Antiplatelet Trialists Collaboration Research Articles

Cardiovascular safety of celecoxib in rheumatoid arthritis and osteoarthritis patients: A systematic review and meta-analysis.

To assess the cardiovascular safety of celecoxib compared to non-selective non-steroid anti-inflammatory drugs or placebo. We included randomized controlled trials of oral celecoxib compared with a non-selective NSAID or placebo in rheumatoid arthritis and osteoarthritis patients. We conducted searches in EMBASE, Cochrane CENTRAL, MEDLINE, China National Knowledge Infrastructure, VIP, Wanfang, and Chinese Biomedical Literature Database. Study selection and data extraction were done by two authors independently. The risk of bias was assessed using Cochrane's risk-of-bias Tool for Randomized Trials. The effect size was presented as a risk ratio with their 95% confidence interval. Until July 22nd, 2021, our search identified 6279 records from which, after exclusions, 21 trials were included in the meta-analysis. The overall pooled risk ratio for Antiplatelet Trialists Collaboration cardiovascular events for celecoxib compared with any non-selective non-steroid anti-inflammatory drugs was 0.89 (95% confidence interval: 0.80-1.00). The pooled risk ratio for all-cause mortality for celecoxib compared with non-selective non-steroid anti-inflammatory drugs was 0.81 (95% confidence interval: 0.66-0.98). The cardiovascular mortality rate of celecoxib was lower than non-selective non-steroid anti-inflammatory drugs (risk ratio: 0.75, 95% confidence interval: 0.57-0.99). There was no significant difference between celecoxib and non-selective non-steroid anti-inflammatory drugs or placebo in the risk of other cardiovascular events. Celecoxib is relatively safe in rheumatoid arthritis and osteoarthritis patients, independent of dose or duration. But it remains uncertain whether this would remain the same in patients treated with aspirin and patients with established cardiovascular diseases.

Strengthening the interpretability of clinical trial results by assessing the effect of informative censoring on the primary estimand in PRECISION.

The ICH E9(R1) addendum states that the strategy to account for intercurrent events should be included when defining an estimand, the treatment effect to be estimated based on the study objective. The estimator used to assess the treatment effect needs to be aligned with the estimand that accounted for intercurrent events. Regardless of the strategy, missing data resulting from patient premature withdrawal could undermine the robustness of the study results. Informative censoring due to dropouts in an events-based study is one such example. Sensitivity analyses using imputation methods are useful to examine the uncertainty due to informative censoring and address the robustness and strength of the study results. We assessed the effect of premature patient withdrawal in the PRECISION study, a randomized non-inferiority clinical trial of patients with chronic arthritic pain that compared the cardiovascular safety of three nonsteroidal anti-inflammatory drugs-based treatment policies or paradigms. The protocol-defined use of concomitant or rescue medications was permitted since changes in pain medications due to insufficient analgesia were expected in patients in this long-term study. Anticipating that premature study discontinuations could potentially lead to informative censoring, a supplementary analysis was pre-specified in which censored outcomes due to the premature study discontinuation were imputed based on adverse events that were clinically associated with the primary endpoint (cardiovascular outcome based on the Antiplatelet Trialists Collaboration composite endpoint). Furthermore, tipping point analyses were conducted to test the robustness of the primary analysis results by assuming data censored not at random. The level of increase at which the primary study conclusion would change was estimated. For the analysis of time to first primary endpoint event through 30 months, 4065 out of the 24,081 enrolled patients were lost to follow-up, withdrew consent, or were no longer willing to participate in the study. These withdrawals occurred gradually and resulted in a cumulative total of 5893 censored patient-years of observation (10.2%). The rate of discontinuation and the baseline characteristics of the discontinued patients were similar across the three treatment groups. The non-inferiority conclusion from the primary analysis was confirmed in the supplementary analysis incorporating relevant adverse events. Furthermore, tipping point analyses demonstrated that in order to lose non-inferiority in the primary analysis, the risk of primary endpoint events during the censored observation time would have to increase by more than 2.7-fold in the celecoxib group while remaining constant in the other nonsteroidal anti-inflammatory drugs groups, demonstrating that the scenarios where the study results are invalid appear not plausible. Supplementary and sensitivity analyses presented to address informative censoring in PRECISION helped to further interpret and strengthen the study results.

