Nader Moazami, MD

Department of Thoracic and Cardiovascular Surgery and Biomedical Engineering, Cleveland Clinic, OH

HeartMate II Pump Thrombosis

From Bedside Observation….From Bedside Observation….From Bedside Observation….From Bedside Observation….

• How it beganHow it began

• What evolvedWhat evolved

• What is the dataWhat is the data

• What was our responsibilityWhat was our responsibility

• What comes nextWhat comes next

Initial Cleveland Clinic Awareness to Action

Mid-2011• Concern about possible increasing incidence

of pump thrombosis• Formation of a “Thrombosis” group lead by

Thoratec• Last meeting of this group in Atlanta

(2/15/2013) several implanting institutions report similar concern

2/22/2013• Chair requests thorough investigation of CCF

experience

Definition

Confirmed• Thrombus within blood contacting

surfaces of device inflow cannulae or outflow conduit or grafts

Suspected• Suggestive pump-related malfunction

• Hemolysis,Unexplained “heart” failure, Abnormal pump parameters

• All cases with anatomic reason excluded

Pump Thrombosis

8 Confirmed

16 Suspected

Timing• 8 before 4th quarter 2011

5 months to 3.4 years post-implant

• 16 since then10 within 3 months post-implant

Question

Is there a relation between risk of pump thrombosis and date of implant?

Confounding factors• Surgeons

• Anticoagulation protocol

Parallel Approach

Random Survival Forest• Non-parametric assumption-free

method

• Machine learning

Temporal Decomposition Model• Parametric

• Machine learning

Free of Thrombosis at 3 Mo.

%%

HeartMate II Implant DateHeartMate II Implant Date

20

40

60

80

100

0 6 12 18 24 30 36 42

Free of Thrombosis

%%

Months after HeartMate II ImplantMonths after HeartMate II Implant

10/04 – 09/11

09/11– 02/13

10

20

30

40

0 6 12 18 24 30 36 42

Risk of Pump Thrombosis

%/y%/y

Months after HeartMate II ImplantMonths after HeartMate II Implant

LDH

mg/dLmg/dL

Months after ImplantMonths after Implant

Before 9/11

Since 9/11Thrombosis

AC:21,122 measurements, 296 devices21,122 measurements, 296 devices

INRINR

Months after ImplantMonths after Implant

Before 9/11

Since 9/11Thrombosis

Single Center Data submitted for Publication May 2013

Single Center Data submitted for Publication May 2013

• The principal shortcoming of your study is that it is based on the experience of a The principal shortcoming of your study is that it is based on the experience of a single centersingle center. . All of the reviewers of your manuscript All of the reviewers of your manuscript

raised this issue in their comments to the editors. In order to publish your work, we will need solid raised this issue in their comments to the editors. In order to publish your work, we will need solid confirmation of your confirmation of your findings from the experience of other centers, registries, or data basesfindings from the experience of other centers, registries, or data bases. . There is concern that center-specific characteristics or practices at Cleveland Clinic may be at play, and it is essential that your study include a There is concern that center-specific characteristics or practices at Cleveland Clinic may be at play, and it is essential that your study include a much broader dataset in order to provide confirmation/validation of the findings at your center. The editors believe that your findings are much broader dataset in order to provide confirmation/validation of the findings at your center. The editors believe that your findings are

interesting and potentially quite important. With that said, we interesting and potentially quite important. With that said, we do not want to take a chance on do not want to take a chance on misleading the medical community without convincing validation of your misleading the medical community without convincing validation of your findingsfindings. .

• In order to publish your work, we will need solid confirmation of your findings from the In order to publish your work, we will need solid confirmation of your findings from the experience of other centers, experience of other centers, registries, or data basesregistries, or data bases. . There is concern that center-specific characteristics or practices at Cleveland Clinic may be There is concern that center-specific characteristics or practices at Cleveland Clinic may be

at play, and it is essential that your study include a much broader dataset in order to provide confirmation/validation of the findings at your at play, and it is essential that your study include a much broader dataset in order to provide confirmation/validation of the findings at your

centercenter. .

• Statistical Reviewer Statistical Reviewer Comments for the Author: Comments for the Author:

This paper reports a dramatic and alarming increase in Heartmate II pump thrombosis after September, 2011 at the Cleveland Clinic. This paper reports a dramatic and alarming increase in Heartmate II pump thrombosis after September, 2011 at the Cleveland Clinic. This This is important information that should be shared widely. is important information that should be shared widely.

