Summary

Background

Magnesium sulphate is a neuroprotective agent that might improve outcome after aneurysmal subarachnoid haemorrhage by reducing the occurrence or improving the outcome of delayed cerebral ischaemia. We did a trial to test whether magnesium therapy improves outcome after aneurysmal subarachnoid haemorrhage.

Methods

We did this phase 3 randomised, placebo-controlled trial in eight centres in Europe and South America. We randomly assigned (with computer-generated random numbers, with permuted blocks of four, stratified by centre) patients aged 18 years or older with an aneurysmal pattern of subarachnoid haemorrhage on brain imaging who were admitted to hospital within 4 days of haemorrhage, to receive intravenous magnesium sulphate, 64 mmol/day, or placebo. We excluded patients with renal failure or bodyweight lower than 50 kg. Patients, treating physicians, and investigators assessing outcomes and analysing data were masked to the allocation. The primary outcome was poor outcome—defined as a score of 4–5 on the modified Rankin Scale—3 months after subarachnoid haemorrhage, or death. We analysed results by intention to treat. We also updated a previous meta-analysis of trials of magnesium treatment for aneurysmal subarachnoid haemorrhage. This study is registered with controlled-trials.com (ISRCTN 68742385) and the EU Clinical Trials Register (EudraCT 2006-003523-36).

Findings

1204 patients were enrolled, one of whom had his treatment allocation lost. 606 patients were assigned to the magnesium group (two lost to follow-up), 597 to the placebo (one lost to follow-up). 158 patients (26·2%) had poor outcome in the magnesium group compared with 151 (25·3%) in the placebo group (risk ratio [RR] 1·03, 95% CI 0·85–1·25). Our updated meta-analysis of seven randomised trials involving 2047 patients shows that magnesium is not superior to placebo for reduction of poor outcome after aneurysmal subarachnoid haemorrhage (RR 0·96, 95% CI 0·86–1·08).

Interpretation

Intravenous magnesium sulphate does not improve clinical outcome after aneurysmal subarachnoid haemorrhage, therefore routine administration of magnesium cannot be recommended.

Funding

Netherlands Heart Foundation, UK Medical Research Council.

Patients with an acute basilar artery occlusion (BAO) have a high risk of long-lasting disability and death. Only limited data are available on functional outcome in elderly patients with BAO. Using data from the Basilar Artery International Cooperation Study, we aimed to determine outcomes in patients ≥75 years. Primary outcome measure was poor functional outcome (modified Rankin scale score 4–6). Secondary outcomes were death, insufficient vessel recanalization (defined as thrombolysis in myocardial infarction score 0–1) and symptomatic intracranial hemorrhage (SICH). Patients were divided into four age-groups, based on quartiles: 18–54, 55–64, 65–74, and ≥75 years. Outcomes were compared between patients ≥75 years and patients aged 18–54 years. Risk ratios with corresponding 95 % confidence intervals (CI) were calculated and Poisson regression analyses were performed to calculate adjusted risk ratios (aRR). We included 619 patients [18–54 years n = 153 (25 %), 55–64 years n = 133 (21 %), 65–74 years n = 171 (28 %), and ≥75 years n = 162 (26 %)]. Compared with patients aged 18–54 years, patients ≥75 years were at increased risk of poor functional outcome [aRR 1.33 (1.14–1.55)] and death [aRR 2.47 (1.75–3.51)]. Nevertheless, 35/162 (22 %, 95 % CI 15–28 %) of patients ≥75 years had good functional outcome. No significant differences between age groups were observed for recanalization rate and incidence of SICH. Although patients ≥75 years with BAO have an increased risk of poor outcome compared with younger patients, a substantial group of patients ≥75 years survives with a good functional outcome.

Electronic supplementary material

The online version of this article (doi:10.1007/s00415-012-6498-2) contains supplementary material, which is available to authorized users.

