Workforce affiliation in primary and secondary prevention Implantable Cardioverter Defibrillator patients - a nationwide Danish study.

BACKGROUND AND AIM: There are a paucity of studies investigating workforce affiliation in connection with first-time ICD-implantation. This study explored workforce affiliation and risk markers associated with not returning to work in patients with ICDs. METHODS: Using the nationwide Danish registers, patients with a first-time ICD-implantation between 2007-2017 and of working age (30-65 years) were identified. Descriptive statistic and logistic regression models were used to describe workforce affiliation and to estimate risk markers associated with not returning to work, respectively. All analyses were stratified by indication for implantation (primary and secondary prevention). RESULTS: Of the 4,659 ICD-patients of working age, 3,300 patients (71%) were members of the workforce (employed, on sick leave or unemployed) (primary: 1428 (43%); secondary:1872 (57%)). At baseline, 842 primary and 1477 secondary prevention ICD-patients were employed. Of those employed at baseline, 81% primary and 75% secondary prevention ICD-patients returned to work within one-year, whereof more than 80% remained employed the following year. Among patients receiving sick leave benefits at baseline, 25% were employed after one-year. Risk markers of not returning to work were 'younger age' in primary prevention ICD-patients, while 'female sex', 'LVEF ≤40', 'lower income' and '≥3 comorbidities' were risk markers in secondary prevention ICD-patients. Lower educational level was a risk marker in both patient groups. CONCLUSIONS: High return-to-work proportions following ICD-implantation, with a subsequent high level of employment maintenance were found. Several significant risk markers of not returning to work were identified including 'lower educational level', that posed a risk in both patient groups.Trial registration number: Capital Region of Denmark, P-2019-051.

Risk of first-time major cardiovascular event among individuals with newly diagnosed type 2 diabetes: data from Danish registers.

AIMS/HYPOTHESIS: We aimed to examine whether individuals with initial omission of glucose-lowering drug treatment (GLDT), including those achieving initial remission of type 2 diabetes, may experience a higher risk of major adverse cardiovascular events (MACE) compared with well-controlled individuals on GLDT after a new type 2 diabetes diagnosis in real-world clinical practice. Furthermore, we examined whether a higher risk could be related to lower initiation of statins and renin-angiotensin system inhibitors (RASi). METHODS: In this cohort study, we used Danish registers to identify individuals with a first measured HbA1c between 48 and 57 mmol/mol (6.5-7.4%) from 2014 to 2020. Six months later, we divided participants into four groups according to GLDT and achieved HbA1c (<48 vs ≥48 mmol/mol [6.5%]): well-controlled and poorly controlled on GLDT; remission and persistent type 2 diabetes not on GLDT. We reported how much the standardised 5 year risk of MACE could be reduced for each group if initiation of statins and RASi was the same as in the well-controlled group on GLDT. RESULTS: We included 14,221 individuals. Compared with well-controlled participants on GLDT, the 5 year standardised risk of MACE was higher in the three other exposure groups: by 3.3% (95% CI 1.6, 5.1) in the persistent type 2 diabetes group not on GLDT; 2.0% (95% CI 0.4, 3.7) in the remission group not on GLDT; and 3.5% (95% CI 1.3, 5.7) in the poorly controlled group on GLDT. Fewer individuals not on GLDT initiated statins and RASi compared with individuals on GLDT. If initiation of statins and RASi had been the same as in the well-controlled group on GLDT, participants not on GLDT could have reduced their risk of MACE by 2.1% (95% CI 1.2, 2.9) in the persistent type 2 diabetes group and by 1.1% (95% CI 0.4, 1.9) in the remission group. CONCLUSIONS/INTERPRETATION: Compared with well-controlled individuals on GLDT, individuals not on initial GLDT had a higher 5 year risk of MACE, even among those achieving remission of type 2 diabetes. This may be related to lower use of statins and RASi.

Frailty, Treatments, and Outcomes in Older Patients With Myocardial Infarction: A Nationwide Registry-Based Study.

