Abbas Kezouh

Problem of immortal time bias in cohort studies: example using statins for preventing progression of diabetes

Immortal time in observational studies can bias the results in favour of the treatment group, but it is not difficult to identify and avoid

Patterns of antibiotic use and risk of hospital admission because of Clostridium difficile infection

Background: Previous observations have indicated that infection with Clostridium difficile occurs almost exclusively after exposure to antibiotics, but more recent observations have suggested that prior antibiotic exposure may be less frequent among cases of community-acquired disease. Methods: We used 2 linked health databases to perform a matched, nested case–control study of elderly patients admitted to hospital with community-acquired C. difficile infection. For each of 836 cases among people 65 years of age or older, we selected 10 controls. We determined the proportion of cases that occurred without prior antibiotic exposure and estimated the risk related to exposure to different antibiotics and the duration of increased risk. Results: Of the 836 cases, 442 (52.9%) had no exposure to antibiotics in the 45-day period before the index date, and 382 (45.7%) had no exposure in the 90-day period before the index date. Antibiotic exposure was associated with a rate ratio (RR) of 10.6 (95% confidence interval [CI] 8.9–12.8). Clindamycin (RR 31.8, 95% CI 17.6–57.6), cephalosporins (RR 14.9, 95% CI 10.9–20.3) and gatifloxacin (RR 16.7, 95% CI 8.3–33.6) were associated with the highest risk. The RR for C. difficile infection associated with antibiotic exposure declined from 15.4 (95% CI 12.2–19.3) by about 20 days after exposure to 3.2 (95% CI 2.0–5.0) after 45 days. Use of a proton pump inhibitor was associated with increased risk (RR 1.6, 95% CI 1.3–2.0), as were concurrent diagnoses of inflammatory bowel disease (RR 4.1, 95% CI 2.6–6.6), irritable bowel syndrome (RR 3.4, 95% CI 2.3–5.0) and renal failure (RR 1.7, 95% CI 1.2–2.2). Interpretation: Community-acquired C. difficile infection occurred in a substantial proportion of individuals with no recent exposure to antibiotics. Among patients who had been exposed to antibiotics, the risk declined markedly by 45 days after discontinuation of use.

The influence of systemic glucocorticoid therapy upon the risk of non-serious infection in older patients with rheumatoid arthritis: a nested case–control study

Background Glucocorticoid therapy is strongly associated with an elevated risk of serious infections in patients with rheumatoid arthritis (RA). The association between glucocorticoids and common non-serious infections (NSI) is not well studied. Methods A cohort of 16 207 patients with RA aged over 65 years was assembled using administrative data from Quebec. Glucocorticoid and disease-modifying antirheumatic drug (DMARD) therapy were identified from drug dispensing records. NSI cases were defined as first occurrence of a community physician billing code for infection or community-dispensed anti-infectives. A nested case–control analysis was performed considering drugs dispensed within 45 days of the index date, adjusting for age, sex, markers of disease severity, DMARD and comorbidity. Results For 13 634 subjects, a NSI occurred during 28 695 person-years of follow-up, generating an incidence rate of 47.5/100 person-years. The crude rate of NSI in glucocorticoid-exposed and unexposed person time was 52.4 and 38.8/100 person-years, respectively. Glucocorticoid therapy was associated with an adjusted RR of 1.20 (95% CI 1.15 to 1.25). A dose response was seen, the adjusted RR increasing from 1.10 (<5 mg prednisolone/day) to 1.85 for doses greater than 20 mg/day. All glucocorticoid risk estimates (including <5 mg/day) were higher than that seen for methotrexate (adjusted RR 1.00; 0.95 to 1.04). Conclusion Glucocorticoid therapy is associated with an increased risk of NSI. The magnitude of risk increases with dose, and is higher than that seen with methotrexate, although residual confounding may exist. While the RR is low at 1.20, the absolute risk is high with one additional infection seen for every 13 patients treated with glucocorticoids for 1 year.

Rheumatoid Arthritis, Its Treatments, and the Risk of Tuberculosis in Quebec, Canada

OBJECTIVEnTo determine the risk of tuberculosis (TB) among a cohort of patients with rheumatoid arthritis (RA) in Quebec and assess whether this risk is associated with exposure to nonbiologic disease-modifying antirheumatic drugs (DMARDs).nnnMETHODSnWe studied a cohort of patients with RA identified from the Quebec provincial physician billing and hospitalization databases for 1980-2003. TB incidence rates were determined for the period 1992-2003 and compared with the general population, standardized for age and sex using the standardized incidence ratio (SIR). Conditional logistic regression was used in a nested case-control analysis to estimate the rate ratio (RR) of TB related to nonbiologic DMARD exposure during the year before the index date.nnnRESULTSnOf the 24,282 patients with RA in the cohort, 50 cases of TB were identified. The standardized incidence rate was 45.8 cases per 100,000 person-years compared with 4.2 cases per 100,000 person-years in the general population of Quebec (SIR 10.9, 95% confidence interval [95% CI] 7.9-15.0). The adjusted RR of TB was 2.4 (95% CI 1.1-5.4) with corticosteroid use and 3.0 (95% CI 1.6-5.8) with nonbiologic DMARD use.nnnCONCLUSIONnThe age- and sex-standardized incidence rate of TB in RA patients is 10 times that of the general population. At least some of this risk may be related to nonbiologic DMARD and corticosteroid therapies. Our data support the role of TB screening before initiation of any immunosuppressive therapy.

