Performance of idarucizumab as antidote of dabigatran in daily clinical practice.

AIMS: Because practice-based data on the usage of idarucizumab for urgent dabigatran reversal is unavailable, we evaluated the appropriateness of idarucizumab usage, its haemostatic effectiveness and clinical outcomes. METHODS AND RESULTS: An observational cohort study was performed including consecutive patients who were treated with idarucizumab between 2016 and 2018. Appropriate usage was assessed with predefined criteria. Post-reversal effectiveness was evaluated according to International Society on Thrombosis and Haemostasis (ISTH) recommendations. Patients were followed for 90 days for occurrence of thromboembolism, (re-)bleeding and death. Idarucizumab was used in 88 patients, of whom 53 (60%) presented with severe bleeding (20 gastrointestinal and 18 intracranial) and 35 (40%) requiring urgent surgical intervention. Use of idarucizumab was judged inappropriate in 25 patients (28%). Effective haemostasis was achieved in 32 of 48 (67%) bleeding patients in whom assessment was possible. Seven of 16 patients with major bleeding who did not achieve effective haemostasis (five intracranial) died, compared with two of 32 patients with effective haemostasis (relative risk 7.0, 95% confidence interval 1.6-30). Four patients (4.2%) developed thromboembolism [2 (2.1%) within 30 days] and four patients (4.2%) re-bleeding, all within 10 days. Seventeen patients (19%) died; 10 (11%) within 5 days. CONCLUSION: In this practice-based cohort, idarucizumab use was considered inappropriate in 28% of patients. Effective haemostasis was achieved in two-third of bleeding patients and was associated with lower mortality risk. Clinical outcomes were similar to those observed in the RE-VERSE AD trial, comprising re-bleeds and thromboembolism, and a high-mortality rate.

Symptom severity is associated with cardiovascular outcome in patients with permanent atrial fibrillation in the RACE II study.

AIMS: Symptoms and symptom burden have a central place in diagnosis and management of atrial fibrillation (AF). The aim of the present study is to investigate whether severity of AF symptoms impacts prognosis in permanent AF. METHODS AND RESULTS: We studied the relation between AF symptom severity [quantified with the Toronto AF Severity Scale (AFSS)] and cardiovascular outcome in patients included in the RACE II study. The primary endpoint was a composite of cardiovascular morbidity and mortality. Secondary outcome was cardiovascular hospitalizations. Of 614 permanent AF patients in RACE II, AFSS questionnaires were available in 558 patients (91%). Mean age was 68 ± 8 years. One hundred and seventy-four patients (31%) reported a low score (score 0-3; lowest tertile), 190 patients (34%) reported a moderate score (score 4-9; middle tertile), and 194 (35%) reported a high score (score 10-35; highest tertile). Patients with the most severe symptoms were more often women, had higher N-terminal prohormone of brain natriuretic peptide concentrations, and had more previous heart failure hospitalizations. Median follow-up was 3.0 (interquartile range 2.3-3.0) years. The primary endpoint occurred most frequently in the highest tertile of the AFSS [16 (9%), 19 (10%), 36 (19%), respectively, P = 0.01], being mainly driven by heart failure hospitalizations [4 (2%), 1 (1%), 16 (8%), respectively, P < 0.001]. After multivariable adjustment, higher AFSS scores were associated with the primary endpoint [hazard ratio 1.38 (1.15-1.66), P = 0.001], as well as with cardiovascular hospitalizations [hazard ratio 1.33 (1.14-1.54), P < 0.001]. CONCLUSION: In permanent AF, after multivariable adjustment, symptom severity is associated with cardiovascular outcome.

Heparin-induced thrombocytopenia after ICD-lead flushing.

Heparin-induced thrombocytopenia (HIT) is a potentially life-threatening prothrombotic complication following heparin administration. We describe a patient, known with idiopathic dilating cardiomyopathy, presenting nine days after a biventricular ICD implantation with dyspnoea and thrombocytopenia. Thirteen days after administration of a single heparin flush during ICD implantation, the patient developed venous thrombosis in two extremities and pulmonary embolism caused by HIT. HIT is the development of thrombocytopenia, caused by IgG antibodies against complexes of platelet factor 4 and heparin, leading to platelet aggregation. HIT may be accompanied by thrombosis in 20-50% of patients and untreated mortality rates are high. Once HIT is suspected, heparin should be replaced by an alternative anti-factor Xa or anti-factor II therapy. Regardless of the low incidence of HIT, because of the widespread use of heparin and the potentially life-threatening course of HIT, all physicians should be aware of it.

