Long-Term Incidence of Ischemic Stroke After Transient Ischemic Attack: A Nationwide Study From 2014 to 2020.

BACKGROUND: The short-term incidence of ischemic stroke after a transient ischemic attack (TIA) is high. However, data on the long-term incidence are not well known but are needed to guide preventive strategies. METHODS: Patients with first-time TIA (index date) in the Danish Stroke Registry (January 2014-December 2020) were included and matched 1:4 with individuals from the background population and 1:1 with patients with a first-time ischemic stroke on the basis of age, sex, and calendar year. The incidences of ischemic stroke and mortality from index date were estimated by Aalen-Johansen and Kaplan-Meier estimators, respectively, and compared between groups using multivariable Cox regression. RESULTS: We included 21 500 patients with TIA, 86 000 patients from the background population, and 21 500 patients with ischemic stroke (median age, 70.8 years [25th-75th percentile, 60.8-78.7]; 53.1% males). Patients with TIA had more comorbidities than the background population, yet less than the control stroke population. The 5-year incidence of ischemic stroke after TIA (6.1% [95% CI, 5.7-6.5]) was higher than the background population (1.5% [95% CI, 1.4-1.6], P<0.01; hazard ratio, 5.14 [95% CI, 4.65-5.69]) but lower than the control stroke population (8.9% [95% CI, 8.4-9.4], P<0.01; hazard ratio, 0.58 [95% CI, 0.53-0.64]). The 5-year mortality for patients with TIA (18.6% [95% CI, 17.9-19.3]) was higher than the background population (14.8% [95% CI, 14.5-15.1], P<0.01; hazard ratio, 1.26 [95% CI, 1.20-1.32]) but lower than the control stroke population (30.1% [95% CI, 29.3-30.9], P<0.01; hazard ratio, 0.41 [95% CI, 0.39-0.44]). CONCLUSIONS: Patients with first-time TIA had an ischemic stroke incidence of 6.1% during the 5-year follow-up period. After adjustment for relevant comorbidities, this incidence was approximately 5-fold higher than what was found for controls in the background population and 40% lower than for patients with recurrent ischemic stroke.

Effect of Implantable Cardioverter-defibrillators in Nonischemic Heart Failure According to Background Medical Therapy: Extended Follow-up of the DANISH Trial.

BACKGROUND: The Heart Failure Collaboratory (HFC) score integrates types and dosages of guideline-directed pharmacotherapies for heart failure (HF) with reduced ejection fraction (HFrEF). We examined the effects of cardioverter-defibrillator (ICD) implantation according to the modified HFC (mHFC) score in 1116 patients with nonischemic HFrEF from the Danish Study to Assess the Efficacy of ICDs in Patients with Nonischemic Systolic HF on Mortality (DANISH). METHODS AND RESULTS: Patients were assigned scores for renin-angiotensin-system inhibitors, beta-blockers and mineralocorticoid receptor antagonists (0, no use; 1, < 50% of maximum dosage; 2, ≥ 50% of maximum dosage). The maximum score was 6, corresponding to ≥ 50% of maximum dosage for all therapies. The median baseline mHFC score was 4, and the median follow-up was 9.5 years. Compared with an mHFC score of 3-4, an mHFC score of 1-2 was associated with a higher rate of all-cause death (mHFC = 1-2: adjusted HR 1.67 [95% CI, 1.23-2.28]; mHFC = 3-4, reference; mHFC = 5-6: adjusted HR 1.07 [95% CI, 0.87-1.31]). ICD implantation did not reduce all-cause death compared with control (reference) (HR 0.89 [95% CI, 0.74-1.08]), regardless of mHFC score (mHFC = 1-2: HR 0.98 [95% CI, 0.56-1.71]; mHFC = 3-4: HR 0.89 [95% CI,0.66-1.20]; mHFC = 5-6: HR 0.85 [95% CI, 0.64-1.12]; Pinteraction, 0.65). Similarly, ICD implantation did not reduce cardiovascular death (HR 0.87 [95% CI, 0.70-1.09]), regardless of mHFC score (Pinteraction, 0.59). The ICD group had a lower rate of sudden cardiovascular death (HR, 0.60 [95% CI,0.40-0.92]); this association was not modified by mHFC score (Pinteraction, 0.35). CONCLUSIONS: Lower mHFC scores were associated with higher rates of all-cause death. ICD implantation did not result in an overall survival benefit in patients with nonischemic HFrEF, regardless of mHFC score.

Heart Failure, Investigator-Reported Sleep Apnea and Dapagliflozin: A Patient-Level Pooled Meta-Analysis of DAPA-HF and DELIVER.

