Associations of anaemia with bleeding and thrombotic complications in patients with atrial fibrillation treated with warfarin: a registry-based nested case-control study.

OBJECTIVES: We studied association of laboratory testing beyond the international normalised ratio (INR) with bleeding and stroke/transient ischaemic attack (TIA) outcomes in patients with atrial fibrillation treated with warfarin. DESIGN: This was a retrospective nested case-control study from the Finnish Warfarin in Atrial Fibrillation (FinWAF) registry (n=54 568), reporting the management and outcome in warfarin-anticoagulated patients. Associations of blood count test frequency and results were assessed together with risk of bleeding or stroke/TIA during 5-year follow-up. SETTING: National FinWAF registry, with data from all six hospital districts. Follow-up period for complications was 1 January 2007-31 December 2011. PARTICIPANTS: A total of 54 568 warfarin-anticoagulated patients. RESULTS: The number of patients with bleeding was 4681 (9%) and stroke/TIA episodes, 4692 (9%). In patients with bleeds, lower haemoglobin (within 3 months) preceded the event compared with the controls (median 126 vs 135 g/L; IQR 111-141 g/L vs 123-147 g/L, p<0.001), while patients with stroke/TIA had only modestly lower INR (median 2.2 vs 2.3; 1.8-2.6 vs 2.1-2.7, p<0.001). When the last measured haemoglobin was below the reference value (130 g/L for men, 120 g/L for women), the OR for a bleeding complication was 2.9 and stroke/TIA, 1.5. If the haemoglobin level was below 100 g/L, the complication risk increased further by 10-fold. If haemoglobin values were repeatedly (more than five times) low during the preceding 3 months, future OR was for bleeds 2.3 and for stroke/TIA 2.4. CONCLUSIONS: The deeper the anaemia, the higher the risk of bleeding and stroke/TIA. However, INR remained mainly at its target and only occasionally deviated, failing to detect the complication risk. Repeated low haemoglobin results, compatible with persistent anaemia, refer to suboptimal management and increased the complication risk in anticoagulated patients.

Radiotherapy-induced diffuse myocardial fibrosis in early-stage breast cancer patients - multimodality imaging study with six-year follow-up.

BACKGROUND: Breast radiotherapy (RT) induces diffuse myocardial changes, which may increase the incidence of heart failure with preserved ejection fraction. This study aimed to evaluate the early signs of diffuse fibrosis after RT and their evolution during a six-year follow-up. METHODS: Thirty patients with early-stage left-sided breast cancer were studied with echocardiography and electrocardiography (ECG) at baseline, after RT, and at three-year and six-year follow-up visits. Echocardiography analysis included an off-line analysis of integrated backscatter (IBS). ECG was analysed for fragmented QRS (fQRS). In addition, cardiac magnetic resonance (CMR) imaging was performed at the six-year control. The left ventricle 16-segment model was used in cardiac imaging, and respective local radiation doses were analysed. RESULTS: Regional myocardial reflectivity in inferoseptal segments increased by 2.02 (4.53) dB (p = 0.026) and the percentage of leads with fQRS increased from 9.2 to 16.4% (p = 0.002) during the follow-up. In CMR imaging, abnormal extracellular volume (ECV) and T1 mapping values were found with anteroseptal and apical localization in a median of 3.5 (1.00-5.75) and 3 (1.25-4.00) segments, respectively. A higher left ventricle radiation dose was associated with an increased likelihood of having changes simultaneously in CMR and echocardiography (OR 1.26, 95% Cl. 1.00-1.59, p = 0.047). CONCLUSIONS: After radiotherapy, progressive changes in markers of diffuse myocardial fibrosis were observed in a multimodal manner in ECG and echocardiography. Changes in echocardiography and abnormal values in CMR were localized in the septal and apical regions, and multiple changes were associated with higher radiation doses.

Transseptal snaring technique as a bailout from valvuloplasty balloon entrapment within a self-expanding valve: a case report.