Background Guidelines recommend that patients with myocardial infarction (MI) receive equal care regardless of age. However, withholding treatment may be justified in elderly and frail patients. This study aimed to investigate trends in treatments and outcomes of older patients with MI according to frailty. Methods and Results All patients aged ≥75 years with first-time MI during 2002 to 2021 were identified through Danish nationwide registries. Frailty was categorized using the Hospital Frailty Risk Score. One-year risk and hazard ratios (HRs) for days 0 to 28 and 29 to 365 were calculated for all-cause death. A total of 51 022 patients with MI were included (median, 82 years; 50.2% women). Intermediate/high frailty increased from 26.7% in 2002 to 2006 to 37.1% in 2017 to 2021. Use of treatment increased substantially regardless of frailty: for example, 28.1% to 48.0% (statins), 21.8% to 33.7% (dual antiplatelet therapy), and 7.6% to 28.0% (percutaneous coronary intervention) for high frailty (all P-trend <0.001). One-year death decreased for low frailty (35.1%-17.9%), intermediate frailty (49.8%-31.0%), and high frailty (62.8%-45.6%), all P-trend <0.001. Age- and sex-adjusted 29- to 365-day HRs (2017-2021 versus 2002-2006) were 0.53 (0.48-0.59), 0.62 (0.55-0.70), and 0.62 (0.46-0.83) for low, intermediate, and high frailty, respectively (P-interaction=0.23). When additionally adjusted for treatment, HRs attenuated to 0.74 (0.67-0.83), 0.83 (0.74-0.94), and 0.78 (0.58-1.05), respectively, indicating that increased use of treatment may account partially for the observed improvements. Conclusions Use of guideline-based treatments and outcomes improved concomitantly in older patients with MI, irrespective of frailty. These results indicate that guideline-based management of MI may be reasonable in the elderly and frail.

Long-term mortality, cardiovascular events, and bleeding in stable patients 1 year after myocardial infarction: a Danish nationwide study.

AIMS: Outcomes after myocardial infarction (MI) improved during recent decades alongside better risk factor management and implementation of guideline-recommended treatments. However, it is unknown whether this applies to stable patients who are event-free 1 year after MI. METHODS AND RESULTS: Using nationwide Danish registries, we included all patients with first-time MI during 2000-17 who survived 1 year free from bleeding and cardiovascular events (n = 82 108, median age 64 years, 68.2% male). Follow-up started 1 year after MI and continued through January 2022. Crude risks of mortality, cardiovascular events, and bleeding were estimated in consecutive 3-year periods. Standardized risks were calculated with respect to the distribution of age, sex, comorbidities, and treatments in the latter period. Guideline-recommended treatment use increased during the study period: e.g. statins (68.6-92.5%) and percutaneous coronary intervention (23.9-68.2%). The crude 5-year risks of outcomes decreased (all P-trend <0.001): Mortality, 18.6% (95% confidence interval [CI]: 17.9-19.2) to 12.5% (CI: 11.9-13.1); Recurrent MI, 7.5% (CI: 7.1-8.0) to 5.5% (CI: 5.1-6.0); Bleeding, 3.9% (CI: 3.6-4.3) to 2.7% (CI: 2.4-3.0). Crude 5-year risk of mortality in 2015-17 was as low as 2.6% for patients aged <60 years. Use of guideline-recommended treatments was associated with improved outcomes: After standardization for changes in treatments, 5-year risk of mortality in 2000-02 was 15.5% (CI: 14.9-16.2). CONCLUSIONS: For patients who were event-free 1 year after MI, the long-term risks of mortality, cardiovascular events, and bleeding decreased significantly, along with an improved use of guideline-recommended treatments between 2000 and 2017. In the most recent period, 1 year after MI, the risk of additional events was lower than previously reported.

Temporal trends in major cardiovascular events following first-time myocardial infarction in the reperfusion era - a Danish nationwide cohort study from 2000 to 2017.

AIM: We investigated temporal trends in major cardiovascular events following first-time myocardial infarction (MI) and trends in revascularization and pharmacotherapy from 2000 to 2017. METHODS AND RESULTS: Using nationwide registries, we identified 120 833 Danish patients with a first-time MI between 2000 and 2017. We investigated 30-day and 1-year mortality and the 1-year risk of first-time admission for heart failure (HF) and recurrent MI. Patients were younger with a higher prevalence of hypertension and diabetes in 2015-2017 compared with 2000-2002. The patients were predominantly male (65.6%), and the median age declined by 3 years through the periods. Percutaneous coronary interventions within 7 days after first-time MI increased significantly (2000: 11.4% vs. 2017: 68.6%; Ptrend < 0.001). Cardiovascular medication after first-time MI changed significantly in the same period. Absolute risks and adjusted rates of outcomes were significantly lower in 2015-2017 compared with 2000-2002: 30-day mortality: 6.5% vs. 14.1% [hazard ratio (HR) 0.52, 95% confidence interval (CI): 0.48-0.55); 1-year mortality 10.7% vs. 21.8% (HR 0.52, 95% CI: 0.50-0.55); recurrent MI: 4.0% vs. 7.8% (HR 0.56, 95% CI: 0.51-0.62); and first-time admission for HF: 2.9% vs. 3.7% (HR 0.82, 95% CI: 0.73-0.92). The rates of 30-day/1-year mortality and recurrent MI showed significantly decreasing trends (Ptrend < 0.001). The rates of first-time admission for HF were borderline significant (Ptrend = 0.045). CONCLUSION: From 2000 to 2017, we observed a decreasing risk of recurrent MI, first-time admission for HF, and all-cause mortality in patients with a first-time MI. In the same period, we observed a high rate of guideline-recommended pharmacological treatment after first-time MI as well as increasing rate of early revascularization in Denmark. TRANSLATIONAL PERSPECTIVES: The results from the current study portrait the risk of all-cause mortality, recurrent MI, and first-time admission for HF in a real-life setting with a very high utilization of early revascularization and guideline-recommended pharmacological therapy. We observed a temporal trend of improved survival, reduced risk of recurrent MI, as well as reduced risk of first-time admission for HF after first-time MI from 2000 through 2017. We observed an increase in the overall use of revascularization, as well as early revascularization and use of guideline-recommended pharmacotherapy. Our study reveals important results from real-life, nationwide data, showing a reduced risk of cardiovascular outcomes after first-time MI during the past 20 years. Current guidelines are based on results from clinical trials. Our real-life results add additionally important knowledge on patients' prognosis after first-time MI and underline the importance of treating MI according to guideline recommendations.

