Transcript fatal PE - British Hip Society

Myths and facts of modern thromboprophylaxis
without routine use of potent anticoagulation.
Alejandro Gonzalez Della Valle, Stavros G. Memtsoudis,
Nigel E. Sharrock and Eduardo A. Salvati
Hospital for Special Surgery – New York
Presented at the British Hip Society Meeting – Torquay, March 2011
Authors
Alejandro Gonzalez Della Valle, MD (*)
Stavros G. Memtsoudis, MD, PhD (**)
Nigel E. Sharrock, MB, ChB (**)
Eduardo A. Salvati, MD (*)
From the Depertment of Orthopaedic Surgery (*) and the Department of
Anesthesia (**) at Hospital for Special Surgery – Weill Medical College of
Cornell University, New York City.
Correspondence to Alejandro Gonzalez Della Valle, MD. Hospital for Special
Surgery. 535 East 70th Street. New York, NY 10021. Tel: +1 212 774 7124.
Fax: +1 212 774 7505. Email: [email protected]
Conflict of interest: None
Indicates that the data was generated at Hospital for Special Surgery
Indicates that the data was generated by investigators in the UK.
In the unlikely event of a mortality
following elective primary total joint
replacement, the surgeon has a
tendency to believe that the death
was probably caused by a
pulmonary embolism (PE).
Why do we think that way?
Because…
• Orthopaedic surgeons have historically feared
the occurrence of PE and fatal PE
• Have seen PE as a preventable complication
• PE is a “thrombotic phenomenon”, thus the
medical team has been prone to recommend
potent anticoagulation as the only means of
thromboprophylaxis
The choice of thromboprophylaxis is
also affected by external factors
• Litigious medical environment
• Restrictive ACCP guidelines widely adopted
by the internal medicine community
• Intensive marketing campaign by industry
Salvati E, Sharrock N, Gonzalez Della Valle A, et al.
2007 Nicholas Andry Award
Three decades of clinical, basic, and applied research
on thromboembolic disease after THA.
Clin Orthop 2007;459:246-254.
Multimodal approach with selective
use of anticoagulants for elective THR
• Perfected in HSS over the last 30 years
• Clinical and basic research
• Pre-, intra-, and post-operative measures
• SAFE and INEXPENSIVE
• Address all three pillars of Virchow’s Triad
• Surgeons, anesthesiologists, internists, RN, PT
Clin Orthop 2007;459:246-254
Multimodal
thromboprophylaxis
• PRE-operative measures
• INTRA-operative measures
• POST-operative measures
Multimodal thromboprophylaxis
Pre-operative measures
1. Risk stratification to determine personal
and familiar (genetic) risk of VTE
Beksac B, et al. Clin Orthop 2006;453:211-24.
Salvati E, et al. Clin Orthop 2005;441:40-55.
2. Discontinuation of procoagulant meds
Beksac B, et al. Clin Orthop 2006;453:211-24.
3. Autologous blood donation
Bae H, et al. J Bone Joint Surg Br. 2001;83(5):676-9.
Multimodal thromboprophylaxis
Intra-operative measures
1. Hypotensive epidural anesthesia
Sharrock NE, et al. Acta Orthop Scand 1996;67(1):91-107.
2. Intraoperative iv sodium heparin (10-15U/kg)
Sharrock NE, et al. Clin Orthop 1995;319:16-27.
3. Minimization of femoral work time and
concomitant venous stasis
Sharrock NE, et al. J Arthroplasty 2005;20(4):499-502.
4. Expedient surgery
Sharrock NE, et al. Anesth Analg 1993;76(4):765-71.
Multimodal thromboprophylaxis
Post-operative measures
1. Pneumatic compression devices
Westrich G, et al. Clin Orthop 2000;372:180-91.
Ryan M, et al. J Bone Joint Surg Am 2002;84(11):1998-2004.
2. Foot + ankle exercises and prompt
rehabilitation
Markel DC, et al. Clin Orthop 1997;334:168-74.
