306 research outputs found
Coxibs, Traditional NSAIDs, and Cardiovascular Safety Post-PRECISION: What We Thought We Knew Then and What We Think We Know Now
No full textThe aim of the present review is to analyze how thinking about the cardiovascular safety of nonsteroidal antiinflammatory drugs has evolved during the past two decades, and discuss to what extent the additional information from the Prospective Randomized Evaluation of Celecoxib Integrated Safety Versus Ibuprofen or Naproxen study may alter our current mechanistic understanding and/or clinical practice
Low-dose aspirin for the prevention of atherothrombosis
No full textn engl j med 353;22www.nejm.orgdecember 1, 2005The new england journal of medicine2373review articledrug therapyLow-Dose Aspirin for the Prevention of AtherothrombosisCarlo Patrono, M.D., Luis A. García Rodríguez, M.D., Raffaele Landolfi, M.D., and Colin Baigent, B.M., B.Ch.From the Department of Pharmacology,University of Rome La Sapienza, Rome(C.P.); the Spanish Center for Pharmaco-epidemiologic Research, Madrid (L.A.G.R.);the Department of Medicine, Catholic Uni-versity School of Medicine, Rome (R.L.);and the Clinical Trial Service Unit and Epi-demiological Studies Unit, University ofOxford, Oxford, United Kingdom (C.B.).Address reprint requests to Dr. Patrono atUniversity of Rome La Sapienza, OspedaleSant’Andrea, Via di Grottarossa 1035,00189 Rome, Italy, or at [email protected] Engl J Med 2005;353:2373-83.Copyright © 2005 Massachusetts Medical Society.therosclerosis, the major cause of ischemic coronary arterydisease and cerebrovascular disease, is a chronic inflammatory disorder inwhich immune mechanisms interact with metabolic risk factors to initiate,propagate, and activate vascular lesions.1 Arterial thrombosis, an acute complicationthat develops on the surface of a ruptured atheromatous plaque or as a consequence ofendothelial erosion,1 may cause myocardial infarction or ischemic stroke. Platelets arekey cellular components of arterial occlusive thrombi and may participate in the devel-opment and progression of atheromatous plaques.2 Platelets are also vital componentsof hemostasis, the physiologic process that arrests hemorrhage after tissue trauma andvascular injury. Although the adhesion and activation of platelets can be viewed as arepair-oriented response to sudden fissuring or rupture of an atheromatous plaque,uncontrolled progression of such a process through a series of self-sustaining amplifi-cation loops may lead to the intraluminal formation of thrombus, vascular occlusion,and transient ischemia or infarction. The ability of platelets to participate in both nor-mal hemostasis and atherothrombosis depends on their adhesive properties and theircapacity to become activated very quickly in response to various stimuli.2Currently available antiplatelet drugs interfere with certain steps in the activationprocess by selectively blocking key platelet enzymes or receptors, reducing the risk ofarterial thrombosis through mechanisms that cannot be dissociated from an increasedrisk of bleeding complications.3 In particular, randomized trials indicate that low-doseaspirin can prevent arterial thrombosis under various circumstances, including firstvascular events among low-risk, healthy subjects and recurrent vascular events amongpatients with known acute or chronic occlusive vascular disease.3The aim of this review is to integrate our current understanding of the molecularmechanism of action of aspirin with the results of clinical trials and epidemiologicstudies of aspirin as an antiplatelet agent, placing special emphasis on the benefits andrisks in various patient populations
Do selective cyclo-oxygenase-2 inhibitors and traditional non-steroidal anti-inflammatory drugs increase the risk of atherothrombosis? Meta-analysis of randomised trials.
