Michel Cucherat

University of Lyon, Lyons, Rhône-Alpes, France

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Publications (133)373.93 Total impact

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    ABSTRACT: Two enoxaparin dosage regimens are used as comparators to evaluate new anticoagulants for thromboprophylaxis in patients undergoing major orthopaedic surgery, but so far no satisfactory direct comparison between them has been published. Our objective was to compare the efficacy and safety of enoxaparin 3,000 anti-Xa IU twice daily and enoxaparin 4,000 anti-Xa IU once daily in this clinical setting by indirect comparison meta-analysis, using Bucher's method. We selected randomised controlled trials comparing another anticoagulant, placebo (or no treatment) with either enoxaparin regimen for venous thromboembolism prophylaxis after hip or knee replacement or hip fracture surgery, provided that the second regimen was assessed elsewhere versusthe same comparator. Two authors independently evaluated study eligibility, extracted the data, and assessed the risk of bias. The primary efficacy outcome was the incidence of venous thomboembolism. The main safety outcome was the incidence of major bleeding. Overall, 44 randomised comparisons in 56,423 patients were selected, 35 being double-blind (54,117 patients). Compared with enoxaparin 4,000 anti-Xa IU once daily, enoxaparin 3,000 anti-Xa IU twice daily was associated with a reduced risk of venous thromboembolism (relative risk [RR]: 0.53, 95% confidence interval [CI]: 0.40 to 0.69), but an increased risk of major bleeding (RR: 2.01, 95% CI: 1.23 to 3.29). In conclusion, when interpreting the benefit-risk ratio of new anticoagulant drugs versus enoxaparin for thromboprophylaxis after major orthopaedic surgery, the apparently greater efficacy but higher bleeding risk of the twice-daily 3,000 anti-Xa IU enoxaparin regimen compared to the once-daily 4,000 anti-Xa IU regimen should be taken into account.
    Thrombosis and haemostasis. 06/2014; 112(3).
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    ABSTRACT: To assess the efficacy of low-molecular-weight heparin (LMWH) venous thromboprophylaxis in patients with transient reduced mobility in the non-major orthopaedic setting. A meta-analysis was conducted using data from all available randomized trials comparing LMWH with placebo or no prophylactic treatment in patients with leg immobilization for fracture or soft-tissue injury of the lower limb or in patients undergoing knee arthroscopy. The primary endpoint was the incidence of major venous thromboembolic events (VTEs), including asymptomatic proximal deep-vein thrombosis, symptomatic VTEs, and VTE-related death. The Mantel-Haenszel method was used to generate the summary statistics for the overall effect of LMWH. Fourteen studies were included (4,726 patients). The weighted rate of major VTEs was estimated to be 2.9% (95% confidence interval [CI], 2.2% to 3.7%) without LMWH prophylaxis. Overall, a significant 68% reduction in the risk of major VTEs was observed with LMWH prophylaxis (relative risk [RR], 0.32; 95% CI, 0.20 to 0.51; P < .001). The treatment effect was not modified by the clinical setting, that is, distal lower limb injury (7 studies; 1,711 patients; RR, 0.42; 95% CI, 0.20 to 0.86) or knee arthroscopy (6 studies; 2,428 patients; RR, 0.27; 95% CI, 0.15 to 0.49). A nonsignificant 35% increase in the risk of major bleeding was observed in the LMWH prophylaxis group (RR, 1.35; 95% CI, 0.53 to 3.47). This meta-analysis indicates potential efficacy of LMWH in preventing thromboembolic events in patients with reduced mobility in the non-major orthopaedic setting compared with placebo or no treatment. However, the decision of whether to implement LMWH prophylaxis in each specific setting should also take into account the risk of VTEs in the absence of prophylaxis, the potential adverse effects of LMWH, and the cost. Level II, meta-analysis of Level II studies or Level I studies with inconsistent results.
