Managing Patients with Hemophilia: Coordinated Care for Optimal Clinical Outcomes

Transcription

1 Managing Patients with Hemophilia: Coordinated Care for Optimal Clinical Outcomes Surabhi Palkimas, PharmD Pharmacy Clinical Coordinator, Hematology University of Virginia Health System

2 Presentation Objectives Discuss genetics and diagnosis of hemophilia Describe clinical features of hemophilia Discuss current and emerging treatment of hemophilia Discuss treatment of congenital inhibitors

3 Hemophilia: An Inherited Disorder X linked recessive bleeding disorder resulting in: Spontaneous bleeding Bleeding following trauma or surgery Typically expressed in males XY XX XY XY XX XX Affected Unaffected Carrier May also be expressed in females Characterized by a deficiency of one or more clotting factors Factor VIII (hemophilia A) XY XX Factor IX (hemophilia B) XY XY XX XX Centers for Disease Control and Prevention. Hemophilia facts. Accessed October 2016.

4 Detection and Diagnosis of Hemophilia Family history Positive family history Identify carriers Pre conception counseling Cord blood testing of males Defer testing of females until symptoms or considering pregnancy Negative family history Bleeding with birth trauma, circumcision, immunizations Joint bleeds and hematomas appear when child begins to walk Laboratory Values Hemoglobin/Hematocrit Platelet count Prothrombin time Activated partial thromboplastin time (aptt) Clotting factor tests Normal Mild Moderate Severe Normal or low Normal Normal Significantly prolonged in severe hemophilia May be normal in mild and moderate cases Levels of Factor VIII/IX 50% to 100% >5% to <50% 1% to 5% <1% Centers for Disease Control and Prevention. Hemophilia diagnosis. Accessed October 2016.

5 Clinical Classification Classification Mild (30 to 40% of patients) Moderate (10% of patients) Severe (30 to 40% of patients) Factor VIII or factor IX activity 5% to <50% of normal 1% to 5% of normal <1% of normal Pattern of bleeding episodes Uncommon ~4 to 6 per year ~2 to 4 per month Cause of bleeding episodes Major trauma/surgery Minor trauma Spontaneous More clotting factor Less clotting factor Franchini M, et al. J Thromb Haemost. 2010;8: Centers for Disease Control and Prevention. Hemophilia diagnosis. Accessed October 2016.

6 Types of Bleeds Joint (knee) Soft tissue (buttocks) Deep muscle (thigh) Intracranial

7 Hemophilia Care and Treatment Goals Approach Strategies Rapid and effective replacement of missing coagulation factor: Bleed prevention: decrease frequency and severity of bleeding Raise factor levels Prevent the complications of bleeding Comprehensive Hemophilia Treatment Center (HTC) comprised of a multidisciplinary team of experts who care for patients with bleeding disorders including hematologists, orthopedic surgeons, nurses, pharmacists, physical therapists, social workers, and laboratory medicine Episodic or on demand factor replacement Prophylactic factor replacement Continuous infusion for long surgical procedures Centers for Disease Control. Hemophilia. Accessed October 2016.

8 Evolution of Hemophilia Treatment Low purity pd concentrates Intermediatepurity concentrates rfviii available Manufacturing changes for rfviii product Mid 1960s 1970s Early 1980s Mid 1980s Late 1980s Early 1990s Late 1990s Early 2000s Late 2000s Today Cryoprecipitate High purity concentrates rfix available Extended half life factor VIII and IX rfviii=recombinant factor VIII rfix=recombinant factor IX

9 Hemophilia Treatment Options Replacement of missing clotting protein Hemophilia A: Plasma derived and recombinant Factor VIII (FVIII) products Hemophilia B: Plasma derived and recombinant Factor IX (FIX) products Desmopressin acetate (DDVAP)/Stimate Synthetic vasopressin analog used in many patients with mild hemophilia A for minor bleeding, and before and after surgery Adjunctive therapies Antifibrinolytic agents Supportive measures including immobilization and protection, rest, ice, compression, elevation (PRICE) National Hemophilia Foundation. Disorders/Types of Bleeding Disorders. Accessed October 2016.

10 Control of Acute Bleeding Bleeding Episode Factor Level Required (% of normal) Frequency of Administration Usual Duration of Treatment Minor Early hemarthrosis Minor muscle or oral bleed Every hours ± antifibrinolytic 7 to 10 days Moderate Bleeding into muscles or oral cavity Definite hemarthrosis Every hours until resolved 7 to 10 days Major GI, intracranial, intraabdominal, intrathoracic, CNS, or retroperitoneal bleeding Every hours until resolved 7 to 10 days World Federation of Hemophilia pdf. Accessed October 2016.