Background: Transcatheter aortic valve replacement (TAVR) has become the dominant treatment strategy for severe aortic stenosis in patients with high and intermediate surgical risk. Although complications are significant cause of increasing mortality after TAVR and bailout techniques have been well established, we still encounter a rare complication without widely accepted bailout option. We present a rare complication of valvuloplasty balloon entrapment to a self-expanding valve strut with successful bailout. Case summary: A 71-year-old man complaining of dyspnoea underwent valve-in-valve TAVR for failed surgical aortic valve. However, he developed acute decompensated heart failure due to high residual aortic gradient (peak aortic velocity of 4.0 m/s and mean aortic gradient of 37 mmHg) on the 3rd day after TAVR. Computed tomography demonstrated underexpansion of transcatheter heart valve (THV) within the surgical valve. Therefore, urgent balloon valvuloplasty was performed. The balloon entrapment in the THV stent frame happened during the procedure. Percutaneous removal through transseptal approach using snaring technique was successfully performed. Discussion: Balloon entrapment within a THV is a rare complication and potentially requires urgent surgical removal. To our knowledge, this is the first report utilizing the snaring technique through transseptal approach for balloon entrapment within a THV. Through the current report, we highlight the utility and effectiveness of the transseptal snaring technique with using a steerable transseptal sheath. Moreover, this case shows the importance of the multiprofessional approach to resolve unexpected complications.

Novel findings of an old algorithm: PVC response "Atrial Pace'' initiates atrial arrhythmias in Abbott ICD and CRT-D devices.

BACKGROUND: Many algorithms have been developed to ensure the safety and accuracy of cardiac implantable electric devices (CIED). A specific algorithm designed to prevent pacemaker induced tachycardia (PMT) after a premature ventricular complex (PVC response) is available in all Abbott (former St. Jude Medical) CIED. However, a few case reports suggest that this algorithm may be proarrhythmic when programmed to Atrial Pace (A-Pace on PVC). METHODS: We analyzed the data of all (n = 333) Abbot implantable cardioverter defibrillator (ICD) and cardiac resynchronization defibrillator (CRT-D) devices followed remote using the Merlin.net Patient Care Network in our institute in 2020. Status of the PVC response algorithm A-Pace on PVC or Off was collected, and all atrial mode switch (AMS) episodes longer than 30 s were thoroughly evaluated. Data on clinical characteristics of the patients was collect from the electronic patient records. RESULTS: A total of 173 patients had A-Pace on PVC and twenty-five of them (14%) had at least one atrial high rate episode (AHRE) >30 s (AHRE) triggered by the action of this algorithm. The median PVC count was higher in patients who had algorithm triggered AHRE than in those with no algorithm-triggered AHRE (1.7% [IQR 0-3.2] vs. 0% [IQR 0-1.1], p < .0001). The major clinical characteristics were comparable in the two groups. CONCLUSION: The A-Pace on PVC setting was frequently used in our patients. Our study shows that a considerable number of patients had at least one AHRE triggered by the algorithm. The use of this algorithm should be carefully reconsidered.

Dynamic Integrated Backscatter Detects Radiotherapy-induced Cardiac Changes Better than Strain Analysis - A Prospective Three-year Study.

BACKGROUND/AIM: Radiotherapy (RT) related myocardial changes were analyzed by deformation imaging echocardiography in this study. PATIENTS AND METHODS: Ninety-nine breast cancer patients were studied at baseline, after chemotherapy, after RT, and three years after RT (3Y). Eighty patients received RT only, and twenty patients had right-sided breast cancer. Echocardiography included cyclic variation of the integrated backscatter in the septum (sCV) and posterior wall (pCV), global longitudinal strain (GLS), and left ventricular ejection fraction (LVEF). RESULTS: In patients with left-sided breast cancer, sCV declined from 11.3±3.3 dB at baseline to 10.3±2.9 dB after RT (p=0.001). No changes were observed after chemotherapy (p=0.211) or in patients with right-sided breast cancer after RT (p=0.977). No other parameters declined after RT. The decline in sCV was independently associated with the left anterior descending coronary artery radiation dose (ß=-0.290, p=0.020). CONCLUSION: In contrast to other parameters, sCV correlated with heart radiation dose.

A Higher Mean Heart Radiation Dose Induces Higher Frequency of Multiple Cardiac Changes.

BACKGROUND/AIM: Radiotherapy (RT) induces late changes in all cardiac structures. Most studies of early changes focus on individual parameters. PATIENTS AND METHODS: Data from eighty early-stage breast cancer patients at baseline, post-RT and three-year follow-up visit were assessed prospectively. Changes in ten cardiac parameters were collected including electrocardiogram (ECG), echocardiography, and biomarkers. A percentage of abnormal changes was calculated. RESULTS: The mean heart radiation dose (Dmean) was independently associated with the increased incidence of changes post-RT (ß=0.403, p<0.001) and at the three-year follow-up (ß=0.353, p=0.001). Each 1-Gray increase in Dmean increased the cardiac changes by 3.7% (95%CI=1.9-5.6%) after RT and 3.1% (95%CI=1.3, 4.9%) at the three-year follow-up. CONCLUSION: A higher cardiac radiation dose was independently associated with a higher incidence of changes in cardiac parameters. Multiparameter changes imply that the early phase after RT is already characterized by several overlapping cardiac changes.

