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Hunt, L., Ben-Shlomo, Y., Whitehouse, M., Porter, M., & Blom, A. (2017). The Main Cause of Death Following Primary Total Hip and Knee Replacement for Osteoarthritis: A Cohort Study of 26,766 Deaths Following 332,734 Hip Replacements and 29,802 Deaths Following 384,291 Knee Replacements. Journal of Bone and Joint Surgery (American edition), 99(7), 565-575. DOI: 10.2106/JBJS.16.00586 Publisher's PDF, also known as Version of record License (if available): Unspecified Link to published version (if available): 10.2106/JBJS.16.00586 Link to publication record in Explore Bristol Research PDF-document This is the final published version of the article (version of record). It first appeared online via Wolters Kulwer at http://journals.lww.com/jbjsjournal/fulltext/2017/04050/the_main_cause_of_death_following_primary_total.4.a spx. Please refer to any applicable terms of use of the publisher. University of Bristol - Explore Bristol Research General rights This document is made available in accordance with publisher policies. Please cite only the published version using the reference above. Full terms of use are available: http://www.bristol.ac.uk/pure/about/ebr-terms.html

Page 1 Charlson Comorbidity Subgroups We defined these Charlson Comorbidity subgroups in exactly the same way as we had in our studies of short-term mortality following hip and knee replacement 2,3. The original Charlson comorbidities 25 were 19 diagnostic categories defined from sets of International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) diagnoses prevalent in hospitalized patients; these categories were weighted and used to calculate an index for prediction of 1-year mortality. Quan et al. 26 later provided coding algorithms to define 17 comorbidities (combining 3 malignancy subgroups) from ICD-10 (Tenth Revision) that were used by others to predict in hospital and 1-year mortality. We used the same ICD-10 codes that Quan et al. had used, to define comorbidities from all of the diagnosis codes noted in any of the reported HES episodes within the 5 years prior to, and including, the primary operation. We created indicator variables (0/1) for each. We did not attempt to calculate an index. Because a patient may have, for example, mild liver disease and moderate liver disease reported on different occasions, we interpreted mild liver disease to be in the absence of moderate or severe liver disease; that is, we forced the 2 categories to be mutually exclusive. Similarly, diabetes without complications excluded patients who also had diabetes with complications, and cancer excluded patients who also had metastatic cancer.

Page 2 TABLE E-1 Comparison Between Sex and Age of Patients with and without HES Linkage Hip Cohort (N = 424,156) Knee Cohort (N = 469,989) With HES Linkage No HES Records* With HES Linkage No HES Records* No. of patients 332,734 91,422 384,291 85,698 No. of males (%) 134,263 (40.4%) 39,127 (42.8%) 164,998 (42.9%) 38,375 (44.8%) Median age at primary operation (IQR) (yr) 70 (62 to 76) 69 (61 to 76) 70 (63 to 76) 69 (62 to 76) *No HES records were available for any procedure in the registry.

Page 3 TABLE E-2 Main Causes of Death No. of Deaths (%) Hip Cohort Knee Cohort Certain infectious and parasitic diseases (A00 to B99) 346 (1.3%) 374 (1.3%) Neoplasms (C00 to D48) 9,237* (34.5%) 10,166 (34.1%) Diseases of the blood and blood-forming organs and certain disorders involving the 51 (0.2%) 69 (0.2%) immune mechanism (D50 to D89) Endocrine, nutritional, and metabolic diseases (E00 to E90) 226 (0.8%) 299 (1.0%) Mental and behavioral disorders (F00 to F99) 679 (2.5%) 824 (2.8%) Diseases of the nervous system (G00 to G99) 578 (2.2%) 790 (2.7%) Diseases of the ear and mastoid process (H60 to H95) 1 (<0.01%) 0 (0%) Diseases of the circulatory system (I00 to I99) 8,784 (32.8%) 9,932 (33.3%) Diseases of the respiratory system (J00 to J99) 2,928 (10.9%) 2,932 (9.8%) Diseases of the digestive system (K00 to K93) 1,465 (5.5%) 1,572 (5.3%) Diseases of the skin and subcutaneous tissue (L00 to L99) 126 (0.5%) 115 (0.4%) Diseases of the musculoskeletal system and connective tissue (M00 to M99) 643 (2.4%) 752 (2.5%) Diseases of the genitourinary system (N00 to N99) 523 (2.0%) 589 (2.0%) Pregnancy, childbirth, and the puerperium (O00 to O99) 1 (<0.01%) 0 (0%) Congenital malformations, deformations, and chromosomal abnormalities (Q00 to 27 (0.1%) 19 (0.1%) Q99) Symptoms, signs, and abnormal clinical and laboratory findings, not elsewhere 285 (1.1%) 299 (1.0%) classified (R00 to R99) External causes of morbidity and mortality (V01 to Y98) 482 (1.8%) 571 (1.9%) Codes for special purposes (U00 to U89) 4 (0.01%) 15 (0.05%) Unable to link (cause unknown) 380 (1.4%) 484 (1.6%) Total deaths 26,766 (100%) 29,802 (100%) *In the hip cohort, 200 deaths were attributed to D codes: 20 were caused by benign neoplasms, and 180 were caused by neoplasms of uncertain or unknown behavior. In the knee cohort, 249 deaths were attributed to D codes: 32 were caused by benign neoplasms, and 217 were caused by neoplasms of uncertain or unknown behavior.

