analysis of pump thrombosis in the intermacs database...analysis of pump thrombosis in the intermacs...

Analysis of Pump Thrombosis in the Intermacs Database

Michael Acker William Measey Professor of Surgery

Chief of Division of Cardiovascular Surgery Director of Heart and Vascular Center

University of Pennsylvania Health System

1

Disclosures

• Consultant for Thoratec and Heartware

2

3

• Perceived increase in incidence of HMII pump thrombosis after 2011 by several large VAD centers compared to HMII pivotal trial • FDA/NHLBI request Intermacs to investigate

INTERMACS: HeartMate II Pump Analysis Implants: April 2008 – December 2012, n=6910 Follow-up: Through June 2013

4 Months post implant

Event: Death – with a device in place (censored at transplant and recovery)

% S

urvi

val

Overall Survival

Months post implant % Survival 1 95% 3 91%

6 87% 12 80%

24 69% 36 58% 48 46%

n=6910, deaths=1772

Figure 1




% S

urvi

val

p(overall) =.63

Implant Year n Deaths (with a device in place) 2008 459 139 2009 866 247 2010 1585 522 2011 1845 481 2012 2155 383 Totals 6910 1772

Figure 2

No change in survival by Implant year



Event: Device Exchange (censored at death, transplant and recovery)

% F

reed

om fr

om D

evic

e Ex

chan

ge

Implant Year n Events 2008 459 38 2009 866 60 2010 1585 158 2011 1845 157 2012 2155 148 Totals 6910 561

p(overall) < .0001

Figure 3

Increase in pump exchange per year

7


Main Event Exchanges or deaths due to thrombus

n=382

Device Removal Events n Removed (exchanged) due to a problem 561 Thrombus 288 Elective 94 Emergent 177 Unknown 17 Probable Thrombus 49 Elective 25 Emergent 21 Unknown 3 Infection (Not thrombus) 76 Elective 38 Emergent 11 Unknown 27 Not Thrombus/Unknown Infection 120 Elective 52 Emergent 68 Not Thrombus/Not Infection 28 Unknown 28 Device removed due to recovery 133 Death: Device not functionally normally 98 Thrombus 27 Probable Thrombus 18 Not Thrombus 53 Totals 792

Table 1

% Freedom at Implant Year n Events 6 mos 12 mos 36 mos 2008 459 18 99% 98% 92% 2009 866 23 99% 99% 95% 2010 1585 88 98% 97% 90% 2011 1845 118 96% 94% ---- 2012 2155 135 94% 93% ---- Totals 6910 382



Event: Device Exchange or death due to thrombus* (censored at death, transplant and recovery) %

Fre

edom

from

Dev

ice

Exch

ange

or

dea

th d

ue to

thro

mbu

s

p(overall) < .0001

Increase in pump exchange/death due to thrombus or death from 1% to 6%

*Thrombus events include ‘probable’ thrombus events

Figure 5


Pump Exchanges due to Thrombus: n=337

Exchange Era Elective Emergent Total 2008-2010 9 (24.3%) 28 (75.7%) 37 (100.0%) 2011-2013* 110 (39.3%) 170 (60.7%) 280 (100.0%) Overall p value = .08

* 2013 includes exchanges from 01/01/2013 through 06/30/2013

Table 2


10

Months post Implant

Event: Device exchange or death due to thrombus

% F

reed

om fr

om e

xcha

nge

or d

eath

du

e to

thro

mbu

s

n=6910, events=382

Hazard

Events/Month

Figure 4

Months % Freedom 6 97% 12 95% 24 92% 48 86%



Event: Device Exchange or death due to thrombus* (censored at death, transplant and recovery)

% F

reed

om fr

om D

evic

e Ex

chan

ge

or d

eath

due

to th

rom

bus

p(overall) < .0001

% Freedom by implant year

*Thrombus events include ‘probable’ thrombus events

Figure 6 Events/M

onth

Hazard by implant year

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

Starling RC et al. N Engl J Med 2014;370:33-40

INTERMACS: HeartMate II Pump Analysis Implants: April 2008 – December 2012, n=6910 Follow-up: Through June 2013 Risk Factors for Device Exchange or Death due to Thrombus (Time Zero = 1 Month Post Implant)

Table 4

Risk Factor hazard ratio p-value Implant year (later) 1.46 < .0001 Age (younger) 1.251 < .0001 White race 1.42 .0003 BMI (larger) 1.202 .01 LVEF above 20% 1.44 .003 LDH at 1 month (higher) 3.163 < .0001 1 Hazard ratio denotes the increased risk for a 60 year compared to a 70 year old patient 2 Hazard ratio denotes the increased risk for a 10 unit increase in BMI 3 Hazard ratio denotes the increased risk for an increase in LDH from 500 to 1000 units BMI, body mass index; LVEF, left ventricular ejection fraction; LDH, lactate dehydrogenase

LDH group n Events Missing 4581 223 0-400 1318 52 401-1000 819 66 > 1000 192 41 Totals 6910 382


14

Months post implant

Event: Device Exchange due to Thrombus** (censored at death, transplant and recovery)