CDWP Cooperative ConsortiumCDWP Cooperative Consortium

CDWP Cooperative ConsortiumCDWP Cooperative Consortium

• Centers combined data of all HM II device Centers combined data of all HM II device implants and reported CONFIRMED PUMP implants and reported CONFIRMED PUMP THROMBOSISTHROMBOSIS- CCF10/2004 – 2/2013 CCF10/2004 – 2/2013 3/5/2013*3/5/2013* n=296 n=296- Duke 5/2005 – 5/2013 Duke 5/2005 – 5/2013 5/16/20135/16/2013 n=292 n=292- Wash U 1/2004 – 4/2013 Wash U 1/2004 – 4/2013 9/10/20139/10/2013 n=307 n=307- Penn 11/2005 – Penn 11/2005 – 10/17/201310/17/2013 n=163 n=163

- 1058 Devices from 4 centers1058 Devices from 4 centers- *Non-uniform closing dates*Non-uniform closing dates

Occurrence and Incidence of Confirmed Pump Thrombosis Stratified According to Implantation Date.

Starling RC et al. N Engl J Med 2013. DOI: 10.1056/NEJMoa1313385

CONFIRMED Pump Thrombosis at 3 Months after HeartMate II Implantation.

Starling RC et al. N Engl J Med 2013. DOI: 10.1056/NEJMoa1313385

Overall Occurrence of CONFIRMED Pump Thrombosis after HeartMate II Implantation.

Starling RC et al. N Engl J Med 2013. DOI: 10.1056/NEJMoa1313385

7.5%4.7% 12.3%

Percentage of Devices with Confirmed Pump Thrombosis at 3 Months after HeartMate II Implantation.

Rame JE et al. N Engl J Med 2014;370:1466-1467.

Penn

4 centers

Mortality According to Management Strategy after Confirmed Pump Thrombosis.

Starling RC et al. N Engl J Med 2013. DOI: 10.1056/NEJMoa1313385

Elevated Lactate Dehydrogenase (LDH) Levels within 3 Months after HeartMate II Implantation.

Starling RC et al. N Engl J Med 2013. DOI: 10.1056/NEJMoa1313385

INTERMACS Registry Analysis Pump ThrombosisLDH

Kirklin J. JHLT 2013

66% missing LDH

8.2% Events (192/2329)

21.4% Events LDH >1000(41/192)

Early HM 2 Pump Thrombosis has Early HM 2 Pump Thrombosis has Increased. Why?Increased. Why?

Early HM 2 Pump Thrombosis has Early HM 2 Pump Thrombosis has Increased. Why?Increased. Why?

• Four Four EXPERIENCED EXPERIENCED centers with consistent centers with consistent observations-not only isolated to these 4 centersobservations-not only isolated to these 4 centers- Are patients different?Is reporting different? Is Are patients different?Is reporting different? Is

management different?management different?• Is the device different? Is the device different?

- >17,000 implants worldwide (50-100/wk)>17,000 implants worldwide (50-100/wk)- Pump thrombosis seen with previous mechanical Pump thrombosis seen with previous mechanical

pivot-based bearing devicespivot-based bearing devices- Pathological reports show 60-70% laminated Pathological reports show 60-70% laminated

thrombus at inlet (front-loaded) bearingthrombus at inlet (front-loaded) bearing- Do some pumps have a lower tolerance to sub Do some pumps have a lower tolerance to sub

therapeutic anticoagulation, INR<2?therapeutic anticoagulation, INR<2?

PUMP POWER ELEVATIONPUMP POWER ELEVATIONPUMP POWER ELEVATIONPUMP POWER ELEVATION

1.3 1.47 1.64 1.81 1.98 2.15 2.32 2.49 2.66 2.83 34

6

8

10

12

Days Post ImplantP

ow

er

(W)

4.6 5.02 5.44 5.86 6.28 6.7 7.12 7.54 7.96 8.38 8.84

6

8

10

12

Days Post Implant

Po

we

r (W

)

Group 1

Group 2

Group 3

1.4 1.91 2.42 2.93 3.44 3.95 4.46 4.97 5.48 5.99 6.54

6

8

10

12

Days Post Implant

Po

we

r (W

)N=9

N=8

N=2

What is Next For Us?What is Next For Us?What is Next For Us?What is Next For Us?• Collaborative data collection: Cleveland Clinic, Wash Collaborative data collection: Cleveland Clinic, Wash

Univ, Duke, Penn, ColumbiaUniv, Duke, Penn, Columbia• All HM II implants through Dec 31, 2013All HM II implants through Dec 31, 2013• 90 Days follow up: common closing date March 31, 90 Days follow up: common closing date March 31,

20142014• Thoratec invited to collaborate to provide all device Thoratec invited to collaborate to provide all device

related variablerelated variable• Extensive patient level variables from INTERMACS and Extensive patient level variables from INTERMACS and

site data collectionsite data collection• Pump measurements via xrays Pump measurements via xrays • Data analysis team led by Eugene Blackstone MDData analysis team led by Eugene Blackstone MD• IRB approvals in progressIRB approvals in progress