The Shared Ethical Responsibility of Medically and Non-medically Qualified Experts in Human Drug Development Teams.

The complexity of developing and applying increasingly sophisticated new medicinal products has led to the participation of many non-medically qualified scientists in multi-disciplinary non-clinical and clinical drug development teams world-wide. In this introductory paper to the "IFAPP International Ethics Framework for Pharmaceutical Physicians and Medicines Development Scientists" it is argued that all members of such multidisciplinary teams must share the scientific and ethical responsibilities since they all influence directly or indirectly both the outcome of the various phases of the medicines development projects and the safety of the research subjects involved. The participating medical practitioner retains the overriding responsibility and the final decision to stop a trial if the well-being of the research subjects is seriously endangered. All the team members should follow the main ethical principles governing human research, the respect for autonomy, justice, beneficence and non-maleficence. Nevertheless, the weighing of these principles might be different under various conditions according to the specialty of the members.

An audit of cancer of unknown primary notifications: A cautionary tale for population health research using cancer registry data.

BACKGROUND: Cancer of unknown primary (CUP) is a common cancer yet little is known about the reliability of incidence data. METHODS: We audited 574 CUP (C80.9) diagnoses (median age 81 years) registered by the New South Wales (NSW) Central Cancer Registry (2004-2007) in a cohort of Australian Government Department of Veterans' Affairs clients. The registry did not clarify diagnoses with notifiers during this period due to interpretation of privacy legislation. For the audit, current registry practice was applied by seeking additional information from CUP notifiers and reclassifying diagnoses as necessary. In addition, clinicopathological characteristics were extracted from notifications. Fisher's exact test and Student's t-test were used to compare the demographic and clinicopathological characteristics of the CUP subgroups. Age/sex-standardised CUP incidence rates and 95% confidence intervals were calculated, standardised to the 2001 Australian population. RESULTS: 172 (30.0%) cases were reclassified to a known primary site, mostly cutaneous, and nine (1.6%) were found to be non-malignant diagnoses. After the audit the age/sex-standardised CUP incidence rates decreased from 26.0 (95% CI 21.2-30.8) to 15.9 (95% CI 12.5-19.3) per 100,000 person-years. Of the 393 remaining CUP cases, 202 (51%) were registered on the basis of a clinical diagnosis (46 by death certificate only) and 191 (49%) by pathological diagnosis (79 by cytology alone). Compared to cases with a pathological diagnosis, cases with a clinical diagnosis were older (85.6 vs. 82.0 years, p<0.001), and the reported number and location of metastases differed (p<0.001); metastatic sites were more likely to be unspecified for clinical diagnoses (36.1% vs. 4.2%). CONCLUSIONS: Cancer registry processes can markedly influence CUP incidence. Future population-based CUP research should take this into account, and consider stratification by basis of diagnosis due to differences in patient and tumour characteristics.

The UK Standardisation of Breast Radiotherapy (START) trials of radiotherapy hypofractionation for treatment of early breast cancer: 10-year follow-up results of two randomised controlled trials.

