Teresa A. Simon

A meta-analysis of the incidence of malignancy in adult patients with rheumatoid arthritis

IntroductionThe risk of malignancies in patients with rheumatoid arthritis (RA) has raised some concern, particularly with immunosuppressive approaches to disease management.MethodsWe conducted a systematic review of the literature and meta-analysis characterizing the associated risk of overall malignancy and four site-specific malignancies (lymphoma, lung, colorectal, and breast cancer) in patients with RA. A Medline search from 1990 to 2007 was conducted using specified search terms and predefined inclusion criteria for identification of relevant observational studies that provide estimates of relative risk of malignancy associated with RA. Study-specific estimates of the relative risk, as measured by standardized incidence ratios (SIRs) and estimated in comparison with the general population, were combined using a random effects model.ResultsA total of 21 publications were identified, of which 13 reported the SIR for overall malignancy, 14 for lymphoma, 10 for colorectal, 12 for lung, and 9 for breast cancer. Compared with the general population, the overall SIR estimates suggest that RA patients have approximately a two-fold increase in lymphoma risk (SIR 2.08, 95% confidence interval [CI] 1.80 to 2.39) and greater risk of Hodgkin than non-Hodgkin lymphoma. The risk of lung cancer was also increased with an SIR of 1.63 (95% CI 1.43 to 1.87). In contrast, a decrease in risk was observed for colorectal (SIR 0.77, 95% CI 0.65 to 0.90) and breast (SIR 0.84, 95% CI 0.79 to 0.90) cancer. The SIR for overall malignancy was 1.05 (95% CI 1.01 to 1.09).ConclusionPatients with RA appear to be at higher risk of lymphoma and lung cancer and potentially decreased risk for colorectal and breast cancer compared with the general population.

Malignancies in the rheumatoid arthritis abatacept clinical development programme: an epidemiological assessment

Objective: To provide context for the malignancy experience in the rheumatoid arthritis (RA) abatacept clinical development programme (CDP) by performing comparisons with similar RA patients and the general population. Methods: Malignancy outcomes included total malignancy (excluding non-melanoma skin cancer (NMSC)), breast, colorectal, lung cancers and lymphoma. Comparisons were made between the observed incidence in patients within the abatacept CDP and RA patients on disease-modifying antirheumatic drugs (DMARD) identified from five data sources: the population-based British Columbia RA Cohort, the Norfolk Arthritis Register, the National Data Bank for Rheumatic Diseases, the Sweden Early RA Register and the General Practice Research Database. Age and sex-adjusted incidence rates (IR) and standardised incidence ratios (SIR) were used to compare events in the abatacept trials with the RA DMARD cohorts and the general population. Results: A total of 4134 RA patients treated with abatacept in seven trials and 41 529 DMARD-treated RA patients in the five observational cohorts was identified for study inclusion. In the abatacept-treated patients, the 51 malignancies (excluding NMSC), seven cases of breast, two cases of colorectal, 13 cases of lung cancer and five cases of lymphoma observed were not greater than the range of expected cases from the five RA cohorts. The SIR comparing RA patients with the general population were consistent with those reported in the literature. Conclusions: The IR of total malignancy (excluding NMSC), breast, colorectal, lung cancers and lymphoma in the abatacept CDP were consistent with those in a comparable RA population. These data suggest no new safety signals with respect to malignancies, which will continue to be monitored.

Initiation of warfarin in patients with atrial fibrillation: early effects on ischaemic strokes

AIMS An increased risk of stroke was observed in two atrial fibrillation (AF) trials of oral factor Xa inhibitors, when patients were transitioned to open label warfarin at the end of the study. The objective of this study is to determine whether initiation of warfarin is associated with an increased risk of stroke in patients with AF. METHODS AND RESULTS Using the UK Clinical Practice Research Datalink, a nested case-control analysis was conducted within a cohort of 70 766 patients with AF between 1993 and 2008. Stroke cases were randomly matched with up to 10 controls on age, sex, date of AF diagnosis, and time since AF diagnosis. Conditional logistic regression was used to estimate adjusted rate ratios (RRs) with 95% confidence intervals (CIs) of stroke associated with current warfarin use classified according to time since initiation of treatment (<30 days, 31-90 days, and >90 days), when compared with non-use. A total of 5519 patients experienced a stroke during follow-up. Warfarin was associated with a 71% increased risk of stroke in the first 30 days of use (RR: 1.71, 95% CI: 1.39-2.12), while decreased risks were observed with initiation >30 days before the event (31-90 days: RR: 0.50, 95% CI: 0.34-0.75 and >90 days: RR: 0.55, 95% CI: 0.50-0.61, respectively). CONCLUSION Patients initiating warfarin may be at an increased risk of stroke during the first 30 days of treatment, supporting the biological plausibility of a transient hypercoagulable state at the start of the treatment, although additional studies are needed to confirm these findings.