BACKGROUND: Sleep apnea is more common in patients with heart failure (HF) than in the general population, but little is known about its association with clinical outcomes in various HF phenotypes or how it might modify the effect of HF therapy. OBJECTIVES: To examine the prevalence of sleep apnea, its association with outcomes and the effects of dapagliflozin in patients with HF with and without sleep apnea in a pooled analysis of 2 trials comparing dapagliflozin to placebo in HFrEF (DAPA-HF trial) and HFmrEF/HFpEF (DELIVER trial). METHODS: A history of sleep apnea was investigator-reported. The primary outcome was a composite of worsening HF or cardiovascular death. RESULTS: The prevalence of sleep apnea was 5.7% and 7.8% in patients with HFrEF and HFmrEF/HFpEF, respectively. The primary outcome occurred at a rate of 16.0 in participants with sleep apnea compared to 10.6 per 100 person-years in those without (adjusted HR 1.29 [95%CI, 1.10-1.52]). Compared with placebo, dapagliflozin reduced the risk of the primary endpoint to the same extent in patients with (HR 0.78 [95% CI, 0.59-1.03]) and without sleep apnea (HR 0.79 [0.72-0.87]) [Pinteraction = 0.93]. The beneficial effects of dapagliflozin on other clinical outcomes and symptom burden, physical function, and quality of life were consistent in participants with and without sleep apnea. CONCLUSIONS: In DAPA-HF and DELIVER, the true prevalence of sleep apnea was likely underestimated. An investigator-reported history of sleep apnea was associated with higher rates of worsening HF events. The benefits of dapagliflozin on clinical outcomes were consistent in patients with and without sleep apnea. CLINICAL TRIAL REGISTRATION: Unique identifiers: NCT01920711 CONDENSED ABSTRACT: In a pooled analysis of the DAPA-HF and DELIVER trials of more than 11,000 patients with heart failure (HF) across the range of ejection fractions, an investigator-reported history of sleep apnea was associated with higher rates of worsening HF events but not mortality. The beneficial effects of dapagliflozin on clinical outcomes were consistent in patients with and without sleep apnea. These findings provide further evidence for dapagliflozin as a new treatment option for patients with heart failure across the range of ejection fractions.

Anthropometric measures and adverse outcomes in heart failure with reduced ejection fraction: revisiting the obesity paradox.

AIMS: Although body mass index (BMI) is the most commonly used anthropometric measure, newer indices such as the waist-to-height ratio, better reflect the location and amount of ectopic fat, as well as the weight of the skeleton, and may be more useful. METHODS AND RESULTS: The prognostic value of several newer anthropometric indices was compared with that of BMI in patients with heart failure (HF) and reduced ejection fraction (HFrEF) enrolled in prospective comparison of ARNI with ACEI to determine impact on global mortality and morbidity in heart failure. The primary outcome was HF hospitalization or cardiovascular death. The association between anthropometric indices and outcomes were comprehensively adjusted for other prognostic variables, including natriuretic peptides. An 'obesity-survival paradox' related to lower mortality risk in those with BMI ≥25 kg/m2 (compared with normal weight) was identified but this was eliminated by adjustment for other prognostic variables. This paradox was less evident for waist-to-height ratio (as an exemplar of indices not incorporating weight) and eliminated by adjustment: the adjusted hazard ratio (aHR) for all-cause mortality, for quintile 5 vs. quintile 1, was 1.10 [95% confidence interval (CI) 0.87-1.39]. However, both BMI and waist-to-height ratio showed that greater adiposity was associated with a higher risk of the primary outcome and HF hospitalization; this was more evident for waist-to-height ratio and persisted after adjustment e.g. the aHR for HF hospitalization for quintile 5 vs. quintile 1 of waist-to-height ratio was 1.39 (95% CI 1.06-1.81). CONCLUSION: In patients with HFrEF, alternative anthropometric measurements showed no evidence for an 'obesity-survival paradox'. Newer indices that do not incorporate weight showed that greater adiposity was clearly associated with a higher risk of HF hospitalization.

Importance of cystatin C in estimating glomerular filtration rate: the PARADIGM-HF trial.

AIMS: The 2021 Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation combining creatinine and cystatin C provides a better estimation of glomerular filtration rate (GFR) compared to the creatinine-only equation. METHODS AND RESULTS: CKD-EPI creatinine-cystatin C equation (creatinine-cystatin) was compared to creatinine-only (creatinine) equation in a subpopulation of Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure (PARADIGM-HF). Patients were categorized according to difference in eGFR using the two equations: Group 1 (<-10 mL/min/1.73 m2, i.e. creatinine-cystatin more than 10 mL/min lower than creatinine), Group 2 (>-10 and <10 mL/min/1.73 m2), and Group 3 (>10 mL/min/1.73 m2, i.e. creatinine-cystatin more than 10 mL/min higher than creatinine). Cystatin C and creatinine were available in 1966 patients at randomization. Median (interquartile range) eGFR difference was -0.7 (-6.4-4.8) mL/min/1.73 m2. Compared to creatinine, creatinine-cystatin led to a substantial reclassification of chronic kidney disease stages. Overall, 212 (11%) and 355 (18%) patients were reallocated to a better and worse eGFR category, respectively. Compared to patients in Group 2, those in Group 1 (lower eGFR with creatinine-cystatin) had higher mortality and those in Group 3 (higher eGFR with creatinine-cystatin) had lower mortality. Increasing difference in eGFR (due to lower eGFR with creatinine-cystatin compared to creatinine) was associated with increasing elevation of biomarkers (including N-terminal pro-B-type natriuretic peptide and troponin) and worsening Kansas City Cardiomyopathy Questionnaire clinical summary score. The reason why the equations diverged with increasing severity of heart failure was that creatinine did not rise as steeply as cystatin C. CONCLUSION: The CKD-EPI creatinine-only equation may overestimate GFR in sicker patients. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov; Unique Identifier: NCT01035255.

