Non-compliance with clinical guidelines increases the risk of complications after primary total hip and knee joint replacement surgery.

BACKGROUND: Total hip and total knee replacement (THR/TKR) are common and effective surgeries to reduce the pain and disability associated with arthritis but are associated with small but significant risks of preventable complications such as surgical site infection (SSI) and venous-thrombo-embolism (VTE). This study aims to determine the degree to which hospital care was compliant with clinical guidelines for the prevention of SSI and VTE after THR/TKR; and whether non-compliant prophylaxis is associated with increased risk of complications. METHODS AND
FINDINGS: A prospective multi-centre cohort study was undertaken in consenting adults with osteoarthritis undergoing elective primary TKR/THR at one of 19 high-volume Australian public or private hospitals. Data were collected prior to surgery and for one-year post-surgery. Four adjusted logistic regression analyses were undertaken to explore associations between binary non-compliance and the risk of surgical complications: (1) composite (simultaneous) non-compliance with both (VTE and antibiotic) guidelines and composite complications [all-cause mortality, VTE, readmission/reoperation for joint-related reasons (one-year) and non-joint-related reasons (35-days)], (2) VTE non-compliance and VTE outcomes, (3) antibiotic non-compliance and any SSI, and (4) antibiotic non-compliance and deep SSI. Data were analysed for 1875 participants. Guideline non-compliance rates were high: 65% (VTE), 87% (antibiotics) and 95% (composite guideline). Composite non-compliance was not associated with composite complication (12.8% vs 8.3%, adjusted odds ratio [AOR] = 1.41, 95%CI 0.68-3.45, p = 0.40). Non-compliance with VTE guidelines was associated with VTE outcomes (5% vs 2.4%, AOR = 2.83, 95%CI 1.59-5.28,p < 0.001). Non-compliance with antibiotic guidelines was associated with any SSI (14.8% vs 6.1%, AOR = 1.98, 95%CI 1.17-3.62,p = 0.02) but not deep infection (3.7% vs 1.2%,AOR = 2.39, 95%CI 0.85-10.00, p = 0.15).
CONCLUSIONS: We found high rates of clinical variation and statistically significant associations between non-compliance with VTE and antibiotic guidelines and increased risk of VTE and SSI, respectively. Complications after THR/TKR surgery may be decreased by improving compliance with clinical guidelines.

Background

Primary elective total hip replacement (THR) and total knee replacement (TKR) are effective surgical procedures that reduce pain and disability associated with severe arthritis [1, 2]. In 2019, over 97,000 THR and TKR were performed in Australia [3] and nearly 232,000 in the United [4]. Demand for these procedures continues to grow [5, 6]. Although these procedures are cost-effective, they are associated with a small but important risk of complications that increase mortality, morbidity and cost [1, 7].

THR and TKR patients are considered at risk of venous thromboembolism (VTE) and surgical site infection (SSI), both of which are associated with poorer patient experience, high disease burden and increased costs for patients and the health system [8-10]. There is strong evidence that prophylaxis for VTE and SSI after THR and TKR is effective [11, 12]. Compliance with the available evidence-based clinical guidelines [13-15] is thought to be low and contributes to unwarranted variation in current VTE and antibiotic prophylaxis between surgeons and hospitals [16-18]. Although patient care may need to be varied from recommended care to address patient-specific issues, unwarranted variation may increase costs and negatively impact patient outcomes and service capacity [19, 20]. Consequently, programs to improve compliance with clinical guidelines are being implemented internationally due to the potential to improve the value of THR and TKR [21-23].

Despite clinical guidelines being evidence-based, prospective studies have not explored the association between compliance with recommended care and complications. Using a prospective cohort of participants who underwent elective TKR or THR in Australian hospitals, this study aims to determine the magnitude of guideline non-compliance and answer the following questions:

Is there an association between simultaneous non-compliance with both (antibiotic and VTE) guidelines and the rate of surgical complications after elective primary total joint replacement surgery?

Is there an association between non-compliance with VTE prophylaxis guidelines and VTE after elective primary total joint replacement surgery?

Is there an association between non-compliance with antibiotic guidelines and postoperative infection rate (considering all SSI and deep SSI requiring readmission/reoperation) after elective primary total joint replacement surgery?

Methods

Registration and data collection

A prospective observational cohort study of people undergoing elective primary total hip or knee replacement for osteoarthritis in one of 19 high-volume institutions in Australia was performed to examine the relationship between non-compliance with nationally recommended contemporaneous VTE prophylaxis guidelines and antibiotic guidelines and patient outcomes. Eligible sites included private and public Australian hospitals with high annual surgical volume (over 275 cases per year) of THR and TKR surgery. Inclusion criteria for participants in the study were: consenting adults (over 18 years) with a primary diagnosis of osteoarthritis undergoing primary TKR or THR; sufficient English to comprehend the protocol; and available to participate in follow-up for 12 months.

Investigators identified 36 eligible sites, including 27 identified through random selection from eligible sites listed on the Australian ’My Hospitals’ website and an additional nine sites identified by convenience sampling [24]. Twenty sites elected to participate, but one was denied governance approval leaving 19 participating sites. Sites were provided with face-to-face and remote training, study resources, ongoing support, and reimbursement for each eligible participant with complete acute data. Site coordinators screened and recruited participants during routine pre-admission assessment. Consecutive screening of all potential participants was planned although staff absences interrupted screening at some sites. Prior to commencement, the study protocol was registered (NCT01899443) [25] and ethical approval was obtained from nine human research ethics committees.

Prior to data collection informed written consent was obtained from eligible participants and the signed consent form was witnessed by the site coordinator. The site coordinators collected prospective pre-operative data from participants via interview, including socio-demographic information, past medical history, indications, and contraindications for VTE and antimicrobial prophylaxis, and acute care data from the medical records. Participants provided post-acute data via telephone follow-up at approximately 35, 90, and 365 days post-surgery. Participants and sites provided details regarding prophylaxis and surgical complications.

The researchers completed an audit of all medical records and by contacting surgeons, primary care physicians and other hospitals to verify the accuracy of patient-reported and acute complications. Any reported complication was coded as a dichotomous variable to indicate whether the participant did or did not experience the complication. The primary outcome was a composite outcome comprising all-cause mortality, any VTE and any reoperation or readmissions within 35 days for medical issues or within 365 days for joint-related complications. Secondary outcomes included any VTE event [pulmonary embolism (PE) or deep vein thrombosis (DVT)], any SSI (requiring oral or IV antibiotics, readmission, or reoperation) and only deep SSI (requiring readmission or reoperation) up to 365 days post-surgery.

Criteria for compliance with clinical guidelines

Compliance was calculated with the recommendations of two nationally produced guidelines for Australian health services:

National Health and Medical Research Council (NHMRC) Clinical Practice Guideline for the Prevention of Venous Thromboembolism (Deep Vein Thrombosis and Pulmonary Embolism) in Patients admitted to Australian hospitals (2009) [13]; and

Therapeutic Guidelines: Antibiotic Version 14 (2010) [14]

These guidelines were current during the study. Discrete elements of compliance were identified from the recommendations in each guideline. Investigators engaged in an a priori iterative consensus process to determine clear criteria for compliance versus non-compliance with each element of care compliance that could be consistently applied to assess the variety of prophylactic regimens (See Table 1). This process was vital where recommendations were ambiguous or hard to define and allowed patient appropriate deviation to be considered compliant.