3. Chemoprophylaxis for 4 to 6 wks
•
•
•
Aspirin for the vast majority of patients who have
no risk factors for VTE (≈87%)
Warfarin in those considered at high risk (≈ 12%)
Rarely: LMWH or VCF (<1%)
What is throboprophylaxis for?
To prevent…
Minor
complications
PPS
DVT
Major
PE
complications
Death
Complications of prophylaxis
The routine use of
potent anticoagulation
to prevent VTE in
elective TJR surgery
would be justified if …
Hypothesis #1
PE and fatal PE
are frequent
complications of
surgery
Hypothesis #2
PE and fatal PE are
preventable with
routine use of potent
anticoagulants
Hypothesis #3
All-cause mortality
is lower with the
routine use of
anticoagulants
Hypothesis #4
The proportion of deaths
due to PE can be lowered
with the routine use of
anticoagulants
Without
anticoagulation
With
anticoagulation
Fatal
PE
Other
deaths
Fatal
PE
Other
deaths
These four hypotheses
may be based on historic
concepts and may not be
true today in patients
undergoing elective joint
replacement surgery
Hypothesis #1
PE and fatal PE are
frequent rare
complications of
elective TJR surgery
PE was the leading cause of death
in the 1960s and 1970s
Fredin et al. Fatal pulmonary embolism after total hip
replacement. Acta Orthop Scand 1982;53(3):407.
•
•
•
•
•
•
90-day mortality
1,324 THRs (1969 – 1978)
Thromboprophylaxis with Dextran
16 deaths (14 autopsies)
9 FATAL PEs (56%) (8 autopsy-proven)
Pneumonia (3); MI (2); CCI (1)
Johnson R, Charnley J, et al. Pulmonary
embolism prophylaxis following Charnley THA.
Clin Orthop 1977;127:123-132
•
•
•
•
•
7959 THRs
1962 – 1973
Symptomatic PE and death
With and without prophylaxis
88% of fatal PEs confirmed by
autopsy
15%
15.2
WITHOUT prophylaxis
PE
Symptomatic
Fatal
10
WITH prophylaxis
7.9
5
2.3
1
0
1960s and 70s
Johnson R, Charnley J, et al.
Pulmonary embolism prophylaxis
following Charnley THA.
Clin Orthop 1977;127:24-30
7959 THR (1962-1973)
The execution of THRs
has substantially
changed since then!
Time
THA in 1960s-1970s
60’-70’
90’-present
Rudimentary
Advanced
General
Regional
Surgical time
>=3h
<1.5h
Bleeding
>=1l
<250cc
Bed rest
Prolonged
No
Minimal
Advanced
Variable
Surgical technique
Anesthesia
Knowledge on VTE
Coventry et al JBJS 1973
Johnson, Charnley CORR 1977
Symptomatic PE
Fatal PE
All-cause mortality
7.8%
1
HSS Data
30-day data
0.5
13X
23 of 5874
TJRs
10 of 9685
TJRs
0.1
Fatal PE
7 of 23
1962 to 1973
R. Johnson
CORR, 1978
90-day data
Fatal PE
2 of 10
No fatal PE
in 1947 pts
20X
1981 to 1985
1994 to 2003
1987 to 1991
Sharrock N, et al.
Gonzalez Della Valle A, et al.
Anesth Analg 1995; 80(2):242-8.
Clin Orthop 2006;443:146-53.
Fatal PE and mortality following TKA/THA
(anticoagulation only used in high-risk patients)
1.4
Fatal PE
Mortality
1.2
1
0.8
34%
anticoag
0.6
0.4
0.2
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19
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19
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0
Given today’s
low prevalence of fatal PE and
mortality when no routine
anticoagulation is used…
…the use of potent
anticoagulants in every patient
seems unjustified.
Hypothesis #2
PE and fatal PE are
not always preventable
with routine use of potent
anticoagulants
Has the frequency of
postoperative VTE and PE
diminished since the use of
routine potent anticoagulation
for prophylaxis?
No evidence suggesting
that this is the case
Howie C, et al. Venous thromboembolism
associated with THR and TKR over a 10-year period.
J Bone Joint Surg [Br] 2005;87(12):1675-1680.