Female gender, age above 60 years, and an aneurysm larger than 5 mm or location on the posterior circulation are associated with a higher rupture risk of intracranial aneurysms. We hypothesized that this association is explained by a higher susceptibility to (one of) the eight trigger factors that were recently identified. We included 250 patients with aneurysmal subarachnoid hemorrhage. We calculated relative risks (RR) with 95% confidence intervals (95% CI) of aneurysmal rupture for trigger factors according to sex, age, site, and size of the aneurysms by means of the case-crossover design. None of the triggers except for physical exercise differed according to patient and aneurysm characteristics. In the hour after exposure to physical exercise: (1) patients over the age of 60 have a six-times-higher risk of rupture (RR 13; 95% CI 6.3−26) than those of 60 years of age and under (RR 2.3; 1.3−4.1); (2) aneurysms at the internal carotid artery have a higher risk than those at other locations (RR 17; 7.8−37), but this was only statistically significant when compared to anterior communicating artery aneurysms (RR 3.2; 1.6−6.1); (3) aneurysms 5 mm or smaller had a higher risk of rupture (RR 9.5; 4.6−19) than larger aneurysms (RR 2.4; 1.3−4.3); and (4) women and men had similar risks. A higher susceptibility to exercise might explain part of the higher risk of rupture in older patients. Why women and patients with aneurysms larger than 5 mm or posterior circulation aneurysms have a higher risk of rupture remains to be settled.

Delayed cerebral ischemia (DCI) is an important cause of poor outcome after aneurysmal subarachnoid hemorrhage (SAH). We studied differences in incidence and impact of DCI as defined clinically after coiling and after clipping in the International Subarachnoid Aneurysm Trial. We calculated odds ratios (OR) for DCI for clipping versus coiling with logistic regression analysis. With coiled patients without DCI as the reference group, we calculated ORs for poor outcome at 2 months and 1 year for coiled patients with DCI and for clipped patients without, and with DCI. With these ORs, we calculated relative excess risk due to Interaction (RERI). Clipping increased the risk of DCI compared to coiling in the 2,143 patients OR 1.24, 95% confidence interval (95% CI 1.01–1.51). Coiled patients with DCI, clipped patients without DCI, and clipped patients with DCI all had higher risks of poor outcome than coiled patients without DCI. Clipping and DCI showed no interaction for poor outcome at 2 months: RERI 0.12 (95% CI −1.16 to 1.40) or 1 year: RERI −0.48 (95% CI −1.69 to 0.74). Only for patients treated within 4 days, coiling and DCI was associated with a poorer outcome at 1 year than clipping and DCI (RERI −2.02, 95% CI −3.97 to −0.08). DCI was more common after clipping than after coiling in SAH patients in ISAT. Impact of DCI on poor outcome did not differ between clipped and coiled patients, except for patients treated within 4 days, in whom DCI resulted more often in poor outcome after coiling than after clipping.

Summary

Background

The MTHFR 677C→T polymorphism has been associated with raised homocysteine concentration and increased risk of stroke. A previous overview showed that the effects were greatest in regions with low dietary folate consumption, but differentiation between the effect of folate and small-study bias was difficult. A meta-analysis of randomised trials of homocysteine-lowering interventions showed no reduction in coronary heart disease events or stroke, but the trials were generally set in populations with high folate consumption. We aimed to reduce the effect of small-study bias and investigate whether folate status modifies the association between MTHFR 677C→T and stroke in a genetic analysis and meta-analysis of randomised controlled trials.

Methods

We established a collaboration of genetic studies consisting of 237 datasets including 59 995 individuals with data for homocysteine and 20 885 stroke events. We compared the genetic findings with a meta-analysis of 13 randomised trials of homocysteine-lowering treatments and stroke risk (45 549 individuals, 2314 stroke events, 269 transient ischaemic attacks).

