Assessment of a systematic approach for implementing novel medications in clinical practice: an observational study with dapagliflozin.

OBJECTIVE: To assess a systematic implementation approach for introducing dapagliflozin to individuals with heart failure and reduced ejection fraction in an outpatient clinical setting. METHODS: Retrospective medical record data were analysed. All individuals diagnosed with heart failure who resided within the hospital catchment area and had visited cardiology or internal medicine department between 2010 and 2019 were screened by using the main inclusion criteria from the DAPA-HF trial. The effectiveness of the previously described seven-step systematic implementation approach was assessed by the proportion receiving information letter, dapagliflozin treatment, follow-ups at 2-12 weeks and 12 months post-dapagliflozin initiation, persistence on dapagliflozin, adverse events, and reasons for discontinuation. RESULTS: Of the 2433 individuals, 352 met the main DAPA-HF trial criteria in step 2. After exclusions in steps 3 and 4, 191 individuals remained. Of these, 158 were invited for eligibility discussion in step 5, with 107 having received an information letter beforehand. In step 6, dapagliflozin was prescribed to 69 individuals, and in step 7, follow-ups were conducted with 56 individuals at 2-12 weeks and 62 individuals at 12 months. Sixty out of 69 persisted on dapagliflozin after 12 months. Adverse events were reported by nine individuals. Discontinuation was attributed to reasons such as urinary tract infections, genital or abdominal discomfort, and hypotension. CONCLUSION: The systematic introduction of dapagliflozin to heart failure patients was effective. Despite this, challenges in uniformly implementing procedures across patients were evident, emphasizing the necessity for a systematic implementation approach.

Serious adverse drug events associated with psychotropic treatment of bipolar or schizoaffective disorder: a 17-year follow-up on the LiSIE retrospective cohort study.

Introduction: Mood stabilisers and other psychotropic drugs can lead to serious adverse drug events (ADEs). However, the incidence remains unknown. We aimed to (a) determine the incidence of serious ADEs in patients with bipolar or schizoaffective disorders, (b) explore the role of lithium exposure, and (c) describe the aetiology. Methods: This study is part of the LiSIE (Lithium-Study into Effects and Side Effects) retrospective cohort study. Between 2001 and 2017, patients in the Swedish region of Norrbotten, with a diagnosis of bipolar or schizoaffective disorder, were screened for serious ADEs to psychotropic drugs, having resulted in critical, post-anaesthesia, or intensive care. We determined the incidence rate of serious ADEs/1,000 person-years (PY). Results: In 1,521 patients, we identified 41 serious ADEs, yielding an incidence rate of 1.9 events per 1,000 PY. The incidence rate ratio (IRR) between ADEs with lithium present and causally implicated and ADEs without lithium exposure was significant at 2.59 (95% CI 1.20-5.51; p = 0.0094). The IRR of ADEs in patients <65 and ≥65 years was significant at 3.36 (95% CI 1.63-6.63; p = 0.0007). The most common ADEs were chronic lithium intoxication, oversedation, and cardiac/blood pressure-related events. Discussion: Serious ADEs related to treatment of bipolar (BD) or schizoaffective disorder (SZD) were uncommon but not rare. Older individuals were particularly at risk. The risk was higher in individuals exposed to lithium. Serum lithium concentration should always be checked when patients present with new or unclear somatic symptoms. However, severe ADEs also occurred with other mood stabilisers and other psychotropic drugs.

Estimating the clinical and budgetary impact of using angiotensin receptor neprilysin inhibitor as first line therapy in patients with HFrEF.