    Arthroscopy The Journal of Arthroscopic and Related Surgery 05/2014; · 3.10 Impact Factor
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    ABSTRACT: To date no network meta-analysis (NMA) has accounted for baseline variations in viral load when assessing the relative efficacy of interventions for chronic hepatitis B (CHB). We undertook baseline-adjusted and unadjusted analyses using the same data to explore the impact of baseline viral load (BVL) on CHB treatment response. We searched Embase, Medline, Medline in Process and the Cochrane CENTRAL databases for randomised clinical trials (RCTs) of monotherapy interventions at licensed doses for use in CHB. Search strategies comprised CHB disease and drug terms (a combination of controlled vocabulary and free text terms) and also a bespoke RCT filter.The NMA was undertaken in WinBUGs using fixed and random effects methods, using data obtained from a systematic review. Individual patient data (IPD) from an entecavir clinical trial were used to quantify the impact of different baseline characteristics (in particular undetectable viral load (UVL) at 1 year) on relative treatment effect. Study level mean baseline values from all identified studies were used. Results were generated for UVL and presented as relative risks (RRs) and 95% credible intervals (CrIs) using entecavir as reference treatment. Overall, for all eight relevant interventions we identified 3,000 abstracts. Following full text review a total of 35 (including the contents of six clinical study reports) met the inclusion critera; 19 were in hepatitis B e antigen (HBeAg)-positive patients and 14 of the 19 contained outcome information of relevance to the NMA.Entecavir and tenofovir studies had heterogeneous patient populations in terms of BVL (mean values 9.29 and 8.65 log10 copies/ml respectively). After adjusting UVL for BVL using an informative prior based on the IPD analysis, the difference between entecavir and tenofovir was not statistically significant (RR 1.27, 95% CrI 0.96 to 1.47 - fixed effects). A similar conclusion was found in all sensitivity analyses. Adjusted tenofovir results were more consistent with observed clinical trial response rates. This study demonstrates the importance of adjusting for BVL when assessing the relative efficacy of CHB interventions in achieving UVL. This has implications for both clinical and economic decision making.
    Systematic reviews. 03/2014; 3(1):21.
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    ABSTRACT: Introduction.– Les essais randomisés en ouvert avec évaluation à l’aveugle (PROBE) permettent de limiter les biais d’évaluation par rapport aux études en ouvert simple, et sont parfois considérés comme aussi performants que les essais en double insu pour l’évaluation d’une stratégie thérapeutique. Cependant, si l’exagération de l’effet traitement liée aux études en ouvert est bien estimée, celle liée aux études PROBE n’a jamais été estimée. Nous avons cherché à quantifier le biais d’estimation lié au schéma d’études PROBE par rapport aux études en double insu à partir des essais évaluant un nouvel anticoagulant oral dans la fibrillation atriale. Me´thodes.– Tous les essais randomisés évaluant un nouvel anticoagulant par rapport au traitement de référence (anti-vitamine K) dans la prévention des événements emboliques dans la fibrillation atriale ont été inclus. Les bases de données consultées étaient MEDLINE, EMBASE, la library Cochrane, les sites web de l’ « US National Institute of Health, Meta-Embol » et les registres d’essais cliniques. Le critère principal d’évaluation et les critères secondaires étaient communs à toutes les études : accidents vasculaires cérébraux et embolies systémiques (AVC-ES), AVC hémorragiques, hémorragies majeures, hémorragies intracrâniennes, et mortalité cardiovas- culaire. L’effet traitement commun a été estimé pour les études PROBE et pour les études en double insu en combinant le logarithme des risques relatifs (RR) de chacune des études pondéré par l’inverse de la variance, selon un modèle à effets fixes ou à effets aléatoires. L’exagération de l’effet traitement a été estimée par le rapport des effets communs entre les études PROBE et les études en double insu ; le test d’interaction a été considéré comme significatif au seuil de 0,10. Re´sultats.– Au total, 8 études (59 238 patients) ayant comparé l’apixaban, l’edoxaban, le dabigatran, l’AZD0837, le ximelagatran, ou le rivaroxaban aux anti-vitamine K ont été incluses. De fac¸on globale, une réduction significative est observée avec les nouveaux anticoagulants oraux sur le critère principal AVC-ES (RR = 0,84 ; IC95 % 0,76–0,92) ainsi que sur tous les autres critères. L’estimation de l’efficacité des nouveaux anticoagulants oraux sur le critère primaire était plus importante à partir des études PROBE (5 essais, 22 947 patients ; RR = 0,76, IC95 % 0,65–0,90) comparé aux études en double insu (3 essais, 36 387 patients ; RR = 0,88, IC95 % 0,78–0,98), soit une majoration non significative de 16 % (test d’interaction p = 0,17). L’interaction était évidente pour les AVC hémorragiques (test d’interaction p = 0,05) avec une majoration de 72 % de l’effet traitement dans les études PROBE (RR = 0,32 ; IC95 % 0,20–0,49) par rapport études en double insu (RR = 0,55 ; IC95 % 0,41–0,73). Aucune autre interaction n’a été significative sur les autres critères. Conclusions.– Les études PROBE peuvent influencer les résultats d’un essai clinique en faveur du nouveau traitement. Cependant, l’influence d’un facteur confondant comme la classe pharmacologique ne peut être exclue. L’étude avec l’edoxaban dont le suivi est en cours, devrait permettre d’affiner les estimations. Il s’agit de rester prudent lors des comparaisons indirectes de ces molécules entre elles lors des méta-analyses en réseau.