Impact of socioeconomic position on initiation of SGLT-2 inhibitors or GLP-1 receptor agonists in patients with type 2 diabetes - a Danish nationwide observational study.

BACKGROUND: Low socioeconomic position may affect initiation of sodium-glucose cotransporter-2 inhibitors (SGLT-2i) and glucacon-like-peptide-1 receptor agonists (GLP-1RA) among patients with type 2 diabetes (T2D). We examined the association between socioeconomic position and initiation of SGLT-2i or GLP-1RA in patients with T2D at time of first intensification of antidiabetic treatment. METHODS: Through nationwide registers, we identified all Danish patients on metformin who initiated second-line add-on therapy between December 10, 2012, and December 31, 2020. For each time period (2012-2014, 2015-2017, and 2018-2020), we used multivariable multinomial logistic regression to associate disposable income, as proxy for socioeconomic position, with the probability of initiating a specific second-line treatment at time of first intensification. We reported probabilities standardised to the distribution of demographics and comorbidities of patients included in the last period (2018-2020). FINDINGS: We included 48915 patients (median age 62 years; 61·7% men). In each time period, high-income patients were more often men and had less comorbidities as compared with low income-patients. In each time period, the standardised probability of initiating a SGLT-2i or a GLP-1RA was significantly higher in the highest income group compared with the lowest: 11·4% vs. 9·5% (probability ratio [PR] 1·21, 95 % confidence interval [CI] 1·01-1·44) in 2012-2014; 22·6% vs. 19.6% (PR 1·15, CI 1·05-1·27) in 2015-2017; and 65·8% vs. 54·8% (PR 1·20, CI 1·16-1·24) in 2018-2020. The differences by income were consistent across multiple subgroups. INTERPRETATION: Despite a universal healthcare system, low socioeconomic position was consistently associated with a lower probability of initiating a SGLT-2i or a GLP-1RA. These disparities may widen the future socioeconomic gap in cardiovascular outcomes. FUNDING: The work was funded by unrestricted grants from 'Region Sjaelland Den Sundhedsvidenskabelige Forskningsfond' and 'Murermester Lauritz Peter Christensen og hustru Kirsten Sigrid Christensens Fond'.

Socioeconomic position and first-time major cardiovascular event in patients with type 2 diabetes: a Danish nationwide cohort study.

AIMS: The association between socioeconomic position and cardiovascular disease has not been well studied in patients with type 2 diabetes. We aimed to examine the association between socioeconomic position and first-time major adverse cardiovascular events (MACE) in patients with type 2 diabetes. METHODS AND RESULTS: Through the Danish nationwide registers, we identified all residents with newly diagnosed type 2 diabetes between 2012 and 2017. Based on sex-stratified multivariable cause-specific Cox regression models, we calculated the standardized absolute 5-year risk of the composite outcome of first-time myocardial infarction, stroke, or cardiovascular mortality (MACE) according to income quartiles. A total of 57 106 patients with type 2 diabetes were included. During 155 989 person years, first-time MACE occurred in 2139 patients. Among both men and women, income was inversely associated with the standardized absolute 5-year risk of MACE. In men, the 5-year risk of MACE increased from 5.7% [95% confidence interval (CI) 4.9-6.5] in the highest income quartile to 9.3% (CI 8.3-10.2) in the lowest income group, with a risk difference of 3.5% (CI 2.4-4.7). In women, the risk of MACE increased from 4.2% (CI 3.4-5.0) to 6.1% (CI 5.2-7.0) according to income level, with a risk difference of 1.9% (CI 0.8-2.9). CONCLUSION: Despite free access to medical care in Denmark, low-socioeconomic position was associated with a higher 5-year risk of first-time MACE in patients with incident type 2 diabetes. Our results suggest prevention strategies could be developed specifically for patients with low-socioeconomic position.

