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					         Effient® (prasugrel)
for the reduction of atherothrombotic events
   in ACS in patients with UA, NSTEMI and
           STEMI managed with PCI

         Therapeutic Review
    Prepared for Pitt Street Health
              Kimberly Garrison
                  Jaewoo Lee
             Aleksandra Stojkoska
              Brittany Thompson
                                Outline
• Acute Coronary Syndrome
    –   Epidemiology
    –   Demographics and Cost
    –   Diagnosis
    –   Treatment
• Thienopyridine Pharmacokinetics/Pharmacodynamics
• CYP2C19 Interactions
    – Non-responders
    – Proton Pump Inhibitor use
•   JUMBO-TIMI 26
•   TRITON-TIMI 38
•   PRINCIPLE-TIMI 44
•   Economic Considerations
•   Recommendation
      Acute Coronary Syndrome
                             Epidemiology

• Leading cause of death in The United States
  – 25% of deaths
• 445,687 people died from coronary heart
  disease in 2005
• 17,600,000 people alive with coronary heart
  disease
• 316.4 billion dollars in costs in 2010


            CDC: Heart Disease Facts. [Internet]. Atlanta: Center for Disease Control and Prevention. America's Heart Disease
                         Burden; 2010 Dec 21 [Cited 2011 Jan 15]; Available from: http://www.cdc.gov/heartdisease/facts.htm
           Acute Coronary Syndrome
                   Pitt Street Health Demographics

      Plan Enrollment:                                   Patients Patients
         2,650,000                                         <65     65-74   Patients
                                               Incidence years     years   ≥75 years                                           Total
Diagnosis with ACS                                     0.51%             5,755             3,033                4,688           13,476
Undergoing a PCI                                       30.8%             2,283                 973                 897            4,153


                                  Cost per day associated with ACS events
                                         Repeat PCI                                     $20,060
                                            Stroke                                      $12,143
                                            Angina                                       $4,794
                                               MI                                       $15,086
                                            CABG                                        $46,002
                              Other Vascular Intervention                               $18,280

                               Other Cardiac Conditions                                  $9,683

               Effient® (prasugrel) Dossier. Eli Lilly and Daiichi-Sankyo. Prepared using AMCP format for formulary submissions, version 2.1.
Acute Coronary Syndrome
        Diagnosis




                    Alpert et al. J Am Coll Cardiol 36 (3): 959–69
         Acute Coronary Syndrome
                                Treatment
• Upon hospital arrival:
   – MONA
        • Morphine, oxygen, nitroglycerine, aspirin
   – Beta blockers
        • Only if an increase in heart rate is present
• Upon discharge:
   –   Statin
   –   Beta-blocker
   –   Aspirin
   –   Ace Inhibitor/ARB
   –   Thienopyridine
                               Blais D. Acute coronary syndromes. Presentation given at: The Ohio State University chapter of
                                  Academy of Managed Care Pharmacy. General body meeting. 2010 Nov 9th; Columbus,OH.
                 Platelet Inhibitors
                              Thienopyridines
                       Clopidogrel                     Prasugrel                        Ticagolor
Loading Dose           300-600 mg                      60mg                             180mg
Maintenance Dose       75 mg daily                     10 mg daily                      90 mg twice
                                                                                        daily
Route                  Oral                            Oral                             Oral
Binding to P2Y12       Irreversible                    Irreversible                     Reversible
Prodrug                Yes                             Yes                              No
Hepatic                CYP C219                        CYP 3A, 2B6,2C19                 None
Metabolism
Platelet Inhibition    40%                             ~70%                             95%


Onset                  2 hours                         30- 60 minutes                   2 hours


                      DRUGDEX® System [Internet database]. Greenwood Village, Colo: Thomson Healthcare. Updated periodically.
Platelet Inhibitors
  Mechanism of Action




                        Schomig a. N Engl J Med. 361:1108-
CYP2C19 Interactions
  Therapeutic Non-response




                         Bonello et al. J Am Coll Cardiol. 2010;56:919-33
            CYP2C19 Interactions
                  Therapeutic Non-response




Primary Outcome      Composite of death from cardiovascular causes,
                     nonfatal myocardial infarction, or stroke


                                             Pare et al. N Engl J Med. 2010 Oct 28;363(18):1704-14
              CYP2C19 Interactions
                       Proton Pump Inhibitors




•Clopidogrel is converted to its active metabolite
via CYP enzymes, particulary CYP2C19
•PPI’s, shown as omeprazole, are inactivated via
the same CYP450 enzymes that activate
clopidogrel
•Concomitant use of clopidogrel with PPI’s
theoretically reduces clopidogrel effectiveness
which leads to worse outcomes