    Revue d Épidémiologie et de Santé Publique 02/2014; 62:S38–S39. · 0.69 Impact Factor
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    ABSTRACT: Purpose To assess the efficacy of low-molecular-weight heparin (LMWH) venous thromboprophylaxis in patients with transient reduced mobility in the non-major orthopaedic setting. Methods A meta-analysis was conducted using data from all available randomized trials comparing LMWH with placebo or no prophylactic treatment in patients with leg immobilization for fracture or soft-tissue injury of the lower limb or in patients undergoing knee arthroscopy. The primary endpoint was the incidence of major venous thromboembolic events (VTEs), including asymptomatic proximal deep-vein thrombosis, symptomatic VTEs, and VTE-related death. The Mantel-Haenszel method was used to generate the summary statistics for the overall effect of LMWH. Results Fourteen studies were included (4,726 patients). The weighted rate of major VTEs was estimated to be 2.9% (95% confidence interval [CI], 2.2% to 3.7%) without LMWH prophylaxis. Overall, a significant 68% reduction in the risk of major VTEs was observed with LMWH prophylaxis (relative risk [RR], 0.32; 95% CI, 0.20 to 0.51; P < .001). The treatment effect was not modified by the clinical setting, that is, distal lower limb injury (7 studies; 1,711 patients; RR, 0.42; 95% CI, 0.20 to 0.86) or knee arthroscopy (6 studies; 2,428 patients; RR, 0.27; 95% CI, 0.15 to 0.49). A nonsignificant 35% increase in the risk of major bleeding was observed in the LMWH prophylaxis group (RR, 1.35; 95% CI, 0.53 to 3.47). Conclusions This meta-analysis indicates potential efficacy of LMWH in preventing thromboembolic events in patients with reduced mobility in the non-major orthopaedic setting compared with placebo or no treatment. However, the decision of whether to implement LMWH prophylaxis in each specific setting should also take into account the risk of VTEs in the absence of prophylaxis, the potential adverse effects of LMWH, and the cost. Level of Evidence Level II, meta-analysis of Level II studies or Level I studies with inconsistent results.
    Arthroscopy The Journal of Arthroscopic and Related Surgery 01/2014; · 3.10 Impact Factor
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    ABSTRACT: The well-known limitations of vitamin K antagonists (VKA) led to development of new oral anticoagulants (NOAC) in non-valvular atrial fibrillation (NVAF). The aim of this meta-analysis was to determine the consistency of treatment effects of NOAC irrespective of age, comorbidities, or prior VKA exposure. All randomized, controlled phase III trials comparing NOAC to VKA up to October 2012 were eligible provided their results (stroke/systemic embolism (SSE) and major bleeding (MB)) were reported according to age (≤ or >75 years), renal function, CHADS2 score, presence of diabetes mellitus or heart failure, prior VKA use or previous cerebrovascular events. Interactions were considered significant at p <0.05. Three studies (50,578 patients) were included, respectively evaluating apixaban, rivaroxaban, and dabigatran versus warfarin. A trend towards interaction with heart failure (p = 0.08) was observed with respect to SSE reduction, this being greater in patients not presenting heart failure (RR = 0.76 [0.67-0.86]) than in those with heart failure (RR = 0.90 [0.78-1.04]); Significant interaction (p = 0.01) with CHADS2 score was observed, NOAC achieving a greater reduction in bleeding risk in patients with a score of 0-1 (RR 0.67 CI 0.57-0.79) than in those with a score ≥2 (RR 0.85 CI 0.74-0.98). Comparison of MB in patients with (RR 0.97 CI 0.79-1.18) and without (RR 0.76 CI 0.65-0.88) diabetes mellitus showed a similar trend (p = 0.06). No other interactions were found. All subgroups derived benefit from NOA in terms of SSE or MB reduction. NOAC appeared to be more effective and safer than VKA in reducing SSE or MB irrespective of patient comorbidities. Thromboembolism risk, evaluated by CHADS2 score and, to a lesser extent, diabetes mellitus modified the treatment effects of NOAC without complete loss of benefit with respect to MB reduction.
