Impact of Nationwide COVID-19 Lockdowns on the Implantation Rate of Cardiac Implantable Electronic Devices.

AIM: The COVID-19 pandemic resulted in a significant decrease in the number of hospital admissions for severe emergent cardiovascular diseases during lockdowns worldwide. This study aimed to determine the impact of both the first and the second Danish nationwide lockdown on the implantation rate of cardiac implantable electronic devices (CIEDs). METHODS: We retrospectively analysed the number of CIED implantations performed in Denmark and stratified them into 3-week intervals. RESULTS: The total number of de novo CIED implantations decreased during the first lockdown by 15.5% and during the second by 5.1%. Comparing each 3-week interval using rate ratios, a significant decrease in the daily rates of the total number of de novo and replacement CIEDs (0.82, 95% CI [0.70, 0.96]), de novo CIEDs only (0.82, 95% CI [0.69, 0.98]), and non-acute pacemaker implantations (0.80, 95% CI [0.63, 0.99]) was observed during the first interval of the first lockdown. During the second lockdown (third interval), a significant decrease was seen in the daily rates of de novo CIEDs (0.73, 95% CI [0.55, 0.97]), and of pacemakers in total during both the second (0.78, 95% CI [0.62, 0.97]) and the third (0.60, 95% CI [0.42, 0.85]) intervals. Additionally, the daily rates of acute pacemaker implantation decreased during the second interval (0.47, 95% CI [0.27, 0.79]) and of non-acute implantation during the third interval (0.57, 95% CI [0.38, 0.84]). A significant increase was observed in the number of replacement procedures during the first interval of the second lockdown (1.70, 95% CI [1.04, 2.85]). CONCLUSIONS: Our study found only modest changes in CIED implantations in Denmark during two national lockdowns.

Feasibility of randomizing Danish citizens aged 65-79 years to high-dose quadrivalent influenza vaccine vs. standard-dose quadrivalent influenza vaccine in a pragmatic registry-based setting: rationale and design of the DANFLU-1 Trial.

BACKGROUND: High-dose influenza vaccines provide better protection against influenza infection than standard-dose in persons aged 65 years and above; however, in most countries, high-dose vaccines are not widely implemented. Assessing the relative effectiveness of high-dose compared to standard-dose vaccines on hospitalizations and mortality would enable more robust public health and cost-effectiveness estimates. This study aims to investigate the feasibility of conducting a pragmatic randomized clinical trial in Denmark comparing high-dose to standard-dose vaccines utilizing existing vaccination infrastructure and the Danish nationwide health registries for data collection. METHODS: The DANFLU-1 trial (NCT05048589) is a pragmatic, open-label, active-controlled randomized trial randomizing Danish citizens aged 65-79 years to either high-dose quadrivalent influenza vaccine or standard-dose quadrivalent influenza vaccine. The study utilizes the infrastructure of a private vaccination provider (Danske Lægers Vaccinations Service) for recruitment, inclusion, randomization, and vaccination. All collection of baseline and follow-up data including safety monitoring is performed centrally by the Department of Cardiology at Herlev and Gentofte Hospital, Copenhagen, Denmark using the Danish nationwide health registries. The study aims to include 40,000 participants during the 2021/2022 influenza season. The primary endpoints address feasibility and include the number of participants enrolled, randomization balance, and representativeness compared to the Danish general population. Relative vaccine effectiveness will also be assessed, however, this feasibility study is not powered for clinical outcomes and may be affected by the COVID-19 pandemic. DISCUSSION: The DANFLU-1 study is investigating the feasibility of conducting a large-scale pragmatic clinical trial in Denmark utilizing existing infrastructure and the Danish nationwide registries. This will provide valuable insight, especially for potential future fully powered vaccine trials, but also for trials wishing to investigate other interventions. TRIAL REGISTRATION: Clinicaltrials.gov : NCT05048589 , registered September 17, 2021.

