Accelerated Surgery Versus Standard Care in Hip Fracture (HIP ATTACK-1): A Kidney Substudy of a Randomized Clinical Trial.

Acute kidney injury (AKI) is a lesser-known complication of hip fracture that may come about owing to decreased kidney perfusion and heightened inflammation from trauma, pain, bleeding, and fasting.1Sharfuddin A.A. Molitoris B.A. Pathophysiology of ischemic acute kidney injury.Nat Rev Nephrol. 2011; 7: 189-200Crossref PubMed Scopus (549) Google Scholar,2Kinsey G.R. Li L. Okusa M.D. Inflammation in acute kidney injury.Nephron Exp Nephrol. 2008; 109: e102-e107Crossref PubMed Scopus (320) Google Scholar Approximately 15%-20% of patients undergoing surgery for a hip fracture develop AKI, with 0.5%-1.8% receiving dialysis.3Bennet S.J. Berry O.M.B. Goddard J. Keating J.F. Acute renal dysfunction following hip fracture.Injury. 2010; 41: 335-338Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar, 4Ulucay C. Eren Z. Kaspar E.C. et al.Risk factors for acute kidney injury after hip fracture surgery in the elderly individuals.Geriatr Orthop Surg Rehabil. 2012; 3: 150-156Crossref PubMed Scopus (52) Google Scholar, 5Hong S.E. Kim T.-Y. Yoo J.-H. et al.Acute kidney injury can predict in-hospital and long-term mortality in elderly patients undergoing hip fracture surgery.PLoS One. 2017; 12e0176259Crossref Scopus (26) Google Scholar A strategy of accelerating the time to surgery after a hip fracture was recently compared with standard care in HIP ATTACK-1 (ClinicalTrials.gov identifier NCT02027896), a multinational randomized clinical trial.6Borges F.K. Bhandari M. Patel A. et al.Rationale and design of the HIP fracture Accelerated surgical TreaTment And Care tracK (HIP ATTACK) Trial: a protocol for an international randomised controlled trial evaluating early surgery for hip fracture patients.BMJ Open. 2019; 9e028537Crossref Scopus (18) Google Scholar,7Borges F.K. Bhandari M. Guerra-Farfan E. et al.Accelerated surgery versus standard care in hip fracture (HIP ATTACK): an international, randomised, controlled trial.Lancet. 2020; 395: 698-708Abstract Full Text Full Text PDF PubMed Scopus (137) Google Scholar Enrollment occurred March 2014 through May 2019, and 2,970 patients from 69 hospitals in 17 countries were randomized. Compared with standard care, accelerated medical assessment and surgical repair did not significantly lower the risk of the 2 co–primary outcomes (mortality and major perioperative complications), although it did decrease the risk of delirium, moderate-to-severe pain, and urinary tract infection, and resulted in faster mobilization and a shorter hospital stay.7Borges F.K. Bhandari M. Guerra-Farfan E. et al.Accelerated surgery versus standard care in hip fracture (HIP ATTACK): an international, randomised, controlled trial.Lancet. 2020; 395: 698-708Abstract Full Text Full Text PDF PubMed Scopus (137) Google Scholar We conducted a prespecified kidney substudy of HIP ATTACK-1 to examine the effect of accelerated surgical treatment versus standard care on AKI in patients with a hip fracture.8Borges F.K. Devereaux P.J. Cuerden M. et al.Effects of accelerated versus standard care surgery on the risk of acute kidney injury in patients with a hip fracture: a substudy protocol of the hip fracture Accelerated surgical TreaTment and Care tracK (HIP ATTACK) international randomised controlled trial.BMJ Open. 2019; 9e033150Google Scholar Eligibility criteria for the main trial and the kidney substudy are provided in Table S1, and substudy methods are detailed in Item S1; minor changes in substudy execution compared to the published protocol8Borges F.K. Devereaux P.J. Cuerden M. et al.Effects of accelerated versus standard care surgery on the risk of acute kidney injury in patients with a hip fracture: a substudy protocol of the hip fracture Accelerated surgical TreaTment and Care tracK (HIP ATTACK) international randomised controlled trial.BMJ Open. 2019; 9e033150Google Scholar are summarized in Table S2. Briefly, eligible patients aged ≥45 years who presented to the emergency department with a hip fracture were randomly allocated (1:1) to receive accelerated surgical repair or standard care. The primary outcome of the substudy was AKI, defined as an Scr increase (from the prerandomization value) of ≥0.3 mg/dL (26.5 μmol/L) within 48 hours after randomization, or an increase of ≥50% within 7 days after randomization.9Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury Work GroupKDIGO clinical practice guideline for acute kidney injury.Kidney Int Suppl. 