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Therapy Misalignment


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Therapy Misalignment

  1. 1. Randomization in clinical trials of titrated therapies: Unintended consequences of using fixed treatment protocols Tim Sable MD PGY-3 Cleveland Clinic September 5, 2007
  2. 2. Goals <ul><li>Understand how level of therapy and severity of disease play a role in clinical practice </li></ul><ul><li>How does randomization invalidate the conclusions we draw from important studies based on this fact </li></ul><ul><li>Why is this important? </li></ul><ul><li>TRICC and ARMA studies as examples </li></ul><ul><li>Can we design better studies? </li></ul>
  3. 3. Disease and Therapy <ul><li>Intensivists adjust dose of therapy based on severity of disease </li></ul><ul><li>ie blood transfusion, fluid management, ventilation </li></ul><ul><li>Based on a knowledge of physiology, experience, and judgement </li></ul>
  4. 4. Disease and Therapy <ul><li>To improve the practice of medicine, we use Randomized Clinical Trials (RCTs) </li></ul><ul><li>It is difficult to simulate the relationship of therapy titration and disease severity in RCTs </li></ul><ul><li>Simplification is used to increase the power of RCTs </li></ul><ul><li>Patients are randomized to two fixed, separate treatment protocols </li></ul><ul><li>This creates a practice misalignment </li></ul>
  5. 5. Practice Misalignment <ul><li>A disruption of the relationship between level of therapy and disease severity that can invalidate results, making them useless for clinical practice </li></ul><ul><li>Two major misalignments </li></ul><ul><li>Half the patients with mild disease receive a low level of therapy consistent with clinical practice, the other half a high level </li></ul><ul><li>Half of patients with severe disease receive a high level of therapy consistent with medical practice, the other half a low level </li></ul>
  6. 6. Illustrated Thusly Misalignment High level of treatment Low level of treatment Patients with mild disease High level of treatment Low level of treatment Patients with severe disease Study Wing 2 Study Wing 1
  7. 7. TRICC Trial <ul><li>The Canadian Transfusion Requirements in Clinical Care Trial </li></ul><ul><li>Purpose: do restrictive or liberal red cell transfusion strategies produce equivalent results in critically ill patients? </li></ul><ul><li>Randomization of adequately resuscitated critically ill patients who are not actively bleeding to one of two arms: </li></ul><ul><ul><li>Liberal threshold (10 g/dl Hgb) </li></ul></ul><ul><ul><li>Restrictive threshold (7 g/dl Hgb) </li></ul></ul><ul><ul><li>Independent of comorbidities </li></ul></ul>
  8. 8. TRICC Trial <ul><li>Results - in 838 critically ill patients, mortality rate was higher in the liberal vs restrictive group (28.1% vs 22.2%, p=0.05) </li></ul><ul><li>Conclusion - most critically ill patients should not be transfused until Hgb falls below 7 g/dl (exclusions of patients with acute MI and unstable angina per authors) </li></ul>
  9. 9. Clinical Practice <ul><li>But what was the standard of practice at the time (1999)? </li></ul><ul><li>Investigators surveyed 193 Canadian physicians for their transfusion strategies </li></ul><ul><li>They found that transfusion thresholds per clinicians depend on clinical assessment and lab data, like age, APACHE II scores, and the presence of shock, coronary ischemia, or anemia </li></ul><ul><li>Physicians transfused to a Hgb level of 8.3 g/dl and adjusted upward to an average of 9.5 g/dl based on age, illness severity, history of ischemic heart disease, and presence of shock </li></ul>
  10. 10. TRICC Trial <ul><li>The control trial did not include a control group that followed this practice pattern </li></ul><ul><li>All patients were randomized to 1 of 2 groups differing by the transfusion trigger (7 and 10 g/dl) </li></ul><ul><li>In practice, 3% of physicians would use the low trigger on patients with a history of ischemic heart disease, 12% would use the high trigger for healthy young patients </li></ul><ul><li>So, in each arm, there was a subgroup of patients that received treatment opposite and contrary to standard of care </li></ul>
  11. 11. TRICC Trial <ul><li>Analysis of TRICC Trial (meta-analysis) </li></ul><ul><li>Patients with ischemic heart disease pre-randomization had a different response (p=0.03) to the two fixed protocols than patients without heart disease </li></ul><ul><li>In the restrictive group, they had a higher 30 day mortality than those without ischemic heart disease, results contrary to TRICC findings </li></ul><ul><li>Younger (age <55) healthier (APACHE II < 20) patients also contributed significantly to the higher mortality rates in the 10 g/dl threshold group </li></ul>
  12. 14. TRICC Trial <ul><li>The results of the trial were strongly influenced by practice misalignments in both arms of the study </li></ul><ul><li>Ischemic heart patients seem to have done better under the liberal protocol, and younger healthier patients seem to have had a strong influence in the results of the study </li></ul><ul><li>Therefore, it remains unclear whether using set transfusion parameters is better than adjusting therapy based on individual patient characteristics </li></ul>