Temporal trends in the incidence of malignancy in heart failure: a nationwide Danish study.

AIMS: Cancer and heart failure (HF) share risk factors, pathophysiological mechanisms, and possibly genetics. Improved HF survival may increase the risk of cancer due to a competing risk. Whether the incidence of cancer has increased over time in patients with HF as survival has improved is unclear. Therefore, temporal trends of new onset cancer in HF patients between 1997 and 2016 were investigated. METHODS AND RESULTS: Using Danish nationwide registers, 103 711 individuals alive, free of cancer, and aged 30-80 years 1 year after HF diagnosis (index date) were included between 1 January 1997 and 31 December 2016. A five-year incidence rate of cancer for each year after index date was calculated. The median age and proportion of women at the index date decreased with advancing calendar time [1997-2001: 70.3 interquartile range (Q1-Q3 62.5-75.7), 60.9% men; 2012-16: 67.6 (59.2-73.8), 67.5% men]. The five-year incidence rate of cancer was 20.9 and 20.2 per 1,000 person-years in 1997 and 2016, respectively. In a multivariable Cox regression model, the hazard rates between index years 1997 (reference) and 2016 were not significantly different [hazard ratio 1.09 (0.97-1.23)]. The five-year absolute risk of cancer did not change with advancing calendar year, going from 9.0% (1997-2001) to 9.0% (2012-16). Five-year cumulative incidence of survival for HF patients increased with advancing calendar year, going from 55.9% (1997-2001) to 74.3% (2012-2016). CONCLUSION: Although cancer rates during 1997-2016 have remained stable within 1-6 years after the HF diagnosis, long-term survival following a HF diagnosis has increased significantly.

Stroke in patients with heart failure and reduced or preserved ejection fraction.

AIMS: Stroke is an important problem in patients with heart failure (HF), but the intersection between the two conditions is poorly studied across the range of ejection fraction. The prevalence of history of stroke and related outcomes were investigated in patients with HF. METHODS AND RESULTS: Individual patient meta-analysis of seven clinical trials enrolling patients with HF with reduced (HFrEF) and preserved ejection fraction (HFpEF). Of the 20 159 patients with HFrEF, 1683 (8.3%) had a history of stroke, and of the 13 252 patients with HFpEF, 1287 (9.7%) had a history of stroke. Regardless of ejection fraction, patients with a history of stroke had more vascular comorbidity and worse HF. Among those with HFrEF, the incidence of the composite of cardiovascular death, HF hospitalization, stroke, or myocardial infarction was 18.23 (16.81-19.77) per 100 person-years in those with prior stroke vs. 13.12 (12.77-13.48) in those without [hazard ratio 1.37 (1.26-1.49), P < 0.001]. The corresponding rates in patients with HFpEF were 14.16 (12.96-15.48) and 9.37 (9.06-9.70) [hazard ratio 1.49 (1.36-1.64), P < 0.001]. Each component of the composite was more frequent in patients with stroke history, and the risk of future stroke was doubled in patients with prior stroke. Among patients with prior stroke, 30% with concomitant atrial fibrillation were not anticoagulated, and 29% with arterial disease were not taking statins; 17% with HFrEF and 38% with HFpEF had uncontrolled systolic blood pressure (≥140 mmHg). CONCLUSION: Heart failure patients with a history of stroke are at high risk of subsequent cardiovascular events, and targeting underutilization of guideline-recommended treatments might be a way to improve outcomes in this high-risk population.

Heart failure, peripheral artery disease, and dapagliflozin: a patient-level meta-analysis of DAPA-HF and DELIVER.