11 Dosing of FVIII and FIX Products Dose* FVIII Products 20 to 50 units / kg body weight FIX Products 40 to 100 units / kg body weight Half life 8to 12 hours 18 to 24 hours Average change in plasma factor activity with each unit/kg infused *Dosing of FVIII: (Patient weight in kg) x 50 units/kg = 100% correction *Dosing of FIX: (Patient weight in kg) x 100 units/kg = 100% correction +2% +1% National Hemophilia Foundation. Disorders/Types of Bleeding Disorders. Accessed October National Hemophilia Foundation. Guide Chapter 6 Treatment of Hemophilia A B.pdf. Accessed October 2016.

12 Prophylactic Hemophilia Treatment Prophylaxis: Standard of care for children Can be continued into adulthood when started in childhood Benefits Reduces joint bleeds Reduces joint damage (as assessed by MRI) Disability prevention Challenges Requires frequent factor administration Adherence Invasive, may require port access Reimbursement Oldenburg J. Blood. 2015;26;125: Kempton CL, Meeks SL. Blood. 2014;124: Manco Johnson MJ, et al. N Engl J Med. 2007;357: Walsh CE, Valentino LA. Haemophilia.2009;15: Ragni MV, et al. Haemophilia.2012;18:63 68.

13 Hemophilia Management Challenges Prophylaxis/Treatment of Acute Bleeding <50% of adults treat prophylactically Identification of optimal trough levels Peri surgical considerations Inhibitor Formation Genetic predisposition Associated with high morbidity Fischer K, et al. Blood. 2013;122: Manco Johnson MJ, et al. Haemophilia. 2013;19: Gringeri A, et al. Haemophilia. 2012;18: Simpson ML, Valentino LA. Expert Rev Hematol. 2012;5: Sørensen B, et al. Haemophilia. 2012;18: Konkle BA. Am J Hematol. 2012;87(Suppl 1):S Shapiro A. Hematology Am Soc Hematol Educ Program. 2013;2013:37 43.

14 New and Emerging Therapeutics Extended half life (EHL) products allow for fewer infusions, longer protection Several EHL FVIII and FIX factor replacement products have been recently approved and several more expected in the next few years Safe, well tolerated Improved half life (t½), recovery; delayed clearance Efficacy and safety comparable to rfviii and rfix products rfviii=recombinant factor VIII; rfix=recombinant factor IX Mahlangu J, et al. Blood. 2014;123: Konkle BA, et al. Blood. 2015;126: Powell JS, et al. N Engl J Med. 2013;369: Collins PW, et al. Blood. 2014;124:

15 Sustained Factor Levels >1% Can Be Achieved with EHL Products Treatment with a rfviiifc for prophylaxis was associated with continued protection against bleeds FVIII Activity >1%: Standard Half Life Product FVIII Activity >1%: Extended Half Life Product rfviii=recombinant FVIII (Advate) rfviiifc=recombinant FVIII Fc fusion protein (Eloctate) Mahlangu J, et al. Blood. 2014;123:

16 New and Emerging Treatment Options Agent Manufacturer Description Status Recombinant Factor VIII Products (rfviii) AFSTYLA (rviii SingleChain) CSL Behring rfviii Approved May 2016 KOVALTRY Bayer rfviii Approved March 2016 NUWIQ Octapharma rfviii Approved September 2015 NovoEight (turoctocog alfa) Novo Nordisk rfviii Approved October 2013 ADYNOVATE Shire rviii, long acting Approved November 2015 ELOCTATE Biogen rviii, long acting Approved June 2014 N8 GP (turoctocog alfa pegol) Novo Nordisk rviii, long acting Phase 3 Recombinant Factor IX Products (rfix) IXINITY (trenonacog alfa) Emergent Biosolutions rfix Approved June 2015 RIXUBIS Shire rfix Approved June 2013 IDELVION CSL Behring rfix, long acting Approved March 2016 ALPROLIX Biogen rfix, long acting Approved March 2014 N9 GP (nonacog beta pegol) Novo Nordisk rfix, long acting BLA submitted

17 Inhibitors: Definition and Prevalence Definition Polyclonal allo antibodies to the infused replacement factor Neutralize the procoagulant effect of the infused factor as well as naturally produced factor protein Prevalence Develop in ~15 20% of patients; greater prevalence in hemophilia A (~30%) vs hemophilia B (2 5%) Age of Onset Typically develop early in life (median age years) Burden Associated with high health care resource utilization (factor use, hospitalization, etc) and increased morbidity and mortality DiMichele D. World Hemophilia Federation. Inhibitors in Hemophilia: A Primer. Available at: pdf. Accessed October Soucie JM, et al. Haemophilia. 2001;7:

