Therapy Misalignment

50 %
50 %
Information about Therapy Misalignment

Published on September 5, 2007

Author: shivabirdi

Source: slideshare.net

Randomization in clinical trials of titrated therapies: Unintended consequences of using fixed treatment protocols Tim Sable MD PGY-3 Cleveland Clinic September 5, 2007

Goals Understand how level of therapy and severity of disease play a role in clinical practice How does randomization invalidate the conclusions we draw from important studies based on this fact Why is this important? TRICC and ARMA studies as examples Can we design better studies?

Understand how level of therapy and severity of disease play a role in clinical practice

How does randomization invalidate the conclusions we draw from important studies based on this fact

Why is this important?

TRICC and ARMA studies as examples

Can we design better studies?

Disease and Therapy Intensivists adjust dose of therapy based on severity of disease ie blood transfusion, fluid management, ventilation Based on a knowledge of physiology, experience, and judgement

Intensivists adjust dose of therapy based on severity of disease

ie blood transfusion, fluid management, ventilation

Based on a knowledge of physiology, experience, and judgement

Disease and Therapy To improve the practice of medicine, we use Randomized Clinical Trials (RCTs) It is difficult to simulate the relationship of therapy titration and disease severity in RCTs Simplification is used to increase the power of RCTs Patients are randomized to two fixed, separate treatment protocols This creates a practice misalignment

To improve the practice of medicine, we use Randomized Clinical Trials (RCTs)

It is difficult to simulate the relationship of therapy titration and disease severity in RCTs

Simplification is used to increase the power of RCTs

Patients are randomized to two fixed, separate treatment protocols

This creates a practice misalignment

Practice Misalignment A disruption of the relationship between level of therapy and disease severity that can invalidate results, making them useless for clinical practice Two major misalignments Half the patients with mild disease receive a low level of therapy consistent with clinical practice, the other half a high level Half of patients with severe disease receive a high level of therapy consistent with medical practice, the other half a low level

A disruption of the relationship between level of therapy and disease severity that can invalidate results, making them useless for clinical practice

Two major misalignments

Half the patients with mild disease receive a low level of therapy consistent with clinical practice, the other half a high level

Half of patients with severe disease receive a high level of therapy consistent with medical practice, the other half a low level

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

TRICC Trial The Canadian Transfusion Requirements in Clinical Care Trial Purpose: do restrictive or liberal red cell transfusion strategies produce equivalent results in critically ill patients? Randomization of adequately resuscitated critically ill patients who are not actively bleeding to one of two arms: Liberal threshold (10 g/dl Hgb) Restrictive threshold (7 g/dl Hgb) Independent of comorbidities

The Canadian Transfusion Requirements in Clinical Care Trial

Purpose: do restrictive or liberal red cell transfusion strategies produce equivalent results in critically ill patients?

Randomization of adequately resuscitated critically ill patients who are not actively bleeding to one of two arms:

Liberal threshold (10 g/dl Hgb)

Restrictive threshold (7 g/dl Hgb)

Independent of comorbidities

TRICC Trial Results - in 838 critically ill patients, mortality rate was higher in the liberal vs restrictive group (28.1% vs 22.2%, p=0.05) 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)

Results - in 838 critically ill patients, mortality rate was higher in the liberal vs restrictive group (28.1% vs 22.2%, p=0.05)

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)

Clinical Practice But what was the standard of practice at the time (1999)? Investigators surveyed 193 Canadian physicians for their transfusion strategies 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 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

But what was the standard of practice at the time (1999)?

Investigators surveyed 193 Canadian physicians for their transfusion strategies

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

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

TRICC Trial The control trial did not include a control group that followed this practice pattern All patients were randomized to 1 of 2 groups differing by the transfusion trigger (7 and 10 g/dl) 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 So, in each arm, there was a subgroup of patients that received treatment opposite and contrary to standard of care

The control trial did not include a control group that followed this practice pattern

All patients were randomized to 1 of 2 groups differing by the transfusion trigger (7 and 10 g/dl)

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

So, in each arm, there was a subgroup of patients that received treatment opposite and contrary to standard of care

TRICC Trial Analysis of TRICC Trial (meta-analysis) Patients with ischemic heart disease pre-randomization had a different response (p=0.03) to the two fixed protocols than patients without heart disease In the restrictive group, they had a higher 30 day mortality than those without ischemic heart disease, results contrary to TRICC findings Younger (age <55) healthier (APACHE II < 20) patients also contributed significantly to the higher mortality rates in the 10 g/dl threshold group

Analysis of TRICC Trial (meta-analysis)

Patients with ischemic heart disease pre-randomization had a different response (p=0.03) to the two fixed protocols than patients without heart disease

In the restrictive group, they had a higher 30 day mortality than those without ischemic heart disease, results contrary to TRICC findings

Younger (age <55) healthier (APACHE II < 20) patients also contributed significantly to the higher mortality rates in the 10 g/dl threshold group

 

 

TRICC Trial The results of the trial were strongly influenced by practice misalignments in both arms of the study 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 Therefore, it remains unclear whether using set transfusion parameters is better than adjusting therapy based on individual patient characteristics

The results of the trial were strongly influenced by practice misalignments in both arms of the study

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

Therefore, it remains unclear whether using set transfusion parameters is better than adjusting therapy based on individual patient characteristics

ARMA Trial The Acute Respiratory Distress Syndrome Network trial of low tidal volume ventilation 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

The Acute Respiratory Distress Syndrome Network trial of low tidal volume ventilation

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

ARMA Trial 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) Conclusion - “this lower tidal volume protocol should be used in patients with acute lung injury and ARDS”

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)

Conclusion - “this lower tidal volume protocol should be used in patients with acute lung injury and ARDS”

Clinical Practice What was the standard? 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 Before ARMA, the American College of Chest Physicians in 1993 recommended tidal volumes be adjusted to maintain airway pressure below certain levels

What was the standard?

