Evaluation of Painful Prostheses

• Indication Overview
• Methods
• Search Results
• Summary Table
• References
• Appendix 1
• Appendix 2
• Appendix 3

Indication Overview

Total hip arthroplasty (THA) and total knee arthroplasty (TKA) are major orthopedic procedures that can improve function and mobility and relieve pain and deformity associated with joint deterioration in appropriately selected patients.¹ Joint arthroplasty involves removing the damaged or diseased joint and replacing it with a prosthetic joint. For the hip, osteoarthritis is the most common underlying cause of joint deterioration, but inflammatory arthritic conditions, congenital or developmental defects or disorders, trauma, cancers, and osteonecrosis are also conditions that cause joint deterioration requiring THA.¹ For the knee, osteoarthritis and rheumatoid arthritis are the most common underlying causes of damage, necessitating the need for TKA; however, avascular necrosis, tumours, and congenital deformities are also underlying causes.

As with any major surgery, there is a risk of complications with joint arthroplasty.^2,3 Post-operative complications of joint arthroplasty can be categorized as early or delayed.⁴ Aseptic loosening of the prosthetic joint and infection are the two most frequently encountered delayed complications, and may be suspected when a patient complains of pain in a previously healed prosthetic joint. These complications can be difficult to differentiate from one another, requiring a clinical workup, laboratory testing, and diagnostic imaging to arrive at a differential diagnosis.⁴ Examples of other, less common, delayed post-operative complications associated with pain in the prosthetic joint include component failure, instability, osteolysis, heterotrophic ossification, and soft tissue syndromes.⁵

Population: Patients with joint prostheses and symptoms such as pain or fever.

Intervention: Bone scintigraphy with technetium-99m–labelled methylene diphosphonate (^99mTc-MDP), technetium-99m sulphur colloid (^99mTc-SC), and technetium-99m–labelled white blood cells (^99mTc-WBC).

A number of nuclear imaging studies use the medical isotope ^99mTc to assess painful prosthetic joints. Nuclear imaging techniques are useful in assessing orthopedic joints because the image quality is not affected by the joint prostheses, as may be the case with some other imaging techniques, such as magnetic resonance imaging (MRI) and computed tomography (CT).⁶

Bone Scintigraphy with ^99mTc-MDP
Bone scintigraphy (commonly referred to as bone scanning) involves intravenous administration of the radiopharmaceutical ^99mTc-MDP, which then localizes in bone.^{7 99m}Tc-MDP is preferentially taken up in areas with newly formed bone and images are acquired two to four hours following injection.⁷ In the triple-phase bone scan, sequences of images are performed immediately following injection of the radiopharmaceutical to assess blood flow and blood pooling, 15 minutes following injection, and four hours following injection.⁸ Other imaging protocols may also be used for the triple-phase bone scan, and may include delayed images taken 24 hours after injection.⁷ Clearly, negative bone scintigraphy can help rule out aseptic loosening and infection;⁷ however, in the case of positive bone scintigraphy, additional imaging studies may be necessary to determine the underlying cause of the positive imaging study.^7,9 Therefore, bone scintigraphy may be considered a preliminary test that may be combined with other nuclear imaging tests to arrive at a differential diagnosis.^9,10

^99mTc-SC
A ^99mTc-SC scan can be used in conjunction with white blood cells (WBCs) labelled with a radiopharmaceutical such as ^99mTc hexamethylpropyleneamine oxime (^99mTc-HMPAO) or Indium-111 (¹¹¹In) to diagnose infection as the underlying cause of pain in a prosthetic joint.¹¹ For the procedure, ^99mTc-SC is injected intravenously and images are acquired approximately 60 to 90 minutes following injection. Following injection, ^99mTc-SC accumulates in the bone marrow, allowing for its imaging. Labelled WBCs accumulate at sites of infection and in the bone. When combined, ^99mTc-SC and labelled WBCs can indicate whether accumulation of the labelled WBCs is in marrow versus a site of infection. WBC accumulation without corresponding activity on marrow images suggests an infection. This is important in the assessment of prosthetic joints; hematopoietically active marrow develops around prosthetic joints, which can reduce the diagnostic accuracy of labelled WBCs if bone marrow and infection cannot be distinguished.¹¹

^99mTc-Labelled WBCs
Leukocytes (WBCs) labelled with ^99mTc (^99mTc-WBC) are used to image infections in immunocompetent patients.⁹ One of the most commonly used radiopharmaceuticals to label WBCs is HMPAO, also known as exametazime.^{9 99m}Tc-WBCs are produced by an in vitro labelling technique in which 40 mL to 50 mL of the patient's blood is withdrawn and WBCs are separated from the erythrocytes (RBCs) and platelets.⁹ The WBCs are then incubated with the radiolabel (^99mTc), washed, and reinjected into the patient. The process of labelling generally takes two to three hours.⁹ Images are taken within a few hours of reinjection. ^99mTc-WBCs are useful for differentiating between pain due to aseptic loosening and pain associated with infection, as the labelled WBCs will migrate to areas of inflammation and infection.⁹

Comparators: For this report, the following diagnostic tests are considered as alternatives to isotope studies:

• Positron Emission Tomography (PET; 18F-fluoride PET [¹⁸F-PET] for investigation of loosening and 18F-fluorodeoxyglucose PET (¹⁸FDG-PET) for investigation of infection): PET is an imaging technique in which a radiotracer is administered. The radiotracer accumulates in a specific area of the body and emits gamma rays, which are detected by a gamma camera or PET scanner, providing details on the structure and function of organs and tissues.¹²
• Arthrography: Arthrography is a technique that uses fluoroscopy to image a joint following injection of contrast media directly into the joint being imaged. This technique has been used to evaluate loose prosthetic joints.⁴ During the procedure, a local anesthetic is injected into the joint, followed by administration of contrast media (e.g., an iodinated contrast media or air, if the contrast media is contraindicated). A radionuclide contrast agent can also be used, such as ¹¹¹In or ^99mTc-SC.¹³ A sequence of images is then projected onto a fluorescent screen or monitor and still images are created.¹⁴
• ¹¹¹In-WBC: ¹¹¹In-labelled WBCs are also used to image infections, in a manner analogous to ^99mTc-labelled WBCs.⁹ The technique for preparation is the same as for ^99m Tc-WBCs, but the compound used for labelling is ¹¹¹In-oxyquinoline. Disadvantages of ¹¹¹In-WBC include a delay of 18 to 24 hours between isotope injection and imaging and lower resolution images compared with ^99mTc.⁹ However, ¹¹¹In-WBCs have the advantage of a normal distribution of activity to the liver, spleen, and bone marrow, whereas the distribution of ^99mTc-WBCs tends to be more broad (to reticuloendothelial system, urinary tract, large intestine, and gall bladder).⁹

Outcomes: Eleven outcomes (referred to as criteria) are considered in this report:

• Criterion 1: Size of the affected population
• Criterion 2: Timeliness and urgency of test results in planning patient management
• Criterion 3: Impact of not performing a diagnostic imaging test on mortality related to the underlying condition
• Criterion 4: Impact of not performing a diagnostic imaging test on morbidity or quality of life related to the underlying condition
• Criterion 5: Relative impact on health disparities
• Criterion 6: Relative acceptability of the test to patients
• Criterion 7: Relative diagnostic accuracy of the test
• Criterion 8: Relative risks associated with the test
• Criterion 9: Relative availability of personnel with expertise and experience required for the test
• Criterion 10: Accessibility of alternative tests (equipment and wait times)
• Criterion 11: Relative cost of the test.

Definitions of the criteria are in Appendix 1.

Methods

The literature search was performed by an information specialist using a peer-reviewed search strategy.

Published literature was identified by searching the following bibliographic databases: MEDLINE with In-Process records and daily updates via Ovid; Cochrane Library via Ovid; University of York Centre for Reviews and Dissemination (CRD) databases; and PubMed. The search strategy consisted of both controlled vocabulary, such as the National Library of Medicine's MeSH (Medical Subject Headings), and keywords. The main search concepts were radionuclide imaging and prostheses.