Feasibility of randomizing Danish citizens aged 65–79 years to high-dose quadrivalent influenza vaccine vs. standard-dose quadrivalent influenza vaccine in a pragmatic registry-based setting: rationale and design of the DANFLU-1 Trial

Background High-dose influenza vaccines provide better protection against influenza infection than standard-dose in persons aged 65 years and above;however, in most countries, high-dose vaccines are not widely implemented. Assessing the relative effectiveness of high-dose compared to standard-dose vaccines on hospitalizations and mortality would enable more robust public health and cost-effectiveness estimates. This study aims to investigate the feasibility of conducting a pragmatic randomized clinical trial in Denmark comparing high-dose to standard-dose vaccines utilizing existing vaccination infrastructure and the Danish nationwide health registries for data collection. Methods The DANFLU-1 trial (NCT05048589) is a pragmatic, open-label, active-controlled randomized trial randomizing Danish citizens aged 65–79 years to either high-dose quadrivalent influenza vaccine or standard-dose quadrivalent influenza vaccine. The study utilizes the infrastructure of a private vaccination provider (Danske Lægers Vaccinations Service) for recruitment, inclusion, randomization, and vaccination. All collection of baseline and follow-up data including safety monitoring is performed centrally by the Department of Cardiology at Herlev and Gentofte Hospital, Copenhagen, Denmark using the Danish nationwide health registries. The study aims to include 40,000 participants during the 2021/2022 influenza season. The primary endpoints address feasibility and include the number of participants enrolled, randomization balance, and representativeness compared to the Danish general population. Relative vaccine effectiveness will also be assessed, however, this feasibility study is not powered for clinical outcomes and may be affected by the COVID-19 pandemic. Discussion The DANFLU-1 study is investigating the feasibility of conducting a large-scale pragmatic clinical trial in Denmark utilizing existing infrastructure and the Danish nationwide registries. This will provide valuable insight, especially for potential future fully powered vaccine trials, but also for trials wishing to investigate other interventions. Trial registration Clinicaltrials.gov: NCT05048589, registered September 17, 2021.

Prognostic implications of serial high-sensitivity cardiac troponin testing among patients with COVID-19: A Danish nationwide registry-based cohort study.

Background: Although troponin elevation is associated with worse outcomes among patients with coronavirus disease 2019 (COVID-19), prognostic implications of serial troponin testing are lacking. We investigated the association between serial troponin measurements and adverse COVID-19 outcomes. Methods: Using Danish registries, we identified COVID-19 patients with a high-sensitivity troponin measurement followed by a second measurement within 1-24 h. All measurements during follow-up were also utilized in subsequent time-varying analyses. We assessed all-cause mortality associated with the absence/presence of myocardial injury (≥1 troponin measurement >99th percentile upper reference limit) and absence/presence of dynamic troponin changes (>20% relative change if first measurement elevated, >50% relative change if first measurement normal). Results: Of 346 included COVID-19 patients, 56% had myocardial injury. Overall, 20% had dynamic troponin changes. In multivariable Cox regression models, myocardial injury was associated with all-cause mortality (HR = 2.56, 95%CI = 1.46-4.51), as were dynamic troponin changes (HR = 1.66, 95%CI = 1.04-2.64). We observed a low incidence of myocardial infarction (4%) and invasive coronary procedures (4%) among patients with myocardial injury. Conclusions: Myocardial injury and dynamic troponin changes determined using serial high-sensitivity troponin testing were associated with poor prognosis among patients with COVID-19. The risk of developing myocardial infarction requiring invasive management during COVID-19 hospitalization was low.

Glycated haemoglobin levels among 3295 hospitalized COVID-19 patients, with and without diabetes, and risk of severe infection, admission to an intensive care unit and all-cause mortality.

