The use of selective cyclooxygenase (COX)-2 inhibitors (coxibs) has been associated with an increased cardiovascular risk. The aim of the present study was to evaluate the association of coxib use and future risk of cardiovascular events in a population-based cohort followed after the warnings concerning the cardiovascular safety of this class of drugs were issued.
A nation-wide, population-based cohort of 7 million subjects, integrating data from the Prescribed Drug, Patient, Cause of Death, Income, Educational and Emigration Registers, was followed from 1 July 2005 to 31 December 2008. Analyses were performed for different cardiovascular outcomes in the whole population after exclusion of individuals with prior cardiovascular diagnosis (incident primary cardiovascular events; sample size, n = 6 991 645). Cox proportional hazard ratios (HRs) revealed no significant association of coxib use with risk for myocardial infarction, ischaemic stroke, or heart failure. In contrast to these findings, coxib use was associated with an increased risk for a first episode of atrial fibrillation [HR 1.16; 95% confidence interval (CI) 1.05-1.29]. A post hoc analysis for different coxibs revealed a significant association with incident atrial fibrillation for etoricoxib (HR 1.35; 95% CI 1.19-1.54) but not for celecoxib (HR 0.94; 95% CI 0.79-1.11).
Whereas safety measures appear to have limited serious cardiovascular consequences of COX-2 inhibitors, the risk of developing atrial fibrillation may have been overlooked and may necessitate consideration and precautions.
There is conflicting evidence regarding bisphosphonates and atrial fibrillation (AF) risk in osteoporosis patients. However, bisphosphonates are used in much higher doses in treatment of bone metastasis and hypercalcemia, but little is known about the AF risk in cancer patients.
We conducted a nationwide population-based cohort study using Danish databases. All cancer patients exposed to intravenous bisphosphonates during 2000-2008 were matched with two non-exposed cancer patients by cancer type, distant metastasis presence at diagnosis, age, and gender. We used Cox proportional hazard regression to estimate hazards ratios (HRs) of AF/flutter adjusting for important confounding factors.
Of the 3981 cancer patients exposed to intravenous bisphosponates, 128 (3.2%) developed AF/flutter. This condition occurred in 192 (2.4%) of the 7906 non-exposed cancer patients, corresponding to an adjusted HR of 1.7 (95% CI: 1.2-2.4).
Intravenous bisphosphonates may increase AF/flutter risk in cancer patients.
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To examine the risk of atrial fibrillation or flutter associated with use of non-selective non-steroidal anti-inflammatory drugs (NSAIDs) or selective cyclo-oxygenase (COX) 2 inhibitors.
Population based case-control study using data from medical databases.
Northern Denmark (population 1.7 million).
32 602 patients with a first inpatient or outpatient hospital diagnosis of atrial fibrillation or flutter between 1999 and 2008; 325 918 age matched and sex matched controls based on risk-set sampling.
Exposure to NSAID use at the time of admission (current use) or before (recent use). Current use was further classified as new use (first ever prescription redemption within 60 days before diagnosis date) or long term use. We used conditional logistic regression to compute odds ratios as unbiased estimates of the incidence rate ratios.
2925 cases (9%) and 21 871 controls (7%) were current users of either non-selective NSAIDs or COX 2 inhibitors. Compared with no use, the incidence rate ratio associating current drug use with atrial fibrillation or flutter was 1.33 (95% confidence interval 1.26 to 1.41) for non-selective NSAIDs and 1.50 (1.42 to 1.59) for COX 2 inhibitors. Adjustments for age, sex, and risk factors for atrial fibrillation or flutter reduced the incidence rate ratio to 1.17 (1.10 to 1.24) for non-selective NSAIDs and 1.27 (1.20 to 1.34) for COX 2 inhibitors. Among new users, the adjusted incidence rate ratio was 1.46 (1.33 to 1.62) for non-selective NSAIDs and 1.71 (1.56 to 1.88) for COX 2 inhibitors. Results for individual NSAIDs were similar.
Use of non-aspirin NSAIDs was associated with an increased risk of atrial fibrillation or flutter. Compared with non-users, the association was strongest for new users, with a 40-70% increase in relative risk (lowest for non-selective NSAIDs and highest for COX 2 inhibitors). Our study thus adds evidence that atrial fibrillation or flutter needs to be added to the cardiovascular risks to be considered when prescribing NSAIDs.