Table 1

Criteria for compliance with NHMRC guidelines for prevention VTE (2009) [13] and therapeutic guidelines antibiotics (2010) [14].

Criteria for compliance:	VTE prophylaxis
1. Right drug	If no contraindications one or more recommended drugs: Low molecular weight heparins (LMWH—enoxaparin or dalteparin), fondaparinux, rivaroxaban, dabigatran etexilate; warfarin / unfractionated heparin (UFH). Use of other drugs, for example aspirin was ignored in determining compliance.
2. Right dose	≥40mg enoxaparin sodium (or ≥20mg if renal impairment); ≥5000u dalteparin (or ≥2500u if renal impairment), ≥2.5mg fondaparinux, ≥10mg rivaroxaban, ≥150mg dabigatran etexilate, any dose warfarin or UFH. Every dose of all recommended drugs used must be at the dose recommended in the guidelines or higher
3. Right duration of chemical prophylaxis	At least one recommended drug commences on Day 0 (day of surgery) or Day 1 AND continues for at least the minimum recommended duration for that drug, with no more than 2 missed days for any reason. The recommended duration is ≥ 27 days for THR and ≥ 9 days for TKR. Any duration was considered compliant if VTE was diagnosed within this period.
4. Right mechanical device/s used	If eligible for chemical and mechanical prophylaxis, THR to use at least one of: foot pumps, calf compressors, or graduated compression stockings (GCS). TKR to use at least one of either foot pumps or calf compressors.
	If not eligible for chemical prophylaxis, both THR and TKR to use two mechanical devices, unless contraindicated.
	If not eligible for either chemical or mechanical prophylaxis can use or not use any device without penalty.
VTE compliance	Compliant with 1 AND 2 AND 3 AND 4
Criteria for compliance:	Antibiotic Prophylaxis
5. Right drug	Only cefazolin OR flucloxacillin OR vancomycin (only if indicated*)
6. Right dose	1g (or 2g if ≥ 80kg) cefazolin; 2g flucloxacillin; 25mg/kg up to 1.5g (≥ 60kg = 1.5g) vancomycin. If surgery time exceeds 3 hours or is continuing 4 hours after first dose, patients should receive a second dose of cefazolin or flucloxacillin intra-operatively.
7. Right pre-op timing	The first dose of any antibiotic is given at the time of induction (up to any time prior to skin incision). We ignored the recommendation re commencing antibiotics when tourniquet used in TKR at if given within 5 mins prior to tourniquet inflation, or just before release).
8. Right duration	Prophylactic antibiotics were ceased within 27 hours and if vancomycin was used only a single dose given.
Antibiotic compliance	Compliant with 1 AND 2 AND 3 AND 4
Composite compliance	Compliant with all VTE guideline elements 1 AND 2 AND 3 AND 4, AND all Antibiotic guideline elements 1 AND 2 AND 3 AND 4

*Indications: allergy to penicillin, cephalosporins or all beta-lactam antibiotics, history of multi-resistant organisms, hospital admission longer than 5 days within 3 months preoperatively.

The study criteria for VTE compliance for the appropriate prophylactic agent and dose were more lenient than the guideline recommendations. The NHMRC recommendations were ambiguous about the use of warfarin in relation to the concurrent management of cardiovascular disease [13]. We allowed (as ’compliant’) the use of warfarin or UFH and higher than recommended doses for any recommended drug. While neither warfarin nor heparin are commonly used for primary VTE prophylaxis in Australia, this enabled clinically appropriate decisions regarding therapy for comorbid conditions to take priority over preventing a potential VTE. We could not reach agreement regarding the duration of mechanical prophylaxis based on the recommendation to use ’until regained full mobility’, so compliance with mechanical prophylaxis was not included [13].

The guideline recommendations regarding antibiotic prophylaxis were less ambiguous [14]. We used patient-reported indications and contraindications to indicate when vancomycin was used appropriately but did not impose penalty for non-use of vancomycin given participants may not be accurate in reporting allergies. Regarding the criteria for compliant duration of antibiotics, we allowed 3 hours longer than the 24 hours recommended to accommodate minor variations in scheduled drug administration.

Compliance was assessed as a series of dichotomous variables for each element of the guideline, for patients who completed at least one follow-up. Prophylaxis was considered non-compliant with the overall guideline if one or more elements were considered non-compliant. Composite (overall) compliance required prophylaxis that was compliant with all elements of both the VTE and the antibiotic guidelines.

Determining compliance required assessment of complex data describing the prophylaxis received as well as patient specific indications and contra-indications. Computer-based algorithms were developed in R to automatically generate compliance results. This ensured the consistent application of the criteria for compliance and the accuracy of these data was confirmed by comparing these results with manually calculated compliance results.

Sample size calculation

Based on a previous study [26], the a priori compliance to non-compliance ratio in these participants was taken to be 2:1 (i.e. 67% versus 33%), and the prevalence of the composite outcome to be 7% in the compliance subgroup (reference group). Calculation determined that 1102 participants in the compliant group and 551 participants in the non-compliant group (1653 in total) would provide 80% power at a 5% significance level to detect a significant Relative Risk (RR) of 1.6 for non-compliance. The prevalence of the composite outcome was estimated to be 11% in the non-compliant group compared to 7% in the compliant group. The planned sample size was increased to 2200 to consider a multiple correlation coefficient of 0.1 among known confounders and allow for 7% loss to follow-up by 35 days.

Data analyses

All data were entered into a designated REDCap database hosted by the University of New South Wales [27]. Initial analysis was performed (by WX) using SAS [28]. All final analyses were conducted Independently (by TC, HB and IAH) using Foundation for Statistical Computing Platform (version 3.6.1) [29]. Descriptive statistics were calculated to profile site-level and participant-level characteristics. Results were presented as the median and inter-quartile range (IQR) or mean and standard deviation (SD). Some variables [bilateral joint, smoking status, American Society of Anesthesiology score (ASA), education, neuraxial anaesthesia] were collapsed to allow for adequate sample size or clinically meaningful groups to be included in analyses. Bivariable analyses were undertaken for each outcome.

We conducted four conducted multiple logistic regression analyses to explore associations between non-compliance and risk of outcomes as follows: (1) non-compliance with both VTE and antibiotic guidelines and composite outcomes (2) VTE non-compliance and VTE outcomes, (3) antibiotic non-compliance with any SSI and (4) antibiotic non-compliance and deep SSI. Patient and care factors known to increase the risk of surgical complications (including VTE and SSI) were considered as potential confounders [30-32]. Factors identified on univariate analysis with a p-value < 0.25 were entered into a backwards, stepwise multivariable logistic regression model (using the Akaike information criterion–AIC) to identify the association between guidelines compliance and complication outcomes for each analysis. We reported the final model after backwards stepwise regression using AIC and forcing only the main predictor (non-compliance) into each model.

Missing data were imputed using multivariate imputation by chained equations (MICE). Model selection was performed using one of the imputed datasets, and effect estimates were taken from the pooled estimates using the five imputed datasets. We tested the models with all two-way interaction terms entered, and none of these was significant. Sensitivity analyses were performed using complete case analysis and Bayesian information criterion (BIC). Further sensitivity analyses were completed without including routine doppler ultrasound (DUS), given this may mediate VTE complication outcomes. Interaction terms for the main predictor (non-compliance) against each other variable were tested in the final model for each analysis. A de-identified version of the data set and the full R code for all analyses are available (https://doi.org/10.26190/c46r-ne05).