• Scottish Morbidity Record System
• Registrar General’s death records
• 1992 - 2001
– Symptomatic VTE (DVT, PE)
– Fatal PE
– Fatal MI
– Fatal CVE
Howie C, et al. Venous thromboembolism associated
with hip and knee replacement over a 10-year period.
J Bone Joint Surg [Br] 2005;87(12):1675-1680.
25
20
15
10
5
THA
TKA
VTE
No change in VTE or PE despite increased use of heparin by
the members of the British Orthopaedic Association
Fatal PE
0
1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001
Two surveys of the membership of
the British Orthopaedic Association
demonstrated that the use of
anticoagulants among British
orthopaedic surgeons increased
during the study period.
Howie C, et al. Venous thromboembolism associated
with hip and knee replacement over a 10-year period. J
Bone Joint Surg [Br] 2005;87(12):1675-1680.
25
20
15
10
5
0
THA
TKA
Brenkel et al.
Br J Hosp Med (1989)
50% Chemoprophylaxis .
17% Heparin
17%
1989 1990
VTE
Francis et al.
Br J Hosp Med (1997)
84% Chemoprophylaxis
61% LMWH; 11% Heparin
Fatal PE
72%
1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001
Jameson S, et al. The impact of national
guidelines for the prophylaxis of VTE on the
complications of arthroplasty of the lower limb.
J Bone Joint Surg (Br) 2010;92(1):123-9.
• National Joint Registry
• 219,602 patients
• 12 months before and after NICE guidelines
(2007)
• 90-day VTE rate
• Return to OR rate
• HITT
NO CHANGE
INCREASED
Diagnosis of in-hospital
PE and mortality in the US
Memtsoudis S, Gonzalez Della Valle A, et al. Trends in demographics,
complications, and mortality of TKA performed in the United States. A study
of 3,830,420 patients operated between 1990 and 2004.
J of Arthroplasty 2008;24(4):518-527.
González Della Valle A, Memtsoudis SG, et al. Trends in mortality,
complications, and demographics for primary THA in the United States.
2,288,579 patients operated between 1990 and 2004.
Int Orthop 2009,33(3):643-651.
• National Hospital Discharge Survey from the
Center for Disease Control.
• Three periods: (‘90-’94, ’95-’99, ’00-’04)
Events/1000 in-patient days
Trends in in-hospital diagnosis of death
and PE following THA and TKA in US
(1990-2004)
1.4
1.2
1
0.8
PE (TKA)
0.6
PE (THA)
0.4
0.2
0
1990-1994
1995-1999
2000-2004
Events/1000 in-patient days
Trends in in-hospital diagnosis of death
and PE following THA and TKA in US
(1990-2004)
1.4
1.2
1
0.8
0.6
PE (THA)
0.4
0.2
Mortality (THA)
0
1990-1994
1995-1999
2000-2004
Trends in volume, hospital stay and inhospital mortality in US (1995-2004)
20
18
16
14
12
10
8
6
4
2
0
González Della Valle A, Memtsoudis SG, et al. Int Orthop 2009,33(3):643-651.
1.8M
1.2M
4.88
1995-1999
4.18
2000-2004
Trends in volume, hospital stay and inhospital mortality in US (1995-2004)
20
18
16
14
12
10
8
6
4
2
0
González Della Valle A, Memtsoudis SG, et al. Int Orthop 2009,33(3):643-651.
1.8M
1.2M
4.88
0.24%
1995-1999
Mortality (X10)
4.18
0.28%
2000-2004
Trends in volume, hospital stay and inhospital mortality in US (1995-2004)
20
18
16
14
12
10
8
6
4
2
0
González Della Valle A, Memtsoudis SG, et al. Int Orthop 2009,33(3):643-651.
1.8M
1.2M
4.88
0.29%
0.24%
1995-1999
PE (x10)
Mortality (X10)
0.52%
4.18
0.28%
2000-2004
Unpublished data from
National In-Patient Sample (NIS)
(20% of all admissions in the US)
Events/1000 in-patient days
1
2,290,751 TJR patients
1998-2008
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
Mortality
0.1
Pulmonary Embolism
0
1998
1999
2000 2001
2002
2003
2004
2005 2006
2007
2008
Hypothesis #3
All-cause mortality is
higher?
lower with the routine
use of anticoagulats
Sharrock NE, González Della Valle A, Salvati EA, et al.