    PLoS ONE 01/2014; 9(3):e91398. · 3.53 Impact Factor
  • J ROULAND, M CUCHERAT
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    ABSTRACT: Purpose For the evaluation of hyperaemia, differences in measurement process could exist between the trial in terms of definition, procedure, follow-up, etc. These differences make the comparison of absolute rate or proportion of patients with hyperaemia between the trial inappropriate and potentially confused by these differences. To avoid this problem, meta-analysis does not pool absolute proportion but odds ratio (or risk ratio). Odds ratios make implicit adjustment for this kind of difference by using the value observed in the control group as reference. The technique of “adjusted indirect comparisons” are based on this principle and were used to assess tolerability of a preservative free latanoprost compared to preserved prostaglandins for the treatment of open-angle glaucoma (OAG) and ocular hypertension (OH) Methods The meta-analysis was performed according to a protocol established before the start of the literature search and data analysis. It was conducted and reported according to the recent PRISMA statement. The main endpoints were intraocular pressure (IOP) and hyperaemia Results Twenty-one studies were included. The risk of hyperaemia was statistically significantly lower with preservative-free latanoprost than with polyquaternium-1-travoprost (OR [95%CI]: 0.24 , sofzia-travoprost (0.37 ), BAK-bimatoprost 0.03% (0.18 ]), BAK-bimatoprost 0.01% (0.27 ), BAK-tafluprost (0.18 ), BAK-travoprost (0.25 ) and BAK-latanoprost (0.52 [ Conclusion The risk of hyperaemia was found statistically significantly lower with preservative free latanoprost than with all the preserved prostaglandin analogs comprised in the metaanalysis. Commercial interest
    Acta ophthalmologica 08/2013; 91(s252). · 2.44 Impact Factor
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    ABSTRACT: AIM:: To assess the relative efficacy and tolerability of preservative-free latanoprost (T2345) compared with other prostaglandin analogues (PGA) for the treatment of open-angle glaucoma and ocular hypertension by adjusted indirect comparison meta-analysis. Randomized, controlled trials evaluating PGA for the treatment of open-angle glaucoma and ocular hypertension were identified by a systematic literature review in MEDLINE, EMBASE, and Cochrane Controlled Trials Register (up to December 2011) databases. The effect size for each treatment and heterogeneity were assessed by classical pairwise meta-analysis (direct comparisons). Adjusted indirect comparisons were performed by using Bucher method. The main endpoints were intraocular pressure (IOP) measured at 3 months and incidence of hyperemia. Twenty-one studies were included in the meta-analysis. No statistically significant differences in IOP at 3 months were seen between T2345 and travoprost [preserved with benzalkonium chloride (BAK), polyquaternium-1 or sofzia], and other BAK-preserved PGA: bimatoprost 0.03%, bimatoprost 0.01%, or latanoprost. T2345 was statistically significantly superior to BAK-tafluprost (mean difference: 0.47 mm Hg, 95% confidence interval, [-1.52;-0.28]). The risk of hyperemia was statistically significantly lower with T2345 than with all the other PGA. Indirect comparisons never found preservative-free latanoprost (T2345) to be statistically significantly inferior to the other PGA in terms of efficacy on IOP and showed statistically significant superiority over BAK-tafluprost. The risk of hyperemia was statistically significantly lower with T2345 than with all the other PGA.
    Journal of glaucoma 07/2013; · 1.74 Impact Factor
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    ABSTRACT: BACKGROUND: The prospective, randomised, open, blinded endpoint evaluation (PROBE) design has been proposed as a valid alternative to the double-blind (DB) design for trials comparing new oral anticoagulants (NOA) to INR-adjusted vitamin K antagonists in patients with non-valvular atrial fibrillation (NVAF). OBJECTIVES: To determine whether the observed treatment effects of NOA in patients with NVAF differ between PROBE/open-label trials and DB trials. METHODS: All phase II or III trials were eligible. Main efficacy and safety outcomes were stroke/systemic embolism (SSE) and major bleeding, respectively. Other outcomes included ischaemic SSE, haemorrhagic stroke, intracranial and extracranial bleeding, myocardial infarction, all-cause and cardiovascular mortality. Interaction (Cochran's χ(2) ) between PROBE and DB designs was tested. RESULTS: Thirteen studies (61,620 patients) were included. For SSE, a greater treatment effect of NOA versus INR-adjusted warfarin was observed in PROBE trials (RR 0.76, CI 0.65-0.89) compared to DB trials (RR 0.88, CI 0.78-0.98), but the interaction test was non-significant (p = 0.16). A significant 67% enhancement of treatment effect was found with PROBE/open-label trials compared to DB trials (interaction test: p = 0.05) for haemorrhagic stroke. No other interaction was significant. A non-significant interaction (p = 0.07) between oral direct thrombin inhibitors (RR 0.33; 0.22-0.51) and factor Xa inhibitors (RR 0.54; 0.40-0.72) was seen. No heterogeneity was found for any outcome. CONCLUSIONS: Our meta-analysis showed no significant interaction of study design for the main efficacy and safety outcomes. However, the non-significantly exaggerated reduction in SSE suggests interdependence of treatment effect and PROBE design, especially for haemorrhagic stroke. This article is protected by copyright. All rights reserved.
