TOTAL

Stroke in the TOTAL trial: Randomized trial of

manual aspiration Thrombectomy in STEMI

TOTAL Trial Investigators

TOTAL

Disclosures

TOTAL trial was funded by:• Canadian Institutes of Health Research• Canadian Network and Centre for Trials Internationally (CANNeCTIN)• Medtronic Inc.

TOTAL

The TOTAL Trial Study Design

PCI Alone(only bailout thrombectomy)

Routine Upfront Manual Thrombectomyfollowed by PCI

Primary Outcome: CV death, MI, cardiogenic shock and class IV heart failure ≤180 days

Safety Outcome: Stroke ≤30 days

1:1 Randomization between strategies

Bailout Thrombectomy allowed if PCI alone strategy fails:• Persistent TIMI 0 or 1 flow with large thrombus after balloon pre-dilatation

• Persistent large thrombus after stent deployment at target lesion

STEMI with Primary PCI ≤12 hours of symptom onsetSample size of 10,700 for 80% power to detect a 20% Relative Risk Reduction

Jolly SS, et al. Am Heart J. 2014. 167 (3):315-21.

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Key Findings of TOTAL

Jolly SS, et al. N Engl J Med. 2015. 372:1389-1398.

No Difference in Primary Efficacy Outcome Increase in Stroke

Hazard ratio 0.99 (95% CI 0.85-1.15), P=0.86

Hazard ratio 2.00 (95% CI 1.25-3.20), P=0.003

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Objectives of Detailed Stroke Analysis• To better understand Stroke findings in TOTAL trial

• To explore:• Timing of Stroke• Stroke severity• Subtypes of Stroke• Independent Predictors of Stroke

• To incorporate findings into updated Meta-analysis

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Objectives of Detailed Stroke Analysis• To understand stroke findings, specifically:

• Timing of Stroke• Stroke severity• Subtypes of Stroke• Independent Predictors of Stroke

• To incorporate findings into updated Meta-analysis

• All strokes were adjudicated by Neurologists blinded to treatment

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PCI Procedure and Therapies over follow up

ThrombectomyN=5033

PCI aloneN=5030

P

Upfront Glycoprotein IIb/IIIa 22.7% 25.4% P=0.002

PCI Procedure time (median) 39 min 35 min <0.001

≤ 5 French Catheters 0.8% 2.5% <0.001

6 French Catheters 96.7% 95.4% 0.001

≥ 2 guide catheters 12.9% 11.9%% 0.10

No differences in oral antiplatelet, anticoagulant or anti-hypertensive therapy over follow up

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Landmark Analysis for Stroke Thrombectomy

(N=5033) (%)PCI alone

(N=5030) (%) HR 95% CI

0 to 48 hours 15 (0.30%) 5 (0.10%) 3.00 1.09-8.25

>48 hours to

<7 days5 (0.10%) 4 (0.08%) 1.25 0.34-4.66

7 to <30 days 13 (0.26%) 7 (0.14%) 1.85 0.74−4.65

30 to <90 days 11 (0.23%) 8 (0.16%) 1.37 0.55-3.41

90 to 180 days 8 (0.17%) 2 (0.04%) 3.99 0.85-18.8

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Stroke Severity Rankin Score Thrombectomy

(N=5033) (%)PCI alone

(N=5030) (%) HR 95% CI p

Minor or no

disability (0-2)

18 (0.4%) 13 (0.3%) 1.38 0.68-2.82 0.37

Major disability or

fatal (3-6)

35 (0.7%) 13 (0.3%) 2.69 1.42-5.08 0.002

1 Full recovery from all symptoms 4 Patient needs help from another person to perform everyday activities

2 Persistent symptoms which do not limit patient’s functional status

5 Patient incapacitated, unable to perform everyday activities even with help

3 Some functional impairment but patient can manage all activities independently

6 Death

Rankin Score

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Stroke Subtype during 180 days Thrombectomy

