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. Author manuscript; available in PMC: 2012 Dec 1.
Published in final edited form as: Stroke. 2011 Sep 29;42(12):3637–3639. doi: 10.1161/STROKEAHA.111.627745

Carotid Occlusion Surgery Study (COSS): Failure of Cerebral Hemodynamic Selection in General or of Specific PET Methodology?

Andrew P Carlson 1, Howard Yonas 1, Yue-Fang Chang 2, Edwin M Nemoto 1
PMCID: PMC3226849  NIHMSID: NIHMS324767  PMID: 21960571

Abstract

Background and Purpose

The Carotid Occlusion Surgery Study (COSS) was an improvement over the extracranial-Intracranial (EC-IC) bypass study, which did not utilize physiological selection. To assess possible reasons for the early closure of COSS trial, we reviewed COSS methods used to identify high-risk patients and compared results with separate quantitative data.

Methods

Increased oxygen extraction fraction (OEF) by positron emission tomography (PET) is a gold standard for ischemia, but the specific thresholds and equivalency of the semi-quantitative OEF ratio utilized in COSS and quantitative OEF are at issue.

Results

The semi-quantitative hemispheric OEF ratio used in COSS did not identify the same group of patients as quantitative OEF using a threshold of 50%.

Conclusions

The failure of COSS is likely due to a failure of the semi-quantitative, hemispheric OEF ratio method rather than the concept of selection for bypass based on hemodynamic compromise.

Keywords: Cerebrovascular reserve, carotid occlusion, stroke, oxygen extraction fraction, positron emission tomography

Introduction

The Carotid Occlusion Surgery Study (COSS)1, 2 represented a methodological advance over the failed extracranial-intracranial (EC-IC) bypass study3 where patients were not screened for hemodynamic compromise. The COSS trial1 screened patients with hemodynamic compromise by semi-quantitative oxygen extraction fraction (OEF) hemispheric ratio by positron emission tomography (PET), an independent predictor of increased stroke risk in patients with occlusive vascular disease (OVD)4. COSS appeared to have addressed the major criticisms of the failed EC-IC bypass trial, but was prematurely terminated. There were 98 patients randomized to medical treatment and 97 randomized EC-IC bypass, of which 93 had surgery. The two year stroke rate in the medical group was 23% and in the surgical group, 21%2. These stroke rates are similar to the 18% medical and 20% surgical in the original bypass trial3. We review the methods used in COSS to assess possible reasons for its failure.

Thresholds and ratio-based techniques

Quantitative OEF to define ischemic thresholds based on 95% CI shows that increased OEF is an independent predictor of increased stroke risk5, 6. In 40 symptomatic patients with OVD and ten normal controls studied by quantitative OEF, Yamauchi et al6 reported OEF of 42.6 ± 5.1 % (mean ± SD) in 20 normal hemispheres and a 95% CI OEF threshold of 53.3%. In 5 years, there were 5/7 (71%) strokes in high OEF and 6/33 (18%) strokes in normal OEF patients. Hokari5 measured quantitative OEF in 9 volunteers with OEF of 40.0 ± 5% (mean ± SD) and threshold of 50% (mean +2SD). At 3.1 years, strokes occurred in 3/9 (33%) of high OEF and 0/11 of normal OEF patients. These support the threshold of around 50% we have used7, 8.

COSS was based upon the 1998 study by Grubb et al4 where stroke risk was assessed in unilateral carotid occlusion using hemispheric semi-quantitative OEF ratio by a count-rate method9. The range of ratios in 18 normal volunteers was 0.914–1.082 and the upper limit of 1.082 used as the threshold for increased OEF, which is roughly equivalent to an absolute threshold of 43%, well below the 50% threshold of quantitative OEF. Using this threshold, strokes occurred in 12/39 (31%) of patients with elevated OEF ratio compared to 3/42 (7%) with normal OEF ratio.

Yamauchi6 evaluated the OEF ratio method and reported 6/14 (43%) strokes in patients with OEF asymmetry outside of the 95% CI compared to 5/26 (19%) of patients without OEF asymmetry, which was not significant, compared to the significant quantitative data in the same group. Derdeyn et al10 compared the absolute OEF values in the patients from Grubb’s study4 to two ratio based methods: the quantitative OEF hemispheric ratio method used by Yamauchi6 and a semi-quantitative “count-based” hemispheric OEF ratio9. The mean OEF in the 18 volunteers was 41 ± 9% (mean ± SD). The authors quote a 95% CI threshold in normals of 44%, which predicted 8/9 strokes. The actual 95% CI based on their data should have been 58.6% (mean+ 1.96*SD), and would have identified only 3/9 strokes.

QUOVADIS compared the COSS semi-quantitative hemispheric ratio method with quantitative OEF with their respective thresholds (Figure 1 shows comparison of the regions of interest used) in 14 patients with unilateral carotid occlusion and found that they do not identify the same patients (Figure 2) (Unpublished results). These preliminary data suggest that the count rate ratio method does not adequately identify patients with hemodynamic compromise.

Figure 1.

Figure 1

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(A) Regions of interest (ROI) volumes used in the Carotid Occlusion Surgery Study (COSS)1 to evaluate hemodynamic compromise. (B) Volumes of interest used to evaluate hemodynamic compromise in the Quantitative Occlusive Vascular Disease Study (QUOVADIS)8

Figure 2.

Figure 2

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Correlation between COSS hemispheric OEF ratio (threshold- 1.12) versus quantitative OEF (threshold- 50%) in fourteen patients with unilateral carotid occlusion. The patients identified with hemodynamic compromise by the COSS OEF ratio were not the same patients identified by the quantitative OEF measured in QUOVADIS (unpublished).

Powers and colleagues had good reason to conduct COSS using a semi-quantitative ratio method. First, of the 70+ PET facilities in the US, only 4–6 perform quantitative OEF, and second, quantitative OEF requires arterial catheterization, which is problematic in patients on anticoagulants. Compromises were made in COSS to increase enrollment. First, the threshold was lowered from 1.16 to 1.12. Second, up to 12% of patients with contralateral stenosis ≥ 60% or occlusion was allowed.

Powers2 suggested that the lower than expected stroke risk in this group may be due to improvements in medical treatment such as statins11. Without stroke data from the patients deemed “low risk” in their study, this explanation cannot be evaluated, and seems equally likely that a high-risk group was not identified by the PET methodology, especially given the very similar stroke rates to the initial bypass trial.

Conclusion

The failure in COSS was likely due to failure to select patients at high risk for stroke. It seems that we have not yet answered the question as to whether EC-IC bypass has a role in the care of advanced OVD patients.

Acknowledgements

Sources of Funding: NIH Grants NS061216 and NS051639

Footnotes

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Disclosures: None

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