BACKGROUND: 5-year results of the UK Standardisation of Breast Radiotherapy (START) trials suggested that lower total doses of radiotherapy delivered in fewer, larger doses (fractions) are at least as safe and effective as the historical standard regimen (50 Gy in 25 fractions) for women after primary surgery for early breast cancer. In this prespecified analysis, we report the 10-year follow-up of the START trials testing 13 fraction and 15 fraction regimens. METHODS: From 1999 to 2002, women with completely excised invasive breast cancer (pT1-3a, pN0-1, M0) were enrolled from 35 UK radiotherapy centres. Patients were randomly assigned to a treatment regimen after primary surgery followed by chemotherapy and endocrine treatment (where prescribed). Randomisation was computer-generated and stratified by centre, type of primary surgery (breast-conservation surgery or mastectomy), and tumour bed boost radiotherapy. In START-A, a regimen of 50 Gy in 25 fractions over 5 weeks was compared with 41·6 Gy or 39 Gy in 13 fractions over 5 weeks. In START-B, a regimen of 50 Gy in 25 fractions over 5 weeks was compared with 40 Gy in 15 fractions over 3 weeks. Eligibility criteria included age older than 18 years and no immediate surgical reconstruction. Primary endpoints were local-regional tumour relapse and late normal tissue effects. Analysis was by intention to treat. Follow-up data are still being collected. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN59368779. FINDINGS: START-A enrolled 2236 women. Median follow-up was 9·3 years (IQR 8·0-10·0), after which 139 local-regional relapses had occurred. 10-year rates of local-regional relapse did not differ significantly between the 41·6 Gy and 50 Gy regimen groups (6·3%, 95% CI 4·7-8·5 vs 7·4%, 5·5-10·0; hazard ratio [HR] 0·91, 95% CI 0·59-1·38; p=0·65) or the 39 Gy (8·8%, 95% CI 6·7-11·4) and 50 Gy regimen groups (HR 1·18, 95% CI 0·79-1·76; p=0·41). In START-A, moderate or marked breast induration, telangiectasia, and breast oedema were significantly less common normal tissue effects in the 39 Gy group than in the 50 Gy group. Normal tissue effects did not differ significantly between 41·6 Gy and 50 Gy groups. START-B enrolled 2215 women. Median follow-up was 9·9 years (IQR 7·5-10·1), after which 95 local-regional relapses had occurred. The proportion of patients with local-regional relapse at 10 years did not differ significantly between the 40 Gy group (4·3%, 95% CI 3·2-5·9) and the 50 Gy group (5·5%, 95% CI 4·2-7·2; HR 0·77, 95% CI 0·51-1·16; p=0·21). In START-B, breast shrinkage, telangiectasia, and breast oedema were significantly less common normal tissue effects in the 40 Gy group than in the 50 Gy group. INTERPRETATION: Long-term follow-up confirms that appropriately dosed hypofractionated radiotherapy is safe and effective for patients with early breast cancer. The results support the continued use of 40 Gy in 15 fractions, which has already been adopted by most UK centres as the standard of care for women requiring adjuvant radiotherapy for invasive early breast cancer. FUNDING: Cancer Research UK, UK Medical Research Council, UK Department of Health.

Association of hospital and surgeon procedure volume with patient-centered outcomes of total knee replacement in a population-based cohort of patients age 65 years and older.

OBJECTIVE: To study the association between procedure volume and patient-centered outcomes such as functional status. METHODS: We performed an observational study of a stratified random sample of Medicare beneficiaries who underwent primary total knee replacement (TKR) in 2000. Low-volume surgeons were defined as surgeons performing < or =6 TKRs per year in the Medicare population, and low-volume centers were defined as those in which < or =25 TKRs per year were performed. The primary outcome was the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) functional status score (0-100 scale; 100 = best) 2 years after TKR. We defined a WOMAC functional status score of <60 as a poor functional outcome. Analyses were adjusted for sociodemographic factors, preoperative functional status, and comorbidities. RESULTS: Fifty-eight percent of 1,597 eligible patients agreed to participate. Twelve percent of participating patients had a WOMAC score <60 2 years following TKR. Patients operated upon by low-volume surgeons in low-volume hospitals were twice as likely to have a poor WOMAC functional status score as patients operated upon by higher volume surgeons and in higher volume hospitals (odds ratio 2.1, 95% confidence interval 1.1-4.2). CONCLUSION: Patients operated upon in low-volume hospitals by low-volume surgeons had worse functional outcomes 2 years after TKR. These findings add a new and important dimension to the discussion of whether to promote selective referral of procedures such as TKR to high-volume centers.

Neighborhoods matter: use of hospitals with worse outcomes following total knee replacement by patients from vulnerable populations.