Evidence that a number of drugs can cause atrial fibrillation has been accumulating since the 2000s. A case-control analysis of a UK general medicine database showed statistically significant increases in the risk of chronic atrial fibrillation in patients taking NSAIDs, after as little as one month of treatment. When NSAID treatment lasted more than 30 days, the incidence was 9.4%, versus 4.7% in the control group, corresponding to a relative risk (RR) of 1.57 (95% confidence interval (95% CI): 1.15 to 2.15). Similar results were found in patients with no history of heart failure. A Danish case-control study yielded similar results. In the UK case-control study, a statistically significant increase in the risk of chronic atrial fibrillation was found in patients taking corticosteroids (5% versus 1.4% in the control group, RR=2.5, 95% CI: 1.6 to 4). The risk increased with the dose. Another Danish case-control study showed that hospitalisation for atrial fibrillation or flutter was twice as frequent among patients exposed to corticosteroids. In contrast, trials in which corticosteroids were given shortly after cardiac surgery, a highly specific setting, showed a decreased risk of atrial fibrillation. In practice, the risk of atrial fibrillation should be taken into account before deciding whether or not to prescribe a corticosteroid or an NSAID, especially to a patient with known risk factors for atrial fibrillation. The heart rate of treated patients should be closely monitored.
Bisphosphonates have been associated with an increased risk of atrial fibrillation and may thus be associated with an increased risk of ischemic stroke. This would have substantial clinical and public health implications. We found no evidence of an association between bisphosphonate use and risk of ischemic stroke.
Bisphosphonates have been associated with an increased risk of atrial fibrillation in some studies and may be associated with an increased risk of ischemic stroke. However, data regarding these possibilities are limited.
We conducted a population-based case-control study of 6,257 female cases of ischemic stroke and 31,285 age- and gender-matched population controls. Data on bisphosphonate use, other medication use, comorbidity, and ischemic stroke were obtained from medical databases. Current bisphosphonate use was defined as at least one redeemed prescription within 90 days before diagnosis/index date. We estimated the odds ratio (OR) of ischemic stroke among users and nonusers of bisphosphonates using conditional logistic regression, controlling for potential confounding factors.
One hundred eighty-two (2.9%) cases and 901 (2.9%) controls were current users of bisphosphonates. Etidronate and alendronate were prescribed with similar frequency among cases and controls. The adjusted OR of ischemic stroke for bisphosphonate users compared with nonusers was 0.97 (95% confidence interval [CI], 0.82-1.15). New and continuing bisphosphonate users had adjusted ORs for ischemic stroke of 1.16 (95% CI, 0.69-1.96) and 0.97 (95% CI, 0.81-1.16), respectively. Excluding patients with known atrial fibrillation/flutter yielded an OR of 1.00 (95% CI, 0.85-1.19). The OR for ischemic stroke was 0.59 (95% CI, 0.32-1.09) among patients with a history of previous hospitalization for cardiovascular disease and 1.07 (95% CI, 0.88-1.18) among those without (P
We studied the association between bisphosphonate use and risk of atrial fibrillation or flutter and the effect of confounders such as heart and lung disease in a nationwide retrospective cohort from Denmark. All users of bisphosphonates and other drugs against osteoporosis between 1996 and 2006 (n = 103,562) were the exposed group and three age- and gender-matched controls from the general population (n = 310,683) were the nonexposed group. The main outcome measure was atrial fibrillation or atrial flutter. Before initiation of treatment against osteoporosis, no excess of atrial fibrillation or flutter was present for any drug except for etidronate (OR = 1.22, 95% CI 1.15-1.29). After initiation of treatment, raloxifene was not associated with any excess risk of atrial fibrillation (OR = 0.98, 95% CI 0.72-1.33). Etidronate (HR = 1.08, 95% CI 1.02-1.14) and alendronate (HR = 1.09, 95% CI 1.00-1.20) were associated with an excess risk of atrial fibrillation after treatment start if statistical adjustments were made for cardiovascular disease. However, this association disappeared upon statistical adjustment for chronic obstructive pulmonary disease (COPD) (etidronate HR = 1.04, 95% CI 0.98-1.10; alendronate HR = 1.05, 95% CI 0.96-1.15). In patients using etidronate (12.5% vs. 3.8%) and alendronate (11.4% vs. 4.6%) major differences were present in prevalence of COPD at start of treatment compared to matched controls. In conclusion, oral bisphosphonates do not seem to be associated with an excess risk of atrial fibrillation. Any excess risk seen in prior studies may be due to confounding from COPD.