AIM: To determine the risk of adverse outcomes across the spectrum of glycated haemoglobin (HbA1c) levels among hospitalized COVID-19 patients with and without diabetes. MATERIALS AND METHODS: Danish nationwide registries were used to study the association between HbA1c levels and 30-day risk of all-cause mortality and the composite of severe COVID-19 infection, intensive care unit (ICU) admission and all-cause mortality. The study population comprised patients hospitalized with COVID-19 (3 March 2020 to 31 December 2020) with a positive polymerase chain reaction (PCR) test and an available HbA1c ≤ 6 months before the first positive PCR test. All patients had at least 30 days of follow-up. Among patients with diabetes, HbA1c was categorized as <48 mmol/mol, 48 to 53 mmol/mol, 54 to 58 mmol/mol, 59 to 64 mmol/mol (reference) and >64 mmol/mol. Among patients without diabetes, HbA1c was stratified into <31 mmol/mol, 31 to 36 mmol/mol (reference), 37 to 41 mmol/mol and 42 to 47 mmol/mol. Thirty-day standardized absolute risks and standardized absolute risk differences are reported. RESULTS: We identified 3295 hospitalized COVID-19 patients with an available HbA1c (56.2% male, median age 73.9 years), of whom 35.8% had diabetes. The median HbA1c was 54 and 37 mmol/mol among patients with and without diabetes, respectively. Among patients with diabetes, the standardized absolute risk difference of the composite outcome was higher with HbA1c < 48 mmol/mol (12.0% [95% confidence interval {CI} 3.3% to 20.8%]) and HbA1c > 64 mmol/mol (15.1% [95% CI 6.2% to 24.0%]), compared with HbA1c 59 to 64 mmol/mol (reference). Among patients without diabetes, the standardized absolute risk difference of the composite outcome was greater with HbA1c < 31 mmol/mol (8.5% [95% CI 0.5% to 16.5%]) and HbA1c 42 to 47 mmol/mol (6.7% [95% CI 1.3% to 12.1%]), compared with HbA1c 31 to 36 mmol/mol (reference). CONCLUSIONS: Patients with COVID-19 and HbA1c < 48 mmol/mol or HbA1c > 64 mmol/mol had a higher associated risk of the composite outcome. Similarly, among patients without diabetes, varying HbA1c levels were associated with higher risk of the composite outcome.

The association between cardiovascular disease admission rates and the coronavirus disease 2019 lockdown and reopening of a nation: a Danish nationwide cohort study.

AIMS: To investigate the admission rates of cardiovascular diseases, overall and according to subgroups, and subsequent mortality rates during the coronavirus disease 2019 societal lockdown (12 March 2020) and reopening phase (15 April 2020) in Denmark. METHODS AND RESULTS: Using Danish nationwide registries, we identified patients with a first-time acute cardiovascular admission in two periods: (i) 2 January-16 October 2019 and (ii) 2 January-15 October 2020. Weekly incidence rates of a first-time cardiovascular admission, overall and according to subtypes, in the two periods were calculated. The incidence rate of first-time cardiovascular admissions overall was significantly lower during the first weeks of lockdown in 2020 compared with a similar period in 2019 but increased after the gradual reopening of the Danish society. A similar trend was observed for all subgroups of cardiovascular diseases. The mortality rate among patients admitted after March 12 was not significantly different in 2020 compared with 2019 [mortality rate ratio 0.98; 95% confidence interval (CI) 0.91-1.06)]. CONCLUSION: In Denmark, we observed a substantial decrease in the rate of acute cardiovascular admissions, overall and according to subtypes, during the first weeks of lockdown. However, after the gradual reopening of the Danish society, the admission rates for acute cardiovascular diseases increased and returned to rates similar to those observed in 2019. The mortality rate in patients admitted with cardiovascular diseases during lockdown was similar to that of patients during the same period in 2019.

Association of Angiotensin-Converting Enzyme Inhibitor or Angiotensin Receptor Blocker Use With COVID-19 Diagnosis and Mortality.

IMPORTANCE: It has been hypothesized that angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin receptor blockers (ARBs) may make patients more susceptible to coronavirus disease 2019 (COVID-19) and to worse outcomes through upregulation of the functional receptor of the virus, angiotensin-converting enzyme 2. OBJECTIVE: To examine whether use of ACEI/ARBs was associated with COVID-19 diagnosis and worse outcomes in patients with COVID-19. DESIGN, SETTING, AND PARTICIPANTS: To examine outcomes among patients with COVID-19, a retrospective cohort study using data from Danish national administrative registries was conducted. Patients with COVID-19 from February 22 to May 4, 2020, were identified using ICD-10 codes and followed up from day of diagnosis to outcome or end of study period (May 4, 2020). To examine susceptibility to COVID-19, a Cox regression model with a nested case-control framework was used to examine the association between use of ACEI/ARBs vs other antihypertensive drugs and the incidence rate of a COVID-19 diagnosis in a cohort of patients with hypertension from February 1 to May 4, 2020. EXPOSURES: ACEI/ARB use was defined as prescription fillings 6 months prior to the index date. MAIN OUTCOMES AND MEASURES: In the retrospective cohort study, the primary outcome was death, and a secondary outcome was a composite outcome of death or severe COVID-19. In the nested case-control susceptibility analysis, the outcome was COVID-19 diagnosis. RESULTS: In the retrospective cohort study, 4480 patients with COVID-19 were included (median age, 54.7 years [interquartile range, 40.9-72.0]; 47.9% men). There were 895 users (20.0%) of ACEI/ARBs and 3585 nonusers (80.0%). In the ACEI/ARB group, 18.1% died within 30 days vs 7.3% in the nonuser group, but this association was not significant after adjustment for age, sex, and medical history (adjusted hazard ratio [HR], 0.83 [95% CI, 0.67-1.03]). Death or severe COVID-19 occurred in 31.9% of ACEI/ARB users vs 14.2% of nonusers by 30 days (adjusted HR, 1.04 [95% CI, 0.89-1.23]). In the nested case-control analysis of COVID-19 susceptibility, 571 patients with COVID-19 and prior hypertension (median age, 73.9 years; 54.3% men) were compared with 5710 age- and sex-matched controls with prior hypertension but not COVID-19. Among those with COVID-19, 86.5% used ACEI/ARBs vs 85.4% of controls; ACEI/ARB use compared with other antihypertensive drugs was not significantly associated with higher incidence of COVID-19 (adjusted HR, 1.05 [95% CI, 0.80-1.36]). CONCLUSIONS AND RELEVANCE: Prior use of ACEI/ARBs was not significantly associated with COVID-19 diagnosis among patients with hypertension or with mortality or severe disease among patients diagnosed as having COVID-19. These findings do not support discontinuation of ACEI/ARB medications that are clinically indicated in the context of the COVID-19 pandemic.

