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					Advancements In
 Anticoagulation

  John Devlin, Pharm D
      Feb 4, 2009
                        Agenda
1. Unmet needs in anticoagulation
2. Niche for new anticoagulants
3. Dabigatran Etexilate
4. Evidence for efficacy and safety from phase 3 randomized
   trials
5. Implications for clinical practice
6. Comparing agents
7. Future developments
 Currently available anticoagulants

Parenteral Agents           Oral Agents
 Heparins
    UFH
                            • VKA’s
    LMWH (3 agents)            – Warfarin
 Heparinoids
                               – Acenocoumarol
 Anti-Xa
    Fondaparinux
 DTIs
    Bivalirudin / hirudin
    Argatroban
                Place in therapy

Venous thrombosis       Arterial thrombosis
• Prevention            • Treatment
  – In-hospital            – ACS
  – Out-of-hospital     • Prevention
• Treatment                – Stroke (AF, CHF,
  – Initial                  Prosthetic valves)
  – Long term              – Post MI
                           – PCI / HD
                   The “Magic Bullet”
Oral Dosage Form
Little or no monitoring required
Equally efficacious and safe to current treatments
Consistent dosing regimen (wide therapeutic window)
Predictable PK and PD
     Free from alcohol and food interactions
     Free from drug interactions
     Un phased by genetic factors (VKOR, CYP2C9)
     Un phased by organ dysfunction
Reversibility
Rapid onset and offset
Inexpensive
Urgent Need to Replace
      Warfarin!
        Where Can We Improve?

Venous thrombosis     Arterial thrombosis
• Prevention          • Treatment
  – In-hospital         – ACS
  – Out-of-hospital   • Prevention
• Treatment             – Stroke (AF, CHF,
  – Initial               Prothestic heart
  – Long term             valves)
                        – Post MI
                        – PCI / HD
              VTE Prevention
      “Call to Action” on DVT and PE
September 15, 2008 (Washington, DC) - The Office of the Surgeon
General called today for a coordinated, multifaceted plan to reduce
the incidence of deep vein thrombosis (DVT) and pulmonary embolism
(PE) in the us. The “call to action” is intended to increase awareness
about these silent conditions and emphasize the importance of
evidence based practices in the management of DVT.
                       Out of Hospital
Underuse of Extended Prophylaxis after major Orthopedic
                       Surgery

ACCP guidelines for extended prophylaxis:
   Hip fracture 1A
   Hip arthroplasty 1A
   Knee arthroplasty 2B
Reasons for underuse
   Need for subcut injection
   Need for monitoring and dose adjustment of VKA therapy
   Coordinating drug coverage
            VTE Prevention
       Non Traditional Prophylaxis
Medical patients (EXCLAIM trial)
  4000 patients
  6-14 days vs 1 month with LMWH
  > 14 days?

Knee arthroscopy (KANT trial)
  1800 patients
  Nadroparin 3800 units vs elastic stockings for 7 days
  0.9% vs 3.2 %

Thalidomide associated VTE
               Long Term
        Secondary VTE Prophylaxis
Duration of anticoagulation for first unprovoked VTE
  Proximal DVT or PE, no bleeding risk factors, and good
  monitoring is available
  Those with permanent risk factors (ie Cancer)
  Unprovoked VTE with strong preference for less frequent
  monitoring.
                          Aterial Thrombosis
                       Underuse of Warfarin in AF
                                                                       AFASAK II
                                                                              LASAF
                                                          EAFT
                            Oral Anticoagulant                                PATAF
                  60                                         SPAF II
                            Aspirin                   SPINAF    SPAF III           Japanese
% on Medication




                                                                                   NVAF study
                  50                              SPAF I
                                                  CAFA
                  40
                                             BAATAF
                  30
                                       AFASAK I
                  20

                  10

                  0



                                             Visit Year
New Oral Agents
                                            New Oral Agents

     Feature                        Dabigatran Etexilate                          Rivaroxaban                    Apixiban