Page 4 TABLE E-3 ICD-10 Codes for the Hip and Knee-Replacement Patients Who Died within 90 Days Postoperatively from Disorders of the Digestive System Main Cause of Death Hip Cohort (N = 141) Knee Cohort (N = 147) K20: esophagitis 2 0 K21: gastroesophageal reflux disease 0 1 K22: other diseases of esophagus 4 4 K25: gastric ulcer 7 8 K26: duodenal ulcer 22 25 K27: peptic ulcer, site unspecified 4 3 K29: gastritis and duodenitis 3 1 K31: other diseases of stomach and duodenum 1 0 K40: inguinal hernia 0 2 K41: femoral hernia 1 0 K42: umbilical hernia 1 0 K43: ventral hernia 2 1 K46: unspecified abdominal hernia 2 1 K51: ulcerative colitis 0 1 K52: other noninfective gastroenteritis and colitis 3 6 K55: vascular disorders of intestine 20 27 K56: paralytic ileus and intestinal obstruction without hernia 14 10 K57: diverticular disease of intestine 15 17 K59: other functional intestinal disorders 1 0 K63: other diseases of intestine 7 8 K65: peritonitis 3 1 K66: other disorders of peritoneum 1 0 K70: alcoholic liver disease 5 0 K72: hepatic failure, not elsewhere classified 1 2 K73: chronic hepatitis, not elsewhere classified 1 1 K74: fibrosis and cirrhosis of liver 3 5 K75: other inflammatory liver diseases 0 1 K76: other diseases of liver 2 1 K80: cholelithiasis 0 2 K81: cholecystitis 2 1 K82: other diseases of gallbladder 2 0 K83: other diseases of biliary tract 0 2 K85: acute pancreatitis 3 5 K86: other diseases of pancreas 0 1 K90: intestinal malabsorption 1 0 K92: other diseases of digestive system 8 10

Page 5 TABLE E-4 American Society of Anesthesiologists (ASA) Physical Status of Hip and Knee Cohorts at the Time of the Primary Operation and Charlson Comorbidity Subgroups Hip Cohort (N = 332,734) Knee Cohort (N = 384,291) ASA at primary operation P1 56,778 (17.1%) 51,140 (13.3%) P2 227,678 (68.4%) 274,953 (71.6%) P3 46,609 (14.0%) 56,706 (14.8%) P4 or P5 1,669 (0.5%) 1,492 (0.4%) Charlson comorbidity subgroups No. available for analysis* 326,673 378,865 Myocardial infarction 8,691 (2.7%) 10,300 (2.7%) Congestive heart failure 6,811 (2.1%) 7,472 (2.0%) Peripheral vascular disease 6,158 (1.9%) 6,920 (1.8%) Cerebrovascular disease 6,198 (1.9%) 7,783 (2.1%) Dementia 1,138 (0.4%) 1,029 (0.3% Chronic pulmonary disease 38,801 (11.9%) 51,203 (13.5%) Connective tissue disease or rheumatic disease 10,883 (3.3%) 14,929 (3.9%) Peptic ulcer disease 4,233 (1.3%) 5,701 (1.5%) Liver disease Mild 1,604 (0.5%) 1,994 (0.5%) Moderate or severe 371 (0.1%) 409 (0.1%) Diabetes Without complications 26,329 (8.1%) 42,290 (11.2%) With complications 1,454 (0.5%) 2,289 (0.6%) Paraplegia or hemiplegia 1,154 (0.4%) 1,523 (0.4%) Renal disease 8,370 (2.6%) 9,988 (2.6%) AIDS and/or HIV 15 (<0.01%) 7 (<0.01%) Cancer 11,949 (3.7%) 13,769 (3.6%) Metastatic cancer 1,752 (0.5%) 1,671 (0.4%) *There are slightly fewer cases (6,061 fewer hip-replacement cases and 5,426 fewer knee-replacement cases) listed as available for analysis than are listed for the full cohort because we included only cases that had had HES records within a 5-year window up to and including the primary operation for the specific joint and excluded primary procedures performed in the final month of 2012 (as our HES extract only included records of procedures performed through November 2012). AIDS = acquired immune deficiency syndrome, and HIV = human immunodeficiency virus.