2012; 2: 1-138Google Scholar Six secondary definitions of AKI (listed in Item S1) were also examined. Of 2,970 patients randomized in HIP ATTACK-1, 2,445 (82%) were included in the substudy (Figure S1). Baseline characteristics of patients in the substudy are shown in Table 1 (corresponding data for the main trial are in Table S3). The baseline, prerandomization Scr was obtained at the time of hospital admission for 99% of patients and before the hospital admission for 1%. The accelerated surgery group had surgery earlier than the standard care group and the mean between-group difference in the time from hip fracture diagnosis to surgery was 18 (95% CI, 15-20) hours.Table 1Baseline Characteristics and Surgical DetailsAccelerated Surgery (n = 1,216)Standard Care (n = 1,229)Sociodemographic characteristicsAge, y79 ± 1279 ± 11Female sex852 (70%)852 (69%)Ethnicity White755 (62%)767 (62%) Asian363 (30%)360 (29%) Hispanic/Latino50 (4%)60 (5%) Black/African descent39 (3%)38 (3%) Other9 (1%)4 (<1%)Health history before hip fractureHistory of tobacco use in 5 years before randomization338 (28%)294 (24%)Residing in a nursing home219 (18%)234 (19%)Comorbidities Hypertension736 (61%)750 (61%) Needing assistance with activities of daily living392 (32%)431 (35%) Diabetes271 (22%)250 (20%) Dementia210 (17%)226 (18%) Osteoporosis201 (17%)200 (16%) Chronic obstructive pulmonary disease127 (10%)106 (9%) Stroke107 (9%)95 (8%) Myocardial infarction103 (8%)93 (8%) Hip fracture80 (7%)104 (8%) Congestive heart failure86 (7%)61 (5%) Coronary revascularization77 (6%)72 (6%) Chronic atrial fibrillation63 (5%)65 (5%) Active canceraA patient with a diagnosis of cancer who is receiving, or has received, active cancer treatment (eg, chemotherapy, radiation, or surgery) in the previous 6 months.62 (5%)61 (5%) Transient ischemic attack60 (5%)67 (5%) Peripheral vascular disease37 (3%)44 (4%) Aortic stenosis29 (2%)25 (2%) Deep venous thrombosis21 (2%)26 (2%) Subarachnoid hemorrhage15 (1%)7 (1%) Pulmonary embolism13 (1%)8 (1%) Kidney failure receiving dialysis0 (0%)0 (0%) Coronary artery bypass graft42 (3%)37 (3%) Percutaneous coronary intervention47 (4%)41 (3%)New diagnoses from time of hip fracture until randomizationInfection27 (2%)27 (2%)Atrial fibrillation8 (1%)9 (1%)Significant hyponatremia or hypernatremia8 (1%)9 (1%)Significant hypokalemia or hyperkalemia9 (1%)4 (<1%)Non-ST-elevation MI without mechanical complicationbMechanical complication included acute papillary muscle rupture or ventricular septal defect.10 (1%)4 (<1%)MI with ST elevation or mechanical complicationbMechanical complication included acute papillary muscle rupture or ventricular septal defect.2 (<1%)2 (<1%)Congestive heart failure0 (0%)2 (<1%)Glasgow Coma Scale <12 of unknown origin2 (<1%)1 (<1%)Subarachnoid hemorrhage1 (<1%)2 (<1%)Stroke0 (0%)1 (<1%)Expanded acute medical conditioncOccurred after the hip fracture but before randomization (eg, cardiac or central nervous system conditions; full details in Item S2).66 (5%)56 (5%)Prerandomization physiological measurementsBody mass index, kg/m224 [21, 27]24 [21, 27]Obesity: body mass index ≥30 kg/m2129 (11%)110 (10%)Systolic blood pressure, mm Hg141 [130, 160]141 [126, 160]Diastolic blood pressure, mm Hg78 [70, 86]77 [69, 85]Heart rate, beats per minute80 [71, 89]80 [70, 90]Prerandomization laboratory measurementsHemoglobin, g/L121 ± 18121 ± 18Scr, mg/dL0.95 ± 0.400.96 ± 0.41eGFR, mL/min/1.73 m269 ± 2368 ± 22 <30 mL/min/1.73 m259 (5%)60 (5%) 30-44 mL/min/1.73 m2143 (12%)156 (13%) 45-59 mL/min/1.73 m2212 (17%)248 (20%) 60-89 mL/min/1.73 m2596 (49%)582 (47%) ≥90 mL/min/1.73 m2206 (17%)183 (15%)Medications taken at least once 7 days to 24 h before surgeryACEI/ARB412 (34%)410 (33%)Antiplatelet agent351 (29%)322 (26%)Statin310 (25%)327 (27%)β-blocker286 (24%)274 (22%)Prophylactic antithrombotic59 (5%)156 (13%)Therapeutic