3-Year Follow-Up of Radiation-Associated Changes in Diastolic Function by Speckle Tracking Echocardiography.

BACKGROUND: Radiation therapy (RT) results in myocardial changes consisting of diffuse fibrosis, which may result in changes in diastolic function. OBJECTIVES: The aim of this study was to explore RT-associated changes in left ventricular (LV) diastolic function. METHODS: Sixty chemotherapy-naive patients with left-sided, early-stage breast cancer were studied with speckle tracking echocardiography at 3 time points: prior to, immediately after, and 3 years after RT. Global and regional early diastolic strain rate (SRe) were quantified, as were parameters of systolic function. RESULTS: Regional changes in SRe, particularly the apical and anteroseptal segments, were observed over time and were more evident than global changes. The apical SRe declined from a median of 1.24 (interquartile range: 1.01 to 1.39) s-1 at baseline to 1.02 (interquartile range: 0.79 to 1.15) s-1 at 3 years of follow-up (p < 0.001). This decline was associated with the left ventricular maximal radiation dose (ß = 0.36, p = 0.007). The global SRe was <1.00 s-1 (SRedep) in 11 (18.3%) patients at baseline, 21 (35%) patients (p = 0.013) post-RT, and 17 (28.3%) patients (p = 0.051) at 3 years. SRedep post-RT was independently associated with baseline cardiac abnormalities (odds ratio: 0.26; 95% confidence interval: 0.08 to 0.84; p = 0.025); SRedep at 3 years of follow-up was associated with the baseline Charlson comorbidity index (odds ratio: 2.36; 95% confidence interval: 1.17 to 4.77; p = 0.017). Diastolic function abnormalities were evident even in patients with preserved global longitudinal strain at 3 years. CONCLUSIONS: RT resulted in changes in the SRe in the apical and anteroseptal segments over 3 years of follow-up. Changes in SRe apical segments were present even in patients with preserved systolic function and were independently associated with RT dose and cardiovascular comorbidities.

Atrial fibrillation burden, episode duration and frequency in relation to quality of life in patients with implantable cardiac monitor.

AIMS: To assess the relation between atrial fibrillation (AF) characteristics and health-related quality of life (QoL), and which AF characteristic had the greatest impact. METHOD: The AF characteristics burden (percentage of time in AF), duration and number of AF episodes/month were obtained from implantable cardiac monitors during the 2-month run-in period in 150 patients included in the randomized CAPTAF trial comparing early ablation and antiarrhythmic drug therapy. The QoL was measured by the General Health and Vitality dimensions of the 36-Item Short-Form Health Survey. AF characteristics were analysed continuously and in quartiles (Q1-Q4). RESULTS: Greater AF burden (p = 0.003) and longer AF episodes (p = 0.013) were associated with impaired QoL (Vitality score only) in simple linear regression analyses. Greater AF burden was, however, the only AF characteristic associated with lower QoL, when adjusted for sex, type of AF, hypertension, heart rate above 110 beats per minute during AF, and beta-blocker use in multiple linear regression analyses. For every 10% increase in AF burden there was a 1.34-point decrease of Vitality score (95% confidence interval (CI) -2.67 to -0.02, p = 0.047). The Vitality score was 12 points lower (95% CI -22.73 to -1.27, p = 0.03) in patients with an AF burden > 33% (Q4) versus those with < 0.45% (Q1), but only in unadjusted analysis. CONCLUSION: AF burden had a greater impact on QoL (Vitality), than the duration and number of AF episodes, corroborating that AF burden may be the preferred outcome measure of rhythm control in trials including relatively healthy AF populations.

Risk profile, antithrombotic treatment and clinical outcomes of patients in Nordic countries with atrial fibrillation - results from the GARFIELD-AF registry.

