Stroke prevention with aspirin, warfarin and ximelagatran in patients with non-valvular atrial fibrillation: a systematic review and meta-analysis.
Lip GY, Edwards SJ.
Haemostasis Thrombosis and Vascular Biology Unit, University Department of Medicine, City Hospital, Birmingham, UK. g.y.h.lip@bham.ac.uk
Abstract
OBJECTIVE: To compare the effectiveness of aspirin, warfarin, and ximelagatran as thromboprophylaxis in patients with non-valvular atrial fibrillation (NVAF).
METHODS: Systematic review of randomised controlled trials in patients with NVAF treated with adjusted-dose warfarin and aspirin, fixed low-dose (FLD) warfarin, ximelagatran or placebo. Outcome measures studied were ischaemic stroke, systemic embolism, mortality and haemorrhage. Meta-analysis was performed using a fixed effects model.
RESULTS: We identified 13 trials (n=14,423 participants) of sufficient quality to be included in the analysis. Adjusted-dose warfarin significantly reduced the risk of ischaemic stroke or systemic embolism compared with aspirin (relative risk [RR] 0.59; 95% confidence interval [CI]: 0.40 to 0.86), FLD warfarin (RR 0.36; 95% CI: 0.23 to 0.58), or placebo (RR 0.33; 95% CI: 0.24 to 0.45). However, aspirin and placebo had a lower risk of major bleeding compared to warfarin (RR 0.58; 95% CI: 0.35 to 0.97 and RR 0.45; 95% CI: 0.25 to 0.82, respectively). The oral direct thrombin inhibitor, ximelagatran was as effective as adjusted-dose warfarin in the prevention of ischaemic strokes or systemic emboli (RR 1.04; 95% CI: 0.77 to 1.40) with less risk of major bleeding (RR 0.74; 95% CI: 0.56 to 0.96). Adjusted-dose warfarin significantly reduced mortality compared to placebo (RR 0.69; 95% CI: 0.53 to 0.89), but not for any of the other comparisons (aspirin: RR 0.87; 95% CI: 0.67 to 1.13; FLD warfarin: RR 1.11; 95% CI: 0.81 to 1.52; ximelagatran: RR 1.04; 95% CI: 0.86 to 1.26).
CONCLUSIONS: We have extended previous analyses, making this the largest systematic review and meta-analysis of thromboprophylaxis trial data in AF--and have included recent trials with the new oral direct thrombin inhibitor, ximelagatran. This systematic review confirms the superiority of anticoagulation therapy over aspirin as thromboprophylaxis in patients with NVAF. The new oral direct thrombin inhibitor, ximelagatran, appears as effective as adjusted-dose warfarin for the prevention of thromboembolic events in NVAF, with a lower risk of bleeding.
PMID: 16198396 [PubMed - indexed for MEDLINE]

Treatments for stroke prevention in atrial fibrillation: a network meta-analysis and indirect comparisons versus dabigatran etexilate.
Roskell NS, Lip GY, Noack H, Clemens A, Plumb JM.
Neil Roskell, RTI Health Solutions, Williams House, Manchester Science Park, Lloyd Street North, Manchester M15 6SE, UK. nroskell@rti.org
Abstract
Patients with atrial fibrillation at moderate to high risk of stroke are not always anticoagulated despite a lack of contraindications to vitamin K antagonists (VKAs) like warfarin. These patients are treated with aspirin, aspirin-clopidogrel combination therapy or even receive no thromboprophylaxis. The oral direct thrombin inhibitor, dabigatran etexilate 150 mg BID and 110 mg BID, might represent an alternative for these patients; however, no head-to-head clinical trial data exist versus these alternative treatments. A network meta-analysis (NMA) was performed to indirectly compare dabigatran etexilate with antiplatelets and placebo. Compared with placebo, dabigatran etexilate 150 mg BID was estimated to significantly reduce the risk of any stroke (ischaemic and haemorrhagic) by 75% (relative risk [RR] 0.25; 95% confidence interval [CI] 0.12-0.51), ischaemic stroke by 77% (RR 0.23; 95% CI 0.14-0.38), systemic embolism by 83% (RR 0.17; 95% CI 0.05-0.50) and mortality by 36% (RR 0.64; 95% CI 0.45-0.91). Dabigatran etexilate 150 mg BID was estimated to significantly reduce the risk of any stroke compared with aspirin monotherapy by 63% (RR 0.37; 95% CI 0.20-0.69) and aspirin plus clopidogrel by 61% (RR 0.39; 95% CI 0.21-0.72). Trends toward reduced risk with both dabigatran etexilate regimens were found for most clinical outcomes. Relative risk estimates of dabigatran etexilate versus adjusted-dose VKAs within the NMA were consistent with results from the head-to-head randomised trial of these two strategies. Indirect evidence suggests treatment with dabigatran etexilate offers benefit for the prevention of stroke, systemic embolism and mortality over antiplatelets and placebo. There was no indication of increased intracranial or extracranial haemorrhage with dabigatran etexilate compared to antiplatelet agents.
