A Randomized Controlled Trial Comparing Apixaban With the Vitamin K Antagonist Phenprocoumon in Patients on Chronic Hemodialysis: The AXADIA-AFNET 8 Study.

Patients with non-valvular atrial fibrillation (NVAF) have a substantial risk of stroke and thromboembolism compared with age-matched people in sinus rhythm. This risk ranges from less than 1% to more than 20% per year depending on associated comorbidities and demographic characteristics (1). Thus, the prime challenge facing physicians caring for patients with NVAF is to identify patients at substantial risk for stroke and thromboembolism, and provide appropriate antithrombotic treatment whether as primary or secondary prevention. This has led to the development of stroke risk stratification schema, such as the CHADS2 score, whereby ‘high risk’ patients can be targeted for oral anticoagulation therapy; this is despite limitations of simple risk scores (2, 3). Until recently the vitamin K antagonists (VKAs) were the only orally administered agents able proven to lower the risk of stroke and mortality in patients with NVAF, although these benefits were balanced against small changes in the annual rate of major haemorrhage, including intracranial bleeding (4, 5). One recent ‘real world’ nationwide cohort analysis found that the net clinical benefit (balancing stroke against intracranial haemorrhage) was only negative for warfarin compared to no treatment in ‘truly low risk’ patients, defined using the ESC guidelines (1). Given the improvement in efficacy and safety with the new oral anticoagulants, the net clinical benefit is likely to be even greater. The absolute reduction in stroke risk attributable to oral anticoagulation highlights the effectiveness of anticoagulation, which is even greater amongst elderly subjects. Nonetheless, treatment with VKAs has important caveats. Indeed, the optimal anticoagulation intensity for patients with NVAF has been a subject of debate, although anticoagulation intensities with international normalised ratios (INRs) between 2.0 and 3.0 appear to provide the best protection from stroke and death, when balanced against the risk of bleeding (6, 7). Even with the optimal anticoagulation intensity established, keeping patients in the VKAs therapeutic range has not been an easy task. In general, implementation of evidence in practice has been proved slow and incomplete in the field of stroke prevention in AF. As a result, a large proportion of patients at high risk are either not treated or suboptimally treated with VKAs. Thus, it become crucial to evaluate the quality of anticoagulation and the time in therapeutic range (TTR) emerged as the most promising index. The TTR is the ratio of estimated duration of anticoagulation intensity within a pre-determined range to total duration, and Rosendaal et al. designed a method to calculate TTR based on the assumption that anticoagulation intensity shifts linearly between any two consecutive measurements (8). TTR is recognised as a marker of the quality of anticoagulation control in patients taking VKAs, and used to demonstrate the effectiveness of patient education and self-monitoring (9, 10). Moreover TTR has been used to appraise the quality of anticoagulation in the VKA arms of randomised clinical trials that evaluated the efficacy of novel antithrombotic drugs. In the latter setting it become apparent that even in the ideal environment of clinical trials the mean time spent in the therapeutic range rarely exceeds 65% (11). In the current issue of Thrombosis and Haemostasis, Gallagher et al. (12) evaluated the association between TTR and the risk of stroke and mortality, in a study cohort that included 37,907 AF patients from the UK General Practice Research Database. The large sample size allowed the authors to compare outcomes of VKA users with different percentages of time spent within therapeutic range. The authors concluded that good anticoagulation control was associated with a reduction in the risk of stroke versus no therapy, whilst TTR was a strong predictor of the risk of stroke. Indeed, poorer anticoagulation control was generally associated with a much larger risk of stroke (12). Previous studies have reported similar results regarding the importance of TTR on the outcome of VKA-treated patients with NVAF. For example, in an ancillary analysis of the ACTIVE W trial the benefit of anticoagulation compared with antiplatelet therapy was demonstrated only at medical centres where the average TTR was above 65% (the mean TTR for all patients in the study was 63.4%) (13). Similarly, a metaanalysis that included data from 21 studies and a total of 6,248 patients concluded that in patients with NVAF, the risk of ischaemic stroke with insufficient VKA anticoagulation (defined as INR 3) are significantly higher relative to patients with AF maintained within the recommended INR (14). Beyond the anticipated concluding remarks, the study by Gallagher et al. (12) has important unique points, including the use of data from the ‘real world’ practice. Until now, most data on the impact of TTR on the outcome of VKA-treated patients have come from the VKA arms of randomised clinical trials (15). Secondly, in this ‘real