Consequences of coronavirus disease-2019 (COVID-19) lockdown on infection-related hospitalizations among the pediatric population in Denmark.

It remains unknown how Coronavirus disease-2019 (COVID-19) prevention measures implemented on March 12, 2020, have affected the rate of pediatric infection-related hospitalizations in Denmark. Therefore, we investigated the rate of pediatric infection-related hospitalizations during the COVID-19 pandemic. We used a retrospective cohort design and included all Danish children < 18 years. Infection-related hospitalizations were assessed during study periods in 2020 vs. 2018/2019, and we computed incidence rate ratios (IRRs) with 95% confidence intervals (CIs) using Poisson regression. In the 2020 study period, 3093 children were hospitalized with an infection, while the corresponding figures for 2018 and 2019 study periods were 4824 and 3830, respectively. When comparing the 2020 to the 2018/2019 study period prior to nationwide lockdown, we observed a decline in infection-related hospitalizations (12.68 (95% CI, 12.22-13.16) vs. 15.49 (95% CI, 15.12-15.86) per 1000 person-years). We further observed decreased IRRs, especially during the lockdown period (week 11: 0.64 (95% CI, 0.55-0.75); week 12: 0.26 (95% CI, 0.21-0.33); week 13: 0.13 (95% CI, 0.10-0.19)).Conclusion: The rate of pediatric infection-related hospitalizations in Denmark declined during the COVID-19 pandemic in 2020 compared to that in 2018/2019, with a 36% decline during initiation of the nationwide lockdown period. What is Known: • Due to the COVID-19 pandemic, several countries have implemented mitigation strategies such as lockdown of non-critical business functions. Most of these strategies have previously been proven effective on interruption of infection transmission. • It remains unclear how the mitigation strategies have affected the rate of pediatric infection-related hospitalizations. What is New: • Insight on how COVID-19 prevention measures have affected the frequency of infection-related hospitalization. • Valuable knowledge on how to act in potential future pandemics.

Incidence of infective endocarditis during the coronavirus disease 2019 pandemic: A nationwide study.

BACKGROUND: The incidence of infective endocarditis (IE) has increased in recent decades. Societal lockdown including reorganization of the healthcare system during the COVID-19 pandemic may influence the incidence of IE. This study sets out to investigate the incidence of IE during the Danish national lockdown. METHODS: In this nationwide cohort study, patients admitted with IE in either one of two periods A) A combined period of 1 January to 7 May for 2018 and 2019, or B) 1 January to 6 May 2020, were identified using Danish nationwide registries. Weekly incidence rates of IE admissions for the 2018/2019-period and 2020-period were computed and incidence rate ratios (IRR) for 2020-incidence vs 2018/2019-incidence were calculated using Poisson regression analysis. RESULTS: In total, 208 (67.3% men, median age 74.1 years) and 429 (64.1% men, median age 72.7 years) patients were admitted with IE in 2020 and 2018/2019, respectively. No significant difference in incidence rates were found comparing the 2020-period and 2018/2019-period (IRR: 0.96 (95% CI: 0.82-1.14). The overall incidence rate pre-lockdown (week 1-10: 1 January to 11 March 2020) was 14.2 IE cases per 100,000 person years (95% CI: 12.0-16.9) as compared with 11.4 IE cases per 100,000 person years (95% CI: 9.1-14.1) during lockdown (week 11-18: 12 March to 6 May 2020) corresponding to an IRR of 0.80 (95% CI: 0.60-1.06) and thus no significant difference pre- versus post-lockdown. CONCLUSION: In this nationwide cohort study, no significant difference in the incidence of IE admissions during the national lockdown due to the COVID-19 pandemic was found.

