Regulation of Coagulation in Orthopedic Surgery to Prevent Deep Venous Thrombosis and Pulmonary Embolism 1 (RECORD 1 )

Journal ClubGeneral Surgery Rotation

Background

Prophylactic anticoagulation: standard practice after total hip arthroplasty (THA)

Minimum recommended duration = 10 days

Extended prophylaxis x 5 wks (↓ symptomatic & asymptomatic VTE) > short-term prophylaxis

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

F=80%

Peak: 2.5-4 hours

Dose finding studies: 10 mg OD suitable for phase 3 trials

Inclusion Criteria

> 18 years

Scheduled to undergo elective total hip arthroplasty

Exclusion Criteria

Scheduled to undergo staged, bilateral hip arthroplasty

Pregnant or breastfeeding

Active bleeding

At high risk of bleeding

CI for prophylaxis with enoxaparin or a condition that might require an adjusted dose of enoxaparin

Exclusion Criteria

Conditions preventing bilateral venography

Substantial liver disease

Severe renal impairment (CrCl < 30 ml/min)

Concomitant use of protease inhibitors

Planned intermittent pneumatic compression

Requirement for anticoagulation that could not be stopped

Baseline Characteristics

Baseline Characteristics

Study Design

Randomized, multinational, double-blind

R started 6-8 hrs after wound closure

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 outcomeR = 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

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

13/15370.8%

50/14923.4%

2.5% (1.5-3.6)

Major VTE 2/1622 0.1%

29/16041.8%

1.7%(1.0-2.4)

Results: Incidence of efficacy events (Modified ITT)

Outcome Rivaroxaban Enoxaparin ARR P Value

1 efficacy outcome

18/15951.1%(0.7-1.8)

58/15583.7(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 on-tx

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

Nonfatal PE 4/1595 0.3%(0.1-0.6)

1/1558 0.1(<0.1 to 0.4)

0.2(-0.1 to 06.) 0.37

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

Similar number of adverse events

Similar safety profiles

CASP RCT Checklist

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

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

More safety data required

Needs to be tested in other populations (e.g. fracture, trauma patients)

Terminology 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).