18 Risk Factors for Inhibitor Development Product Exposure Genetic Mutation Inhibitor Immune Response Genetic Factor deficiency Disease severity Hemophilia gene defect Family history of inhibitor Race/ethnicity individuals of African or Hispanic descent have 2x greater risk Immune response and modifying genes Treatment related Frequency and intensity of exposure to factor products Type and structure of product used (SIPPET trial) Greatest risk for inhibitor development occurs within first 50 exposures to infused product Ragni MV, et al. Haemophilia. 2009;15: Peyvandi F, et al. N Engl J Med. 2016;374:

19 Diagnosis of Inhibitors A poor clinical response to factor products of lower FVIII/FIX level after factor product administration suggests the presence of inhibitors A Bethesda inhibitor assay confirms their existence Amount of antibody is reported as a number of Bethesda units (BU), or a Bethesda titer High titer: >5 BU Low titer: <5 BU Higher the titer the more inhibitor is present Collins PW, et al. Br J Haematol. 2013;160:

20 Currently Treatment Options for Inhibitors Inhibitor Characteristics Patients with low inhibitor titer (<5BU) Treat with higher amounts of factor concentrate to overcome the inhibitor and still form a clot Patients with high inhibitor titer Instead of replacing the missing factor, treatment involves going around (or bypassing) the factors blocked by the inhibitor Treatment Immune Tolerance Induction (ITI) FVIII products Activated prothrombin complex concentrates (FEIBA VH; Baxter) +/ Recombinant factor VIIa (NovoSeven RT; Novo Nordisk) Kempton CL, Meeks SL. Blood. 2014;124:

21 Immune Tolerance Induction Regular infusions of factor VIII or IX administered for a period of weeks to years in an effort to increase tolerance of the immune system Limitations include Variable efficacy (70 85% for FVIII and ~30% for FIX) Time consuming and expensive Patients whose peak inhibitor levels have never reached >200 BU/mL and have ideally stayed <50 BU/mL Initiate immediately regardless of BU level; time to remission is decreased if started when inhibitors are <10 BU/mL (ideally <5 BU/mL) Initiating ITI within 5 years of inhibitor diagnosis DiMichele D. World Hemophilia Federation. Inhibitors in Hemophilia: A Primer. Available at: pdf. Accessed October 2016.

22 Pro FEIBA: Study Results In comparison to apcc on demand treatment, apcc prophylaxis given at 85 U/kg ± 15% on 3 nonconsecutive days per week Reduced all bleeding by 62% (P<0.001) Reduced joint bleeding by 61% (P<0.001) Reduced target joint bleeding by 72% (P<0.001) apcc=activated prothrombin complex concentrate (FEIBA) Leissinger C, et al. N Engl J Med. 2011;365:

23 PROOF Study Results In comparison to apcc on demand treatment, apcc prophylaxis given at 85 U/kg ± 15% every other day Reduced median ABR for all bleeds by 72.5% (P=0.0003) Reduced median ABR for joint bleeds by 73.8% (P=0.0006) Reduced median ABR in new target joints* by 100% (P=0.0271) *Ankles, knees, elbows and/or hips with 4 bleeds over 6 months apcc=activated prothrombin complex concentrate (FEIBA) ABR=annual bleed rate Antunes S, et al. Haemophilia. 2014;20:65 72.

24 Recombinant Factor VIIa (rfviia) Complexed with tissue factor can activate coagulation factor X and factor IX Minimizes risk of systemic coagulation seen with FEIBA Dose 90 mcg/kg every 2 hours until hemostasis is achieved NovoSeven RT (coagulation factor VIIa [recombinant] Prescribing information. Novo Nordisk. October 2015.