AIMS: Because an increased risk of amputation with canagliflozin was reported in the CANVAS trials, there has been a concern about the safety of sodium-glucose cotransporter 2 inhibitors in patients with peripheral artery disease (PAD) who are at higher risk of amputation. METHODS AND RESULTS: A patient-level pooled analysis of the DAPA-HF and DELIVER trials, which evaluated the efficacy and safety of dapagliflozin in patients with heart failure (HF) with reduced, mildly reduced/preserved ejection fraction, respectively, was conducted. In both trials, the primary outcome was the composite of worsening HF or cardiovascular death, and amputation was a prespecified safety outcome. Peripheral artery disease history was available for 11 005 of the total 11 007 patients. Peripheral artery disease was reported in 809 of the 11 005 patients (7.4%). Median follow-up was 22 months (interquartile range 17-30). The rate of the primary outcome (per 100 person-years) was higher in PAD patients than that in non-PAD patients: 15.1 [95% confidence interval (CI) 13.1-17.3) vs. 10.6 (10.2-11.1]; adjusted hazard ratio 1.23 (95% CI 1.06-1.43). The benefit of dapagliflozin on the primary outcome was consistent in patients with [hazard ratio 0.71 (95% CI 0.54-0.94)] and without PAD [0.80 (95% CI 0.73-0.88)] (Pinteraction = 0.39). Amputations, while more frequent in PAD patients, were not more common with dapagliflozin, compared with placebo, irrespective of PAD status (PAD, placebo 4.2% vs. dapagliflozin 3.7%; no PAD, placebo 0.4% vs. dapagliflozin 0.4%) (Pinteraction = 1.00). Infection rather than ischaemia was the main trigger for amputation, even in patients with PAD. CONCLUSION: The risk of worsening HF or cardiovascular death was higher in patients with PAD, as was the risk of amputation. The benefits of dapagliflozin were consistent in patients with and without PAD, and dapagliflozin did not increase the risk of amputation.

Long-Term Follow-Up of DANISH (The Danish Study to Assess the Efficacy of ICDs in Patients With Nonischemic Systolic Heart Failure on Mortality).

BACKGROUND: DANISH (The Danish Study to Assess the Efficacy of Implantable Cardioverter Defibrillators [ICDs] in Patients With Nonischemic Systolic Heart Failure on Mortality) found that primary-prevention ICD implantation was not associated with an overall survival benefit in patients with nonischemic systolic heart failure during a median follow-up of 5.6 years, although there was a beneficial effect on all-cause mortality in patients ≤70 years. This study presents an additional 4 years of follow-up data from DANISH. METHODS: In DANISH, 556 patients with nonischemic systolic heart failure were randomized to receive an ICD and 560 to receive usual clinical care and followed until June 30, 2016. In this long-term follow-up study, patients were followed until May 18, 2020. Analyses were conducted for the overall population and according to age (≤70 and >70 years). RESULTS: During a median follow-up of 9.5 years (25th-75th percentile, 7.9-10.9 years), 208/556 patients (37%) in the ICD group and 226/560 patients (40%) in the control group died. Compared with the control group, the ICD group did not have significantly lower all-cause mortality (hazard ratio [HR] 0.89, [95% CI, 0.74-1.08]; P = 0.24). In patients ≤70 years (n = 829), all-cause mortality was lower in the ICD group than the control group (117/389 [30%] versus 158/440 [36%]; HR, 0.78 [95% CI, 0.61-0.99]; P = 0.04), whereas in patients >70 years (n = 287), all-cause mortality was not significantly different between the ICD and control group (91/167 [54%] versus 68/120 [57%]; HR, 0.92 [95% CI, 0.67-1.28]; P = 0.75). Cardiovascular death showed similar trends (overall, 147/556 [26%] versus 164/560 [29%]; HR, 0.87 [95% CI, 0.70-1.09]; P = 0.20; ≤70 years, 87/389 [22%] versus 122/440 [28%]; HR, 0.75 [95% CI, 0.57-0.98]; P = 0.04; >70 years, 60/167 [36%] versus 42/120 [35%]; HR, 0.97 [95% CI, 0.65-1.45]; P = 0.91). The ICD group had a significantly lower incidence of sudden cardiovascular death in the overall population (35/556 [6%] versus 57/560 [10%]; HR, 0.60 [95% CI, 0.40-0.92]; P = 0.02) and in patients ≤70 years (19/389 [5%] versus 49/440 [11%]; HR, 0.42 [95% CI, 0.24-0.71]; P = 0.0008), but not in patients >70 years (16/167 [10%] versus 8/120 [7%]; HR, 1.34 [95% CI, 0.56-3.19]; P = 0.39). CONCLUSIONS: During a median follow-up of 9.5 years, ICD implantation did not provide an overall survival benefit in patients with nonischemic systolic heart failure. In patients ≤70 years, ICD implantation was associated with a lower incidence of all-cause mortality, cardiovascular death, and sudden cardiovascular death. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00542945.

Efficacy and Safety of Dapagliflozin According to Frailty in Patients With Heart Failure: A Prespecified Analysis of the DELIVER Trial.