Results

Sample ascertainment

Seventy-seven percent (2529/3285) of all patients screened were eligible for participation (See Fig 1). Of these, 2143 people provided consent preoperatively, and data were received for 1905 (88.9%) consenting participants as some did not proceed to surgery or no acute data were received by investigators. Thirty (1.6%) people were excluded from analyses as they did not have any post-acute follow up. Missing data for each variable was less than 2% for all variables except ASA class (2.2% missing).

Fig 1

Participant recruitment, eligibility, and participation results.

Sites, surgeon and participant characteristics

Site, surgeon, and participant characteristics are provided in Table 2. There were 19 sites from five Australian states. Sites included 10 public hospitals that completed 45.9% of surgical procedures, the other sites being private hospitals. The number of participants ranged from 12 to 294 from each site, and 1–125 per surgeon. Routine Doppler ultrasound was performed by one site and two surgeons at two other sites.

Table 2

Site, surgeon and participant characteristics.

Site & surgeon Characteristics	Description, N (%), median (IRQ)	Results
Sites	Public	10 (54%)
	Private	9 (46%)
Number surgeons		121
Number participants	Per surgeon [Median (IQR)]	8 (16)
	Per site [Median (IQR)]	70 (44)
Length of stay (days)	Median (IQR)	5 (3)
Participant characteristics	Description, N (%), median (IRQ)	N = 1875
Joint (all surgeries)	Hip	815 (43.5%)
	Knee	1060 (56.5%)
Bilateral joint replacement	Hip	10 (0.5%)
	Knee	81 (4.3%)
Public hospital	Yes	861 (45.9%)
Duration of surgery (mins)	Median (IQR)	70 (44)
Age (years)	Median (IQR)	67.6 (12.9)
Sex	Female	1017 (54.2%)
Insurance status	Public	821 (43.8%)
	Private health insurance	980 (52.3%)
	Self-funded (private)	29 (1.5%)
	Other insurance / compensation	16 (0.9%)
	Department of Veterans Affairs	29 (1.5%)
Post-school education	Up to school completion	895 (48%)
status (N = 1866)	Post school qualification	971 (52%)
BMI	Median (IQR)	29.7 (7.9)
Current smoker	No	1710 (91.7%)
(N = 1865)	Yes	155 (8.3%)
Comorbid conditions	Heart disease	474 (25.3%)
	History stroke	113 (6%)
	Bleeding disorder	19 (1%)
	Previous VTE (N = 1873)	149 (8%)
	Diabetes	306 (16.3%)
	Hypertension	1142 (60.9%)
	High cholesterol	702 (37.4%)
	Kidney disease	63 (3.4%)
	Liver disease	49 (2.6%)
	Current cancer (any type)	41 (2.2%)
	History of any type cancer (N = 1873)	220 (11.7%)
	Lung disease	341 (18.2%)
	Anxiety / depression	350 (18.7%)
	Mental health disorder	22 (1.2%)
	Gastro-intestinal Reflux Disorder (GORD)	486 (25.9%)
	Sleep apnoea	133 (7.1%)
	Neurological conditions	53 (2.8%)
	Musculoskeletal conditions (N = 1873)	907 (48.4%)
	Any other comorbid conditions	729 (38.9%)
Previous total joint replacement	Hip	244 (13%)
	Knee	308 (16.4%)
Medications taken for	Paracetamol	1086 (57.9%)
osteoarthritis	Non-steroidal anti-inflammatories (NSAIDS)	523 (27.9%)
	Opioids	385 (20.5%)
	Antidepressant / antiepileptics	36 (1.9%)
	Steroids	6 (.3%)
Recommended indications for vancomycin	Self-reported allergy to penicillin, cephalosporin, or all beta-lactam ABs	222 (11.8%)
	Patient history of MRSA infection / swab	85 (4.5%)
	Patient history of gram-negative infection(s)	1 (0.1%)
	Hospital admission with LOS > 5 days within 3 months of THR or TKR	14 (0.7%)
American Association Anaesthetists (ASA) score(N = 1833)	1 or 2	1246 (68%)
	3 or 4	587 (32%)
Acute processes of care	Routine doppler performed (N = 1847)	347 (18.8%)
	Cement fixation used (N = 1874)	1204 (64.2%)
	Tranexamic acid used (N = 1868)	1127 (60.3%)
	Neuraxial anaesthesia (N = 1874)	1182(63.0%)
	Intra-articular Drain (N = 1869)	825 (44.1%)
	Tourniquet (only used for TKA)	909 (48.5%)
	Blood transfusion (N = 1868)	332 (17.8%)
Mobilisation post-surgery	First mobilised day 0 or 1	1395 (74.7%)

Indications for appropriate use of vancomycin were reported for 17.2% (N = 322) of the sample, although vancomycin was used appropriately in 31.6% of the 136 of people who received it and not used in 14.1% of participants with relevant indications (See Table 3 and S1 and S2 Tables in S1 File). Almost 30% of all participants were taking pre-operative medications commonly used for postoperative VTE prophylaxis, and this included 20.4% of people who reported taking medication for comorbid heart disease (See S3 Table in S1 File).

Table 3

Prevalence of complications at one year included in the composite outcome.

Outcome	Yes
Mortality	12 (0.6%)
All VTE events	76 (4.1%)
Hospital readmissions	160 (8.5%)
Re-operations	107 (5.7%)
Total number of complication events	355
Number of people with a composite outcome	234 (12.5%)
All joint/ surgical site infections (treated with oral / IV antibiotics, readmission, reoperation)*	256 (13.7%)
Deep joint infections (treated with readmission or reoperation)	63 (3.4%)

*Participants with joint infection that required hospital readmission, or a reoperation were included in the composite outcome.

Participant outcomes: Surgical complications up to one year

There were 355 surgical complications that met the criteria for the composite complication that were experienced by 234 (12.5%) participants (See Table 3). Five participants died from surgical complications, and seven died from medical causes unrelated to the surgery. The incidence of VTE was 4.1% (N = 76), with nearly three-quarters of the cases being DVT alone (See Table 3 & S4 Table in S1 File). Joint-related complications in the first year after surgery accounted for 85.9% (N = 159/185) of all readmissions and 88.8% (119/134) of all reoperations (See Table 3 & S5-S7 Tables in S1 File). Deep infection included joint or wound infections requiring intravenous (IV) antibiotics or readmission (N = 46) or reoperation (N = 17) and were experienced by 3.4% (N = 63) of the participants. Bleeding complications requiring readmission/reoperation were experienced by 7 (0.37%) people for joint-related bleeding and 10 (0.53%) people for on-joint related bleeding (See S8 Table in S1 File) [33].

VTE, antibiotic and combined (composite) compliance

Table 4 reports all compliance results. The level of compliance with both VTE and antibiotic guidelines was 4.5%. Overall compliance with all VTE recommendations was 35.3% [13]. Contrary to expectation, the use of multiple medications for postoperative VTE prophylaxis was common, with 45.5% (N = 854) of people receiving 2–4 different medications (See S2 Table in S1 File). Nearly a third of participants took a drug at higher or lower than recommended dose, and the duration of prophylaxis was longer than recommended for 33% THR and 58% TKR participants [13]. Overall compliance with antibiotic guidelines was 13.2% [14]. Fewer than half the sample received a single prophylactic antibiotic (46.4%), while 8.1% received 3 or 4 different antibiotics (See S1 & S2 Tables in S1 File). The most used antibiotic was cephazolin (90.7%).

