MISTIE III

Mistie I

MISTIE III

Minimally Invasive Surgery in with thrombolysis in intracerebral haemorrhage evacuation
Aim: minimally invasive catheter evacuation followed by thrombolysis (MISTIE), with the aim of decreasing clot size to 15 mL or less,
Phase 3, 242 patients, 78 sites in the USA
N=499; surgical cohort 242 patients; 78 sites; Patients randomized to MISTIE + 1.0 mg alteplase or standard medical therapy.
Vol >30
GCS <14
1.0 mg alteplase every 8 h for up to nine doses

Primary & sensitivity analysis

Feature	Result	Statistic	p-value
Functional outcome	mRS 0-3 not different	Risk diff=4%	0.33
Ordinal mRS	mRS=6 less likely: MISTIE	AOR=0.6	0.03
Subgroup analyses	No difference by treatment arm	No difference	NS

Ordered secondary analyses

Feature	Result	Statistic	p-value
All-cause mortality	Lower hazard of death: MISTIE	HR=0.67	0.037
Clot removal	Clot removal=better function	AOR=0.68	<0.001
EOT ≤15 mL (surgical target)	Increased % mRS 0-3	Risk diff=10.5%	0.03
ICU duration	No difference	10 vs 10	0.46
30-day mortality	Less mortality in MISTIE	9.4% vs 14.3%	0.09
Safety: AEs/SAEs	More total SAE: Control	126 vs 142	0.01

Design

Phase 3 explanatory trial
Open-label, blinded endpoint
Image-guided, catheter-based removal of intracerebral haemorrhage (supratentorial) of 30 mL or more, measured with the ABC/2 method
N=78 hospitals
N=499pts

Technique

Conclusion

For moderate to large intracerebral haemorrhage, MISTIE did not improve the proportion of patients who achieved a good response 365 days after intracerebral haemorrhage.
Exploratory

Mortality at 365 days seemed to be lower in the MISTIE group than the standard medical care group, without a net increase in the proportion of patients with severe disability. This increased survival is, at best, a modest effect based on a secondary analysis.
An association between extent of removal and lower mRS scores (0–3).

Inclusion

Aged 18 years or older
Spontaneous, non-traumatic, supratentorial intracerebral haemorrhage
Haemorrhage of 30 mL or more due to cerebral small-vessel disease,
GCS <= 14 or NIHSS >= 6
mRS score of 0 or 1 before the bleed,
Intracerebral haemorrhage that remained the same size (growth <5 mL) for at least 6 h after diagnostic CT.

Exclusion (https://clinicaltrials.gov/ProvidedDocs/46/NCT01827046/Prot_003.pdf)

Patient expressed care limitations or those deemed to have life-threatening mass effect requiring surgery.
Infratentorial haemorrhage

Outcome

Primary end point

Primary efficacy outcome was good functional outcome, defined as the proportion of patients who achieved an mRS score of 0–3 at 365 days

mRS scores 6% (n-15) MISTIE (n-30) (n-249) Standard medical care (n=30) (n-240) 26% (n•64) (n-58) (n-60) (n-56) 12% (nz31) (n-48) (n-62)

Secondary end point

eGOS score dichotomised as good (4–8) vs poor (1–3) at 365 days after stroke

eGOSatday 365 Upper good recovery Lower good recovery Upper moderate disability Lower moderate disability Upper severe disability Lower severe disability Vegetative state Dead % (n=8) 5% (n-ll) MISTIE 9% (n-21) (n.244) 6% (n-13) 6% (n•14) Standard medical care (n.234) 10 (n=48) 16% (n—37) 30 39% (n=96) 36% (n-85) 20 40 50 60 70 80 20% (n=48) 27% (n-62) 90 100

All-cause mortality 365 days after stroke

Estimated all-cause mortality differed by 6–8% throughout the 365-day period (log-rank p=0·08), and was significantly lower in the MISTIE group than the standard medical care group at 365 days (severity adjusted Cox proportional hazard ratio 0·67, 95% CI 0·45–0·98; p=0·037).

100 75 50 25 Number at risk MISTIE 250 Standard medical care 249 Figure 3: Overall survival HR 0-67 (95% 045-0.98), Log-rank p=O.084 — 95% Cl MISTIE — 95% Cl Standard medical care 100 216 193 200 Time from onset (days) 210 187 204 181 Data was censored at day 365. Shaded areas show 95% Cls. HR=hazard ratio. — Overall survival. Data was censored at day 365. Shaded areas show 95% CIs. HR=hazard ratio.

Association between functional outcome and clot removal quantified as weighted clot volume by area under the curve (AUC) and clot volume at end of treatment, patient disposition, efficacy 180 days after stroke, type and intensity of intensive care unit management;
Health-related quality of life (electronic visual analogue scale and EQ-5D scores).

Safety end point

ㅤ	Study stop threshold	MISTIE (n=255)	Standard medical care (n=251)	p value
Died within 0–7 days	10%	2 (1%)	10 (4%)	0.018
Died within 0–30 days	60%	24 (9%)	37 (15%)	0.066
Died within 0–180 days	NA	39 (15%)	57 (23%)	0.033
Bacterial brain infection within 0–30 days	15%	2 (1%)	0	0.160
Symptomatic brain bleeds within 72 h after last dose*	25%	6 (2%)	3 (1%)	0.325
Asymptomatic brain bleeds within 72 h after last dose*	NA	81 (32%)	21 (8%)	<0.0001
Number of serious adverse events within 30 days	NA	126	142	0.012

Data are n, or n (%). NA=not applicable. *For patients in the MISTIE group who achieved the endpoint before alteplase dosing and for patients in the standard medical care group, this was calculated as the corresponding median time from randomisation. Safety analyses were done for the full randomised cohort (n=506), including the seven patients randomised in error.
These findings suggest MISTIE has few negative consequences.

Limitations

Open label

Strengths

A high level of safety was achieved in a large group of surgeons who had not previously done the procedure.