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

Before ARMA, the American College of Chest Physicians in 1993 recommended tidal volumes be adjusted to maintain airway pressure below certain levels

Clinical Practice A survey of intensivists at the time showed that 96% believed airway pressure was an important factor when choosing tidal volume for ARDS patients 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) Thus, tidal volume was adjusted based on severity of lung injury as measured by airway pressures and compliance

A survey of intensivists at the time showed that 96% believed airway pressure was an important factor when choosing tidal volume for ARDS patients

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)

Thus, tidal volume was adjusted based on severity of lung injury as measured by airway pressures and compliance

ARMA Trial In the trial, the effects of tidal volumes were very different depending on lung compliance 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 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

In the trial, the effects of tidal volumes were very different depending on lung compliance

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

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

 

ARMA Trial Again, results of the trial seem to have been strongly influenced by noncomparable subgroups receiving care contrary to standard of practice 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)

Again, results of the trial seem to have been strongly influenced by noncomparable subgroups receiving care contrary to standard of practice

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)

Can we design better studies? 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 This results in different and opposite effects in the subgroups that lead to erroneous conclusions at best, and detrimental patient outcomes at worst 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

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

This results in different and opposite effects in the subgroups that lead to erroneous conclusions at best, and detrimental patient outcomes at worst

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

Can we design better studies? Characterize current practices Surveys, expert guidelines Identify patient characteristics used to titrate therapy As above, chart reviews Simulate the randomization of target populations Prospective studies, pilot studies

Characterize current practices

Surveys, expert guidelines

Identify patient characteristics used to titrate therapy

As above, chart reviews

Simulate the randomization of target populations

Prospective studies, pilot studies

Can we design better studies? Monitor safety and efficacy by comparing your study current practices Include a current practices arm Narrow population being studied Ie. Only patients with low lung compliance Employ an analysis that includes practice misalignments Disadvantage - difficult to interpret, often produce nonsignificant results and have low power

Monitor safety and efficacy by comparing your study current practices

Include a current practices arm

Narrow population being studied

Ie. Only patients with low lung compliance

Employ an analysis that includes practice misalignments

Disadvantage - difficult to interpret, often produce nonsignificant results and have low power

Conclusion Practice misalignments create problems in interpreting data, can create misleading results, and often lead to recommendations that are not clinically relevant Identifying these potential problems allows one to minimize them in future studies, improving trial safety and interpretibility

Practice misalignments create problems in interpreting data, can create misleading results, and often lead to recommendations that are not clinically relevant

Identifying these potential problems allows one to minimize them in future studies, improving trial safety and interpretibility

Thank you!

References 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. 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. A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care. Hebert, Wells et al. NEJM. 1999. Vol 340, No. 6 409-417.

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.

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.

A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care. Hebert, Wells et al. NEJM. 1999. Vol 340, No. 6 409-417.

Add a comment

Related presentations

Related pages

Effects of Spinal Misalignments Chart - PHYSICAL THERAPY

get the latest; Sign up today and be the first to know about new healthcare products and special offers.
Read more

Subluxation / Spinal Misalignment Treatment

Back and Neck Center of Brick, LLC provides local residents with chiropractic services such as Subluxation / spinal misalignment treatment. Call 732-477-6767
Read more

TEMPORAL BONE MISALIGNMENT AND MOTION - IAHE

Temporal Bone Misalignment and Vertigo ALTERNATIVE THERAPIES, nov/dec 2009, VOL. 15, NO. 6 39 tinnitus, aural pressure, headaches, cyclical vomiting, motion
Read more

Treatment | Sarton Physical Therapy

Evaluation and treatment procedures at Sarton Physical Therapy. Sarton Physical Therapy. Hope and ... misalignment of pelvic, sacroiliac, spine, ...
Read more

What is Posture MISALIGNMENT? - The POSTURE Clinic

What is Posture Misalignment? BEFORE & AFTER ---- Astounding!!!! ... YES, this is the SAME woman AFTER using this method of alignment therapy. Oh, ...
Read more

back pain causes - Dorn Method

The Dorn Method a wholistic manual therapy and true self help method for Back Pain. ... Back Pain – Causes ... Misalignment and a twisted Hip-Blade:
Read more

Chart of Effects of Spinal Misalignment - Kozik Chiropractic

Chart of Effects of Spinal Misalignment. To be healthy, it is essential that your nervous system function properly and free from any interference caused by ...
Read more

Atlas correction is ideal for headaches, back pain, neck ...

Learn what a single Atlas correction treatment can do for migraines, headaches, back pain, scoliosis, pelvic obliquity, whiplash, vertigo, dizziness.
Read more

Coping With a Misaligned Jaw - Dental Health Center ...

Coping With a Misaligned Jaw. Ask Dr. James Jacobs ... Behavioral therapy and relaxation therapy to try to relax the muscles around your joints ;
Read more