LOWER LIMB SURGERY Ann R Coll Surg Engl 2016; 98: 507–515 doi 10.1308/rcsann.2016.0197
Efficacy and safety of rivaroxaban thromboprophylaxis after arthroplasty of the hip or knee: retrospective cohort study V Loganathan1, A Hua1, S Patel1, C Gibbons2, MP Vizcaychipi1 1 2
Magill Department of Anaesthesia, Chelsea and Westminster Hospital, UK Department of Orthopaedics, Chelsea and Westminster Hospital, UK
ABSTRACT INTRODUCTION
Venous thromboembolism (VTE) is a potentially fatal complication of hip arthroplasty and knee arthroplasty. The National Institute for Health and Care Excellence recommend rivaroxaban for VTE prevention. Amid concerns over bleeding complications, the modified thromboprophylaxis policy of Chelsea and Westminster Hospital (CWH; London, UK) advises enoxaparin given after surgery in the inpatient setting followed by rivaroxaban upon hospital discharge. This retrospective study investigated the efficacy and safety of rivaroxaban in this novel, modified venous-prophylaxis regimen in a surgical orthopaedic cohort at CWH. METHODS A total of 479 patients who received modified thromboprophylaxis treatment at CWH after hip arthroplasty or knee arthroplasty between April 2013 and October 2014 formed the study cohort. Seven outcomes based on efficacy and safety while undergoing treatment with rivaroxaban were investigated: symptomatic deep-vein thrombosis (DVT), pulmonary embolism (PE), death, stroke, myocardial infarction (MI), major bleeding episodes (MBEs) and non-major bleeding episodes (NMBEs). Median follow-up was 369 days. Fisher’s exact and Mann–Whitney U-tests were adopted to identify associations with these outcomes. RESULTS Prevalence of symptomatic PE, DVT, death, stroke and MI during treatment was zero. One (0.2%) MBE and nine (1.9%) NMBEs occurred. The MBE (a wound haematoma) required a return to theatre for aspiration. Off-treatment VTEs occurred in four (0.8%) patients after completion of a course of rivaroxaban, and were associated with known risk factors. CONCLUSIONS Rivaroxaban is an effective and safe anticoagulant for thromboprophylaxis after hip arthroplasty or knee arthroplasty if used in a modified regimen involving enoxaparin administered in the inpatient setting followed by rivaroxaban upon hospital discharge.
KEYWORDS
Venous thromboembolism – Replacement – Arthroplasty – Rivaroxaban – Knee – Hip Accepted 20 October 2015 CORRESPONDENCE TO Vinothan Loganathan, E: [email protected]
Venous thromboembolism (VTE) is a potentially fatal complication of hip arthroplasty and knee arthroplasty. VTE commonly manifests as deep-vein thrombosis (DVT) and pulmonary embolism (PE).1 Despite adequate thromboprophylaxis with low-molecular-weight heparin (LMWH) or direct/indirect inhibitors of factor Xa or factor IIa, a metaanalysis involving 44,844 cases found that ≈0.5% and ≈1% of patients after hip arthroplasty and knee arthroplasty, respectively, suffered symptomatic VTE before hospital discharge.2 This prevalence increases ≤35 days after surgery, reaching 1.25% for symptomatic DVT and 0.55% for PE on LMWH after major orthopaedic surgery.1 Rivaroxaban is a direct inhibitor of factor Xa and is given via the oral route. Rivaroxaban was introduced into guidelines set by the UK National Institute for Health and Care Excellence (NICE) in 2009. Rivaroxaban is given for VTE prophylaxis after hip replacement surgery or knee replacement surgery in adults for 35 days or 14 days, respectively.3 NICE