Tegaserod Cardiovascular Safety Analysis: Importance of a Methodologic Approach to Drug Safety Analysis

Introduction: In 2007, tegaserod was voluntarily withdrawn from the market due to an imbalance in cardiovascular adverse events (CVAEs; including myocardial infarction, stroke, unstable angina, and transient ischemic attacks) reported by investigators among subjects in 29 placebo-controlled, doubleblind trials across many gastrointestinal indications. In these trials, 11,614 subjects received tegaserod and 7031 received placebo. Initial analysis before complete primary source documents were available, identified 13 CVAEs in the tegaserod group and 1 in the placebo group. We report on the finalized independent blinded second adjudicated analysis performed by the Duke Clinical Research Institute (DCRI) after obtaining full source documentation for adjudication of CV events. Methods: The blinded adjudication by the DCRI of the CVAEs had the unique advantage compared to the previous reviews of using rigorous search methodologies to identify potential CVAEs, broadened potential definitions, and access to all available source materials for the identified potential cases. It used FDA-requested Antiplatelet Trialists’ Collaboration (APTC) classifications (vascular death or non-fatal heart attack or stroke), which are similar to the major adverse cardiovascular events (MACE) classification (CV death, non-fatal MI or stroke). In addition, an exploratory post hoc analysis of females with ≤1 CV risk factor (hypertension, smoking, diabetes, hyperlipidemia, obesity, and age ≥55 years), was performed to evaluate CVAEs in a low cardiovascular risk population. Results: Overall CVAEs (7 events in the tegaserod cohort and 1 in the placebo group, P=NS) and using APTC/MACE definitions (4 vs 0, respectively, P=NS) were adjudicated (Table 1). In the post hoc analysis excluding participants with >1 CV risk factor, there were 7804 participants in the tegaserod group and 4687 in the placebo group; there was only 1 CV event in the tegaserod group and none when APTC/MACE standards were applied. Conclusion: Since 2007, 2 epidemiologic studies have been published that include data from >54,000 patients who received tegaserod (Loughlin, et al. J Cardiovasc Pharmacol Ther.2010;15:151-157; Anderson, et al. J Cardiovasc Pharmacol Ther. 2009;1:170-175). Each failed to identify an increased risk for CV events. Based on a thorough analysis of the tegaserod clinical trial database using rigorous definitions and access to source documents and epidemiologic data, tegaserod appears to have a low risk of CV events.462 Figure 1. Results from Duke Adjudication and Post Hoc Low Cardiovascular Risk Population Analysis

Systemic Safety in Ranibizumab-Treated Patients with Neovascular Age-Related Macular Degeneration: A Patient-Level Pooled Analysis

This study evaluated the cardiovascular/cerebrovascular safety profile of ranibizumab 0.5 mg versus sham ± verteporfin in patients with neovascular age-related macular degeneration (nAMD). In addition, comparisons of ranibizumab 0.3 mg with sham and ranibizumab 0.5 mg to 0.3 mg were performed. Intravitreal anti-vascular endothelial growth factor (VEGF) agents carry potential increased systemic risks, including cardiovascular or cerebrovascular events. Pooled safety analyses allow better interpretation of safety outcomes seen in individual clinical trials, especially for less common events. To our knowledge, this is the largest patient-level pooled analysis of patients with nAMD treated with ranibizumab. Patient-level pooled analysis of data from 7 Genentech- and Novartis-sponsored phase II, III, and IV studies in nAMD that were completed by December 31, 2013. Pairwise comparisons (primary comparison: ranibizumab 0.5 mg [globally approved dose for nAMD] vs. sham or verteporfin) were performed using Cox proportional hazard regression (hazard ratios [HRs], 95% confidence intervals [CIs]) and rates per 100 patient-years. Standardized Medical Dictionary for Regulatory Activities queries (SMQs) and extended searches were used to identify relevant safety endpoints, including arterial thromboembolic events (ATEs), myocardial infarction (MI), stroke or transient ischemic attack (TIA), stroke (excluding TIA), vascular deaths, and major vascular events as defined by the Antiplatelet Trialists' Collaboration (APTC). The HRs (95% CIs) for the primary comparison of ranibizumab 0.5 mg (n=480) versus sham or verteporfin (n=462) were 1.16 (0.72-1.88) for ATE, 1.33 (0.59-2.97) for MI, 1.43 (0.54-3.77) for stroke excluding TIA, 1.25 (0.61-2.55) for stroke or TIA, 0.57 (0.18-1.78) for vascular death, and 1.12 (0.64-1.98) for APTC events. Hazard ratio 95% CIs included 1, indicating no significant treatment differences, for all endpoints for comparison of ranibizumab 0.5 mg versus sham or verteporfin. The rates of cardiovascular and cerebrovascular events were low in these patients with nAMD and not clinically meaningfully different for patients treated with ranibizumab 0.5 mg versus sham or verteporfin, which supports the favorable benefit-risk profile of ranibizumab in the patient population with nAMD. Pooling these studies allows an analysis with higher power and precision compared with individual study analyses.