Incidence of malignancy in adult patients with rheumatoid arthritis: a meta-analysis

IntroductionPatients with rheumatoid arthritis (RA) are at an increased risk of malignancies compared with the general population. This has raised concerns regarding these patients, particularly with the widespread use of immunomodulating therapies, including biologic disease-modifying antirheumatic drugs (DMARDs). We performed a systematic literature review and analysis to quantify the incidence of malignancies in patients with RA and the general population to update previously published data.MethodsA literature search was conducted that was consistent with and similar to that in a meta-analysis published in 2008. MEDLINE, BIOSIS Previews, Embase, Derwent Drug File and SciSearch databases were searched using specified search terms. Predefined inclusion criteria identified the relevant observational studies published between 2008 and 2014 that provided estimates of relative risk of malignancy in patients with RA compared with the general population. Risk data on overall malignancy and site-specific malignancies (lymphoma, melanoma and lung, colorectal, breast, cervical and prostate cancer) were extracted. The standardized incidence ratios (SIRs; a measure of risk) relative to the general population were evaluated and compared with published rates.ResultsA total of nine publications met the inclusion criteria. Seven of these reported SIRs for overall malignancy; eight for lymphoma, melanoma, and lung, colorectal and breast cancer; seven for prostate cancer; and four for cervical cancer. Compared with those in the general population, the SIR estimates for patients with RA suggest a modest increased risk in overall malignancy, as previously observed. Patients with RA continued to show an increased risk of lymphoma and lung cancer compared with the general population. Overall, SIR estimates for colorectal and breast cancers continued to show a decrease in risk, whereas cervical cancer, prostate cancer and melanoma appeared to show no consistent trend in risk among patients with RA compared with the general population.ConclusionsThe additional data evaluated here are consistent with previously reported data. Patients with RA are at an increased risk of lung and lymphoma malignancies compared with the general population. Quantifying differences in malignancy rates between non-biologic and biologic DMARD-treated patients with RA may further highlight which malignancies may be related to treatment rather than to the underlying disease.

Rates of first infection following kidney transplant in the United States

We studied the incidence, trends and clinical correlates of infections following kidney transplantation in the United States Renal Data System over the years 1995-2003 in 46,471 adults with Medicare primary coverage at the time of their first kidney transplant. The incidence of most infections has declined only slightly since 1995 but infection with cytomegalovirus significantly declined while that with hepatitis C significantly increased. Relative frequencies of different types of infections (bacterial, viral, fungal and parasitic) were relatively constant, both during early and late periods following transplant. Using the Cox proportional hazards analysis we found that the clinical correlates for post-transplant bacterial and viral infections included older age, female gender, diabetes as the cause of end-stage renal disease, deceased (vs. living) donor source, time on dialysis before transplant, hepatitis B and C viral pre-transplant serologic status and pre-transplant donor-recipient cytomegalovirus serology. Our study shows that despite identifiable risk factors, the incidence of most post-transplant infections has changed little since 1995.

Safety of irbesartan in the treatment of mild to moderate systemic hypertension.

Nine multicenter, randomized, placebo-controlled studies were conducted to evaluate the safety and tolerability of the angiotensin II subtype 1 receptor blocker (AT1 blocker) irbesartan for the treatment of mild to moderate hypertension. After a 4- to 5-week placebo lead-in phase, patients were randomized to 4 to 12 weeks of double-blind therapy with either placebo (n = 641) or irbesartan (n = 1,965) at doses of 1 to 900 mg orally. All doses of irbesartan were well tolerated with no evidence of dose-related adverse effects. Across the full recommended clinical dose range, although not statistically significantly different, irbesartan use was associated with a lower incidence of adverse events, serious adverse events, and discontinuations due to adverse events compared with placebo. No clinically significant or unexpected changes in laboratory analyses were observed. Withdrawal of irbesartan therapy did not result in rebound hypertension or clinically important adverse events. Thus, irbesartan use in hypertensive patients was associated with a placebo-like safety and tolerability profile.