Table 4

VTE, antibiotic and combined (composite) compliance.

Criteria for VTE compliance	Yes (N, %)
1. Right drug (N = 1875)	1518 (81%)
2. Right dosage (N = 1860)	1323 (70.6%)
3. Right duration (Hip: ≥ 28 days, Knee: ≥ 10 days) (N = 1875)	847 (45.2%)
4. Right mechanical device / joint N = 15	1703 (90.8%)
Compliant with NHMRC (1, 2, 3, 4) (N = 1860)	657 (35.3%)
Criteria for antibiotic compliance	Yes (N, %)
1. Right drug (N = 1875)	1418 (75.7%)
2. Right dosage (including intra-op dose for op > 3hrs) (N = 1874)	446 (23.8%)
3. Right pre-op timing (any) (N = 1875)	1780 (94.9%)
4. Right duration (N = 1875)	1025 (54.7%)
Compliant with TG: AB (Yes 1, 2, 3, 4) (N = 1874)	247 (13.2%)
Combined (composite) VTE and AB compliance (N = 1858)	84 (4.5%)

Association between composite non-compliance and composite surgical complications

The higher incidence of composite outcome in the (overall) non-compliant group was not statistically significant in either the unadjusted or adjusted analyses (See Table 5). There were no differences in any sensitivity analyses, with the effect estimate for composite non-compliance remaining non-significant when routine doppler ultrasound was removed.

Table 5

Association between composite non-compliance and composite outcome.

Unadjusted analyses
Composite non-compliance (N = 1859)	No complications N (%)	Composite complications N (%)	p value (Chi-square)
Non-compliance	1548 (87.3%)	226 (12.7%)	0.23
Compliance	77 (91.7%)	7 (8.3%)
Total	1625 (87.3%)	233 (12.8%)
Adjusted analyses–final regression model results
Variables in the final model		Adjusted OR (95% CI)	p value
Composite non-compliance VTE and antibiotics clinical guidelines		1.41 (0.68–3.45)	0.40
Knee joint (TKR)		2.15 (1.59–2.96)	<0.001	***
Comorbid Kidney disease		2.01 (1.06–3.65)	0.03	*
Routine doppler		1.86 (1.33–2.59)	< .001	***
Comorbid musculoskeletal condition		1.44 (1.09–1.92)	0.01	*
1st day mobilised day 0 or 1		0.73 (0.53–0.99)	0.04	*
Taking NSAIDs for arthritis		0.66 (0.46–0.92)	0.02	*
Premorbid history of stroke		1.51 (0.88–2.48)	0.12
Comorbid GORD		1.30 (0.95–1.76)	0.10	.

Significance. codes

***< 0.001

** <0.01

* <0.05.

Association between VTE non-compliance and VTE outcomes

There was a significantly higher incidence of VTE outcomes in the (VTE prophylaxis guideline) non-compliant group in both the unadjusted (p = 0.008) and adjusted analyses [5.0% vs 2.4%, AOR = 2.75, 95%CI 1.57–5.08, p < 0.001) (See Table 6). There were no meaningful differences in the effect estimate for VTE non-compliance (AOR = 2.62) or model results when routine doppler ultrasound was excluded from the model. There was no significant interaction between the main predictor (non-compliance) and other variables included in the final model and the other three analyses completed.

Table 6

Association between VTE non-compliance and VTE outcomes (final model).

Unadjusted analyses
VTE non-compliance (N = 1860)	No VTE complications N (%)	VTE complications N (%)	p value (Chi-square)
Non-compliance	1143 (95%)	60 (5%)	0.008
Compliance	641 (97.6%)	16 (2.4%)
Total	1784 (95.9%)	76 (4.09%)
Adjusted analyses–final regression model results
Variables in the final model		Adjusted OR (95% CI)	p value
Non-compliance VTE clinical guidelines		2.75 (1.57–5.08)	<0.001	***
Routine doppler		4.00 (2.41–6.65)	<0.001	***
Knee joint (TKR)		2.83 (1.59–5.28)	<0.001	***
Comorbid heart disease		1.81 (1.05–3.07)	0.03	*
History previous VTE		1.85 (0.85–3.67)	0.09	.
Comorbid musculoskeletal condition		1.48 (0.91–2.42)	0.11
Higher BMI		1.03 (0.99–1.07)	0.11
Increasing age		1.03 (1.00–1.06)	0.07	.
Completed any post school education		0.70 (0.43–1.14)	0.15
1st day mobilised day 0 or 1		0.66 (0.40–1.11)	0.11
Higher ASA Score (3 or 4)		0.65 (0.37–1.11)	0.12
Comorbid depression or anxiety		0.61 (0.28–1.18)	0.17

Significance. codes

***< 0.001

** <0.01

* <0.05.

Association between antibiotic non-compliance and all joint infection outcomes

There was a significantly higher incidence of joint infection outcomes in the (antibiotics guideline) non-compliant group in both the unadjusted (p = <0.001) and adjusted analyses (14.8% vs 6.1%, AOR = 1.98, 95%CI 1.17–3.62, p = 0.02) (See Table 7). VTE compliance was included in the SSI models as it was significant on bivariable analysis for both SSI outcomes and a biologically plausible confounder for infection. Non-compliance with VTE guidelines was also associated with all SSI outcomes (AOR = 1.52, 95%CI 1.11–5.42-, p < 0.01). There was no significant interaction between the main predictor (non-compliance) and other variables included in the final model.

Table 7

Association between antibiotic non-compliance and any Surgical Site Infection (SSI) outcome.

Unadjusted analyses
Antibiotic non-compliance (N = 1872)	No SSI	Any SSI complications N (%)	p value (Chi-square)
Non-compliance	1385(85.2%)	241 (14.8%)	< .001
Compliance	232(93.9%)	15 (6.1%)
Total	1616 (86.3%)	256 (13.7%)
Adjusted analyses: Antibiotic compliance and all surgical site infections
Variables in the final model		Adjusted OR (95% CI)	p value
Non-compliance antibiotic clinical guidelines		1.98 (1.17–3.62)	0.02	*
Taking antiepileptic/antidepressant for arthritis		2.54 (1.11–5.42)	0.02	*
Knee joint (TKR)		2.40 (1.75–3.33)	<0.001	***
Comorbid neurological condition		2.13 (1.05–4.06)	0.03	*
Non-compliance VTE clinical guidelines		1.52 (1.13–2.05)	0.01	**
Taking NSAIDs for arthritis		1.37 (1.01–1.84)	0.04	*
Longer surgical duration		1.01 (1.00–1.01)	<0.001	***
Higher BMI		1.04 (1.02–1.06)	<0.001	***
Private hospital		0.70 (0.51–0.95)	0.02	*
Bilateral joint replacement		0.28 (0.11–0.60)	< .001	**
Premorbid history of stroke		1.57 (0.92–2.57)	0.09	.
Comorbid sleep apnoea		1.46 (0.91–2.29)	0.11
Received blood transfusion		1.32 (0.92–1.89)	0.13
Comorbid lung disease		0.72 (0.50–1.04)	0.09	.