     Target                         Thrombin                                      Factor Xa                      Factor Xa
     Prodrug                        Yes                                           No                             No
     Dosing                         Fixed, b.i.d.                                 Fixed, o.d.                    Fixed, b.i.d
     Bioavailability                6%                                            80%                            50%
     Monitoring                     No                                            No                             No
     Half-life (h)                  12-17                                         5-9                            12
     Renal clearance                80%                                           65%                            25%
     Interactions                   P-gp inhibitor                                Combined P-gp                  Potent CYP3A4
                                                                                  and CYP3A4                     inhibitors
                                                                                  inhibitors
     Indications                    VTE prevention                                VTE prevention                 None
     Trials ongoing                 AF, ACS, VTE                                  AF, ACS, VTE                   AF, ACS, VTE
                                    treatment                                     treatment                      prevent/treat




Pradax Product Monograph 2008; Xarelto Product Monograph 2008; Turpie Eur Heart J 2008; Gross, Weitz. Arterioscler Thromb Vasc Biol 2008
       New Oral Anticoagulant Targets

  Initiation    Contact                 TF/ VII
    Phase
                XII               IX
                      XI                Platelet            X
                                        Surface
Amplification
                           VIII
Propagation
   Phase

                                          Xa
                                                                  Rivaroxaban
 Thrombin                                                          Apixaban
                              Common
  Activity                    Pathway
                                        Thrombin                Dabigatran Etexilate



                           Fibrinogen              Fibrin
                   Anti-Xa or Anti-IIa?



       Hirudin
                                       Dalteparin   Fondaparinux
     Bivalirudin
                      Unfractionated   Enoxaparin    Idraparinux
     Argatroban
                         Heparin       Nadroparin    Rivaroxaban
    Ximelagatran
                                        Reviparin     Apixaban
 Dabigatran Etexilate


Anti-IIa                                            Anti-Xa
                     Anti-Xa or Anti-IIa?
                 Pharmacologic Considerations




           Anti-Xa                          Anti-IIa
“Gatekeeper of the coagulation     “Final Common Pathway”
         cascade”

  Block thrombin generation         Block thrombin activity

  Selective “targeted” effect       Block Contact Activation
    Maintain -ve feedback             Block +ve feedback
                                       Platelet Inhibition
Dabigitran Etixilate
The Molecule
             Key Characteristics
Indicated for prevention of VTE post THR & TKR
Dose 110 mg 1-4 hours post surgery followed by 220 mg
daily
          Dabigatran Pharmacokinetics

Absorption
  Oral Bioavailability: ~ 6.5%
  Time to peak: 0.5-2 hours, delayed 2 hours by food


Distribution
  Linear kinetics
  ~35% protein bound
  Vd = 60-70L
         Dabigatran Pharmacokinetics

Metabolism
  Hepatic glucuronidation to active metabolite


Elimination
  Excreted in urine (85%, primarily as unchanged drug); fecal
  (6% of total dose)
  t1/2 = 12-17 hours
                 Drug Interactions
Avoid concomitant use with p-glycoprotein inhibitors & inducers
  Verapamil, Clarithromycin, *Quinidine
  Rifampicin, St. Jonh’s Wort, Tenofovir)

Antacids
  diminished clinical effect; avoid within 24 hours after surgery

Amiodarone
  Adjust dosing to 150 mg daily dabigatran with amiodarone

Pantoprazole
  Co-administration with Dabigatran may diminish clinical effect
            Special Considerations
Contraindications
  Severe renal impairment (CrCl < 30 mL/min)
  Concomitant treatment with strong P-Glycoprotein inhibitors
  (Quinidine)
Antidote
Switching agents
Special Patient Populations
  Age
  Pregnancy
  Weight
  End organ dysfunction
Dabigatran Etixilate
        &
  Phase 3 Trials
   REVOLUTION
                         Dabigatran Phase III Studies:
                                REVOLUTION
                                                                                                               Enoxaparin
                                                                                                                 40 mg QD* OR
                          Start evening before surgery* OR                                                       30 mg BID #
                          12-24 hours post-operatively#