                                                     Madanick et al. Cleve Clin J Med. 2011 Jan;78(1):39-49.
CYP2C19 Interactions
   Proton Pump Inhibitors




           Long-term follow-up and rate of primary endpoint
           (right); Proportion of non-responsders 6h (A) and 15
           days (B) after clopidogrel or prasugrel stratified by the
           use of a PPI in PRINCIPLE-TIMI 44 (left)

                                   O’Donoghue et al. Lancet. 2009 Sep 1; 374:989-97.
              JUMBO-TIMI 26
                    Study Design
Phase 2, multicenter, randomized, parallel-group, ITT,
   double-blind, active comparator-controlled trial




                                      Wiviott et al. Circulation. 2005 Jun 20;111:3366-73.
    JUMBO-TIMI 26
         Outcomes
A    B              C




D    E              F




                    Wiviott et al. Circulation. 2005 Jun 20;111:3366-73.
        TRITON-TIMI 38
           Study Design
                                                       N=
                                                     10,074
 N=
3,534




                          Wibiott et al. Amer Heart Jour. 2006 Oct;152(4):627-35.
TRITON-TIMI 38
 Efficacy Outcomes




             Efficacy Endpoints:
                  • Primary:
                       • Death from CV causes,
                       non-fatal MI or non-fatal
                       stroke
                  • Secondary:
                       • Stent thrombosis,
                       rehospitalization

                                Antman et al. JACC;51(21):2028-33
                   TRITON-TIMI 38
        Safety Outcomes and Net Clinical Benefit

                                         • Safety Outcomes
                                           Stent thrombosis,
                                           rehospitalization, and TIMI
                                           major non-CABG bleed



•Study Strengths:
   Sample size adequate for 90%
   power, length of study,
   randomized, double-blinded
•Study Limitations
   Funding from Eli Lilly, did not use
   highest possible dose of
   clopidogrel, mostly white males
                                                         Antman et al. JACC;51(21):2028-33
  TRITON-TIMI 38
Special Populations - Diabetics




                           Wiviott et al. Circulation. 2008 Aug 31;118:1626-36.
                         TRITON-TIMI 38
             Special Populations – Stent Placements
                                               • The graph to the left shows both early (0-
                                               30 days) and late (30 days on) thrombosis
                                               • At 0-30 days, stent thrombosis was
                                               reduced by 59% for prasugrel vs.
                                               clopidogrel (p<0.0001)
                                               • At 30 days on, stent thrombosis was
                                               reduced by 40% for prasugrel vs.
                                               clopidogrel (p=0.03)




• The table to the right shows the effect of
prasugrel versus clopiogrel in key
subgroups
• The most significant treatment subgroup
favoring prasugrel was in patients with a
previous MI (p=0.047)



                                                                 Wiviott et al. Lancet. 2008 Apr 19;371:1353-63.
PRINCIPLE-TIMI 44
    Study Design




                   Wiviott et al. Circulation. 2007 Dec 3;116:2923-32.
            PRINCIPLE-TIMI 44
                  Loading Dose Phase




• Primary efficacy endpoint significantly greater after prasugrel
vs. clopidogrel (p<0.0001)
• Patients treated with prasugrel had more rapid onset of
inhibition observed at 30 minutes

                                               Wiviott et al. Circulation. 2007 Dec 3;116:2923-32.
               PRINCIPLE-TIMI 44
                  Maintenance Dose Phase




• Primary efficacy endpoint significantly greater for prasugrel vs.
clopidogrel (p<0.0001)
• Patients treated with prasugrel were observed to have more
consistent levels of inhibition and few hyporesponsive episodes

                                                  Wiviott et al. Circulation. 2007 Dec 3;116:2923-32.
         Economic Considerations
                             Budget Impact Model
• Model was designed to estimate the total annual costs for
  treating a population with either prasugrel or clopidogrel
   – Patients with no history of transient ischemic attack that are to
     undergo treatment with a thienopyridine
• Patients took the thienopyridine for up to 15 months after PCI
• Model assumes a 100% compliance rate of clopidogrel and
  prasugrel
• Lacks consideration of other thienopyridine agents
   – Does not take into account other medications required to prevent an
     additional ACS event from occurring
• Model results included a favorable incremental cost
  effectiveness ratio (ICER) over clopidogrel
• Overall cost-benefit analysis conducted found treatment with
  prasugrel to decrease overall costs due to lower rate of
  rehospitalization involving PCI
   – Prasugrel is the economically dominant treatment strategy
            Effient® (prasugrel) Dossier. Eli Lilly and Daiichi-Sankyo. Prepared using AMCP format for formulary submissions, version 2.1.
          Economic Considerations
                  Cost of Thienopyridine per year

