Transcript Journal Club RECORD 1 Trial

Regulation of Coagulation in Orthopedic
Surgery to Prevent Deep Venous
Thrombosis and Pulmonary Embolism 1
(RECORD 1 )
Journal Club
General Surgery Rotation
Background

Prophylactic anticoagulation: standard practice
after total hip arthroplasty (THA)

Minimum recommended duration = 10 days
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Extended prophylaxis x 5 wks (↓ symptomatic &
asymptomatic VTE) > short-term prophylaxis
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DVT incidence without primary
thromboprophylaxis: ~50% of patients
undergoing THR
If DVT present, fatal PE incidence: 0.1-2.0%
Background

Rivaroxaban(R): Oral direct inhibitor of
factor Xa
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F=80%

Peak: 2.5-4 hours

Dose finding studies: 10 mg OD suitable
for phase 3 trials
Inclusion Criteria
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> 18 years
Scheduled to undergo elective total
hip arthroplasty
Exclusion Criteria
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Scheduled to undergo staged, bilateral hip
arthroplasty
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Pregnant or breastfeeding
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Active bleeding
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At high risk of bleeding

CI for prophylaxis with enoxaparin or a
condition that might require an adjusted dose of
enoxaparin
Exclusion Criteria
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Conditions preventing bilateral venography
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Substantial liver disease

Severe renal impairment (CrCl < 30 ml/min)
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Concomitant use of protease inhibitors

Planned intermittent pneumatic compression

Requirement for anticoagulation that could not be
stopped
Baseline Characteristics
Baseline Characteristics
Study Design
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Randomized, multinational, double-blind
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R started 6-8 hrs after wound closure
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Enoxaparin (E) 12 hrs before surgery, restarted 6-8 hrs
after wound closure
Mandatory bilateral venography the day after the last
dose of the study drug (day 36)
Follow-up visit 30-35 days after the last dose of the
study drug
Study Design

Sample calculation based on:

Assumed rate of 8% for 1° efficacy outcome

Noninferiority threshold of 3.5%


1562 patients/ group sufficient to show
noninferiority with a power of 95% and type 1
error = 2.5%
Per-protocol population of R for 1° efficacy
outcome
R = 1537, E = 1492
Outcome Measures


1° Efficacy Outcome: Composite of any
DVT, non-fatal PE or death from any
cause up at 36 days
2 ° Efficacy Outcome: Major VTE

Composite of proximal DVT, nonfatal PE or
death from VTE
Safety Outcome Measures

Major bleeding after first dose & up to 2 days after the last
dose
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Major bleeding

Fatal bleeding, occurred in a critical organ (e.g.
retroperitoneal, intracranial, intraocular, intraspinal)

Required reoperation

Clinically overt extrasurgical-site bleeding & associated
with a fall in Hgb of at least 2 g/dL or requiring blood
transfusion of >2 units of PRBC or whole blood
Hypothesis


Null hypothesis: R inferior to E in per-protocol
population
If non-inferiority: Superiority analysis (mITT)



Absolute margin = 3.5% for 1° efficacy outcome
1.5% for major VTE
mITT= Planned surgery done, study drug taken,
adequate assessment for thromboembolism
Results: Per-protocol Population
Outcome
Rivaroxaban
Enoxaparin
ARR
1 efficacy
outcome
13/1537
0.8%
50/1492
3.4%
2.5% (1.5-3.6)
Major
VTE
2/1622
0.1%
29/1604
1.8%
1.7%(1.0-2.4)
Results: Incidence of efficacy events
(Modified ITT)
Outcome
Rivaroxaban
Enoxaparin
ARR
P Value
1 efficacy
outcome
18/1595
1.1%(0.7-1.8)
58/1558
3.7(2.8-4.8)
-2.6 (-3.7 to 1.5)
<0.001
Major VTE
4/1686
0.2%(0.1-0.6)
33/1678
2.0(1.4-2.8)
-1.7(-2.5 to 1.0)
<0.001
Death
during ontx
4/1595
0.3%(0.1-0.6)
4/1558
0.3(0.1-0.7)
0.0 (-0.4 to
0.4)
1.00
1/1558
0.1(<0.1 to
0.4)
0.2(-0.1 to 06.) 0.37
Nonfatal PE 4/1595
0.3%(0.1-0.6)
Results: Symptomatic VTE Incidence
Results: Safety Outcome
Event
Rivaroxaban
(N=2209)
Enoxaparin
(N=2224)
P
Value
Any on-treatment
bleeding
133 (6.0)
131 (5.9)
0.94
Major bleeding
6 (0.3)
2(0.1)
0.18
Non-major
bleeding
128 (5.8)
129(5.8)
Study withdrawal
due to adverse
effect
85 (3.8)
100 (4.5)
Results: Safety
Investigators’ Conclusion

Rivaroxaban 10 mg OD > for
extended thromboprophylaxis than
SC Enoxaparin 40 mg OD
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Similar number of adverse events
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Similar safety profiles
CASP RCT Checklist
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


Did the study ask a clearly focused question?
Yes
Was this a randomized controlled trial (RCT)
and was it appropriately so? Yes
Were participants appropriately allocated to
intervention and control groups? Yes
Were participants, staff and study personnel
‘blind’ to participants’ study group? Yes
CASP RCT Checklist




Were all of the participants who entered the trial
accounted for at its conclusion? Yes
Were the participants in all groups followed up and data
collected in the same way? Yes
Did the study have enough participants to minimize the
play of chance? Yes
How are the results presented and what is the main
result? Extended thromboprophylaxis with R: very
low incidence of thrombosis vs. E with a safety
profile similar to that of E
CASP RCT Checklist


How precise are these results?
 Definitions of bleed are different amongst
different trials
 8% outcome expected; found: 3.7% and
1.1%
Were all important outcomes considered so the
results can be applied? Yes except surgical site
bleeding not considered as major bleeding
Limitations
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No details regarding allocation
concealment
Generalizability of results limited, low #
of patients




with a previous hx of VTE
>than 75 y
at extremities of weight
Planned THR patients included but not
fracture or trauma patients
Limitations


Patients with severe renal, hepatic failure
or at high risk of bleeding excluded
Clinically important outcomes not
assessed:




Post-DVT complications (post thrombotic
syndrome)
length of hospital stay
health related QoL
surgical outcomes (infection, wound healing,
drainage, range of motion, chronic pain)
Limitations




Surgical site bleeding excluded from major bleeding
events
Clinical importance of asymptomatic DVTs as a
surrogate measure of symptomatic events not fully
elucidated
Low incidence of symptomatic VTE, death & major
bleeding events: interpret with caution
 Not powered to investigate differences for these
low-frequency events
Timing of dose
Implications to Practice

Rivaroxaban approved and in use

No antidote for rivaroxaban
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More safety data required

Needs to be tested in other populations
(e.g. fracture, trauma patients)
Terminology

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mITT: any dvt, non-fatal PE, or all cause mortality
patients who were considered valid for mITT
analysis if they had undergone the appropriate
surgery, had taken the study drug, and had an
adequate assessment for thromboembolism
mITT (major VTE): patients valid for mITT
analysis for major VTE if they had undergone the
appropriate surgery, had taken the study drug,
and had an adequate assessment for
thromboembolism in proximal veins
Terminology



Per-protocol population: Patients who were valid for
mITT analysis and had an adequate assessment of
thromboembolism with no major protocol deviations
Safety population: took at least 1 dose of study
drug
Symptomatic VTE: safety population of patients
who underwent surgery (independent of obtaining
evaluable venograms).