BACKGROUND: Neighborhood sociodemographic characteristics are associated with health care utilization across many conditions. There has been little study of whether total knee replacement (TKR) recipients from vulnerable populations, including racial and ethnic minorities, the poor, the elderly, and the less well educated, are more likely to use low-volume hospitals (LVHs). METHODS: We used Medicare claims and census data to identify a national cohort of Medicare beneficiaries who had elective TKR. We defined an LVH as a center performing fewer than 26 TKRs per year, and we used geocoding to identify "bypassers" (patients who had a high-volume hospital closer to their residence than the one where they had TKR). We used multivariate logistic regression to examine the association of patient and neighborhood characteristics with utilization of LVHs and bypassing. We derived a summative measure of neighborhood vulnerability that included 4 high-risk characteristics (factors were high proportions of residents who are minority individuals, who have foreign-born status, with low income, and with low education). RESULTS: Of 113 015 TKR recipients, 13 120 (11.6%) used LVHs. Of all the TKR recipients, 9815 (8.7%) bypassed a center with a higher TKR volume than the one they used. Multivariate analyses showed that nonwhite (odds ratio [OR], 1.24; 95% confidence interval [CI], 1.16-1.33), poor (OR, 1.94; 95% CI, 1.83-2.08), and nonurban (OR, 1.94; 95% CI, 1.87-2.01) subjects were more likely to use LVHs. The TKR recipients from neighborhoods with 3 or 4 vulnerability factors were more likely than patients in neighborhoods with no vulnerability factors to use an LVH and bypass a high-volume hospital. CONCLUSION: Efforts to inform patients about the association of volume with TKR outcomes should target rural areas and vulnerable populations in urban settings.

Bilateral total knee replacement: staging and pulmonary embolism.

BACKGROUND: When a bilateral total knee replacement is indicated, it is not clear whether it is preferable to operate on both knees during the same hospitalization (simultaneously) or to stage the procedures in two separate hospital stays. A greater risk of pulmonary embolism after simultaneous total knee replacement has been reported by some authors, but little national data are available. METHODS: We reviewed the records of 122,385 United States Medicare enrollees who had had a total knee replacement in 2000. We noted whether they had had a unilateral procedure or two procedures and, if they had had two procedures, whether both had been done during the same hospitalization or whether the operations had been performed during two separate hospital stays. Age, sex, race, residence, Medicaid eligibility (a proxy for low income), and the Charlson comorbidity score were documented for each patient as were the total numbers of total knee replacements performed in the year 2000 by the hospital and the surgeon. The probability of a symptomatic pulmonary embolism developing in the first three months after surgery was calculated for the simultaneous, staged, and unilateral procedures. RESULTS: Simultaneous procedures were much more likely to be performed in high-volume hospitals and by high-volume surgeons than were staged procedures. Men had proportionately more simultaneous procedures than did women. Hospitals in the northeastern United States were the most likely to perform simultaneous procedures. A pulmonary embolism developed in the first three months in 0.81% of the patients who had had a single procedure compared with 1.44% of the patients who had undergone a simultaneous procedure (adjusted hazard ratio 1.81; 95% confidence interval, 1.49, 2.20). CONCLUSIONS: The systematic differences in patient gender, hospital and surgeon volume, and geographic region between those who undergo simultaneous total knee replacements and those who undergo staged procedures should be borne in mind when outcomes are being compared. The adjusted risk of pulmonary embolism is about 80% higher in the three months after a simultaneous procedure than in the three months after a single procedure, which suggests that the sum of the risks associated with the two operations of a staged procedure may equal or exceed the risk of simultaneous total knee replacement.

Extent of followup care after elective total hip replacement.

OBJECTIVE: To estimate the extent of radiographic and orthopedic followup among recipients of total hip replacement (THR), and to identify patients who are less likely to have consistent followup over 6 years postoperatively. METHODS: We studied a population-based sample of 622 patients who received THR in 1995. We developed a multivariate ordinal regression model with the extent of radiographic followup as the dependent variable (none, early, and consistent), adjusting for demographic and preoperative clinical characteristics, and hospital and surgeon volume. RESULTS: Ninety-four (15%) patients indicated that they had no followup radiographs, 269 (43%) had early followup only, and 259 (42%) had consistent followup radiographs over 6 years. Ninety percent of those with consistent followup orthopedic visits also had consistent followup radiographs over 6 years. Multivariate analyses revealed that older patients were less likely to have radiographic followup than younger patients (OR 0.76, 95% CI 0.65, 0.89) per each 5-year increase in age. Subjects with no college education were less likely to have radiographic followup than those with more education (OR 0.58, 95% CI 0.41, 0.83), and those with lower income were less likely to have radiographic followup than those with a higher income (OR 0.50, 95% CI 0.27, 0.92). CONCLUSION: Only 42% of THR recipients reported consistent radiographic followup. Older patients, patients with lower income, and those with lower education level were less likely to have consistent radiographic followup over 6 years after THR. These population groups can serve as targets for interventions to improve followup after elective THR.