BACKGROUND: Frailty is increasing in prevalence. Because patients with frailty are often perceived to have a less favorable risk/benefit profile, they may be less likely to receive new pharmacologic treatments. We investigated the efficacy and tolerability of dapagliflozin according to frailty status in patients with heart failure with mildly reduced or preserved ejection fraction randomized in DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure). METHODS: Frailty was measured using the Rockwood cumulative deficit approach. The primary end point was time to a first worsening heart failure event or cardiovascular death. RESULTS: Of the 6263 patients randomized, a frailty index (FI) was calculable in 6258. In total, 2354 (37.6%) patients had class 1 frailty (FI ≤0.210; ie, not frail), 2413 (38.6%) had class 2 frailty (FI 0.211-0.310; ie, more frail), and 1491 (23.8%) had class 3 frailty (FI ≥0.311; ie, most frail). Greater frailty was associated with a higher rate of the primary end point (per 100 person-years): FI class 1, 6.3 (95% CI 5.7-7.1); class 2, 8.3 (7.5-9.1); and class 3, 13.4 (12.1-14.7; P<0.001). The effect of dapagliflozin (as a hazard ratio) on the primary end point from FI class 1 to 3 was 0.85 (95% CI, 0.68-1.06), 0.89 (0.74-1.08), and 0.74 (0.61-0.91), respectively (Pinteraction=0.40). Although patients with a greater degree of frailty had worse Kansas City Cardiomyopathy Questionnaire scores at baseline, their improvement with dapagliflozin was greater than it was in patients with less frailty: placebo-corrected improvement in Kansas City Cardiomyopathy Questionnaire Overall Summary Score at 4 months in FI class 1 was 0.3 (95% CI, -0.9 to 1.4); in class 2, 1.5 (0.3-2.7); and in class 3, 3.4 (1.7-5.1; Pinteraction=0.021). Adverse reactions and treatment discontinuation, although more frequent in patients with a greater degree of frailty, were not more common with dapagliflozin than with placebo irrespective of frailty class. CONCLUSIONS: In DELIVER, frailty was common and associated with worse outcomes. The benefit of dapagliflozin was consistent across the range of frailty studied. The improvement in health-related quality of life with dapagliflozin occurred early and was greater in patients with a higher level of frailty. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03619213.

Long-term risk of heart failure and other adverse cardiovascular outcomes in primary Sjögren's syndrome.

BACKGROUND: Data on long-term cardiovascular outcomes in primary Sjögren's syndrome (PSS) are scarce. OBJECTIVES: We aim to investigate the long-term rate of incident heart failure (HF) and other adverse cardiovascular endpoints in patients with PSS compared with the general population and to investigate mortality in individuals with incident HF with or without a history of PSS. METHODS: Using Danish nationwide registries, PSS patients (diagnosed 1996-2018) without a history of other autoimmune diseases were each matched with four individuals from the general population by sex, age, and comorbidities. Multivariable Cox regression was used to estimate the rate of cardiovascular outcomes. In addition, the rate of death from any cause was compared between PSS patients with incident HF and four age- and sex-matched HF patients without PSS. RESULTS: In total, 5092 patients with newly diagnosed PSS were matched with 20,368 individuals from the general population (median age 57 years, 87.3% women, median follow-up 7.4 years). The cumulative incidence of HF at 10 years was 4.0% for PSS patients and 2.8% for matched individuals. After adjustment, patients with PSS had a higher associated rate of incident HF (hazard ratios [HR] 1.42 [95% CI, 1.20-1.68]) and other cardiovascular outcomes, compared with the background population. PSS patients with incident HF had a similar rate of death from all-cause mortality compared with HF patients without PSS (HR 0.94 [0.74-1.19]). CONCLUSIONS: Patients with PSS had a higher associated rate of incident HF and other cardiovascular outcomes compared with the general population. In individuals with incident HF, a history of PSS was not associated with increased mortality.

Mortality and rehospitalization after mitral valve surgery as a function of age and key comorbidities.

BACKGROUND: Mitral valve surgery is associated with substantial perioperative risk and long-term complications. Data on long-term outcomes following surgery remain scarce and are hypothetically modified by age and comorbidities. METHODS: This Danish nationwide study included patients ≥60 years of age undergoing mitral valve surgery from 2000-2018. Patients were observed from day of surgery until outcome of interest (ie, rehospitalization or death) or maximum 1 year of follow-up. The absolute risks of outcomes were assessed, and associated factors were evaluated. Based on age and comorbidities, patients were stratified in 4 groups: low (<75 years + 0 comorbidities), low intermediate (≥75 years/1 comorbidity), high intermediate (≥75 years + 1 comorbidity/2 comorbidities), and high risk of death (≥75 years + ≥2 comorbidities). RESULTS: In total, 4,202 patients (62.9% men) were identified. Within 1 year after surgery, 504 (12.0%) died and 2,456 (58.5%) were rehospitalized. Factors associated with death included older age (>75 years), chronic obstructive lung disease, heart failure, prior myocardial infarction, prior stroke, liver disease, and kidney disease. The 1-year risks of death among patients in low, low-intermediate, high-intermediate, and high risk of death were 3.6%, 10.3%, 19.6%, and 27.7%, respectively. Diabetes mellitus and chronic obstructive lung disease were associated with an increased incidence of rehospitalization, and the incidence of rehospitalization was similar among the 4 abovementioned groups (57.8%-62.8%). CONCLUSIONS: Mortality and rehospitalization risks after mitral valve surgery varied substantially with age and comorbidities. High-risk patients with >25% 1-year mortality may be easily identified using readily available clinical features. TRIAL REGISTRATION: In Denmark, registry-based studies that are conducted for the sole purpose of statistics and scientific research do not require ethical approval or informed consent by law. However, the study is approved by the data responsible institute (the Capital Region of Denmark [approval number: P-2019-348]) in accordance with the general data protection regulation.