Significance. codes

***< 0.001

** <0.01

* <0.05.

Association between antibiotic non-compliance and deep joint infection outcomes

The higher rate of deep infections in the non-compliant group (3.7%) than the compliant group (1.2%) was statistically significant in the unadjusted analysis but not in the adjusted analysis (3.7% vs 1.2%, AOR = 2.39, 95%CI 0.85–10.00, p = 0.15) (See Table 8).

Table 8

Association between antibiotic non-compliance and deep SSI outcomes.

Unadjusted analyses
Antibiotic non-compliance (N = 1873)	No deep SSI	Deep SSI complications N (%)	p value (Chi-square)
Non-compliance	1566 (96.3%)	60 (3.7%)	0.04
Compliance	244 (98.8%)	3 (1.2%)
Total	1810 (96.6%)	63 (3.4%)
Antibiotic compliance and deep surgical site infection outcomes
Variables in the final model		Adjusted OR (95% CI)	p value
Non-compliance antibiotic clinical guidelines		2.39 (0.85–10.00)	0.15
Current smoker		2.76 (1.32–5.33)	< .001	*
Knee joint (TKR)		2.70 (1.46–5.40)	< .001	*
Higher BMI		1.07 (1.03–1.10)	<0.001	***
Comorbid neurological condition		2.48 (0.72–6.56)	0.10	.
Premorbid history of stroke		2.22 (0.89–4.82)	0.06	.

Significance. codes

***< 0.001

** <0.01

* <0.05.

Sensitivity analyses using a complete case analysis and using BIC model selection criteria did not demonstrate different results (See S1-S8 Tables in S1 File).

Discussion

This is the first study to systematically examine the relationship between patient appropriate recommended care using Australian clinical guidelines for the prevention of VTE and infection after elective THA and TKA and adverse patient outcomes. The study showed important and statistically significant associations between non- compliance with VTE prophylaxis guidelines and VTE complications, and non-compliance with antibiotic prophylaxis guidelines and increased risk of surgical site infection.

These results are consistent with one previous study that demonstrated increased risk of infection associated with non-compliance with the Therapeutic Guidelines Antibiotic (OR = 2.74, 95% CI 1.15–6.53), although this study also included patients undergoing THR for hip fracture [34]. Direct comparison with other studies is difficult due to variation in clinical guidelines used, the criteria for compliance, mixed surgical caseloads, limitations associated with administrative data and lack of follow-up in some studies [26, 35, 36]. These factors may explain the variation reported in previous studies. While some previous studies reported significant association between complications and adherence to evidence-based antibiotic [34, 37, 38] and VTE prophylaxis [39], other studies showed no significant difference in outcomes [23, 35, 40]. Unlike previous research, we did not observe a significant association between risk of complications and non-compliance with a composite process of care [26]. While the use of a composite measure aimed to reflect overall service quality, this may have masked the association between specific processes of care and outcomes [41, 42].

This study also demonstrated extremely high rates of non-compliance with both guidelines (95.6%), and VTE (63.5%) and antibiotic prophylaxis (86.7%) guidelines individually. The rate of VTE non-compliance was higher than other Australian studies (38–53% and 42% respectively) [18, 43]. The rate of antibiotic non-compliance reported in this study was much higher than recent Australian studies using the same antibiotic guidelines which reported 34% and 38.7% non-compliance [34, 44], but consistent with earlier Australian studies (86% and 86.7%) [43, 45]. In contrast, a Surgical Care Improvement Project study from the United States reported non-compliance rates as low as 4% for preventing infection and 2.5% for preventing VTE using administrative data [35]. International studies also reported wide variation in VTE and antibiotic guideline adherence, but again direct comparison remains difficult due to the use of different study methods, lack of adjustment for patient-appropriate variations and mixed patient populations [17, 46].

Our study also demonstrated high levels of unwarranted clinical variation in routine care to prevent infection and VTE after TKR and THR. The use of multiple prophylactic drugs, higher than recommended dose, and longer than recommended duration of prophylaxis, were surprising given the risks associated with inappropriate care [16, 47–50]. Prolonged VTE prophylaxis may increase the risk of bleeding; conversely when the duration or dose is insufficient, prophylaxis may be inadequate [50]. The high level of antibiotic overuse is concerning given the evidence suggesting that longer duration provides no additional protection against infection and has been associated with an increased risk of adverse events, antibiotic resistance, and higher cost of care [51, 52]. Nearly 60% of participants received more than one antibiotic when a single pre-operative dose of a single antibiotic is considered sufficient [12]. Inadequate prophylaxis due to underdosing is associated with higher risk of infections [53]. Given the risks associated with inappropriate care, further efforts to increase the implementation of evidence-based prophylaxis are urgently needed to improve the value and outcomes from THR and TKR [20, 21, 54].

This study has several limitations. Our sample was relatively consistent with national joint registry data for age, sex, body mass index (BMI) and ASA scores but included a higher proportion of THR and higher rate of surgery performed in public versus private hospitals [3]. Alternative approaches to determine compliance and use of different clinical guidelines may yield different results, however we considered our criteria to be more lenient than a strict interpretation of the guidelines. Further research should explore whether specific features of prophylactic regimes have greater impact on reducing risk of complications. Replicating this study with current Australian and international guidelines for the prevention of VTE and surgical site infection is recommended [55].

A key strength of this study lies in the prospectively collected and audited clinical data and low rate of missing data that describes care provided in detail as opposed to large administrative data that may be prone to coding errors [56-58]. The current study allowed more comprehensive analyses of detailed processes of care from evidence-based clinical guidelines for the prevention of VTE and infection than previous studies [26, 59, 60]. We used robust criteria and computer-based algorithms for assessing compliant care that addressed patient-specific variations, as clinical decisions made in the patient’s best interests may be deemed ’technically’ non-compliant. The rigour of our approach and use of prospectively collected clinical data may help to explain the much higher rates of non-compliance we reported compared to most previous studies [9, 58].

The increased risk of VTE and infection complications associated with low levels of compliance with evidence-based prophylaxis suggest that further work to improve the implementation of clinical guidelines is needed. Reducing unnecessary clinical variation and preventing avoidable VTE and infection complications will improve the patient and service outcomes and should support cost-containment [20, 61]. Optimising patient outcomes from THR and TKR will improve the value and sustainability of these procedures.

Additional results.

(DOCX)

Click here for additional data file.

Transfer Alert

This paper was transferred from another journal. As a result, its full editorial history (including decision letters, peer reviews and author responses) may not be present.

26 Mar 2021

Submitted filename: Response to Reviewers_Badge_PONE-D-18-18793_26_03_2021_FINAL.pdf

Click here for additional data file.

11 Oct 2021

PONE-D-21-07165Non-compliance with clinical guidelines increases the risk of complications after total hip and knee joint replacement surgeryPLOS ONE

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Reviewer #1: First, thank you so much for providing the opportunity to evaluate this work. This study gives important additional knowledge about complications after total hip and knee joint replacement surgery and need of compliance with evidence-based guidelines. The paper highlights a problem in a specific area which requires urgent attention. I congratulate the authors on the magnificent efforts and worthy research work. I think this work is acceptable for publication in your prestigious journal.

