Spotlight Case July 2004

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Spotlight Case July 2004

• Preventing Inappropriate Use of Novel Therapeutic
  Agents

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Source and Credits

• This presentation is based on the July 2004 AHRQ
  WebMM 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 WebMM Robert Wachter, MD
• Spotlight Editor Tracy Minichiello, MD
• Managing Editor Erin Hartman, MS

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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

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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.

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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.

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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. 2003311250-60
Angus DC, et al. Crit Care Med. 2001291303-10
Bernard GR, et al. N Engl J Med.
2001344699-709.
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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 gt 25

Physicians' Desk Reference. 2003
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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. 2001344699-709.
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PROWESS Inclusion

• Included patients with known or suspected
  infection, sepsis-induced dysfunction of at least
  one organ system for lt24 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 lt32 mmHg,
  mechanical ventilation
• WBC of ?12,000/mm3, ?4,000/mm3, or gt10 immature
  neutrophils

Bernard GR, et al. N Engl J Med. 2001344699-709.
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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 lt30,000/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. 2001344699-709.
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PROWESS Mortality Benefit

• Mortality benefit greatest in patients with
  APACHE II gt25
• 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. 2002122(Suppl)51S.
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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 patients organ dysfunction was due
  to severe rhabdomyolysis.

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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

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Challenges with Novel Therapeutics

• Off-label use of medications is permitted
• Guidelines are expensive to develop and often
  ignored
• Pharmaceutical industry detailing

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Case (cont.) Novel Drug Misuse

• The patient later died due to complications from
  his multiple injuries.

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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.
2003601345-52 Jacobi J. Am J Health Syst
Pharm. 200461203-4.

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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. 20043631314-20
Stafford RS, Radley DC. J Am Coll Cardiol.
20034156-61.
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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. 200461203-4.
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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. 2003311-11
Cabana MD, et al. JAMA. 19992821458-65 Peck
P. Medscape Medical News serial online. 2004.
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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

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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.