Association of Decreased Left Atrial Strain and Strain Rate with Stroke in Chronic Atrial Fibrillation.
Shih JY, Tsai WC, Huang YY, Liu YW, Lin CC, Huang YS, Tsai LM, Lin LJ.
Tainan Hospital Sin-Hua Branch, Tainan, Taiwan.
Abstract
BACKGROUND: The objective of this study was to investigate myocardial deformation of the left atrium (LA) assessed by two-dimensional speckle tracking echocardiography in patients with permanent atrial fibrillation (AF) and its value for risk stratification for stroke.
METHODS: We recruited 66 consecutive patients with permanent AF who were referred to our echocardiography laboratory for evaluation. These patients were divided into two groups according to the presence of previous stroke or not.
RESULTS: Peak positive longitudinal strain (LASp) during atrial filling, peak strain rate in the reservoir phase of LA (LASRr), and peak strain rate in the conduit phase (LASRc) were identified from LA strain and strain rate curves. The ratio of peak early filling velocity (E) of mitral inflow to early diastolic annulus velocity (E') of the medial annulus (E/E') was calculated. LASp (10.44% ± 4.2% vs. 15.69% ± 5.1%, P < .001), LASRr (1.09 ± 0.27 1/s vs. 1.37 ± 0.32 1/s, P = .001), and LASRc (-1.28 ± 0.38 1/s vs. -1.62 ± 0.43 1/s, P = .002) were significantly lower in patients with AF with stroke than those without stroke. By multivariate analysis controlling for age, LA volume index, and left ventricular ejection fraction, LASp (OR 0.787, 95% CI, 0.639-0.968, P = .023) and LASRr (OR 0.019, 95% CI, 0.001-0.585, P = .023) were independently associated with stroke but not LASRc, E', and E/E' ratio.
Stroke prevention and treatment
Marsh JD, Keyrouz SG.
Department of Internal Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA. jdmarsh@uams.edu
The decline in stroke incidence and mortality in the U.S. over the past 20 years is reaching a plateau, and the number of strokes may actually start to increase as the population ages. However, recent clinical trials have demonstrated that there are numerous opportunities to improve stroke prevention strategies and also opportunities to effectively intervene in and treat acute strokes. For patients with diabetes and for those with prior strokes or transient ischemic attacks, it has become evident that aggressive low-density lipoprotein lowering with statin medications will decrease the risk for total and fatal strokes. Optimal anticoagulation and antiplatelet therapy for primary and secondary stroke prevention in atrial fibrillation is being carefully defined. With numerous novel factor Xa and direct thrombin inhibitor drugs completing phase III clinical trials, it is likely that additional oral anticoagulant drugs will be clinically available for stroke prevention soon. Additionally, a major clinical trial is nearing completion that may resolve the role of carotid stenting and carotid endarterectomy in primary and secondary stroke prevention. There are recent notable advances in the acute treatment of stroke. It is likely that the time window for thrombolysis for appropriate patients with strokes will be increased from 3 to 4.5 h, permitting the inclusion of more patients in this treatment approach. There is ongoing investigation of intra-arterial thrombolysis and of acute intra-arterial thrombus extraction for treatment of selected patients with strokes. Unlike the progress in treatment of ischemic strokes, treatment of hemorrhagic stroke is progressing more slowly.