                                                                                                               Dabigatran etexilate
                          Start 1-4 hours* OR                                                                  75 / 150 mg QD
         R
                          6-12 hours# post-operatively

                                                                                                               Dabigatran etexilate
                                                                                                               110 / 220 mg QD
                                                        Venography                             Follow-up
                                               Within 12 hours of last dose                   12–14 weeks

  *RE-MODEL and RE-NOVATE                                                                                          Therapy          Enoxaparin
                                                                               Study                               Duration         Dose (mg)
  #RE-MOBILIZE
                                                                               RE-MODEL                Knee        6-10 days          40 QD
                                                                               RE-NOVATE                 Hip      28-35 days          40 QD
  Design:         Non-Inferiority in Modified
                  Intention-To-Treat Population                                RE-MOBILIZE             Knee       12-15 days          30 BID


Eriksson et al. J Thromb Haemost 2007; Eriksson et al. Lancet 2007; Ginsberg et al. J Arthroplast. DOI:10.1016/j.arth.2008.01.132
                               Methods - Procedures
                       Trial                             Countries                           # Sites         Sample Size
                RE-MODEL                                                                        105                 2101
                                         Europe, Australia, South Africa
                RE-NOVATE                                                                       115                 3494
                RE-MOBILIZE                   US , Canada, Mexico, UK                            58                 2615


         Primary efficacy outcome:
              Composite of total venous thromboembolic events (VTE) (symptomatic or
              venographic DVT and/or pulmonary embolism [PE]), and all-cause mortality
              during treatment

         Secondary efficacy outcomes:
              Composite of major VTE (proximal DVT and PE) and VTE-related mortality
              Proximal DVT
              Incidence of total VTE and all-cause mortality during follow-up
              Individual components of the primary outcome


Eriksson et al. J Thromb Haemost 2007; Eriksson et al. Lancet 2007; Ginsberg et al. J Arthroplast. DOI:10.1016/j.arth.2008.01.132
                               Methods - Procedures

           Primary safety outcome:
              – Major bleeding events
                    – Associated with ≥2 g/dL drop in haemoglobin or required transfusion of
                      ≥2 units blood
                    – Fatal, retroperitoneal, intracranial, intraocular, or intraspinal
                    – Warranted treatment cessation or re-operation
              – Clinically relevant non-major bleeding events
              – Minor bleeding events


           Events were classified by an independent, expert adjudication
           committee



Eriksson et al. J Thromb Haemost 2007; Eriksson et al. Lancet 2007; Ginsberg et al. J Arthroplast. DOI:10.1016/j.arth.2008.01.132
                     Baseline characteristics

                                        RE-MOBILIZE   RE-MODEL   RE-NOVATE

Patient Characteristics

  Age (mean) - years                          66          68          64

  Females - %                                 58          66          56

  Weight (mean) – kg                          88          83          79

Anesthetic Details

  General - %                                 53          38          31

Study Drug Administration

  Time to first oral dose* (mean) – h         9.5         3.5        3.4

  Treatment duration (median) – d             13          8           33
       Primary Efficacy Outcome: Total VTE or All-Cause
                           Mortality
                            Enoxaparin
                       P=0.0003 for                                                                                          P<0.0001 for
                       non-inferiority                                 Dabigatran
                                                                                                                             non-inferiority
                      P=0.017 for
                      non-inferiority                                                                                      P<0.0001 for
                                                                             P=0.02 *                                      non-inferiority



                                                                    P=0.0009 *




                     RE-MODEL                                   RE-MOBILIZE †                         RE-NOVATE
                                                (Knee) * P-value that the margin of 9.2% as the upper    (Hip)
 † Confidence intervals not reported
                                                                  limit of the 95% CI for ARD was exceeded

Eriksson et al. J Thromb Haemost 2007; Ginsberg et al. J Arthroplast. DOI:10.1016/j.arth.2008.01.132; Eriksson et al. Lancet 2007
      Safety Outcome: Major Bleeding Events
                                  No significant differences between either dose of
                                        dabigatran etexilate and enoxaparin.