Findings

The effect of the MTHFR 677C→T variant on homocysteine concentration was larger in low folate regions (Asia; difference between individuals with TT versus CC genotype, 3·12 μmol/L, 95% CI 2·23 to 4·01) than in areas with folate fortification (America, Australia, and New Zealand, high; 0·13 μmol/L, −0·85 to 1·11). The odds ratio (OR) for stroke was also higher in Asia (1·68, 95% CI 1·44 to 1·97) than in America, Australia, and New Zealand, high (1·03, 0·84 to 1·25). Most randomised trials took place in regions with high or increasing population folate concentrations. The summary relative risk (RR) of stroke in trials of homocysteine-lowering interventions (0·94, 95% CI 0·85 to 1·04) was similar to that predicted for the same extent of homocysteine reduction in large genetic studies in populations with similar folate status (predicted RR 1·00, 95% CI 0·90 to 1·11). Although the predicted effect of homocysteine reduction from large genetic studies in low folate regions (Asia) was larger (RR 0·78, 95% CI 0·68 to 0·90), no trial has evaluated the effect of lowering of homocysteine on stroke risk exclusively in a low folate region.

Interpretation

In regions with increasing levels or established policies of population folate supplementation, evidence from genetic studies and randomised trials is concordant in suggesting an absence of benefit from lowering of homocysteine for prevention of stroke. Further large-scale genetic studies of the association between MTHFR 677C→T and stroke in low folate settings are needed to distinguish effect modification by folate from small-study bias. If future randomised trials of homocysteine-lowering interventions for stroke prevention are undertaken, they should take place in regions with low folate consumption.

Funding

Full funding sources listed at end of paper (see Acknowledgments).

Subfebrile temperature or fever is present in about a third of patients on the first day after stroke onset and is associated with poor outcome. However, the temporal profile of this association is not well established. We aimed to assess the relationship between body temperature on admission as well as the change in body temperature from admission to 24 h thereafter and functional outcome and death. We analyzed data of 1,332 patients admitted within 12 h of stroke onset. The relation between body temperature on admission or the change in body temperature from admission to 24 h thereafter (adjusted for body temperature on admission) on the one hand and unfavorable outcome (death, or a modified Rankin Scale score >2) at 3 months on the other were expressed as odds ratio per 1.0°C increase in body temperature. Adjustments for potential confounders were made with a multiple logistic regression model. No relation was found between admission body temperature and poor outcome (aOR 1.06; 95% CI 0.85–1.32) and death (aOR 1.23; 95% CI 0.95–1.60). In contrast, increased body temperature in the first 24 h after stroke onset was associated with poor outcome (aOR 1.30; 95% CI 1.05–1.63) and death (aOR 1.51; 95% CI 1.15–1.98). An early rise in body temperature rather than high body temperature on admission is a risk factor for unfavorable outcome in patients with acute stroke.

Patients who recover from aneurysmal subarachnoid haemorrhage (SAH) often remain disabled or have persisting symptoms with a reduced quality of life (QoL). We assessed functional outcome and QoL 5 and 12.5 years after SAH. In a consecutive series of 64 patients with mean age at SAH of 51 years, initial outcome assessments had been performed at 4 and 18 months after SAH. At the initial and current outcome assessments, functional outcome was measured with the modified Rankin Scale (mRS) and QoL with the SF-36 and a visual analogue scale (VAS). We studied the change in outcome measurements over time. We used the non-parametric Wilcoxon test to compare differences in mRS grades and calculated differences with corresponding 95% confidence intervals in the domain scores of the SF-36 and the VAS. After 5 years, seven patients had died and five patients had missing data. Compared with the 4-month follow-up, the mRS had improved in 29 of the 52 patients, remained similar in 19 patients. The overall QoL (SF-36 domains and VAS score) was better. At 12.5 years an additional six patients had died. Compared to the 4-month study, 25 of the 46 remaining patients had improved mRS, 12 had remained the same and in nine patients the mRS had worsened. Between the 5 and the 12.5 years follow-up, the improvement in mRS had decreased but patients reported overall a better QoL. Among long-time survivors, QoL may improve more than a decade after SAH.