AIMS: Recent updates of international treatment guidelines for heart failure with reduced ejection fraction (HFrEF) differ regarding the use of angiotensin receptor neprilysin inhibitor (ARNI) as first-line treatment. The American Heart Association/American College of Cardiology/Heart Failure Society of America (AHA/ACC/HFSA) 2022 guidelines gives ARNI a Class IA recommendation for HFrEF patients while the European Society of Cardiology's guidelines are less clear when ARNI could be considered as first line treatment option in de novo patients. This study aimed to model the clinical and budgetary outcomes of implementing these guidelines, comparing conservative ARNI prescription patterns with less conservative in Sweden and in the United Kingdom. METHODS AND RESULTS: A health economic model was developed to compare different treatment patterns for HFrEF. Incident cohorts were included on an annual basis and followed over 10 years. The model included treatment specific all-cause mortality and hospitalization rates, as well as drug acquisition, monitoring, and hospitalization costs. Increasing the use of ARNI could lead to about 7000-12 300 life years gained and 2600-4600 hospitalizations prevented in Sweden. These health benefits come with an additional cost of 112-195 million euros. Similar results were estimated for the United Kingdom, albeit on a larger population. CONCLUSIONS: Increasing the proportion of patients receiving ARNI instead of angiotensin converting enzyme inhibitors as first-line treatment of HFrEF will lead to a considerable number of additional life years gained and prevented hospitalizations but with additional cost in terms of health care expenditure in Sweden and in the United Kingdom.

Risk of arrhythmias following COVID-19: nationwide self-controlled case series and matched cohort study.

Aims: COVID-19 increases the risk of cardiovascular disease, especially thrombotic complications. There is less knowledge on the risk of arrhythmias after COVID-19. In this study, we aimed to quantify the risk of arrhythmias following COVID-19. Methods and results: This study was based on national register data on all individuals in Sweden who tested positive for SARS-CoV-2 between 1 February 2020 and 25 May 2021. The outcome was incident cardiac arrhythmias, defined as international classification of diseases (10th revision) codes in the registers as follows: atrial arrhythmias; paroxysmal supraventricular tachycardias; bradyarrhythmias; and ventricular arrhythmias. A self-controlled case series study and a matched cohort study, using conditional Poisson regression, were performed to determine the incidence rate ratio and risk ratio, respectively, for an arrhythmia event following COVID-19.A total of 1 057 174 exposed (COVID-19) individuals were included in the study as well as 4 074 844 matched unexposed individuals. The incidence rate ratio of atrial tachycardias, paroxysmal supraventricular tachycardias, and bradyarrhythmias was significantly increased up to 60, 180, and 14 days after COVID-19, respectively. In the matched cohort study, the risk ratio during Days 1-30 following COVID-19/index date was 12.28 (10.79-13.96), 5.26 (3.74-7.42), and 3.36 (2.42-4.68), respectively, for the three outcomes. The risks were generally higher in older individuals, in unvaccinated individuals, and in individuals with more severe COVID-19. The risk of ventricular arrhythmias was not increased. Conclusion: There is an increased risk of cardiac arrhythmias following COVID-19, and particularly increased in elderly vulnerable individuals, as well as in individuals with severe COVID-19.

Low carbohydrate high fat-diet in real life assessed by diet history interviews.

BACKGROUND: Low carbohydrate high fat (LCHF) diet has been a popular low carbohydrate diet in Sweden for 15 years. Many people choose LCHF to lose weight or control diabetes, but there are concerns about the effect on long-term cardiovascular risks. There is little data on how a LCHF diet is composed in real-life. The aim of this study was to evaluate the dietary intake in a population with self-reported adherence to a LCHF diet. METHODS: A cross-sectional study of 100 volunteers that considered themselves eating LCHF was conducted. Diet history interviews (DHIs) and physical activity monitoring for validation of the DHIs were performed. RESULTS: The validation shows acceptable agreement of measured energy expenditure and reported energy intake. Median carbohydrate intake was 8.7 E% and 63% reported carbohydrate intake at potentially ketogenic levels. Median protein intake was 16.9 E%. The main source of energy was dietary fats (72.0 E%). Intake of saturated fat was 32 E% and cholesterol was 700 mg per day, both of which exceeded the recommended upper limits according to nutritional guidelines. Intake of dietary fiber was very low in our population. The use of dietary supplements was high, and it was more common to exceed the recommended upper limits of micronutrients than to have an intake below the lower limits. CONCLUSIONS: Our study indicates that in a well-motivated population, a diet with very low carbohydrate intake can be sustained over time and without apparent risk of deficiencies. High intake of saturated fats and cholesterol as well as low intake of dietary fiber remains a concern.

Prevalence and prognostic impact of left ventricular systolic dysfunction or pulmonary congestion after acute myocardial infarction.