AIMS: The objective was to evaluate the clinical characteristics, management and two-year outcomes of patients with newly diagnosed non-valvular atrial fibrillation at risk for stroke in Nordic countries. METHODS: We examined the baseline characteristics, antithrombotic treatment, and two-year clinical outcomes of patients from four Nordic countries. RESULTS: A total of 52,080 patients were enrolled in the GARFIELD-AF. Out of 29,908 European patients, 2,396 were recruited from Nordic countries. The use of oral anticoagulants, alone or in combination with antiplatelet (AP), was higher in Nordic patients in all CHA2DS2-VASc categories: 0-1 (72.8% vs 60.3%), 2-3 (78.7% vs 72.9%) and ≥4 (79.2% vs 74.1%). In Nordic patients, NOAC ± AP was more frequently prescribed (32.0% vs 27.7%) and AP monotherapy was less often prescribed (10.4% vs 18.2%) when compared with Non-Nordic European patients. The rates (per 100 patient years) of all-cause mortality and non-haemorrhagic stroke/systemic embolism (SE) were similar in Nordic and Non-Nordic European patients [3.63 (3.11-4.23) vs 4.08 (3.91-4.26), p value = .147] and [0.98 (0.73-1.32) vs 1.02 (0.93-1.11), p value = .819], while major bleeding was significantly higher [1.66 (1.32-2.09) vs 1.01 (0.93-1.10), p value < .001]. CONCLUSION: Nordic patients had significantly higher major bleeding than Non-Nordic-European patients. In contrast, rates of all-cause mortality and non-haemorrhagic stroke/SE were comparable. CLINICAL TRIAL REGISTRATION: Unique identifier: NCT01090362. URL: http://www.clinicaltrials.gov. KEY MESSAGE: Nordic countries had significantly higher major bleeding than Non-Nordic-European countries. Rates of mortality and non-haemorrhagic stroke/SE were similar .

Seventh time lucky-A case report of multiple radiofrequency ablations for right ventricular outflow tract tachycardia.

Right ventricular outflow tachycardia initially refractory to radiofrequency ablation may be successfully treated after radiofrequency ablation at multiple sites. Repeated radiofrequency ablations as well as cooperation across borders with referral to an international center of excellence may be required in complicated cases.

ST2 levels increased and were associated with changes in left ventricular systolic function during a three-year follow-up after adjuvant radiotherapy for breast cancer.

OBJECTIVES: To search for biomarkers of RT-induced cardiotoxicity, we studied the behavior of ST2 during RT and three years after RT, and the associations with echocardiographic changes. MATERIALS AND METHODS: We measured soluble ST2 (ng/ml) in serum samples from 63 patients receiving RT for early breast cancer. Sampling and echocardiography were performed at baseline, after RT and at the three-year follow-up. Patients were grouped by >15% (group 1) and ≤15% (group 2) relative worsening in global longitudinal strain (GLS). RESULTS: ST2 levels tended to increase during RT, from a median (interquartile range; IQR) of 17.9 (12.4-22.4) at baseline to 18.2 (14.1-23.5) after RT (p = 0.075). By the three-year follow up, ST2 levels increased to 18.7 (15.8-24.2), p = 0.018. The increase in ST2 level was associated with worsening cardiac systolic function at three-year follow-up, GLS (rho = 0.272, p = 0.034) and left ventricular ejection fraction (LVEF) (rho = â”€0.343, p = 0.006). Group 1 (n = 14) had a significant increase in ST2 levels from 17.8 (12.3-22.5) at baseline to 18.4 (15.6-22.6) after RT, p = 0.035 and to 19.9 (16.0-25.1) three years after RT, p = 0.005. ST2 levels were stable in group 2 (n = 47): 17.8 (12.3-22.0) at baseline, 17.7 (12.6-23.5) after RT and 18.0 (15.5-22.4) at three years. CONCLUSION: ST2 may be useful for determining which patients are at risk for long-term cardiovascular toxicity following adjuvant breast cancer RT, but prospective clinical studies are needed to confirm this hypothesis.

Transforming growth factor beta 1 levels predict echocardiographic changes at three years after adjuvant radiotherapy for breast cancer.

