Summary Background Oral anticoagulants are better than aspirin for secondary prevention after myocardial infarction and after cerebral ischaemia in combination with non-rheumatic atrial fibrillation. ...The European/Australasian Stroke Prevention in Reversible Ischaemia Trial (ESPRIT) aimed to determine whether oral anticoagulation with medium intensity is more effective than aspirin in preventing future vascular events in patients with transient ischaemic attack or minor stroke of presumed arterial origin. Methods In this international, multicentre trial, patients were randomly assigned within 6 months after a transient ischaemic attack or minor stroke of presumed arterial origin either anticoagulants (target INR range 2·0–3·0; n=536) or aspirin (30–325 mg daily; n=532). The primary outcome was the composite of death from all vascular causes, non-fatal stroke, non-fatal myocardial infarction, or major bleeding complication, whichever occurred first. In a post hoc analysis anticoagulants were compared with the combination of aspirin and dipyridamole (200 mg twice daily). Treatment was open, but auditing of outcome events was blinded. Primary analysis was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial (number ISRCTN73824458) and with ClinicalTrials.gov ( NCT00161070 ). Findings The anticoagulants versus aspirin comparison of ESPRIT was prematurely ended because ESPRIT reported previously that the combination of aspirin and dipyridamole was more effective than aspirin alone. Mean follow-up was 4·6 years (SD 2·2). The mean achieved INR was 2·57 (SD 0·86). A primary outcome event occurred in 99 (19%) patients on anticoagulants and in 98 (18%) patients on aspirin (hazard ratio HR 1·02, 95% CI 0·77–1·35). The HR for ischaemic events was 0·73 (0·52–1·01) and for major bleeding complications 2·56 (1·48–4·43). The HR for the primary outcome event comparing anticoagulants with the combination treatment of aspirin and dipyridamole was 1·31 (0·98–1·75). Interpretation Oral anticoagulants (target INR range 2·0–3·0) are not more effective than aspirin for secondary prevention after transient ischaemic attack or minor stroke of arterial origin. A possible protective effect against ischaemic events is offset by increased bleeding complications.
Essentials The association between chronic kidney disease and bleeding is unknown. We followed 10 347 subjects at high cardiovascular risk for bleeding events. Chronic kidney disease was associated ...with a 1.5-fold increased bleeding risk. Especially albuminuria rather than decreased kidney function was associated with bleeding events.
Background There are indications that patients with chronic kidney disease have an increased bleeding risk. Objectives To investigate the association between chronic kidney disease and bleeding in patients at high cardiovascular risk. Methods We included 10 347 subjects referred to the University Medical Center Utrecht (the Netherlands) from September 1996 to February 2015 for an outpatient visit with classic risk factors for arterial disease or with symptomatic arterial disease (Second Manifestation of Arterial disease SMART cohort). Patients were staged according to the KDIGO guidelines, on the basis of estimated glomerular filtration rate (eGFR) and albuminuria, and were followed for the occurrence of major hemorrhagic events until March 2015. Hazard ratios (HRs) with 95% confidence intervals (CIs) for bleeding were calculated with Cox proportional hazards analyses. Results The incidence rate for bleeding in subjects with chronic kidney disease was 8.0 per 1000 person-years and that for subjects without chronic kidney disease was 3.5 per 1000 person-years. Patients with chronic kidney disease (n = 2443) had a 1.5-fold (95% CI 1.2-1.9) increased risk of bleeding as compared with subjects without chronic kidney disease (n = 7904) after adjustment. Subjects with an eGFR of < 45 mL min
1.73 m
with albuminuria had a 3.5-fold (95% CI 2.3-5.3) increased bleeding risk, whereas an eGFR of < 45 mL min
1.73 m
without albuminuria was not associated with an increased bleeding risk (HR 1.3, 95% CI 0.7-2.5). Conclusion Chronic kidney disease is a risk factor for bleeding in patients with classic risk factors for arterial disease or with symptomatic arterial disease, especially in the presence of albuminuria.