    Journal of Thrombosis and Haemostasis 05/2013; · 6.08 Impact Factor
  • Value in Health 05/2013; 16(3):A211-2. · 2.19 Impact Factor
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    ABSTRACT: Open-label, randomized controlled trials (RCTs) are subject to observer bias. If patient management is conducted without blinding, a difference between groups may be explained by other factors than study treatment. One factor may come from taking concomitant treatments with an efficacy on the studied outcomes. In type 2 diabetes, some antihypertensive or lipid-lowering drugs are effective against diabetic complications. We wanted to determine if these concomitant treatments were correctly reported in articles of RCTs on type 2 diabetes and if they might have influenced the outcome. We performed a systematic review using Medline, Embase, and the Cochrane Library (from January 1950 to July 2010). Open-label RCTs assessing the effectiveness of intensive blood-glucose control in type 2 diabetes were included. We chose five therapeutic classes with proven efficacy against diabetes complications: angiotensin-converting enzyme inhibitors (ACEIs), angiotensin II receptor antagonists (AIIRAs), fibrates, statins, and aspirin. Differences between concomitant treatments were considered statistically significant when p < 0.05. A total of eight open-label RCTs were included, but only three (37.5%) of them published concomitant treatments. In two studies (ACCORD and ADVANCE), a statistically significant difference was observed between the two groups for aspirin (p = 0.02) and ACEIs (p = 0.02). Few concomitant treatments were published in this sample of open-label RCTs. We cannot completely eliminate an observer bias for these studies. This bias probably influenced the results to an extent that has yet to be determined.
    BMC Medical Research Methodology 01/2013; 13(1):107. · 2.21 Impact Factor
  • M CUCHERAT, JF ROULAND
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    ABSTRACT: Purpose Adjusted indirect comparison (AIC) were performed to assess the relative efficacy and tolerability of T2345 compared to the other prostaglandin analogs for the treatment of open-angle glaucoma (OAG) and ocular hypertension (OH) Methods We performed a systematic literature review to identify randomized controlled trials evaluating prostaglandin analogs with or without preservative for the treatment of OAG and OH. AIC were conducted using Bucher’s method. The main endpoints was intraocular pressure (IOP) measured at 3 months and hyperhemia or ocular redness Results Twenty-one studies were included. No statistically significant difference in IOP were found between T2345 and BAK-free travoprost (mean difference and 95%CI 0.47 [-0.58;1.51]), bimatoprost (0.49 [-0.13;1.10]), bimatoprost 0.01% (0.19 [-0.69;1.06]), travoprost (.27 [-0.50;1.03]) and latanoprost (0.40 [-0.02;0.82]). T2345 was found statistically significantly superior to tafluprost (-0.90 [-1.52;-0.28]). For hyperhemia or ocular redness, T2345 was found statistically significantly superior to BAK-free travoprost (odds ratio 95% CI 0.30 [0.14;0.61]), bimatoprost (0.18 [0.10;0.33]), bimatoprost 0.01% (0.27 [0.13;0.56]), tafluprost (0.18 [0.05;0.65]), travoprost (0.25 [0.14;0.46]) and latanoprost (0.52 [0.31;0.86]) Conclusion In terms of efficacy on IOP, indirect comparisons never found T2345 statistically significantly inferior to the others. T2345 was found superior to tafluprost and an almost statistically significant trend was found in favor of bimatoprost for IOP. For hyperemia or ocular redness, T2345 latanoprost was statistically significantly superior to all the others Commercial interest
    Acta ophthalmologica 09/2012; 90(s249). · 2.44 Impact Factor
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    ABSTRACT: The UK Prospective Diabetes Study showed that metformin decreases mortality compared to diet alone in overweight patients with type 2 diabetes mellitus. Since then, it has been the first-line treatment in overweight patients with type 2 diabetes. However, metformin-sulphonylurea bitherapy may increase mortality. This meta-analysis of randomised controlled trials evaluated metformin efficacy (in studies of metformin versus diet alone, versus placebo, and versus no treatment; metformin as an add-on therapy; and metformin withdrawal) against cardiovascular morbidity or mortality in patients with type 2 diabetes. We searched Medline, Embase, and the Cochrane database. Primary end points were all-cause mortality and cardiovascular death. Secondary end points included all myocardial infarctions, all strokes, congestive heart failure, peripheral vascular disease, leg amputations, and microvascular complications. Thirteen randomised controlled trials (13,110 patients) were retrieved; 9,560 patients were given metformin, and 3,550 patients were given conventional treatment or placebo. Metformin did not significantly affect the primary outcomes all-cause mortality, risk ratio (RR)=0.99 (95% CI: 0.75 to 1.31), and cardiovascular mortality, RR=1.05 (95% CI: 0.67 to 1.64). The secondary outcomes were also unaffected by metformin treatment: all myocardial infarctions, RR=0.90 (95% CI: 0.74 to 1.09); all strokes, RR=0.76 (95% CI: 0.51 to 1.14); heart failure, RR=1.03 (95% CI: 0.67 to 1.59); peripheral vascular disease, RR=0.90 (95% CI: 0.46 to 1.78); leg amputations, RR=1.04 (95% CI: 0.44 to 2.44); and microvascular complications, RR=0.83 (95% CI: 0.59 to 1.17). For all-cause mortality and cardiovascular mortality, there was significant heterogeneity when including the UK Prospective Diabetes Study subgroups (I(2)=41% and 59%). There was significant interaction with sulphonylurea as a concomitant treatment for myocardial infarction (p=0.10 and 0.02, respectively). Although metformin is considered the gold standard, its benefit/risk ratio remains uncertain. We cannot exclude a 25% reduction or a 31% increase in all-cause mortality. We cannot exclude a 33% reduction or a 64% increase in cardiovascular mortality. Further studies are needed to clarify this situation.