Potent anticoagulants are associated with a higher all-cause
mortality rate after hip and knee arthroplasty.
Clin Orthop 2008;466:714-72.
Systematic review of
THA and TKA studies
18 publications – 25,000 patients
Goal: assess influence of different
thromboprophylaxis regimens on the rate of:
1. Symptomatic PE
2. All- cause mortality
Why “all-cause mortality”?
• Ultimate goal of prophylaxis: reduce
death for any reason
• Encompasses major benefits and
risks of prophylaxis
• Cause of death is often difficult to
define
Thromboprophylaxis Regimens
1. Potent anticoagulants:
- LMWH
- ximelagatran
- fondaparinux
- rivaroxaban
2. Warfarin
3. Multimodal
Multimodal included
intention to use
• Regional anesthesia
• Pneumatic compression
• Aspirin
• Anticoagulation in selected cases
18 articles identified
# of Articles (*)
Patients
Potent
anticoagulants
10
13380
Warfarin
4
4370
Multimodal
6
7193
All operations performed from 1993 onwards
*2 included warfarin + potent anticoagulation
3 months after surgery
1.2
Non-fatal PE
1
0.019
Mortality
0.008
0.8
% 0.6
0.002
0.4
0.033
0.2
0
PA
W
MM
PA
W
MM
Sharrock NE, et al. Clin Orthop 2008;466:714-72.
Relative risk
RR=1
Symptomatic, non fatal PE
All-cause mortality
(*) indicates statistical significance
W vs PA
MM vs W
*
MM vs PA
*
*
1.5
2
2.5
Sharrock NE, et al. Clin Orthop 2008;466:714-72.
Possible explanations
• Multimodal in high-volume centers
• Regional anesthesia may confer
additional benefit
• Potent anticoagulants: life threatening
side effects (major bleeding, HITT) 
increase all-cause mortality
Sharrock NE, González Della Valle A, Salvati E, et al.
Clin Orthop 2008;466:714-72.
Conclusions
• Routine use of potent anticoagulants
do not prevent symptomatic PE
• Potent anticoagulants appear to result
in higher all-cause mortality
• Multimodal appears to be a safer,
more efficacious prophylaxis
Hypothesis #4
The proportion of deaths due
low
cannot
to PE is high and can be
lowered with the routine use
of anticoagulants
Memtsoudis S, Gonzalez Della Valle A, Salvati E,
Sharrock N, et al. Meta-analysis of cause of death
following elective total joint replacement utilizing
different thromboprophylaxis regimens
AAOS Meeting 2011.
• What are the most frequent causes of
death following surgery (90 days)
TODAY?
• Is cause distribution (% of deaths due to
PE) affected by CURRENT
thromboprophylaxis protocols?
Meta-analysis of last 15 years
• Pubmed, EMBASE and Cochrane databases
• Studies published between 1995 to 2009
• Surgeries performed after 1990
• Represent modern surgical, anaesthetic
techniques, and perioperative care
• Time frame coincides with the introduction of
LMWH to clinical practice
437 abstracts
106 full papers
70 publications included
99,441 patients – 373 deaths
7 thromboprophylaxis regimens
compared for outcomes
Prophylaxis regimens analyzed
1. No routine pharmacologic prophylaxis
2. Aspirin (1 paper only → regimen was excluded)
3. Multimodal (regional + PCD + aspirin)
4. Warfarin
5. Warfarin combined (regional and/or PCD)
6. Potent anticoagulants
7. Potent anticoagulants combined (regional
and/or PCD)
Cause of death
• Autopsy proven
• Likely cause
• Unknown
– Not mentioned
– “unrelated to PE”
– “sudden death”
Mortality rates
0.01
(pooled proportions and 95%CI -
:SS)
0.009
0.008
0.007
0.006
0.59%
0.0059
0.52%
0.0052
0.005
0.004
0.4%
0.004
0.38%
0.0038
0.38%
0.0038
0.003
0.2%
0.002
0.002
0.2%
0.002
0.001
0
Combined
NRT
PA
PAC
W
WC
MM
Memtsoudis S, et al. AAOS Meeting 2011.