AIMS: The aim was to describe the prevalence, characteristics, and outcome of patients with acute myocardial infarction (MI) developing left ventricular (LV) systolic dysfunction or pulmonary congestion by applying different criteria to define the population. METHODS AND RESULTS: In patients with MI included in the Swedish web-system for enhancement and development of evidence-based care in heart disease (SWEDEHEART) registry, four different sets of criteria were applied, creating four not mutually exclusive subsets of patients: patients with MI and ejection fraction (EF) < 50% and/or pulmonary congestion (subset 1); EF < 40% and/or pulmonary congestion (subset 2); EF < 40% and/or pulmonary congestion and at least one high-risk feature (subset 3, PARADISE-MI like); and EF < 50% and no diabetes mellitus (subset 4, DAPA-MI like). Subsets 1, 2, 3, and 4 constituted 31.6%, 15.0%, 12.8%, and 22.8% of all patients with MI (n = 87 177), respectively. The age and prevalence of different co-morbidities varied between subsets. For median age, 70 to 77, for diabetes mellitus, 22 to 33%; for chronic kidney disease, 22 to 38%, for prior MI, 17 to 21%, for atrial fibrillation, 7 to 14%, and for ST-elevations, 38 to 50%. The cumulative incidence of death or heart failure hospitalization at 3 years was 17.4% (95% CI: 17.1-17.7%) in all MIs; 26.9% (26.3-27.4%) in subset 1; 37.6% (36.7-38.5%) in subset 2; 41.8% (40.7-42.8%) in subset 3; and 22.6% (22.0-23.2%) in subset 4. CONCLUSIONS: Depending on the definition, LV systolic dysfunction or pulmonary congestion is present in 13-32% of all patients with MI and is associated with a two to three times higher risk of subsequent death or HF admission. There is a need to optimize management and improve outcomes for this high-risk population.

Characteristics and management of very elderly patients with heart failure: a retrospective, population cohort study.

AIMS: Unmet needs exist in the diagnosis and treatment of heart failure (HF) in the elderly population. Our aim was to analyse and compare data of diagnostics and management of very elderly patients (aged ≥85 years) compared with younger patients (aged 18-84 years) with HF in Sweden. METHODS: Incidence of ≥2 HF diagnosis (ICD-10) was identified from primary/secondary care in Uppsala and Västerbotten during 2010-2015 via electronic medical records linked to data from national health registers. Analyses investigated the diagnosis, treatment patterns, hospitalizations and outpatient visits, and mortality. RESULTS: Of 8702 patients, 27.7% were ≥85 years old, women (60.2%); most patients (80.7%) had unknown left ventricular ejection fraction; key co-morbidities comprised anaemia, dementia, and cerebrovascular disease. More very elderly patients received cardiovascular disease (CVD)-related management after diagnosis in primary care (13.6% vs. 6.5%; P < 0.0001), but fewer patients underwent echocardiography (19.3% vs. 42.9%; P < 0.0001). Within 1 year of diagnosis, very elderly patients were less likely to be hospitalized (all-cause admissions per patient: 1.9 vs. 2.3; P < 0.0001; CVD-related admissions per patient: 1.8 vs. 2.1; P = 0.0004) or prescribed an angiotensin-converting enzyme inhibitor/angiotensin receptor blocker (ACEI/ARB) plus a ß-blocker (45.2% vs. 56.9%; P < 0.0001) or an ACEI/ARB plus a ß-blocker plus a mineralocorticoid receptor antagonist (15.4% vs. 31.7%; P < 0.0001). One-year mortality was high in patients ≥85 years old, 30.5% (CI: 28.3-32.7%) out of 1797 patients. CONCLUSIONS: Despite the large number of very elderly patients with newly diagnosed HF in Sweden, poor diagnostic work-up and subsequent treatment highlight the inequality of care in this vulnerable population.

Effects of Toxic Lithium Levels on ECG-Findings from the LiSIE Retrospective Cohort Study.