Reviewer #2: Review comments: PONE-D-21-07165

1. Does the manuscript provide a valid rationale for the proposed study, with clearly identified and justified research questions?

Reviewer comment:

This study is an important issue, but the authors have to clarify some statements. Are the compliance to the guidelines the only predictor factor to complication post-surgery?

Reference:

Schwartz FH, Lange J. Factors That Affect Outcome Following Total Joint Arthroplasty: a Review of the Recent Literature. Curr Rev Musculoskelet Med. 2017;10(3):346-355. doi:10.1007/s12178-017-9421-8.

Heo, S.M., Harris, I., Naylor, J. et al. Complications to 6 months following total hip or knee arthroplasty: observations from an Australian clinical outcomes registry. BMC Musculoskelet Disord 21, 602 (2020). https://doi.org/10.1186/s12891-020-03612-8.

2. Is the protocol technically sound and planned in a manner that will lead to a meaningful outcome and allow testing the stated hypotheses?

Reviewer comment:

Yes, it is

3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable?

Reviewer comment:

The analysis methods isn’t clear. Logistic regression is used to describe data and to explain the relationship between one dependent binary variable and one or more nominal, ordinal, interval or ratio-level independent variables. This study: Logistic regression was undertaken to explore associations between non-compliance with:

(1) both VTE and antibiotic guidelines and the risk of composite surgical complications [all cause mortality, any VTE, readmission/reoperation for joint-related reasons (one-year) and non-joint-related reasons (35 days)], (2) VTE guidelines and VTE outcomes, (3) antibiotic guidelines and (3) all SSIs, and (4) deep SSIs (requiring readmission/reoperation).

This statement isn’t clear: Guideline non-compliance rates were high: 65% (VTE), 87% (antibiotics) and 95% for both guidelines. What ‘both guidelines’ mean? How 95% came from?

4. Have the authors described where all data underlying the findings will be made available when the study is complete?

The authors stated that all data are fully available without restriction.

5. Is the manuscript presented in an intelligible fashion and written in standard English?

Reviewer comment:

The authors must give attention to space between words in writing. There are some duplication sentences in the manuscript.

Reviewer #3: Thanks for submitting this interesting paper reviewing the association between VTE and SSI prophylaxis and patient outcomes. From the documentation provided the paper has undergone significant changes. The paper is well written and make a valuable contribution to the literature as there are relatively few papers that associate guideline adherence and patient outcomes.

I have a few comments regarding the paper, which are for clarity, as the aims, methods, results, and discussion are well linked and described. Note I am not a statistician and cannot comment on the rigor of the statistical analysis.

Throughout the manuscript there is a broken field link described as an error.

Abstract: please add the word "elective" to the description of the patient cohort in the methods.

The descriptions of the log regressions undertaken is confusing because it starts with "associations between non-compliance". A better description is provided in mid-page 11 that is simpler.

Intro: Add in the word primary to all the research questions. The term major adverse events is used in the first research question but complication is used in the rest of the manuscript. Please use one consistently.

Methods: telephone follow up with participants was performed but the pre-op data collection process was not described.

Discussion: I was unable to access the supplementary files and I am presuming that the data relating to the components of the guidelines that were reported as compliant or not are in these tables. I am checking as the 4th paragraph of the discussion is difficult to follow without this information.

**********

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Reviewer #1: No

Reviewer #2: Yes: Fauna Herawati

Reviewer #3: No

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29 Oct 2021

Reviewer #2 comments:

1. Does the manuscript provide a valid rationale for the proposed study, with clearly identified and justified research questions?

Reviewer feedback:

This study is an important issue, but the authors have to clarify some statements. Are the compliance to the guidelines the only predictor factor to complication post-surgery?

Reference:

Schwartz FH, Lange J. Factors That Affect Outcome Following Total Joint Arthroplasty: a Review of the Recent Literature. Curr Rev Musculoskelet Med. 2017;10(3):346-355. doi:10.1007/s12178-017-9421-8.

Heo, S.M., Harris, I., Naylor, J. et al. Complications to 6 months following total hip or knee arthroplasty: observations from an Australian clinical outcomes registry. BMC Musculoskelet Disord 21, 602 (2020). https://doi.org/10.1186/s12891-020-03612-8.

Response:

We acknowledge that there are many patient, surgeon and care factors associated with the risk of complications after total joint arthroplasty. The main aim of our study was to explore the association between non-compliance with the guidelines and complications, adjusted for likely confounders. The evidence on factors that may be associated with the outcomes informed data collection, and the variables assessed for inclusion in the models. We have listed many possible confounders (other causes or contributing factors) of complications including many of those listed in the references, and these data include many of those described in Table 2 including the participant characteristics ( socio-demographic information, past medical history, indications, and contraindications for VTE and antimicrobial prophylaxis), surgical (surgical duration, neuraxial anaesthesia, use of tranexamic acid etc) and acute processes of care (e.g. early mobilisation). In the results section, Tables 5-8 include the non-compliance and the variables that were retained in the final stepwise regression models for each analysis. To clarify this further we have included some additional text in the Data analyses section and references as suggested:

Extract from abstract (additional words underlined):

“Four adjusted logistic regression analyses were undertaken to explore associations between binary non-compliance and the risk of surgical complications.”

Word limit constraints prevent further elaboration in the abstract.

Extract from manuscript (additional words underlined):

“We conducted four multiple logistic regression analyses to explore associations between non-compliance and risk of outcomes as follows: (1) non-compliance with both VTE and antibiotic guidelines and composite outcomes (2) VTE non-compliance and VTE outcomes, (3) antibiotic compliance and any SSI and (4) antibiotic compliance and deep SSI. Patient and care factors known to increase the risk of surgical complications (including VTE, SSI) were considered as potential confounders (30-32).”

30. Alamanda VK, Springer BD. The prevention of infection: 12 modifiable risk factors. Bone Joint J. 2019 Jan;101-B(1_Supple_A):3-9. doi: 10.1302/0301-620X.101B1.BJJ-2018-0233.R1. PMID: 30648488.

31. Zhang, Zh., Shen, B., Yang, J. et al. Risk factors for venous thromboembolism of total hip arthroplasty and total knee arthroplasty: a systematic review of evidences in ten years. BMC Musculoskelet Disord 16, 24 (2015). https://doi.org/10.1186/s12891-015-0470-0.

32. Schwartz FH, Lange J. Factors that affect outcome following total joint arthroplasty: a review of the recent literature. Curr Rev Musculoskelet Med. 2017;10(3):346-355. doi:10.1007/s12178-017-9421-8.”

3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable?

Reviewer feedback:

The analysis methods isn’t clear. Logistic regression is used to describe data and to explain the relationship between one dependent binary variable and one or more nominal, ordinal, interval or ratio-level independent variables. This study: Logistic regression was undertaken to explore associations between non-compliance with:

(1) both VTE and antibiotic guidelines and the risk of composite surgical complications [all cause mortality, any VTE, readmission/reoperation for joint-related reasons (one-year) and non-joint-related reasons (35 days)], (2) VTE guidelines and VTE outcomes, (3) antibiotic guidelines and (3) all SSIs, and (4) deep SSIs (requiring readmission/reoperation).

Response:

We have amended the description of the logistic regression models undertaken.

