Cindy J. Wong

A Randomized Trial of Arthroscopic Surgery for Osteoarthritis of the Knee

BACKGROUND The efficacy of arthroscopic surgery for the treatment of osteoarthritis of the knee is unknown. METHODS We conducted a single-center, randomized, controlled trial of arthroscopic surgery in patients with moderate-to-severe osteoarthritis of the knee. Patients were randomly assigned to surgical lavage and arthroscopic débridement together with optimized physical and medical therapy or to treatment with physical and medical therapy alone. The primary outcome was the total Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score (range, 0 to 2400; higher scores indicate more severe symptoms) at 2 years of follow-up. Secondary outcomes included the Short Form-36 (SF-36) Physical Component Summary score (range, 0 to 100; higher scores indicate better quality of life). RESULTS Of the 92 patients assigned to surgery, 6 did not undergo surgery. Of the 86 patients assigned to control treatment, all received only physical and medical therapy. After 2 years, the mean (+/-SD) WOMAC score for the surgery group was 874+/-624, as compared with 897+/-583 for the control group (absolute difference [surgery-group score minus control-group score], -23+/-605; 95% confidence interval [CI], -208 to 161; P=0.22 after adjustment for baseline score and grade of severity). The SF-36 Physical Component Summary scores were 37.0+/-11.4 and 37.2+/-10.6, respectively (absolute difference, -0.2+/-11.1; 95% CI, -3.6 to 3.2; P=0.93). Analyses of WOMAC scores at interim visits and other secondary outcomes also failed to show superiority of surgery. CONCLUSIONS Arthroscopic surgery for osteoarthritis of the knee provides no additional benefit to optimized physical and medical therapy. (ClinicalTrials.gov number, NCT00158431.)

Omega-3 Free Fatty Acids for the Maintenance of Remission in Crohn Disease: The EPIC Randomized Controlled Trials

CONTEXT Maintenance therapy for Crohn disease features the use of immunosuppressive drugs, which are associated with an increased risk of infection. Identification of safe and effective maintenance strategies is a priority. OBJECTIVE To determine whether the oral administration of omega-3 free fatty acids is more effective than placebo for prevention of relapse of Crohn disease. DESIGN, SETTING, AND PATIENTS Two randomized, double-blind, placebo-controlled studies (Epanova Program in Crohns Study 1 [EPIC-1] and EPIC-2) conducted between January 2003 and February 2007 at 98 centers in Canada, Europe, Israel, and the United States. Data from 363 and 375 patients with quiescent Crohn disease were evaluated in EPIC-1 and EPIC-2, respectively. INTERVENTIONS Patients with a Crohns Disease Activity Index (CDAI) score of less than 150 were randomly assigned to receive either 4 g/d of omega-3 free fatty acids or placebo for up to 58 weeks. No other treatments for Crohn disease were permitted. MAIN OUTCOME MEASURE Clinical relapse, as defined by a CDAI score of 150 points or greater and an increase of more than 70 points from the baseline value, or initiation of treatment for active Crohn disease. RESULTS For EPIC-1, 188 patients were assigned to receive omega-3 free fatty acids and 186 patients to receive placebo. Corresponding numbers for EPIC-2 were 189 and 190 patients, respectively. The rate of relapse at 1 year in EPIC-1 was 31.6% in patients who received omega-3 free fatty acids and 35.7% in those who received placebo (hazard ratio, 0.82; 95% confidence interval, 0.51-1.19; P = .30). Corresponding values for EPIC-2 were 47.8% and 48.8% (hazard ratio, 0.90; 95% confidence interval, 0.67-1.21; P = .48). Serious adverse events were uncommon and mostly related to Crohn disease. CONCLUSION In these trials, treatment with omega-3 free fatty acids was not effective for the prevention of relapse in Crohn disease. TRIAL REGISTRATION clinicaltrials.gov Identifiers: EPIC-1: NCT00613197, EPIC-2: NCT00074542.