Aspirin Monotherapy Should Not Be Recommended for Cardioprotection in Patients With Symptomatic Peripheral Artery Disease.

Patients with peripheral artery disease (PAD), regardless of disease stage, are at a marked increased risk for systemic cardiovascular events. Therefore, cardiovascular risk reduction is central to the management of these patients. Treatment of hypertension, use of statins, and strategies for smoking cessation are all well-established, evidence-based interventions in the patient with PAD. In contrast, the rationale for use of antiplatelet agents has been more controversial. The 2016 American Heart Association/American College of Cardiology guideline for management of the patient with PAD indicates, “Antiplatelet therapy with aspirin alone (range, 75–325 mg per day) or clopidogrel alone (75 mg per day) is recommended to reduce MI [myocardial infarction], stroke and vascular death in patients with symptomatic PAD.”1 Per the guideline, this class I recommendation (strong) was supported by level A evidence (high quality from more than 1 randomized controlled trial or meta-analyses of randomized controlled trials). The primary evidence supporting the recommendation was the work of the Antiplatelet Trialists’ Collaboration (ATC).2 The ATC found a 22% reduction in vascular events associated with antiplatelet therapy compared with …

Vascular Safety of Ranibizumab in Patients With Diabetic Macular Edema

Patients with diabetic macular edema (DME) are at high risk of vascular complications, including stroke and myocardial infarction (MI). Concerns have been raised that intravitreal dosing of vascular endothelial growth factor inhibitors in DME could be associated with an increase in cardiovascular and cerebrovascular adverse events. To evaluate the cardiovascular and cerebrovascular safety of ranibizumab, 0.5 mg and 0.3 mg, compared with sham with and without laser in DME. Patient-level data from 6 randomized, double-masked, sham- and laser-controlled clinical trials. Company-sponsored (Genentech or Novartis) studies in DME completed as of December 31, 2013. Pairwise comparisons (ranibizumab, 0.5 mg, vs sham and laser; ranibizumab, 0.3 mg, vs sham) were performed using Cox proportional hazard regression (hazard ratios, 95% CIs) and rates per 100 person-years. Data analysis was conducted from June 1 to July 15, 2015. Standardized Medical Dictionary for Regulatory Activities queries and extended searches were prospectively defined to identify relevant safety end points, including arterial thromboembolic events, MI, stroke or transient ischemic attack, vascular deaths, and major vascular events as defined by the Antiplatelet Trialists' Collaboration (APTC). Overall, 936 patients were treated with ranibizumab, 0.5 mg; 250 patients with ranibizumab, 0.3 mg; and 581 patients with sham/laser. The hazard ratios associated with all pairwise comparisons included 1 for all key cardiovascular and cerebrovascular safety end points. For ranibizumab, 0.5 mg, vs sham/laser and ranibizumab, 0.3 mg, vs sham, the hazard ratios were, respectively, arterial thromboembolic events, 1.05 (95% CI, 0.66-1.68) and 0.78 (95% CI, 0.43-1.40); MI, 0.84 (95% CI, 0.41-1.72) and 0.94 (95% CI, 0.43-2.06); stroke or transient ischemic attack, 0.94 (95% CI, 0.44-1.99) and 0.53 (95% CI, 0.19-1.42); stroke (excluding transient ischemic attack), 1.63 (95% CI, 0.65-4.07) and 0.59 (95% CI, 0.14-2.46); vascular death, 2.17 (95% CI, 0.57-8.29) and 2.51 (95% CI, 0.49-12.94); and APTC-defined events, 1.09 (95% CI, 0.63-1.88) and 1.00 (95% CI, 0.51-1.96). This pooled analysis includes 1 of the largest patient-level data sets on treatment of DME with ranibizumab. Although still underpowered to detect small differences for infrequent events, such as stroke, the findings suggest that intravitreous ranibizumab does not increase the risk of systemic vascular events. However, uncertainty remains for patients with DME who are at high risk for vascular disease and were not included in these trials.