Methodological filters were applied to limit retrieval to health technology assessments, systematic reviews, meta-analyses, randomized controlled trials, and non-randomized studies, including diagnostic accuracy studies. No date or human limits were applied for systematic reviews. For primary studies, the retrieval was limited to documents published between January 1, 2006, and February 25, 2011, and human population. The search was also limited to English language documents. Regular alerts were established to update the search until October 2011. Detailed search strategies are located in Appendix 2.

Grey literature (literature that is not commercially published) was identified by searching relevant sections of the CADTH Grey Matters checklist. Google was used to search for additional web-based materials. The searches were supplemented by reviewing the bibliographies of key papers. See Appendix 2for more information on the grey literature search strategy.

Targeted searches were done as required for the criteria, using the aforementioned databases and Internet search engines. When no literature was identified that addressed specific criteria, experts were consulted.

Search Results

The database search identified 754 citations, from which there were 89 articles that underwent full-text screening for inclusion in the report. Of these articles, eight systematic reviews or meta-analyses of studies of diagnostic accuracy of the tests or alternative tests were included in the report.^15-22 The remaining articles from the database search were screened to identify information pertinent to one or more of the 10 remaining criteria. Four reports were found to have relevant information.^4,10,23,24 One report was relevant to criterion 2,⁴ two were relevant to criterion 4,^10,23 and one was relevant to criterion 10.²⁴

Summary table

Table 1: Summary of Criterion Evidence

Domain 1: Criteria Related to the Underlying Health Condition
Criterion		Synthesized Information
1	Size of the affected population	Approximately 6,345 (2 in 10,000) Canadians undergo surgery for revision of a prosthetic joint annually.25,26 These individuals require diagnostic imaging prior to surgery. Additional patients may undergo imaging for painful prosthetic joints, but not require surgery. Therefore, this number is likely to underestimate the total size of the affected population. The size of the affected population is likely more than 1 in 10,000 (0.01%) and less than or equal to 1 in 1,000 (0.1%)
2	Timeliness and urgency of test results in planning patient management	Saskatchewan guidelines for prioritization of imaging studies suggest that diagnostic imaging of a painful prosthetic joint should be performed within 8 to 30 days of test ordering.27,28 For bone scanning specifically, guidelines suggest it be performed within 329 to 730 days of test ordering for urgent cases and 1529 to 3011 days for semi-urgent cases. Canadian guidelines recommend that the target time frame for imaging of painful prostheses or urgent bone scanning should be < 30 days. The target time frame for performing the 99mTc-based test is between 8 and 30 days, and obtaining the test results in the appropriate timely manner for the underlying condition has moderate impact on the management of the condition or the effective use of health care resources.
3	Impact of not performing a diagnostic imaging test on mortality related to the underlying condition	The most frequently cited causes of pain in prosthetic joints are not directly linked to mortality, with the exception of infection. In individuals who are immunocompetent, the risk of mortality from a bone infection is relatively low, but the presence of a prosthetic joint increases the risk of death.31 The mortality rate in individuals with infected prosthetic joints is estimated to be 1% to 3%.32 Based on the available information, diagnostic imaging test results have minimal impact on mortality.
4	Impact of not performing a diagnostic imaging test on morbidity or quality of life related to the underlying condition	The clinical workup of a painful prosthetic joint includes diagnostic imaging to determine both the underlying cause and the appropriate intervention. Delay in initiating antibiotic and surgical treatment can reduce the chance of saving the prosthetic joint and preserving joint function.31 Delay in the diagnosis of aseptic loosening can prolong patients' pain, length of disability, and impairment in function.31 Deep infection, aseptic loosening, and prosthetic malfunction decrease quality of life, while surgical revision improves quality of life, function, and pain.33,34 Diagnostic imaging test results can have significant impact on morbidity or quality of life.

 

Domain 2: Criteria Comparing 99mTc with an Alternative or Comparing Between Clinical Uses
Criterion		Synthesized Information
5	Relative impact on health disparities	To be scored locally.
6	Relative acceptability of the test to patients	Bone scanning Limited information was identified on the acceptability of bone scanning to patients. Patients may have concerns about radiation exposure and the intravenous injection of radiopharmaceutical agent. Arthrography Conventional arthrography is a fluoroscopic x-ray–based imaging test. Patients may have some concern over the injection of the contrast agent and the radiation exposure. In addition, patients may experience some temporary swelling in the joint. PET Patients may have concerns about radiation exposure and the intravenous injection of radiopharmaceutical agent. 111In-WBC scanning or leukocyte scanning Patients may have concerns about radiation exposure and the intravenous injection of radiopharmaceutical agent. Overall, the acceptability to the patient of bone scintigraphy with 99mTc-radiolabelled isotopes: is moderately more acceptable than arthrography is minimally more acceptable than 18FDG-PET is minimally more acceptable than 18F-PET has similar acceptability to patients as leukocyte scanning.
7	Relative diagnostic accuracy of the test	The table presents a summary of the range of pooled estimates for the sensitivity and specificity of the tests and alternatives from the 8 included systematic reviews, by joint (hip or knee) where data were available. Single estimates are presented when only 1 meta-analysis was identified. There was no information regarding 18F-PET. Test Pooled Sensitivity Pooled Specificity 99mTc-MDP Hip: 78% Knee: 71% Hip: 84% Knee: 71% 99mTc-WBC (99mTc-HMPAO–labelled WBC) Hip or knee: 89.0% Hip or knee: 89.1% 99mTc-SC with 111In-WBC Hip or knee: 100.0% Hip or knee: 91% to 98% 18FDG-PET Hip: 82% to 94% Knee: 87% to 98% Hip: 90% to 93% Knee:75% to 79% Arthrography Subt — hip: 86% to 89% Nuclear — Hip: 85% to 87% Subt — hip: 76% to 85% Nuclear — hip: 64% to 83% 111In-WBC Hip or knee: 82.8% Hip or knee: 83.8% 18FDG-PET = 18F-fluorodeoxyglucose positron emission tomography; 111In-WBC = Indium-111 white blood cell; subt = subtraction; 99mTc-MDP = technetium-99m–labelled methylene diphosphonate; 99mTc-SC = technetium-99m sulphur colloid; 99mTc-WBC = technetium-99m–labelled white blood cells. For patients with suspected prosthesis loosening, the diagnostic accuracy of bone scanning with 99mTc-radiolabelled isotopes is: similar to arthrography similar to 18F-PET. For patients with suspected infection, the diagnostic accuracy of bone scanning with 99mTc-radiolabelled isotopes is: similar to arthrography moderately better than 18FDG-PET moderately lower than leukocyte scanning.
8	Relative risks associated with the test	Non–radiation-related risks Bone scanning Mild adverse events (AEs) with 99mTc-labelled tracers (i.e., skin reactions) have been reported.35-38 Serious AEs have been reported with 99mTc-labelled SC (e.g., cardiopulmonary arrest, seizures, and anaphylactic shock), although rates were not provided.37 Arthrography Patients may experience some temporary swelling in the joint and experience reactions to the contrast agent, if used. 18FDG-PET The Pharmacopeia Committee of the Society of Nuclear Medicine conducted a 4-year prospective evaluation of AEs with PET and reported no AEs in 33,925 scans in 22 PET centres in the United States.39 Leukocyte (WBC) scan Mild AEs with 99mTc-labelled tracers, including those used to label WBC (e.g., skin reactions), have been reported, although no reaction rates were provided.35,38,40 Radiation-related Risks Among the modalities to diagnose cause of painful prostheses, 99mTc-MDP, 99mTc-SC, 99mTc-WBC, and PET expose the patient to ionizing radiation. Overall, bone scintigraphy with 99mTc-radiolabelled isotopes is: moderately safer than arthrography minimally safer than 18FDG-PET minimally safer than 18F-PET minimally safer than leukocyte scanning.
9	Relative availability of personnel with expertise and experience required for the test	As of 2006 in Canada, there were 2,034 diagnostic radiologists, 221 nuclear medicine physicians, 12,255 radiological technologists, and 1,781 nuclear medicine technologists available across Canada. Yukon, Northwest Territories, and Nunavut do not have the available personnel to perform and interpret tests to investigate the cause of painful prostheses. Other jurisdictions (e.g., Prince Edward Island) may offer limited nuclear medicine services. Assuming the equipment is available, if bone scanning using 99mTc is not available, it is estimated that: more than 95% of the procedures can be performed in a timely manner using arthrography fewer than 25% of the procedures can be performed in a timely manner using 18FDG-PET fewer than 25% of the procedures can be performed in a timely manner using 18F-PET 75% to 94% of the procedures can be performed in a timely manner using leukocyte scanning.
10	Accessibility of alternative tests (equipment and wait times)	No nuclear medicine cameras are available in the Yukon, Northwest Territories, or Nunavut.41 The average wait time for urgent bone scan in 2010 ranged from 1 to 6 days, and for non-urgent scans, ranged from 7 to 73 days.42 As of November 2010, there were approximately 31 Canadian centres performing publicly funded PET scans.43 These centres are all located in British Columbia, Alberta, Manitoba, Ontario, Quebec, New Brunswick, and Nova Scotia.43 Assuming the necessary expertise is available if bone scanning using 99mTc is not available, it is estimated that: more than 95% of the procedures can be performed in a timely manner using arthrography fewer than 25% of the procedures can be performed in a timely manner using 18FDG-PET fewer than 25% of the procedures can be performed in a timely manner using 18F-PET 75% to 94% of the procedures can be performed in a timely manner using leukocyte scanning.
11	Relative cost of the test	According to our estimates, the cost of bone scan with 99mTc-based radioisotopes is $323.11. Arthrography is the only less costly alternative. Leukocyte scan is moderately more costly. 18F-PET and 18FDG-PET are significantly more costly. Relative Costs Test Total Costs ($) Cost of Test Relative to 99mTc-based Test ($) Bone scan 323.11 Reference Arthrography 171.07 -152.04 Leukocyte scan 586.01 +262.90 18F-PET 850.00 +526.89 18FDG-PET 1050.00 +726.89