No full textOBJECTIVE: To assess the effects of selective cyclo-oxygenase-2 (COX 2) inhibitors and traditional non-steroidal anti-inflammatory drugs (NSAIDs) on the risk of vascular events. DESIGN: Meta-analysis of published and unpublished tabular data from randomised trials, with indirect estimation of the effects of traditional NSAIDs. DATA SOURCES: Medline and Embase (January 1966 to April 2005); Food and Drug Administration records; and data on file from Novartis, Pfizer, and Merck. REVIEW METHODS: Eligible studies were randomised trials that included a comparison of a selective COX 2 inhibitor versus placebo or a selective COX 2 inhibitor versus a traditional NSAID, of at least four weeks' duration, with information on serious vascular events (defined as myocardial infarction, stroke, or vascular death). Individual investigators and manufacturers provided information on the number of patients randomised, numbers of vascular events, and the person time of follow-up for each randomised group. RESULTS: In placebo comparisons, allocation to a selective COX 2 inhibitor was associated with a 42% relative increase in the incidence of serious vascular events (1.2%/year v 0.9%/year; rate ratio 1.42, 95% confidence interval 1.13 to 1.78; P = 0.003), with no significant heterogeneity among the different selective COX 2 inhibitors. This was chiefly attributable to an increased risk of myocardial infarction (0.6%/year v 0.3%/year; 1.86, 1.33 to 2.59; P = 0.0003), with little apparent difference in other vascular outcomes. Among trials of at least one year's duration (mean 2.7 years), the rate ratio for vascular events was 1.45 (1.12 to 1.89; P = 0.005). Overall, the incidence of serious vascular events was similar between a selective COX 2 inhibitor and any traditional NSAID (1.0%/year v 0.9%/year; 1.16, 0.97 to 1.38; P = 0.1). However, statistical heterogeneity (P = 0.001) was found between trials of a selective COX 2 inhibitor versus naproxen (1.57, 1.21 to 2.03) and of a selective COX 2 inhibitor versus non-naproxen NSAIDs (0.88, 0.69 to 1.12). The summary rate ratio for vascular events, compared with placebo, was 0.92 (0.67 to 1.26) for naproxen, 1.51 (0.96 to 2.37) for ibuprofen, and 1.63 (1.12 to 2.37) for diclofenac. CONCLUSIONS: Selective COX 2 inhibitors are associated with a moderate increase in the risk of vascular events, as are high dose regimens of ibuprofen and diclofenac, but high dose naproxen is not associated with such an excess
Systematic overviews of the randomised evidence for the effects of traditional non-steroidal anti-inflammatory drugs and selective inhibitors of cyclo-oxygenase-2 on vascular and upper gastrointestinal outcomes
No full textBackground: Comparative assessments of the vascular and upper gastrointestinal risks of different regimens of non-steroidal anti-inflammatory drugs (NSAIDs) are required. Methods: Meta-analyses were conducted, using individual participant data where possible, of placebo-controlled trials of a selective cyclo-oxygenase [COX]-2 inhibitor ('coxib') or traditional NSAID, or randomised trials of a coxib versus traditional NSAIDs. A prespecified subdivision of traditional NSAID regimens of those with antiplatelet activity (mainly naproxen) and those without (mainly diclofenac) was made. Primary outcomes were major vascular events (MVEs; nonfatal myocardial infarction, nonfatal stroke or vascular death) and upper gastrointestinal complications (UGICs; perforation, obstruction or bleed). Findings: Searches identified 788 trials: 200 comparisons of a coxib vs placebo (88,604 participants, mean follow-up 0.60 years), 206 comparisons of a traditional NSAID vs placebo (43,482 participants, 0.46 years) and 149 comparisons of a coxib vs traditional NSAID (137,466 participants, mean follow-up 0.95 years). Compared to placebo, allocation to a coxib increased the risk of MVEs (rate ratio 1.38, 95% CI 1.14-1.66), vascular mortality (1.58, 1.11-2.24) and UGICs (1.81, 1.17-2.81). Overall, in the population studied, coxibs were associated with three additional major vascular events (one fatal) and two (rarely fatal) upper gastrointestinal