recommended rivaroxaban after four large multicentre phase-III randomised controlled trials (RCTs), RECORD 1–4, showed rivaroxaban to be superior to enoxaparin with regard to efficacy.4–7 The composite of DVT, PE and mortality occurred less frequently in patients taking rivaroxaban compared with enoxaparin: 1.1% vs 3.7% after hip arthroplasty4 and 9.6% vs 18.9% after knee arthroplasty.6 Furthermore, an extended duration of rivaroxaban was more efficacious than short-course enoxaparin,5 as was a once-daily regimen of rivaroxaban compared with a twice-daily regimen of enoxaparin.7 RCTs present their own limitations with respect to evaluation of the clinical impact of rivaroxaban upon VTE prevention. For example, stringent criteria for patient selection can produce study samples that represent the intended population for the drug inaccurately, thereby compromising the applicability of RCT results to routine practice.8 This scenario calls for regular studies to validate their conclusions in real-life
Ann R Coll Surg Engl 2016; 98: 507–515
507
LOGANATHAN HUA PATEL GIBBONS VIZCAYCHIPI
clinical contexts. In the UK, observational studies have primarily investigated rivaroxaban regimens that commence on or within 24 hours of the day of surgery, and have revealed a high prevalence of bleeding and haemorrhagic wound complications relative to LMWH.9–11 Consequently, the modified thromboprophylaxis policy of our institution hospital (Chelsea and Westminster Hospital (CWH), London, UK) advises an initial inpatient course of LMWH (s.c.) postoperatively, then switching to rivaroxaban (p.o.) upon hospital discharge. Our single-centre study aimed to investigate the efficacy and safety of rivaroxaban thromboprophylaxis after hip arthroplasty and knee arthroplasty when used as part of this novel, modified anticoagulation regimen in a cohort of surgical orthopaedic patients in the UK.
EFFICACY AND SAFETY OF RIVAROXABAN THROMBOPROPHYLAXIS AFTER ARTHROPLASTY OF THE HIP OR KNEE: RETROSPECTIVE COHORT STUDY
Table 1 Patient characteristics, procedural information and blood results in the inpatient setting General Female sex – n (%) Age – years median (IQR)
70 (61–75)
Elective – n (%)
446 (93.1)
Duration of stay – days median (IQR)
5 (4–7)
Procedure – n (%) Primary hip arthroplasty Primary knee arthroplasty Revision hip arthroplasty Revision knee arthroplasty
Methods
Medical history – n (%)
This retrospective cohort study was conducted in a 470-bed teaching hospital (CWH) in accordance with the UK Good Clinical Practice code (clinical governance CAPP 924). All adult patients dispensed rivaroxaban (10mg) after elective or emergency, primary or revision, hip arthroplasty or knee arthroplasty between 1 April 2013 and 1 October 2014, were included. Patients not fulfilling these criteria were excluded from the study. Patients were identified using the dispensing records for rivaroxaban of the CWH pharmacy. Prevalence of seven primary outcomes during rivaroxaban treatment were investigated: imaging-confirmed symptomatic pulmonary embolism (PE), imaging-confirmed symptomatic DVT, myocardial infarction (MI), stroke, death, major bleeding episodes (MBEs), and non-major bleeding episodes (NMBEs). “Major bleeding” was defined in accordance with recommendations from the Control of Anticoagulation Subcommittee of the International Society on Thrombosis and Haemostasis as a bleed that was fatal, occurred in a critical area or organ, resulted in a fall in haemoglobin of ≥20g/l, required at least two units of blood transfusion,or a surgical-site bleed necessitating return to theatre for open, arthroscopic or endovascular intervention.12 “Non-major bleeding” encompassed all other types of bleeding. Secondary outcomes comprised the prevalence of off-treatment PE and DVT after completion of rivaroxaban courses until the end of follow-up. Demographic data and details of inpatient admission were obtained from electronic records. Data comprised comorbidities, medication history, operative records, blood results, and thromboprophylaxis management. The followup period began on the day of hospital discharge (day-1 of the rivaroxaban course) and ended on 1 February 2015 for all patients. It entailed review of all correspondence from orthopaedic clinics, discharge summaries from readmissions, and imaging reports of five investigations if they occurred after rivaroxaban had been initiated: computed tomography of the pulmonary arteries, ultrasound Doppler of the lower limbs, ventilation–perfusion scans, echocardiography and endoscopy of the gastrointestinal tract. Guidelines for VTE prophylaxis from CWH recommend mechanical thromboprophylaxis in combination with one of two pharmacological options after elective replacement
Hypertension Diabetes mellitus Ischaemic heart disease COPD Atrial fibrillation Previous VTE Chronic kidney disease Congestive cardiac failure
508
Ann R Coll Surg Engl 2016; 98: 507–515
293 (61.2)
247 (51.6) 205 (42.8) 13 (2.7) 14 (2.9)
222 (46.3) 50 (10.4) 25 (5.2) 15 (3.1) 11 (2.3) 8 (1.7) 3 (0.6) 1 (0.2)
Medication history – n (%) ACEI/ARB Statin Gastric protection CCB Aspirin Thiazide Clopidogrel Anti-retroviral Anticoagulation
149 (31.1) 141 (29.4) 126 (26.3) 100 (20.9) 48 (10.0) 41 (8.6) 6 (1.3) 6 (1.3) 0 (0.0)
Blood results upon hospital discharge – median (IQR) Haemoglobin – g/l Platelets – 109/l PT – s APTT – s Urea – mmol/l Creatinine – µmol/l eGFR – ml/min/1.73 m2 Bilirubin – µmol/l Alanine aminotransferase – iU/l
104 (94.0–113.0) 231 (184.8–289.5) 10.4 (10.1–10.8) 25.2 (23.6–26.8) 4.65 (3.6–6.1) 68 (60.0–80.8) 84 (70.0–91.0) 11 (8.0–15.0) 20 (15.0–30.0)
ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin receptor blocker; IQR = interquartile range; COPD = chronic obstructive pulmonary disease; PT= prothrombin time; APTT = activated partial thromboplastin time; eGFR = estimated glomerular filtration rate; CCB = calcium channel blocker
of the hip or knee. Option one is rivaroxaban (10mg, once daily (OD)) to start 6–10 hours postoperatively and to continue for 35 days after hip arthroplasty or 14 days after knee arthroplasty. Option two is enoxaparin (40mg OD) to start 6–12 hours postoperatively and to continue for the
LOGANATHAN HUA PATEL GIBBONS VIZCAYCHIPI
EFFICACY AND SAFETY OF RIVAROXABAN THROMBOPROPHYLAXIS AFTER ARTHROPLASTY OF THE HIP OR KNEE: RETROSPECTIVE COHORT STUDY
Total number of patients in the study period identified from dispensing records from the pharmacy of Chelsea and Westminster Hospital (London, UK) n = 521
Excluded Discharged without rivaroxaban Ineligible procedure No procedure Rivaroxaban (20mg)
n = 26 n=8 n=6 n=2
Total number of patients included n = 479
Sources of follow-up information Readmission discharge summaries n = 479 Imaging reports (post-discharge) n = 479 Clinic letters (post-discharge)* n = 441
Analyses n = 479
*Clinic letters not available for 38 patients. Follow up for these patients involved review of readmission discharge summaries and imaging reports only
Figure 1 STROBE28 flow diagram showing the number of patients identified, included and analysed during the study period
remainder of hospital admission. In the latter, enoxaparin is replaced by rivaroxaban (10mg OD) upon hospital discharge to achieve a cumulative duration of anticoagulation of 35 days after hip arthroplasty and 14 days after knee arthroplasty. This particular regimen was chosen by CWH to promote greater compliance with postoperative anticoagulation after the introduction of rivaroxaban into NICE guidelines. The regimen of enoxaparin (s.c.) during inpatient stay was familiar to the clinical team, and so minimised confusion in hospital, whereas switching to rivaroxaban (p.o.) upon hospital discharge meant patients could self-administer rivaroxaban conveniently. The guideline for emergency hip replacement comprised mechanical prophylaxis and enoxaparin (40mg OD) only continuing for 28 days after surgery.