Driving following defibrillator implantation: a nationwide register-linked survey study.

AIMS: Patients are restricted from driving following implantable cardioverter defibrillator (ICD) implantation or shock. We sought to investigate how many patients are aware of, and adhere to, the driving restrictions, and what proportion experience an ICD shock or other cardiac symptoms while driving. METHODS AND RESULTS: We performed a nationwide survey of all living Danish residents 18 years or older who received a first-time ICD between 2013 and 2016 (n = 3913) and linked their responses with nationwide registers. Of 2741 respondents (47% primary prevention, 83% male, median age 67 years), 2513 (92%) held a valid driver's license at ICD implantation, 175 (7%) of whom had a license for professional driving. Many drivers were unaware of driving restrictions: primary prevention 58%; secondary prevention 36%; post-appropriate shock 28%; professional drivers 55%. Almost all (94%) resumed non-professional driving after ICD implantation, more than one-third during the restricted period; 35% resumed professional driving. During a median follow-up of 2.3 years, 5 (0.2%) reported receiving an ICD shock while driving, one of which resulted in a traffic accident. The estimated risk of harm was 0.0002% per person-year. CONCLUSION: In this nationwide study, many ICD patients were unaware of driving restrictions, and more than one third resumed driving during a driving restriction period. However, the rate of reported ICD shocks while driving was very low.

Temporal Incidence of Appropriate and Inappropriate Therapy and Mortality in Secondary Prevention ICD Patients by Cardiac Diagnosis.

OBJECTIVES: This study sought to estimate the temporal development in rates and incidences of appropriate and inappropriate implantable cardioverter-defibrillator (ICD) therapy and shocks by cardiac diagnosis in a real-world population of patients with secondary prevention ICDs. BACKGROUND: Data on cardiac diagnoses and temporal development of ICD therapies in patients with secondary prevention ICDs are limited. METHODS: Patients (N = 4,587) with a secondary prevention ICD were identified from the Danish Pacemaker and ICD Register (January 1, 2007, to December 31, 2016) and linked to nationwide administrative registers. The outcome of appropriate and inappropriate ICD therapy and all-cause mortality were analyzed by annual event rates, cumulative incidence plots, and Cox regression models. RESULTS: During a mean follow-up of 3.6 ± 2.4 years, 1,362 patients (30%) experienced appropriate ICD therapy (16.8% shocks), and 350 patients (7.6%) experienced inappropriate ICD therapy (4.6% shocks). From 2007 to 2016, there was a significant temporal reduction in both appropriate and inappropriate ICD therapy from 28.2 (95% confidence interval [CI]: 21.6 to 37.0) to 7.9 (95% CI: 6.8 to 9.1) and 10.0 (95% CI: 6.4 to 15.5) to 1.0 (95% CI: 0.7 to 1.5) per 100 person-years (p for trends <0.001). Multivariate Cox regression analyses showed that arrhythmogenic right ventricular cardiomyopathy was associated with the highest probability of appropriate ICD therapy (hazard ratio: 2.45; 95% CI: 1.77 to 3.39; p < 0.0001), whereas patients with hypertrophic cardiomyopathy had the lowest probability (hazard ratio: 0.62; 95% CI: 0.42 to 0.93; p = 0.0196) when compared to patients with ischemic heart disease. CONCLUSIONS: In this nationwide real-life cohort of patients with secondary prevention ICDs, we observed a significant temporal decline in delivered appropriate and inappropriate shocks and ICD therapies in the last decade. A large proportion of patients still experienced ICD therapy but with significant differences by cardiac diagnosis.

Incidence of appropriate implantable cardioverter-defibrillator therapy and mortality after implantable cardioverter-defibrillator generator replacement: results from a real-world nationwide cohort.