AE = adverse event; CT = computed tomography; FDG = fluorodeoxyglucose; ¹⁸FDG-PET = 18F-fluorodeoxyglucose positron emission tomography; ¹¹¹In-WBC = Indium-111 white blood cell; MDP = methylene diphosphonate; mSv = millisievert; PET = positron emission tomography; SC = sulphur colloid; subt = subtraction; ^99mTc- HMPAO = technetium-99m hexamethylpropyleneamine oxime; ^99mTc-MDP = technetium-99m methylene diphosphonate; ^99mTc-SC = technetium-99m sulphur colloid; ^99mTc-WBC = technetium-99m–labelled white blood cells; WBC = white blood cell.

Criterion 1: Size of affected population (link to definition)

In Canada, information on the level of activity, clinical parameters, and outcomes of primary and revision hip and knee replacement operations over time is captured by the Canadian Joint Replacement Registry. All hospitals in Canada report information to the registry on joint replacements and revisions to joint replacements.²⁶ Based on data from 2006 to 2007, there were 24,253 hospitalizations for THA and 37,943 hospitalizations for TKA (62,196 joint replacements in total) in Canada, excluding the province of Quebec. From 1996-1997 to 2006-2007, there was a 59% increase in the number of THAs and a 140% increase in the number of TKAs. The majority of patients who undergo total joint arthroplasty are older than 65 years (63% of hip and 64% of knee replacement recipients),²⁶ which would suggest population aging will continue to increase the demand for these procedures.³¹

Across Canada, approximately 13.6% of the hospitalizations for THA were for revisions to a joint that had previously been replaced. The most common reasons for revision were aseptic loosening (44%), osteolysis (22%), poly wear (21%), and instability (13%). For TKA, the percentage of revisions was 6.3%, with the most common reasons for revision being aseptic loosening (25%), poly wear (17%), infection (16%), and instability (14%).

Quebec data from 2004-2005 indicate that there were 4,129 hip replacements (462 revisions) and 5,123 knee replacements (340 revisions).²⁵

If it is assumed that all patients who undergo revision require imaging studies prior to surgery, approximately 5,543 patients would require imaging, based on 2006-2007 data. Based on 2004-2005 data, an additional 802 patients from Quebec would require imaging prior to surgical revision, making the total across Canada approximately 6,345, translating to an incidence of approximately two per 10,000 persons in Canada. This would exclude patients who would undergo imaging for a painful prosthetic joint but not require surgery, and likely represents an underestimation of the use of ^99m Tc-based imaging.

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Criterion 2: Timeliness and urgency of test results in planning patient management (link to definition)

In the evaluation of a painful prosthetic joint, a clinical workup, laboratory testing, and diagnostic imaging is needed to arrive at a differential diagnosis in order for a patient to receive appropriate treatment.⁴ A distinction between aseptic loosening, septic loosening, and infection is necessary for patients to undergo surgical revision if needed. A delay in imaging could potentially delay treatment of an infection, placing the patient at risk for loss of the prosthetic joint due to delay of surgery, and prolongation of the patient's pain, length of disability, and impairment in function.³²

According to Saskatchewan guidelines for prioritization of imaging studies, diagnostic imaging of a painful prosthetic joint would likely be considered a Level 3 priority, suggesting the need for imaging within eight to 30 days from test ordering (Patrick Au, Acute and Emergency Services Branch, Saskatchewan Ministry of Health: unpublished data, 2011). According to Canada's Wait Time Alliance, bone scanning should be performed within seven days of test ordering for urgent cases and 30 days for semi-urgent cases,³⁰ while the Canadian Society for Nuclear Medicine recommends that urgent and non-urgent bone scans be performed within three and 15 days, respectively.²⁹

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Criterion 3: Impact of not performing a diagnostic imaging test on mortality related to the underlying condition (link to definition)

The most frequently cited causes of pain in prosthetic joints are not directly linked to mortality, with the exception of infection. In individuals who are immunocompetent, the risk of mortality from a bone infection is relatively low, but the presence of a prosthetic joint increases the risk of death.³¹ The mortality rate in individuals with infected prosthetic joints is estimated to be 1% to 3%.³²

Diagnosis of prosthetic joint infections has been described as difficult and complex.³² The diagnosis of infection in a prosthetic joint often requires one or more nuclear imaging study that may involve ^99mTc; for example, labelled WBC imaging combined with bone marrow imaging using ^99mTc-SC.³² The majority of patients with prosthetic joint infections require surgical debridement or removal of the prosthetic joint, in addition to treatment with antibiotics.³² A delay in imaging could delay a differential diagnosis of infection and appropriate treatment, thereby increasing the risk of death.

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Criterion 4: Impact of not performing a diagnostic imaging test on morbidity or quality of life related to the underlying condition (link to definition)

The evaluation of a painful prosthetic joint includes diagnostic imaging to determine the underlying cause.^2,3 Delays in diagnostic imaging can delay the differential diagnosis between aseptic loosening and joint infection, which are two complications that are considered more difficult to diagnose. Other complications, such as heterotrophic ossification, fracture, and dislocation, are less frequently encountered and easier to diagnose.¹⁰ While prosthetic joint infection occurs less frequently than aseptic loosening, it has been associated with high morbidity and cost.²³ Delaying the initiation of antibiotic and surgical treatment (revision, debridement, or removal) can reduce the chance of saving the prosthetic joint and preserving joint function.³¹ Delay in the diagnosis of aseptic loosening can prolong patient's pain, length of disability, and impairment in function.³¹

Deep infection, aseptic loosening, and prosthetic malfunction following joint arthroplasty have been associated with decreased health-related quality of life compared with baseline preoperative values.³⁴ Thus, a delay in differential diagnosis and, therefore, treatment would likely prolong the detrimental effects on health-related quality of life.

Surgical revision in patients with aseptic or septic loosening improves pain, function, and stiffness on the Western Ontario and McMaster Universities Arthritis Index (WOMAC — an osteoarthritis-specific health-related quality of life measure) and improves Harris Hip Scores (a measure of hip function following surgery).⁴⁴ Similarly, patients who undergo revision TKAs for aseptic loosening or infection experience gains in physical and mental health measured using the 36-item Short Form Health Survey (SF-36, a generic health status measure that captures eight domains of health: vitality, physical functioning, pain, general health perceptions, physical role functioning, emotional role functioning, social role functioning, mental health), gains in function (ability to walk and climb stairs), and improvements in Knee Society Scores, which capture pain, stability, and range of motion.³³

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Criterion 5: Relative impact on health disparities (link to definition)

To be scored locally.