(1) Background: Few studies have explored the impact of lithium intoxication on the heart. (2) Methods: We examined electrocardiogram (ECG) changes associated with lithium intoxication in the framework of the LiSIE (Lithium-Study into Effects and Side Effects) retrospective cohort study. We analysed ECGs before, during, and after intoxication. (3) Results: Of the 1136 patients included, 92 patients had experienced 112 episodes of lithium intoxication. For 55 episodes, there was an ECG available at the time; for 48 episodes, there was a reference ECG available before and/or after the lithium intoxication. Lithium intoxication led to a statistically significant decrease in heart rate from a mean 76 beats/min (SD 16.6) before intoxication to 73 beats/min (SD 17.1) during intoxication (p = 0.046). QTc correlated only weakly with lithium concentration (ρ = 0.329, p = 0.014). However, in 24% of lithium intoxication episodes, there were QT prolongations. In 54% of these, QTc exceeded 500 ms; patients with chronic intoxications being more affected. (4) Conclusions: Based on summary statistics, effects of lithium intoxication on HR and QTc seem mostly discrete and not clinically relevant. However, QT prolongation can carry a risk of becoming severe. Therefore, an ECG should always be taken in patients presenting with lithium intoxication.

Risks of deep vein thrombosis, pulmonary embolism, and bleeding after covid-19: nationwide self-controlled cases series and matched cohort study.

OBJECTIVE: To quantify the risk of deep vein thrombosis, pulmonary embolism, and bleeding after covid-19. DESIGN: Self-controlled case series and matched cohort study. SETTING: National registries in Sweden. PARTICIPANTS: 1 057 174 people who tested positive for SARS-CoV-2 between 1 February 2020 and 25 May 2021 in Sweden, matched on age, sex, and county of residence to 4 076 342 control participants. MAIN OUTCOMES MEASURES: Self-controlled case series and conditional Poisson regression were used to determine the incidence rate ratio and risk ratio with corresponding 95% confidence intervals for a first deep vein thrombosis, pulmonary embolism, or bleeding event. In the self-controlled case series, the incidence rate ratios for first time outcomes after covid-19 were determined using set time intervals and the spline model. The risk ratios for first time and all events were determined during days 1-30 after covid-19 or index date using the matched cohort study, and adjusting for potential confounders (comorbidities, cancer, surgery, long term anticoagulation treatment, previous venous thromboembolism, or previous bleeding event). RESULTS: Compared with the control period, incidence rate ratios were significantly increased 70 days after covid-19 for deep vein thrombosis, 110 days for pulmonary embolism, and 60 days for bleeding. In particular, incidence rate ratios for a first pulmonary embolism were 36.17 (95% confidence interval 31.55 to 41.47) during the first week after covid-19 and 46.40 (40.61 to 53.02) during the second week. Incidence rate ratios during days 1-30 after covid-19 were 5.90 (5.12 to 6.80) for deep vein thrombosis, 31.59 (27.99 to 35.63) for pulmonary embolism, and 2.48 (2.30 to 2.68) for bleeding. Similarly, the risk ratios during days 1-30 after covid-19 were 4.98 (4.96 to 5.01) for deep vein thrombosis, 33.05 (32.8 to 33.3) for pulmonary embolism, and 1.88 (1.71 to 2.07) for bleeding, after adjusting for the effect of potential confounders. The rate ratios were highest in patients with critical covid-19 and highest during the first pandemic wave in Sweden compared with the second and third waves. In the same period, the absolute risk among patients with covid-19 was 0.039% (401 events) for deep vein thrombosis, 0.17% (1761 events) for pulmonary embolism, and 0.101% (1002 events) for bleeding. CONCLUSIONS: The findings of this study suggest that covid-19 is a risk factor for deep vein thrombosis, pulmonary embolism, and bleeding. These results could impact recommendations on diagnostic and prophylactic strategies against venous thromboembolism after covid-19.

Motives, frequency, predictors and outcomes of MRA discontinuation in a real-world heart failure population.

