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1.  Risk of acute kidney injury associated with the use of fluoroquinolones 
Background:
Case reports indicate that the use of fluoroquinolones may lead to acute kidney injury. We studied the association between the use of oral fluoroquinolones and acute kidney injury, and we examined interaction with renin–angiotensin-system blockers.
Methods:
We formed a nested cohort of men aged 40–85 enrolled in the United States IMS LifeLink Health Plan Claims Database between 2001 and 2011. We defined cases as men admitted to hospital for acute kidney injury, and controls were admitted to hospital with a different presenting diagnosis. Using risk-set sampling, we matched 10 controls to each case based on hospital admission, calendar time (within 6 wk), cohort entrance (within 6 wk) and age (within 5 yr). We used conditional logistic regression to assess the rate ratio (RR) for acute kidney injury with current, recent and past use of fluoroquinolones, adjusted by potential confounding variables. We repeated this analysis with amoxicillin and azithromycin as controls. We used a case-time–control design for our secondary analysis.
Results:
We identified 1292 cases and 12 651 matched controls. Current fluoroquinolone use had a 2.18-fold (95% confidence interval [CI] 1.74–2.73) higher adjusted RR of acute kidney injury compared with no use. There was no association between acute kidney injury and recent (adjusted RR 0.87, 95% CI 0.66–1.16) or past (RR 0.86, 95% CI 0.66–1.12) use. The absolute increase in acute kidney injury was 6.5 events per 10 000 person-years. We observed 1 additional case per 1529 patients given fluoroquinolones or per 3287 prescriptions dispensed. The dual use of fluoroquinolones and renin–angiotensin-system blockers had an RR of 4.46 (95% CI 2.84–6.99) for acute kidney injury. Our case-time–control analysis confirmed an increased risk of acute kidney injury with fluoroquinolone use (RR 2.16, 95% CI 1.52–3.18). The use of amoxicillin or azithromycin was not associated with acute kidney injury.
Interpretation:
We found a small, but significant, increased risk of acute kidney injury among men with the use of oral fluoroquinolones, as well as a significant interaction between the concomitant use of fluoroquinolones and renin–angiotensin-system blockers.
doi:10.1503/cmaj.121730
PMCID: PMC3708027  PMID: 23734036
2.  Risk of venous thromboembolism in women with polycystic ovary syndrome: a population-based matched cohort analysis 
Background:
There is an increased risk of venous thromboembolism among women taking oral contraceptives. However, whether there is an additional risk among women with polycystic ovary syndrome (PCOS) is unknown.
Methods:
We developed a population-based cohort from the IMS LifeLink Health Plan Claims Database, which includes managed care organizations in the United States. Women aged 18–46 years taking combined oral contraceptives and who had a claim for PCOS (n = 43 506) were matched, based on a propensity score, to control women (n = 43 506) taking oral contraceptives. Venous thromboembolism was defined using administrative coding and use of anticoagulation. We used Cox proportional hazards models to assess the relative risk (RR) of venous thromboembolism among users of combined oral contraceptives with and without PCOS.
Results:
The incidence of venous thromboembolism among women with PCOS was 23.7/10 000 person-years, while that for matched controls was 10.9/10 000 person-years. Women with PCOS taking combined oral contraceptives had an RR for venous thromboembolism of 2.14 (95% confidence interval [CI] 1.41–3.24) compared with other contraceptive users. The incidence of venous thromboembolism was 6.3/10 000 person-years among women with PCOS not taking oral contraceptives; the incidence was 4.1/10 000 person-years among matched controls. The RR of venous thromboembolism among women with PCOS not taking oral contraceptives was 1.55 (95% CI 1.10–2.19).
Interpretation:
We found a 2-fold increased risk of venous thromboembolism among women with PCOS who were taking combined oral contraceptives and a 1.5-fold increased risk among women with PCOS not taking oral contraceptives. Physicians should consider the increased risk of venous thromboembolism when prescribing contraceptive therapy to women with PCOS.
doi:10.1503/cmaj.120677
PMCID: PMC3563911  PMID: 23209115
3.  Beta-blocker use and COPD mortality: a systematic review and meta-analysis 
Background
Despite the benefits of beta-blockers in patients with established or sub-clinical coronary artery disease, their use in patients with chronic obstructive pulmonary disease (COPD) has been controversial. Currently, no systematic review has examined the impact of beta-blockers on mortality in COPD.