Residents of rural and remote areas
In Canada, there is geographic variation in access to nuclear medicine imaging studies and alternative tests, due to a lack of availability, equipment, and expertise in some areas, in particular the Yukon, Northwest Territories, and Nunavut.⁴⁵ As many of the tests and alternatives used for assessment of painful prosthetic joints involve radiopharmaceuticals, geographic access could potentially be similar for imaging techniques involving ^99mTc, and ¹¹¹In. This suggests that the alternate tests may not reduce the health disparities of those who live in rural and remote areas, where availability of imaging with ^99mTc may be limited.

For the alternative test ¹⁸FDG-PET, availability may be particularly limited in that due to the short half-life of the isotope, the imaging study must be performed at a centre close to a cyclotron that produces FDG.⁴⁶ This could limit access for individuals in remote areas or for those who do not live close by or could not travel to the facility where ¹⁸FDG-PET is available.

Age
The majority of joint replacements are performed in individuals older than 65 years.²⁶ Thus, individuals who require diagnostic imaging to assess painful prosthetic joints would generally be in this age group. As such, imaging studies, along with laboratory and clinical workups, could potentially improve quality of life in patients with painful prosthetic joints to help expedite the diagnosis of an underlying cause and treatment (antibiotics, surgical revision, or removal). However, no evidence was identified from the searches to suggest one test or alternative might have greater potential to reduce the health disparity of older adults with painful prosthetic joints.

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Criterion 6: Relative acceptability of the test to patients (link to definition)

Bone scanning
Limited information was identified on the acceptability of bone scanning to patients. Patients may have concerns about radiation exposure and the intravenous injection of radiopharmaceutical agent.

Arthrography
Conventional arthrography is a fluoroscopic x-ray–based imaging test. Local anesthetic and contrast agent are injected into the joint space. Patients may have some concern over the injection of the contrast agent and the radiation exposure. In addition, patients may experience some temporary swelling in the joint.

PET
Patients may have concerns about radiation exposure and the intravenous injection of radiopharmaceutical agent.

¹¹¹In-WBC
Patients may have concerns about radiation exposure and the intravenous injection of radiopharmaceutical agent.

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Criterion 7: Relative diagnostic accuracy of the test (link to definition)

Eight systematic reviews with or without meta-analysis were identified that summarized the diagnostic accuracy of the tests and alternatives used for the evaluation of painful prosthetic joints.^15-22 Details of these studies are summarized in Appendix 3, Table 7. No studies were identified that compared ^99mTc-based imaging with ¹⁸F-PET.

Van der Bruggen et al.¹⁵ performed a systematic review of the literature (without meta-analysis) to determine the diagnostic accuracy of the combination of ¹¹¹In-WBC and ^99mTc-SC, the combination of ¹¹¹In-WBC and ^99mTc-MDP, ¹¹¹In-WBC alone, and ¹⁸FDG-PET in the diagnosis of prosthetic bone and joint infections. Other indications, unrelated to this literature summary, were also included in the review but are not presented. There were nine relevant studies of the tests and alternatives included in Van der Bruggen et al.'s systematic review. The quality of these studies was not reported.

The sensitivity and specificity of the combination of ¹¹¹In-WBC and ^99mTc-SC were 100% and 91% to 98%, respectively. The sensitivity and specificity of the combination of ¹¹¹In-WBC and ^99mTc-MDP were 95% to 97% and 91% to 98%, respectively. For ¹¹¹In-WBC alone, the sensitivity and specificity were 87% to 100% and 53% to 94%, respectively. The included studies of ¹⁸FDG-PET had a wide range of sensitivity (28% to 91%) and specificity (9% to 97%) for the diagnosis of infection of a prosthetic joint. The authors concluded that when relying on conventional scintigraphy, osteomyelitis was best detected using the combination of ¹¹¹In-WBC and ^99mTc-MDP. Despite the wide ranges reported for both sensitivity and specificity, the authors further concluded that using ¹⁸FDG-PET to detect osteomyelitis was feasible and had adequate sensitivity and specificity.

Reinartz¹⁶ performed a systematic review of the literature and meta-analysis to determine the diagnostic accuracy of a triple-phase bone scan (TPBS) with ^99mTc-MDP, WBC imaging, and ¹⁸FDG-PET in patients with painful prosthetic hip or knee joints. In this systematic review, diagnostic accuracy was not determined separately for loosening or suspected infection, but data for hip and knee joints were presented separately.

For the assessment of diagnostic accuracy of labelled WBCs, ¹¹¹In and ^99mTc were analyzed together, and it is important to note that half of the studies actually combined labelled WBCs with a bone scan (n = 2) or bone marrow scan (n = 5). This must be considered when interpreting the sensitivity and specificity of labelled WBCs. The gold standard was unclear for all studies, study quality was not reported, and the methods of the systematic review and meta-analysis were poorly described.

A total of 43 studies were included. For the hip, the sensitivities of TPBS, labelled WBCs, and ¹⁸FDG-PET were 78%, 76%, and 85%, respectively, while the specificities were 84%, 96%, and 90%, respectively. For the knee, the sensitivities of TPBS, labelled WBCs, and ¹⁸FDG-PET were 87%, 95%, and 98%, respectively, while the specificities were 71%, 81%, and 75%, respectively. The authors concluded that ¹⁸FDG-PET is an effective imaging technique for diagnosing complications related to TKA and THA and they would recommend it. They further concluded that WBC imaging combined with bone marrow imaging should still be considered the gold standard, but is complex and time consuming.

Zoccali et al.¹⁷ performed a systematic review and meta-analysis of the ability of ¹⁸FDG-PET to differentiate between septic and aseptic loosening of prosthetic hip joints. Five studies were included in the meta-analysis, the quality of which was not reported; nor was the gold standard used in assessing diagnostic accuracy. The pooled sensitivity for infection of the prosthetic joint was 82.8%. Specificity data were not pooled, and ranged from 77.8% to 96.6% across studies. The authors concluded that the sensitivity and specificity of ¹⁸FDG-PET confirm its importance in the future for evaluating painful prosthetic hip joints.

Kwee et al.¹⁸ performed a systematic review with meta-analysis of the diagnostic accuracy of ¹⁸FDG-PET for the diagnosis of infection in a prosthetic hip or knee joint. Eleven relevant studies were included, with median quality ratings of 82% (82% of items on a checklist of internal or external validity criteria were met). The gold standard for diagnostic accuracy differed across studies, but generally included multiple criteria. Most studies included a systemic infection, microorganism culture from joint aspiration, or positive culture from surgery as a criterion. This was in addition to clinical and laboratory findings. The pooled sensitivity and specificity for infection of a prosthetic hip were 82.1% and 89.9%, respectively. The pooled sensitivity and specificity for infection of a prosthetic knee were 86.6% and 74.8%, respectively. The authors concluded that the diagnostic accuracy of ¹⁸FDG-PET was moderate to high, but that caution was warranted as the studies were heterogeneous.

Zhuang et al.¹⁹ performed a systematic review with meta-analysis of the diagnostic accuracy of ¹⁸FDG-PET for the evaluation of prosthetic joint pain. The methodology of the review was poorly reported. A total of eight relevant studies were identified, the quality of which was not reported; nor was the gold standard for diagnostic accuracy. The pooled sensitivity and specificity for infection of a prosthetic hip was 85.5% and 92.6%, respectively. The pooled sensitivity and specificity for infection of a prosthetic knee were 94.4% and 79.2%, respectively. The authors concluded that ¹⁸FDG-PET should play an important role in distinguishing between aseptic loosening from bone infection.

Temmerman et al. (2007)²⁰ conducted a systematic review with meta-analysis of the diagnostic accuracy of plain radiography, subtraction arthrography, nuclear arthrography, and bone scintigraphy for loosening of the acetabular component of total hip prostheses. Bone scintigraphy was performed with a number of isotopes, including ^99mTc and ⁶⁷Ga, among others. The isotopes used for nuclear arthrography were not reported. In total, 28 studies were included, all of which had a quality rating of 4 on a five-point scale (with 1 being the highest quality).