    PLoS Medicine 04/2012; 9(4):e1001204. · 15.25 Impact Factor
  • Florent Aptel, Michel Cucherat, Philippe Denis
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    ABSTRACT: To evaluate the intraocular pressure (IOP)-lowering effects and tolerability of the 3 prostaglandin-timolol fixed combinations (PG-timolol FCs). Clinical trials comparing directly the PG-timolol FCs or comparing the PG-timolol FCs to their individual components were thoroughly searched. The main outcome measures were efficacy assessed by IOP (taken at 9 am, noon, 4 pm, and over the mean diurnal curve) change at 3 months (or after 1 to 6 months of treatment if no data were available at month 3) from baseline and tolerability assessed by the incidence of conjunctival hyperemia. Twenty trials were identified (n = 4684 patients). Intraocular pressure reduction was usually greater with the 3 PG-timolol FCs than the individual PG (mean difference [MD] 0.00 mmHg to 2.59 mmHg; p>0.1 to p<0.001). The incidence of hyperemia was significantly less with latanoprost- and bimatoprost-timolol FCs than with the individual PG (relative risk = 0.66 and 0.61; p = 0.05 and p<0.001). From direct comparisons, IOP reduction was significantly greatest with bimatoprost-timolol FC, at 9 am, 4 pm, and over the mean diurnal curve compared to latanoprost-timolol FC (MD = 0.90 mmHg to 1.48 mmHg; p<0.001) and at all time points compared to travoprost-timolol FC (MD = 0.66 mmHg to 0.90 mmHg; p<0.001). The incidence of hyperemia was not significantly less with latanoprost-timolol FC than with bimatoprost-timolol FC (relative risk = 1.32; p>0.1). The 3 PG-timolol FCs provide a greater IOP reduction and lower incidence of hyperemia than the 3 PGs alone. The direct comparisons suggest a greater efficacy of the bimatoprost-timolol FC compared with latanoprost- and travoprost-timolol FCs.
    European journal of ophthalmology 01/2012; 22(1):5-18. · 0.91 Impact Factor
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    Heinz Schneider, Emmanuel Maheu, Michel Cucherat
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    ABSTRACT: To perform a meta-analysis of randomized double-blind placebo-controlled clinical trials to assess the efficacy of a specific chondroitin sulfate preparation (Structum®, Laboratoires Pierre Fabre, Castres; France) as a symptom-modifying drug in osteoarthritis (OA) of the knee. A Medline search was conducted up to October 2010 and two articles reporting two trials were identified; one additional trial was identified through contacting the producer of Structum®. There was no evidence of heterogeneity across the trials and results were pooled using a fixed effects model. Pooled results demonstrated a modest, but significant effect of Structum® (1 g daily) over placebo on the reduction of pain during activity following a treatment period of 3-6 months of 6 mm (95% confidence interval (CI) -9.50, -1.72, p=0.005) on the visual analog scale (VAS) and a reduction in the algo-functional Index (AFI) by a weighted mean difference of -0.73 (95% CI -1.28 to -0.18, p=0.01). In addition, the pooled analysis demonstrated a statistically significant increase in OMERACT-OARSI responders in the Structum®-treated patients by 20% (RR of 1.20 (95% CI 1.06 to 1.36, p=0.003)), compared to placebo. These results demonstrate that this chondroitin sulfate preparation (Structum®) is effective on symptoms in patients with OA of the knee compared to placebo, and may therefore have a role in the management of patients with knee osteoarthritis of Kellgren-Lawrence grades II and III.
    The Open Rheumatology Journal 01/2012; 6:183-9.
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    ABSTRACT: Clinical trials are playing an increasingly crucial role in modern evidence based medicine, allowing for rigorous scientific evaluation of treatment strategies and validation of patient care. The results of clinical trials often form the rational basis from which physicians draw information used to adapt their therapeutic practices. Critical reading and analysis of trials involves the assessment of whether the available data provide enough credible evidence that the treatment will result in a clinically significant and relevant improvement. Evaluating the quality of a clinical trial is a process that draws upon sometimes complex methodological and statistical concepts, with which the reader should nonetheless be familiar in order to come to impartial conclusions regarding the raw data presented in the clinical trials. The goal of the current article is to review the methodological and statistical concepts required for the design and interpretation of clinical trials, so as to allow for a critical analysis of publications or presentations of clinical trials. The first section describes the major methodological principles of clinical trial design required for a rigorous evaluation of the treatment benefit, as well as the various pitfalls or biases that could lead to erroneous conclusions. The second section briefly describes the main statistical tests used in clinical trials, as well as certain situations that may increase the risk of false positive findings (type 1 error), such as multiple, subgroup, intermediate and non-inferiority analysis.