Geographic diversity of low-volume hospitals in total knee replacement: implications for regionalization policies.

BACKGROUND/OBJECTIVES: Centers performing low volumes of total knee replacements (TKR) have worse outcomes of TKR than higher volume centers. Regionalization policies that shift patients to higher volume centers are being considered as a means of improving TKR outcomes. We sought to describe geographic diversity in the distribution of low-volume centers and examine state level characteristics associated with states that have a higher proportion of low-volume centers and/or a higher proportion of TKRs performed in low-volume centers. METHODS: We used U.S. Census data and geocoded Medicare claims to ascertain state-level demographic factors, procedure volume, and TKR rates and to conduct our state level analysis. We defined 2 outcomes: 1) proportion of all hospitals with a low annual TKR volume (<26 per year in the Medicare population); and 2) proportion of all TKRs in the Medicare population performed in low-volume centers. We examined linear associations among the 2 outcomes and state factors, and used multivariate regression to identify factors associated independently with these outcomes. RESULTS: Half of hospitals performing TKR in the Medicare population were low-volume centers, accounting for 13% of TKRs. Multivariate analysis revealed lower TKR rates, higher proportion of rural areas and larger state area were associated with a higher proportion of low-volume hospitals in a state. Lower proportion of elderly residents, higher population density and higher proportion of rural areas predicted a higher proportion of TKRs performed in low-volume centers. CONCLUSIONS: The distribution of low-volume hospitals among U.S. states varies substantially. Regionalization of TKR may require different strategies in states with small and large numbers of low-volume centers.

Offering patients the opportunity to choose their hospital for total knee replacement: impact on satisfaction with the surgery.

OBJECTIVE: To describe the extent to which patients were offered a choice between 2 or more hospitals for total knee replacement (TKR); to examine the association between having a choice of hospital for TKR and satisfaction with the surgery; and to identify population groups less likely to be offered a choice. METHODS: We studied a population-based sample of 932 Medicare beneficiaries who underwent elective TKR in 2000. We surveyed patients about their participation in choosing a hospital and their satisfaction with surgery. We examined whether lack of hospital choice influenced satisfaction with surgery after adjusting for age, sex, preoperative function, and socioeconomic status. RESULTS: Among 932 TKR recipients (mean age 74 years, 67% women), more than half (53%) reported having a lack of hospital choice. After adjusting for socioeconomic status, patients reporting lack of choice were approximately twice as likely to be dissatisfied with the results of surgery as patients who reported choosing among 2 or more hospitals for TKR (odds ratio [OR] 2.09, 95% confidence interval [95% CI] 1.13-3.87). Results of logistic regression revealed that patients reporting lack of choice were more likely to be women (OR 1.52, 95% CI 1.14-2.04), >80 years of age (as compared with 65-70 years; OR 1.63, 95% CI 1.03-2.57), living in suburban areas (OR 1.68, 95% CI 1.23-2.30), nonwhite (OR 1.57, 95% CI 0.86-2.87), and were less likely to have TKR performed by a high-volume surgeon (OR 0.71, 95% CI 0.53-0.96). CONCLUSION: More than half of the patients did not have a choice in selecting the hospital where they had TKR. Patients reporting lack of choice were more likely to be dissatisfied with surgery. Interventions to address preferences for hospital may improve satisfaction with care for patients with advanced knee arthritis.

Survival following total hip replacement.