numbers. The Mann–Whitney U-test was used to compare continuous variables and outcomes. Data are presented as medians accompanied by interquartile ranges. p24 hrs 12–24 hrs
Efficacy and safety of rivaroxaban thromboprophylaxis after arthroplasty of the hip or knee: retrospective cohort study V Loganathan1, A Hua1, S Patel1, C Gibbons2, MP Vizcaychipi1 1 2
Magill Department of Anaesthesia, Chelsea and Westminster Hospital, UK Department of Orthopaedics, Chelsea and Westminster Hospital, UK
ABSTRACT INTRODUCTION
Venous thromboembolism (VTE) is a potentially fatal complication of hip arthroplasty and knee arthroplasty. The National Institute for Health and Care Excellence recommend rivaroxaban for VTE prevention. Amid concerns over bleeding complications, the modified thromboprophylaxis policy of Chelsea and Westminster Hospital (CWH; London, UK) advises enoxaparin given after surgery in the inpatient setting followed by rivaroxaban upon hospital discharge. This retrospective study investigated the efficacy and safety of rivaroxaban in this novel, modified venous-prophylaxis regimen in a surgical orthopaedic cohort at CWH. METHODS A total of 479 patients who received modified thromboprophylaxis treatment at CWH after hip arthroplasty or knee arthroplasty between April 2013 and October 2014 formed the study cohort. Seven outcomes based on efficacy and safety while undergoing treatment with rivaroxaban were investigated: symptomatic deep-vein thrombosis (DVT), pulmonary embolism (PE), death, stroke, myocardial infarction (MI), major bleeding episodes (MBEs) and non-major bleeding episodes (NMBEs). Median follow-up was 369 days. Fisher’s exact and Mann–Whitney U-tests were adopted to identify associations with these outcomes. RESULTS Prevalence of symptomatic PE, DVT, death, stroke and MI during treatment was zero. One (0.2%) MBE and nine (1.9%) NMBEs occurred. The MBE (a wound haematoma) required a return to theatre for aspiration. Off-treatment VTEs occurred in four (0.8%) patients after completion of a course of rivaroxaban, and were associated with known risk factors. CONCLUSIONS Rivaroxaban is an effective and safe anticoagulant for thromboprophylaxis after hip arthroplasty or knee arthroplasty if used in a modified regimen involving enoxaparin administered in the inpatient setting followed by rivaroxaban upon hospital discharge.
KEYWORDS
Venous thromboembolism – Replacement – Arthroplasty – Rivaroxaban – Knee – Hip Accepted 20 October 2015 CORRESPONDENCE TO Vinothan Loganathan, E: [email protected]
Venous thromboembolism (VTE) is a potentially fatal complication of hip arthroplasty and knee arthroplasty. VTE commonly manifests as deep-vein thrombosis (DVT) and pulmonary embolism (PE).1 Despite adequate thromboprophylaxis with low-molecular-weight heparin (LMWH) or direct/indirect inhibitors of factor Xa or factor IIa, a metaanalysis involving 44,844 cases found that ≈0.5% and ≈1% of patients after hip arthroplasty and knee arthroplasty, respectively, suffered symptomatic VTE before hospital discharge.2 This prevalence increases ≤35 days after surgery, reaching 1.25% for symptomatic DVT and 0.55% for PE on LMWH after major orthopaedic surgery.1 Rivaroxaban is a direct inhibitor of factor Xa and is given via the oral route. Rivaroxaban was introduced into guidelines set by the UK National Institute for Health and Care Excellence (NICE) in 2009. Rivaroxaban is given for VTE prophylaxis after hip replacement surgery or knee replacement surgery in adults for 35 days or 14 days, respectively.3 NICE