The cost-effectiveness of irbesartan in the treatment of hypertensive patients with type 2 diabetic nephropathy

BACKGROUND End-stage renal disease (ESRD)-related health care costs are substantial. Improving clinical outcomes in patients at risk of progression to ESRD could lead to considerable health care savings. OBJECTIVE We estimated the cost-effectiveness of irbesartan compared with placebo or amlodipine in the treatment of patients with type 2 diabetes mellitus, hypertension, and overt nephropathy. METHODS Three treatments for hypertension patients with type 2 diabetes mellitus and nephropathy were assessed: (1) irbesartan, (2) amlodipine, and (3) placebo. A Markov model was developed based on primary data from the Irbesartan in Diabetic Nephropathy Trial and the United States Renal Data System. Projected survival and costs were compared for each treatment at 3-, 10-, and 25-year time horizons. Different assumptions of treatment benefits and costs were tested with use of sensitivity analyses. RESULTS At 10 and 25 years, the model projected irbesartan to be both the least costly and most effective (ie, demonstrating a survival advantage) strategy. At 25

Infections requiring hospitalization in the abatacept clinical development program: an epidemiological assessment

IntroductionPatients with rheumatoid arthritis (RA) have an increased risk of infection and this risk appears to be higher with anti-TNF (tumor necrosis factor) agents. We pooled data from the cumulative abatacept RA clinical development program, both double-blind and open-label periods, to estimate the incidence rates (IRs) of infections requiring hospitalization including pneumonia and opportunistic infections, in comparison with RA patients treated with non-biologic disease-modifying antirheumatic drugs (DMARDs) from several reference cohorts.MethodsInfections reported in seven abatacept clinical trials of RA patients (double-blind and open-label periods) were tabulated. Comparisons were made between the observed IRs in abatacept-treated patients and those in over 133,000 patients exposed to non-biologic DMARDs in six reference RA cohorts. Age- and sex-adjusted IRs of infections requiring hospitalization, including pneumonia (most frequent hospital infection), were used to estimate the expected IRs with abatacept by the method of indirect adjustment. Standardized incidence ratios (SIR) and 95% CI were calculated comparing incidence in the cumulative abatacept experience with incidence in each RA cohort.ResultsA total of 1,955 (double-blind period) and 4,134 (double-blind + open-label periods with a cumulative exposure of 8,392 person-years) abatacept-treated RA patients were analyzed. Observed IRs for infections requiring hospitalization during the double-blind period were 3.05 per 100-patient years for abatacept-treated patients and 2.15 per 100 patient years for placebo. In the cumulative population, observed IR for infections requiring hospitalization was 2.72 per 100-patient years. Rates for abatacept were similar to expected IRs based on other RA non-biologic DMARD cohorts.ConclusionsIRs of infections requiring hospitalization and pneumonia in abatacept trials are consistent with expected IRs based on reference RA DMARD cohorts. RA patients are at higher risk of infection compared with the general population, making the RA DMARD cohorts an appropriate reference group. The safety of abatacept, including incidence of infections requiring hospitalization, will continue to be monitored in a post-marketing surveillance program.

The efficacy and safety of pharmacological prophylaxis of venous thromboembolism following elective knee or hip replacement: systematic review and network meta-analysis.

The present systematic review was conducted to assess the efficacy and safety of apixaban versus other anticoagulants, for the prevention of venous thromboembolism (VTE) following total hip replacement (THR) and total knee replacement (TKR) surgery. Electronic databases were interrogated to identify relevant randomized controlled trials. A series of direct/indirect comparisons and a network meta-analysis were conducted. Indirect comparisons found that the odds ratio of “all VTE and all-cause death” were significantly higher for dabigatran than for apixaban in patients with THR (odds ratio [OR], 2.51; 95% confidence interval [CI], 1.50-4.21) and TKR (OR, 1.72; 95% CI, 1.22-2.42). Rivaroxaban showed similar efficacy to apixaban in patients with THR and TKR (OR, 0.69; 95% CI, 0.38-1.25 and OR, 0.83; 95% CI, 0.57-1.19, respectively). No significant differences were observed in bleeding outcomes between treatments. The novel anticoagulants apixaban, rivaroxaban, and dabigatran demonstrated similar or improved efficacy and similar safety compared with current therapies in this indication.

The Efficacy and Safety of Oral Anticoagulants in Warfarin-Suitable Patients With Nonvalvular Atrial Fibrillation Systematic Review and Meta-Analysis

The novel oral anticoagulants (NOACs) apixaban, dabigatran, and rivaroxaban have been recently indicated for stroke prevention in patients with atrial fibrillation (AF) . Due to a lack of direct head-to-head trials comparing the NOACs, the current systematic review and network meta-analysis (NMA) were conducted to assess their relative efficacy and safety. Three phase III randomized controlled trials enrolling 50 578 patients were included. Results of the NMA show a clear trend favoring NOACs over warfarin with regard to the key outcomes of stroke/systemic embolism and all-cause mortality, with apixaban also showing a favorable response for major bleeding and total discontinuations. Although there were few significant differences among the NOACS with regard to efficacy outcomes, apixaban and dabigatran 110 mg were associated with significantly lower hazards of major bleeding compared with dabigatran 150 mg and rivaroxaban. The NOACs offer a therapeutic advance over standard warfarin treatment in stoke prevention in patients with nonvalvular AF.