High levels of activated protein–inhibitor complexes of the intrinsic coagulation proteins are associated with ischemic stroke (IS) but not with myocardial infarction (MI). This study was aimed at ...determining whether the antigen levels of coagulation factors(factor XII, FXII, and FXI and prekallikrein (PK)are associated with MI and IS, and whether this association is independent of levels of activated protein–inhibitor complexes.
The RATIO study included young women (< 50 years) with MI (N = 205)and IS (N = 175), and 638 healthy controls. Antigen levels of FXII, FXI and PK were measured and expressed as percentages of of those in pooled normal plasmas. Odds ratios (ORs) and corresponding 99% confidence intervals (CIs) were calculated for high levels (i.e. ≥ 90th percentile of controls) as measures of rate ratios.
After adjustment for potential confounders, high levels of FXII antigen were not associated with MI risk or IS risk(OR(MI) 1.18, 99% CI 0.51–2.74; ORIS 1.03, 9% CI 0.41–2.55). High levels of FXI antigen were slightly associated with an increase in MI risk (OR(MI) 1.55, 9% CI 0.74–3.21), whereas there was a substantial association with IS risk (ORIS 2.65, 9% CI 1.27–5.56). PK antigen was slightly associated with MI risk but not with IS risk(ORMI 1.54, 9% CI 0.67–3.52; ORIS 0.90, 9% CI 0.35–2.33). All associations remained similar after adjustment for levels of protein–inhibitor complexes.
Increased levels of FXI antigen were associated with an increase in IS risk, whereas they showed only a marginal association with MI risk. FXII antigen and PK antigen levels were not substantially associated with MI risk and IS risk.
Secondary ischaemia is a frequent cause of poor outcome in patients with subarachnoid haemorrhage (SAH). Its pathogenesis has been incompletely elucidated, but vasospasm probably is a contributing ...factor. Experimental studies have suggested that calcium antagonists can prevent or reverse vasospasm and have neuroprotective properties.
To determine whether calcium antagonists improve outcome in patients with aneurysmal SAH.
We searched the Cochrane Stroke Group Trials Register (last searched April 2006), MEDLINE (1966 to March 2006) and EMBASE (1980 to March 2006). We handsearched two Russian journals (1990 to 2003), and contacted trialists and pharmaceutical companies in 1995 and 1996.
Randomised controlled trials comparing calcium antagonists with control, or a second calcium antagonist (magnesium sulphate) versus control in addition to another calcium antagonist (nimodipine) in both the intervention and control groups.
Two review authors independently extracted the data and assessed trial quality. Trialists were contacted to obtain missing information.
Sixteen trials, involving 3361 patients, were included in the review; three of the studies were of magnesium sulphate in addition to nimodipine. Overall, calcium antagonists reduced the risk of poor outcome: the relative risk (RR) was 0.81 (95% confidence interval (CI) 0.72 to 0.92); the corresponding number of patients needed to treat was 19 (95% CI 1 to 51). For oral nimodipine alone the RR was 0.67 (95% CI 0.55 to 0.81), for other calcium antagonists or intravenous administration of nimodipine the results were not statistically significant. Calcium antagonists reduced the occurrence of secondary ischaemia and showed a favourable trend for case fatality. For magnesium in addition to standard treatment with nimodipine, the RR was 0.75 (95% CI 0.57 to 1.00) for a poor outcome and 0.66 (95% CI 0.45 to 0.96) for clinical signs of secondary ischaemia.
Calcium antagonists reduce the risk of poor outcome and secondary ischaemia after aneurysmal SAH. The results for 'poor outcome' depend largely on a single large trial of oral nimodipine; the evidence for other calcium antagonists is inconclusive. The evidence for nimodipine is not beyond all doubt, but given the potential benefits and modest risks of this treatment, oral nimodipine is currently indicated in patients with aneurysmal SAH. Intravenous administration of calcium antagonists cannot be recommended for routine practice on the basis of the present evidence. Magnesium sulphate is a promising agent but more evidence is needed before definite conclusions can be drawn.