Highest proportion of autopsy proven
deaths in the NRT and MM groups!
70%
60%
50%
40%
30%
20%
10%
0%
Combined
NRT
PA
AUTOPSY
PAC
LIKELY
W
WC
MM
UNKNOWN
Memtsoudis S, et al. AAOS Meeting 2011.
Cause of death (pooled proportions)
NOT AFFECTED BY PROPHYLAXIS
1 every 4 deaths may be due to PE
n=146
n=54
n=20
n=7
n=16
n=17
Memtsoudis S, et al. AAOS Meeting 2011.
Mortality for known or suspected PE is no
different with the use of potent anticoagulation
0.7
Potent anticoagulant groups
n=0
n=16
0.6
0.5
n=27
n=1
n=6
0.4
n=59
n=9
0.3
pooled pr
0.3545
95% CI-LB
0.3008
95%CI-UB
0.257
0.2321
0.2
0.1634
0.1464
0.1464
0.1
0
Combined
NRT
PA
PAC
W
WC
MM
Memtsoudis S, et al. AAOS Meeting 2011.
Autopsy proven deaths: 64
CP leading cause of mortality
30
27
25
23
20
17
15
10
7
6
5
5
2
0
CP
PE
Bleeding
GI
CNS
Other
PE +
Bleeding
Autopsy proven deaths in the
cardiopulmonary group
Arrhythmia Fat embolism
4%
4%
Cardiac failure
4%
Pulmonary
oedema
4%
Pneumonia
3%
Aspiration
asphyxia
4%
MI
77%
Memtsoudis S, et al. AAOS Meeting 2011.
Murray D, et al. Thromboprophylaxis and
death after total hip replacement.
J Bone Joint Surg [Br] 1996;78(6):863-70
• Meta-analysis of prophylaxis after THA surgery
• 1970s to 1990s (130,000 pts)
• Fatal PE rate: 0.1% - 0.2%
• Mortality rate: 0.3% - 0.4%
• Not enough evidence in the literature to determine if
pharmacologic thromboprophylaxis decreases the
death rate after THA
Shepard M, et al. Fatal pulmonary embolism
following THA and TKA. A study of 2153 cases using
routine mechanical prophylaxis and selective
chemoprophylaxis. Hip Int. 2006;16:53-56.
• 2153 TKAs and THAs
• 8 autopsy-proven deaths
–5 due to ischemic heart disease
Pedersen et al. Short- and long-term mortality
following primary total hip replacement for OA.
JBJS Br 2011;93(2):172-7.
90-day - Danish Hip Arthroplasty Registry (209 pts)
44,558 patients operated on between 1995-2006
21
10
10
10
MI
CHF
PE
Stroke
Pneumonia
UGIB
Cancer
Other
Theoretical benefits of aspirin
•
•
•
•
•
•
•
Acceptable safety profile
Inexpensive
Requires no injections or monitoring
Pain relief
Anti-inflammatory
Prevention of HO
Prevention of acute CAD events
0.75
0.5
1727 pt
17 deaths
9 autopsies
90-day
mortality rate (%)
Bloom A, Bannister G, et al.
Early death following primary
THA. Acta Orthopaedica
2006;77(3):347-50.
1
Parry M, Bloom A, et al.
90-day mortality after elective
THR. J Bone Joint Surg Br
2008;90(3):306-7.
1549 pt
No deaths
0.25
7 MI
0
1993-1996
2003-2006
Mechanical but no
pharmacologic prophylaxis
Mechanical and
aspirin prophylaxis
Concerns with ACCP Guidelines
1
Rely on a reduction in the
asymptomatic DVT rate to
justify the systematic use
of potent anticoagulation
… relegating major bleeding, re-operation, fatal
PE, fatal bleeding and all-cause mortality.
DVT may be the incorrect surrogate
to study the safety and efficacy of
thromboprophylaxis
Dahl O, et al. Risk of clinical PE after joint
surgery in patients receiving LMWH prophylaxis.
