Impella Technology Elective Support Clinical Evidence and Investigations.

Impella Technology

Elective Support

Clinical Evidence and Investigations

PROTECT II

O’Neill et al, Circulation. 2012;126(14):1717-27

PROTECT II Trial Design

IMPELLA 2.5 +PCI

IABP + PCI

Primary Endpoint = 30-day Composite MAE* rate

1:1R

Patients Requiring Prophylactic Hemodynamic Support During Non-Emergent High Risk PCI on

Unprotected LM/Last Patent Conduit and LVEF≤35% OR 3 Vessel Disease and LVEF≤30%

Follow-up of the Composite MAE* rate at 90 days

*Major Adverse Events (MAE) : Death, MI (>3xULN CK-MB or Troponin) , Stroke/TIA, Repeat Revasc, Cardiac or Vascular Operation or Vasc. Operation for limb ischemia, Acute Renal Dysfunction, Increase in Aortic insufficiency, Severe Hypotension, CPR/VT, Angio Failure


4

Baseline Patient CharacteristicsPatient Characteristics IABP

(N=223)Impella

(N=225)p-value

Age 67±11 68±11 0.488

Gender-Male 81.2% 80.0% 0.668

History of CHF 83.4% 91.1% 0.014

Current NYHA (Class III / IV) 64.6% 67.0% 0.632

Diabetes Mellitus 50.7% 52.0% 0.779

Renal insufficiency 30.2% 23.1% 0.091

Peripheral Vascular Disease 26.5% 25.7% 0.851

Implantable Cardiac Defib. 31.1% 34.7% 0.420

Prior CABG 28.7% 38.2% 0.033

LVEF 24.1±6.3% 23.4±6.3% 0.244

STS Mortality score 6±7% 6±6% 0.809

Not Surgical Candidate 64.6% 63.6% 0.822

SYNTAX score 29.3±13.5 30.3±13.1 0.514


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Series1

Hemodynamic Support Effectiveness

Cardiac Power Output

Maximal Decrease in CPO on device Support from Baseline (in x0.01 Watts)

IABP Impella

N=138 N=141

- 4.2 ± 24

- 14.2 ± 27

p=0.001


Procedural Characteristics

Procedural Characteristics IABP(N=223)

Impella(N=225)

p-value

Use of Heparin 83.3% 93.3% <0.001IIb/IIIa Inhibitors 26.0% 13.8% 0.001Total Contrast Media (cc) 241±114 267±142 0.036

Rotational Atherectomy (RA) 9.0% 14.2% 0.083 Median # of RA Passes/lesion (IQ range) 1 (1-2) 3 (2-5) 0.001 Median # of RA passes/pt (IQ range) 2.0 (2.0-4.0) 5.0 (3.5-9.5) 0.003 Median RA time/lesion (IQ range sec) 40 (20-47) 60 (40-118) 0.004 RA of Left Main Artery 3.1% 8.0% 0.024

Total Support Time (hours) 8.4±21.8 1.9±2.7 <0.001Discharge from Cath Lab on device 36.7% 5.9% <0.001


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LVEF and NYHA Improvement Post PCI

LVEF (%)

p<0.001

Baseline 90 days

22%


Baseline 90 daysNYHA Class Distribution

p<0.001

Class I

Class II

Class III

Class IV 58%reduction

in Class III,IV

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PROTECT II: Per Protocol MAE (N=427)

IABP

IMPELLA

30 day MAE 90 day MAE

42.2%

51.0%

34.3%

40.0%

p=0.092

N=216N=211

p=0.023

N=215N=210

21 (12/9) Patients Excluded to Due Not Meeting Inclusion/Exclusion Criteria Prior to Analysis

4 LVEF > 35% 3 Active MI4 No Left Main or 3 V CAD10 Other ExclusionsLog rank test, p=0.048

IABP

IMPELLA


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Pre-Specified Analyses

90 day MAE Relative Risk [95% CI]

Relative Risk [95% CI]

Groupp-value

Interactionp-value

0.79 [0.64, 0.97] 0.023

0.70 [0.55, 0.89] 0.003

1.19 [0.75, 1.91] 0.444

0.82 [0.53, 1.25] 0.3510.78 [0.61, 0.99] 0.039

1.14 [0.75, 1.71] 0.540

0.71 [0.56, 0.91] 0.006

0.92 [0.62, 1.38] 0.697

0.74 [0.58, 0.95] 0.016

Pre-Specified Sub-group Analysis (PP)

With Atherectomy (n=52)

Without Atherectomy (n=373)

STS ≥ 10 (n=71)

STS < 10 (n=354)

1st Impella/IABP Pt per site (n=116)

After 1st Impella/IABP Pt (n=309)

ULM / Last conduit (n=101)

3VD (n=324)

Anatomy

PCI Procedure

STS Mortality Score

Roll in subject

Overall – Per Protocol (n=425)

Impella better IABP better0.0 0.5 1.0 1.5 2.0

0.087

0.845

0.092

0.348

PP= Per Protocol


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O’Neill et al. - Summary

•The use of Impella during high risk PCI was safe and provided better hemodynamic support compared to IABP

•The outcomes in the Impella arm demonstrated a trend towards a reduction of Major Adverse Events (MAE) at 30 days and a significant reduction of the MAE rate at 90 day follow-up in the per protocol population.