AIMS: The safety of omitting implantable cardioverter-defibrillator (ICD) generator replacement in patients with no prior appropriate therapy, comorbid conditions, and advanced age is unclear. The aim was to investigate incidence of appropriate ICD therapy after generator replacement. METHODS AND RESULTS: We identified patients implanted with a primary prevention ICD (n = 4630) from 2007 to 2016, who subsequently underwent an elective ICD generator replacement (n = 670) from the Danish Pacemaker and ICD Register. The data were linked to other databases and evaluated the outcomes of appropriate therapy and death. Predictors of ICD therapy were identified using multivariate Cox regression analyses. A total of 670 patients underwent elective ICD generator replacement. Of these, 197 (29.4%) patients had experienced appropriate therapy in their 1st generator period. During follow-up of 2.0 ± 1.6 years, 95 (14.2%) patients experienced appropriate therapy. Predictors of appropriate therapy in 2nd generator period was low initial left ventricular ejection fraction (≤25%) [hazard ratio (HR) 1.87, confidence interval (CI) 1.13-1.95] and appropriate therapy in 1st generator period (HR 3.95, CI 2.57-6.06). For patients with appropriate therapy in 1st generator period, 4-year incidence of appropriate therapy was 50.6% vs. 16.4% in those without (P < 0.001). Among patients >80 years with no prior appropriate therapy 8.8% of patients experienced appropriate therapy after replacement. Comorbidity burden and advanced age were associated with reduced device utilization after replacement and a high competing risk of death without preceding appropriate therapy. CONCLUSION: A significant residual risk of appropriate therapy in the 2nd generator was present even among patients with advanced age and with a full prior generator period without any appropriate ICD events.

Clinical outcome in patients with implantable cardioverter-defibrillator and cancer: a nationwide study.

AIMS: Patients with cancer are insufficiently represented in randomized clinical trials investigating efficacy of implantable cardioverter-defibrillators (ICDs). We aimed to describe outcomes in patients with a pre-existing diagnosis of cancer at time of ICD implantation. METHODS AND RESULTS: We utilized Danish nationwide registries to identify primary and secondary prevention ICD implantations from 2007 to 2012. Multivariable Cox models were used to assess the risk of appropriate ICD therapy and mortality in patients with and without cancer at time of implantation. During a median follow-up of 2.1 years, 2935 primary prevention ICD and 2730 secondary prevention ICD implantations were identified. Out of these [289 (5.1%)] had pre-existing cancer [primary 140 (4.8%), secondary 149 (5.5%)]. No differential risk for appropriate ICD therapy was found between patients with or without cancer, [primary cancer: 19/140, no cancer: 380/2795, hazard ratio (HR) = 1.07 (0.67-1.69)] and [secondary cancer: 42/149, no cancer: 699/2581, HR = 1.28 (0.93-1.75)]. In primary patients, cancer was not associated with higher risk of 1-year [cancer: 10/140, no cancer: 133/2795, HR = 1.20 (0.84-2.28)] or all-time mortality [cancer: 22/140, no cancer: 339/2795, HR = 1.13 (0.74-1.75)]. In secondary patients, cancer was associated with a higher 1-year [cancer: 19/149, no cancer: 108/2581, HR = 2.62 (1.60-4.29)] and all-time mortality [cancer: 44/149, no cancer: 315/2581, HR = 2.36 (1.71-3.24)]. CONCLUSION: Implantable cardioverter-defibrillators were implanted in a minority of cancer patients. No difference in risk of appropriate therapy was observed between cancer and non-cancer patients, regardless of implant indication. Cancer was associated with increased mortality in secondary prevention ICD patients, but not in primary prevention ICD patients. In secondary prevention ICD patients, the majority of deaths were attributable to cancer.

Driving following defibrillator implantation: development and pilot results from a nationwide questionnaire.

BACKGROUND: Implantable cardioverter defibrillator (ICD) implantation is associated with driving restrictions which may have profound effects on the patient's life. However, there is limited patient-reported data on the information given about driving restrictions, the adherence to the restrictions, the incidence of arrhythmic symptoms while driving, and the driving restrictions' effect on ICD patients' daily life and quality of life factors. A specific questionnaire was designed to investigate these objectives, intended for use in a nationwide ICD cohort. METHODS: The conceptual framework based on literature review and expert opinion was refined in qualitative semi-structured focus group interviews with ten ICD patients. Content validity was pursued through pre-testing, including expert review and 28 cognitive interviews with patients at all ICD implanting centres in Denmark. Finally, the Danish Pacemaker and ICD registry was used to randomly select 50 ICD patients with a first-time implantation between January 1, 2013 and November 30, 2016 for pilot testing, followed by a test-retest on 25 respondents. Test-retest agreement was assessed using kappa statistics or intraclass correlation coefficients. RESULTS: The pilot test achieved a response rate of 78%, whereof the majority were web-based (69%). Only 49% stated they had been informed about any driving restrictions after ICD implantation, whereas the number was 75% after appropriate ICD shock. Among respondents, 95% had resumed private driving, ranging from 1 to 90 days after ICD implantation. In those informed of a significant (≥ 1 month) driving ban, 55% stated the driving restrictions had impeded with daily life, especially due to limitations in maintaining employment or getting to/from work and 25% admitted they had knowingly been driving during the restricted period. There were six episodes of dizziness or palpitations not necessitating stopping the vehicle. Test-retest demonstrated good agreement of questionnaire items, with 69% of Kappa coefficients above 0.60. CONCLUSIONS: We have developed a comprehensive questionnaire on ICD patients' perspective on driving. Pre-testing and pilot testing demonstrated good content validity, feasible data collection methods, and a robust response rate. Thus, we believe the final questionnaire, distributed to almost 4000 ICD patients, will capture essential evidence to help inform driving guidelines in this population.