Background

Magnesium therapy probably reduces the frequency of delayed cerebral ischaemia (DCI) in subarachnoid haemorrhage (SAH) but uncertainty remains about the optimal serum magnesium concentration. We assessed the relationship between serum magnesium concentrations achieved with magnesium sulphate therapy 64 mmol/day and the occurrence of DCI and poor outcome in patients with SAH.

Methods

Differences in magnesium concentrations between patients with and without DCI and with and without poor outcome were calculated. Quartiles of last serum magnesium concentrations before the onset of DCI, or before the median day of DCI in patients without DCI, were related to the occurrence of DCI and poor outcome at 3 months using logistic regression.

Results

Compared with the lowest quartile of serum magnesium concentration (1.10–1.28 mmol/l), the risk of DCI was decreased in each of the higher three quartiles (adjusted odds ratio (OR) in each quartile 0.2; lower 95% CI 0.0 to 0.1; upper limit 0.8 to 0.9). The OR for poor outcome was 1.8 (95% CI 0.5 to 6.9) in the second quartile, 1.0 (95% CI 0.2 to 4.5) in the third quartile and 4.9 (95% CI 1.2 to 19.7) in the highest quartile.

Discussion

Magnesium sulphate 64 mmol/day results in a stable risk reduction of DCI over a broad range of achieved serum magnesium concentrations, and strict titration of the dosage therefore does not seem necessary. However, concentrations ⩽1.28 mmol/l could decrease the effect on DCI while concentrations ⩾1.62 might have a negative effect on clinical outcome.

Introduction

Pulmonary edema (PED) is a severe complication after aneurysmal subarachnoid hemorrhage (SAH). PED is often treated with diuretics and a reduction in fluid intake, but this may cause intravascular volume depletion, which is associated with secondary ischemia after SAH. We prospectively studied intravascular volume in SAH patients with and without PED.

Methods

Circulating blood volume (CBV) was determined daily during the first 10 days after SAH by means of pulse dye densitometry. CBV of 60-80 ml/kg was considered normal. PED was diagnosed from clinical signs and characteristic bilateral pulmonary infiltrates on the chest radiograph. We compared CBV, cardiac index, and fluid balance between patients with and without PED with weighted linear regression, taking into account only measurements from the first day after SAH through to the day on which PED was diagnosed. Differences were adjusted for age, bodyweight, and clinical condition.

Results

In total, 102 patients were included, 17 of whom developed PED after a mean of 4 days after SAH. Patients developing PED had lower mean CBV (56.6 ml/kg) than did those without PED (66.8 ml/kg). The mean difference in CBV was -11.3 ml/kg (95% CI, -16.5 to -6.1); adjusted mean difference, -8.0 ml/kg (95% CI, -14.0 to -2.0). After adjusting, no differences were found in cardiac index or fluid balance between patients with and without PED.

Conclusions

SAH patients developing pulmonary edema have a lower blood volume than do those without PED and are hypovolemic. Measures taken to counteract pulmonary edema must be balanced against the risk of worsening hypovolemia.

Trial registration

NTR1255.

Information on the prognosis of patients with transient ischaemic attack or moderately disabling ischaemic stroke associated with bilateral internal carotid artery (ICA) occlusion is scarce. We prospectively studied 57 consecutive patients (46 men; mean age 60 ± 9 years) with bilateral ICA occlusion who had presented with unilateral transient or moderately disabling cerebral or retinal ischaemic symptoms. We determined the long-term risk of recurrent ischaemic stroke and the composite outcome of stroke, myocardial infarction or vascular death. Four patients had a recurrent ischaemic stroke during a mean follow-up of 5.9 years, resulting in an annual stroke rate of 1.2% (95% confidence interval (CI) 0.3–3.1). Risk factors for recurrent ischaemic stroke could not be identified. Eighteen patients suffered a stroke, myocardial infarction or vascular death, resulting in an annual rate for major vascular events of 5.3% (95% CI 3.1–8.3). Age and a history of ischaemic heart disease were significant risk factors for future vascular events. Patients with transient or moderately disabling symptoms of cerebral or retinal ischaemia associated with bilateral ICA occlusion have a relatively low risk of recurrent ischaemic stroke. Although this study was not designed to compare conservative treatment with surgical intervention, the favourable outcome suggests that a policy of medical therapy and control of risk factors may be justified in these patients.