Nonsteroidal anti-inflammatory drug use and the risk of severe skin and soft tissue complications in patients with varicella or zoster disease

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECTnThree previous epidemiological studies found an increased risk of severe skin and soft tissue infectious complications associated with exposure to NSAIDs in children with varicella. In vitro studies demonstrated that decreases in defences against infections induced by NSAIDs could be due to impairment of neutrophil blood cell function.nnnWHAT THIS STUDY ADDSnThe use of NSAIDs is associated with an increased risk of severe skin and soft tissue complication of varicella in children. The use of NSAIDs is also associated with a small increased risk of such complications in zoster disease in adults and the elderly. This study supports the limited prescription of NSAIDs in VZV infection.nnnAIMSnTo assess the risk of severe skin and soft tissue complications associated with the use of nonsteroidal anti-inflammatory drugs (NSAIDs) in treating patients with varicella zoster virus infection.nnnMETHODSnThe design was a nested case-control study, with matching for age and practice. The setting was primary care in the United Kingdom (United Kingdoms General Practice Research Database). Two population-based cohorts of all patients with a primary varicella (n = 140,111) or zoster (n = 108,257) diagnosis during 1994-2005 were followed up for 2 months after diagnosis. Main outcome measures of severe skin or soft tissue complications (mostly cellulitis and abscess) associated with current NSAID or paracetamol use were estimated, and adjusted for potential confounding factors, including sex, drug use, and comorbidity.nnnRESULTSnIn patients with varicella, there were 386 cases of severe skin or soft tissue complications (rate 2.8 per 1000) during the 2 month follow-up period (mean age 10.7 years). The rate of complications associated with exposure to NSAIDs was increased (rate ratio 4.9; 95% CI 2.1, 11.4). In patients with zoster disease, there were 681 cases of severe skin or soft tissue complications (rate 6.3 per 1000) during the 2 month follow-up (mean age 60.9 years). The rate ratio of complications associated with exposure to NSAIDs was 1.6 (95% CI 1.1, 2.4). In both conditions, there was no increased risk of complication associated with a current exposure to paracetamol.nnnCONCLUSIONSnThe use of NSAIDs is associated with an elevated risk of severe skin and soft tissue complications of varicella zoster virus infection, mostly in children with varicella.

Inhaled Corticosteroids and Risk of Tuberculosis in Patients with Respiratory Diseases

RATIONALEnTreatment with substantial doses of oral corticosteroids (OCS) for prolonged periods increases the risk of tuberculosis (TB). However, little is known about the effect of inhaled corticosteroids (ICS) in this respect.nnnOBJECTIVESnWe quantified the independent contribution of ICS to the risk of TB in a population of patients with airway diseases.nnnMETHODSnA population-based cohort design with a nested case-control analysis was used. A cohort of patients with airways disease was formed using the Quebec databases. TB cases were identified and age-matched control subjects were selected from all subjects who entered the cohort in the same month as the cases. TB incidence among the cohort was compared with the general population of Quebec using the standardized incidence ratio.nnnMEASUREMENTS AND MAIN RESULTSnThe cohort consisted of 427,648 subjects. There were 564 cases of TB identified between 1990 and 2005. The standardized incidence ratio was 3.9 (95% confidence interval [CI], 2.6-5.4). Any and current users of ICS are at an increased risk of TB (rate ratio [RR], 1.27; 95% CI, 1.05-1.53; and RR, 1.33; 95% CI, 1.04-1.71, respectively). Among users of OCS, no significant relationship could be demonstrated. Among subjects without OCS exposure, adjusted RRs were significant for any ICS use (RR, 1.26; 95% CI, 1.02-1.56) and current use (RR, 1.48; 95% CI, 1.11-1.97) and at the current high dose exposure level (RR, 1.97; 95% CI, 1.18-3.3).nnnCONCLUSIONSnExposure to ICS is not associated with risk of TB in the presence of OCS but is associated with increased TB risk in nonusers of OCS.