Extract from abstract (additional words underlined):

“Four adjusted logistic regression analyses were undertaken to explore associations between binary non-compliance and risk of surgical complications: (1) composite (simultaneous) non-compliance with both VTE and antibiotic guidelines and composite complications [all-cause mortality, any VTE, readmission/reoperation for joint-related reasons (one-year) and non-joint-related reasons (35 days)], (2) VTE non-compliance and any VTE, (3) antibiotic compliance and any SSI, and (4) antibiotic compliance and deep SSI.”

Word limit constraints prevent further elaboration in the abstract.

As stated above, we have listed many possible confounders (other causes or contributing factors) of complications including many of those listed in the references, and these data include many of those listed in Table 2, including the participant characteristics (Socio-demographic information, past medical history, indications , and contraindications for VTE and antimicrobial prophylaxis), surgical (surgical duration, neuraxial anaesthesia, use of tranexamic acid etc) and acute processes of care (e.g. early mobilisation). In the results section, Tables 5-8 include the non-compliance and the variables that were retained in the final stepwise regression models for each analysis. To clarify this further we have included some additional text in the Data analyses section and references as suggested:

Extract from manuscript (additional words underlined):

In the Methods (P10) we have already stated that compliance variables were binary:

“Compliance was assessed as a series of dichotomous variables for each element of the guideline, for patients who completed at least one follow-up “.

We have clarified this on Page 11

“We conducted four multiple logistic regression analyses to explore associations between non-compliance and risk of outcomes as follows: (1) non-compliance with both (VTE and antibiotic) guidelines and composite outcomes (2) VTE non-compliance and VTE outcomes, (3) antibiotic non-compliance and any SSI and (4) antibiotic non-compliance and deep SSI. Patient and care factors known to increase the risk of surgical complications (including VTE, SSI) were considered as potential confounders (30-32).”

Reviewer feedback:

This statement isn’t clear: Guideline non-compliance rates were high: 65% (VTE), 87% (antibiotics) and 95% for both guidelines. What ‘both guidelines’ mean? How 95% came from?

Response:

The method section has been revised to clarify the methods that were undertaken and explain that compliance with both guidelines was required for an overall composite compliance as follows:

Extract from abstract (additional words underlined):

In the abstract we clarified that the first regression analysis explored:

(1) “composite (simultaneous) non-compliance with both (VTE and antibiotic) guidelines and composite complications”

and the following sentence has been revised:

“Guideline non-compliance rates were high: 65% (VTE), 87% (antibiotics) and 95% (composite compliance).”

Word limit constraints prevent further elaboration in the abstract.

Extract from manuscript (additional words underlined):

The first research question:

“ 1. Is there an association between simultaneous non-compliance with both (antibiotic and VTE) guidelines and the rate of surgical complications after elective primary total joint replacement surgery?”

In Table One we added

Composite compliance Compliant with all VTE guideline elements 1 AND 2 AND 3 AND 4, and all antibiotic guideline elements 1 AND 2 AND 3 AND 4

In the Methods (page 9) this is already described:

“Composite (overall) compliance required prophylaxis that was compliant with all elements of both the VTE and the antibiotic guidelines.”

Results. In table 4 we added:

Combined (composite) VTE and AB compliance (N=1858) 84 (4.5%)

5. Is the manuscript presented in an intelligible fashion and written in standard English?

Reviewer feedback:

The authors must give attention to space between words in writing. There are some duplication sentences in the manuscript.

Response:

The spacing between words and duplication has been examined and corrected as necessary.

Reviewer #3 comments:

Reviewer feedback:

1. Throughout the manuscript there is a broken field link described as an error.

Response:

Apologies for this oversight; this wasn’t apparent in the word document I had for the previous submission. Captions have been changed to plain font and I have checked that all links are working prior to submitting the revised manuscript.

Reviewer feedback:

2. Abstract: please add the word "elective" to the description of the patient cohort in the methods.

Response:

The abstract methods have been revised as requested:

Extract from abstract (additional words underlined):

“A prospective multi-centre cohort study was undertaken in consenting adults with osteoarthritis undergoing elective primary TKR/THR at one of 19 high-volume Australian public or private hospitals.”

Reviewer feedback:

3. The descriptions of the log regressions undertaken is confusing because it starts with “associations between non-compliance”. A better description is provided in mid-page 11 that is simpler.

Response:

As suggested, we’ve used the description of the logistic regression methods undertaken from mid page 11, with some amendments to ensure the abstract was within the word count limit as follows:

Extract from abstract (additional words underlined):

“Four adjusted logistic regression analyses were undertaken to explore associations between non-compliance and risk of complications: (1) composite (simultaneous) non-compliance with both (VTE and antibiotic) guidelines and composite complications [all-cause mortality, VTE, readmission/reoperation for joint-related reasons (one-year) and non-joint-related reasons (35 days)], (2) VTE non-compliance and VTE, (3) antibiotic compliance and any SSI, and (4) antibiotic compliance and deep SSI.”

Word limit constraints prevent further elaboration in the abstract.

Reviewer feedback:

4. Intro: Add in the word primary to all the research questions. The term major adverse events is used in the first research question but complication is used in the rest of the manuscript. Please use one consistently.

Response:

The word ‘primary’ has been added to the title and research question. The first research question revised, replacing major adverse events with surgical complications.

Extract from manuscript (additional words underlined):

Title:

“Non-compliance with clinical guidelines increases the risk of complications after primary total hip and knee joint replacement surgery.”

Research questions:

“1. Is there an association between non-compliance with both (antibiotic and VTE) guidelines and the rate of surgical complications after elective primary total joint replacement surgery?

2. Is there an association between non-compliance with VTE prophylaxis guidelines and VTE after elective primary total joint replacement surgery?

3. Is there an association between non-compliance with antibiotic guidelines and post-operative infection rate (considering all SSI and deep SSI requiring readmission/reoperation) after elective primary total joint replacement surgery?”

Reviewer feedback:

5. Methods: telephone follow up with participants was performed but the pre-op data collection process was not described.

Response:

The methods have been revised to clarify the methods used to collect preoperative information and clarify how all data were collected:

Extract from manuscript (additional words underlined):

“The site coordinators collected prospective pre-operative data from participants via interview, including socio-demographic information, past medical history, indications, and contraindications for VTE and antimicrobial prophylaxis. They collected acute care data from the medical records. Participants provided post-acute data via telephone follow-up at approximately 35, 90, and 365 days post-surgery. Participants and sites provided details regarding prophylaxis and surgical complications.”

Reviewer feedback:

6. Discussion: I was unable to access the supplementary files and I am presuming that the data relating to the components of the guidelines that were reported as compliant or not are in these tables. I am checking as the 4th paragraph of the discussion is difficult to follow without this information.

Response:

The data relating to the components of the guidelines that were reported as compliant or not are reported in Table 4.

The supplementary files have been uploaded with the revised manuscript and are available. We were not able to include the data included in the Supplementary Tables in the main manuscript due to word count limitations.

Additional requirements for resubmission

Editorial feedback:

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Response:

The file names have been revised accordingly and the files uploaded as part of this resubmission include:

Current manuscript for further review

1. Manuscript revised (tracked changes)

2. Manuscript (clean)

Supplementary file

3. S1 file.doc

Editorial feedback:

2. Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

Response:

The reference list has been checked to ensure it is complete and correct. None of the journal articles have been retracted.