recommended rivaroxaban after four large multicentre phase-III randomised controlled trials (RCTs), RECORD 1–4, showed rivaroxaban to be superior to enoxaparin with regard to efficacy.4–7 The composite of DVT, PE and mortality occurred less frequently in patients taking rivaroxaban compared with enoxaparin: 1.1% vs 3.7% after hip arthroplasty4 and 9.6% vs 18.9% after knee arthroplasty.6 Furthermore, an extended duration of rivaroxaban was more efficacious than short-course enoxaparin,5 as was a once-daily regimen of rivaroxaban compared with a twice-daily regimen of enoxaparin.7 RCTs present their own limitations with respect to evaluation of the clinical impact of rivaroxaban upon VTE prevention. For example, stringent criteria for patient selection can produce study samples that represent the intended population for the drug inaccurately, thereby compromising the applicability of RCT results to routine practice.8 This scenario calls for regular studies to validate their conclusions in real-life
Ann R Coll Surg Engl 2016; 98: 507–515
507
LOGANATHAN HUA PATEL GIBBONS VIZCAYCHIPI
clinical contexts. In the UK, observational studies have primarily investigated rivaroxaban regimens that commence on or within 24 hours of the day of surgery, and have revealed a high prevalence of bleeding and haemorrhagic wound complications relative to LMWH.9–11 Consequently, the modified thromboprophylaxis policy of our institution hospital (Chelsea and Westminster Hospital (CWH), London, UK) advises an initial inpatient course of LMWH (s.c.) postoperatively, then switching to rivaroxaban (p.o.) upon hospital discharge. Our single-centre study aimed to investigate the efficacy and safety of rivaroxaban thromboprophylaxis after hip arthroplasty and knee arthroplasty when used as part of this novel, modified anticoagulation regimen in a cohort of surgical orthopaedic patients in the UK.
EFFICACY AND SAFETY OF RIVAROXABAN THROMBOPROPHYLAXIS AFTER ARTHROPLASTY OF THE HIP OR KNEE: RETROSPECTIVE COHORT STUDY
Table 1 Patient characteristics, procedural information and blood results in the inpatient setting General Female sex – n (%) Age – years median (IQR)
70 (61–75)
Elective – n (%)
446 (93.1)
Duration of stay – days median (IQR)
5 (4–7)
Procedure – n (%) Primary hip arthroplasty Primary knee arthroplasty Revision hip arthroplasty Revision knee arthroplasty
Methods
Medical history – n (%)
This retrospective cohort study was conducted in a 470-bed teaching hospital (CWH) in accordance with the UK Good Clinical Practice code (clinical governance CAPP 924). All adult patients dispensed rivaroxaban (10mg) after elective or emergency, primary or revision, hip arthroplasty or knee arthroplasty between 1 April 2013 and 1 October 2014, were included. Patients not fulfilling these criteria were excluded from the study. Patients were identified using the dispensing records for rivaroxaban of the CWH pharmacy. Prevalence of seven primary outcomes during rivaroxaban treatment were investigated: imaging-confirmed symptomatic pulmonary embolism (PE), imaging-confirmed symptomatic DVT, myocardial infarction (MI), stroke, death, major bleeding episodes (MBEs), and non-major bleeding episodes (NMBEs). “Major bleeding” was defined in accordance with recommendations from the Control of Anticoagulation Subcommittee of the International Society on Thrombosis and Haemostasis as a bleed that was fatal, occurred in a critical area or organ, resulted in a fall in haemoglobin of ≥20g/l, required at least two units of blood transfusion,or a surgical-site bleed necessitating return to theatre for open, arthroscopic or endovascular intervention.12 “Non-major bleeding” encompassed all other types of bleeding. Secondary outcomes comprised the prevalence of off-treatment PE and DVT after completion of rivaroxaban courses until the end of follow-up. Demographic data and details of inpatient admission were obtained from electronic records. Data comprised comorbidities, medication history, operative records, blood results, and thromboprophylaxis management. The followup period began on the day of hospital discharge (day-1 of the rivaroxaban course) and ended on 1 February 2015 for all patients. It entailed review of all correspondence from orthopaedic clinics, discharge summaries from readmissions, and imaging reports of five investigations if they occurred after rivaroxaban had been initiated: computed tomography of the pulmonary arteries, ultrasound Doppler of the lower limbs, ventilation–perfusion scans, echocardiography and endoscopy of the gastrointestinal tract. Guidelines for VTE prophylaxis from CWH recommend mechanical thromboprophylaxis in combination with one of two pharmacological options after elective replacement