BACKGROUND: Transforming growth factor beta 1 (TGF-ß1) and platelet-derived growth factor (PDGF) are cytokines involved in fibrotic processes causing radiotherapy (RT)-induced cardiovascular changes. We aimed to investigate the associations between TGF-ß1 and PDGF and the echocardiographic changes that occur during RT and during three-year follow-up. METHODS: The study included 63 women receiving adjuvant RT for early-stage breast cancer or ductal carcinoma in situ. Serum TGF-ß1 (ng/ml) and PDGF (ng/ml) levels were measured by enzyme-linked immunoassay and echocardiographic examination was performed before RT, after RT and at 3 years. Patients were grouped by biomarker behavior by a trajectory analysis. RESULTS: TGF-ß1 decreased from 19.2 (IQR 17.1-22.3) before RT to 18.8 (14.5-22.0) after RT (p = 0.003) and the decrease persisted at 17.2 (13.7-21.2) 3 years after RT (p = 0.101). PDGF decreased from 15.4 (12.6-19.1) before RT to 13.8 (11.7-16.2) after RT, p = 0.001, and persisted at 15.6 (10.4-18.4) at 3 years, p = 0.661. The TGF-ß1 level before RT (Spearman's rho 0.441, p < 0.001) and the three-year change in TGF-ß1 (rho = - 0.302, p = 0.018) correlated with global longitudinal strain (GLS) in echocardiography at 3 years. In trajectory analysis, two TGF-ß1 behavior groups were found. Group 1 had significantly higher TGF-ß1 levels before RT, 25.6 (22.3-28.6), than group 2, 17.8 (15.9-19.9), p < 0.001. In multivariable analysis, TGF-ß1 trajectory group 1 (ß = 0.27, p = 0.013), left-sided breast cancer (ß = 0.39, p = 0.001) and the use of aromatase inhibitors (ß = 0.29, p = 0.011) were significantly associated with a worsening in GLS from before RT to 3 years. CONCLUSION: An elevated pretreatment TGF-ß1 may predict RT-associated changes in echocardiography.

Left Ventricular Speckle Tracking Echocardiography Changes Among Early-stage Breast Cancer Patients Three Years After Radiotherapy.

BACKGROUND/AIM: Chest radiotherapy (RT) doubles late cardiac mortality. This study aimed to evaluate the evolution of cardiac changes in speckle tracking echocardiography during a three-year follow-up. MATERIALS AND METHODS: This prospective study included 81 chemotherapy-naïve early-stage breast cancer patients who were evaluated at baseline, immediately after RT and three years after RT. Sixty-one patients had left-sided (LSBC) and 20 right-sided breast cancer (RSBC). RESULTS: Global longitudinal strain (GLS) declined from baseline -18.0±3.3% to -17.0±3.0% (p=0.015) at the three-year follow-up examination. A decline over 15% (GLS15) was observed in 19 (27%) patients. GLS15 was independently associated with aromatase inhibitor use (ß=-1.977, p=0.001). In regional analysis, patients with LSBC had apical strain decline by 3.2±5.5% (p<0.001) and patients with RSBC showed basal rotation decline by 1.8° (-0.2°, 3.8°) (p=0.030). CONCLUSION: Even contemporary RT induced progressive global and regional decline in speckle tracking analysis. The regional changes complied with RT fields.

Adjuvant radiotherapy-induced cardiac changes among patients with early breast cancer: a three-year follow-up study.

Background: In this study, we evaluate the evolution of cardiac changes during a three-year follow-up after adjuvant breast radiotherapy (RT). Methods: Sixty patients with left-sided and 20 patients with right-sided early stage breast cancer without chemotherapy were included in this prospective study. Echocardiography and cardiac biomarkers were evaluated before, immediately after and 3 years after RT. Radiation doses to cardiac structures were calculated. Results: In echocardiography, left ventricle (LV) systolic measurements had impaired at 3 years compared to baseline: the mean global longitudinal strain (GLS) worsened from -18 ± 3 to -17 ± 3 (p = .015), LV ejection fraction from 62 ± 5% to 60 ± 4% (p = .003) and the stroke volume from 73 ± 16 mL to 69 ± 15 mL (p = .015). LV diastolic function was also negatively affected: the isovolumetric relaxation time was prolonged (p = .006) and the first peak of diastole decreased (p = .022). Likewise, left atrial (LA) measurements impaired. These changes in echocardiography were more prominent in left-sided than in right-sided patients. The concurrent aromatase inhibitor (AI) use was associated with GLS impairment. In all patients, the N-terminal pro-brain natriuretic peptide (proBNP) values were median (interquartile range) 74 (41-125) ng/L at baseline, 75 (41-125) ng/L at the end of RT and 96 (56-162) ng/L at 3 years (p < .001 from baseline to 3 years). However, proBNP did not increase in right-sided patients. Conclusion: During the 3-year follow-up after RT, negative subclinical changes in cardiac biomarkers and in LV systolic and diastolic function were observed. The measured changes were more pronounced in left-sided patients. In addition, AI use was associated with impaired cardiac systolic function.