Aflibercept, Bevacizumab, or Ranibizumab for Diabetic Macular Edema: Two-Year Results from a Comparative Effectiveness Randomized Clinical Trial

To provide 2-year results comparing anti-vascular endothelial growth factor (VEGF) agents for center-involved diabetic macular edema (DME) using a standardized follow-up and retreatment regimen. Randomized clinical trial. Six hundred sixty participants with visual acuity (VA) impairment from DME. Randomization to 2.0-mg aflibercept, 1.25-mg repackaged (compounded) bevacizumab, or 0.3-mg ranibizumab intravitreous injections performed up to monthly using a protocol-specific follow-up andretreatment regimen. Focal/grid laser photocoagulation was added after 6 months if DME persisted. Visits occurred every 4 weeks during year 1 and were extended up to every 4 months thereafter when VA and macular thickness were stable. Change in VA, adverse events, and retreatment frequency. Median numbers of injections were 5, 6, and 6 in year 2 and 15, 16, and 15 over 2 years in the aflibercept, bevacizumab, and ranibizumab groups, respectively (global P= 0.08). Focal/grid laser photocoagulation was administered in 41%, 64%, and 52%, respectively (aflibercept vs. bevacizumab, P < 0.001; aflibercept vs. ranibizumab, P= 0.04; bevacizumab vs. ranibizumab, P= 0.01). At 2 years, mean VA improved by 12.8, 10.0, and 12.3 letters, respectively. Treatment group differences varied by baseline VA (P= 0.02 for interaction). With worse baseline VA (20/50 to 20/320), mean improvement was 18.1, 13.3, and 16.1 letters, respectively (aflibercept vs. bevacizumab, P= 0.02; aflibercept vs. ranibizumab, P= 0.18; ranibizumab vs. bevacizumab, P= 0.18). With better baseline VA (20/32 to 20/40), mean improvement was 7.8, 6.8, and 8.6 letters, respectively (P > 0.10, for pairwise comparisons). Anti-Platelet Trialists' Collaboration (APTC) events occurred in 5% with aflibercept, 8% with bevacizumab, and 12% with ranibizumab (global P= 0.047; aflibercept vs. bevacizumab, P= 0.34; aflibercept vs. ranibizumab, P= 0.047; ranibizumab vs. bevacizumab, P= 0.20; global P= 0.09 adjusted for potential confounders). All 3 anti-VEGF groups showed VA improvement from baseline to 2 years with a decreased number of injections in year 2. Visual acuity outcomes were similar for eyes with better baseline VA. Among eyes with worse baseline VA, aflibercept had superior 2-year VA outcomes compared with bevacizumab, but superiority of aflibercept over ranibizumab, noted at 1 year, was no longer identified. Higher APTC event rates with ranibizumab over 2 years warrants continued evaluation in future trials.

Intravitreal aflibercept for macular oedema due to branch retinal vein occlusion

AbstractPurpose To evaluate the efficacy and safety of intravitreal aflibercept (IVT‐AFL) injection compared with macular grid laser photocoagulation for the treatment of macular oedema secondary to Branch Retinal Vein Occlusion (BRVO).Methods VIBRANT was a double‐masked, Phase 3 trial with a duration of 52 weeks in which patients with macular oedema secondary to BRVO were randomised 1:1 to receive IVT‐AFL 2 mg every 4 weeks or grid laser from baseline to Week 20. The primary efficacy endpoint was the proportion of eyes that gained ≥15 letters in best‐corrected visual acuity (BCVA) from baseline at Week 24.Results The proportion of eyes that gained ≥15 letters from baseline to Week 24 was 52.7% and 26.7% (P&lt;0.001) in the IVT‐AFL and laser groups, respectively. The mean improvement in BCVA from baseline to Week 24 was 17.0 and 6.9 letters (P&lt;0.0001), respectively. The most common ocular adverse events (AEs) in the IVT‐AFL and laser group were subconjunctival haemorrhage (19.8%) and eye pain (5.4%), respectively. There were no cases of intraocular inflammation in either treatment group. One death due to pneumonia and one Anti‐Platelet Trialists' Collaboration (APTC)‐defined event of nonfatal stroke occurred during the first 24 weeks of study, both in the laser group. Week 52 data will be presented.Conclusion In this study, monthly IVT‐AFL provided statistically significant and clinically meaningful visual benefits which were superior to macular grid laser photocoagulation in eyes with macular oedema due to BRVO over 24 weeks. Compared to IVT‐AFL’s known profile no new safety signals were observed. Commercial interest