Methods
We systematically searched electronic bibliographic databases including MEDLINE, EMBASE and Cochrane Library for clinical studies that examine the association between beta-blocker use and all cause mortality in patients with COPD. Risk ratios across studies were pooled using random effects models to estimate a pooled relative risk across studies. Publication bias was assessed using a funnel plot.
Results
Our search identified nine retrospective cohort studies that met the study inclusion criteria. The pooled relative risk of COPD related mortality secondary to beta-blocker use was 0.69 (95% CI: 0.62-0.78; I2=82%).
Conclusion
The results of this review are consistent with a protective effect of beta-blockers with respect to all cause mortality. Due to the observational nature of the included studies, the possibility of confounding that may have affected these results cannot be excluded. The hypothesis that beta blocker therapy might be of benefit in COPD needs to be evaluated in randomised controlled trials.
doi:10.1186/1471-2466-12-48
PMCID: PMC3499441  PMID: 22947076
Beta-blockers; COPD; Mortality
4.  Inflammatory ocular adverse events with the use of oral bisphosphonates: a retrospective cohort study 
Background:
There have been several published reports of inflammatory ocular adverse events, mainly uveitis and scleritis, among patients taking oral bisphosphonates. We examined the risk of these adverse events in a pharmacoepidemiologic cohort study.
Methods:
We conducted a retrospective cohort study involving residents of British Columbia who had visited an ophthalmologist from 2000 to 2007. Within the cohort, we identified all people who were first-time users of oral bisphosphonates and who were followed to the first inflammatory ocular adverse event, death, termination of insurance or the end of the study period. We defined an inflammatory ocular adverse event as scleritis or uveitis. We used a Cox proportional hazard model to determine the adjusted rate ratios. As a sensitivity analysis, we performed a propensity-score–adjusted analysis.
Results:
The cohort comprised 934 147 people, including 10 827 first-time users of bisphosphonates and 923 320 nonusers. The incidence rate among first-time users was 29/10 000 person-years for uveitis and 63/10 000 person-years for scleritis. In contrast, the incidence among people who did not use oral bisphosphonates was 20/10 000 person-years for uveitis and 36/10 000 for scleritis (number needed to harm: 1100 and 370, respectively). First-time users had an elevated risk of uveitis (adjusted relative risk [RR] 1.45, 95% confidence interval [CI] 1.25–1.68) and scleritis (adjusted RR 1.51, 95% CI 1.34–1.68). The rate ratio for the propensity-score–adjusted analysis did not change the results (uveitis: RR 1.50, 95% CI 1.29–1.73; scleritis: RR 1.53, 95% CI 1.39–1.70).
Interpretation:
People using oral bisphosphonates for the first time may be at a higher risk of scleritis and uveitis compared to people with no bisphosphonate use. Patients taking bisphosphonates must be familiar with the signs and symptoms of these conditions, so that they can immediately seek assessment by an ophthalmologist.
doi:10.1503/cmaj.111752
PMCID: PMC3348220  PMID: 22470169
5.  The association between drospirenone and hyperkalemia: a comparative-safety study 
Background
Drospirenone/ethinyl-estradiol is an oral contraceptive (OC) that possesses unique antimineralocorticoid activity. It is conjectured that drospirenone, taken alone or concomitantly with spironolactone, may be associated with an increased risk of hyperkalemia.
Methods
A retrospective cohort study was conducted evaluating women between 18-46 years of age in the Lifelink™ Health Plan Claims Database. The study was restricted to new users of OCs between 1997-2009. Cox proportional hazards models were used to estimate the time to first occurrence of hyperkalemia diagnosis. The main analysis compared OCs containing drospirenone with OCs containing levonorgestrel, a second generation OC not known to impact potassium homeostasis. Logistic regression evaluated concomitant prescribing of drospirenone and spironolactone
Results
The cohort included 1,148,183 women, averaging 28.8 years of age and 280 days of OC therapy. 2325 cases of hyperkalemia were identified. The adjusted hazard ratio (HR) for hyperkalemia with drospirenone compared to levonorgestrel was 1.10 (95%CI 0.95-1.26). There was an increased risk of hyperkalemia with norethindrone HR 1.15 (95%CI: 1.00-1.33) and norgestimate HR 1.27 (95%CI: 1.11-1.46). Other OCs were unassociated with hyperkalemia. The odds of receiving spironolactone while taking drospirenone were 2.66 (95%CI 2.53-2.80) times higher than the odds of receiving spironolactone and levonorgestrel. Only 6.5% of patients taking drospirenone and spironolactone had a serum potassium assay within 180 days of starting concomitant therapy.