complications per 1000 person-years exposure. There was no evidence of heterogeneity by duration of follow-up, coxib type, dose (other than for celecoxib), or patient characteristics, for the primary outcomes. The risk of MVEs for traditional NSAIDs without antiplatelet activity (mostly diclofenac 75mg bd or ibuprofen 800mg tds) were comparable to coxibs (1.40, 1.15-1.72); but the risk of UGICs (1.98, 1.39-2.84) was significantly greater. For traditional NSAIDs with antiplatelet activity (mostly naproxen 500mg bd) there were no significant excess of MVEs (0.84, 0.66-1.08), but UGICs were substantially increased (4.06, 2.85-5.78). Both coxibs and traditional NSAIDs increased risk of hospitalisation for heart failure by about two-fold. Interpretation: The vascular and upper gastrointestinal risks of coxibs and high-dose tNSAID regimens can be predicted, allowing the choice of analgesia to be tailored for particular patients
The efficacy and safety of aspirin in individuals with and without diabetes: a collaborative meta-analysis of individual participant data from randomised trials
No full textBackground: Whether aspirin is of net clinical benefit for the primary prevention of vascular events in those at high risk, such as some people with diabetes, is uncertain. Methods: Individual participant data from 26 randomised trials (123,361 individuals, 760,000 person-years) assessing aspirin versus control in people with and without diabetes were included. Major outcomes included serious vascular events (SVE: myocardial infarction, stroke or vascular death) and major extracranial bleeding (MEB). Findings: In the primary prevention setting, aspirin reduced SVE (0.65% vs 0.71% per year; relative risk (RR) 0.90 [95% confidence interval (CI) 0.85-0.96]; p=0.0006) and increased MEB (0.10% vs 0.07% per year; RR 1.52 [95% CI 1.30-1.78]; p5%, may derive net clinical benefit in the primary prevention setting. At a 5-year risk level of 5-10%, for example, people without diabetes might have a 1.6% (95% CI 1.1-2.1) reduction in 5-year SVE balanced against a 0.5% (95% CI 0.3-0.8) increase in 5-year MEB. In comparison, people with diabetes and 5-year risk of 5-10% might have a 1.7% (95% CI 1.2-2.2) reduction in 5-year SVE balanced against a 0.3% (95% CI 0.1-0.4) increase in 5-year MEB. Even if an approximate halving of baseline vascular risk by modern preventative measures such as statins is factored in before aspirin therapy is considered, aspirin may still have a worthwhile net clinical benefit in such people at least at moderate vascular risk. Interpretation: Some people without previous disease but at higher vascular risk, such as people with diabetes and 5-year risk >5%, may derive net clinical benefit from aspirin. Further direct randomised evidence in these individuals will help clarify the balance of risks and benefits
Aspirin for everyone older than 50?
No full textCurrent population screening for vascular disease is neither efficient nor effective. Peter Elwood and colleagues believe we should have a public information strategy highlighting the benefits (and risks) of aspirin for older people, but Colin Baigent argues that the evidence of benefit is not yet strong enoug
Multiple testing correction in a meta-analysis of all adverse events recorded in large long-term randomised trials of statin therapy
No full textBackground: Randomised trials have shown that statin therapy reduces the risk of major vascular events (ie, heart attacks, strokes and coronary revascularisation procedures) without any increase in the risk of nonvascular causes of death or of site-specific cancer, but does produce a small increase in the risk of muscle pain or weakness, diabetes and, possibly, haemorrhagic stroke. Although statins are widely prescribed, there are concerns that they might have a range of other side effects. This DPhil addresses these concerns through an individual-participant-data meta-analysis of all recorded adverse events (AEs) in all large, long-term, randomised, double-blind trials of statin therapy, taking into consideration the substantial challenges related to multiple hypotheses testing (MHT).