Phase 2 study of panobinostat with or without rituximab in relapsed diffuse large B-cell lymphoma

The majority of diffuse large B-cell lymphoma (DLBCL) tumors contain mutations in histone-modifying enzymes (HMEs), indicating a potential therapeutic benefit of histone deacetylase inhibitors (HDIs), and preclinical data suggest that HDIs augment the effect of rituximab. In this randomized phase 2 study, we evaluated the response rate and toxicity of panobinostat, a pan-HDI administered 30 mg orally 3 times weekly, with or without rituximab, in 40 patients with relapsed or refractory de novo (n = 27) or transformed (n = 13) DLBCL. Candidate genes and whole exomes were sequenced in relapse tumor biopsies to search for molecular correlates, and these data were used to quantify circulating tumor DNA (ctDNA) in serial plasma samples. Eleven of 40 patients (28%) responded to panobinostat (95% confidence interval [CI] 14.6-43.9) and rituximab did not increase responses. The median duration of response was 14.5 months (95% CI 9.4 to not reached). At time of data censoring, 6 of 11 patients had not progressed. Of the genes tested for mutations, only those in MEF2B were significantly associated with response. We detected ctDNA in at least 1 plasma sample from 96% of tested patients. A significant increase in ctDNA at day 15 relative to baseline was strongly associated with lack of response (sensitivity 71.4%, specificity 100%). We conclude that panobinostat induces very durable responses in some patients with relapsed DLBCL, and early responses can be predicted by mutations in MEF2B or a significant change in ctDNA level at 15 days after treatment initiation. This clinical trial was registered at www.ClinicalTrials.gov (#NCT01238692).

Risk of Lymphoma, Colorectal and Skin Cancer in Patients with IBD Treated with Immunomodulators and Biologics: A Quebec Claims Database Study

Background:Immunomodulatory medications in patients with inflammatory bowel disease (IBD) have been associated with an increased risk of developing certain malignancies. The aim of this study was to evaluate the risk of melanoma, nonmelanoma skin cancer, colorectal cancer and lymphoma associated with immunomodulators and biologics in patients with IBD. Methods:A nested case–control study was carried out using the provincial health insurance database of Québec, Canada (RAMQ/MedECHO). Results:A total of 41,176 patients with IBD were identified of whom 19,582 patients were eligible for inclusion in the study. Treatment with thiopurine for more than 5 years was associated with a significantly increased risk of nonmelanoma skin cancer (odds ratio: 1.78; 95% confidence interval, 1.25–2.54). Immunomodulator treatment was not associated with an increased risk of non-Hodgkins lymphoma (odds ratio: 0.87; 95% confidence interval, 0.53–1.41). Neither immunomodulators nor anti-TNF-&agr; agents were associated with an increased risk of melanoma or colorectal cancer. Conclusions:In a large provincial IBD cohort, treatment with immunomodulators for more than 5 years was associated with an increased risk of non-melanoma skin cancer, whereas the risk of lymphoma, melanoma, and colorectal cancer was not increased. No association was found between the risk of the evaluated malignancies and anti-TNF-&agr; medications.

Antibiotics in Primary Prevention of Stroke in the Elderly

BACKGROUND AND PURPOSEnAn increasing number of reports have linked infections to atherosclerosis and thrombosis. Thus, use of antibiotics may lower the risk of developing cerebrovascular disease. We investigated whether antibiotic use is associated with the risk of stroke in elderly individuals treated for hypertension.nnnMETHODSnA cohort of 29 937 elderly subjects initiating antihypertensive therapy between 1982 and 1995 was formed from the Quebec healthcare insurance database. A nested case-control design was used in which each subject hospitalized with a primary discharge diagnosis of stroke between 1987 and 1995 was matched on calendar time to 5 randomly selected controls from the cohort. Conditional logistic regression was used to estimate odds ratios of stroke after adjustment for predisposing factors.nnnRESULTSnWe identified 1888 cases and 9440 controls. The overall adjusted odds ratio for current antibiotic use was 0.80 (95% confidence interval, 0.63 to 1.01), and that for recent use was 0.81 (95% confidence interval, 0.70 to 0.94). Penicillin was the only individual antibiotic class that showed a protective association across different time windows. No significant association was found between stroke risk and the use of fluoroquinolones, macrolides, tetracyclines, or cephalosporins.nnnCONCLUSIONSnAlthough no clear, consistent associations between overall antibiotic use and cerebrovascular disease could be found, an intriguing association between penicillin use and stroke should be explored further.

Comparison of outcomes among patients aged 80 and over and younger patients with diffuse large B-cell lymphoma: a population based study

Abstract In this retrospective cohort study of 174 consecutive, newly diagnosed cases of diffuse large B-cell lymphoma (DLBCL), clinical and pathological variables, treatment, response and survival were compared for patients aged 80 and over (n = 40) to those under 80. Eastern Cooperative Oncology Group (ECOG) status and International Prognostic Index (IPI) were significantly worse among older patients. Standard treatment was given to only 32.5% of older versus 86.6% of younger patients, and 65% of the elderly did not receive standard therapy. At 12 months, overall and event-free survival were 51.3% (95% confidence interval [CI]: 35–66%) vs. 93% (CI: 88–97%) and 41.9% (CI: 25–58%) vs. 84.8% (CI: 77–90%), for older versus younger patients, respectively. Choice of therapy was significantly associated with survival in the elderly, and low albumin but not comorbidity score was associated with not receiving standard therapy. Patients with DLBCL aged 80 and over are distinct from all other age groups with regard to treatment tolerance. A minority can receive standard therapy, but for the majority, novel therapeutic options are needed.