Plain radiography (which was not one of the tests or alternatives considered for this evidence summary, but is included here for comparative purposes) had a sensitivity of 70% and a specificity of 80%. Subtraction arthrography, nuclear arthrography, and bone scintigraphy had sensitivities of 89%, 87%, and 67%, respectively, and specificities of 76%, 64%, and 75%, respectively. The authors concluded that subtraction arthrography should be used to complement plain radiography when the results of plain radiography are inconclusive.

Prandini et al.²¹ evaluated the diagnostic accuracy of ^99mTc-HMPAO WBCs, ^99mTc- TPBS, ⁶⁷Ga scan, ¹¹¹In WBCs, and ¹⁸FDG-PET for the detection of bone infection due to a prosthetic joint or a peripheral open fracture. Data for the two indications were pooled together in the analysis. Ninety studies were included in the review. No information on methodological quality of the included studies was reported. For ^99mTc-HMPAO WBCs, the sensitivities were 89% and 85.4%, respectively, while the specificities were 89.1% and 75.2%, respectively. For the alternate tests, the sensitivities were 70.1% with ⁶⁷Ga scan, 82.8% with ¹¹¹In WBCs, and 94.1% with ¹⁸FDG-PET, while the specificities for these tests were 81.8%, 83.8%, and 87.3%, respectively. The authors concluded that ¹⁸FDG-PET was the most accurate method for diagnosing bone infections, but had lower specificity than ^99mTc-HMPAO WBCs.

Temmerman et al. (2005)²² conducted a systematic review with meta-analysis of the diagnostic accuracy of plain radiography, subtraction arthrography, nuclear arthrography, and bone scintigraphy for loosening of the femoral component of total hip prostheses. Again, studies of scintigraphy with different isotopes, such as ^99mTc and ⁶⁷Ga, were pooled together for the analysis and the isotopes used for nuclear arthrography were not reported.

In total, 51 studies were included, all of which had a quality rating of 4 on a five-point scale (with 1 being the highest quality). Plain radiography had a sensitivity of 82% and a specificity of 81%. Subtraction arthrography, nuclear arthrography, and bone scintigraphy had sensitivities of 86%, 85%, and 85%, respectively, and specificities of 85%, 83%, and 72%, respectively. The authors concluded that plain radiography and scintigraphy are the preferred techniques for evaluating the femoral component of prosthetic hip, due to the lower morbidity risk to the patient.

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Criterion 8: Relative risks associated with the test (link to definition)

Non–radiation-related Risks

Bone scanning
Several studies^35-38 reported mild AEs with ^99mTc-labelled tracers(e.g., skin reactions) and one identified article³⁷ reported serious AEs with ^99mTc-labelled sulphur colloid (e.g., cardiopulmonary arrest, seizures, and anaphylactic shock). No reaction rates were provided.

Arthrography
Patients may experience some temporary swelling in the joint.

¹⁸F-PET and ¹⁸FDG-PET
The Pharmacopeia Committee of the Society of Nuclear Medicine conducted a four-year prospective evaluation of adverse reactions to PET and reported no adverse reactions among the 33,925 scans conducted in 22 participating PET centres in the United States.³⁹

Leukocyte (WBC) scan
Several studies^35,38,40 reported mild AEs with ^99mTc-labelled tracers, including those used to label WBC (e.g., skin reactions). No reaction rates were provided.

Radiation-related Risks

Among the modalities to diagnose cause of painful prostheses, ^99mTc-MDP, ^99mTc-SC, ^99mTc-WBC and CT, PET, and arthrography expose the patient to ionizing radiation. The average effective dose of radiation delivered with each of these procedures can be found in Table 2. Although different radiopharmaceuticals can be used for the diagnosis of painful prostheses, ^99mTc-MDP, ^99mTc-SC, and ^99mTc-WBC are the most commonly used to evaluate painful prostheses. As the table shows, ⁶⁷Ga delivers larger doses of radiation than ^99mTc-labelled radiopharmaceuticals.

Table 2: Effective Radiation Exposure from Imaging Studies

Imaging Study	Estimated Radiation Dose (mSv)
99mTc-HMPAO	6.947
99mTc-MDP	4.247
99mTc-SC	2.847
99mTc-WBCs	8.147
111In-WBCs	6.747
99mTc-MDP bone scan	4.247
18FDG-PET	7.047
X-ray of knee	0.8 mSv48
X-ray of knee	< 0.1 mSv48
Average background dose of radiation per year	1 to 3.049-51

¹⁸FDG-PET = 18F-fluorodeoxyglucose positron emission tomography; ¹¹¹In-WBC = Indium-111 white blood cell; mSv = millisievert; ^99mTc- HMPAO = technetium-99m hexamethylpropyleneamine oxime; ^99mTc-MDP = technetium-99m methylene diphosphonate; ^99mTc-SC = technetium-99m sulphur colloid; ^99mTc-WBC = technetium-99m–labelled white blood cells.

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Criterion 9: Relative availability of personnel with expertise and experience required for the test (link to definition)

Bone scintigraphy
In Canada, physicians involved in the performance, supervision, and interpretation of bone scans should be nuclear medicine physicians or diagnostic radiologists with training or expertise in nuclear imaging.⁵² Physicians should have a Fellowship of Certification in Nuclear Medicine or Diagnostic Radiology with the Royal College of Physicians and Surgeons of Canada and/or the Collège des médecins du Québec. Nuclear medicine technologists are required to conduct bone scans. Technologists must be certified by the Canadian Association of Medical Radiation Technologists (CAMRT) or an equivalent licensing body.

All alternative imaging modalities
In Canada, physicians involved in the performance, supervision, and interpretation of diagnostic CT scans should be diagnostic radiologists⁴⁵ and must have a Fellowship or Certification in Diagnostic Radiology with the Royal College of Physicians and Surgeons of Canada and/or the Collège des médecins du Québec. Foreign-trained radiologists also are qualified if they are certified by a recognized certifying body and hold a valid provincial license.⁵²

Medical radiation technologists (MRTs) must be certified by CAMRT or an equivalent licensing body.

Service engineers are needed for system installation, calibration, and preventive maintenance of the imaging equipment at regularly scheduled intervals. The service engineer's qualification will be ensured by the corporation responsible for service and the manufacturer of the equipment used at the site.

Qualified medical physicists (on site or contracted part-time) should be available for the installation, testing, and ongoing quality control of CT scanners, MR scanners, and nuclear medicine equipment.⁵²

Arthrography
Arthrography involves the use of fluoroscopy to image a joint. Diagnostic Radiologists should be responsible for the performance, supervision, and interpretation of fluoroscopy.⁵³ Evidence of training in fluoroscopic procedures is required for physicians who use fluoroscopy without supervision of a radiologist and/or x-ray technologist. An MRT is responsible for performing the exam and image technical evaluation and quality. The MRT should have specialized training in fluoroscopy and perform fluoroscopy on a regular basis.

PET
In Canada, physicians involved in the performance, supervision, and interpretation of PET scans should be nuclear medicine physicians or diagnostic radiologists with training or expertise in nuclear imaging. Physicians should have a Fellowship of Certification in Nuclear Medicine or Diagnostic Radiology with the Royal College of Physicians and Surgeons of Canada and/or the Collège des médecins du Québec. Technologists must be certified by CAMRT or an equivalent licensing body.

Leukocyte scan
Leukocyte scanning requires the same personnel as bone scanning with ^99mTc-based radioisotopes. No literature was identified regarding the expertise required for handling and processing of white blood cells.

Table 3: Medical Imaging Professionals in Canada

Jurisdiction	Diagnostic Radiology Physicians	Nuclear Medicine Physicians	Medical Radiation Technologists	Nuclear Medicine Technologists	Sonographers	Medical Physicists
NL	46	3	263	15	NR	NR
NS	71	5	403	71	NR	NR
NB	47	3	387	55	NR	NR
PEI	7	0	57	3	NR	0
QC	522	90	3,342	460	NR	NR
ON	754	69	4,336	693	NR	NR
MB	58	8	501	42	NR	NR
SK	61	4	359	36	NR	NR
AB	227	18	1,229	193	NR	NR
BC	241	21	1,352	212	NR	NR
YT	0	0	0	0	NR	0
NT	0	0	26	1	NR	0
NU	0	0	0	0	NR	0
Total	2,034	221	12,255	1,781	2,900*	322

AB = Alberta; BC = British Columbia; MB = Manitoba; NB = New Brunswick; NL = Newfoundland and Labrador; NR = not reported by jurisdictions; NS = Nova Scotia; NT= Northwest Territories; NU = Nunavut; ON = Ontario; PEI = Prince Edward Island; QC = Quebec; YT = Yukon.

