The DEFUSE data show that for acute stroke patients with PWI/DWI mismatch, the favorable clinical response rate associated with early reperfusion is related to the degree of mismatch. There is a lack of consensus regarding the definition of PWI/DWI mismatch. For the DEFUSE study, the prespecified ratio chosen to define PWI/DWI mismatch was 1.2, and a minimum mismatch volume of 10 mL was required. Although a ratio of > 1.2 has been widely used in stroke trials (Butcher et al, 2005
; Hacke et al, 2005
; Furlan et al, 2006
) as well as nonrandomized stroke studies (Schellinger et al, 2000
; Parsons et al, 2002
), others have defined PWI–DWI mismatch as a ratio > 1.0 (Darby et al, 1999
; Neumann-Haefelin et al, 1999
). To our knowledge, no previous study has attempted to determine the optimal definition for mismatch.
Our data suggest that a more stringent definition of mismatch, requiring a greater mismatch ratio, has the potential to identify patients who have a particularly robust clinical response to early reperfusion. These findings are consistent with the concept that the mismatch provides an estimate of the ischemic penumbra; patients estimated to have a large volume of penumbral tissue are most likely to benefit from reperfusion and most likely to have poor outcomes if reperfusion is not achieved.
The lower favorable clinical response rate in patients with reperfusion and small mismatch ratio has several possible explanations. It is likely that penumbral tissue is being recruited into the ischemic core during the delay between the baseline magnetic resonance imaging and the occurrence of reperfusion. This delay includes the ‘magnetic resonance imaging-to-needle’ time and the time from initiation of therapy to actual reperfusion. As a result, for patients with small mismatch ratios, little salvageable tissue may remain by the time reperfusion occurs. In addition, mismatch areas determined by PWI and DWI likely include regions of benign oligemia that will survive regardless of reperfusion, as well as critically hypoperfused areas at high risk of infarction (Kidwell et al, 1999
). With smaller mismatch ratios, mismatch areas may primarily contain regions of benign oligemia.
A more stringent definition of PWI/DWI mismatch reduces the number of patients designated as having a mismatch. This would decrease the number of patients who are considered to be ‘eligible’ for a trial of a reperfusion therapy if ‘mismatch’ is used as an inclusion criterion for study entry. For example, requiring a mismatch ratio of ≥2.6 would have excluded 25% of the mismatch patients in DEFUSE. In retrospect, a more desirable choice might have been requiring a ratio of ≥1.8 because only about 15% of the patients would have been excluded; yet the odds ratio for achieving a favorable clinical response after early reperfusion would have more than doubled. While requiring a larger mismatch ratio would reduce the number of patients who are eligible for inclusion in a randomized trial of a reperfusion therapy, the anticipated improvement in the clinical response rate among patients with reperfusion (and low rate of favorable response in non-reperfusion patients) would reduce the total sample size estimate for the trial. This approach will require an automated PWI processing program that can rapidly identify the mismatch ratio. Several groups have developed programs that can accomplish this, but these tools have not yet been incorporated into the software packages offered by magnetic imaging imaging manufactures.
This study has some limitations; most importantly, the sample size was small and confirmation of these findings in a large data set is required. In addition, mismatch ratio varies based on the techniques used to analyze PWI data. In DEFUSE, perfusion maps were constructed using Tmax
with a 2-sec delay as the lower threshold indicating hypoperfused brain tissue. Other Tmax
thresholds or other PWI analysis techniques may yield different estimates of the optimal mismatch ratio. Tmax
is the maximum of the tissue residue function characteristic to each voxel and reflects how much the tissue response lags behind the stimulus by an arterial input into the voxel. If the perfusion pressure decreases, the influx into a voxel after an arterial input stimulus is delayed and hence Tmax
will increase. Tmax
can be viewed as the bolus arrival time corrected for the confounding effects of bolus administration (e.g., injection rate and flow, cardiac output). While Tmax
does not measure tissue microperfusion directly, studies (Shih et al, 2003
; Thijs et al, 2004
) have shown that Tmax
is a sensitive surrogate marker that detects perfusion deficits and tissue that is likely destined for infarction if reperfusion does not occur.
It is possible that imbalances in baseline predictors of favorable outcome could confound our results. We believe that this is unlikely, as key baseline predictors of clinical outcomes did not differ between patients with high versus low mismatch ratios. In addition, a multivariate analysis that corrected for baseline imbalances in age, baseline National Institutes of Health Stroke Scale, time to treatment, PWI volume, and glucose was performed as part of the primary analysis of the DEFUSE results. The odds ratio for the association between reperfusion and favorable outcome in mismatch patients increased from 5.4 (95% CI, 1.1 to 25.8, P = 0.039) to 7.7 (95% CI, 1.3 to 44.8, P = 0.022) after correction for baseline imbalances.
A placebo-controlled trial is required to determine if tPA is an effective therapy beyond 3 h. If tPA is more effective than placebo for some patient subgroups beyond 3 h, our data argue that a larger mismatch ratio may identify tPA responders because large mismatch ratios are associated with a very high rate of good outcome if reperfusion occurs and a very low rate if reperfusion does not occur. However, it is uncertain whether tPA is associated with a higher reperfusion rate than placebo in patients with large mismatch ratios and whether the adverse effects of tPA differ based on mismatch ratio.
In conclusion, use of larger PWI/DWI mismatch ratios than have typically been chosen to define mismatch may provide greater power for detecting beneficial clinical effects of reperfusion in future clinical trials.