25 FEIBA and NovoSeven Appear to Exhibit a Similar Effect on Joint Bleeds FENOC Study Prospective, open label randomized, crossover equivalency trial to test the equivalence of FEIBA and NovoSeven in the treatment of ankle, knee, and elbow joint bleeding Parameter of interest: percentage of patients reporting efficacy in response to FEIBA vs NovoSeven A difference of 15% determined to be a indicative of equivalence of the 2 products Primary endpoint: Bleeding episodes 6 hours after treatment % of Patients Reporting Efficacy at 6 Hours % CI: P= % FEIBA 78.7% NovoSeven FENOC=FEIBA NovoSeven Comparative (FENOC) Study FEIBA (factor VIII inhibitor bypassing activity)=an activated prothrombin complex concentrate (apcc) NovoSeven=recombinant factor VIIa (rfviia) Astermark J, et al. Blood. 2007;109:

26 Dilemmas Encountered in Treating Inhibitors Treating and preventing bleeds No universally effective agent apcc work in some, not all rfviia works in some, not all No laboratory test that accurately predicts or confirms hemostasis rfviia has short half life, needs frequent infusions

27 Emerging Agents for the Management of Inhibitors Agent Description Status LR769 rfviia Phase 3 CSL689 rfviia FP Phase 2/3 ACE910 FVIIIa mimetic bispecific antibody Phase 2/3* ALN AT3 sirna knockdown of antithrombin Phase 2/3 Factor VIIa CTP rviia CTP, long acting Phase 2 *breakthrough therapy designation

28 Summary Hemophilia treatment goals include rapid and effective replacement of missing coagulation factor to prevent and/or decrease the severity of bleeding and prevent bleeding related complications Emerging therapeutics in the form of EHL agents and therapies with novel mechanisms of action present promising options for the advancement of prophylaxis and management of hemophilia Inhibitors and prophylaxis considerations represent two of the greatest clinical challenges in the treatment of hemophilia Aggressive and vigilant therapeutic intervention is crucial to success and minimization of morbidity/mortality

29 Jointly provided by This activity is supported by independent educational grants from Alnylam Pharmaceuticals, Novo Nordisk, Inc., and Shire. A Midday Symposium conducted at the 51 st ASHP Midyear Clinical Meeting and Exhibition.

30 Optimizing the Pre Certification and Prior Authorization Process Amber Federizo, APRN, FNP BC Nurse Practitioner Hemophilia Treatment Center of Nevada

31 Learning Objective Describe current and evolving strategies for healthsystem pharmacists to facilitate high quality care for patients with hemophilia

32 What is Prior Authorization (PA)? Approval of a health care service before it is delivered Proactive process to verify medical necessity and appropriateness of services Often used as a costcontainment tool Criteria are based on clinical guidelines and medical literature, and can vary by payer Academy of Managed Care Pharmacy. April Accessed October 2016.

33 What is Pre Certification? An administrative procedure that confirms patient eligibility for coverage prior to the delivery of care Often required before hospital admissions, inpatient or outpatient surgeries, and elective procedures Emergencies are usually exempt American Medical Association. Standardization of prior authorization process for medical services white paper. June 2011.

34 Role of the Pharmacist in PA and Pre Certification Possible roles for the pharmacist include Collecting patient information Verifying patients health insurance benefits Submitting the required forms Conducting regular status checks on the approval process Filing an appeal if coverage is denied

35 PA Submission Process Collect Information Verify Benefits Submit Request Follow Up Appeals

36 PA Submission Process: Collect Information Collect Information Patient information including signed consent/release form Plan type Insurance number Contact information Diagnosis code(s) Office notes History and physical exam Statement of medical necessity

37 PA Submission Process: Verify Benefits Verify Benefits Contact payer to verify benefits and patient out of pocket expenses (eg, co pay, deductible, out of pocket maximum) Verify eligibility and medical policy requirements Verify physician and facility contract network status with payer Verify payer requirements for prior authorization

38 PA Submission Process: Submit Request Submit Request Contact payer to see if they have a required payer submission form Complete the required forms Attach requested clinical documentation alert Submit request and create a follow up alert

39 PA Submission Process: Follow Up Routinely follow up with payers Follow Up Document calls and interactions with payer (date, time, name of contact person, etc) Obtain reference numbers for all communication with payer Prior authorization approval can generally take between 3 and 30 days depending on the payer If approved, document approval number

40 PA Submission Process: Appeals Process Appeals Make sure the physician and patient want to appeal the pre appeal denial If an appeal is required, contact payer to determine their appeals process Attach requested documentation to appeal form and submit Follow up with payer for final prior authorization decision

41 Optimizing the Approval Process

42 Approval Processes Can Be Lengthy and Cumbersome Day 1 Day 1 Day 1 14 Day? Physician sends a prescription to the pharmacy Pharmacist informs patient the medication requires a PA and initiates PA Provider and payer exchange multiple calls, faxes, and forms After waiting days or possibly weeks, payer grants PA request Patient is notified the prescription is available for pick up AMCP Electronic Prior Authorization Work Group. J Manag Care Spec Pharm. 2015;21:

43 Streamlining Approval is a Top Priority for Payers Current Gaps Prescriber often not aware that prescribed drug requires PA PA criteria not visible to the prescriber Implementation of one off workarounds to bypass or expedite PA process Paper forms require manual entry and potential for error Routes to obtain PA are not standardized and vary depending on the health plan, drug, pharmacy, and patient situation

44 Optimizing the Approval Process: Best Practices Be familiar with the rules and appropriate procedures of each payer Document events as they occur Communicate clearly, precisely, and in a timely manner Utilize electronic submission when available

45 Current Methods of Communication Between Prescribers and Payers Paper based Pre printed paper forms faxed Telephone based Person to person/voice mail Electronic Digital systems integrated into the EMR and/or other online systems

46 Streamlining the Process: Electronic PA Benefit & formulary data referenced ELIGIBILITY REQUEST / RESPONSE PA INITIATION REQUEST / RESPONSE PHYSICIAN Notified if selected drug needs prior authorization Pre approved e prescription PBM Academy of Managed Care Pharmacy/National Council for Prescription Drug Programs. Accessed October 2016.

47 Advantages of Electronic PA Leverages eligibility and formulary data to notify providers of PA requirements before prescribing PA questions are sent to the EHR, based on patient, plan, and medication Pre population of required patient information adds efficiency and accuracy to administrative tasks Real time communications with payer (eg, PBM) to complete PA review before sending prescription to the pharmacy Preapproved prescriptions routed to pharmacy Minimizes delays in medication delivery to the patient Academy of Managed Care Pharmacy/National Council for Prescription Drug Programs. Accessed October 2016.

48 Caveat: Electronic PA Implementation Varies Across Prescriber and Payer Settings Capability Prescriber Portal Payer Portal Fully Integrated Integrated into physician EHR workflow Prospective workflow capabilities Retrospective workflow capability Integrated into the e prescribing workflow Automatically pull patient medical history from EHR into PA question set Broad connections to several PBMs/payers Bi directional network of PBM/payers and providers/ehrs Academy of Managed Care Pharmacy/National Council for Prescription Drug Programs. Accessed October 2016.

49 Summary PA is used to verify medical necessity and appropriateness of services, including prescription drugs Pre certification is an administrative procedure that confirms patient eligibility for coverage prior to delivery of care Best practices for optimizing the approval process include Increased familiarity with the procedures of each payer Real time documentation of events Clear and timely communication between involved parties Use of electronic submission where available

50 Jointly provided by This activity is supported by independent educational grants from Alnylam Pharmaceuticals, Novo Nordisk, Inc., and Shire. A Midday Symposium conducted at the 51 st ASHP Midyear Clinical Meeting and Exhibition.

51 Emergency Department Patient Case Study: HTC and Health System Pharmacy Collaboration: Steps for Success Amber Federizo, APRN, FNP BC Nurse Practitioner Hemophilia Treatment Center of Nevada Surabhi Palkimas, PharmD Pharmacy Clinical Coordinator, Hematology University of Virginia Health System

52 Learning Objectives Explain hemophilia related complications associated with emergency department (ED) visits and its significant clinical and economic consequences Identify processes for health system pharmacists to improve communications and collaborations with hemophilia treatment centers (HTCs)

53 Patient Introduction 30 year old, 14 weeks gravid female; G3P2A0 with mild Factor VIII deficiency (27%) Examined in the Emergency Department for vaginal bleeding Examination reveals gravid uterus and continuous vaginal bleeding Husband reports they told ED staff at her bedside she has VWD and Hemophilia A ED staff indicated they would contact the HTC Attending on the case states that women do not have hemophilia and therefore the bleeding is only related to threatened miscarriage Orders monitoring only

54 Diagnosis and Initial Treatment PTT: 38 seconds H and H fell precipitously within 4 hours Required replacement with 10 units PRBCs OB was finally contacted Patient underwent an emergency D and C Patient discharged at Day 3 with what was reported as spotting

55 Follow Up Patient was seen in follow up at the HTC and provided with daily infusions for 3 days to stop the bleeding She was subsequently referred to counseling secondary to severe grief

56 Critical Issues Coordination of care between the ED, ICU, and HTC Lack of adequate training Lack of factor replacement product Discharge and ongoing follow up care and monitoring

57 Best Practice Contact HTC provider for any patient presenting with a suspected bleeding disorder On call provider at the HTC sent to hospital to consult care or consult with ER and GYN Pharmacy should stock factor on consignment ER staff is trained to recognize, assess, and treat bleeding disorders Patient receives replacement as soon as possible Patient is scheduled with follow up visit at HTC clinic upon discharge