• Additional upcoming evidence should provide more insight on the potential benefit of Impella

Dangas et al, Am. Journ of Cardiol. 2014 Jan 15;113(2):222-8

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Background

1 Moussa et al. JACC 2013; 2 Ioannidis et al, JACC, 2003;

3 Kini et al, JACC, 1999; 4 Stone et al, Circulation, 2001

• The significance of the clinical importance of small elevations of markers of myocardial injury post-PCI is subject of debate

• Despite an overall statistical association, it has been recognized that small to medium level elevation has a benign clinical course2,3

• A prognostic relationship with subsequent mortality exists when new Q-wave infarction or a CK-MB elevation above eight times the upper normal value are detected4

• We therefore investigated the performance of the Impella 2.5 vs the IABP in the PROTECT-II trial using prognostically important outcomes (periprocedural MI CKMB rise >8x ULN)

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PROTECT II MACCE*

Log rank test, p=0.042

*Death, Stroke, Myocardial Infarction, Repeat revascularization

IABP

IMPELLA


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PROTECT II ResultsPer-Protocol Treated

PopulationIntention-To-Treat

population

Impella 2.5

(n=216)

IABP(n=211)

P-value

Impella 2.5

(n=224)

IABP (n=219)

P-value

30-day event rates

Major Adverse Events (MAE) 30% 40% 0.04 31% 38% 0.11

Major Adverse Cardiac and Cerebrovascular Events (MACCE)

14% 20% 0.10 15% 19% 0.23

Myocardial Infarction 5.6% 7.1% 0.51 5.8% 6.8% 0.67

90-day event rates

Major Adverse Events (MAE) 37% 49% 0.01 37% 47% 0.03

Major Adverse Cardiac and Cerebrovascular Events (MACCE)

22% 31% 0.03 22% 30% 0.06

Myocardial Infarction 5.6% 11% 0.04 5.8% 10.5% 0.07


16Multivariate analysispredictors of MAE and MACCE at 90 days

Odds Ratio Estimate

95% confidence interval P-Value

MAE

Intention-To-treat Population

Use of atherectomy during PCI 1.41 1.03 – 1.92 0.03

Renal Insufficiency 1.4 1.11 – 1.76 0.005

Device: IMPELLA 0.79 0.64 - 0.96 0.02

Per-Protocol Population

Use of atherectomy during PCI 1.41 1.03 - 1.93 0.03

Renal Insufficiency 1.37 1.08-1.74 0.01

Device: IMPELLA 0.75 0.61 - 0.92 0.007

MACCE

Intention-To-treat Population

Device: IMPELLA 0.77 0.61 - 0.96 0.02

Per-Protocol Population

Device: IMPELLA 0.8 0.64 - 0.99 0.042


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Dangas et al. - Summary

• Hemodynamic support with Impella in comparison to IABP during high risk PCI in the PROTECT-II trial resulted in improved event-free survival at 3-month follow-up

• This finding was further supported by multivariate analyses


Cohen et al, Catheter Cardiovasc Interv. 2013 (In press)

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PROTECT II MAE OutcomePre-specified High Risk PCI Without Atherectomy Group

MAE= Major Adverse Event Rate

41.9%

50.1%

29.3%

35.5%

30 day MAE 90 day MAE

↓ 30% MAE

p=0.003

N=183N=190

p=0.01

N=184N=191

↓ 30% MAE

IMPELLA

IABP

Log rank test, p=0.005

Per Protocol (N=374)


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Cohen et al. - Summary

• Operators tended to use RA to a larger extent in patients supported with Impella in comparison with IABP

• Accompanying this differential RA use we observed less frequent repeat revascularization counterbalanced by a higher frequency of cardiac enzyme elevation >3x ULN in Impella-treated patients

• Although our results suggest that a more aggressive RA use in patients treated with Impella is not associated with less favorable outcomes and potentially reduces the repeat revascularization rate in comparison with IABP


Henriques et al, Am Heart J. 2013

PROTECT II

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51.9% 50.8% 50.8%

45.8%

35.9% 36.8%

2008 2009 2010MAE= Major Adverse Event Rate

N=83N=81 N=64N=63 N=68N=65

IABP

IMPELLA

Study Device Learning Curve EffectPer Protocol Population 90day Outcome


Study Device Learning Curve Effect


First patientRemaining patients

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Henriques et al. - Summary

• Significantly lower 90-day rates of MAE were observed with use of the Impella 2.5 compared to the IABP after exclusion of the first patient at each site

• This prespecified analysis is suggestive of a learning curve associated with use of the Impella 2.5 during its initial introductory period affecting the outcome of the study

• This finding likely applies to other new medical devices. Clinical trials should therefore specifically address the training aspect of new devices


Impella Technology Elective Support Clinical Evidence and Investigations.

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