A Simplified Approach to the Treatment of Uncomplicated Hypertension: A Cluster Randomized, Controlled Trial

Notwithstanding the availability of antihypertensive drugs and practice guidelines, blood pressure control remains suboptimal. The complexity of current treatment guidelines may contribute to this problem. To determine whether a simplified treatment algorithm is more effective than guideline-based management, we studied 45 family practices in southwestern Ontario, Canada, using a cluster randomization trial comparing the simplified treatment algorithm with the Canadian Hypertension Education Program guidelines. The simplified treatment algorithm consisted of the following: (1) initial therapy with a low-dose angiotensin-converting enzyme inhibitor/diuretic or angiotensin receptor blocker/diuretic combination; (2) up-titration of combination therapy to the highest dose; (3) addition of a calcium channel blocker and up-titration; and (4) addition of a non—first-line antihypertensive agent. The proportion of patients treated to target blood pressure (systolic blood pressure <140 mm Hg and diastolic blood pressure <90 mm Hg for patients without diabetes mellitus or systolic blood pressure <130 mm Hg and diastolic blood pressure <80 mm Hg for diabetic patients) at 6 months was analyzed at the practice level. The proportion of patients achieving target was significantly higher in the intervention group (64.7% versus 52.7%; absolute difference: 12.0%; 95% CI: 1.5% to 22.4%; P=0.026). Multivariate analysis of patient-level data showed that assignment to the intervention arm increased the chance of reaching the target by 20% (P=0.028), when adjusted for other covariates. In conclusion, the Simplified Treatment Intervention to Control Hypertension Study indicates that a simplified antihypertensive algorithm using initial low-dose fixed-dose combination therapy is superior to guideline-based practice for the management of hypertension.

A Randomized, Double-Blind, Sham-Controlled Study of Granulocyte/Monocyte Apheresis for Active Ulcerative Colitis

BACKGROUND & AIMS Activated granulocytes and monocytes/macrophages are implicated in the pathogenesis of ulcerative colitis. Open-label studies and clinical experience in Japan and Europe have suggested that granulocyte/monocyte apheresis is safe and effective in treating ulcerative colitis. METHODS We evaluated the efficacy of granulocyte/monocyte apheresis in a randomized, double-blind, sham-controlled trial in patients with active moderate-to-severe ulcerative colitis (Mayo score 6-11) in community-based and tertiary care centers. As intervention, we used granulocyte/monocyte apheresis with the Adacolumn Apheresis System (JIMRO, Ltd, Takasaki, Japan) or sham apheresis in a 2:1 ratio for 9 weeks of treatment in a North American pivotal study (N = 168) and in a smaller, companion study of identical design conducted in Europe and Japan (N = 47). RESULTS In the pivotal study, clinical remission rates (Mayo score 0-2, with scores of 0 on rectal bleeding and 0 or 1 on endoscopic examination) were 17% and 11% for the granulocyte/monocyte apheresis (n = 112)- and sham-treatment groups, respectively (n = 56; P = .361). Clinical response (Mayo score reduction of >/=3 points from baseline) was observed in 44% and 39% of patients, respectively (P = .620). Similar changes were observed for the apheresis- and sham-treatment groups for endoscopic remission and response, and changes in Mayo and quality-of-life scores. The companion study and pooled data from both studies also yielded similar results. CONCLUSIONS In this study, granulocyte/monocyte apheresis was well tolerated but did not demonstrate efficacy for induction of clinical remission or response in patients with moderate-to-severe ulcerative colitis.

Ciprofloxacin or metronidazole for the treatment of perianal fistulas in patients with Crohn's disease: a randomized, double-blind, placebo-controlled pilot study.

Background: Although metronidazole and ciprofloxacin are used to treat perianal Crohns disease (CD), no placebo‐controlled trials have been performed. Methods: We performed a placebo‐controlled pilot trial to evaluate the efficacy and safety of metronidazole and ciprofloxacin in patients with perianal CD. Twenty‐five patients with CD and actively draining perianal fistulas were randomized to receive ciprofloxacin 500 mg, metronidazole 500 mg, or placebo twice daily for 10 weeks. Remission and response of perianal fistulas were defined as closure of all fistulas and closure of at least 50% of fistulas that were draining at baseline, respectively. The primary endpoint was remission at 10 weeks. Results: Ten patients were randomized to ciprofloxacin, 7 to metronidazole, and 8 to placebo. Remission at week 10 occurred in 3 patients (30%) treated with ciprofloxacin, no patients (0%) treated with metronidazole, and 1 patient (12.5%) treated with placebo (P = 0.41). Response at week 10 occurred in 4 patients (40%) treated with ciprofloxacin, 1 patient (14.3%) treated with metronidazole, and 1 patient (12.5%) treated with placebo (P = 0.43). Termination of the trial prior to week 10 occurred in 1 patient (10%) treated with ciprofloxacin, 5 patients (71.4%) treated with metronidazole, and 1 patient (12.5%) treated with placebo (P < 0.02). No serious adverse events occurred. Conclusion: Remission and response occurred more frequently in patients treated with ciprofloxacin but the differences were not significant in this pilot study. Ciprofloxacin was well tolerated.

