:
What we’ve all been waiting for!

       Gerald A Soff, MD
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.
Heparin: “An Indirect Anticoagulant”
             Dependent of Antithrombin III




•   Katzung BG et al. Basic & Clinical Pharmacology, 11th
    Edition, McGraw-Hill, 2009.
• 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.
Prothrombin Time Titration of Vitamin
           K Antagonist.




       Target PT ratio 2-3 X Control
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.
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!
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.
New Oral Anticoagulants: (Direct)




•   http://cenblog.org/the-haystack/tag/bmy/, © 2011 American Chemical Society
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
Drug        Trade Name    Manufacturer

 Apixaban      Eliquis ®   Pfizer/Bristol-Myers
                                  Squibb

Rivaroxaban    Xarelto ®    Bayer/Johnson &
                            Johnson (Janssen)

Dabigatran     Pradaxa ®       Boehringer
                               Ingelheim
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
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
• “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.
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
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.
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
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;
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
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.
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
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
RECOVER Study: Cumulative Risk of
  Recurrent VTE or Related Death




 Schulman S et al. NEJM 2009;361:2342-2352.
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.
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.
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.
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.
new oral anticoagulants
RECORD Trials
 (REgulation of Coagulation in ORthopaedic
surgery to prevent Deep vein thrombosis and
            pulmonary embolism)
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.
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.
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.
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.
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.
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.
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.
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)
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%)
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.
Cumulative Event Rates for the Principal Safety
           Outcome in the Acute DVT Study.




The EINSTEIN Investigators. NEJM 2010;363:2499-2510.
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.
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
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.
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
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
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.
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.
Apixaban
August, 2010




 August, 2011
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.
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.
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.
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.
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.
Kaplan–Meier Curves for the Primary Efficacy Outcome.




Alexander JH et al. N Engl J Med 2011;365:699-708.
Kaplan–Meier Curves for the Primary Safety Outcome.




Alexander JH et al. N Engl J Med 2011;365:699-708.
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
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!
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!
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)
new oral anticoagulants
•   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.
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.

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new oral anticoagulants

  • 1. New Oral Anticoagulants: What we’ve all been waiting for! Gerald A Soff, MD
  • 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.
  • 5. Prothrombin Time Titration of Vitamin K Antagonist. Target PT ratio 2-3 X Control
  • 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.
  • 9. New Oral Anticoagulants: (Direct) • http://cenblog.org/the-haystack/tag/bmy/, © 2011 American Chemical Society
  • 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.