Non-vitamin K oral anticoagulants (NOACs) have consistently demonstrated superior efficacy in terms of stroke prevention and safety in terms of bleeding over vitamin K antagonist (VKA) in patients with non-valvular atrial fibrillation (AF). The potential use of NOACs in AF patients requiring antiplatelet therapy (APT) has only been assessed in small meta-analyses reporting consistent benefits of NOACs over VKAs. However, the prescription costs of NOACs are higher than those of VKAs. The aim of his study was to estimate the cost-effectiveness (CE) of NOACs compared to VKAs in patients with non-valvular AF also requiring APT with the Dutch healthcare system used as a surrogate of many European healthcare systems. A decision tree was constructed to analyse the CE of NOACs compared to VKAs in patients with non-valvular AF with an indication for APT over a horizon of 1 year. Beside the base-case analysis, univariate probabilistic sensitivity and two sensitivity analyses were performed: first, we assessed the impact of VKA home monitoring; second, we varied the NOACs price assuming patent expiration. Use of NOACs instead of VKA is associated with a health gain of 0.0171 quality-adjusted life years (QALYs) and with an incremental cost of €357, resulting in an incremental cost-effectiveness ratio of €20919, which is almost equal to the generally accepted CE threshold of €20000 used in the Netherlands. The probability that NOACs are cost-effective at a conservative willingness-to-pay threshold of €20000 per QALY was 50%. Introducing home monitoring increased VKAs costs so much that NOACs became the dominant option (less costly and more effective). Price drops associated to patent expiration of NOACs increased its CE. This analysis suggests that the use of NOACs is a cost-effective alternative of VKAs in patients with AF needing APT. Our findings in the Netherlands healthcare system are probably consistent with other European populations.

Although vitamin K antagonists (VKAs) are effective for long-term thromboprophylaxis in atrial fibrillation (AF), their limitations have led to widespread underutilisation, especially in the developing world. Novel oral anticoagulants (NOACs) have emerged as promising alternatives to VKAs, although there are some particular considerations and challenges to their introduction in developing countries. This review summarises the current state of antithrombotic management of AF in the developing world, explores the early evidence for the NOACs and describes some of the special considerations that must be taken into account when considering the role of the NOACs within developing countries' health care systems. A literature search was conducted via PubMed and Google Scholar to find articles published in English between the years 2000 to 2014. Search terms used were "atrial fibrillation", "oral anticoagulants", "warfarin", "NOACs", "dabigatran", "rivaroxaban", "apixaban", "edoxaban", "time in therapeutic range", "International Normalized Ratio" "cost-effectiveness", "stroke", "adverse-drug reactions" and "drug-drug interactions", together with the individual names of developing countries as listed by the World Bank. We reviewed the results of randomized clinical trials, relevant retrospective and prospective studies, case-studies and review articles. Many developing countries lack or have sporadic data on the quality of AF management, making it difficult to anticipate the potential impact of NOACs in these settings. The utilisation of anticoagulants for AF appears highly variable in developing countries. Given the issues associated with VKA therapy in many developing countries, NOACs offer some potential advantages; however, there is insufficient evidence to advocate the widespread replacement of warfarin at present. VKAs may continue to have a role in selected patients or countries, especially if alternative monitoring strategies can be utilised. The evaluation of the introduction of NOACs should consider safety, budget concerns and the quality of oral anticoagulation care achieved by each country. Prospective registries will be important in developing countries to better elucidate the comparative safety, efficacy and cost-effectiveness of NOACs and VKAs as NOACs are introduced into practice.