Introduction

Patients who have suffered aneurysmal subarachnoid haemorrhage (SAH) often have derangements in blood volume, contributing to poor outcome. To guide fluid management, regular assessments of volume status must be conducted. We studied the ability of nursing staff to predict hypovolaemia or hypervolaemia, based on their interpretation of available haemodynamic data.

Methods

In a prospective cohort study, intensive care unit and medium care unit nurses, currently treating patients with recent SAH, were asked to predict present volume status. For their assessment they could use all available haemodynamic parameters (for example, heart rate, blood pressure, fluid balance). The nurses' assessments were compared with the actual circulating blood volume (CBV), as measured daily with pulse dye densitometry during the first 10 days after SAH. Normovolaemia was defined as a CBV of 60 to 80 ml/kg body weight; hypovolaemia as CBV under 60 ml/kg; severe hypovolaemia as CBV under 50 ml/kg and hypervolaemia as CBV above 80 ml/kg.

Results

A total of 350 combinations of volume predictions and CBV measurements were obtained in 43 patients. Prediction of hypovolaemia had a sensitivity of 0.10 (95% confidence interval [CI] = 0.06 to 0.16) and a positive predictive value of 0.37 (95% CI = 0.23 to 0.53) for actual hypovolaemia. The prediction of hypervolaemia had a sensitivity of 0.06 (95% CI = 0.01 to 0.16) and a positive predictive value of 0.06 (95% CI = 0.02 to 0.19) for actual hypervolaemia. Mean CBV was significantly lower in instances considered hypervolaemic than in instances considered normovolaemic.

Conclusions

Assessment of haemodynamic condition in patients with SAH by intensive care unit or medium care unit nurses does not adequately predict hypovolaemia or hypervolaemia, as measured using pulse dye densitometry. Fluid therapy after SAH may require guidance with more advanced techniques than interpretation of usual haemodynamic parameters.

Background

The Paracetamol (Acetaminophen) In Stroke (PAIS) study is a phase III multicenter, double blind, randomized, placebo-controlled clinical trial of high-dose acetaminophen in patients with acute stroke. The trial compares treatment with a daily dose of 6 g acetaminophen, started within 12 hours after the onset of symptoms, with matched placebo. The purpose of this study is to assess whether treatment with acetaminophen for 3 days will result in improved functional outcome through a modest reduction in body temperature and prevention of fever.

The previously planned statistical analysis based on a dichotomization of the scores on the modified Rankin Scale (mRS) may not make the most efficient use of the available baseline information. Therefore, the planned primary analysis of the PAIS study has been changed from fixed dichotomization of the mRS to a sliding dichotomy analysis.

Methods

Instead of taking a single definition of good outcome for all patients, the definition is tailored to each individual patient's baseline prognosis on entry into the trial.

Conclusion

The protocol change was initiated because of both advances in statistical approaches and to increase the efficiency of the trial by improving statistical power.

Trial Registration

Current Controlled Trials [ISCRTN74418480]