The risks of intracranial haemorrhage (ICH) associated with antithrombotic drugs outside clinical trials are gaining increased attention. The aim of this nationwide study was to investigate the risk of ICH requiring hospital admission in users of antithrombotic drugs.
Data from the Norwegian Patient Registry and Norwegian Prescription Database were linked on an individual level. The primary outcome was incidence rates of ICH associated with use of antithrombotic drugs. Secondary endpoints were risk of ICH and fatal outcome following ICH assessed by Cox models. Among 3,131,270 individuals =18 years old observed from 2008 through 2014, there were 729,818 users of antithrombotic medications and 22,111 ICH hospitalizations. Annual crude ICH rates per 100 person-years were 0.076 (95% CI, 0.075-0.077) in non-users and 0.30 (95% CI, 0.30-0.31) in users of antithrombotic medication, with the highest age and sex adjusted rates observed for aspirin-dipyridamole plus clopidogrel (0.44; 95% CI, 0.19-0.69), rivaroxaban plus aspirin (0.36; 95% CI, 0.16-0.56), warfarin plus aspirin (0.34; 95% CI, 0.26-0.43), and warfarin plus aspirin and clopidogrel (0.33; 95% CI, 0.073-0.60). With no antithrombotic medication as reference, the highest adjusted hazard ratios (HR) for ICH were observed for aspirin-dypiridamole plus clopidogrel (6.29; 95% CI 3.71-10.7), warfarin plus aspirin and clopidogrel (4.38; 95% CI 2.71-7.09), rivaroxaban plus aspirin (3.82; 95% CI, 2.46-5.95), and warfarin plus aspirin (3.40; 95% CI, 2.99-3.86). All antithrombotic medication regimens were associated with an increased risk of ICH, except dabigatran monotherapy (HR 1.20; 95% CI, 0.88-1.65) and dabigatran plus aspirin (HR 1.79; 95% CI, 0.96-3.34). Fatal outcome within 90 days was more common in users (2,603 of 8,055) than non-users (3,228 of 14,056) of antithrombotic medication (32.3% vs 23.0%, p
OBJECTIVE: To assess the association between atrial fibrillation and flutter and use of bisphosphonates for osteoporosis among women. DESIGN: Population based case-control study, using medical databases from Denmark. SETTING: Northern Denmark. PARTICIPANTS: 13 586 patients with atrial fibrillation and flutter and 68 054 population controls, all with complete hospital and prescription history. MAIN OUTCOME MEASURE: Adjusted relative risk of atrial fibrillation and flutter. RESULTS: 435 cases (3.2%) and 1958 population controls (2.9%) were current users of bisphosphonates for osteoporosis. Etidronate and alendronate were used with almost the same frequency among cases and controls. The adjusted relative risk of current use of bisphosphonates compared with non-use was 0.95 (95% confidence interval 0.84 to 1.07). New users had a relative risk of 0.75 (95% confidence interval 0.49 to 1.16), broadly similar to the estimate for continuing users (relative risk 0.96, 95% confidence interval 0.85 to 1.09). The relative risk estimates were independent of number of prescriptions and the position of the atrial fibrillation and flutter diagnosis in the discharge record, and were similar for inpatients and outpatients. CONCLUSION: No evidence was found that use of bisphosphonates increases the risk of atrial fibrillation and flutter.
Snus is a smokeless tobacco product, widely used among Swedish men and increasingly so elsewhere. There is debate as to whether snus is an acceptable "harm-reduction" tobacco product. Since snus use delivers a dose of nicotine equivalent to cigarettes, and has been implicated in cardiac arrhythmia because of associations with sudden cardiovascular death, a relation with atrial fibrillation is plausible and important to investigate.
To assess the relation between use of snus and risk of atrial fibrillation, we carried out a pooled analysis of 7 prospective Swedish cohort studies. In total, 274,882 men, recruited between 1978 and 2004, were followed via the National Patient Register for atrial fibrillation. Primary analyses were restricted to 127,907 never-smokers. Relative risks were estimated using Cox proportional hazard regression.
The prevalence of snus use was 25% among never-smokers. During follow-up, 3,069 cases of atrial fibrillation were identified. The pooled relative risk of atrial fibrillation was 1.07 (95% confidence interval = 0.97-1.19) in current snus users, compared with nonusers.
Findings from this large national pooling project indicate that snus use is unlikely to confer any important increase in risk of atrial fibrillation.