*This represents a total for all of the jurisdictions.

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Criterion 10: Accessibility of alternative tests (equipment and wait times) (link to definition)

There are notable variations in the availability of medical imaging technologies across Canada. Table 4 provides an overview of the availability of equipment required to evaluate patients with painful prostheses. Data for nuclear medicine cameras (including SPECT) are current to January 1, 2007. The number of CT, MRI, and SPECT/CT scanners is current to January 1, 2010. Information on the availability of PET and PET/CT scanners is current to November 30, 2010.

Table 4: Diagnostic Imaging Equipment in Canada^41,43,45

	Nuclear Medicine Cameras	SPECT/CT Scanners	PET or PET/CT Scanners
Number of devices	60345	9641	3643
Average number of hours of operation per week (2006-2007)45	40	NA	NA
Provinces and Territories with no devices available	YT, NT, NU	PEI, YT, NT, NU	NL, PEI, SK, YT, NT, NU

MRI = magnetic resonance imaging; NA = not available; NL = Newfoundland and Labrador; NT = Northwest Territories; NU = Nunavut; PEI = Prince Edward Island; PET = positron emission tomography; SK = Saskatchewan; SPECT/CT = single-photon emission computed tomography/computed tomography; YT = Yukon.

Bone scanning
For bone scintigraphy, nuclear medicine facilities with gamma cameras (including SPECT) are required. Three jurisdictions, the Yukon, the Northwest Territories, and Nunavut, do not have any nuclear medicine equipment.⁴⁵

PET
A 2010 Environmental Scan published by CADTH reported that approximately 31 Canadian centres are equipped to perform PET scans.⁴³ These centres are located in the provinces of British Columbia, Alberta, Manitoba, Ontario, Quebec, New Brunswick, and Nova Scotia.⁴³ There are 36 PET or PET/CT scanners, four of which are used for research purposes only.⁴³

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Criterion 11: Relative cost of the test (link to definition)

Fee codes from the Ontario Schedule of Benefits were used to estimate the relative costs of bone scanning and its alternatives. Technical fees are intended to cover costs incurred by the hospital (i.e., radiopharmaceutical costs, medical or surgical supplies, and non-physician salaries). Maintenance fees are not billed to OHIP — estimates here were provided by St. Michael's Hospital in Toronto. Certain procedures (i.e., PET scan, CT scan, MRI scan) are paid for, in part, out of the hospital's global budget; these estimates were provided by The Ottawa Hospital. It is understood that the relative costs of imaging will vary from one institution to the next.

According to our estimates (Table 5), the cost of bone scan with ^99mTc-based radioisotopes is $323.11. Arthrography is the only less costly alternative. Leukocyte scan is moderately more costly. ¹⁸F-PET and ¹⁸FDG-PET are significantly more costly.

Table 5: Cost Estimates Based on the Ontario Schedule of Benefits for Physician Services Under the Health Insurance Act (September 2011)⁵⁴

Fee code	Description		Tech. Fees ($)		Prof. Fees ($)	Total Costs ($)
Bone scan
J867	Blood flow and pool imaging		58.75	29.30		88.05
J851	Bone scintigraphy — single site		87.00	50.95		137.95
J866	Application of tomography (SPECT)		44.60	31.10		75.70
Maintenance fees — global budget			21.41			21.41
TOTAL			211.76	111.35		323.11
Arthrography
X196	Fluoroscopy — skeleton		9.50	14.95		24.45
J001	Arthrogram, tenogram, or bursogram			29.55 (Spec) 105.07 (Anes)		134.62
	Maintenance fees — global budget		12.00			12.00
TOTAL			21.50	149.57		171.07
Leukocyte scan
J884B/J884C		111In leukocyte scintigraphy — single site	329.00		50.95	379.95
J866B/J866C		Application of tomography (SPECT)	44.60		31.10	75.7
J867B/J867C		First transit — with blood pool images	58.75		29.30	88.05
Maintenance fees — from global budget			42.31			42.31
TOTAL			474.66		111.35	586.01
18F-PET
Professional fee for PET					250.00	250.00
Technical cost — from global budget			600.00			600.00
TOTAL			800.00		250.00	850.00
18FDG-PET
Professional fee for PET					250.00	250.00
Technical cost — from global budget			800.00			800.00
TOTAL			800.00		250.00	1,050.00

Anes = anesthetic; ¹⁸F-PET = 18F- fluoride positron emission tomography; ¹⁸FDG-PET = 18F-fluorodeoxyglucose position emission tomography; ¹¹¹In = Indium-111; PET = positron emission tomography; prof. = professional; spec = specialist; SPECT = single-photon emission computed tomography; tech. = technical.

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Appendix 1: Multi-Criteria Decision Analysis Definitions

Domain 1: Criteria Related to the Underlying Health Condition
Criterion	Definition
1. Size of the affected population	The estimated size of the patient population that is affected by the underlying health condition and which may potentially undergo the test. The ideal measure is point prevalence, or information on how rare or common the health condition is.
2. Timeliness and urgency of test results in planning patient management	The timeliness and urgency of obtaining the test results in terms of their impact on the management of the condition and the effective use of health care resources.
3. Impact of not performing a diagnostic imaging test on mortality related to the underlying condition	Impact of not performing the test, in whatever way, on the expected mortality of the underlying condition. Measures could include survival curves showing survival over time, and/or survival at specific time intervals with and without the test.
4. Impact of not performing a diagnostic imaging test on morbidity or quality of life related to the underlying condition	Impact of not performing the test, in whatever way, on the expected morbidity or on the quality of life reduction of the underlying condition. Measures of impact may include natural morbidity outcome measures such as events or disease severity, or might be expressed using generic or disease-specific quality of life rating scales with and without the test.
Domain 2: Criteria Comparing 99mTc with an Alternative, or Comparing between Clinical Uses
Criterion	Definition
5. Relative impact on health disparities	Health disparities are defined as situations where there is a disproportionate burden (e.g., incidence, prevalence, morbidity, or mortality) amongst particular population groups (e.g., gender, age, ethnicity, geography, disability, sexual orientation, socioeconomic status, and special health care needs). Impact on health disparities is assessed by estimating the proportion of current clients of the 99mTc-based test that are in population groups with disproportionate burdens. (Explanatory note: The implication of this definition is that, everything else being the same, it is preferable to prioritize those clinical uses that have the greatest proportion of clients in groups with disproportionate burdens.)
6. Relative acceptability of the test to patients	Acceptability of the 99mTc-based test from the patient's perspective compared with alternatives. Patient acceptability considerations include discomfort associated with the administration of the test, out-of-pocket expenses or travel costs, factors that may cause great inconvenience to patients, as well as other burdens. This criterion does not include risks of adverse events but is about everything related to the experience of undergoing the test.
7. Relative diagnostic accuracy of the test	Ability of the test to correctly diagnose the patients who have the condition (sensitivity) and patients who do not have the condition (specificity) compared with alternatives.
8. Relative risks associated with the test	Risks associated with the test (e.g., radiation exposure, side effects, adverse events) compared with alternatives. Risks could include immediate safety concerns from a specific test or long-term cumulative safety concerns from repeat testing or exposure.
9. Relative availability of personnel with expertise and experience required for the test	Availability of personnel with the appropriate expertise and experience required to proficiently conduct the test and/or interpret the test findings compared with alternatives.
10. Accessibility of alternatives (equipment and wait times)	Availability (supply) of equipment and wait times for alternative tests within the geographic area. Includes consideration of the capacity of the system to accommodate increased demand for the alternatives. Excludes any limitation on accessibility related to human resources considerations.
11. Relative cost of the test	Operating cost of test (e.g., consumables, heath care professional reimbursement) compared with alternatives.