Conclusions
A clinically significant signal for hyperkalemia with drospirenone was not demonstrated in the current study. Despite the bolded warning for hyperkalemia with joint drospirenone and spironolactone administration, physicians are actually using them together preferentially, and are not following the recommended potassium monitoring requirements in the package insert.
doi:10.1186/1472-6904-11-23
PMCID: PMC3265420  PMID: 22208934
6.  Oral contraceptives and the risk of gallbladder disease: a comparative safety study 
Background
Recent concerns have been raised about the risk of gallbladder disease associated with the use of drospirenone, a fourth-generation progestin used in oral contraceptives. We conducted a study to determine the magnitude of this risk compared with other formulations of oral contraceptives.
Methods
We conducted a retrospective cohort study using the IMS LifeLink Health Plan Claims Database. We included women who were using an oral contraceptive containing ethinyl estradiol combined with a progestin during 1997–2009. To be eligible, women had to have been taking the oral contraceptive continuously for at least six months. We computed adjusted rate ratios (RRs) for gallbladder disease using a Cox proportional hazards model. In the primary analysis, gallbladder disease was defined as cholecystectomy; in a secondary analysis, it was defined as hospital admission secondary to gallbladder disease.
Results
We included 2 721 014 women in the cohort, 27 087 of whom underwent surgical or laparoscopic cholecystectomy during the follow-up period. Compared with levonorgestrel, an older second-generation progestin, a small, statistically significant increase in the risk of gallbladder disease was associated with desogestrel (adjusted RR 1.05, 95% confidence interval [CI] 1.01–1.09), drospirenone (adjusted RR 1.20, 95% CI 1.16–1.26) and norethindrone (adjusted RR 1.10, 95% CI 1.06–1.14). No statistically significant increase in risk was associated with the other formulations of oral contraceptive (ethynodiol diacetate, norgestrel and norgestimate).
Interpretation
In a large cohort of women using oral contraceptives, we found a small, statistically significant increase in the risk of gallbladder disease associated with desogestrel, drospirenone and norethindrone compared with levonorgestrel. However, the small effect sizes compounded with the possibility of residual biases in this observational study make it unlikely that these differences are clinically significant.
doi:10.1503/cmaj.110161
PMCID: PMC3091897  PMID: 21502354
7.  Nonsteroidal anti-inflammatory drugs and prostate cancer: a systematic review of the literature and meta-analysis 
Prostate cancer is the most common visceral cancer in men. Many studies have shown that nonsteroidal anti-inflammatory drugs (NSAIDs) may reduce the risk of prostate cancer. We systematically searched all relevant databases (MEDLINE, EMBASE, The Cochrane Collaboration, CINAHL, Database of Abstracts of Review of Effects and ACP Journal Club) to March 2008. We also explored bibliographies of the articles, pertinent journals and conferences. We selected relevant articles according to predefined inclusion criteria by 2 independent reviewers. We used both fixed and random-effect models for meta-analysis. We performed subgroup and sensitivity analysis based on predefined variables. From 962 extracted articles, 20 met the inclusion criteria with a total of 25 768 participants. All the studies had an observational design. There was a statistically significant protective effect for NSAIDs on risk of prostate cancer (odds ratio [OR] 0.92, 95% confidence interval [CI] 0.86–0.97). Subgroup analysis did not show any effect of study design or quality score on the results. There was a small but statistically significant protective effect for acetylsalicylic acid (ASA) (OR 0.95, 95% CI 0.91–1.00). Exposure to non-ASA NSAIDs was associated with a slightly reduced likelihood of prostate cancer (OR 0.92, 95% CI 0.85–1.00). With the available data, we were not able to determine an optimum dosage for NSAIDs. We conclude that taking NSAIDs may reduce the risk of prostate cancer. Nevertheless, the effect is small.
PMCID: PMC2723875  PMID: 19672448
8.  Risk of ischaemic stroke in people with migraine: systematic review and meta-analysis of observational studies 
BMJ : British Medical Journal  2005;330(7482):63.
Objective To explore the association between migraine and risk of ischaemic stroke.
Design Systematic review and meta-analysis.
Data sources Observational studies published between 1966 and June 2004 (identified through Medline and Embase) that examined the association between migraine and risk of ischaemic stroke.
Results 14 studies (11 case-control studies and 3 cohort studies) were identified. These studies suggest that the risk of stroke is increased in people with migraine (relative risk 2.16, 95% confidence interval 1.89 to 2.48). This increase in risk was consistent in people who had migraine with aura (relative risk 2.27, 1.61 to 3.19) and migraine without aura (relative risk 1.83, 1.06 to 3.15), as well as in those taking oral contraceptives (relative risk 8.72, 5.05 to 15.05).