(N=5033) (%)PCI alone

(N=5030) (%) HR 95% CI p

Ischemic 37 (0.7%) 21 (0.4%) 1.71 1.03-3.00 0.036

Primary hemorrhagic 10 (0.2%) 2 (0.04%) 4.98 1.09-22.7 0.021

Uncertain Etiology 5 (0.1%) 3 (0.1%) 1.66 0.40-6.96 0.48

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Cumulative Ischemic Neurologic Events (includes TIA) over time

Thrombectomy (N=5033) (%)

PCI alone (N=5030) (%) HR 95% CI p

12 hours 6 (0.12%) 4 (0.08%) 1.50 0.42-5.31 0.53

24 hours 11 (0.22%) 5 (0.10%) 2.20 0.76-6.33 0.13

48 hours 15 (0.30%) 6 (0.12%) 2.50 0.97-6.44 0.050

96 hours 19 (0.38%) 11 (0.22%) 1.73 0.82-3.63 0.14

7 days 21 (0.42%) 14 (0.28%) 1.50 0.76-2.95 0.24

14 days 28 (0.56%) 16 (0.32%) 1.75 0.95-3.23 0.07

30 days 35 (0.70%) 19 (0.38%) 1.84 1.05-3.22 0.030

90 days 46 (0.91%) 28 (0.56%) 1.64 1.03-2.63 0.037

180 days 52 (1.03%) 29 (0.58%) 1.79 1.14-2.82 0.011

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Subgroup Analysis Stroke

0.5 2.0 8.0

OVERALL

TIMI Thrombus Grade:≥4<4

Initial TIMI Flow:0-12-3

Site Primary PCI Volume:Tertile 1Tertile 2Tertile 3

History of Hypertension:NoYes

Age:<=65 yrs>65 yrs

Previous Stroke:NoYes

Gender:MaleFemale

Access site:RadialFemoral

Operator thrombectomy Volume:Tertile 1Tertile 2Tertile 3

10063

79192134

74432519

245021395474

50105049

66623401

9750309

77972266

68653191

352232713243

Thrombectomy (%)

1.00

1.140.65

1.140.78

1.220.651.10

0.721.34

0.601.91

0.924.43

0.801.80

0.931.25

1.191.150.75

PCI Alone (%)

0.50

0.600.19

0.560.32

0.330.750.51

0.360.68

0.450.64

0.471.99

0.361.09

0.610.31

0.570.500.49

P (INTERACTION)

0.484

0.783

0.143

0.983

0.095

0.893

0.504

0.090

0.796

Favours Thrombectomy Favours PCI Alone

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Independent Predictors of Stroke

0.5 1.0 2.0 4.0 8.0

Thrombectomy vs PCI

Age per 10 years

Female

Peripheral Vascular Disease

Previous stroke

Prior diabetes

Intra aortic balloon

CABG

TIMI thrombus grade

HR (95%CI)

2.00 (1.24-3.24)

1.27 (1.04-1.55)

2.10 (1.31-3.36)

2.56 (1.09-6.03)

2.54 (1.23-5.24)

2.41 (1.51-3.85)

2.98 (1.15-7.73)

2.16 (0.90-5.17)

1.20 (0.97-1.47)

Stepwise Cox Regression Model

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Meta-Analysis for Stroke

0.8% Thrombectomy vs. 0.5% PCI alone, OR 1.59; 95% CI 1.11-2.27, p=0.01

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Meta-Analysis for Mortality

3.8% Thrombectomy vs. 4.3% PCI alone, OR 0.87; 95% CI 0.76-1.00, p=0.05

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Mortality of Stroke within 180 days

30.8%

3.4%

Months of Follow-up

Cum

ulat

ive

% o

f Dea

th

0

0.05

0.10

0.15

0.20

0.25

0.30

0.35

0 1 2 3 4 5 6

With Stroke

Without Stroke

Hazard ratio, 10.17 (95%CI, 6.70-15.45); P<0.0001)

No. at Risk

With Stroke

Without Stroke

78 62 58 56 54 54 53

9985 9713 9658 9630 9614 9597 9570

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Conclusions• Routine thrombectomy was associated with increased risk of stroke that

was evident within 48 hours

• Increase in primarily ischemic strokes but also hemorrhagic strokes

• Future trials of thrombectomy devices need to carefully collect stroke outcomes (safety) to determine safety and in addition to efficacy