 

Appendix 2: Literature Search Strategy

OVERVIEW
Interface:			Ovid
Databases:		Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations, Ovid MEDLINE(R) Daily and Ovid MEDLINE(R) 1946 to February 25, 2011 EBM Reviews - ACP Journal Club 1991 to February 2011 EBM Reviews - Cochrane Central Register of Controlled Trials 1st Quarter 2011 EBM Reviews - Cochrane Database of Systematic Reviews 2005 to February 2011 EBM Reviews - Cochrane Methodology Register 1st Quarter 2011 EBM Reviews - Database of Abstracts of Reviews of Effects 1st Quarter 2011 EBM Reviews - Health Technology Assessment 1st Quarter 2011 Note: Duplicates between databases were removed in Ovid.
Date of Search:		February 25, 2011
Alerts:		Monthly search updates began February 25, 2011 and ran until October, 2011
Study Types:		Health technology assessments, systematic reviews, meta-analyses, randomized controlled trials, none-randomized studies, and diagnostic accuracy studies.
Limits:		Publication years 2006-February 25, 2011 for primary studies; no date limits for systematic reviews English language Human limit for primary studies
SYNTAX GUIDE
/	At the end of a phrase, searches the phrase as a subject heading
MeSH	Medical Subject Heading
fs	Floating subheading
exp	Explode a subject heading
*	Before a word, indicates that the marked subject heading is a primary topic; or, after a word, a truncation symbol (wildcard) to retrieve plurals or varying endings
ADJ	Requires words are adjacent to each other (in any order)
ADJ#	Adjacency within # number of words (in any order)
.ti	Title
.ab	Abstract
.hw	Heading Word; usually includes subject headings and controlled vocabulary
.pt	Publication type
.tw .nm .mp .jw /ri	Text word Name of substance word Mapped word Journal words Radionuclide imaging

 

Multi-database Strategy
#	Searches
1	exp "Prostheses and Implants"/ or exp joint prosthesis/ or exp arthroplasty, replacement/ or prosthesis-related infections/ or prosthesis failure/
2	(prostheses or prosthesis or prosthetic* or periprosthetic* or arthroplast*).ti,ab.
3	((bone* or joint* or knee* or hip or hips or ankle* or finger* or shoulder* or elbow* or joint or joints or lumbar) adj3 (replace* or replacing* or replacement* or artificial or implant*)).ti,ab.
4	or/1-3
5	Technetium/ or exp Technetium Compounds/ or exp Organotechnetium Compounds/ or exp Radiopharmaceuticals/
6	(Technetium* or Tc-99 or Tc99 or Tc-99m or Tc99m or 99mTc or 99m-Tc).tw,nm.
7	Radionuclide Imaging/ or Perfusion Imaging/
8	radionuclide imaging.fs.
9	radioisotope*.mp.
10	((radionucl* or nuclear or radiotracer*) adj2 (imag* or scan* or test* or diagnos*)).ti,ab.
11	Tomography, Emission-Computed, Single-Photon/
12	(single-photon adj2 emission*).ti,ab.
13	(SPECT or scintigraph* or scintigram* or scintiphotograph*).ti,ab.
14	(HMPAO or Tc-MDP or HM-PAO).tw, nm.
15	exp Joints/ri
16	exp "bone and bones"/ri
17	Bone marrow/ri
18	Osteomyelitis/ri
19	((bone or bones or joint or joints) adj2 (scan* or imag* or scintigraph*)).ti,ab.
20	or/5-19
21	4 and 20
22	((prosthes* or arthroplast*) adj2 (scan* or imag* or scintigraph*)).ti,ab.
23	21 or 22
24	meta-analysis.pt.
25	meta-analysis/ or systematic review/ or meta-analysis as topic/ or exp technology assessment, biomedical/
26	((systematic* adj3 (review* or overview*)) or (methodologic* adj3 (review* or overview*))).ti,ab.
27	((quantitative adj3 (review* or overview* or synthes*)) or (research adj3 (integrati* or overview*))).ti,ab.
28	((integrative adj3 (review* or overview*)) or (collaborative adj3 (review* or overview*)) or (pool* adj3 analy*)).ti,ab.
29	(data synthes* or data extraction* or data abstraction*).ti,ab.
30	(handsearch* or hand search*).ti,ab.
31	(mantel haenszel or peto or der simonian or dersimonian or fixed effect* or latin square*).ti,ab.
32	(met analy* or metanaly* or health technology assessment* or HTA or HTAs).ti,ab.
33	(meta regression* or metaregression* or mega regression*).ti,ab.
34	(meta-analy* or metaanaly* or systematic review* or biomedical technology assessment* or bio-medical technology assessment*).mp,hw.
35	(medline or Cochrane or pubmed or medlars).ti,ab,hw.
36	(cochrane or health technology assessment or evidence report).jw.
37	(meta-analysis or systematic review).md.
38	or/24-37
39	23 and 38
40	exp "Sensitivity and Specificity"/
41	False Positive Reactions/
42	False Negative Reactions/
43	du.fs.
44	sensitivit*.tw.
45	(predictive adj4 value*).tw.
46	Comparative Study.pt.
47	(Validation Studies or Evaluation Studies).pt.
48	Randomized Controlled Trial.pt.
49	Controlled Clinical Trial.pt.
50	(Clinical Trial or Clinical Trial, Phase II or Clinical Trial, Phase III or Clinical Trial, Phase IV).pt.
51	Multicenter Study.pt.
52	(random* or sham or placebo*).ti.
53	((singl* or doubl*) adj (blind* or dumm* or mask*)).ti.
54	((tripl* or trebl*) adj (blind* or dumm* or mask*)).ti.
55	(control* adj3 (study or studies or trial*)).ti.
56	(non-random* or nonrandom* or quasi-random* or quasirandom*).ti.
57	(allocated adj "to").ti.
58	Cohort Studies/
59	Longitudinal Studies/
60	Prospective Studies/
61	Follow-Up Studies/
62	Retrospective Studies/
63	Case-Control Studies/
64	Cross-Sectional Study/
65	(observational adj3 (study or studies or design or analysis or analyses)).ti.
66	cohort.ti.
67	(prospective adj7 (study or studies or design or analysis or analyses or cohort)).ti.
68	((follow up or followup) adj7 (study or studies or design or analysis or analyses)).ti.
69	((longitudinal or longterm or (long adj term)) adj7 (study or studies or design or analysis or analyses or data or cohort)).ti.
70	(retrospective adj7 (study or studies or design or analysis or analyses or cohort or data or review)).ti.
71	((case adj control) or (case adj comparison) or (case adj controlled)).ti.
72	(case-referent adj3 (study or studies or design or analysis or analyses)).ti.
73	(population adj3 (study or studies or analysis or analyses)).ti.
74	(cross adj sectional adj7 (study or studies or design or research or analysis or analyses or survey or findings)).ti.
75	(distinguish* or differentiat* or enhancement or identif* or detect* or diagnos* or accura* or comparison*).tw.
76	or/40-75
77	76 not case reports.pt.
78	23 and 77
79	remove duplicates from 78
80	limit 79 to english language [Limit not valid in ACP Journal Club,CCTR,CDSR,CLCMR,DARE; records were retained]
81	80 use pmez
82	limit 81 to yr="2006-current" [Limit not valid in DARE; records were retained]
83	80 use acp,cctr,coch,dare,clcmr,clhta
84	82 or 83
85	exp animals/
86	exp animal experimentation/
87	exp models animal/
88	exp animal experiment/
89	nonhuman/
90	exp vertebrate/
91	animal.po.
92	or/85-91
93	exp humans/
94	exp human experiment/
95	human.po.
96	or/93-95
97	92 not 96
98	84 not 97
99	remove duplicates from 39
100	from 98 keep 1-397
101	limit 99 to english language [Limit not valid in ACP Journal Club,CCTR,CDSR,CLCMR,DARE; records were retained]

 

OTHER DATABASES
PubMed March 8, 2011	Same MeSH, keywords, limits, and study types used as per MEDLINE search, with appropriate syntax used.