Association Between Male Sex and Outcomes of Coronavirus Disease 2019 (COVID-19)-A Danish Nationwide, Register-based Study.

BACKGROUND AND OBJECTIVES: Male sex has been associated with severe coronavirus disease 2019 (COVID-19) infection. We examined the association between male sex and severe COVID-19 infection and if an increased risk remains after adjustment for age and comorbidities. METHODS: Nationwide register-based follow-up study of COVID-19 patients in Denmark until 16 May 2020. Average risk ratio comparing 30-day composite outcome of all-cause death, severe COVID-19 diagnosis or intensive care unit (ICU) admission for men versus women standardized to the age and comorbidity distribution of all patients were derived from multivariable Cox regression. Included covariates were age, hypertension, diagnoses including obesity, alcohol, sleep apnea, diabetes, chronic obstructive pulmonary disease, previous myocardial infarction (MI), ischemic heart disease (IHD), heart failure (HF), atrial fibrillation (AF), stroke, peripheral artery disease, cancer, liver, rheumatic, and chronic kidney disease (CKD). RESULTS: Of 4842 COVID-19 patients, 2281 (47.1%) were men. Median age was 57 [25%-75% 43-73] for men versus 52 [38-71] for women (P < .001); however, octogenarians had equal sex distribution. Alcohol diagnosis, diabetes, hypertension, sleep apnea, prior MI and IHD (all P < .001) as well as AF, stroke, and HF (all P = .01) were more often seen in men, and so was CKD (P = .03). Obesity diagnosis (P < .001) were more often seen in women. Other comorbidity differences were insignificant (P > .05). The fully adjusted average risk ratio was 1.63 [95% CI, 1.44-1.84]. CONCLUSIONS: Men with COVID-19 infection have >50% higher risk of all-cause death, severe COVID-19 infection, or ICU admission than women. The excess risk was not explained by age and comorbidities.

New-onset atrial fibrillation: incidence, characteristics, and related events following a national COVID-19 lockdown of 5.6 million people.

AIM: To determine the incidence, patient characteristics, and related events associated with new-onset atrial fibrillation (AF) during a national COVID-19 lockdown. METHODS AND RESULTS: Using nationwide Danish registries, we included all patients, aged 18-90 years, receiving a new-onset AF diagnosis during the first 3 months of 2019 and 2020. The main comparison was between patients diagnosed during lockdown (12 March 12-1 April 2020) and patients diagnosed in the corresponding period 1 year previously. We found a lower incidence of new-onset AF during the 3 weeks of lockdown compared with the corresponding weeks in 2019 [incidence rate ratios with 95% confidence intervals (CIs) for the 3 weeks: 0.66 (0.56-0.78), 0.53 (0.45-0.64), and 0.41 (0.34-0.50)]. There was a 47% drop in total numbers (562 vs. 1053). Patients diagnosed during lockdown were younger and with a lower CHA2DS2-VASc score, while history of cancer, heart failure, and vascular disease were more prevalent. During lockdown, 30 (5.3%) patients with new-onset AF suffered an ischaemic stroke and 15 (2.7%) died, compared with 45 (4.3%) and 14 (1.3%) patients during the corresponding 2019 period, respectively. The adjusted odds ratio of a related event (ischaemic stroke or all-cause death) during lock-down compared with the corresponding weeks was 1.41 (95% CI 0.93-2.12). CONCLUSIONS: Following a national lockdown in Denmark, a 47% drop in registered new-onset AF cases was observed. In the event of prolonged or subsequent lockdowns, the risk of undiagnosed AF patients developing complications could potentially translate into poorer outcomes in patients with AF during the COVID-19 pandemic.