Protocol of the Febuxostat versus Allopurinol Streamlined Trial (FAST): a large prospective, randomised, open, blinded endpoint study comparing the cardiovascular safety of allopurinol and febuxostat in the management of symptomatic hyperuricaemia

IntroductionGout affects 2.5% of the UK's adult population and is now the most common type of inflammatory arthritis. The long-term management of gout requires reduction of serum urate levels and...

Methodology of a large prospective, randomised, open, blinded endpoint streamlined safety study of celecoxib versus traditional non-steroidal anti-inflammatory drugs in patients with osteoarthritis or rheumatoid arthritis: protocol of the standard care versus celecoxib outcome trial (SCOT)

IntroductionCyclooxygenase 2 (COX-2) inhibitors have less upper gastrointestinal toxicity than traditional non-steroidal anti-inflammatory drugs (NSAIDs). However, both COX-2 inhibitors and traditional NSAIDs may be associated with adverse cardiovascular side effects....

Cardiovascular safety of lumiracoxib: a meta-analysis of randomised controlled trials in patients with osteoarthritis

PurposeTo re-evaluate the cardiovascular risk of lumiracoxib compared with other non-steroidal anti-inflammatory drugs (NSAIDs) or placebo in patients with osteoarthritis.MethodsWe conducted a meta-analysis of randomised controlled trials of lumiracoxib versus placebo or other NSAIDs in patients with osteoarthritis reported up to January 2010. Both published and unpublished trials were included. PubMed searches using predefined search criteria (lumiracoxib AND osteoarthritis, limits: none; COX-189 AND osteoarthritis, limits: none) were used to obtain the relevant published trials. Novartis granted explicit access to their company studies and the right to use these study reports for the purposes of publication in peer reviewed journals. Endpoints were the Antiplatelet Trialists’ Collaboration (APTC) endpoint and individual cardiovascular endpoints.ResultsMeta-analysis of 6 trials of lumiracoxib versus placebo revealed no difference in cardiovascular outcomes. Meta-analysis of 12 trials of lumiracoxib versus other NSAIDs also revealed no difference. The pooled odds ratios were: 1.16 (95% CI 0.82, 1.63); 1.66 (95% CI 0.84, 3.29); 0.95 (95% CI 0.52, 1.76) and 1.04 (95% CI 0.60, 1.80) for the APTC endpoint, myocardial infarction, stroke and cardiovascular death respectively.ConclusionsThe results suggest that there were no significant differences in cardiovascular outcomes between lumiracoxib and placebo or between lumiracoxib and other NSAIDs in patients with osteoarthritis. Wide confidence intervals mean that further research is needed in this area to confirm these findings.

Aspirin in Neurology

Aspirin is widely used for the prevention of recurrent stroke in patients with transient ischaemic attack (TIA) of arterial origin, because it is effective and inexpensive. Clopidogrel and the combination of aspirin and extended-release dipyridamole are more effective than aspirin, but are also much more expensive. No other antithrombotic regimens provide significant advantages over aspirin, although cilostazol and the novel platelet protease-activated receptor-1 antagonist, SCH 530348, are currently being evaluated. Numerous trials have examined the efficacy of antiplatelet drugs, primarily aspirin for prevention of vascular events in patients with a prior TIA or stroke. Although many were small and inconclusive, the Antiplatelet Trialists’ Collaboration (ATC) individual patient data meta-analysis reported that among more than 23000 patients (from 21 randomized controlled trials), antiplatelet therapy (usually aspirin) compared with placebo or untreated control continued for a mean of 29 months was associated with a 22% reduction in the odds of recurrent ischemic stroke, myocardial infarction (MI), or vascular death (17.8% versus 21.4%, P=0.001).