BACKGROUND: Several studies have shown that patients who undergo total hip replacement live longer than control subjects, but the reason for this apparent protective effect is not clear. The purpose of our investigation was to assess whether the association had the characteristics of a causal relationship or whether it might appear to be due to comorbidity or other factors. METHODS: We compared survival over a six-year period for 28,469 Medicare enrollees who had elective primary total hip replacement in 1996 and a control group from the general Medicare population, matched 5:1 on year of birth, sex, race, and whether the Medicaid program paid the Medicare premium (a proxy for low income). For both the patients treated with total hip replacement and the control subjects, we used Medicare hospital claims to ascertain comorbidity, that is, whether the patient had had any of sixteen serious discharge diagnoses in the year prior to the total hip replacement (or an equivalent date for the controls). The survival patterns for the total hip arthroplasty and control cohorts were compared with use of proportional hazards regression for three follow-up periods: the first ninety days after surgery (or an equivalent date for the controls), ninety days to five years after surgery, and more than five years after surgery. RESULTS: The total hip replacement cohort had less comorbidity than the controls, with an approximately 30% lower prevalence for most serious diseases. Sex, age, Medicaid eligibility, and earlier serious comorbid diagnoses were important predictors of survival, but, even in analyses that adjusted for these variables, the total hip replacement cohort had better long-term survival than the controls. The patients who had a total hip replacement had a higher rate of mortality than the controls immediately after surgery, but, by three months postoperatively, the mortality rate for the patients was well below that for the controls. The overall rate of survival during the first ninety days was comparable for the two groups. From three months to five years after surgery, the mortality rate for the patients who had a total hip replacement was only two-thirds of that for the controls. After five years, the mortality rates for the two groups appeared to be converging. CONCLUSIONS: Total hip replacement recipients survive longer than do matched controls in the Medicare population. The very rapid emergence of the lower mortality rate suggests that it is due to the selection of low-risk patients for elective surgery. However, our admittedly crude adjustment for comorbidity did not diminish the protective effect, so some effect of the procedure itself cannot be ruled out.

Epidemiology of total knee replacement in the United States Medicare population.

BACKGROUND: There are limited population-based data on the utilization and outcomes of total knee replacement. The aim of the present study was to describe the rates of primary and revision total knee replacement and selected outcomes in persons older than sixty-five years of age in the United States. METHODS: Using Medicare claims, we computed annual incidence rates of unilateral elective primary and revision total knee replacement among United States Medicare beneficiaries in the year 2000. Poisson regression was used to assess the relationships between demographic characteristics and the incidence rates of primary and revision knee replacement. Proportional hazards models were used to examine the relationships between the ninety-day rates of complications and demographic and clinical factors. RESULTS: The rate of primary knee replacement was lower in blacks than in whites and in those qualifying for Medicaid supplementation than in those with higher incomes. The complications observed during the ninety days following primary knee replacement included mortality (0.7%), readmission (0.9%), pulmonary embolus (0.8%), wound infection (0.4%), pneumonia (1.4%), and myocardial infarction (0.8%). The complications observed during the ninety days following revision knee replacement were mortality (1.1%), readmission (4.7%), pulmonary embolus (0.5%), wound infection (1.8%), pneumonia (1.4%), and myocardial infarction (1.0%). Blacks had higher rates of mortality, readmission, and wound infection after primary knee replacement than whites did. Patients who qualified for Medicaid supplementation had higher complication rates, particularly after primary knee replacement. CONCLUSIONS: Overall, the rates of postoperative complications during the ninety days following total knee replacement are low. In the United States, blacks and individuals with low income undergo total knee replacement less frequently and generally have higher rates of adverse outcomes following primary knee replacement.

Utilization of low-volume hospitals for total hip replacement.

OBJECTIVE: To identify factors associated with utilization of low-volume hospitals for total hip replacement (THR) and to estimate differences in the distances that Medicare beneficiaries had to travel to reach low- or high-volume hospitals. METHODS: We studied a population-based sample of 1,146 Medicare beneficiaries who underwent elective THR in 1995. Using multiple data sources including medical record review, Medicare claims data, 1990 Census data, and a patient survey, we examined factors independently associated with utilization of low-volume hospitals for elective THR. We estimated the magnitude of difference in distances for patients undergoing THR in low- and high-volume hospitals. We determined the distance between each patient's residence and the treating hospital using MapQuest. RESULTS: Rural residency, low income, and low educational attainment, as well as belief in the importance of convenient location in the choice of hospital, were associated with higher utilization of low-volume hospitals. Rural and suburban patients who went to low-volume hospitals traveled much less than patients operated upon in high-volume centers. CONCLUSION: Policies aimed at restricting THR to high-volume centers would differentially affect poor, less educated, and rural patients. Voluntary efforts to shift THR to high-volume centers should involve educating these patients and their referring physicians about differences in both short-term and longer-term outcomes between high- and low-volume centers.