Postimplantation ventricular ectopic burden and clinical outcomes in cardiac resynchronization therapy-defibrillator patients: a MADIT-CRT substudy.

BACKGROUND: Frequent ventricular ectopy on preimplantation Holter has been associated with attenuated benefit from cardiac resynchronization therapy (CRT). However, it is unclear whether ectopic burden measured post-CRT implantation can be utilized to evaluate long-term prognosis. We aimed to describe the association between post-CRT implantation ectopic burden and subsequent risk of clinical outcomes. METHODS: At the 12-month follow-up visit, 24-hour Holter recordings were performed in 698 CRT-D patients from the MADIT-CRT study. The mean number of ventricular premature complexes (VPCs/hour) was calculated. High ectopic burden was defined as >10 VPCs/hour and low burden as ≤10 VPCs/hour. Multivariate Cox proportional hazards models were utilized to assess the association between 12-month ectopic burden and the risk of the end points of heart failure (HF) or death and ventricular tachyarrhythmias (VT/VF). RESULTS: At 12 months, 282 (40%) patients presented with low ectopic burden and 416 (60%) patients presented with high ectopic burden. The 3-year risk of HF/death and VT/VF was lower in patients with a low burden (7% and 8%) and significantly higher (25% and 24%) in patients with high burden. In multivariate analyses, patients with a high ectopic burden had approximately threefold increased risk of both HF/death (HR=2.76 [1.62-4.70], p < .001) and VT/VF (HR=2.79 [1.69-4.58], p < .001). CONCLUSION: In CRT-D patients with mild heart failure, high ectopic burden at 12-month follow-up was associated with a high 3-year risk of HF/death and VT/VF and threefold increased risk as compared to patients with low burden. Ectopic burden at 12 months may be a valuable approach for evaluating long-term prognosis.

The use of guideline recommended beta-blocker therapy in primary prevention implantable cardioverter defibrillator patients: insight from Danish nationwide registers.

Aims: We aimed to examine the use of guideline recommended beta-blocker therapy prior to and after primary prevention implantable cardioverter defibrillator (ICD) implantation in a 'real-life' setting. Methods and results: From the Danish Pacemaker and ICD Registry we identified all 1st-time primary prevention ICD and cardiac resynchronization therapy defibrillator (CRT-D) implantations in Denmark from 2007-12 (n = 2935). Use of beta-blocker, type and dose was acquired through the Danish Prescription Registry. According to guideline recommendations, we defined target daily doses as ≥50 mg carvedilol and ≥200 mg metoprolol. Prior to implantation 2427 of 2935 (83%) patients received beta-blocker therapy, with 2166 patients (89%) having initiated treatment 3 months or more prior to implantation. The majority of patients was prescribed carvedilol (52%) or metoprolol (41%). Patients on carvedilol reached target dosages more frequently than patients on metoprolol, with 39% of patients on carvedilol and 26% of patients on metoprolol at the time of implantation (P < 0.001 for all time-points). Increase in proportion of patients reaching target daily doses was observed for both carvedilol and metoprolol after ICD implantation. Carvedilol treatment was a strong predictor for being on target dose of BB at time of implant, as was treatment with angiotensin-converting enzyme inhibitors and/or spironolactone, no history of myocardial infarction, younger age and less pronounced heart failure symptoms. Conclusion: In a real-life setting of primary prevention ICD patients, 39% and 26% of patients were titrated to optimal target dose of carvedilol or metoprolol prior to implantation. A higher proportion of patients on carvedilol reached target dose, as compared with metoprolol.

The impact of co-morbidity burden on appropriate implantable cardioverter defibrillator therapy and all-cause mortality: insight from Danish nationwide clinical registers.