                                                                       Enoxaparin
                                                                       Dabigatran




                          RE-MODEL                                   RE-MOBILIZE*                                      RE-NOVATE
                                                               * Confidence intervals not reported

Eriksson et al. J Thromb Haemost 2007; Ginsberg et al. J Arthroplast. DOI:10.1016/j.arth.2008.01.132; Eriksson et al. Lancet 2007
    Interpretational Considerations

Failure to demonstrate non-inferiority of dabigatran in
Re-Mobilize
   Factors that may have contributed
     Higher dose of enoxaparin (30 mg BID vs 40 mg QD in
     RE-MODEL)
     Comparator event rate was lower than anticipated
     (25.3% versus 37.7% in RE-MODEL)
     Different median duration of treatment
     Delayed initiation of dabigatran dosing
   Efficacy by Timing of Initiation of
   Dabigatran
     Total VTE Rate
                     (%)
                                                    P = 0.0005




                                        (70/498)                  (121/539)




                                                   A post-hoc analysis from BISTRO II (THR
                                                               & TKR patients)
Eriksson et al. J Thromb Haemost 2005
            Meta-Analysis of RE-MODEL, RE-MOBILIZE, RE-
                               NOVATE:
                   Total VTE & All-Cause Mortality
                     Dabigatran etexilate
     Study or           220 mg QD        Enoxaparin
     sub-                    n/N            n/N                               RR                    RR [95% CI]
     category
     RE-MOBILIZE               188/604           163/643                                       1.23 [1.03, 1.47]
     RE-MODEL                  183/503           193/512                                       0.97 [0.82, 1.13]
     RE-NOVATE                  53/880            60/897                                       0.90 [0.63, 1.29]

     Total events: 424 (dabigatran etexilate), 416 (enoxaparin)
     Test for heterogeneity: Chi2 = 4.73, df = 2 (P=0.09), I2 = 57.7%



     Random Effects Analysis
     Total (95% CI)              1987               2052                                     1.05 [0.87, 1.26]
     Test for overall effect: Z = 0.47 (P = 0.64)



                                                         0.1 0.2        0.5   1    2     5   10
                                                           Favours                      Favours
   Analysis is based on the 220 mg                    Dabigatran Etexilate             Enoxaparin
   QD dose of dabigatran etexilate.
Wolowacz et al. Thromb Haemost 2009
               The “Magic Bullet”…….
Oral Dosage Form
Little or no monitoring required
Equally efficacious and safe to current treatments
Consistent dosing regimen
Predictable PK and PD
     Free from alcohol and food interactions
     Free from drug interactions
     Un phased by genetic factors (VKOR, CYP2C9)
     Un phased by organ dysfunction
Reversibility
Rapid onset and offset
Inexpensive
      …..Not entirely yet much better!
Oral Dosage Form 
Little or no monitoring required 
Equally efficacious and safe to current treatments 
Consistent dosing regimen 
Predictable PK and PD 
     Free from alcohol and food interactions 
     Free from drug interactions X
     Un phased by genetic factors (VKOR, CYP2C9) 
     Un phased by organ dysfunction X
Reversibility X
Rapid onset and offset 
Inexpensive 
    Implications for Clinical Practice
Dabigatran etexilate is safe and effective for prevention of
VTE in patients undergoing hip or knee arthroplasty
Potential to replace LMWH or fondaparinux
Major unmet need is out of hospital prophylaxis
Potential to improve guideline adherence and reduce VTE
disease burden
                  Summary

Massive unmet need for new oral anticoagulant
Dabigatran etexilate
   Simple
   Convenient, unmonitored
   Safe
   Effective
First in AF (September 2009)
Closing the care gap – more patients treated
appropriately with improved quality of life.
Excellent replacement for warfarin
Questions?   Questions?

				
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