A disease-specific questionnaire for assessing quality of life in patients on hemodialysis.

A disease-specific questionnaire was developed for patients receiving chronic hemodialysis by interviewing patients to determine which aspects of their quality of life were adversely affected by their disease. The final questionnaire contained 26 questions in five dimensions (physical symptoms, fatigue, depression, relationships with others, frustration). The questionnaire demonstrated construct validity when compared with the Sickness Impact Profile, time trade-off technique and an exercise stress test. It was reproducible in stable, placebo-treated patients (correlation coefficient 0.85-0.98 for the 5 dimensions). It was more responsive than other measures in detecting an improvement with erythropoietin therapy in a randomized, placebo-controlled trial. This questionnaire should be useful for the assessment of the effect of various interventions upon the quality of life of hemodialysis patients.

Erythropoietin with Iron Supplementation To Prevent Allogeneic Blood Transfusion in Total Hip Joint Arthroplasty: A Randomized, Controlled Trial

Total hip joint arthroplasty is frequently associated with transfusion of allogeneic blood (1, 2). Although serologic screening has reduced the risk for viral infection to a low level (3, 4), the public is highly concerned about this potential complication of transfusion (5). Therefore, further refinement of strategies to avoid exposure to allogeneic blood is needed. The most commonly used preventive strategy is autologous blood donation (6). Blood is collected from the patient before surgery and is reinfused if transfusion is necessary. In the past decade, this maneuver, which reduces exposure to pathogens and red cell alloimmunization, has become a standard of care in orthopedic surgery (7, 8). However, autologous blood donation has several disadvantages. First, donation and banking of autologous blood are inconvenient to patients (9, 10). Second, phlebotomy increases the prevalence of postoperative anemia and transfusion (either autologous or allogeneic) (11). Third, use of autologous blood is not without risk (12, 13). Bacterial contamination of predonated blood (14) and major transfusion reactions (due to administrative error) (15) are rare but may be life-threatening. Finally and most important, many patients are not eligible for predonation because of concomitant medical conditions (16). Erythropoietin, a glycoprotein produced by the kidney, stimulates production of red blood cells from the bone marrow (17). Administration of recombinant human erythropoietin (epoetin alfa) reduces the risk for allogeneic blood transfusion in patients undergoing total hip joint arthroplasty (18, 19). Factors that influence the response to epoetin alfa include the dose and timing of treatment (20), coadministration of iron (21, 22), and baseline hemoglobin concentration (23). Although several different preoperative regimens have been described, the regimen approved by the U.S. Food and Drug Administration consists of four subcutaneous injections of epoetin alfa, 600 U/kg of body weight, administered before surgery (weeks 3, 2, and 1 and the day of surgery) (24). Thus, a person weighing 70 kg would require a total dose of 168 000 U. On the basis of subgroup analysis from a previous study (18), we hypothesized that a high dose of oral iron used in conjunction with a more prolonged epoetin alfa dosing schedule might produce a better hematologic response than that obtained with the standard regimen. We therefore evaluated the efficacy of two different epoetin alfa dose regimens. Methods Patients The study was a double-blind, randomized, parallel-group, multicenter clinical trial comparing the efficacy of epoetin alfa (Eprex, Janssen-Ortho Inc., Toronto, Ontario, Canada) with placebo in adult patients undergoing total hip joint arthroplasty. The trial was conducted at 13 teaching and 4 community hospitals in Canada from May 1996 to April 1999. The protocol was approved by the institutional review board of each participating center. Eligible patients had a hemoglobin concentration of 98 to 137 g/L and did not predonate blood. At centers where an autologous blood donation program was available, blood predonation was discussed with patients; those who participated in the study were either ineligible for predonation because of medical contraindication or declined this option. Persons with rheumatoid arthritis, recent gastrointestinal or intracranial bleeding, iron deficiency, seizures, blood dyscrasias, or uncontrolled hypertension (diastolic blood pressure>100 mm Hg) were excluded from the study. Patients who required revision arthroplasty or those in whom red cell salvage devices were considered essential were not enrolled. All patients gave written informed consent. Baseline and Randomization Procedures Participants were screened for eligibility 7 weeks before surgery. A history and physical examination were performed, and a complete blood count, iron studies, and blood chemistry were obtained; patients then began oral iron therapy. Six weeks before surgery, eligible patients were randomly assigned to one of three treatment groups. Randomization was performed according to a computer-generated schedule using a block size of 13 and an allocation ratio of 3:5:5 to the high-dose epoetin group, low-dose epoetin group, or placebo group, respectively. Treatment Regimens Patients began daily oral iron therapy at least 42 days before surgery and continued therapy until