                                  Prasugrel                                   Clopidogrel
 Year 1                            $307,638                                    $4,954,940
 Year 2                           $1,154,511                                   $9,977,162
 Year 3                           $2,115,008                                   $7,055,834
 Year 4                           $2,402,058                                   $3,029,085
 Year 5                           $1,951,077                                   $3,192,024
             At year 2 generic clopidogrel is introduced to the market

 Number of eligible for treatment with a thienopyridine: 3093
Percent of patients taking prasugrel / Percent of patients taking clopidogrel:

              Year 1: 5 /95    Year 2: 10/90     Year 3: 12/88
                      Year 4: 13/87    Year 5: 15/85
                                      . The Congress of the United States: Congressional Budget Office. July 1998: 1-70.
                                                                             Hong SH et al.JMCP. 2005;11(9):746-754.
              Economic Considerations
                                  Cost-Benefit Analysis
Prasugrel         Year 1                    Year 2                   Year 3                    Year 4                  Year 5
Total           $270,523                $1,099,534               $1,918,375                $2,074,988                 $657,125
Cost/year
PMPM               $0.09                     $0.26                    $0.37                     $0.32                    $0.20
PTMPM             $1,583                    $1,508                   $1,436                    $1,368                   $1,303




Clopidogrel     Year 1                   Year 2                   Year 3                    Year 4                    Year 5
Total         $5,285,669               $9,829,033               $9,449,897                $4,290,514                $3,793,547
Cost/year
PMPM               $1.99                    $3.71                    $3.57                     $1.62                     $1.43
PTMPM            $1,658                   $1,579                    $1,620                    $1,678                    $1,360



               Effient® (prasugrel) Dossier. Eli Lilly and Daiichi-Sankyo. Prepared using AMCP format for formulary submissions, version 2.1.
         Economic Considerations
                           Cost-Benefit Analysis


                    Direct Medical                       PMPM                                 PTMPM
                    Savings
Year 1              $5,015,147                           $1.89                                $1,621
Year 2              $9,037,202                           $3.41                                $1,461
Year 3              $8,312,709                           $3.14                                $1,344
Year 4              $3,271,909                           $1.23                                $1,074
Year 5              $3,136,422                           $1.18                                $1,035




          Effient® (prasugrel) Dossier. Eli Lilly and Daiichi-Sankyo. Prepared using AMCP format for formulary submissions, version 2.1.
                Recommendation
              for Pitt Street Health Formulary

• Movement of prasugrel from non-preferred
  brand to preferred brand
   – Requires a prior authorization
Approved dose                  Prasugrel 10 milligrams daily
Age Restrictions               Not approved for patients >75
                               yoa
Ineligible for treatment       Patients <60kg, prior TIA or
                               CVA or CABG scheduled in
                               next 7 days
Recommended follow-up          Two weeks, 1 month, then
                               every 3 months thereafter
Recommended length of          Left to the discretion of the
therapy                        health-care team
               Recommendation
            Flow-chart for Decision Making
         UA                     ACS patient                   STEMI


                                                          First event?
                            NSTEMI
                                                          N           Y

                                           Diabetic or                     TIMI
        TIMI                               previous stent?

                                          N         Y               0-4           5+
0-2                  5+
         3-4                   Intermediate        High

Low                  High                                      Intermediate

      Intermediate                                                            High
                          •High Risk:           prasugrel
                          •Intermediate Risk:   prasugrel or clopidogrel
                          •Low Risk:            clopidogrel
                 Recommendation
              Role of Health-Care Practitioners
• Physician/Cardiologist
   – Identifying patients as high, intermediate or low risk
   – Prescribing the appropriate dose of chosen thienopyridine
   – Monitoring of safety/efficacy of agent chosen
• Clinical Pharmacist
   – Assisting the physician in identifying high, intermediate or low
      risk patients and determining the appropriate dose
   – Follow up with patient to assess safety/efficacy
   – Appropriately educating patient on proper use of thienopyridine
• Community Pharmacist
   – Dispensing correct product from pharmacy
   – Medication therapy management and drug-utilization review of
      all medications the patient is currently taken
         Effient® (prasugrel)
for the reduction of atherothrombotic events
   in ACS in patients with UA, NSTEMI and
           STEMI managed with PCI

         Therapeutic Review
    Prepared for Pitt Street Health
              Kimberly Garrison
                  Jaewoo Lee
             Aleksandra Stojkoska
              Brittany Thompson

				
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