Is a systolic blood pressure target <140 mmHg indicated in all hypertensives? Subgroup analyses of findings from the randomized FEVER trial.
Zhang Y, Zhang X, Liu L, Zanchetti A; for the FEVER Study Group.
Division of Hypertension, FuWai Hospital and Cardiovascular Institute, Chinese Academy of Medical Sciences, Beijing, China.
Abstract
Aims Major guidelines recommend lowering systolic blood pressure (SBP) to <140 mmHg in all hypertensives, but evidence is missing whether this is beneficial in (i) uncomplicated hypertensives, (ii) grade 1 hypertensives, and (iii) elderly hypertensives. Providing this missing evidence is important to justify efforts and costs of aggressive therapy in all hypertensives. Methods and results Felodipine Event Reduction (FEVER) was a double-blind, randomized trial on 9711 Chinese hypertensives, in whom cardiovascular outcomes were significantly reduced by more intense therapy (low-dose hydrochlorothiazide and low-dose felodipine) achieving a mean of 138 mmHg SBP compared with less-intense therapy (low-dose hydrochlorothiazide and placebo) achieving a mean of 142 mmHg. FEVER included older and younger patients, and patients with and without diabetes or cardiovascular disease. In the analyses here reported, Cox regression models assessed outcome differences between more and less-intense treatments in groups of patients with different baseline characteristics. Significant reductions in stroke were found in uncomplicated hypertensives (-39%, P = 0.002), in hypertensives with randomization SBP <153 mmHg (-29%, P = 0.03), and in elderly hypertensives (-44%, P < 0.001), when their SBP was lowered by more intense treatment. Significant reductions (between -29 and -47%, P = 0.02 to <0.001) were also found in all cardiovascular events and all deaths. Achieving mean SBP values <140 mmHg by adding a small dose of a generic drug prevented 2.1 (uncomplicated hypertensives) and 5.2 (elderly) cardiovascular events every 100 patients treated for 3.3 years. Conclusions These analyses provide strong support, missing so far, to guidelines recommending goal SBP <140 mmHg in uncomplicated hypertensives, individuals with moderately elevated BP and elderly hypertensives. The FEVER trial has been registered on www.clinicaltrials.gov, n. NCT01136863.
Hypertension, dietary salt intake, and the role of the thiazide-sensitive sodium chloride transporter NCCT.

A high salt intake in industrialized countries is an important cardiovascular risk factor. It remains at typically twice the maximum recommended levels of 5-6 g/day, and halving this would have enormous public health benefit in preventing stroke and cardiovascular disease. Salt homeostasis can also be affected pharmacologically by diuretic drugs that target mechanisms within the distal kidney nephron to cause salt wasting. Indeed, thiazide-type diuretics are among the most widely used agents in the management of hypertension and work by blocking NCCT, the NaCl-transporter in the distal nephron. The biology of this membrane transporter was not previously well understood until the discovery of the molecular basis of a rare familial form of hypertension called Gordon syndrome (pseudohypoaldosteronism type 2, PHAII). This has established that the NCCT transporter is dynamically regulated in the kidney by WNK kinases and a signaling cascade using a second kinase called SPAK. Common polymorphisms in the SPAK gene have recently been shown to affect blood pressure in human cohorts and removing its function lowers blood pressure in mice. The SPAK-deficient mouse actually has a phenotype reminiscent of Gitelman syndrome. This suggests that specific inhibitors of SPAK kinase may provide a novel class of diuretic drugs to lower blood pressure through salt wasting. The expectation is that SPAK inhibitors would mimic the on-target effects of thiazides but not their adverse off-target effects. An antihypertensive drug that could lower blood pressure with the efficacy of a thiazide without producing metabolic side effects such as hyperuricaemia or impaired glucose tolerance is therapeutically very attractive. It also exemplifies how data coming from the rare monogenic hypertension syndromes can together with genome-wide association studies in hypertension deliver novel druggable targets.
© 2010 Blackwell Publishing Ltd.