INTRODUCTION: Mineralocorticoid receptor antagonists (MRAs) reduce mortality and morbidity in patients with heart failure and reduced ejection fraction (HFrEF), but are largely underused. We evaluated the frequency, motives, predictors and outcomes of MRA discontinuation in a real-world heart failure population. METHODS AND RESULTS: This was a single-centre, retrospective cohort study where medical record-based data were collected on patients with HFrEF between 2010 and 2018. In the final analysis, 572 patients were included that comprised the continued MRA group (n=275) and the discontinued MRA group (n=297). Patients that discontinued MRA were older, had a higher comorbidity index and a lower index estimated glomerular filtration rate (eGFR). Predictors of MRA discontinuations were increased S-potassium, lower eGFR, lower systolic blood pressure, higher frequency of comorbidities and a higher left ventricular ejection fraction. The most common reason for MRA discontinuation was renal dysfunction (n=97, 33%) with 59% of these having an eGFR <30 mL/min/1.73m2, and elevated S-potassium (n=71, 24%) with 32% of these having an S-potassium >5.5 mmol/L. Discontinuation of MRA increased the adjusted risk of all-cause mortality (HR 1.48; 95% CI 1.07 to 2.05; p=0.019). CONCLUSIONS: Half of all patients with HFrEF initiated on MRA discontinued the treatment. A substantial number of patients discontinued MRA without meeting the guideline-recommended levels of eGFR and S-potassium where mild to moderate hyperkalaemia seems to be the most decisive predictor. Further, MRA discontinuation was associated with increased adjusted risk of all-cause mortality.

Prevalence and treatment of diabetes and pre-diabetes in a real-world heart failure population: a single-centre cross-sectional study.

AIMS: The aim of this study was to investigate a real-world heart failure (HF) cohort regarding (1) prevalence of known diabetes mellitus (DM), undiagnosed DM and pre-diabetes, (2) if hf treatment differs depending on glycaemic status and (3) if treatment of DM differs depending on HF phenotype. METHODS: All patients who had received a diagnosis of HF at Umeå University Hospital between 2010 and 2019 were identified and data were extracted from patient files according to a prespecified protocol containing parameters for clinical characteristics, including echocardiogram results, comorbidities, fasting plasma glucose (FPG) and hemoglobin A1c (HbA1c) values. Patients' HF phenotype was determined using the latest available echocardiogram. The number of patients with previous DM diagnosis was assessed. Patients without a previous diagnosis of DM were classified as non-DM, pre-diabetes or probable DM according to FPG and HbA1c levels using WHO criteria. RESULTS: In total, 2326 patients (59% male, mean age 76±13 years) with HF and at least one echocardiogram were assessed. Of these, 617 (27%) patients had a previous diagnosis of DM. Of the 1709 patients without a previous diagnosis of DM, 1092 (67%) patients had either an FPG or HbA1c recorded, of which 441 (41%) met criteria for pre-diabetes and 97 (9%) met criteria for probable diabetes, corresponding to 19% and 4% of the entire cohort, respectively. Patients with HF and diabetes were more often treated with diuretics and beta blockers compared with non-DM patients (64% vs 42%, p<0.001 and 88% vs 83%, p<0.001, respectively). There was no difference in DM treatment between HF phenotypes. CONCLUSIONS: DM and pre-diabetes are common in this HF population with 50% of patients having either known DM, probable DM or pre-diabetes. Patients with HF and DM are more often treated with common HF medications. HF phenotype did not affect choice of DM therapy.

Healthcare resource utilisation and costs associated with a heart failure diagnosis: a retrospective, population-based cohort study in Sweden.