Results of trials of aspirin and dipyridamole combined versus aspirin alone for the secondary prevention of vascular events after ischaemic stroke of presumed arterial origin are inconsistent. Our ...aim was to resolve this uncertainty.
We did a randomised controlled trial in which we assigned patients to aspirin (30–325 mg daily) with (n=1363) or without (n=1376) dipyridamole (200 mg twice daily) within 6 months of a transient ischaemic attack or minor stroke of presumed arterial origin. Our primary outcome event was the composite of death from all vascular causes, non-fatal stroke, non-fatal myocardial infarction, or major bleeding complication, whichever happened first. Treatment was open, but auditing of outcome events was blinded. Primary analysis was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial (number ISRCTN73824458) and with
ClinicalTrials.gov (NCT00161070).
Mean follow-up was 3·5 years (SD 2·0). Median aspirin dose was 75 mg in both treatment groups (range 30–325); extended-release dipyridamole was used by 83% (n=1131) of patients on the combination regimen. Primary outcome events arose in 173 (13%) patients on aspirin and dipyridamole and in 216 (16%) on aspirin alone (hazard ratio 0·80, 95% CI 0·66–0·98; absolute risk reduction 1·0% per year, 95% CI 0·1–1·8). Addition of the ESPRIT data to the meta-analysis of previous trials resulted in an overall risk ratio for the composite of vascular death, stroke, or myocardial infarction of 0·82 (95% CI 0·74–0·91). Patients on aspirin and dipyridamole discontinued trial medication more often than those on aspirin alone (470
vs 184), mainly because of headache.
The ESPRIT results, combined with the results of previous trials, provide sufficient evidence to prefer the combination regimen of aspirin plus dipyridamole over aspirin alone as antithrombotic therapy after cerebral ischaemia of arterial origin.
Previous studies have suggested that gadolinium enhancement of the wall of unruptured intracranial aneurysms on MR imaging may reflect aneurysm wall instability. However, all previous studies were ...cross-sectional. In this longitudinal study, we investigated whether aneurysm wall enhancement is associated with an increased risk of aneurysm instability.
We included all patients 18 years of age or older with ≥1 unruptured aneurysm from the University Medical Center Utrecht, the Netherlands, who were included in 2 previous studies with either 3T or 7T aneurysm wall MR imaging and for whom it was decided not to treat the aneurysm but to monitor it with follow-up imaging. We investigated the risk of growth or rupture during follow-up of aneurysms with and without gadolinium enhancement of the aneurysm wall at baseline and calculated the risk difference between the 2 groups with corresponding 95% confidence intervals.
We included 57 patients with 65 unruptured intracranial aneurysms. After a median follow-up of 27 months (interquartile range, 20-31 months), growth (
= 2) or rupture (
= 2) was observed in 4 of 19 aneurysms (21%; 95% CI, 6%-54%) with wall enhancement and in zero of 46 aneurysms (0%; 95% CI, 0%-8%) without enhancement (risk difference, 21%; 95% CI, 3%-39%).
Gadolinium enhancement of the aneurysm wall on MR imaging is associated with an increased risk of aneurysm instability. The absence of wall enhancement makes it unlikely that the aneurysm will grow or rupture in the short term. Larger studies are needed to investigate whether aneurysm wall enhancement is an independent predictor of aneurysm instability.