AIMS: In a nationwide cohort of primary (PP-ICD) and secondary prevention (SP-ICD) implantable cardioverter defibrillator (ICD) patients, we aimed to investigate the association between co-morbidity burden and risk of appropriate ICD therapy and mortality. METHODS AND RESULTS: We identified all patients >18 years, implanted with first-time PP-ICD (n = 1873) or SP-ICD (n = 2461) in Denmark from 2007 to 2012. Co-morbidity was identified in administrative registers of hospitalization and drug prescription from pharmacies. Co-morbidity burden was defined as the number of pre-existing non-ICD indication-related co-morbidities including atrial fibrillation, diabetes, chronic obstructive pulmonary disease, chronic renal disease, liver disease, cancer, chronic psychiatric disease, and peripheral and/or cerebrovascular disease, and divided into four groups (co-morbidity burden 0, 1, 2, and ≥3). Through Cox models, we assessed the impact of co-morbidity burden on appropriate ICD therapy and mortality. Increasing co-morbidity burden was not associated with increased risk of appropriate therapy, irrespective of implant indication [all hazard ratios (HRs) 1.0-1.4, P = NS]. Using no co-morbidities as reference, increasing co-morbidity burden was associated with increased mortality risk in PP-ICD patients (co-morbidity burden 1, HR 2.1; comorbidity burden 2, HR 3.7; co-morbidity burden ≥3, HR 6.6) (all P < 0.001) and SP-ICD patients (co-morbidity burden 1, HR 2.2; co-morbidity burden 2, HR 3.8; co-morbidity burden ≥3, HR 5.8). With increasing co-morbidity burden, an increasing frequency of patients died without having utilized their device, with 72% PP-ICD and 45% SP-ICD patients with co-morbidity burden ≥3 dying without prior appropriate ICD therapy. CONCLUSION: Increasing co-morbidity burden was not associated with increased risk of appropriate ICD therapy. With increasing co-morbidity burden, mortality increased, and a higher proportion of patients died, without ever having utilized their device.

Validation of an automatic diagnosis of strict left bundle branch block criteria using 12-lead electrocardiograms.

AIMS: Strict left bundle branch block (LBBB) criteria were recently proposed to identify LBBB patients to benefit most from cardiac resynchronization therapy (CRT). The aim of our study was to automate identification of strict LBBB in order to facilitate its broader application. METHODS: We developed a series of algorithms to automatically detect and measure parameters required for strict LBBB criteria and proposed a definition of QRS notch detection. The algorithms were developed using training (n = 20) and validation (n = 592) sets consisting of signal-averaged 12-lead ECGs (1,000 Hz sampling) recorded from 612 LBBB patients from Multicenter Automatic Defibrillator Implantation Trial-CRT. Four trained clinicians independently performed adjudication on 148 different ECGs for comparing automatic and manually adjudicated results, in addition to 13 ECGs for evaluation of intraobserver variability and 32 ECGs for interobserver variability. We assessed the performance of the automated algorithms using manually adjudicated ECGs as references. RESULTS: Overall sensitivity and specificity for detecting strict LBBB were 95% and 86%, respectively. The mean absolute deviation (MAD) of QRS duration and notch/slur locations for the automated method versus the manual method was below 1 ms, and MAD values were lower than 2 ms for interobserver and intraobserver variability. Sensitivity and specificity for detecting notch and slur locations were 87% and 96% for notches and 78% and 90% for slurs using the automatic method. In addition 95% and 93% agreements for notches and 90% and 88% agreements for slurs were reached for intra- and interobserver. CONCLUSION: The proposed algorithms automatically measure QRS features for the diagnosis of strict LBBB. Our study shows good performance in reference to manual results.

Relation of QRS Duration to Clinical Benefit of Cardiac Resynchronization Therapy in Mild Heart Failure Patients Without Left Bundle Branch Block: The Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy Substudy.

BACKGROUND: There are conflicting data regarding the efficacy of cardiac resynchronization therapy (CRT) in patients with heart failure (HF) and without left bundle branch block. METHODS AND RESULTS: We evaluated the long-term clinical outcomes of 537 non-left bundle branch block patients with mild HF enrolled in the Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy (MADIT-CRT) study by QRS duration or morphology further stratified by PR interval. At 7 years of follow-up, the cumulative probability of HF hospitalization or death was 45% versus 56% among patients randomized to implantable cardioverter-defibrillator and CRT with defibrillator (CRT-D), respectively (P=0.209). Multivariable-adjusted subgroup analysis by QRS duration showed that patients from the lower quartile QRS duration group (≤ 134 ms) experienced 2.4-fold (P=0.015) increased risk for HF hospitalization or death with CRT-D versus implantable cardioverter-defibrillator only therapy, whereas the effect of CRT-D in patients from the upper quartiles group (QRS>134 ms) was neutral (hazard ratio [HR] =0.97, P=0.86; P value for interaction =0.024). In a second analysis incorporating PR interval, patients with prolonged QRS (>134 ms) and prolonged PR (>230 ms) were protected with CRT-D (HR=0.31, P=0.003), whereas the association was neutral with prolonged QRS (>134 ms) and shorter PR (≤ 230 ms;, HR=1.19, P=0.386; P value for interaction =0.002). The effect was neutral, regardless of morphology, right bundle branch block (HR=1.01, P=0.975), and intraventricular conduction delay (HR=1.31, P=0.172). CONCLUSIONS: Overall, patients with mild HF but without left bundle branch block morphology did not derive clinical benefit with CRT-D during long-term follow-up. Relatively shorter QRS was associated with a significantly increased risk with CRT-D relative to implantable cardioverter-defibrillator -only. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifiers: NCT00180271, NCT01294449, and NCT02060110.