Two references are no longer current but have been retained:

The first has been rescinded but is directly relevant to the study:

The NHMRC guideline (2009) were rescinded in 2016 and replaced with a clinical care standard (ACQSHC, 2020), rather than a clinical guideline. However, the NHMRC guidelines were current at the time the initial study commenced and were used for the initial evaluation of the association between guideline compliance and risk of VTE, so the reference has been retained.

- Rescinded guideline:

National Health and Medical Research Council. Clinical practice guideline for the prevention of venous thromboembolism (deep vein thrombosis and pulmonary embolism) in patients admitted to Australian hospitals. Melbourne: National Health and Medical Research Council; 2009.

- Current clinical care standard (however not relevant tostudy)

ACQSHC (2020). Venous Thromboembolism Prevention Clinical Care Standard. Sydney. ACQSHC. https://www.safetyandquality.gov.au/standards/clinical-care-standards/venous-thromboembolism-prevention-clinical-care-standard.

The second is a website that is no longer functioning but was source of information that informed site recruitment:

The following website is no longer available but was the source of information to identify surgical volumes for site eligbility, so has been retained:

Australian Government. My Hospitals 2012 [Available from: https://www.myhospitals.gov.au/.

The following changes have been made to references:

- The Hamilton (2012) (previously reference 3) has been removed as it is not needed given other references included – this will help reduce word count

- The AOA annual report (previously reference 4) has been updated from the 2019 to 2020 report to reflect the most recent information available and pre-COVID pandemic.

- Mulder (2012) (previously reference 9) and Peel (2015) (previously reference 10) have been replaced with Springer (2017) and Shahi (2016)

- Removed AAOS (2012) reference as not needed

- Removed Runciman (2102) and Arecelus (2013 (previously reference 16-19)) – too old and replaced with a more recent systematic review - Farfan (2016),

- Remove Bull (2006) due to age and replaced with Leaper (Ab)

- Removed second reference re Redcap (Harris, 2019) as only the one directly related to the software is relevant (Vanderbuilt University)

- (30-32) additional references added as per reviewer 2’s suggestions. We included the Schwartz (2017) reference recommended by reviewer 2 and included two systematic reviews (Zhang, 2019; Alamanda,2019) (as stated above in our response to reviewer 2’s feedback).

- Replaced Mulder (2012) and Bozic (2013) with a recent systematic review (Tan, 2019) for

The high level of antibiotic overuse is concerning given the evidence suggesting that longer duration provides no additional protection against infection and has been associated with an increased risk of adverse events, antibiotic resistance, and higher cost of care.

- Removed Marshall and Elshaug (2013) (previously (66-68) for

Reducing unnecessary clinical variation and preventing avoidable VTE and infection complications will improve the patient and service outcomes and should support cost-containment.

- Removed Wang (2012) (more related to link with SSI and anticoagulation) as used same SCIP data and replaced with Gouvea and Bozic (2013), the latter which was used to inform the study design for this publication for

Direct comparison with other studies is difficult due to variation in clinical guidelines used, the criteria for compliance, mixed surgical caseloads, limitations associated with administrative data and lack of follow-up in some studies.

Editorial feedback:

1. Please provide additional details regarding participant consent. In the ethics statement in the Methods and online submission information, please ensure that you have specified (1) whether consent was informed and (2) what type you obtained (for instance, written or verbal, and if verbal, how it was documented and witnessed). If your study included minors, state whether you obtained consent from parents or guardians. If the need for consent was waived by the ethics committee, please include this information.

Once you have amended this/these statement(s) in the Methods section of the manuscript, please add the same text to the “Ethics Statement” field of the submission form (via “Edit Submission”).

Response:

In the manuscript the consent process was clarified:

“ Prior to data collection informed written consent was obtained from eligible participants and the signed consent form was witnessed by the site coordinator.”

This statement has been added to the “Ethics Statement” field of the submission form

Editorial feedback:

6. We note that you have stated that you will provide repository information for your data at acceptance. Should your manuscript be accepted for publication, we will hold it until you provide the relevant accession numbers or DOIs necessary to access your data. If you wish to make changes to your Data Availability statement, please describe these changes in your cover letter and we will update your Data Availability statement to reflect the information you provide.

Response:

The DOI is now available and has been included in the revised manuscript:

Extract from manuscript (additional words underlined):

A deidentified version of the data set and the full R code for all analyses are available (https://doi.org/10.26190/mddw-by48).

Editorial feedback:

7. Your abstract cannot contain citations. Please only include citations in the body text of the manuscript, and ensure that they remain in ascending numerical order on first mention.

Response:

The abstract doesn’t include any citations, the numbers reflect the four separate logistic regression analyses that were undertaken. This has been reworded to clarify this:

Extract from manuscript (additional words underlined):

“Four adjusted logistic regression analyses were undertaken to explore associations between non-compliance and risk of complications: (1) composite (simultaneous) non-compliance with both (VTE and antibiotic) guidelines and composite complications [all-cause mortality, VTE, readmission/reoperation for joint-related reasons (one-year) and non-joint-related reasons (35 days)], (2) VTE non-compliance and VTE, (3) antibiotic compliance and any SSI, and (4) antibiotic compliance and deep SSI.”

Editorial feedback:

8. Please upload a copy of Figure 1, to which you refer in your text on pages 10 and 13. If the figure is no longer to be included as part of the submission please remove all reference to it within the text.

Response:

Figure 1 was included in the body of the manuscript and has now been uploaded as a separate file with the revised manuscript.

Editorial feedback:

9. Please upload a copy of Supporting Information file 1,file 2, and Supplementary table 1-8 which you refer to in your text on page 37.

Response:

Supplementary file 3 is now Supplementary file 1 and includes table 1-8. This has been uploaded with the revised manuscript (See S1_file).

The references to Supplementary files 1 (page 10) and 2 (page 12) have been removed as these are now available online.

The last sentence in the methods section of the original submission has been deleted: The full R code for all analyses are included in a supplementary file (Supplementary File 2).

Extract from manuscript (additional words underlined):

New information has been added:

“A deidentified version of the data set and the full R code for all analyses are available (https://doi.org/10.26190/mddw-by48).”

Submitted filename: Response to reviewers.docx

Click here for additional data file.

4 Nov 2021

Non-compliance with clinical guidelines increases the risk of complications after total hip and knee joint replacement surgery

PONE-D-21-07165R1

Dear Dr. Badge,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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Kind regards,

Tim Schultz

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Thank-you for your thorough revision of this manuscript in light of reviewer and editorial feedback.

The suggested revisions address the feedback appropriately.

Two minor suggestions for revision for the final manuscript:

1. line 47 (abstract) states "(2) VTE non-compliance and VTE", this could be clarified to "VTE non-compliance and VTE outcomes" as occurs later in the text, or "VTE non-compliance and any VTE" as per other outcomes.

2. the broken field link has recurred in this version; suggest just overwrite this with text rather cross-references in MS-Word

Lastly, the DOI link for the R analysis did not work https://doi.org/10.26190/mddw-by4

Reviewers' comments:

9 Nov 2021

PONE-D-21-07165R1

Non-compliance with clinical guidelines increases the risk of complications after primary total hip and knee joint replacement surgery

Dear Dr. Badge:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

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Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Tim Schultz

Academic Editor

PLOS ONE