Caveolin-1 (Cav-1) is a regulatory protein of the arterial wall, but its role in human atherosclerosis remains unknown. We have studied the relationships between Cav-1 abundance, atherosclerotic plaque characteristics and clinical manisfestations of atherosclerotic disease.We determined Cav-1 expression by western blotting in atherosclerotic plaques harvested from 378 subjects that underwent carotid endarterectomy. Cav-1 levels were significantly lower in carotid plaques than non-atherosclerotic vascular specimens. Low Cav-1 expression was associated with features of plaque instability such as large lipid core, thrombus formation, macrophage infiltration, high IL-6, IL-8 levels and elevated MMP-9 activity. Clinically, a down-regulation of Cav-1 was observed in plaques obtained from men, patients with a history of myocardial infarction and restenotic lesions. Cav-1 levels above the median were associated with absence of new vascular events within 30 days after surgery [0% vs. 4%] and a trend towards lower incidence of new cardiovascular events during longer follow-up. Consistent with these clinical data, Cav-1 null mice revealed elevated intimal hyperplasia response following arterial injury that was significantly attenuated after MMP inhibition. Recombinant peptides mimicking Cav-1 scaffolding domain (Cavtratin) reduced gelatinase activity in cultured porcine arteries and impaired MMP-9 activity and COX-2 in LPS-challenged macrophages. Administration of Cavtratin strongly impaired flow-induced expansive remodeling in mice.This is the first study that identifies Cav-1 as a novel potential stabilizing factor in human atherosclerosis. Our findings support the hypothesis that local down-regulation of Cav-1 in atherosclerotic lesions contributes to plaque formation and/or instability accelerating the occurrence of adverse clinical outcomes. Therefore, given the large number of patients studied, we believe that Cav-1 may be considered as a novel target in the prevention of human atherosclerotic disease and the loss of Cav-1 may be a novel biomarker of vulnerable plaque with prognostic value.

Background

Patients with a hemispheric infarct and massive space-occupying brain oedema have a poor prognosis. Despite maximal conservative treatment, the case fatality rate may be as high as 80%, and most survivors are left severely disabled. Non-randomised studies suggest that decompressive surgery reduces mortality substantially and improves functional outcome of survivors. This study is designed to compare the efficacy of decompressive surgery to improve functional outcome with that of conservative treatment in patients with space-occupying supratentorial infarction

Methods

The study design is that of a multi-centre, randomised clinical trial, which will include 112 patients aged between 18 and 60 years with a large hemispheric infarct with space-occupying oedema that leads to a decrease in consciousness. Patients will be randomised to receive either decompressive surgery in combination with medical treatment or best medical treatment alone. Randomisation will be stratified for the intended mode of conservative treatment (intensive care or stroke unit care). The primary outcome measure will be functional outcome, as determined by the score on the modified Rankin Scale, at one year.

Background

In patients with acute stroke, increased body temperature is associated with large lesion volumes, high case fatality, and poor functional outcome. A 1°C increase in body temperature may double the odds of poor outcome. Two randomized double-blind clinical trials in patients with acute ischemic stroke have shown that treatment with a daily dose of 6 g acetaminophen (paracetamol) results in a small but rapid and potentially worthwhile reduction of 0.3°C (95% CI: 0.1–0.5) in body temperature. We set out to test the hypothesis that early antipyretic therapy reduces the risk of death or dependency in patients with acute stroke, even if they are normothermic.

Methods/design

Paracetamol (Acetaminophen) In Stroke (PAIS) is a randomized, double-blind clinical trial, comparing high-dose acetaminophen with placebo in 2500 patients. Inclusion criteria are a clinical diagnosis of hemorrhagic or ischemic stroke and the possibility to start treatment within 12 hours from onset of symptoms. The study will have a power of 86% to detect an absolute difference of 6% in the risk of death or dependency at three months, and a power of 72% to detect an absolute difference of 5%, at a 5% significance level.

Discussion

This is a simple trial, with a drug that only has a small effect on body temperature in normothermic patients. However, when lowering body temperature with acetaminophen does have the expected effectiveness, 20 patients will have to be treated to prevent dependency or death in one.

Objective

To evaluate whether risk assessment scales can be used to identify patients who are likely to get pressure ulcers.

Design

Prospective cohort study.

Setting

Two large hospitals in the Netherlands.

Participants

1229 patients admitted to the surgical, internal, neurological, or geriatric wards between January 1999 and June 2000.

Main outcome measure

Occurrence of a pressure ulcer of grade 2 or worse while in hospital.