the day of hospital discharge. Three capsules per day were recommended. In patients who were intolerant of iron, the number of capsules was reduced to the point of tolerability. The iron preparation prescribed was Niferex-150 (Schwarz Pharma, Mequon, Wisconsin). This polysaccharideiron complex was selected because of its good tolerability and high bioavailability of elemental iron (150 mg per capsule) (25). Patients received four weekly subcutaneous injections of placebo, high-dose epoetin alfa (40 000 U), or low-dose epoetin alfa (20 000 U) starting 4 weeks before surgery. The total possible dose was 160 000 U in the high-dose group and 80 000 U in the low-dose group. The study drug was withheld if the hemoglobin concentration was 150 g/L or more, systolic blood pressure was 200 mm Hg or more, or the diastolic blood pressure was 105 mm Hg or more. During the trial, the study coordinator at the data coordinating center, who was aware of the patients hemoglobin concentration, authorized administration of study drug before each visit. This person had no contact with patients and did not assess outcomes. Follow-up Schedule Patients were evaluated 28, 21, 14, and 7 days before surgery. At these visits, vital signs and adverse events were recorded by the visiting nurse. Patients, surgeons, and nurses were unaware of treatment assignments and laboratory results. Hemoglobin concentration on the day of surgery was available to the surgeon and other health care personnel, but the reticulocyte count and the previous hemoglobin concentration were not. Blood loss was quantified by weighing sponges and measuring suction volume intraoperatively and subtracting the volume of the irrigation fluid. Patients were seen 1, 3, and 5 days after surgery; blood work was performed at these times. On the fifth day after surgery, patients underwent duplex ultrasonography (26, 27) to evaluate both legs for the presence of deep venous thrombosis. Transfusion Policy Transfusion of allogeneic blood was performed according to the usual practice of attending surgeons and anesthesiologists. We did not establish criteria for transfusion; however, the usual policy in Canada is not to perform transfusion in asymptomatic patients on the basis of a specific hemoglobin threshold. No patient donated or received autologous blood. Outcome Measures The primary outcome measure was occurrence of allogeneic blood transfusion. Secondary outcomes were changes in reticulocyte count and hemoglobin concentration. Adverse events were determined according to World Health Organization criteria (28). The proportion of patients who experienced thromboembolic disease (proximal or distal deep venous thrombosis and pulmonary embolus) and serious adverse events was compared among the treatment groups. Statistical Analysis Before the start of the study, retrospective chart review was performed to estimate the transfusion rate in patients undergoing hip arthroplasty (n =471) who had characteristics similar to those of our patients. In those patients, the rate of allogeneic transfusion was 39% (95% CI, 34% to 43%). The reduction in the transfusion rate considered clinically important was 20%. On the basis of pharmacokinetic data, the higher dose of epoetin alfa was judged likely to be more efficacious (29) than the lower dose. Therefore, we estimated that the transfusion rate would decrease from 40% to 15% in the high-dose group and from 40% to 20% in the low-dose group. In accordance with these assumptions, we used an asymmetric randomization schedule that allocated a greater number of patients to the low-dose epoetin alfa and placebo groups (5 patients for every 3 that were allocated to the high-dose epoetin alfa group). This maneuver ensured adequate statistical power (80%) to compare the transfusion rate in the high-dose and low-dose groups with that in the placebo group. Since an allowance of 5% was made for unevaluable patients, 83 patients per group were required in the low-dose and placebo groups and 50 patients were needed in the high-dose group. Accordingly, the total sample size requirement was 216 patients. All statistical analyses of efficacy measures were performed on an intention-to-treat basis, which was prospectively defined to include patients who had received at least one dose of study medication and subsequently underwent surgery within 1 week of the scheduled date. Separate chi-square tests were done to compare the proportion of patients who required transfusion in the placebo group with that among patients assigned to the low-dose epoetin alfa group or the high-dose epoetin alfa group. Bonferroni correction was used as a conservative method of adjusting for multiple comparisons (30). Accordingly, an error of 0.025 was considered to indicate statistical significance. Continuous outcome measures were compared by using analysis of variance. Logistic regression analyses were performed to explore the relationship between occurrence of transfusion and age, sex, weight, body mass index, predicted blood volume, baseline reticulocyte count, preoperative reticulocyte count, change in reticulocyte count, baseline hemoglobin concentration, preoperative hemoglobin concentration, change in hemoglobin concentration, baseline serum ferritin level, preoperative serum ferritin level, baseline serum iron level, preoperative serum iron level, number of days receiving iron therapy before surgery, baseline erythropoietin level, and treatment with epoetin alfa. Variables significant at the 0.10 level were examined further in a multiv