OBJECTIVES: To examine healthcare resource use (HRU) and costs among heart failure (HF) patients using population data from Sweden. DESIGN: Retrospective, non-interventional cohort study. SETTING: Two cohorts were identified from linked national health registers (cohort 1, 2005-2014) and electronic medical records (cohort 2, 2010-2012; primary/secondary care patients from Uppsala and Västerbotten). PARTICIPANTS: Patients (aged ≥18 years) with primary or secondary diagnoses of HF (≥2 International Classification of Diseases and Related Health Problems, 10th revision classification) during the identification period of January 2005 to March 2015 were included. OUTCOME MEASURES: HRU across the HF phenotypes was assessed with logistic regression. Costs were estimated based on diagnosis-related group codes and general price lists. RESULTS: Total annual costs of secondary care of prevalent HF increased from SEK 6.23 (€0.60) to 8.86 (€0.85) billion between 2005 and 2014. Of 4648 incident patients, HF phenotype was known for 1715: reduced ejection fraction (HFrEF): 64.5%, preserved ejection fraction (HFpEF): 35.5%. Within 1 year of HF diagnosis, the proportion of patients hospitalised was only marginally higher for HFrEF versus HFpEF (all-cause (95% CI): 64.7% (60.8 to 68.4) vs 63.7% (60.8 to 66.5), HR 0.91, p=0.14; cardiovascular disease related (95% CI): 61.1% (57.1 to 64.8) vs 60.9% (58.0 to 63.7), HR 0.93, p=0.28). Frequency of hospitalisations and outpatient visits per patient declined after the first year. All-cause secondary care costs in the first year were SEK 122 758 (€12 890)/patient/year, with HF-specific care accounting for 69% of the costs. Overall, 10% of the most expensive population (younger; predominantly male; more likely to have comorbidities) incurred ~40% of total secondary care costs. CONCLUSIONS: HF-associated costs and HRU are high, especially during the first year of diagnosis. This is driven by high hospitalisations rates. Understanding the profile of resource-intensive patients being at younger age, male sex and high Charlson comorbidity index scores at the time of the HF diagnosis is most likely a sign of more severe disease.

Mineralocorticoid receptor antagonists use in patients with heart failure and impaired renal function.

AIMS: Impaired renal function is a major contributor to the low proportion of mineralocorticoid receptor antagonist (MRA) treatment in patients with heart failure with reduced ejection fraction (HFrEF). Our aims were to investigate the impact of MRA treatment on all-cause mortality and worsening renal function (WRF) in patients with HFrEF and moderately impaired renal function. METHODS: Retrospective data between 2010-2018 on HFrEF patients from a single-centre hospital with estimated glomerular renal function (eGFR) < 60 ml/min/1.73 m2 were analysed. WRF was defined as a decline of by eGFR ≥ 20%. RESULTS: 416 patients were included, 131 patients on MRA and 285 without MRA, mean age was 77 years (SD ± 9) and 82 years (SD ± 9), respectively. Median follow-up was 2 years. 128 patients (32%) experienced WRF, 25% in the MRA group and 30% in patients without MRA (p = 0.293). In multivariable analysis, hospitalization for heart failure and systolic blood pressure were associated with WRF (p = 0.015 and p = <0.001), but not use of MRA (p = 0.421). MRA treatment had no impact on the risk of adjusted all-cause mortality (HR 0.93; 95% CI, 0.66-1.32 p = 0.685). WRF was associated with increased adjusted risk of all-cause mortality (HR 1.43; 95% CI, 1.07-1.89 p = 0.014). Use of MRA did not increase the adjusted overall risk of mortality even when experiencing WRF (HR 1.15; 95% CI, 0.81-1.63 p = 0.422). CONCLUSION: In this cohort of elderly HFrEF patients with moderately impaired renal function, MRA did not increase risk for WRF or all-cause mortality.

Avoiding bias in self-controlled case series studies of coronavirus disease 2019.

Many studies, including self-controlled case series (SCCS) studies, are being undertaken to quantify the risks of complications following infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes coronavirus disease 2019 (COVID-19). One such SCCS study, based on all COVID-19 cases arising in Sweden over an 8-month period, has shown that SARS-CoV-2 infection increases the risks of AMI and ischemic stroke. Some features of SARS-CoV-2 infection and COVID-19, present in this study and likely in others, complicate the analysis and may introduce bias. In the present paper we describe these features, and explore the biases they may generate. Motivated by data-based simulations, we propose methods to reduce or remove these biases.

Risk of acute myocardial infarction and ischaemic stroke following COVID-19 in Sweden: a self-controlled case series and matched cohort study.