Risk factors and the effect of cardiac resynchronization therapy on cardiac and non-cardiac mortality in MADIT-CRT.

AIMS: To understand modes of death and factors associated with the risk for cardiac and non-cardiac deaths in patients with cardiac resynchronization therapy with implantable cardioverter-defibrillator (CRT-D) vs. implantable cardioverter-defibrillator (ICD) therapy, which may help clarify the action and limitations of cardiac resynchronization therapy (CRT) in relieving myocardial dysfunction. METHODS AND RESULTS: In Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy (MADIT-CRT), during 4 years of follow-up, 169 (9.3%) of 1820 patients died of known causes, 108 (63.9%) deemed cardiac, and 61 (36.1%) non-cardiac. In multivariate analysis, increased baseline creatinine was significantly associated with both cardiac and non-cardiac deaths [hazard ratio (HR) 2.97, P < 0.001; HR 1.80, P = 0.035, respectively], as was diabetes (HR 1.79, P = 0.006; HR 1.73, P = 0.038, respectively), and the worst New York Heart Association Class > II more than 3 months prior to enrolment (HR 1.90, P = 0.012; HR 2.46, P = 0.010, respectively). Baseline left atrial volume index was significantly associated only with cardiac mortality (HR 1.28 per 5 unit increase, P < 0.001). Ischaemic cardiomyopathy was associated only with non-cardiac death (HR 3.54, P = 0.001). CRT-D vs. an ICD-only was associated with a reduced risk for cardiac death in patients with left bundle branch block (LBBB) (HR 0.56, P = 0.029) but was associated with an increased risk for non-cardiac death in non-LBBB patients (HR 3.48, P = 0.048). CONCLUSIONS: In MADIT-CRT, two-thirds of the deaths were cardiac and one-third non-cardiac. Many of the same risk factors were associated with both cardiac and non-cardiac mortalities. CRT-D was associated with a reduced risk for cardiac death in LBBB but an increased risk for non-cardiac death in non-LBBB. CLINICAL TRIAL REGISTRATION: Information for the MADIT-CRT main study http://www.clinicaltrials.gov, NCT00180271.

Digoxin therapy and associated clinical outcomes in the MADIT-CRT trial.

BACKGROUND: Digoxin's pharmacological, hemodynamic, and electrophysiological properties are well understood. However, in modern heart failure (HF) treatment, its effect has yet to be fully investigated. OBJECTIVE: The aim of the present study was to determine the effects of digoxin on outcomes in patients with mild HF implanted with an implantable cardioverter-defibrillator (ICD) or cardiac resynchronization therapy with defibrillator (CRT-D) device. METHODS: We investigated the effect of digoxin treatment on the end points of HF/death, HF alone, death alone, and ventricular tachycardia or ventricular fibrillation (VT/VF) in 1820 patients with mild HF (New York Heart Association class I and II), prolonged QRS duration (≥130 ms), and reduced left ventricular ejection fraction (≤30%) enrolled in the Multicenter Automatic Defibrillator Implantation Trial - Cardiac Resynchronization Therapy trial. Multivariate Cox proportional hazards regression models were used to determine the effect of time-dependent digoxin usage on the end points. RESULTS: Digoxin therapy was not associated with an increased or decreased risk of HF/death (hazard ratio [HR] 1.07; 95% confidence interval [CI] 0.86-1.33; P = .0.56), HF alone (HR 1.1.04; 95% CI 0.82-1.32; P = .76), or death alone (HR 0.93; 95% CI 0.67-1.32; P = .71). However, digoxin was associated with a significant 41% increased risk of VT/VF (HR 1.41; 95% CI 1.14-1.75; P = .002), which was driven by a significantly increased risk of VT/VF with heart rate ≥200 beats/min (HR 1.65; 95% CI 1.27-2.15; P ≤ .001), whereas no increased risk of VT/VF with heart rate <200 beats/min was evident (HR 1.20; 95% CI 0.92-1.57; P = .19). No significant differences in digoxin's effect on any of the end points were found between patients with ICD and patients with CRT-D (interaction P > .5). CONCLUSION: The use of digoxin in patients with mild HF implanted with an ICD or CRT-D device was not associated with reductions in HF/death events. However, digoxin therapy was associated with an increased risk of high-rate VT/VF (≥200 beats/min).