Patient characteristics and long-term outcomes in patients undergoing transcatheter aortic valve implantation in a failed surgical prosthesis vs in a native valve: A Danish nationwide study.

BACKGROUND: Valve-in-valve-transcatheter aortic valve implantation (TAVI) is a feasible and increasingly used treatment option for failed surgical aortic prosthesis, but data from clinical practice are limited. We aimed to examine patient characteristics and outcomes of patients undergoing TAVI in a surgival valve (valve-in-valve TAVI) compared with patients undergoing TAVI in a native valve. METHODS: Using nationwide registries, we identified all Danish citizens, who underwent TAVI from January 1, 2008, to December 31, 2020. RESULTS: A total of 6,070 patients undergoing TAVI were identified; 247 (4%) patients had a history of SAVR (The valve-in-valve cohort). The median age of the study population was 81 (25th-75th percentile 77-85) and 55% were men. Patients with valve-in-valve-TAVI were younger but had a greater burden of cardiovascular comorbidities compared with patients with native-valve-TAVI. Within 30 days post procedure, 11 (0.2%) and 748 (13.8%) patients who underwent valve-in-valve-TAVI and native-valve-TAVI, respectively, had a pacemaker implantation. The cumulative 30-day risk of death among patients with valve-in-valve-TAVI was 2.4% (95% CI: 1.0%-5.0%) and 2.7% (95% CI: 2.3%-3.1%) in patients with native-valve-TAVI, respectively. Correspondingly, the cumulative 5-year risk of death was 42.5% (95% CI: 34.2%-50.6%) and 44.8% (95% CI: 43.2%-46.4%), respectively. In multivariable Cox proportional hazard analysis, valve-in-valve-TAVI was not associated with a significantly different risk of death at 30 days (Hazard ratio (HR) = 0.95, 95% CI 0.41-2.19) and 5 years (HR = 0.79, 95% CI 0.62-1.00) post-TAVI compared with native-valve-TAVI. CONCLUSIONS: TAVI in a failed surgical aortic prosthesis as compared to TAVI in a native valve, was not associated with significantly different short- and long-term mortality, suggesting that valve-in-valve-TAVI is a safe procedure.

Relationship between the volume of cases and in-hospital mortality in patients with cardiogenic shock receiving short-term mechanical circulatory support.

BACKGROUND: We examined the relationship between annual case volume at each hospital and outcome in cardiogenic shock (CS) patients receiving mechanical circulatory support (MCS) devices. METHODS: This cross-sectional study used the Japanese nationwide database to identify patients receiving short-term MCS for CS between April 2012 and March 2020. Of 65,837 patients, 3 subcohorts were created; the intra-aortic balloon pump (IABP) alone (n = 48,643), the extracorporeal membrane oxygenation (ECMO) (n = 16,871), and the Impella cohorts (n = 696). RESULTS: The median annual case volume was 13.5 (7.4-22.1) in the IABP alone cohort, 6.4 (3.4-11.0) in the ECMO cohort, and 7.5 (4.0-10.7) in the Impella cohort. The highest quintile for the volume of cases in the IABP alone and ECMO had the lowest in-hospital mortality (IABP alone, 25.1% in quintile 1 vs 15.2% in quintile 5; ECMO, 73.7% in quintile 1 in 67.4% in quintile 5). Adjusted ORs for in-hospital mortality decreased as case volume increased (IABP alone, 0.63 [0.58-0.68] in quintile 5; ECMO, 0.73 [0.65-0.82] in quintile 5, with the lowest quintile as reference) but did not decrease significantly in the Impella (0.90 [0.58-1.39] in tertile 3, with the lowest tertile as reference). In the continuous models with the case volume as a continuous variable, adjusted ORs for in-hospital mortality decreased to 28 IABP cases/year and 12 ECMO cases/year. They did not decrease or became almost flat above that. CONCLUSIONS: Higher volumes of IABP and ECMO are associated with a lower mortality. There is an upper limit to the decline. Centralizing patients with refractory CS in a particular hospital might improve patient outcomes in each region.

Long-term incidence of infective endocarditis among patients with congenital heart disease.