Cardio- and cerebrovascular safety of indacaterol vs formoterol, salmeterol, tiotropium and placebo in COPD

As COPD patients commonly suffer cardio- and cerebrovascular (CCV) co-morbidities, our purpose was to establish the CCV safety profile of indacaterol, a novel, inhaled, long-acting β(2)-agonist for COPD. The indacaterol clinical trial database comprised 4635 patients with moderate-to-severe COPD enrolled into studies of ≥6 months' duration treated with indacaterol, placebo or other bronchodilators (formoterol, salmeterol, tiotropium). Adverse events (AEs) were analysed overall and according to Anti-Platelet Trialists' Collaboration (APTC) criteria and baseline cardiovascular risk factors. A subset of patients had Holter monitoring. Compared with placebo, indacaterol did not increase the risk of CCV AEs; relative risks were not significantly different for indacaterol versus other treatments. In all treatment groups, including placebo, most CCV AEs occurred in patients with pre-existing cardiovascular risk factors. The risk of APTC events (e.g. myocardial infarction, stroke, cardiovascular-related death) was not significantly increased for indacaterol versus placebo. The incidence of notable QTc interval increases >60 ms was low with all active treatments (0-0.5%, versus 0.3% with placebo). Holter monitoring in the subset of patients receiving indacaterol, tiotropium or placebo showed no clinically relevant effect of indacaterol or tiotropium relative to placebo on the development of arrhythmias. The number of deaths adjusted for exposure was lower with all active treatments than with placebo, with a trend to reduced risk with indacaterol (relative risk 0.30, p = 0.054). The overall CCV safety profile of indacaterol was similar to placebo and comparable with other long-acting bronchodilators, providing reassurance for regular long-term use of indacaterol in COPD. Data for this analysis were pooled from three studies, registered at ClinicalTrials.gov as: NCT00393458, NCT00463567 and NCT00567996.

Response to Letter by Ernst and Lee

To the Editor: Drs Ernst and Lee1 provide a superficial interpretation of our systematic review, meta-analysis, and meta-regression. This is perhaps not surprising because our review does not provide results that agree with their unpublished umbrella review. Given the much smaller number of studies assessed in other reviews of acupuncture in poststroke treatment, it is not surprising that a different assessment has been made by Ernst and Lee. This does not negate the fact that our systematic review is more recent and incorporates a much larger set of relevant primary data for analysis. We address each point raised by the commentators. Ernst and Lee state that we missed previous relevant systematic reviews. In fact, we did not. The unreferenced …

Febuxostat: a new treatment for hyperuricaemia in gout

Febuxostat is a new non-purine xanthine oxidase inhibitor that is more potent than allopurinol 300 mg daily. In two Phase III trials, significantly more febuxostat-treated gout patients met the primary endpoint [serum urate (sUA) <6 mg/dl (<360 mumol/l) at the last three visits] (48 and 53% with 80 mg; 65 and 62% with 120 mg), compared with those receiving allopurinol 300 mg (22 and 21%; P < 0.001 in both studies). Febuxostat was more effective than allopurinol in the subset with impaired renal function; no dose adjustment is required in mild-to-moderate renal impairment. Long-term extension studies confirmed the efficacy and tolerability of febuxostat. In patients who achieved the sUA target of 6 mg/dl (360 mumol/l), the incidence of gout flares fell steadily and tophi resolved in many patients. The incidence of adverse events such as dizziness, diarrhoea, headache and nausea with febuxostat was similar to allopurinol. The incidence of cardiovascular side-effects (Antiplatelet Trialists Collaboration events) was numerically higher with febuxostat than with allopurinol, but this was not statistically significant. Co-administration of febuxostat with AZA or 6-mercaptopurine is not recommended. Prophylaxis (colchicine and/or NSAIDs) against acute attacks should be used for at least the first 6 months, since early mobilization flares were observed in the clinical trials. In conclusion, febuxostat is more effective than allopurinol 300 mg daily in reducing sUA levels <6 mg/dl (360 mumol/l), the target recommended by EULAR, and offers a new option for the long-term treatment of gout.