    Journal francais d'ophtalmologie 12/2011; 34(10):755-61. · 0.51 Impact Factor
  • Philippe Ryvlin, Michel Cucherat, Sylvain Rheims
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    ABSTRACT: Sudden unexpected death in epilepsy (SUDEP) represents the main cause of death in patients with refractory epilepsy. No evidence-based intervention to prevent SUDEP exists. We postulated that pooling data from randomised placebo-controlled trials in patients with refractory epilepsy might show a lower incidence of SUDEP in patients receiving antiepileptic drugs (AEDs) at efficacious doses than in those receiving placebo. We searched Medline and the Cochrane Library for randomised trials investigating any AED in the add-on treatment of drug-resistant epilepsy in adults. We extracted the number and causes of death in patients allocated to AEDs at doses that were more efficacious than placebo against seizures, AEDs at non-efficacious doses, and placebo. In our primary analysis, we compared the occurrence of definite or probable SUDEP between patients given efficacious AED doses and those given placebo using the Mantel-Haenszel method, with exclusion of trials with no event. Data of 33 deaths, including 20 deemed as SUDEP, were extracted from 112 eligible randomised trials. 18 deaths were classified as definite or probable SUDEP and two as possible SUDEP. Definite or probable SUDEP, all SUDEP, and all causes of death were significantly less frequent in the efficacious AED group than in the placebo group, with odds ratios of 0·17 (95% CI 0·05-0·57, p=0·0046), 0·17 (0·05-0·57, p=0·0046), and 0·37 (0·17-0·81, p=0·0131), respectively. Rates of definite or probable SUDEP per 1000 person-years were 0·9 (95% CI 0·2-2·7) in patients who received efficacious AED doses and 6·9 (3·8-11·6) in those allocated to placebo. Treatment with adjunctive AEDs at efficacious doses may have reduced the incidence of definite or probable SUDEP by more than seven times compared with placebo in patients with previously uncontrolled seizures. This result provides evidence in favour of active treatment revision for patients with refractory epilepsy. None.
    The Lancet Neurology 09/2011; 10(11):961-8. · 23.92 Impact Factor
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    ABSTRACT: Because of the lack of head-to-head adjunctive-therapy trials of antiepileptic drugs (AEDs) in refractory partial epilepsy, meta-analyses of placebo-controlled randomized controlled trials (RCTs) represent a potentially important source of evidence to guide treatment decisions. However, such indirect comparisons raise various methodologic issues that may hamper their relevance. All RCTs in adult refractory partial epilepsy were analyzed to assess whether efficacy outcomes are influenced by: characteristics of patients and trials ; use of last observation carried forward (LOCF) analysis; evaluation period (entire period versus maintenance period); and year of publication. A meta-analysis of these AEDs was then performed taking these factors into consideration. Sixty-three RCTs evaluating 20 AEDs were included. The following variables influenced efficacy estimates: (1) responder rates correlated positively with duration of the entire treatment period (p = 0.038); (2) response to placebo was significantly greater in the maintenance period than in the entire treatment period (p = 0.005); (3) responder rates increased over the years both for AEDs (p < 0.001) and for placebo (p = 0.001); (4) LOCF analysis overestimated responder rates for AEDs (p < 0.001) and for placebo (p = 0.001) compared with completer-based analysis, and the overestimation correlated positively with withdrawal rates (p < 0.001). A meta-analysis of available data showed large differences in efficacy ranking in relation to dose selection and type of analysis, but these were mostly nonsignificant due to statistical power limitations. Several methodologic issues hamper the relevance of indirect comparisons of AEDs in the adjunctive-therapy of refractory partial epilepsy. Some of these issues could be overcome by improved standardization in the reporting of efficacy outcomes.
    Epilepsia 02/2011; 52(2):219-33. · 3.96 Impact Factor
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    ABSTRACT: The prediction of the public health impact of a preventive strategy provides valuable support for decision-making. International guidelines for hypertension management have introduced the level of absolute cardiovascular risk in the definition of the treatment target population. The public health impact of implementing such a recommendation has not been measured. We assessed the efficiency of three treatment scenarios according to historical and current versions of practice guidelines on a Realistic Virtual Population representative of the French population aged from 35 to 64 years: 1) BP≥160/95 mm Hg; 2) BP≥140/90 mm Hg and 3) BP≥140/90 mm Hg plus increased CVD risk. We compared the eligibility following the ESC guidelines with the recently observed proportion of treated amongst hypertensive individuals reported by the Etude Nationale Nutrition Santé survey. Lowering the threshold to define hypertension multiplied by 2.5 the number of eligible individuals. Applying the cardiovascular risk rule reduced this number significantly: less than 1/4 of hypertensive women under 55 years and less than 1/3 of hypertensive men below 45 years of age. This was the most efficient strategy. Compared to the simulated guidelines application, men of all ages were undertreated (between 32 and 60%), as were women over 55 years (70%). By contrast, younger women were over-treated (over 200%). The global CVD risk approach to decide for treatment is more efficient than the simple blood pressure level. However, lack of screening rather than guideline application seems to explain the low prescription rates among hypertensive individuals in France. Multidimensional analyses required to obtain these results are possible only through databases at the individual level: realistic virtual populations should become the gold standard for assessing the impact of public health policies at the national level.