The use of generic and specific quality-of-life measures in hemodialysis patients treated with erythropoietin

The effect of recombinant human erythropoietin (EPO) on the quality of life and exercise capacity of 118 hemodialysis patients was assessed in a randomized, double-masked placebo-controlled trial. Patients were randomized into three groups: 1) placebo, 2) EPO to achieve a hemoglobin of 95-110 g/L and 3) EPO to achieve a hemoglobin of 115-130 g/L. Patients were followed for six months. Quality of life was assessed using a disease-specific measure [the Kidney Disease Questionnaire (KDQ)] and two generic measures [Sickness Impact Profile (SIP) and the Time Trade OFF (TTO)]. The KDQ contains five dimensions. Functional capacity was assessed with a Six-Minute Walk test (SMW) and an Exercise Stress Test (EST). The mean hemoglobin at six months was 74, 102, and 117 gm/l in groups one, two and three, respectively. There was a marked improvement in quality of life with EPO therapy, but no difference between groups 2 and 3. The outcome measure that was the most responsive to change was the KDQ (P less than .001 for the fatigue and physical symptoms dimensions). The aggregate global (P less than .02) and physical (P = .005) scores of the SIP improved with EPO therapy, the psychosocial score did not. There was no improvement in the TTO. There was an improvement in the EST (P = .02) but not in the SMW. The reproducibility of the outcome measures in placebo-treated patients varied between 0.80 and 0.98 (intra-class correlation coefficient). The correlation among the outcome measures at six months was statistically significant in most cases, as was the correlation of change scores between baseline and six months.

Disease-specific questionnaire for patients with a renal transplant

A disease-specific questionnaire to assess the quality of life of renal transplant recipients was developed. A list of items of potential relevance to these patients was created and 50 transplant recipients rated the importance of each item. A combination of factor analysis and clinical judgment was then used to create the final questionnaire which consists of 25 questions in 5 dimensions (physical symptoms, fatigue, uncertainty/fear, appearance and emotions). The physical symptoms dimension is patient specific. All questions are scored on a 7-point Likert scale. The reproducibility of the questionnaire when it was administered to stable transplant recipients was high (intraclass correlation coefficients between 0.82 and 0.91 for the 5 dimensions). The scores of all dimensions except appearance improved 6 months after transplantation, when compared to pretransplantation scores. Patients who had a well-functioning graft (creatinine < 250 mmol/l) had higher scores than those with poorly functioning grafts. This questionnaire is easy to administer and is valid, reproducible in stable patients and responsive to change.

A cluster-randomized controlled trial of a blood conservation algorithm in patients undergoing total hip joint arthroplasty.

BACKGROUND: The optimum strategy for reducing allogeneic blood transfusion in patients undergoing total hip joint arthroplasty (THJA) is unknown.