% F

reed

om fr

om D

evic

e Ex

chan

ge

or D

eath

due

to T

hrom

bus

p(overall) < .0001

By LDH Groups

** Thrombus events include ‘probable’ thrombus LDH, lactate dehydrogenase

Figure 13




% S

urvi

val

1st device, n=6910, deaths=1604

Exchange due to Thrombus n=337, deaths=80

p(overall) < .0001

Figure 8

Exchange due to Infection/Other n=224, deaths=66

INTERMACS: HeartMate II Pump Analysis Implants: April 2008 – December 2012, n=6910 Follow-up: Through June 2013 Primary Cause of Death within 3 months Table 3

After Pump Exchange or After Primary Implant* death due to Thrombus Primary Cause of Death n % n % Circulatory Failure 217 34.7% 5 33.3% Multisystem Organ Failure 114 18.2% 6 40.0% CNS Event 88 14.1% 2 13.3% Infection 51 8.1% 1 6.7% Respiratory Failure 48 7.7% 1 6.7% Device Malfunction 11 1.8% 0 0.0% * Censored at devices exchange CNS, central nervous system


17

Months post Implant

Event: Time to first Infection

% F

reed

om fr

om In

fect

ion

p = .008

n=6910, events=3206

n=337, events=131

Figure 9


18

Months post Implant

Event: Time to first CVA

% F

reed

om fr

om C

VA

p < .0001

n=6910, events=619

n=337, events=37

Figure 10

CVA, cerebrovascular accident

19

40

7580 80

70 7278

55

75 7580

75

0

10

20

30

40

50

60

70

80

90

100

INTERMACS: HeartMate II Pump Analysis Implants: April 2008 – December 2012, n=6910 Follow-up: Through June 2013 Main Event n=337: Exchanges due to Thrombus

Med

ian

Visu

al A

nalo

g S

cale

(VA

S)

1st Operation (n) 181 119 90 53 36 21 12 5 2 2 2 1 2nd Operation (n) 23 86 72 29 17 6 4 2 1 1 ---- ----

2nd Operation (exchanges due to thrombus)

Median

p value .05 .72 .83 .79 .61 .31 .53 --- ---- ---- ----- -----

Figure 12

1st Operation (prior to exchange)

20

1.9 1.9 1.9 1.91.8 1.8

1.71.8

1.71.8 1.8 1.8

1.91.8

1.92 2 2 2 2

1.3

1.51.4

1.51.4 1.4 1.4 1.4 1.4 1.4 1.4

1.5 1.5 1.5 1.51.6 1.6 1.6 1.65 1.6

2.32.4 2.4

2.32.2 2.2 2.2 2.2

2.12.2 2.2

2.32.4

2.3 2.32.4

2.52.4

2.5 2.5

0

0.5

1

1.5

2

2.5

3

1st operationQ1-25%Q3-75%

INTERMACS: HeartMate II Pump Analysis Implants: April 2008 – December 2012, n=6910 Follow-up: Through June 2013 Median INR – 1month post implant forward

INR

Post Implant Follow-up by Quarter/Year

Figure 14

INR, International normalized ratio

Limitations • Pump Design/Production • Intermacs can not give granular data on

subtle differences/changes in clinical practice/patient selection overtime that may affect outcome – Implantation techniques ie inflow angles – Intensity of anticoagulation; compulsive f/u – heparin bridging; – Pump speed vs AV opening – BP management

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Changes Over Time

• GI bleeding – decrease in anticoagulation goals – Elimination of heparin bridging – Decrease rpms to allow AV opening

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• Pump Design/Production – 2011 changes in outflow graft ; bend relief

software changes – 2011 Marked ramp up in production

Summary

• 6 fold Increase in Pump Exchange or death due to thrombosis in 2011 to 6% from 1% in 2009

• Early Hazard of Pump thrombosis in first 3 months after 2011 not seen prior to 2011

• Overall survival not changed (I yr 80%) BUT if you have a pump exchanged for thrombosis your survival is decrease (1 yr 70%) and your chance of stroke or infection is increased

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Summary

• Risk factors for early Pump thrombosis is predominantly Pt year (2011) and early LDH rise after implant; other risk factors younger age; white; large BMI; LVEF > 20%

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Conclusions (personal not intermacs)

• Most important change post 2011 is not increase rate of thrombosis but new early hazard of thrombosis< 3 months;

– different than late thrombosis – Whatever is happening is happening in the OR or early postop – Importance of HMII inflow cannulae ventricular alignment; bridging heparin – Early LDH rise not seen prior to 2011—causative or result of early thrombus?

• Great variations of incidence of thrombosis between sites ( 1% to >20%)

– Detailed statistical review of different site practices (consortium of high and low incident sites) is needed to determine subtle difference in operative/implantation and pt care practices that may elucidate important risk factors for thrombosis

– Will allow hypothesis generation to validate in prospective study (PREVENT)

• Therapeutic window for HMII is more narrow now than prior to 2011 – Multifactorial etiology- pump; implantation; pump management (anticoagulation,

speed); patient; patient care • ?Anticoagulation goals in high thrombosis incident sites higher now than

prior to 2011 • Importance of pump flow pass the bearing to dissipate heat—rpms > 9000 if

possible

• Continued Thoratec review of manufacturing practices and changes made in pump in 2011

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analysis of pump thrombosis in the intermacs database...analysis of pump thrombosis in the intermacs...

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