dose vitamin K antagonist37 (3%)43 (4%)Therapeutic non–vitamin K antagonist anticoagulant25 (2%)28 (2%)Prothrombin complex concentrate3 (<1%)2 (<1%)Medications taken ≤24 h before surgeryACEI/ARB288 (24%)244 (20%)Antiplatelet agent201 (17%)130 (11%)Statin223 (18%)226 (18%)β-blocker215 (18%)216 (18%)Prophylactic antithrombotic123 (10%)325 (26%)Therapeutic dose vitamin K antagonist19 (2%)4 (<1%)Therapeutic non–vitamin K antagonist anticoagulant22 (2%)29 (2%)Prothrombin complex concentrate16 (1%)8 (1%)Type of fracturedSome patients had more than 1 type of fracture.Intertrochanteric631 (52%)638 (52%)Femoral neck527 (43%)528 (43%)Subtrochanteric76 (6%)71 (6%)Other2 (<1%)1 (<1%)Intraoperative anestheticNeuraxial766 (63%)782 (64%)General406 (34%)395 (33%)General and neuraxial36 (3%)36 (3%)Type of hip surgery performedOpen reduction and internal fixation779 (64%)777 (63%)Arthroplasty427 (35%)434 (35%) Hemiarthroplasty351 (29%)356 (29%) Total hip arthroplasty71 (6%)77 (6%) Other arthroplasty5 (<1%)1 (<1%)Other3 (<1%)1 (<1%)Data presented as mean ± SD, median [25th, 75th percentile], or number (percentage). Body mass index was missing in 137 participants (6% in accelerated surgery group and 6% in standard care group); missing data on other variables was <2%. Abbreviations: ACEI/ARB, angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker; eGFR, estimated glomerular filtration rate (calculated with CKD-EPI equation10Levey A.S. Stevens L.A. Schmid C.H. et al.A New Equation to Estimate Glomerular Filtration Rate.Ann Intern Med. 2009; 150: 604-612Crossref PubMed Scopus (16605) Google Scholar); MI, myocardial infarction; Scr, serum creatinine concentration.a A patient with a diagnosis of cancer who is receiving, or has received, active cancer treatment (eg, chemotherapy, radiation, or surgery) in the previous 6 months.b Mechanical complication included acute papillary muscle rupture or ventricular septal defect.c Occurred after the hip fracture but before randomization (eg, cardiac or central nervous system conditions; full details in Item S2).d Some patients had more than 1 type of fracture. Open table in a new tab Data presented as mean ± SD, median [25th, 75th percentile], or number (percentage). Body mass index was missing in 137 participants (6% in accelerated surgery group and 6% in standard care group); missing data on other variables was <2%. Abbreviations: ACEI/ARB, angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker; eGFR, estimated glomerular filtration rate (calculated with CKD-EPI equation10Levey A.S. Stevens L.A. Schmid C.H. et al.A New Equation to Estimate Glomerular Filtration Rate.Ann Intern Med. 2009; 150: 604-612Crossref PubMed Scopus (16605) Google Scholar); MI, myocardial infarction; Scr, serum creatinine concentration. AKI occurred in 13.5% (163/1,204) in the accelerated surgery group and in 14.9% (179/1,203) in the standard care group (postrandomization Scr was missing in 38 [1.6%] patients and was imputed using fully conditional specification for the primary analysis as described in Item S1). The relative risk (RR) was 0.91 (95% CI, 0.74-1.13), and the absolute risk difference was 1.3% (95% CI, −1.5% to 4.1%; Table 2). Results were similar in sensitivity analyses (Tables S4-S5). The mean between-group difference in the percentage and absolute change in Scr to the peak value was −1.5 (95% CI, −5.2 to 2.2) and −1.9 (95% CI, −5.1 to 1.3), respectively. The time to AKI after randomization in each group is shown in Figure S2. Pre-existing chronic kidney disease (CKD) did not significantly modify the effect of the accelerated surgery intervention versus standard care on AKI (Table S6), nor did prerandomization eGFR considered as a continuous variable (P = 0.1 for the interaction between the group allocation and eGFR).Table 2Accelerated Hip-Repair Surgery Versus Standard Care and the Risk of AKINo. (%) of eventsaBased on all participants with at least 1 postrandomization Scr in the first 7 days after randomization.RR (95% CI)bA modified Poisson regression model that accounts for the treating center and planned surgery type (open reduction and internal fixation or arthroplasty) was used to estimate the RR and 95% CI for AKI