The Ideal Antiplatelet Drug for Stroke Prevention—Still Elusive

See related article, pages 1358–1363. Since the publication of the Antiplatelet Trialists Collaboration meta-analyses well over a decade ago1 showing a relative risk reduction of 25% from aspirin for all secondary vascular ischemic events in patients presenting with a variety of vascular disorders, there have been numerous attempts to improve on these modest benefits. Reducing the dose of aspirin reduced the risks of bleeding while maintaining therapeutic effectiveness,2 but using other antiplatelet drugs with different pharmacological actions such as ticlopidine, clopidogrel, or dipyrimadole have so far not produced any impresssive differences from those early data. The many attempts to pool the results of tens of thousands of patients using meta-analyses from the accumulating data of all these antiplatelet trials have also proven contentious. The problem with any meta-analysis is that the investigator must be selective, so introducing bias, but clearly should not include trials with obvious outdated methodology, incomplete data sets or where the patient cohort is so selective it can be generalized only to a minority of patients. This issue of Stroke includes a fresh attempt at an extensive meta-analysis of results from trials of the combination …

Risk of Cardiovascular Events in Patients Receiving Celecoxib: A Meta-Analysis of Randomized Clinical Trials

Some nonsteroidal anti-inflammatory drugs (NSAIDs), including cyclooxygenase-2 selective inhibitors, have been associated with increased cardiovascular (CV) events in recent clinical trials or observational studies. To determine whether the cyclooxygenase-2 selective inhibitor celecoxib affects CV risk, the incidence of CV events was analyzed in patients treated with celecoxib, placebo, or nonselective NSAIDs in the clinical trial database for celecoxib using defined Antiplatelet Trialists' Collaboration end points of nonfatal myocardial infarction, nonfatal stroke, and CV death. Patient data were derived from studies in osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, low back pain, and Alzheimer's disease. This meta-analysis included (1) 7,462 patients exposed to celecoxib 200 to 800 mg/day for 1,268 patient-years compared with 4,057 patients treated with placebo for 585 patient-years, and (2) 19,773 patients treated with celecoxib 200 to 800 mg/day for 5,651 patient-years compared with 13,990 patients treated with nonselective NSAIDs (diclofenac, ibuprofen, naproxen, ketoprofen, and loxoprofen) for 4,386 patient-years. CV events were adjudicated by a 3-member expert end point committee (WBW, JSB, PBG) blinded to treatment group and study. The incidence rates of the combined CV events were not significantly different between patients treated with celecoxib and placebo or between those treated with celecoxib and nonselective NSAIDs. Event rates were similar for adjudicated and nonadjudicated data. Dose of celecoxib, the use of aspirin, or the presence of CV risk factors did not alter these results. In conclusion, these analyses failed to demonstrate an increased CV risk with celecoxib relative to placebo and demonstrated a comparable rate of CV events with celecoxib treatment compared with nonselective NSAIDs.

Is aspirin effective in diabetic patients? No

Is aspirin effective in diabetic patients? No

Cardiovascular safety of lumiracoxib: A meta-analysis of all randomized controlled trials ≥1 week and up to 1 year in duration of patients with osteoarthritis and rheumatoid arthritis

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 > or =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 > or =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 > or =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).

Quelle place pour l’aspirine en prophylaxie antithrombotique veineuse ?

Since Virchow triade, it is well established that venous thrombosis is a multifactorial process involving various cellular and plasmatic protagonists. Aspirin antihrombotic efficacy seems not only due to its antiplatelet effects and thromboxane A2 synthesis inhibition. Anti-Platelet Trialists Collaboration metaanalysis stressed in 1994 the interest of aspirin treatment leading to 40% reduction of thrombosis relative risk. Regarding studies heterogeneity and outcomes criteria variety, its use in such context remains a matter of debate. Is the recent publication of PEP trial showing a significant decrease of pulmonary embolism mortality (0.6 versus 0.3%, p = 0.03) able to reinforce aspirin use in venous thrombosis prophylaxis? Were numerous and consecutive criticisms justified? Is there still a potential indication for aspirin in this setting? The experts of the last ACCP consensus conference recommended not to recommend aspirin in venous thrombosis prophylaxis with the highest level of evidence (grade A).