Association between hospital and surgeon procedure volume and the outcomes of total knee replacement.

BACKGROUND: The annual volume of major cardiovascular and oncologic procedures performed in hospitals and by surgeons has been inversely associated with the rates of perioperative mortality and complications. The relationship between hospital and surgeon volume and perioperative outcomes following total knee replacement has received little study. METHODS: We analyzed claims data for Medicare patients who had elective primary total knee replacement between January 1 and August 31, 2000. Hospital and surgeon volumes were defined as the number of primary and revision total knee replacements performed in the hospital or by the surgeon in Medicare recipients in 2000. We examined the associations between the annual volumes of total knee replacement performed in the hospitals and by the surgeons and the rates of mortality and complications (infection, pulmonary embolus, myocardial infarction, or pneumonia) in the first ninety days postoperatively. The analyses were adjusted for age, gender, comorbid conditions, Medicaid eligibility (a marker of low income), and arthritis diagnosis. Analyses of hospital volume were adjusted for surgeon volume and vice versa. RESULTS: Twenty-five percent of the primary total knee replacements were done by surgeons who performed twelve of these procedures or fewer in the Medicare population annually, and 11% were done in hospitals with an annual volume of twenty-five of these procedures or fewer. Compared with the patients who had a primary total knee replacement in hospitals with an annual volume of twenty-five procedures or fewer, those managed in hospitals with an annual volume exceeding 200 procedures had a lower risk of pneumonia (odds ratio, 0.65; 99% confidence interval, 0.47 to 0.90) and any of the adverse outcomes examined (death, pneumonia, pulmonary embolus, acute myocardial infarction, or deep infection) (odds ratio, 0.74; 99% confidence interval, 0.60 to 0.90). Similarly, patients who had a primary total knee replacement done by surgeons who performed more than fifty such procedures in Medicare recipients annually had a lower risk of pneumonia (odds ratio, 0.72; 99% confidence interval, 0.54 to 0.95) and any adverse outcome (odds ratio, 0.81; 99% confidence interval, 0.68 to 0.98) compared with patients of surgeons with an annual volume of twelve procedures or fewer. CONCLUSIONS: Patients managed at hospitals and by surgeons with greater volumes of total knee replacement have lower risks of perioperative adverse events following primary total knee replacement. Patients and clinicians should incorporate these findings into discussions about selecting a surgeon and a hospital for total knee replacement. These data should also be integrated into the policy debate about the advantages and drawbacks of regionalizing total joint replacement to high-volume centers.

Early failures of total hip replacement: effect of surgeon volume.

OBJECTIVE: To determine whether provider volume is associated with early failures following total hip replacement (THR) requiring revision. METHODS: Claims data were analyzed to follow a cohort of 57,488 Medicare beneficiaries who underwent elective primary THR in 1995-1996 in 3,044 hospitals in the US. Patients were followed through the end of 1999. Failure of primary THR was defined as a subsequent revision THR, as determined by International Classification of Diseases, Ninth Revision codes in hospital claims. Hospitals were stratified into 4 volume groups: low (<25 THRs/year), medium (26-50, 51-100 THRs/year), and high (>100 THRs/year). Low-volume surgeons were defined as those surgeons performing <12 elective primary THRs annually in the Medicare population. Associations between the rates of revision and surgeon volume were determined by hazard ratios from a proportional hazard model, with adjustment for hospital volume, patient age, poverty status, sex, and comorbidities. We also examined whether the effect of surgeon volume on revision rates differed between the first 18 months postoperatively and later time periods. RESULTS: Among 57,488 patients who had elective primary THR in 1995-1996, 2,537 (4.4%) had at least 1 revision THR by the end of 1999, with 1,437 (56.6%) of these revisions occurring within the first 18 months after the index primary THR. Median followup time was 47 months (range 0-54). Patients of high-volume surgeons were less likely to have revision THRs than patients of low-volume surgeons, regardless of hospital volume stratum. Further analysis revealed that the effect of surgeon volume on revisions was striking in the first 18 months after surgery but was not evident in the subsequent years. CONCLUSION: Patients of low-volume surgeons have higher rates of revision THR than patients of high-volume surgeons, particularly within the first 18 months postoperatively. Referring clinicians should consider including surgeon volume among the factors influencing their choice of surgeon for elective THR.