comparing the randomized groups. A missing outcome variable was imputed using multiple imputation; standard methods were used to combine estimates from each imputed dataset, as detailed in Item S2. For the outcomes of AKI or death, stage 2 AKI or higher, and stage 3 AKI, complete-case analysis was used, since<2 patients had missing outcome status.PcCalculated for the primary outcome only; for this analysis, missing data on postrandomization Scr (12 [1.0%] in the accelerated surgery group; 26 [2.1%] in the standard care group) were imputed using fully conditional specification (detailed in Item S2).Accelerated Surgery Group (n = 1,216)Standard Care Group (n = 1,229)AKI163/1,204 (13.5%)179/1,203 (14.9%)0.91 (0.74-1.13)0.4AKI or deathdA composite of AKI (primary outcome definition) or death within 48 hours after randomization. For patients with at least 48 hours of follow-up postrandomization (to assess the death outcome) who were missing all postrandomization Scr, a value of 0 (no AKI or death within 48 hours) was imputed.166/1,216 (13.7%)180/1,229 (14.7%)0.93 (0.77-1.12)--Stage 2 AKI or highereDefined as a postrandomization increase in Scr of≥100% from the prerandomization value within 7 days after randomization or an increase to an absolute value of≥4.0mg/dL (353.6μmol/L) within 7 days after randomization (when the primary outcome definition of AKI was met) or receipt of dialysis within 30 days after randomization. A patient was considered to have observed outcome data if≥1 Scr was provided within 7 days after randomization or the patient was followed for≥30 days after randomization to assess dialysis status.35/1,215 (2.9%)38/1,228 (3.1%)0.93 (0.65-1.33)--Stage 3 AKIfDefined as a postrandomization increase in Scr of≥200% from the prerandomization value within 7 days after randomization or an increase to an absolute value of≥4.0mg/dL (353.6μmol/L) within 7 days after randomization or receipt of dialysis within 30 days after randomization. A patient was considered to have observed outcome data if≥1 Scr was provided within 7 days after randomization or the patient was followed for≥30 days after randomization to assess dialysis status.5/1,215 (0.4%)12/1,228 (1.0%)0.42 (0.20-0.91)--Receipt of dialysisgReceipt of dialysis within 30 days after randomization. A patient was considered to have observed outcome data if the patient was followed for≥30 days after randomization to assess dialysis status.0/1,213 (0.0%)1/1,226 (0.1%)----a Based on all participants with at least 1 postrandomization Scr in the first 7 days after randomization.b A modified Poisson regression model that accounts for the treating center and planned surgery type (open reduction and internal fixation or arthroplasty) was used to estimate the RR and 95% CI for AKI comparing the randomized groups. A missing outcome variable was imputed using multiple imputation; standard methods were used to combine estimates from each imputed dataset, as detailed in Item S2. For the outcomes of AKI or death, stage 2 AKI or higher, and stage 3 AKI, complete-case analysis was used, since <2 patients had missing outcome status.c Calculated for the primary outcome only; for this analysis, missing data on postrandomization Scr (12 [1.0%] in the accelerated surgery group; 26 [2.1%] in the standard care group) were imputed using fully conditional specification (detailed in Item S2).d A composite of AKI (primary outcome definition) or death within 48 hours after randomization. For patients with at least 48 hours of follow-up postrandomization (to assess the death outcome) who were missing all postrandomization Scr, a value of 0 (no AKI or death within 48 hours) was imputed.e Defined as a postrandomization increase in Scr of ≥100% from the prerandomization value within 7 days after randomization or an increase to an absolute value of ≥4.0 mg/dL (353.6 μmol/L) within 7 days after randomization (when the primary outcome definition of AKI was met) or receipt of dialysis within 30 days after randomization. A patient was considered to have observed outcome data if ≥1 Scr was provided within 7 days after randomization or the patient was followed for ≥30 days after randomization to assess dialysis status.f Defined