Cyclo-oxygenase 2 (COX2)-selective inhibitors should reduce ulcer complications compared with non-selective non-steroidal anti-inflammatory drugs, but evidence is limited, and the possibility that ...these inhibitors increase cardiovascular events has been raised. The Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET) aimed to assess gastrointestinal and cardiovascular safety of the COX2 inhibitor lumiracoxib compared with two non-steroidal anti-inflammatory drugs, naproxen and ibuprofen.
18 325 patients age 50 years or older with osteoarthritis were randomised to lumiracoxib 400 mg once daily (n=9156), naproxen 500 mg twice daily (4754), or ibuprofen 800 mg three times daily (4415) for 52 weeks, in two substudies of identical design (lumiracoxib
vs ibuprofen or naproxen). Randomisation was stratified for low-dose aspirin use and age. The primary endpoint was the difference in time-to-event distribution of upper gastrointestinal ulcer complications (bleeding, perforation, or obstruction); analysis was by modified intention to treat. The principle measure of adverse cardiovascular events was the Antiplatelet Trialists' Collaboration endpoint (myocardial infarction, stroke, or cardiovascular death); this analysis was intention to treat.
81 (0·44%) patients did not start treatment and 7120 (39%) did not complete the study. In patients not taking aspirin, the cumulative 1-year incidence of ulcer complications was 1·09% (95% CI 0·82–1·36) with non-steroidal anti-inflammatory drugs (64 events) versus 0·25% (95% CI 0·12–0·39) with lumiracoxib (14 events; hazard ratio 0·21 95% CI 0·12–0·37, p<0·0001). Reductions in ulcer complications were also significant in the overall population (0·34 0·22–0·52, p<0·0001) but not in those taking aspirin (0·79 0·40–1·55, p=0·4876). In the overall population, 0·55% (50/9127) of those on non-steroidal anti-inflammatory drugs and 0·65% (59/9117) of those on lumiracoxib reached the cardiovascular endpoint (1·14 0·78–1·66, p=0·5074).
Lumiracoxib showed a three to four-fold reduction in ulcer complications compared with non-steroidal anti-inflammatory drugs without an increase in the rate of serious cardiovascular events, suggesting that lumiracoxib is an appropriate treatment for patients with osteoarthritis.
The potential for cyclo-oxygenase 2 (COX2)-selective inhibitors to increase the risk for myocardial infarction is controversial. The Therapeutic Arthritis Research and Gastrointestinal Event Trial ...(TARGET) aimed to assess gastrointestinal and cardiovascular safety of the COX2 inhibitor lumiracoxib compared with two non-steroidal anti-inflammatory drugs, naproxen and ibuprofen.
18 325 patients age 50 years or older with osteoarthritis were randomised to lumiracoxib 400 mg once daily (n=9156), naproxen 500 mg twice daily (4754), or ibuprofen 800 mg three times daily (4415) in two substudies of identical design. Randomisation was stratified for low-dose aspirin use and age. The primary cardiovascular endpoint was the Antiplatelet Trialists' Collaboration endpoint of non-fatal and silent myocardial infarction, stroke, or cardiovascular death. Analysis was by intention to treat.
81 (0·44%) patients did not start treatment and 7120 (39%) did not complete the study. At 1-year follow-up, incidence of the primary endpoint was low, both with lumiracoxib (59 events 0·65%) and the non-steroidal anti-inflammatory drugs (50 events 0·55%; hazard ratio 1·14 95% CI 0·78–1·66, p=0·5074). Incidence of myocardial infarction (clinical and silent) in the overall population in the individual substudies was 0·38% with lumiracoxib (18 events) versus 0·21% with naproxen (ten) and 0·11% with lumiracoxib (five) versus 0·16% with ibuprofen (seven). In the naproxen substudy, rates of myocardial infarction (clinical and silent) did not differ significantly compared with lumiracoxib in the population not taking low-dose aspirin (hazard ratio 2·37 95% CI 0·74–7·55, p=0·1454), overall (1·77 0·82–3·84, p=0·1471), and in patients taking aspirin (1·36 0·47–3·93, p=0·5658). In the ibuprofen substudy, these rates did not differ between lumiracoxib and ibuprofen in the population not taking low-dose aspirin (0·75 0·20–2·79, p=0·6669), overall (0·66 0·21–2·09, p=0·4833), and in patients taking aspirin (0·47 0·04–5·14, p=0·5328).
The primary endpoint, including incidence of myocardial infarction, did not differ between lumiracoxib and either ibuprofen or naproxen, irrespective of aspirin use. This finding suggests that lumiracoxib is an appropriate treatment for patients with osteoarthritis, who are often at high cardiovascular risk and taking low-dose aspirin.
Abstract
The cardiovascular (CV) safety of non-steroidal anti-inflammatory drugs (NSAIDs) and selective cyclooxygenase-2 inhibitors has been the subject of considerable debate.
The objective of this ...study was to determine the risk of CV events with lumiracoxib by meta-analysis of all completed, randomized controlled trials (RCTs) of ≥1 week and up to 1 year in duration of patients with osteoarthritis and rheumatoid arthritis.