Hypertension Diabetes mellitus Ischaemic heart disease COPD Atrial fibrillation Previous VTE Chronic kidney disease Congestive cardiac failure
508
Ann R Coll Surg Engl 2016; 98: 507–515
293 (61.2)
247 (51.6) 205 (42.8) 13 (2.7) 14 (2.9)
222 (46.3) 50 (10.4) 25 (5.2) 15 (3.1) 11 (2.3) 8 (1.7) 3 (0.6) 1 (0.2)
Medication history – n (%) ACEI/ARB Statin Gastric protection CCB Aspirin Thiazide Clopidogrel Anti-retroviral Anticoagulation
149 (31.1) 141 (29.4) 126 (26.3) 100 (20.9) 48 (10.0) 41 (8.6) 6 (1.3) 6 (1.3) 0 (0.0)
Blood results upon hospital discharge – median (IQR) Haemoglobin – g/l Platelets – 109/l PT – s APTT – s Urea – mmol/l Creatinine – µmol/l eGFR – ml/min/1.73 m2 Bilirubin – µmol/l Alanine aminotransferase – iU/l
104 (94.0–113.0) 231 (184.8–289.5) 10.4 (10.1–10.8) 25.2 (23.6–26.8) 4.65 (3.6–6.1) 68 (60.0–80.8) 84 (70.0–91.0) 11 (8.0–15.0) 20 (15.0–30.0)
ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin receptor blocker; IQR = interquartile range; COPD = chronic obstructive pulmonary disease; PT= prothrombin time; APTT = activated partial thromboplastin time; eGFR = estimated glomerular filtration rate; CCB = calcium channel blocker
of the hip or knee. Option one is rivaroxaban (10mg, once daily (OD)) to start 6–10 hours postoperatively and to continue for 35 days after hip arthroplasty or 14 days after knee arthroplasty. Option two is enoxaparin (40mg OD) to start 6–12 hours postoperatively and to continue for the
LOGANATHAN HUA PATEL GIBBONS VIZCAYCHIPI
EFFICACY AND SAFETY OF RIVAROXABAN THROMBOPROPHYLAXIS AFTER ARTHROPLASTY OF THE HIP OR KNEE: RETROSPECTIVE COHORT STUDY
Total number of patients in the study period identified from dispensing records from the pharmacy of Chelsea and Westminster Hospital (London, UK) n = 521
Excluded Discharged without rivaroxaban Ineligible procedure No procedure Rivaroxaban (20mg)
n = 26 n=8 n=6 n=2
Total number of patients included n = 479
Sources of follow-up information Readmission discharge summaries n = 479 Imaging reports (post-discharge) n = 479 Clinic letters (post-discharge)* n = 441
Analyses n = 479
*Clinic letters not available for 38 patients. Follow up for these patients involved review of readmission discharge summaries and imaging reports only
Figure 1 STROBE28 flow diagram showing the number of patients identified, included and analysed during the study period
remainder of hospital admission. In the latter, enoxaparin is replaced by rivaroxaban (10mg OD) upon hospital discharge to achieve a cumulative duration of anticoagulation of 35 days after hip arthroplasty and 14 days after knee arthroplasty. This particular regimen was chosen by CWH to promote greater compliance with postoperative anticoagulation after the introduction of rivaroxaban into NICE guidelines. The regimen of enoxaparin (s.c.) during inpatient stay was familiar to the clinical team, and so minimised confusion in hospital, whereas switching to rivaroxaban (p.o.) upon hospital discharge meant patients could self-administer rivaroxaban conveniently. The guideline for emergency hip replacement comprised mechanical prophylaxis and enoxaparin (40mg OD) only continuing for 28 days after surgery.
numbers. The Mann–Whitney U-test was used to compare continuous variables and outcomes. Data are presented as medians accompanied by interquartile ranges. p24 hrs 12–24 hrs