as a postrandomization increase in Scr of ≥200% from the prerandomization value within 7 days after randomization or an increase to an absolute value of ≥4.0 mg/dL (353.6 μmol/L) within 7 days after randomization or receipt of dialysis within 30 days after randomization. A patient was considered to have observed outcome data if ≥1 Scr was provided within 7 days after randomization or the patient was followed for ≥30 days after randomization to assess dialysis status.g Receipt of dialysis within 30 days after randomization. A patient was considered to have observed outcome data if the patient was followed for ≥30 days after randomization to assess dialysis status. Open table in a new tab The strengths of this substudy include its randomized concealed allocation, recruitment from 69 hospitals in 17 countries, and standardized collection of postrandomization Scr. Three limitations merit discussion. First, baseline Scr was obtained at the time of hospital admission for 99% of patients. Depending on the circumstances of the fracture, instability in the baseline measurement could complicate detecting an acute rise in postrandomization Scr, which is needed to identify AKI. That said, the average baseline Scr was 0.96 mg/dL, a level considered normal. Second, urine output data were not collected, given challenges with accurate measurement in an international setting. Third, we were underpowered to detect an RR reduction <30% for the primary AKI outcome. Therefore, we conducted prespecified analyses of the percentage change and the absolute change to the peak postrandomization Scr; however, no statistically significant between-group differences were observed. In summary, the risk of perioperative AKI was not significantly different in patients allocated to accelerated surgery versus standard care for hip fracture. AKI occurred nearly twice as often in patients with versus without CKD (21% vs 11%); however, regardless of CKD status, the risk of AKI was not significantly lower with accelerated surgery versus standard care. Research idea and study design: AXG, FKB, JMS, PJD; data acquisition: ANN, AO, AP, ARL, AS, AXG, BMB, CYW, EGF, FKB, GCAW, GS, JN, JSM, JTH, JV, KB, MB, MBC, MT, MTR, MU, PJD, PSancheti, PŚlęczka, RJ, RJF, SP, VH, VT, WS; data analysis/interpretation: AXG, FKB, JMS, KB, MC, PJD; statistical analysis: KB, MC; supervision or mentorship: AXG, FKB, JMD, PJD. Each author contributed important intellectual content during manuscript drafting or revision and agrees to be personally accountable for their own contributions and to ensure that questions pertaining to the accuracy or integrity of any portion of the work, even one in which the author was not directly involved, are appropriately investigated and resolved, including with documentation in the literature if appropriate. A list of the HIP ATTACK-1 collaborators is in Item S3. This work was supported by the Canadian Institutes of Health Research (CIHR) Foundation Award, CIHR’s Strategy for Patient-Oriented Research (SPOR), through the Ontario SPOR Support Unit (OSSU), as well as the Ontario Ministry of Health and Long-Term Care, and a grant from Smith & Nephew to recruit 300 patients in Spain. Grants to support this substudy were provided by the Department of Medicine at Western University. FKB holds a McMaster University Department of Medicine Career Research Award. PJD was supported by a Tier 1 Canada Research Chair in Perioperative Medicine. AXG was supported by the Dr Adam Linton Chair in Kidney Health Analytics and a CIHR Clinician Investigator Award. No funding entity had a role in data collection, statistical analysis, manuscript writing, or the decision to publish. The authors declare that they have no other relevant financial interests. The conduct, trial analyses, the composing of this manuscript, and its final contents are solely the authors’ incumbency. Received August 12, 2021. Evaluated by 2 external peer reviewers, with direct editorial input from a Statistics/Methods Editor, an Associate Editor, and the Editor-in-Chief. Accepted in revised form January 14, 2022. Download .pdf (.42 MB) Help with pdf files Supplementary File (PDF)Figures S1-S2; Items S1-S3; Tables S1-S6.