I wanted to elicit perspectives on the interpretation of a randomized trial that has been much discussed in the neurocritical care community: INTERACT-2.
While this trial is several years old, I was recently summarizing itfor a lecture and was interested in what the datamethods community thought about a few points. Some thoughts I will raise have already been discussed in previous threads, but I wanted to make sure I’m interpreting things okay.
Clinical background: there is an acute hypertensive response that is commonly appreciated after a patient experiences an acute onset of intracerebral hemorrhage (ICH). This has been variably associated with an increased risk of hematoma expansion, development of perihematomal edema, and increased risk for death and disability.
Two major randomized trials, INTERACT-2, published in 2013 and ATACH-2 published in 2016 have both examined if lowering blood pressure within several hours of symptom onset would lead to decreased death and disability at 3 months as measured by the ordinal modified Rankin Scale (mRS, range 0-6, lower scores = less disability, 6 = death). I will leave out discussion on ATACH-2 for now to keep this post relatively short.
INTERACT-2 randomized patients within 6 hours of symptom onset to two different blood pressure goals: < 180 mm Hg and < 140 mm Hg, to be maintained for 7 days post-injury. The primary outcome was a dichotimization of the mRS to “good outcome” of 0-3 vs. “bad outcome” of 4-6 at 3 months. For this outcome, there was an odds ratio of 0.87 (95% CI 0.75–1.01) in favor of the intensive lowering group (< 140). There was also a similar odds ratio when using a secondary ordinal analysis on the entire mRS (0.87 95% CI 0.77–1.00).
The community’s interpretation of this was variable. In general, here were the main comments:
- On one hand, clinicians thought that given the 95% CI, there was a strong likelihood of benefit in intensive blood pressure lowering to < 140 mm Hg, especially with the lack of any data showing harm. Proponents also pointed to the likely benefit as appreciated in the secondary outcomes including the ordinal analysis as well as the quality of life data.
- Others pointed to the p value being > 0.05, and the lack of any data showing a difference in hematoma expansion to claim that there was no difference in either blood pressure goal. They also pointed to the lack of blinding that could have biased the results.
My questions/thought about this study:
- Overall, there is a lot of variation (and resulting controversy) in the use of the modified Rankin scale as an outcome measure in neurocritical care. The two main points of contention seem to be what to use as a cut-off for a good outcome; commonly this is 0-2 vs 3-6 or 0-3 vs 4-6. Some studies have also used 0-4 vs 5-6. Some trials have also used an ordinal regression, but mostly as a secondary outcome. While I assume that most of the datamethods community would advocate for the use of an ordinal regression, this seems to be particularly controversial on Twitter. I think a lot of this has to do with the suspicion that trialists are trying to gain statistical power in any way they can in an effort to show “positive” results. I also think that us physicians are used to analyzing dichotomous, whether that is good or bad. Any tips on how to translate the results of an ordinal regression to the general medical community?
- Given that the odds ratios of both the dichotomous outcome and ordinal regression were similar, doesn’t that imply that the proportional odds assumption is valid, making the ordinal regression a valid way to interpet the outcome?
- Critics of ordinal regression have pointed to the lack of inter-rater reliability in measuring the mRS, thus negating any potential increased power that may be gained by using this method vs. dichotomizing the results. How would you reconcile these seemingly opposing viewpoints?
Hopefully my questions make sense. I’m happy to provide any clarification or further clinical background. Thank you and looking forward to discussing further.