Catheter ablation for atrial fibrillation (AF) is associated with a transitory increase in the risk of both thromboembolic and bleeding events. Evidence on the use of nonvitamin K antagonist oral anticoagulants (NOACs) in patients undergoing AF ablation mostly comes from small observational studies, underpowered to detect differences in clinical outcomes between NOACs and vitamin K antagonists (VKAs) treated patients. This updated meta-analysis aimed to determine the safety and efficacy of periprocedural anticoagulation with NOACs compared with VKAs in AF patients undergoing catheter ablation. We searched MEDLINE, Cochrane library, and web sources for randomized and observational studies comparing periprocedural treatment with NOACs and VKAs in patients undergoing AF ablation. The primary safety endpoint was major bleeding events, and the primary efficacy endpoint was thromboembolic events (a composite of systemic thromboembolism, transient ischemic attack, and stroke). A total of 29 studies with 12644 patients were included in the meta-analysis. Overall, patients on NOACs had a significantly lower risk of major bleeding compared to VKAs either in observational studies (Peto OR 0.68; 95% CI: 0.48-0.95; P=0.022; I2 =20%) or in RCTs (Peto OR 0.30; 95% CI: 0.14-0.62; P=0.001; I2 =28%). Uninterrupted NOACs reduced the risk of major bleeding when compared to uninterrupted VKAs (Peto OR 0.66; 95% CI: 0.45-0.96; P=0.028; I2 =1%), similarly, interrupted NOACs lowered the risk of major bleeding compared to interrupted VKAs (Peto OR 0.29; 95% CI: 0.13-0.66; P=0.003; I2 =0%; Pinteraction =0.076). The rate of thromboembolic complications was very low and did not significantly differ between the study groups either in observational studies (Peto OR 0.91; 95% CI: 0.49-1.67; P=0.755; I2 =0%) or in RCTs (Peto OR 0.14; 95% CI: 0.01-1.30; P=0.083; I2 =0%). Use of NOACs compared to VKAs significantly reduced the risk of bleeding in patients with AF ablation. Similarly, the risk of bleeding was lower with uninterrupted NOACs than with uninterrupted VKAs, and with interrupted NOACs than with interrupted VKAs. The rate of thromboembolic complications was extremely low in both study groups without any differences.

Patients with non-valvular atrial fibrillation (NVAF) receiving vitamin K antagonists (VKAs) with time in therapeutic international normalized ratio (INR) range (TTR) <70%, despite good adherence, are by guidelines recommended to switch to non-VKA oral anticoagulants (NOACs). The aim was to assess if patients are switched from VKA to NOAC when TTR is <70% in a real-world setting. Non-valvular atrial fibrillation patients receiving VKA (1 January 2010 to 31 December 2012) were identified in nationwide registries. Time in therapeutic range was calculated by the Rosendaal method by a minimum of three INR values. Time in therapeutic range of patients continuing VKA (non-switchers) were compared with patients switched from VKA to dabigatran or rivaroxaban (switchers), the only NOACs available at that time. Factors associated with switching were analysed in a multivariable logistic regression model. 7276 patients with NVAF receiving VKA were included; of these, 6437 (88.5%) patients continued VKA [57.9% male, median age 76.7 years (Q1-Q3 68.9-83.5)] and 839 (11.5%) switched to NOAC [54.0% male, median age 76.5 years (Q1-Q3 68.4-83.6)]. No significant differences in CHA2DS2-VASc and HAS-BLED scores were seen between the groups. The mean TTR for non-switchers was 64.0 [standard deviation (SD) 27.8] and 52.9 (SD 28.1) for switchers. Among non-switchers, 51% had a TTR <70% vs. 69% among switchers. 85% of patients with TTR <70%, were not switched contrary to recommendations. Time in therapeutic range <70% was associated with the switch [odds ratio 2.28, 95% confidence interval (1.92-2.72)]. A TTR below 70% was associated with switching from VKA to NOAC, yet by guidelines, most patients were still not switched.