 

GREY LITERATURE SEARCHING
Dates for Search:	February to March 2011
Keywords:	Included terms for prostheses and radionuclide imaging
Limits:	Publication years 2006 to Feb/March 2011 for primary studies; no date limits for systematic reviews and guidelines

The following sections of the CADTH grey literature checklist, "Grey matters: a practical search tool for evidence-based medicine" (http://www.cadth.ca/en/resources/grey-matters) were searched:

• Health Technology Assessment Agencies (selected)
• Clinical Practice Guidelines
• Databases (free)
• Internet Search

 

Appendix 3: Diagnostic Accuracy

Table 7: Diagnostic Accuracy of Tests and Alternatives Based on the Information Presented in the Included Studies

Study	Tests and Indication	Study Eligibility	Number of Included Studies	Search	Quality of Included Studies	Diagnostic Accuracy versus Gold Standard
van der Bruggen et al. 201015	111In-WBC with 99mTc-SC 111In-WBC with 99mTc- MDP 111In-WBC FDG-PET Diagnosis of prosthetic bone and joint infections	English language Case reports, meeting reports, editorials, letters excluded. Animal studies and studies with < 5 patients excluded.	111In-WBC with 99mTc-SC — 2 111In-WBC with 99mTc-MDP — 2 FDG-PET — 3 111In-WBC — 2	1980 to 2008	Not reported	111In-WBC with 99mTc-SC (GS not reported)	111In-WBC with 99mTc-MDP (GS not reported)	Alternative tests
						Sensitivity†: 100% Specificity†: 91% to 98%	Sensitivity†: 95% to 97% Specificity†: 93% to 100%	111In-WBC (GS not reported) Sensitivity†: 87% to 100% Specificity†: 53% to 94% FDG-PET (Variable GS) Sensitivity†: 28% to 91% Specificity†: 9% to 97%
Reinartz 200916	Triple-phase bone scan (99mTc-MDP) WBC imaging FDG-PET Diagnosis of pathological processes of hip and knee arthroplasty.	Diagnostic procedure performed according to guidelines Could determine sensitivity and specificity from the data Patient cohort not too specialized (e.g., a single new type of prosthesis) Minimum 6-month follow-up.	TPBS — 16 WBCs — 14 FDG-PET — 13	1988 to 2008	Not reported	TPBS (GS not Reported)	Labelled WBCs (GS not Reported)	FDG-PET (GS not Reported)
						Hip: Sensitivity: 78% Specificity: 84% Knee: Sensitivity: 87% Specificity: 71% Mixed study population (hip or knee):† Sensitivity: 33% to 100% Specificity: 0% to 86%	Hip: Sensitivity: 76% Specificity: 96% Knee: Sensitivity: 95% Specificity: 81% Mixed study population (hip or knee):† Sensitivity: 80% to 100% Specificity: 71% to 91%	Hip: Sensitivity: 85% Specificity: 90% Knee: Sensitivity: 98% Specificity: 75% Mixed study population (hip or knee):‡ Sensitivity: 36% Specificity: 97%
Zoccali et al. 200917	FDG-PET Differential diagnosis of septic and aseptic loosening of prosthetic hip joints	Prospective studies to detect loosening PET performed ~ 1 year following surgery Images evaluated by 1 to 2 experts Minimum 6-month follow-up	5	Up to 2007	Not reported	FDG-PET — Hip for Infection (GS not reported)
						Sensitivity: 82.8% Specificity†: –77.8% to 96.6%
Kwee et al. 200818	FDG-PET Diagnosis of prosthetic joint infection.	Diagnostic performance of FDG-PET for prosthetic hip or knee infection. No restriction on reference standard, other than could not include FDG-PET. Excluded review articles, meta-analyses, abstracts, editorials, case reports, guidelines, animal and ex vivo studies, studies with fewer than 15 patients, studies that used FDG with a gamma camera and studies with insufficient data to determine sensitivity and specificity.	11	Up to 2008 (no beginning date limit)	Assessed with a checklist for internal and external validity Scores presented as a percentage of maximum and ranged from 45% to 91% (median of 82%).	FDG-PET — Hip (Variable GS)	FDG-PET — Knee (Variable GS)		FDG-PET — Knee and hip pooled (Variable GS)
						Sensitivity: 82.1% Specificity: 89.8%	Sensitivity: 86.6% Specificity: 74.8%		Sensitivity: 84.6% Specificity: 84.0%
Zhuang et al. 200719	FDG-PET Evaluation of painful prosthetic joints	English language studies No other criteria reported	8	Not reported	Not reported	FDG-PET: Hip (GS not reported)	FDG-PET: Knee (GS not reported)
						Sensitivity: 85.5% Specificity: 92.6%	Sensitivity: 94.4% Specificity: 79.2%
Temmerman et al. 200720	Plain radiography Subtraction arthrography Nuclear arthrography Bone scintigraphy Diagnosis of loose acetablular component of total hip prosthesis	Studies that evaluated diagnostic performance of any of the 4 imaging techniques in patients suspected of having loosening of a hip prosthesis. Minimum of 1-year follow-up or operation as a gold standard. Minimum of 10 patients. Sufficient data to determine sensitivity and specificity. Aseptic loosening only. Excluded reviews, abstracts, editorials, letters and comments.	28	1975 to 2004	Modified Cochrane checklist used to generate a level of evidence ranging from 1 to 5, with "1" representing the highest level. All studies were rated a "4" due to lack of independent application of a reference standard or lack of blinding	Subtraction arthrography (GS: operation)	Nuclear arthrography (GS: operation)		Bone scintigraphy (GS: operation)
						Sensitivity: 89% (95% CI, 84% to 93%) Specificity: 76% (95% CI, 68% to 82%)	Sensitivity: 87% (95% CI, 57% to 97%) Specificity: 64% (95% CI, 40% to 82%)		Sensitivity: 67% (95% CI, 57% to 76%) Specificity: 75% (95% CI, 64% to 83%)
Prandini et al. 200621	99mTc-WBCs 99mTc-BS 67Ga scan FDG-PET 111In-WBCs Diagnosis of bone infection due to peripheral open fractures or prosthetic joint implants	Included diagnostic studies of peripheral open fractures or prosthetic joint infections. Excluded papers regarding diabetic foot infections.	99mTc-WBCs — 22 99mTc TPBS —29 FDG-PET — 6 111In-WBCs — 26	1984 to 2004	Not reported	99mTc-WBCs (HMPAO) (GS not reported)	99mTc-TPBS (GS not reported)		Alternate Tests (GS not reported)
						Sensitivity: 89.0% Specificity: 89.1%	Sensitivity: 85.4% Specificity: 75.2%		FDG-PET Sensitivity: 94.1% Specificity: 87.3% 111In-WBCs Sensitivity: 82.8% Specificity: 83.8%
Temmerman et al. 200522	Plain radiography Subtraction arthrography Nuclear arthrography Bone scintigraphy Diagnosis of aseptic loosening of femoral component of a hip prosthesis	Studies that evaluated diagnostic performance of any of the 4 imaging techniques. Minimum of 1-year follow-up or operation as a gold standard. Minimum of 10 patients. Sufficient data to determine sensitivity and specificity. Excluded reviews, abstracts, editorials, letters and comments.	Plain radiography —17 Subtraction arthrography — 9 Nuclear arthrography —10 Bone scintigraphy — 15	1975 to 2004	Modified Cochrane checklist used to generate a level of evidence ranging from 1 to 5, with "1" representing the highest level All studies were rated a "4" due to lack of independent application of a reference standard or lack of blinding	Subtraction arthrography (GS: operation)	Nuclear arthrography (GS: operation)		Bone scintigraphy (GS: operation)
						Sensitivity: 86% (95% CI, 74% to 93%) Specificity: 85% (95% CI, 77% to 91%)	Sensitivity: 85% (95% CI, 75% to 91%) Specificity: 83% (95% CI, 75% to 89%)		Sensitivity: 85% (95% CI, 79% to 89%) Specificity: 72% (95% CI, 64% to 79%)

BS = bone scan; CI = confidence interval; FDG = ¹⁸fluorodeoxyglucose radiotracer; ⁶⁷Ga = gallium 67; GS = gold standard ; HMPAO = hexamethylpropyleneamine oxime; ¹¹¹In = Indium-111; MDP = methylene diphosphonate; NR = not reported; NS = not specified; PET = positron emission tomography; ^99mTc = technetium-99m; TPBS = triple-phase bone scan; WBC = white blood cell
† Data not pooled ‡ Single study