Conclusions Data from observational studies suggest that migraine may be a risk factor in developing stroke. More studies are needed to explore the mechanism of this potential association. In addition, the risk of migraine among users of oral contraceptives must be further investigated.
doi:10.1136/bmj.38302.504063.8F
PMCID: PMC543862  PMID: 15596418
12.  Effect of non-steroidal anti-inflammatory drugs on risk of Alzheimer's disease: systematic review and meta-analysis of observational studies 
BMJ : British Medical Journal  2003;327(7407):128.
Objectives To quantify the risk of Alzheimer's disease in users of all non-steroidal anti-inflammatory drugs (NSAIDs) and users of aspirin and to determine any influence of duration of use.
Design Systematic review and meta-analysis of observational studies published between 1966 and October 2002 that examined the role of NSAID use in preventing Alzheimer's disease. Studies identified through Medline, Embase, International Pharmaceutical Abstracts, and the Cochrane Library.
Results Nine studies looked at all NSAIDs in adults aged > 55 years. Six were cohort studies (total of 13 211 participants), and three were case-control studies (1443 participants). The pooled relative risk of Alzheimer's disease among users of NSAIDs was 0.72 (95% confidence interval 0.56 to 0.94). The risk was 0.95 (0.70 to 1.29) among short term users (< 1 month) and 0.83 (0.65 to 1.06) and 0.27 (0.13 to 0.58) among intermediate term (mostly < 24 months) and long term (mostly > 24 months) users, respectively. The pooled relative risk in the eight studies of aspirin users was 0.87 (0.70 to 1.07).
Conclusions NSAIDs offer some protection against the development of Alzheimer's disease. The appropriate dosage and duration of drug use and the ratios of risk to benefit are still unclear.
PMCID: PMC165707  PMID: 12869452
14.  Tamsulosin treatment for benign prostatic hyperplasia and risk of severe hypotension in men aged 40-85 years in the United States: risk window analyses using between and within patient methodology  
Objective To characterize risk of hypotension requiring admission to hospital in middle aged and older men treated with tamsulosin for benign prostatic hyperplasia.
Design Population based retrospective cohort study (between patient methodology) and self controlled case series (within patient methodology).
Setting Healthcare claims data from the IMS Lifelink database in the United States.
Participants Men aged 40-85 years with private US healthcare insurance entering the cohort at their first dispensing for tamsulosin or for a 5α reductase inhibitor (5ARI) between January 2001 and June 2011after a minimum of six months’ enrolment.
Main outcomes measures Hypotension requiring admission to hospital. Cox proportional hazards models estimated rate ratios at time varying intervals during follow-up: weeks 1-4, 5-8, and 9-12 after tamsulosin initiation; weeks 1-4, 5-8, and 9-12 after restarting tamsulosin (after a four week gap); and maintenance tamsulosin treatment (remaining exposed person time). Covariates included age, calendar year, demographics, antihypertensive use, healthcare use, and a Charlson comorbidity score. A self controlled case series, having implicit control for time invariant covariates, was additionally conducted.
Results Among 383 567 new users of study drugs (tamsulosin 297 596; 5ARI 85 971), 2562 admissions to hospital for severe hypotension were identified. The incidence for hypotension was higher for tamsulosin (42.4 events per 10 000 person years) than for 5ARIs (31.3 events per 10 000 person years) or all accrued person time (29.1 events per 10 000 person years). After tamsulosin initiation, the cohort analysis identified an increased rate of hypotension during weeks 1-4 (rate ratio 2.12 (95% confidence interval 1.29 to 3.04)) and 5-8 (1.51 (1.04 to 2.18)), and no significant increase at weeks 9-12. The rate ratio for hypotension also increased at weeks 1-4 (1.84 (1.46 to 2.33)) and 5-8 (1.85 (1.45 to 2.36)) after restarting tamsulosin, as did maintenance tamsulosin treatment (1.19 (1.07 to 1.32)). The self controlled case series gave similar results as the cohort analysis.
Conclusions We observed a temporal association between tamsulosin use for benign prostatic hyperplasia and severe hypotension during the first eight weeks after initiating treatment and the first eight weeks after restarting treatment. This association suggests that physicians should focus on improving counseling strategies to warn patients regarding the “first dose phenomenon” with tamsulosin.
doi:10.1136/bmj.f6320
PMCID: PMC3817852  PMID: 24192967

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