Effect of a nurse-coordinated prevention programme on cardiovascular risk after an acute coronary syndrome: main results of the RESPONSE randomised trial.

OBJECTIVE: To quantify the impact of a practical, hospital-based nurse-coordinated prevention programme on cardiovascular risk, integrated into the routine clinical care of patients discharged after an acute coronary syndrome, as compared with usual care only. DESIGN: RESPONSE (Randomised Evaluation of Secondary Prevention by Outpatient Nurse SpEcialists) was a randomised clinical trial. SETTING: Multicentre trial in secondary and tertiary healthcare settings. PARTICIPANTS: 754 patients admitted for acute coronary syndrome. INTERVENTION: A nurse-coordinated prevention programme, consisting of four outpatient nurse clinic visits, focusing on healthy lifestyles, biometric risk factors and medication adherence, in addition to usual care. MAIN OUTCOME MEASURES: The main outcome was 10-year cardiovascular mortality risk as estimated by Systematic Coronary Risk Evaluation at 12 months follow-up. Secondary outcomes included Framingham Coronary Risk Score at 12 months, in addition to changes in individual risk factors. Risk factor control was classified as 'poor' if 0 to 3 factors were on target, 'fair' if 4 to 6 factors were on target, and 'good' if 7 to 9 were on target. RESULTS: The mean Systematic Coronary Risk Evaluation at 12 months was 4.4 per cent (SD 4.5) in the intervention group and 5.4 per cent (SD 6.2) in the control group (p=0.021), representing a 17.4% relative risk reduction. At 12 months, risk factor control classified as 'good' was achieved in 35% of patients in the intervention group compared with 25% in the control group (p=0.003). Attendance to the nurse-coordinated prevention programme was 92%. In the intervention group, 86 rehospitalisations were observed against 132 in the control group (relative risk reduction 34.8%, p=0.023). CONCLUSIONS: The nurse-coordinated hospital-based prevention programme in addition to usual care is a practical, yet effective method for reduction of cardiovascular risk in patients with coronary disease. Our data suggest that the counselling component of the programme may lead to a reduction in hospital readmissions. TRIAL REGISTRATION TRIALREGISTERNL IDENTIFIER: TC1290.

Familial evaluation in catecholaminergic polymorphic ventricular tachycardia: disease penetrance and expression in cardiac ryanodine receptor mutation-carrying relatives.

BACKGROUND: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmia syndrome associated with mutations in the cardiac ryanodine receptor gene (Ryr2) in the majority of patients. Previous studies of CPVT patients mainly involved probands, so current insight into disease penetrance, expression, genotype-phenotype correlations, and arrhythmic event rates in relatives carrying the Ryr2 mutation is limited. METHODS AND RESULTS: One-hundred sixteen relatives carrying the Ryr2 mutation from 15 families who were identified by cascade screening of the Ryr2 mutation causing CPVT in the proband were clinically characterized, including 61 relatives from 1 family. Fifty-four of 108 antiarrhythmic drug-free relatives (50%) had a CPVT phenotype at the first cardiological examination, including 27 (25%) with nonsustained ventricular tachycardia. Relatives carrying a Ryr2 mutation in the C-terminal channel-forming domain showed an increased odds of nonsustained ventricular tachycardia (odds ratio, 4.1; 95% CI, 1.5-11.5; P=0.007, compared with N-terminal domain) compared with N-terminal domain. Sinus bradycardia was observed in 19% of relatives, whereas other supraventricular dysrhythmias were present in 16%. Ninety-eight (most actively treated) relatives (84%) were followed up for a median of 4.7 years (range, 0.3-19.0 years). During follow-up, 2 asymptomatic relatives experienced exercise-induced syncope. One relative was not being treated, whereas the other was noncompliant. None of the 116 relatives died of CPVT during a 6.7-year follow-up (range, 1.4-20.9 years). CONCLUSIONS: Relatives carrying an Ryr2 mutation show a marked phenotypic diversity. The vast majority do not have signs of supraventricular disease manifestations. Mutation location may be associated with severity of the phenotype. The arrhythmic event rate during follow-up was low.

The effect of rate control on quality of life in patients with permanent atrial fibrillation: data from the RACE II (Rate Control Efficacy in Permanent Atrial Fibrillation II) study.