Results

135 patients developed pressure ulcers during four weeks after admission. The weekly incidence of patients with pressure ulcers was 6.2% (95% confidence interval 5.2% to 7.2%). The area under the receiver operating characteristic curve was 0.56 (0.51 to 0.61) for the Norton scale, 0.55 (0.49 to 0.60) for the Braden scale, and 0.61 (0.56 to 0.66) for the Waterlow scale; the areas for the subpopulation, excluding patients who received preventive measures without developing pressure ulcers and excluding surgical patients, were 0.71 (0.65 to 0.77), 0.71 (0.64 to 0.78), and 0.68 (0.61 to 0.74), respectively. In this subpopulation, using the recommended cut-off points, the positive predictive value was 7.0% for the Norton, 7.8% for the Braden, and 5.3% for the Waterlow scale.

Conclusion

Although risk assessment scales predict the occurrence of pressure ulcers to some extent, routine use of these scales leads to inefficient use of preventive measures. An accurate risk assessment scale based on prospectively gathered data should be developed.

What is already known on this topicThe incidence of pressure ulcers in hospitalised patients varies between 2.7% and 29.5%Guidelines for prevention of pressure ulcers base the allocation of labour and resource intensive measures on the outcome of risk assessment scalesMost risk assessment scales are based on expert opinion or literature review and have not been evaluatedThe sensitivity and specificity of risk assessment scales varyWhat this study addsThe effectiveness of available risk assessment scales is limitedUse of the outcome of risk assessment scales leads to inefficient allocation of preventive measures

Objective

To evaluate quantitatively articles that compared effects of second and third generation oral contraceptives on risk of venous thrombosis.

Design

Meta-analysis.

Studies

Cohort and case-control studies assessing risk of venous thromboembolism among women using oral contraceptives before October 1995.

Main outcome measures

Pooled adjusted odds ratios calculated by a general variance based random effects method. When possible, two by two tables were extracted and combined by the Mantel-Haenszel method.

Results

The overall adjusted odds ratio for third versus second generation oral contraceptives was 1.7 (95% confidence interval 1.4 to 2.0; seven studies). Similar risks were found when oral contraceptives containing desogestrel or gestodene were compared with those containing levonorgestrel. Among first time users, the odds ratio for third versus second generation preparations was 3.1 (2.0 to 4.6; four studies). The odds ratio was 2.5 (1.6 to 4.1; five studies) for short term users compared with 2.0 (1.4 to 2.7; five studies) for longer term users. The odds ratio was 1.3 (1.0 to 1.7) in studies funded by the pharmaceutical industry and 2.3 (1.7 to 3.2) in other studies. Differences in age and certainty of diagnosis of venous thrombosis did not affect the results.

Conclusions

This meta-analysis supports the view that third generation oral contraceptives are associated with an increased risk of venous thrombosis compared with second generation oral contraceptives. The increase cannot be explained by several potential biases.

What is already known on this topicThird generation oral contraceptives have been reported to increase the risk of venous thrombosis compared with second generation oral contraceptivesThe findings have been vigorously debated, with suggestions that the results can be explained by confounding or bias, or both.What this study addsWomen taking third generation oral contraceptives have a 1.7-fold increased risk of venous thrombosis compared with those taking second generation oral contraceptivesRisk is highest in first time usersThe biases were not large enough to account for the observed results

The cornerstone in clinical evidence of the relative efficacy of thienopyridines (clopidogrel, ticlopidine) versus aspirin in the secondary prevention of vascular disease is the Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events trial. This trial showed a modest benefit in the reduction of vascular events by clopidogrel. The results differed according to qualifying disorder: myocardial infarction, -3.7%; ischaemic stroke, +7.3%; and peripheral arterial disease, +23.8% (P = 0.042). Similar results were found for ticlopidine after brain ischaemia. The safety of clopidogrel appears to be similar to that of aspirin and better than that of ticlopidine. However, the recent report of thrombotic thrombocytopenic purpura in association with clopidogrel causes concern.