Acta Orthopaedica 2003;74(3):299-309.
• 3,954 patients (THR, TKR, NHF)
• LMWH during hospital stay
• 50 PE was confirmed
• Only 6 of 50 pts (12%) had a DVT
Concerns with ACCP Guidelines
2
Authors of clinical
guidelines and supporting
studies may have conflict
of interest with the
pharmaceutical industry
Choudhry N, et al. Relationships between authors of
clinical practice guidelines and the pharmaceutical
industry. JAMA 2002;287;5:612-617.
Sharrock N, Salvati E, Gonzalez Della Valle A,
et al. Response to letter to the Editor.
Clin Orthop 2008;466(8):2012–2014.
Clayton R, Howie C, et al. Letter to the Editor.
J Bone Joint Surg (Br) 2008;90(11):468.
Dean B. Thromboembolic propaganda.
J Bone Joint Surg (Br) 2010;92:123-129.
Concerns with ACCP Guidelines
3
Validity of ACCP
guidelines
methodology has
been recently
questioned
Brown G. Award paper by AAHKS. VTE prophylaxis
afetr major orthopaedic surgery. A pooled analysis of
RCT. J of Arthroplasty 2009;24(6 suppl):77-83.
• Pooled analysis of 14 RCT cited by ACCP
• Pentasaccharides, LMWH, warfarin, aspirin and
placebo
• Rates of symptomatic VTE, fatal PE and bleeding.
• Symptomatic VTE
• Fatal PE
• Bleeding
NO DIFFERENCE
HIGHER WITH LMWH
Concerns with ACCP Guidelines
4
Safety and efficacy
concerns are
proliferating in the
orthopaedic literature
… persistent wound drainage, hematoma
formation, neurological injury, reoperation,
infection, and fatal bleeding.
Jensen C, et al. Return to theatre following THR
and TKR, before and after the introduction of
rivaroxaban. J Bone Joint Surg Br 2011;93(1):91-5.
• 30-day reoperation rate for wound-related
problems
• 489 patients on tinzaparin
• 599 patients on rivaroxaban
• Similar demographics and co-morbidities
Jensen C, et al. Return to theatre following total hip and
knee replacement, before and after the introduction of
rivaroxaban. J Bone Joint Surg Br 2011;93(1):91-5.
4
3.5
3
2.5
2
22 patients
14 (+) cultures
2 revisions
9 patients
5 (+) cultures
1 revision
1.5
1
0.5
0
Tinzaparin
Re-operation
Rivaroxaban
Deep infection
PE
Rate of sciatic palsy (%)
Butt A, McCoy G, et al. Sciatic nerve palsy
secondary to hematoma formation in primary
THR. J Bone Joint Surg (Br) 2005;87(11)1465-7.
1.8
1.6
1.4
1.2
1
0.8
0.6
0.4
0.2
0
1-year
experience
6/355 patients
Tinzaparin/enoxaparin
3 delayed diagnosis had
no or incomplete recovery
10-year
experience
Pre-LMWH
LMWH
Routine potent anticoagulation as
a sole means of thromboprophylaxis
• Increases bleeding risks
• Local complications of surgery
– Hematoma formation – neurological injury
– Superficial and deep infection
– Reoperation
• May not diminish VTE risk or mortality
• INCREASE THE COST OF CARE
Conclusions
• Patients die rarely after elective TJR surgery
despite adequate thromboprophylaxis.
• The majority of fatalities are unrelated to PE.
• Fatal PE rates are not improved by the use of
potent anticoagulation in every case.
• Symptomatic PE and fatal PE should not be
regarded as a fully preventable complication
Conclusions
Routine postoperative potent anticoagulation of
patients undergoing elective TJR surgery
• …does not diminish mortality or fatal PE
• …may promote major bleeding, wound
complications and increase re-operation rate
• …should not be the regarded as the gold
standard for thromboprophylaxis
Future efforts should focus on:
1. Risk stratification for rational
utilization of prophylactic drugs
and resources
2. Prevention of mortality for any
cause