    PLoS ONE 01/2011; 6(3):e17508. · 3.53 Impact Factor
  • Michel Lièvre, Michel Cucherat
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    ABSTRACT: We updated the 2002 Antiplatelet Trialists' Collaboration meta-analysis of antiplatelet therapy to assess the effects of aspirin alone in the secondary prevention of different types of thrombotic arterial disease. Results of randomized, placebo-controlled trials of aspirin in patients with confirmed cardiovascular disease were abstracted and synthesized by the Mantel-Haenszel method. We defined three cardiovascular disease groups according to the qualifying disease at entry: coronary artery disease (CAD), cerebrovascular disease (CRVD), and peripheral arterial disease (PAD). Results are given as odds ratios (OR) and 95% confidence intervals (95% CI). Compared with placebo, aspirin decreased significantly the risk of all-cause death in CAD and CRVD (OR = 0.80, 95% CI 0.75-0.86 and 0.91, 95% CI 0.85-0.98, respectively), and of vascular events in CAD, CRVD, and PAD (OR = 0.71, 95% CI 0.67-0.76, 0.87, 95% CI 0.82-0.93, and 0.50, 95% CI 0.29-0.88, respectively). The risk of non-fatal stroke was decreased in the CAD, CRVD, and PAD (OR = 0.64, 95% CI 0.50-0.83, 0.81, 95% CI 0.74-0.89, and 0.26, 95% CI 0.07-0.94, respectively). The risk of non-fatal myocardial infarction was decreased significantly in the CAD and CRVD (OR = 0.59, 95% CI 0.53-0.67, and 0.63, 95% CI 0.48-0.84, respectively), but not in the PAD (OR = 0.43, 95% CI 0.15-1.25). Aspirin nearly doubled the risk of major bleeds (OR = 1.87, 95% CI 1.51-2.32 for all clinical conditions). This meta-analysis confirms that aspirin decreases the risk of thrombotic events in patients with confirmed disease of the coronary, cerebrovascular, or peripheral artery beds.
    Fundamental and Clinical Pharmacology 09/2009; 24(3):385-91. · 1.99 Impact Factor

Publication Stats

3k Citations
373.93 Total Impact Points

Institutions

  • 2004–2014
    • University of Lyon
      Lyons, Rhône-Alpes, France
  • 1997–2014
    • Claude Bernard University Lyon 1
      • • Laboratoire de biométrie et biologie evolutive (LBBE)
      • • Faculté de médecine
      Villeurbanne, Rhône-Alpes, France
  • 2013
    • Université Jean Monnet
      Saint-Étienne, Rhône-Alpes, France
    • Oxford Outcomes
      Oxford, England, United Kingdom
    • Universitair Ziekenhuis Leuven
      Louvain, Flanders, Belgium
  • 2011
    • French National Centre for Scientific Research
      • Laboratoire de Biométrie et Biologie Évolutive (LBBE)
      Lutetia Parisorum, Île-de-France, France
    • Universidad de Valparaíso (Chile)
      • Department of Pre Clinic
      Ciudad de Valparaíso, Valparaíso, Chile
  • 2009
    • Hôpital Paul-Brousse – Hôpitaux universitaires Paris-Sud
      Île-de-France, France
  • 2001–2008
    • Lyon Natecia Hospital
      Lyons, Rhône-Alpes, France
    • CHU de Lyon - Groupement Hospitalier Edouard Herriot
      Lyons, Rhône-Alpes, France
  • 2007
    • Centre Hospitalier Universitaire de Nice
      Nice, Provence-Alpes-Côte d'Azur, France
  • 2006
    • Hôpital Avicenne – Hôpitaux Universitaires Paris-Seine-Saint-Denis
      Bobigny, Île-de-France, France
  • 2004–2005
    • Bellevue University
      Bellevue, Nebraska, United States
  • 1998–2005
    • Hospices Civils de Lyon
      Lyons, Rhône-Alpes, France
  • 2003
    • CHU de Lyon - Service de Consultations et de Traitements Dentaires
      Lyons, Rhône-Alpes, France
  • 2002
    • Centre Hospitalier Universitaire de Saint-Étienne
      Saint-Étienne, Rhône-Alpes, France