Background and aim:To update our 1996 review on the incidence of subarachnoid haemorrhage (SAH) and assess the relation of incidence with region, age, gender and time period.Methods:We searched for ...studies on the incidence of SAH published until October 2005. The overall incidences with corresponding 95% confidence intervals were calculated. We determined the relationship between the incidence of SAH and determinants by means of univariate Poisson regression.Results:We included 51 studies (33 new), describing 58 study populations in 21 countries, observing 45 821 896 person-years. Incidences per 100 000 person-years were 22.7 (95% CI 21.9 to 23.5) in Japan, 19.7 (18.1 to 21.3) in Finland, 4.2 (3.1 to 5.7) in South and Central America, and 9.1 (8.8 to 9.5) in the other regions. With age category 45–55 years as the reference, incidence ratios increased from 0.10 (0.08 to 0.14) for age groups younger than 25 years to 1.61 (1.24 to 2.07) for age groups older than 85 years. The incidence in women was 1.24 (1.09 to 1.42) times higher than in men; this gender difference started at age 55 years and increased thereafter. Between 1950 and 2005, the incidence decreased by 0.6% (1.3% decrease to 0.1% increase) per year.Conclusions:The overall incidence of SAH is approximately 9 per 100 000 person-years. Rates are higher in Japan and Finland and increase with age. The preponderance of women starts only in the sixth decade. The decline in incidence of SAH over the past 45 years is relatively moderate compared with that for stroke in general.
Abstract 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 topic Third generation oral contraceptives have been reported to increase the risk of venous thrombosis compared with second generation oral contraceptives The findings have been vigorously debated, with suggestions that the results can be explained by confounding or bias, or both. What this study adds Women taking third generation oral contraceptives have a 1.7-fold increased risk of venous thrombosis compared with those taking second generation oral contraceptives Risk is highest in first time users The biases were not large enough to account for the observed results
Type 2 diabetes is a condition associated with a state of low-grade inflammation caused by adipose tissue dysfunction and insulin resistance. High sensitive-CRP (hs-CRP) is a marker for systemic ...low-grade inflammation and higher plasma levels have been associated with cardiovascular events in various populations. The aim of the current study is to evaluate the relation between hs-CRP and incident cardiovascular events and all-cause mortality in high-risk type 2 diabetes patients.
Prospective cohort study of 1679 type 2 diabetes patients included in the Second Manifestations of ARTerial disease (SMART). Cox proportional hazard models were used to evaluate the risk of hs-CRP on cardiovascular events (composite of myocardial infarction, stroke and vascular mortality) and all-cause mortality. Hs-CRP was log-transformed for continuous analyses. Findings were adjusted for age, sex, BMI, current smoking and alcohol use, non-HDL-cholesterol and micro-albuminuria.
307 new cardiovascular events and 343 deaths occurred during a median follow-up of 7.8 years (IQR 4.2-11.1). A one unit increase in log(hs-CRP) was related to an increased vascular- and all-cause mortality risk (HR 1.21, 95% CI 1.01-1.46 and HR 1.26, 95% CI 1.10-1.45 respectively). No relation was found between log(hs-CRP) and myocardial infarction or stroke. The relations were similar in patients with and without previous vascular disease.
Low grade inflammation, as measured by hs-CRP, is an independent risk factor for vascular- and all-cause mortality but not for cardiovascular events in high-risk type 2 diabetes patients. Chronic low-grade inflammation may be a treatment target to lower residual cardiovascular risk in type 2 diabetes patients.
Myocardial infarction (MI) and ischemic stroke (IS) are acute forms of arterial thrombosis and share some, but not all, risk factors, indicating different pathophysiological mechanisms.
This study ...aims to determine if hypercoagulability has a differential effect on the risk of MI and IS.
We reviewed the results from the Risk of Arterial Thrombosis in Relation to Oral Contraceptives study, a population-based case-control study involving young women (< 50 years) with MI, non-cardioembolic IS and healthy controls. From these data, relative odds ratios (ORIS /ORMI ) and their corresponding confidence intervals for all prothrombotic factors that were studied in both subgroups were calculated.
Twenty-nine prothrombotic risk factors were identified as measures of hypercoagulability. Twenty-two of these risk factors (21/29, 72%) had a relative odds ratios > 1; for 12 (41%), it was > 2; and for 5 (17%), it was > 2.75. The five risk factors with the largest differences in associations were high levels of activated factor XI (FXI) and FXII, kallikrein, the presence of lupus anticoagulans, and a genetic variation in the FXIII gene.
In young women, prothrombotic factors are associated more with the risk of IS than with MI risk, suggesting a different role of hypercoagulability in the mechanism leading to these two diseases.
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