OBJECTIVES: The aim of this study was to investigate the influence of rate control on quality of life (QOL). BACKGROUND: The RACE II (Rate Control Efficacy in Permanent Atrial Fibrillation II) trial showed that lenient rate control is not inferior to strict rate control in terms of cardiovascular morbidity and mortality. The influence of stringency of rate control on QOL is unknown. METHODS: In RACE II, a total of 614 patients with permanent atrial fibrillation (AF) were randomized to lenient (resting heart rate [HR] <110 beats/min) or strict (resting HR <80 beats/min, HR during moderate exercise <110 beats/min) rate control. QOL was assessed in 437 patients using the Medical Outcomes Study 36-item Short-Form Health Survey (SF-36) questionnaire, AF severity scale, and Multidimensional Fatigue Inventory-20 (MFI-20) at baseline, 1 year, and end of study. QOL changes were related to patient characteristics. RESULTS: Median follow-up was 3 years. Mean age was 68 ± 8 years, and 66% were males. At the end of follow-up, all SF-36 subscales were comparable between both groups. The AF severity scale was similar at baseline and end of study. At baseline and at end of study there were no differences in the MFI-20 subscales between the 2 groups. Symptoms at baseline, younger age, and less severe underlying disease, rather than assigned therapy or heart rate, were associated with QOL improvements. Female sex and cardiovascular endpoints during the study were associated with worsening of QOL. CONCLUSIONS: Stringency of heart rate control does not influence QOL. Instead, symptoms, sex, age, and severity of the underlying disease influence QOL. (Rate Control Efficacy in Permanent Atrial Fibrillation; NCT00392613).

Lenient versus strict rate control in patients with atrial fibrillation.

BACKGROUND: Rate control is often the therapy of choice for atrial fibrillation. Guidelines recommend strict rate control, but this is not based on clinical evidence. We hypothesized that lenient rate control is not inferior to strict rate control for preventing cardiovascular morbidity and mortality in patients with permanent atrial fibrillation. METHODS: We randomly assigned 614 patients with permanent atrial fibrillation to undergo a lenient rate-control strategy (resting heart rate <110 beats per minute) or a strict rate-control strategy (resting heart rate <80 beats per minute and heart rate during moderate exercise <110 beats per minute). The primary outcome was a composite of death from cardiovascular causes, hospitalization for heart failure, and stroke, systemic embolism, bleeding, and life-threatening arrhythmic events. The duration of follow-up was at least 2 years, with a maximum of 3 years. RESULTS: The estimated cumulative incidence of the primary outcome at 3 years was 12.9% in the lenient-control group and 14.9% in the strict-control group, with an absolute difference with respect to the lenient-control group of -2.0 percentage points (90% confidence interval, -7.6 to 3.5; P<0.001 for the prespecified noninferiority margin). The frequencies of the components of the primary outcome were similar in the two groups. More patients in the lenient-control group met the heart-rate target or targets (304 [97.7%], vs. 203 [67.0%] in the strict-control group; P<0.001) with fewer total visits (75 [median, 0], vs. 684 [median, 2]; P<0.001). The frequencies of symptoms and adverse events were similar in the two groups. CONCLUSIONS: In patients with permanent atrial fibrillation, lenient rate control is as effective as strict rate control and is easier to achieve. (ClinicalTrials.gov number, NCT00392613.)

RAte Control Efficacy in permanent atrial fibrillation: a comparison between lenient versus strict rate control in patients with and without heart failure. Background, aims, and design of RACE II.

BACKGROUND: Recent studies demonstrated that rate control is an acceptable alternative for rhythm control in patients with persistent atrial fibrillation (AF). However, optimal heart rate during AF is still unknown. OBJECTIVE: To show that in patients with permanent AF, lenient rate control is not inferior to strict rate control in terms of cardiovascular mortality, morbidity, neurohormonal activation, New York Heart Association class for heart failure, left ventricular function, left atrial size, quality of life, and costs. METHODS: The RACE II study is a prospective multicenter trial in The Netherlands that will randomize 500 patients with permanent AF (< or = 12 months) to strict or lenient rate control. Strict rate control is defined as a mean resting heart rate < 80 beats per minute (bpm) and heart rate during minor exercise < 110 bpm. After reaching the target, a 24-hour Holter monitoring will be performed. If necessary, drug dose reduction and/or pacemaker implantation will be performed. Lenient rate control is defined as a resting heart rate < 110 bpm. Patients will be seen after 1, 2, and 3 months (for titration of rate control drugs) and yearly thereafter. We anticipate a 25% 2.5-year cardiovascular morbidity and mortality in both groups. RESULTS: Enrollment started in January 2005 in 29 centers in The Netherlands and is expected to be concluded in June 2006. Follow-up will be at least 2 years with a maximum of 3 years. CONCLUSION: This study should provide data how to treat patients with permanent AF.