ObjectivesTo examine the characteristics and persistence in patients newly initiated with oral anticoagulants (OACs) for stroke prevention in non-valvular atrial fibrillation (NVAF).DesignCohort study in Clinical Practice Research Datalink.SettingUK primary care.Participants15 242 patients with NVAF newly prescribed apixaban, rivaroxaban, dabigatran or vitamin K antagonists (VKAs) between 1 December 2012 and 31 October 2014. 13 089 patients were OAC naïve.Outcome measuresPatient characteristics and risk of non-persistence compared to apixaban using Cox regression models over the entire follow-up and using a time-partitioned approach to handle non-proportional hazards.ResultsAmong the OAC naïve patients, VKAs were most common (78.1%, n=10 218), followed by rivaroxaban (12.1%, n=1589), dabigatran (5.7%, n=741) and apixaban (4.1%, n=541). High baseline stroke risk (CHA2DS2VASc ≥2) ranged from 80.2% (dabigatran) to 88.4% (apixaban and rivaroxaban). History of stroke and bleeding was the highest among apixaban (23.7% and 31.6%) and lowest among VKA patients (15.9% and 27.5%). Across the entire follow-up period, adjusting for differences in characteristics, there was no evidence of a difference in non-persistence between VKA and apixaban (HR 0.92 (95% CI 0.68 to 1.23)). Non-persistence was higher with dabigatran (HR 1.67 (1.20 to 2.32)) and rivaroxaban (HR 1.41 (1.02 to 1.93)) than apixaban. Using the partitioned approach, non-persistence was lower with VKA (HR 0.33 (0.22 to 0.48)), and higher with dabigatran (HR 1.65 (1.08 to 2.52)) compared to apixaban in the first 2 months of follow-up. After 2 months, non-persistence was higher with VKA (HR 1.70 (1.08 to 2.66)) and dabigatran (HR 2.10 (1.30 to 3.41)). Pooling OAC naïve and experienced patients, non-persistence was also higher with rivaroxaban compared to apixaban after 2 months of follow-up (HR 1.69 (1.19 to 2.39)).ConclusionsObserved differential prescribing of OACs can result in channelling bias in comparative effectiveness research. Persistence patterns changed over follow-up time, but there are indications of improved persistence rates with apixaban over other OACs in the UK. A larger study with longer follow-up is needed to corroborate findings. This study is registered on ClinicalTrials.gov (NCT02488421).

SAMe-TT2R2 in tunisian population: Results from the NATURE AF registry

Objective: The optimal anticoagulation strategy for patients with bioprosthetic valves and atrial fibrillation remain uncertain. Thus, we conducted a meta-analysis using updated evidence comparing direct anticoagulants (DOAC) and vitamin K antagonist (VKA) in patients with bioprosthetic valves and atrial fibrillation. Methods: MEDLINE and EMBASE were searched through March, 2021 to identify randomized control trials (RCT) and observational studies that investigated the outcomes of DOAC and VKA in patients with bioprosthetic valves and atrial fibrillation. The outcomes of interest were all-cause death, major bleeding, and stroke or systemic embolism. Results: Our analysis included 4 RCTs and 6 observational studies which enrolled a total of 6,405 patients with bioprosthetic valves and atrial fibrillation assigned to the DOAC group (n =2,142) and VKA (n =4,263). Pooled analysis demonstrated the similar rates of all-cause death (HR [95% confidence interval [CI]] =0.90 [0.77-1.05]; P =0.18; I 2 =0%)between the DOAC and VKA groups. However, the rates of major bleeding were significantly lower in the DOAC group compared to the VKA group (HR [95% CI] =0.66 [0.48-0.89]; P =0.006; I 2 =0%) (Figure), while the rates of stroke or systemic embolism were similar (HR [95% CI] =0.72 [0.44-1.17]; P =0.18; I 2 =39%). Conclusion: DOAC was associated with lower rates of major bleeding without increasing the risk of stroke or systemic embolism or all-cause death compared to VKA in patients with bioprosthetic valves and atrial fibrillation.

Introduction: Direct oral anticoagulants (DOACs) are indicated for prevention of stroke in non-valvular atrial fibrillation (AF) and for both treatment and prevention of recurrence of venous thromboembolism (VTE). Very little is known about efficacy and safety of these agents in patients identifying as Black or African-American (AA), as landmark trials demonstrating their non-inferiority to vitamin K antagonists (VKAs) are notable for discrepancies in enrollment by patient’s race. As the primary efficacy and safety outcomes for both AF and VTE are similar, we hypothesized that the cumulative efficacy and safety of DOACs in AA patients would be similar to that of the general population. Methods: A systematic review was conducted of clinical trials that investigated the comparison between DOACs and VKAs in patients for both AF and VTE. The Mantel-Haenszel Method was used to estimate pooled risk ratios (RRs) and corresponding confidence intervals (CIs) for the efficacy and safety of DOACs in AAs compared to the general population. Primary efficacy outcome was defined as stroke or systolic embolism in AF or symptomatic, recurrent VTE. Primary safety outcome was defined as major bleeding in both AF and VTE. Results: Nine studies were used for meta-analysis, with 26 eliminated due to lack of randomization or subgroup data for AAs. A total of 80,688 of patients were analyzed with 1.67% being AA. Regarding efficacy, the RR for AAs using DOACs compared to VKAs was 0.98 (95% CI 0.62,1.55; I 2 =0%; p=0.94), while the RR for the entire population was 0.90 (CI 0.78,1.04; I 2 =41%; p=0.1). Regarding safety, the RR for AAs using DOACs compared to VKAs was 0.83 (CI 0.56,1.25; I 2 =0%; p=0.92), while the RR for the entire population was 0.78 (CI 0.65,0.93; I 2 =76%; p&lt;0.01). Conclusions: The use of DOACs versus VKAs in AF and VTE for AAs results in similar efficacy to the general population. DOACs are non-inferior to VKAs with respect to safety outcomes in AF and VTE for AAs. It is uncertain why superiority of safety outcomes seen in the general population are not seen in the AA population, and will require further studies.