The Novartis Lumiracoxib Clinical Trial Database, which includes all clinical studies conducted to date with lumiracoxib, was reviewed. Data were extracted from RCTs of ≥1 week and up to 1 year in duration, the maximum study duration; 34,668 patients were included in standard and cumulative meta-analyses. Twenty-two RCTs of lumiracoxib 100 to 1200 mg daily were identified; 22,781 patients were included in 1-year trials. Mean age of the patients was 61.5 years and 74% were female. More than 50% of the patients in these studies had hypertension at baseline and 6% had diabetes. Parameters analyzed were the Antiplatelet Trialists' Collaboration (APTC) composite CV end point of myocardial infarction (MI), stroke (ischemic and hemorrhagic), and CV death; MI alone; and stroke alone. Twenty-one of the 22 RCTs have been published.
For all 3 parameters, relative risk (RR) was calculated versus non-naproxen NSAIDs, naproxen, and placebo. The results were as follows: for the APTC end point versus non-naproxen NSAIDs: RR 0.83, 95% CI, 0.46–1.51; versus naproxen: RR 1.49, 95% CI, 0.94–2.36; versus placebo: RR 1.08, 95% CI, 0.41–2.86; for MI alone versus non-naproxen NSAIDs: RR 0.80, 95% CI, 0.28–2.25; versus naproxen: RR 1.69, 95% CI, 0.82–3.48; versus placebo: RR 1.27, 95% CI, 0.25–6.56; and for stroke alone versus non-naproxen NSAIDs: RR 0.91, 95% CI, 0.35–2.35; versus naproxen: RR 1.42, 95% CI, 0.70–2.91; versus placebo: RR 0.59, 95% CI, 0.13–2.74. Cumulative meta-analyses of lumiracoxib versus all comparators (placebo, diclofenac, ibuprofen, celecoxib, rofecoxib, and naproxen) did not find any significant differences in APTC, MI alone, or stroke alone.
This meta-analysis of 34,668 patients receiving ≥1 week and up to 1 year of treatment found no evidence that lumiracoxib was associated with a significant increase in CV risk compared with naproxen, placebo, or all comparators (placebo, diclofenac, ibuprofen, celecoxib, rofecoxib, and naproxen).
Sustained forms of atrial fibrillation (AF) may be associated with a higher risk of adverse outcomes, but few if any long-term studies took into account changes of AF type and co-morbidities over ...time. We prospectively followed 3843 AF patients and collected information on AF type and co-morbidities during yearly follow-ups. The primary outcome was a composite of stroke or systemic embolism (SE). Secondary outcomes included myocardial infarction, hospitalization for congestive heart failure (CHF), bleeding and all-cause mortality. Multivariable adjusted Cox proportional hazards models with time-varying covariates were used to compare hazard ratios (HR) according to AF type. At baseline 1895 (49%), 1046 (27%) and 902 (24%) patients had paroxysmal, persistent and permanent AF and 3234 (84%) were anticoagulated. After a median (IQR) follow-up of 3.0 (1.9; 4.2) years, the incidence of stroke/SE was 1.0 per 100 patient-years. The incidence of myocardial infarction, CHF, bleeding and all-cause mortality was 0.7, 3.0, 2.9 and 2.7 per 100 patient-years, respectively. The multivariable adjusted (a) HRs (95% confidence interval) for stroke/SE were 1.13 (0.69; 1.85) and 1.27 (0.83; 1.95) for time-updated persistent and permanent AF, respectively. The corresponding aHRs were 1.23 (0.89, 1.69) and 1.45 (1.12; 1.87) for all-cause mortality, 1.34 (1.00; 1.80) and 1.30 (1.01; 1.67) for CHF, 0.91 (0.48; 1.72) and 0.95 (0.56; 1.59) for myocardial infarction, and 0.89 (0.70; 1.14) and 1.00 (0.81; 1.24) for bleeding. In this large prospective cohort of AF patients, time-updated AF type was not associated with incident stroke/SE.
ObjectiveTo examine sex differences in prevalence, volume and distribution of vascular brain lesions on MRI among patients with atrial fibrillation (AF).MethodsIn this cross-sectional analysis, we ...included 1743 patients with AF (27% women) from the multicentre Swiss Atrial Fibrillation study (SWISS-AF) with available baseline brain MRI. We compared presence and total volume of large non-cortical or cortical infarcts (LNCCIs), small non-cortical infarcts, microbleeds (MB) and white matter hyperintensities (WMH, Fazekas score ≥2 for moderate or severe degree) between men and women with multivariable logistic regression. We generated voxel-based probability maps to assess the anatomical distribution of lesions.ResultsWe found no strong evidence for an association of female sex with the prevalence of all ischaemic infarcts (LNCCI and SNCI combined; adjusted OR 0.86, 95% CI 0.67 to 1.09, p=0.22), MB (adjusted OR 0.91, 95% CI 0.68 to 1.21, p=0.52) and moderate or severe WMH (adjusted OR 1.15, 95% CI 0.90 to 1.48, p=0.27). However, total WMH volume was 17% larger among women than men (multivariable adjusted multiplicative effect 1.17, 95% CI 1.01 to 1.35; p=0.04). Lesion probability maps showed a right hemispheric preponderance of ischaemic infarcts in both men and women, while WMH were distributed symmetrically.ConclusionWomen had higher white matter disease burden than men, while volume and prevalence of other lesions did not differ. Our findings highlight the importance of controlling risk factors for cerebral small vessel disease in patients with AF, especially among women.
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