Mortality and pulmonary embolism after fracture in the elderly.

Hip fracture has repeatedly been associated with increases in the risks of death and pulmonary embolism (PE), but few studies have considered whether other fractures are also associated with these adverse outcomes. The authors estimated the 90-day risks and relative risks of mortality and PE after fractures, and the longer-term relative risks of mortality, for each of ten fracture sites. Using the 5% US standard sample of the Medicare population, we identified 81,181 fractures of the pelvis, patella, and long bones occurring between July 1, 1986, and June 30, 1990, among beneficiaries aged 65 years or older. The fractures were randomly matched by sex, race, and year of birth with a beneficiary who did not suffer that particular fracture, to form ten control cohorts. All patients were followed up until December 31, 1990. The 90-day risk of death was greater than 9% after hip, nonhip femur, and pelvic fractures, with risks relative to their matched control cohorts of 4.7 to 6.7. For white patients with these three fracture types these relative risks decreased substantially with age. White patients who had a hospitalization in the 2 years before hip fracture were more likely to die in the first 90 days than those who had no hospitalization before the hip fracture, but this effect, too, decreased with age. Patients who survived 1 year after most fracture types had no clinically significant excess mortality compared with their surviving controls. For patients with hip, nonhip femur, and pelvis fractures, however, there remained an elevated risk of 1.6 to 1.8, and for patients with proximal humerus fractures the risk ratio was 1.4. All lower-limb fractures carried a higher risk of PE than any upper-limb fracture.

A systematic review of the antifungal effectiveness and tolerability of amphotericin B formulations.

OBJECTIVE: A systematic review was performed to compare the effectiveness and tolerability of lipid-based amphotericin B (AmB) formulations and conventional AmB in the treatment of systemic fungal infections. METHODS: The literature and unpublished studies were searched using MEDLINE, EMBASE, Biological Abstracts, AIDSLINE, CANCERLIT, CRD database, Cochrane Controlled Trials Register, and other databases. Search terms included: amphotericin, liposom*, lipid*, colloid*, antifungal agents, and mycoses. Studies were selected according to predetermined criteria. The outcome measures reviewed were efficacy, mortality, renal toxicity, and infusion-related reactions. Meta-analyses and number-needed-to-treat (NNT) analyses were performed. RESULTS: Seven studies (8 publications) met the entry criteria. Meta-analysis showed that lipid-based formulations significantly reduced all-cause mortality risk by an estimated 28% compared with conventional AmB (odds ratio [OR], 0.72; 95% CI, 0.54 to 0.97). There was no significant difference in efficacy between the lipid-based formulations and conventional AmB (OR, 1.21; 95% CI, 0.98 to 1.49). AmB lipid complex (ABLC) and liposomal AmB (L-AmB) significantly reduced the risk of doubling serum creatinine by an estimated 58% (OR, 0.42; 95% CI, 0.33 to 0.54). There was no significant reduction in risk of infusion-related reactions with lipid-based formulations, although this was difficult to interpret given the lack of consistent control of confounding factors. Comparing the lipid-based formulations with conventional AmB, the overall NNT to prevent 1 death was 31. The NNT to prevent a doubling of serum creatinine for both ABLC and L-AmB compared with conventional AmB was 6. CONCLUSIONS: This study demonstrates advantages with lipid-based formulations over conventional AmB in terms of reduced risk of mortality and renal toxicity. Future trials in patients with proven fungal infection should control for factors such as premedication, infusion rates, fluid preloading, sodium/potassium supplementation, and concomitant medication.

Accuracy of Medicare claims data for rheumatologic diagnoses in total hip replacement recipients.