Background Patients with atrial fibrillation (AF) and end-stage renal disease on chronic haemodialysis (HD) are at risk for thromboembolic and bleeding events. The safety and efficacy of direct oral anticoagulants (DOACs) compared with vitamin K antagonists (VKAs) in this population remains unclear. Purpose This systematic review and meta-analysis aimed to compare DOACs with VKAs in patients with AF on chronic HD with regards to cardiovascular mortality, all-cause mortality, ischaemic or uncertain type of stroke, and major or life-threatening bleeding. Methods We systematically searched PubMed, EMBASE, and Cochrane Library for randomised controlled trials (RCTs) comparing DOACs with VKAs in patients with AF on chronic HD from inception to February 2023 in accordance with PRISMA guidelines. Statistical analyses were performed using Review Manager 5.4.1. Heterogeneity was evaluated using I2 statistics. We performed the data extraction following the intention-to-treat principle. Results We selected three RCTs including 341 patients, of whom 176 (51.6%) were randomised to DOACs. Follow-up ranged from 174 days to 3.38 years. There was no significant difference between groups in terms of cardiovascular mortality (RR 1.35; 95% CI 0.71–2.60; p=0.36; I2=0%; Fig. 1A), all-cause mortality (RR 0.99; 95% CI 0.76–1.30; p=0.96; I2=11%; Fig. 1B), ischaemic or uncertain type of stroke (RR 0.52; 95% CI 0.18–1.48; p=0.22; I2=0%; Fig. 2A), or major or life-threatening bleeding (RR 0.69; 95% CI 0.42–1.14; p=0.15; I2=20%; Fig. 2B), with an overall low between-study heterogeneity. Conclusion In this meta-analysis, no significant difference was observed between DOACs and VKAs in cardiovascular mortality, all-cause mortality, ischaemic or uncertain type of stroke, nor major or life-threatening bleeding in patients with AF on chronic HD.Figure 1Figure 2

Direct oral anticoagulants (DOACs) are widely used in patients with atrial fibrillation and venous thromboembolism. The lack of the need for laboratory monitoring and a better safety than vitamin K antagonists (VKAs) has probably changed the quality of life of patients on these oral anticoagulants. This was a real-life prospective observational cohort study. The aim was to evaluate if a long-term treatment with DOACs could offer a better quality of life than VKAs. Moreover, age, gender, education level, time in therapeutic range for VKAs, taking medication once or twice a day for DOACs, the total daily number of medications and thrombotic and bleeding complications were considered as variables probably associated with the quality of life of these patients. Between January and December 2021, the Duke Anticoagulation Satisfaction Scale (DASS) 25-items was administered as an interview to patients on either VKAs or DOACs therapy. During the follow-up period, all of the patients were closely monitored to evaluate possible bleeding and thrombotic events. The analysis included 300 outpatients treated with VKAs and 254 treated with DOACs. In general, the quality of life was better in patients taking DOACs (DASS total score: DOACs = 44.7, 42.9-46.5 vs. VKAs = 51, 49.2-52.8, p < 0.0001) as the daily-life limitations, hassles and burdens and the psychological impact were less important than in patients on VKAs therapy. VKAs negatively influence the daily-life of the patients in terms of both less satisfaction and time-consuming tasks. DOACs confer a better quality of life even if some concerns emerge from not knowing how their therapy is working.