BACKGROUND: Patients with congenital heart disease (CHD) are at lifelong high risk of infective endocarditis (IE). The risk of IE presumably differs among different CHD, but little knowledge exists on the area. METHODS: In this observational cohort study, all CHD-patients born in 1977 to 2018 were identified using Danish nationwide registries and followed from the date of birth until first-time IE, emigration, death, or end of study (December 31, 2018). The comparative risk of IE among CHD-patients vs age- and sex-matched controls from the background population was assessed. The risk of IE was stratified according to the type of CHD and factors associated with IE including sex and relevant time-varying coefficients (ie, cyanosis, cardiac prostheses, diabetes mellitus, chronic kidney disease, and cardiac implantable electronic devices) were examined using Cox-regression analysis. RESULTS: A total of 23,464 CHD-patients (50.0% men) were identified and matched with 93,856 controls. During a median follow-up of 17.7 years, 217(0.9%) CHD-patients and 4(0.0%) controls developed IE, corresponding to incidence rates of 5.2(95%CI 4.6-6.0) and 0.02(95%CI 0.01-0.1) per 10,000 person-years, respectively. The incidence of IE was greatest among patients with tetralogy of fallot, malformations of the heart chambers (including transposition of the great arteries, univentricular heart, and truncus arteriosus), atrioventricular septal defects, and heart valve defects. Factors associated with IE among CHD-patients included male sex, cyanosis, cardiac prostheses, chronic kidney disease, and cardiac implantable electronic devices. CONCLUSIONS: CHD-patients have a substantially higher associated incidence of IE than the background population. With the increasing longevity of these patients, relevant guidelines concerning preventive measures are important.

Long-term risk of new-onset arrhythmia in ST-segment elevation myocardial infarction according to revascularization status.

AIMS: Emerging data show that complete revascularization (CR) reduces cardiovascular death and recurrent myocardial infarction in ST-segment elevation myocardial infarction (STEMI). However, the influence of revascularization status on development of arrhythmia in the long-term post-STEMI phase is poorly described. We hypothesized that incomplete revascularization (ICR) compared with CR in STEMI is associated with an increased long-term risk of new-onset arrhythmia. METHODS AND RESULTS: Patients with STEMI treated with primary percutaneous coronary intervention (PPCI) at Copenhagen University Hospital, Rigshospitalet, Denmark, with CR or ICR were identified via the Eastern Danish Heart registry from 2009 to 2016. Using unique Danish administrative registries, the outcomes were assessed. The primary outcome was new-onset arrhythmia defined as a composite of atrial fibrillation/flutter (AF), sinoatrial block, advanced second- or third-degree atrioventricular block, ventricular tachycardia/fibrillation (VT), or cardiac arrest (CA), with presentation >7 days post-PPCI. Secondary outcomes were the components of the primary outcome and all-cause mortality. A total of 5103 patients (median age: 62.0 years; 76% men) were included, of whom 4009 (79%) and 1094 (21%) patients underwent CR and ICR, respectively. Compared with CR, ICR was associated with a higher risk of new-onset arrhythmia [hazard ratio (HR), 1.33; 95% confidence interval (CI), 1.07-1.66; P = 0.01], AF (HR, 1.29; 95% CI, 1.00-1.66; P = 0.05), a combined outcome of VT and CA (HR, 1.77; 95% CI, 1.10-2.84; P = 0.02) and all-cause mortality (HR, 1.27; 95% CI, 1.05-1.53; P = 0.01). All HRs adjusted. CONCLUSION: Among patients with STEMI, ICR was associated with an increased long-term risk of new-onset arrhythmia and all-cause mortality compared with CR.

Glaucoma is probably not useful as a red flag for amyloidosis.

Purpose. Transthyretin is produced in the retina and approximately one quarter of patients with variant transthyretin amyloidosis (ATTRv) develop ocular involvement. Glaucoma is the most important ocular manifestation, leading to rapid loss of vision. The usefulness of glaucoma as a red flag for cardiac amyloidosis is unknown. Materials and Methods. On a national scale, we investigated the association between glaucoma and development of amyloidosis, compared to an age- and sex-matched population from the general population. Results. The study population included 365,496 subjects (1:1 ratio). Adjusted Cox-models showed no significant association between glaucoma and future diagnosis of amyloidosis (hazard ratio: 1.16 [0.80-1.70], p = .44). Conclusion. We conclude that while ocular involvement is a possible early manifestation of ATTRv, nationwide data suggest that glaucoma is probably not useful as a red flag for cardiac amyloidosis.

Efficacy and Safety of Dapagliflozin According to Frailty in Heart Failure With Reduced Ejection Fraction : A Post Hoc Analysis of the DAPA-HF Trial.