Methods: Double-blind randomised trials of statin therapy with at least 1,000 participants and a scheduled treatment duration of at least 2 years were included. Individual participant data on all AEs reported in 19 trials of statin vs placebo (123,940 randomised participants) and 4 trials of a more intensive versus a less intensive statin regimen (30,724 randomised participants) were analysed. A literature review identified potentially relevant MHT methods and simulation studies were done to assess their expected performance (ie, control of false positive [FP] and false negative results). Adverse event data were organised and coded according to a common medical dictionary based upon the Medical Dictionary for Regulatory Activities (MedDRA). Under the selected strategy, inverse-variance-weighted meta-analyses of the effects on all AEs were performed using time-to-event analyses for the first occurrence of each outcome among participants randomly assigned into each trial.
Results: The literature review identified 6,569 eligible papers, of which 337 were included for full text review. Five MHT methods (Holm, Hochberg, Hommel, Benjamini & Hochberg and Mehrotra & Adewale) were selected as the most appropriate based on their statistical control of type I and II error rates. Simulation analyses identified the Mehrotra & Adewale method, which controls the false discovery rate (FDR), as the most suitable as it resulted in a low expected number of FP results whilst maintaining reasonable statistical power to detect any real effects of statin therapy. Blinded (ie, using a ‘shuffled’ treatment allocation) meta-analyses of the trials of statin vs placebo were first done, which confirmed that no correction for MHT resulted in 179 (4.4%) FP findings while the Mehrotra & Adewale MHT method led to zero FPs. Unblinded analyses (ie, using the actual treatment allocation) of all non-lipid-related AEs then confirmed the already known beneficial effects of statins on major vascular events. They also showed that statin therapy was FDR-significantly associated with a reduced risk of having an arteriogram or an angiogram procedure. Subsequent analyses which ignored the already known beneficial or harmful effects of statin therapy, very rare outcomes and irrelevant overlap in tests, identified two new benefits of statin therapy: reductions in the risk of peripheral embolism and thrombosis (361 [0.6%] vs 451 [0.7%], rate ratio [RR] 0.72, 95% confidence interval [CI]: 0.61−0.83, p=0.0012), and carotid endarterectomy (47 [<0.1%] vs 83 [0.1%], RR 0.57, 95% CI: 0.40−0.80, p= 0.0013). However, statins were also FDR-significantly associated with an increased risk of hepatobiliary investigations (1,349 [2.2%] vs 1,025 [1.7%], RR 1.32, 95% CI: 1.22–1.43, p<0.0001) and the extremely rare outcome parosmia (18 vs 2, p=0.00036). The meta-analyses of the 4 trials of more vs less statin revealed that more intensive statin therapy was associated with an FDR-significantly reduced risk of coronary artery disorders (3,518 [22.9%] vs 3,779 [24.6%], RR 0.92, 95% CI: 0.88−0.96, p= 0.00025), general system disorders (5,098 [33.1%] vs 5,682 [37.1%],RR 0.87, 95% CI: 0.84−0.91, p<0.0001), any surgical and medical procedures (4,067 [26.4%] vs 4,333 [28.3%],RR 0.93, 95% CI: 0.89−0.97, p= 0.00059) and the rare AE of renal therapeutic procedures (30 [0.2%] vs 57 [0.4%], RR 0.54, 95% CI: 0.35−0.82, p= 0.0038). More intensive statin regimens were also FDR-significantly associated with an increased risk of hepatobiliary investigations (502 [3.3%] vs 253 [1.6%], RR 1.95, 95% CI: 1.69–2.25, p<0.0001) and high blood creatine phosphokinase (223 [1.4%] vs 146 [1.0%], RR 1.51, 95% CI: 1.24−1.86, p<0.0001).
Conclusion: These findings highlight the importance of using appropriate statistical methods to control for multiple testing. The results confirmed the already known benefits of statin therapy while identifying some new potential benefits and harms. However, the nature and frequency of the newly detected harms confirm that the benefits of statin therapy greatly outweigh the potential harms
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Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomised trials
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