Oral anticoagulants (OACs) are first-line drugs for stroke prevention in patients with atrial fibrillation (AF). The introduction of new lines of therapy with direct oral anticoagulants (DOACs) has led to a decreased use of vitamin K antagonists (VKAs). Comparative analyses of DOACs in clinical trials are scarce and the comparator has mostly been warfarin. Their impact on health outcomes in observational studies has not always been consistent. The aim of this study is to evaluate the effectiveness and safety of DOACs and VKAs in patients with AF using Real-World Data (RWD). Population-based retrospective cohort study using RWD from actual practice. Period: January 2012-December 2020. Inclusion criteria: patients with AF who had not taken OACs in the previous 12 months. Exclusion criteria: <40 years, with severe mitral stenosis, or valvular heart disease or aortic and/or mitral valve procedures. Data source: The Andalusian Population Health Database, Spain. Outcome measures: a) Effectiveness: ischaemic stroke, transient ischaemic attack, systemic and pulmonary embolism, and death; b) Safety: gastrointestinal and intracranial haemorrhaging; Independent variables: age, sex, comorbidities, medication and health resource use, CHA2DS2-VASC, HAS-BLED, and analytical tests. Statistical analysis: crude incidence analysis, survival models, Kaplan-Meier, Cox regression analysis adjusted for possible confounding and paired analysis by propensity score matching.

Mechanical prosthetic heart valves: Quality of anticoagulation and thromboembolic risk. The observational multicenter PLECTRUM study

Catheter ablation has been established as a rhythm control strategy in selected patients with atrial fibrillation (AF) who have failed or wish to avoid anti-arrhythmic drugs. Uninterrupted oral anticoagulation with vitamin K antagonists (VKAs) peri-ablation is associated with a lower risk of thromboembolic and bleeding complications as compared to interrupted oral anticoagulation and bridging heparin. However, a substantial portion of patients with AF are treated with non-vitamin K antagonist oral anticoagulants (NOACs). Herein, we perform an in-depth review and comparison of three recent randomized trials of uninterrupted oral anticoagulation with NOACs vs VKAs in patients undergoing AF catheter ablation. Furthermore, we report pooled results of these randomized trials. The pooled incidence of major bleeding was significantly lower with NOACs as compared to VKAs (2% vs 4.9%, respectively; odds ratio [OR] 0.40; 95% confidence intervals [CI] 0.16-0.99). Similarly, cardiac tamponade was also reduced in the NOAC group (0.4% vs 1.5%; OR 0.27; 95% CI 0.07-0.97). Thromboembolic complications were not significantly different between groups. Overall, these findings support the 2017 HRS/EHRA/ECAS/APHRS/SOLAECE expert consensus statement's class I recommendation for uninterrupted NOAC use in patients undergoing AF catheter ablation.

Our study aimed to describe the efficacy and safety of oral anticoagulation (OAC) use in elderly patients (> or = 80 years-old) with atrial fibrillation (AF) and concomitant anaemia. Data for this study were sourced from AF Research Database (NCT03760874). AF patients aged ≥ 80 who received OAC treatment, both direct oral anticoagulant (DOAC) and vitamin K antagonist (VKA) were selected. Participants were categorized as anaemic and non-anaemic. The primary outcome was the occurrence of overall bleeding. The primary effectiveness outcome was the occurrence of thromboembolic events (a composite of ischemic stroke, transient ischemic attack and systemic embolism). The secondary safety and effectiveness outcomes were major, minor bleedings and mortality, respectively. A total of 958 patients were included in the study, 120 (12.5%) were anaemic; among them, 93 patients (76.6%) were treated with VKAs and 28 (23.3%) with DOAC. Kaplan-Meier curves for major bleedings showed significant differences between anemic- and non-anemic groups (log-rank p = 0.005). In multivariate analysis, among patients on OAC, anaemia was independently associated with major bleeding (HR 2.36; 95% IC 1.2-4.4; p = 0.006), intracranial hemorrhages (HR 3.81; 95% IC 1.35-10.7; p = 0.01) and minor bleedings (HR 2.40; 95%IC 1.1-5.2; p = 0.02); these associations were not confirmed in the DOACs subgroup. No difference in survival was shown between anaemic- and non-anaemic groups and among anaemic patients, between DOAC and VKAs subgroups. Anaemic octogenarians with AF on OAC therapy showed a significantly increased risk of major bleedings, in particular ICH, and mortality compared to non-anaemic.