Effect of Catheter Ablation vs Antiarrhythmic Medication on Quality of Life in Patients With Atrial Fibrillation: The CAPTAF Randomized Clinical Trial.

Importance: Quality of life is not a standard primary outcome in ablation trials, even though symptoms drive the indication. Objective: To assess quality of life with catheter ablation vs antiarrhythmic medication at 12 months in patients with atrial fibrillation. Design, Setting, and Participants: Randomized clinical trial at 4 university hospitals in Sweden and 1 in Finland of 155 patients aged 30-70 years with more than 6 months of atrial fibrillation and treatment failure with 1 antiarrhythmic drug or ß-blocker, with 4-year follow-up. Study dates were July 2008-September 2017. Major exclusions were ejection fraction <35%, left atrial diameter >60 mm, ventricular pacing dependency, and previous ablation. Interventions: Pulmonary vein isolation ablation (n = 79) or previously untested antiarrhythmic drugs (n = 76). Main Outcomes and Measures: Primary outcome was the General Health subscale score (Medical Outcomes Study 36-Item Short-Form Health Survey) at baseline and 12 months, assessed unblinded (range, 0 [worst] to 100 [best]). There were 26 secondary outcomes, including atrial fibrillation burden (% of time) from baseline to 12 months, measured by implantable cardiac monitors. The first 3 months were excluded from rhythm analysis. Results: Among 155 randomized patients (mean age, 56.1 years; 22.6% women), 97% completed the trial. Of 79 patients randomized to receive ablation, 75 underwent ablation, including 2 who crossed over to medication and 14 who underwent repeated ablation procedures. Of 76 patients randomized to receive antiarrhythmic medication, 74 received it, including 8 who crossed over to ablation and 43 for whom the first drug used failed. General Health score increased from 61.8 to 73.9 points in the ablation group vs 62.7 to 65.4 points in the medication group (between-group difference, 8.9 points; 95% CI, 3.1-14.7; P = .003). Of 26 secondary end points, 5 were analyzed; 2 were null and 2 were statistically significant, including decrease in atrial fibrillation burden (from 24.9% to 5.5% in the ablation group vs 23.3% to 11.5% in the medication group; difference -6.8% [95% CI, -12.9% to -0.7%]; P = .03). Of the Health Survey subscales, 5 of 7 improved significantly. Most common adverse events were urosepsis (5.1%) in the ablation group and atrial tachycardia (3.9%) in the medication group. Conclusions and Relevance: Among patients with symptomatic atrial fibrillation despite use of antiarrhythmic medication, the improvement in quality of life at 12 months was greater for those treated with catheter ablation compared with antiarrhythmic medication. Although the study was limited by absence of blinding, catheter ablation may offer an advantage for quality of life. Trial Registration: clinicaltrialsregister.eu Identifier: 2008-001384-11.

Poor Quality of Warfarin Treatment Increases the Risk of All Types of Intracranial Hemorrhage in Atrial Fibrillation.

BACKGROUND: Intracranial hemorrhage (ICH) is a devastating complication of oral anticoagulation. The aim of this study was to describe the spectrum of ICH and to evaluate the association of warfarin control with the risk of ICH in a nationwide cohort of unselected atrial fibrillation (AF) patients. Methods and Results: The FinWAF is a retrospective registry-linkage study. Data were collected from several nationwide Finnish health-care registers and laboratory databases. The primary outcome was any ICH (traumatic or non-traumatic). The quality of warfarin therapy was assessed continuously by calculating the time in therapeutic range in a 60-day window (TTR60). Adjusted Cox proportional hazard models were used. A total of 53,953 patients were included (53% men; mean age, 73 years; mean follow-up, 2.94 years; mean TTR, 63%). In 129,684 patient-years, 1,196 patients had ICH (non-traumatic, 53.5%; traumatic, 43.6%; traumatic subdural, 38.6%); crude annual rate, 0.92%; 95% CI: 0.87-0.98). A lower TTR60 was significantly associated with higher risk of ICH (TTR60 ≤40% vs. TTR60 >80%; adjusted hazard ratio, 2.16; 95% CI: 1.83-2.54). Other variables independently associated with ICH included age >65 years, previous stroke, male sex, low hemoglobin, thrombocytopenia, elevated alanine aminotransferase, and previous bleeding other than ICH. CONCLUSIONS: Poor control of warfarin treatment was associated with elevated risk of ICH. Approximately half of the ICH were traumatic, mainly subdural.