# Presentation: 750504

## EMBOL-X Aortic Filter, Statistical Comments

- Gerry Gray

## Outline 

- Judging the results of the trial
- Particulate capture as a surrogate
- Subgroup analyses and Higgins risk score

## How do we judge the results?

- Bottom line: trade-off between probable benefit versus potential risk
- What is the appropriate
- Set of endpoints?
- Comparator (control) group?

## How do we judge the results?

- Results are judged internally to the study
- Clinical outcomes compared to control group
- Results are judged in comparison to other devices and/or studies
- Clinical results compared to other similar devices
- Results are judged narrowly based on the proposed claims
- Measurements of capability as a “tool” are compared to pre-defined criteria
- No demonstration of clinical effect required

## Internal: adverse event composite

- Randomized 1289 patients 1:1 to EMBOL-X versus Control
- Outcome is major adverse event rate

|  | COMPOSITE EVENTS |
| --- | --- |
| EMBOL-X | 110/645 (17.1%) |
| CONTROL | 122/644 (18.9%) |

- Statistical tests: non-inferiority strongly rejected (p < 0.001)
- 		superiority not significant (p = 0.38).
- Conclusion regarding adverse event rate: equivalent but not superior clinical performance to the control.

## Internal: particulate capture

- Outcome is proportion of filters that capture at least one particle
- No control group for comparison ... can’t judge this outcome internally

## Internal: other safety endpoints

- Remarkably similar results for safety:
- Individual comparisons of all types of serious adverse event (32 in all); smallest p-value was 0.25.
- Increase in aortic endothelial injury (secondary safety endpoint)
- 2.0% vs. 9.2%
- BUT, no detectable effect of aortic injury on clinical adverse events (short term, only 42 randomized patients).

## Compared to other devices

- 510(k) Predicate is a combination of:
- PercuSurge balloon/aspiration catheter for SVG patients
- CPB arterial filters
- EMBOL-X and PercuSurge differ in
- Mechanism of action
- Patient population
- 	... thus a clinical trial was required.
- Different trial endpoints; direct comparison to PercuSurge results problematic

## Based on proposed claims

- “To contain and remove particulate emboli”
- Successful deployment in 618/645 (95.8%) of patients.
- Successful capture of one or more particle in 598/618 evaluable filters (96.8%) or 598/645 (92.4%) of patients.
- Easily meets pre-defined criteria of capture in 75% of filtered patients.

## Summary

- Internal: equivalent safety, no evidence of any effect on adverse event rates.
- External: comparisons difficult.
- Tool: captures particulate material.

## Particulate capture as a surrogate

- Conditions for a valid surrogate
- Correlated with clinical outcome of interest
- Captures most of the effect of the treatment on the outcome of interest
- Is particulate capture (number or surface area) by a mesh filter a valid surrogate for clinical adverse events?

## Particulate capture as a surrogate

| Particulate Capture | COMPOSITE EVENT |  |
| --- | --- | --- |
|  | YES | NO |
| YES | 102 (17.1%) | 494 |
| NO | 130 (18.7%) | 563 |

- Correlation coefficient: -0.02
- Similar results hold for total number of particles captured and total area of particles captured.

## Distribution of # of particles

## Distribution of total particle area

## Summary

- Particulate capture does not meet condition #1: it is not correlated with the clinical outcome of interest.
- Similar results hold for other adverse events not included in the composite.
- Thus there is no evidence that particulate capture by a mesh filter is a valid surrogate for any of the clinical adverse events recorded in this trial.

## Post-hoc subgroup analyses

- Table 6 of the panel package reports on 36 different post-hoc subgroup analyses.
- Three smallest p-values are 0.02 (EF  25%), 0.04 (cerebrovascular disease), and 0.05 (BMI < 25 kg/m2)
- None are “significant” if any reasonable multiplicity adjustment is applied.

## Preoperative risk score

- An additional post-hoc subgroup analysis
- For patients with Higgins risk ≥ 5, filter arm had a lower composite event rate (241 patients, p = 0.047).
- Driven by a reduction in RI for the EMBOL-X patients with Higgins risk ≥ 5.
- Reasonable adjustment for multiplicity means a “significant” p-value should be smaller than 0.05.
- Various Higgins risk cut-offs were investigated
- If Higgins risk is considered as a continuous variable (using logistic regression, the risk score range is 0 – 10) the odds ratio is 1.19 (not significant).

## Summary

- Subgroup analyses do not provide evidence for superiority in terms of adverse event rates.