Spotlight Case July 2004

1. Spotlight Case July 2004 Preventing Inappropriate Use of Novel Therapeutic Agents

2. Source and Credits • This presentation is based on the July 2004 AHRQ WebM&M Spotlight Case in Critical Care Medicine • See the full article at http://webmm.ahrq.gov • CME credit is available through the Web site • Commentary by: Derek C. Angus, MD, MPH, andEric B. Milbrandt, MD, MPH, University of Pittsburgh School of Medicine • Editor, AHRQ WebM&M: Robert Wachter, MD • Spotlight Editor: Tracy Minichiello, MD • Managing Editor: Erin Hartman, MS

3. Objectives At the conclusion of this educational activity, participants should be able to: • Describe the approved indications for drotrecogin alfa (activated) (Xigris™) • Outline the roles that the FDA, hospitals, professional medical societies, and the pharmaceutical industry play in ensuring appropriate use of novel therapeutics • Understand the importance of errors of commission and omission

4. Case: Novel Drug Misuse A 48-year-old man was admitted to the intensive care unit after a motor vehicle collision. The patient experienced severe crush injuries after spending 7 hours pinned under a large vehicle while awaiting rescue. He underwent bilateral fasciotomies of the lower extremities for compartment syndrome.

5. Case (cont.): Novel Drug Misuse Post-operatively, the patient developed renal failure; an APACHE II score was 26. Recalling an article in the New England Journal of Medicine reporting the decrease in mortality associated with early administration of drotrecogin alfa (activated) to patients with elevated APACHE scores and sepsis, the team decided to start the patient on the drug.

6. Sepsis • Severe sepsis (sepsis associated with acute organ dysfunction) is common and deadly • 750,000 cases annually in the US • 25% mortality • Protein C is an important modulator of the coagulation and inflammation associated with severe sepsis Levy MM, et al. Crit Care Med. 2003;31:1250-60; Angus DC, et al. Crit Care Med. 2001;29:1303-10; Bernard GR, et al. N Engl J Med. 2001;344:699-709.

7. Drotrecogin Alfa (Activated) • Recombinant form of human activated protein C • Approved by FDA for adult patients with severe sepsis with a high risk of death, defined by APACHE II score > 25 Physicians' Desk Reference. 2003

8. PROWESS Study • Large multicenter, randomized, placebo-controlled trial (PROWESS) showed that treatment with drotrecogin alfa (activated) was associated with a 6.1% absolute reduction in 28-day mortality in patients with severe sepsis Bernard GR, et al. N Engl J Med. 2001;344:699-709.

9. PROWESS Inclusion • Included patients with known or suspected infection, sepsis-induced dysfunction of at least one organ system for <24 hours, and 3 or more signs of systemic inflammation: • temperature 38o C or 36o C • heart rate 90 beats/min • respiratory rate 20 breaths/min, PaCO2 <32 mmHg, mechanical ventilation • WBC of 12,000/mm3, 4,000/mm3, or >10% immature neutrophils Bernard GR, et al. N Engl J Med. 2001;344:699-709.

10. PROWESS Exclusion • Drotrecogin alfa has anticoagulant properties, so patients at high risk of bleeding were excluded: • Active internal bleeding • Recent hemorrhagic stroke • Intracranial or intraspinal surgery • Severe head trauma, intracranial mass lesion • Platelet count <30,000/mm3 • Trauma with an increased risk of life-threatening bleeding • Trend toward increased incidence of serious bleeding in therapy arm: 3.5% vs. 2.0% Bernard GR, et al. N Engl J Med. 2001;344:699-709.

11. PROWESS: Mortality Benefit • Mortality benefit greatest in patients with APACHE II >25 • Benefit sustained over a follow-up period of greater than 2.5 years • Follow-up study has found little benefit in less sick patients Angus DC, et al. Chest. 2002;122(Suppl):51S.

12. Case (cont.): Novel Drug Misuse Eighteen hours after infusion, the patient developed severe bleeding and hemodynamic instability requiring multiple transfusions and aggressive fluid resuscitation to maintain hemodynamic stability. Review of the case by the clinical pharmacist noted that the patient did not have signs or symptoms consistent with sepsis. The patient’s organ dysfunction was due to severe rhabdomyolysis.

13. Ensuring Appropriate Use of Novel Therapeutics • FDA-approved labeling indications • Mandatory consults, checklists • Pharmacy review to control use • Provider education • Evidence-based guidelines developed by professional medical societies

14. Challenges with Novel Therapeutics • Off-label use of medications is permitted • Guidelines are expensive to develop and often ignored • Pharmaceutical industry detailing

15. Case (cont.): Novel Drug Misuse The patient later died due to complications from his multiple injuries.

16. Preventing This Error: Potential Strategies • Provider education: distribute educational materials outlining appropriate indications for drug use along with contraindications • Checklist-based pharmacy review prior to administration of drug • Require infectious disease and critical care approval Wong-Beringer A, et al. Am J Health Syst Pharm. 2003;60:1345-52; Jacobi J. Am J Health Syst Pharm. 2004;61:203-4.

17. Underutlization of Effective Therapies is Common • Aspirin and beta-blockers for coronary artery disease • ACE inhibitors for congestive heart failure • Pharmacologic prophylaxis for deep venous thrombosis prevention Angus DC, Black N. Lancet. 2004;363:1314-20; Stafford RS, Radley DC. J Am Coll Cardiol. 2003;41:56-61.

18. Underutilization of Novel Therapeutics • Anecdotal reports suggest drotrecogin alfa (activated) is underutilized • Cost • Safety concerns • Failure to recognize eligible patients Jacobi J. Am J Health Syst Pharm. 2004;61:203-4.

19. Preventing Underutilization of Novel Therapeutics • Interventions to prevent omission of appropriate therapy • Provider education • Cost-effectiveness analysis • Computer-based reminders • Case audit and feedback • Development of specialized teams to identify high- risk patients in real time Angus DC, et al. Crit Care Med. 2003;31:1-11; Cabana MD, et al. JAMA. 1999;282:1458-65; Peck P. Medscape Medical News [serial online]. 2004.

20. Take-Home Points • Drotrecogin alfa (activated) is FDA approved for mortality reduction in treatment of adult patients with severe sepsis without high risk of bleeding • Use of novel therapeutics in disease treatment requires a thorough understanding of inclusion and exclusion criteria applied in trials

21. Take-Home Points • Provider education, computerized reminders, and case-based feedback can help prevent underutilization of appropriate therapy • Use of automatic checklists, pharmacy review, and mandatory consults prior to drug administration can reduce inappropriate use of beneficial but potentially dangerous novel therapeutics.