This analysis was performed to examine whether Medicare claims accurately document underlying rheumatologic diagnoses in total hip replacement (THR) recipients. We obtained data on rheumatologic diagnoses including rheumatoid arthritis (RA), avascular necrosis (AVN), and osteoarthritis (OA) from medical records and from Medicare claims data. To examine the accuracy of claims data we calculated sensitivity and positive predictive value using medical records data as the "gold standard" and assessed bias due to misclassification of claims-based diagnoses. The sensitivities of claims-based diagnoses of RA, AVN, and OA were 0.65, 0.54, and 0.96, respectively; the positive predictive values were all in the 0.86-0.89 range. The sensitivities of RA and AVN varied substantially across hospital volume strata, but in different directions for the two diagnoses. We conclude that inaccuracies in claims coding of diagnoses are frequent, and are potential sources of bias. More studies are needed to examine the magnitude and direction of bias in health outcomes research due to inaccuracy of claims coding for specific diagnoses.

Association of hospital and surgeon volume of total hip replacement with functional status and satisfaction three years following surgery.

OBJECTIVE: To evaluate whether hospital volume and surgeon volume of total hip replacements (THRs) are associated with patient-reported functional status and satisfaction with surgery 3 years postoperatively. METHODS: We performed a population-based cohort study of a stratified random sample of Medicare beneficiaries who underwent elective primary or revision THR in Ohio, Pennsylvania, or Colorado in 1995. The primary outcomes were the self-reported Harris hip score and a validated scale measuring satisfaction with the results of surgery. Both outcomes were assessed 3 years postoperatively. Hospital volume was defined as the aggregate number of elective primary and revision THRs performed on Medicare beneficiaries in the hospital in 1995. High-volume hospitals were defined as those in which >100 such procedures are performed annually, and low-volume centers were defined as those in which 12 procedures per year. CONCLUSION: Hospital volume and surgeon volume have little effect on 3-year functional outcome following THR, after adjusting for patient sociodemographic and select clinical characteristics. However, satisfaction with primary THR is greater among patients who underwent surgery in high-volume centers, and satisfaction with revisions is greater among patients whose operations were performed by higher-volume surgeons. Referring clinicians should incorporate these findings into their discussion of referral choices with patients considering THR. Conclusions regarding the effect of volume on longevity of the implants must await longer-term followup studies. Finally, further research is warranted to better understand the association between hospital and surgeon procedure volume and patient satisfaction with surgery.

Incidence rates of dislocation, pulmonary embolism, and deep infection during the first six months after elective total hip replacement.

BACKGROUND: The lengths of acute hospital stays following total hip replacement have diminished substantially in recent years. As a result, a greater proportion of complications occurs following discharge. Data on the incidence trends of major complications of total hip replacement would facilitate recognition and management of these adverse events. METHODS: We used Medicare claims data on beneficiaries sixty-five years and older who had had elective, primary total hip replacement for a reason other than a fracture (58,521 patients) or had had revision total hip replacement (12,956 patients) between July 1, 1995, and June 30, 1996. We calculated incidence rates of dislocation, pulmonary embolism, and deep hip infection per 10,000 person-weeks for four time-periods following the admission for the surgery (during the index hospitalization, from discharge to four weeks postoperatively, from five to thirteen weeks postoperatively, and from fourteen to twenty-six weeks postoperatively). We then used life-table methods to estimate the cumulative incidence of each complication over the first six postoperative months. RESULTS: Of the patients who had had a primary total hip replacement, 3.9% had a dislocation, 0.9% had a pulmonary embolism, and 0.2% had a deep infection in the first twenty-six postoperative weeks. In the revision total hip replacement cohort, the proportions with dislocation, pulmonary embolism, and deep infection were 14.4%, 0.8%, and 1.1%, respectively. The rates of these adverse outcomes were highest during the index hospitalization, diminished considerably in the period from discharge to four weeks postoperatively, and continued to drop in the periods from five to thirteen and fourteen to twenty-six weeks postoperatively. CONCLUSIONS: The incidence rates of dislocation, pulmonary embolism, and deep infection are highest immediately after total hip replacement, but they continue to be elevated throughout the first three postoperative months. With the lengths of hospital stays continuing to diminish, an increasing proportion of complications will occur in outpatients. These findings provide a basis for developing strategies to prevent these complications in the postdischarge management of patients who have had elective total hip replacement. LEVEL OF EVIDENCE: Prognostic study, Level II-1 (retrospective study). See p. 2 for complete description of levels of evidence.