  13. 15. ARMA Trial <ul><li>The Acute Respiratory Distress Syndrome Network trial of low tidal volume ventilation </li></ul><ul><li>Purpose: to determine whether low tidal volume mechanical ventilation (6ml/kg) would improve outcome vs high tidal volume ventilation (12 ml/kg) in ARDS patients </li></ul>
  14. 16. ARMA Trial <ul><li>Results - in 861 patients with ARDS, changing tidal volumes from pre-randomization values to 6cc/kg produced a significantly better outcome than 12 cc/kg (31% vs 40 % mortality) </li></ul><ul><li>Conclusion - “this lower tidal volume protocol should be used in patients with acute lung injury and ARDS” </li></ul>
  15. 17. Clinical Practice <ul><li>What was the standard? </li></ul><ul><li>Surveys of routine ventilator management before and during the trial showed clinicians titrated choice of tidal volume to measures of severe lung injury, like airway pressure and lung compliance </li></ul><ul><li>Before ARMA, the American College of Chest Physicians in 1993 recommended tidal volumes be adjusted to maintain airway pressure below certain levels </li></ul>
  16. 18. Clinical Practice <ul><li>A survey of intensivists at the time showed that 96% believed airway pressure was an important factor when choosing tidal volume for ARDS patients </li></ul><ul><li>Pre-randomization data from the ARDS study reveals that as lung compliance decreased and airway pressures increased, physicians used smaller tidal volumes (p=0.008) </li></ul><ul><li>Thus, tidal volume was adjusted based on severity of lung injury as measured by airway pressures and compliance </li></ul>
  17. 19. ARMA Trial <ul><li>In the trial, the effects of tidal volumes were very different depending on lung compliance </li></ul><ul><li>In patients with less compliant lungs (<0.6 ml/cm H20/kg PBW), raising vs lowering tidal volumes increased mortality (42% vs 29%) supporting the study but contrary to standard practices </li></ul><ul><li>In patients with more compliant lungs (>0.6 cc/cm H20/kg PBW), lowering vs raising tidal volumes increased mortality (37% vs 21%), results contrary to standard of practice and contrary to study findings </li></ul>
  18. 21. ARMA Trial <ul><li>Again, results of the trial seem to have been strongly influenced by noncomparable subgroups receiving care contrary to standard of practice </li></ul><ul><li>Therefore, it remains unclear if using lower tidal volumes is better than the established practice of titrating to lung disease severity (by airway pressures and compliance) </li></ul>
  19. 22. Can we design better studies? <ul><li>As we have seen, studies that are prone to practice misalignments are ones in which set parameters were used when, in clinical practice, treatment is titrated based on patient-specific data </li></ul><ul><li>This results in different and opposite effects in the subgroups that lead to erroneous conclusions at best, and detrimental patient outcomes at worst </li></ul><ul><li>In other words, if prescribed dosage or treatment varies with severity of illness or other factors (like amount of vasopressor used in shock), then it makes no sense to randomize all patients to two groups, each with a different set dosage, and expect meaningful outcomes </li></ul>
  20. 23. Can we design better studies? <ul><li>Characterize current practices </li></ul><ul><ul><li>Surveys, expert guidelines </li></ul></ul><ul><li>Identify patient characteristics used to titrate therapy </li></ul><ul><ul><li>As above, chart reviews </li></ul></ul><ul><li>Simulate the randomization of target populations </li></ul><ul><ul><li>Prospective studies, pilot studies </li></ul></ul>
  21. 24. Can we design better studies? <ul><li>Monitor safety and efficacy by comparing your study current practices </li></ul><ul><ul><li>Include a current practices arm </li></ul></ul><ul><li>Narrow population being studied </li></ul><ul><ul><li>Ie. Only patients with low lung compliance </li></ul></ul><ul><li>Employ an analysis that includes practice misalignments </li></ul><ul><ul><li>Disadvantage - difficult to interpret, often produce nonsignificant results and have low power </li></ul></ul>
  22. 25. Conclusion <ul><li>Practice misalignments create problems in interpreting data, can create misleading results, and often lead to recommendations that are not clinically relevant </li></ul><ul><li>Identifying these potential problems allows one to minimize them in future studies, improving trial safety and interpretibility </li></ul>
  23. 26. Thank you!
  24. 27. References <ul><li>Randomization in clinical trials of titrated therapies: Unintended consequences of using fixed treatment protocols. Deans, Minneci et al. Crit Care Med. 2007. Vol 35, No. 6 1509-1515. </li></ul><ul><li>Ventilation with lower tidal volumes as compared with traditional volumes for acute lung injury and the acute respiratory distress syndrome. The Acute Respiratory Distress Syndrome Network. NEJM. 2000. Vol 342, No. 18 1301- 1308. </li></ul><ul><li>A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care. Hebert, Wells et al. NEJM. 1999. Vol 340, No. 6 409-417. </li></ul>