BACKGROUND: Frailty may modify the risk-benefit profile of certain treatments, and frail patients may have reduced tolerance to treatments. OBJECTIVE: To investigate the efficacy of dapagliflozin according to frailty status, using the Rockwood cumulative deficit approach, in DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure). DESIGN: Post hoc analysis of a phase 3 randomized clinical trial. (ClinicalTrials.gov: NCT03036124). SETTING: 410 sites in 20 countries. PATIENTS: Patients with symptomatic heart failure (HF) with a left ventricular ejection fraction of 40% or less and elevated natriuretic peptide. INTERVENTION: Addition of once-daily 10 mg of dapagliflozin or placebo to guideline-recommended therapy. MEASUREMENTS: The primary outcome was worsening HF or cardiovascular death. RESULTS: Of the 4744 patients randomly assigned in DAPA-HF, a frailty index (FI) was calculable in 4742. In total, 2392 patients (50.4%) were in FI class 1 (FI ≤0.210; not frail), 1606 (33.9%) in FI class 2 (FI 0.211 to 0.310; more frail), and 744 (15.7%) in FI class 3 (FI ≥0.311; most frail). The median follow-up time was 18.2 months. Dapagliflozin reduced the risk for worsening HF or cardiovascular death, regardless of FI class. The differences in event rate per 100 person-years for dapagliflozin versus placebo from lowest to highest FI class were -3.5 (95% CI, -5.7 to -1.2), -3.6 (CI, -6.6 to -0.5), and -7.9 (CI, -13.9 to -1.9). Consistent benefits were observed for other clinical events and health status, but the absolute reductions were generally larger in the most frail patients. Study drug discontinuation and serious adverse events were not more frequent with dapagliflozin than placebo, regardless of FI class. LIMITATION: Enrollment criteria precluded the inclusion of very high-risk patients. CONCLUSION: Dapagliflozin improved all outcomes examined, regardless of frailty status. However, the absolute reductions were larger in more frail patients. PRIMARY FUNDING SOURCE: AstraZeneca.

Temporal trends in utilization of transcatheter aortic valve replacement and patient characteristics: A nationwide study.

AIM: To investigate trends in the utilization of transcatheter aortic valve replacement (TAVR) and changes in the characteristics of patients undergoing first-time TAVR. METHODS: Using Danish nationwide registers, we included all patients undergoing TAVR between 2008 and 2020. To compare patient characteristics, the study population was stratified according to calendar year of procedure: 2008-2010, 2011-2013, 2014-2016, and 2017-2020. RESULTS: We identified 6,097 patients undergoing TAVR with year-by-year increases in TAVR penetration rate. Over time, the age of the patients remained stable (2008-2010: median age 82 year [interquartile range (IQR): 77-86] vs 2017-2020: median age 81 years [IQR: 77-85]). Moreover, there was an increase in male patients (2008-2010: 49.9% vs 2017-2020: 57.4%) and patients with diabetes (2008-2010: 14.2% vs 2017-2020: 19.2%). Conversely, a history of stroke (2008-2010: 15.8% vs 2017-2020: 13.1%), previous myocardial infarction (2008-2010: 22.4% vs 2017-2020: 10.0%), heart failure (2008-2010: 40.5% vs 2017-2020: 25.2%), and peripheral artery disease (2008-2010: 14.8% vs 2017-2020: 10.4) decreased among patients. CONCLUSIONS: TAVR utilization increased markedly in the years 2008-2020. Patients undergoing TAVR had less comorbidity over time while age remained stable. Thus, despite expanding to patients at lower surgical risk, TAVR is still offered mainly to older patients.

Gender- and age-specific rates of heart failure and other adverse cardiovascular outcomes in systemic sclerosis.

OBJECTIVE: To investigate the long-term rates of heart failure (HF) and other adverse cardiovascular outcomes, including arrhythmias, myocardial infarction, ischaemic stroke, venous thromboembolism, pulmonary hypertension and pericarditis, in SSc patients according to gender and age. METHODS: Using Danish nationwide registries, SSc patients (diagnosed from 1996 to 2018) were matched with four controls from the background population by gender, age and comorbidities. Cox regression was used to compare the rates of cardiovascular outcomes between SSc patients and controls and the rate of mortality between SSc patients developing HF and HF patients without SSc, according to gender and age (above/below median). RESULTS: In total, 1569 SSc patients were matched with 6276 non-SSc controls (median age 55 years, 80.4% women, median follow-up 7.3 years). SSc had a higher rate of HF in both women [HR 2.99 (95% CI 2.18, 4.09)] and men [HR 3.01 (1.83, 4.95)] (Pinteraction = 0.88), with similar trends for other cardiovascular outcomes. SSc had a higher rate of HF in patients <55 years of age [HR 4.14 (95% CI 2.54, 6.74)] and ≥55 years [HR 2.74 (1.98, 3.78)] (Pinteraction = 0.22), with similar trends for other cardiovascular outcomes. SSc patients with new-onset HF had a higher rate of mortality than HF patients without a history of SSc, irrespective of gender (Pinteraction = 0.53) and age (Pinteraction = 0.43). CONCLUSIONS: SSc was associated with higher rates of HF and other cardiovascular outcomes than matched controls, irrespective of gender and age. Among patients with new-onset HF, a history of SSc was associated with higher mortality.