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  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 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  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 ° 1.5% for major VTE efficacy outcome  mITT= Planned surgery done, study drug taken, adequate assessment for thromboembolism

Results: Per-protocol Population

Outcome 1 efficacy outcome Rivaroxaban 13/1537 0.8% Major VTE 2/1622 0.1% Enoxaparin 50/1492 3.4% 29/1604 1.8% ARR 2.5% (1.5-3.6) 1.7%(1.0-2.4)

Results: Incidence of efficacy events (Modified ITT)

Outcome 1 efficacy outcome Major VTE Rivaroxaban 18/1595 1.1%(0.7-1.8) 4/1686 0.2%(0.1-0.6) Enoxaparin 58/1558 3.7(2.8-4.8) 33/1678 2.0(1.4-2.8) Death during on tx 4/1595 0.3%(0.1-0.6) Nonfatal PE 4/1595 0.3%(0.1-0.6) 4/1558 0.3(0.1-0.7) 1/1558 0.1(<0.1 to 0.4) ARR -2.6 (-3.7 to 1.5) -1.7(-2.5 to 1.0) 0.0 (-0.4 to 0.4) P Value <0.001

<0.001

1.00

0.2(-0.1 to 06.) 0.37

Results: Symptomatic VTE Incidence

Results: Safety Outcome

Event Any on-treatment bleeding Rivaroxaban (N=2209) 133 (6.0) Major bleeding 6 (0.3) Non-major bleeding 128 (5.8) Study withdrawal due to adverse effect 85 (3.8) Enoxaparin (N=2224) 131 (5.9) P Value 0.94

2(0.1) 129(5.8) 0.18

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).