BACKGROUND: COVID-19 is a complex disease targeting many organs. Previous studies highlight COVID-19 as a probable risk factor for acute cardiovascular complications. We aimed to quantify the risk of acute myocardial infarction and ischaemic stroke associated with COVID-19 by analysing all COVID-19 cases in Sweden. METHODS: This self-controlled case series (SCCS) and matched cohort study was done in Sweden. The personal identification numbers of all patients with COVID-19 in Sweden from Feb 1 to Sept 14, 2020, were identified and cross-linked with national inpatient, outpatient, cancer, and cause of death registers. The controls were matched on age, sex, and county of residence in Sweden. International Classification of Diseases codes for acute myocardial infarction or ischaemic stroke were identified in causes of hospital admission for all patients with COVID-19 in the SCCS and all patients with COVID-19 and the matched control individuals in the matched cohort study. The SCCS method was used to calculate the incidence rate ratio (IRR) for first acute myocardial infarction or ischaemic stroke following COVID-19 compared with a control period. The matched cohort study was used to determine the increased risk that COVID-19 confers compared with the background population of increased acute myocardial infarction or ischaemic stroke in the first 2 weeks following COVID-19. FINDINGS: 86 742 patients with COVID-19 were included in the SCCS study, and 348 481 matched control individuals were also included in the matched cohort study. When day of exposure was excluded from the risk period in the SCCS, the IRR for acute myocardial infarction was 2·89 (95% CI 1·51-5·55) for the first week, 2·53 (1·29-4·94) for the second week, and 1·60 (0·84-3·04) in weeks 3 and 4 following COVID-19. When day of exposure was included in the risk period, IRR was 8·44 (5·45-13·08) for the first week, 2·56 (1·31-5·01) for the second week, and 1·62 (0·85-3·09) for weeks 3 and 4 following COVID-19. The corresponding IRRs for ischaemic stroke when day of exposure was excluded from the risk period were 2·97 (1·71-5·15) in the first week, 2·80 (1·60-4·88) in the second week, and 2·10 (1·33-3·32) in weeks 3 and 4 following COVID-19; when day of exposure was included in the risk period, the IRRs were 6·18 (4·06-9·42) for the first week, 2·85 (1·64-4·97) for the second week, and 2·14 (1·36-3·38) for weeks 3 and 4 following COVID-19. In the matched cohort analysis excluding day 0, the odds ratio (OR) for acute myocardial infarction was 3·41 (1·58-7·36) and for stroke was 3·63 (1·69-7·80) in the 2 weeks following COVID-19. When day 0 was included in the matched cohort study, the OR for acute myocardial infarction was 6·61 (3·56-12·20) and for ischaemic stroke was 6·74 (3·71-12·20) in the 2 weeks following COVID-19. INTERPRETATION: Our findings suggest that COVID-19 is a risk factor for acute myocardial infarction and ischaemic stroke. This indicates that acute myocardial infarction and ischaemic stroke represent a part of the clinical picture of COVID-19, and highlights the need for vaccination against COVID-19. FUNDING: Central ALF-funding and Base Unit ALF-Funding, Region Västerbotten, Sweden; Strategic funding during 2020 from the Department of Clinical Microbiology, Umeå University, Sweden; Stroke Research in Northern Sweden; The Laboratory for Molecular Infection Medicine Sweden.

Combining ECG and echocardiography to identify transthyretin cardiac amyloidosis in heart failure.

AIMS/BACKGROUND: Transthyretin amyloid (ATTR) amyloidosis cardiomyopathy is an underdiagnosed, causatively treatable cause of heart failure (HF). The aim of this study was to evaluate the efficacy of electrocardiogram (ECG) and echocardiography on patients with increased interventricular septum diameter (IVSd) to identify ATTR cardiac amyloidosis (ATTR-CA) patients. METHODS: We investigated 58 patients with HF and an IVSd > 14 mm. Included were 33 ATTR-CA patients and 25 controls that consisted of non-amyloidosis HFpatients with negative 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid (DPD) scintigraphy. We used echocardiography including 2D speckle-tracking strain and a 12-lead ECG to test the accuracy to differentiate the groups. RESULTS: We found high diagnostic accuracy (98%) for differentiating ATTR-CA from HF controls using a combination of R amplitude in -aVR from ECG and relative wall thickness acquired from echocardiography. With this combined model (RWT/R in -aVR), the sensitivity was 100% and specificity was 95% using a cut-off value of 0.90. Furthermore, the area under the curve was 99% and the negative predictive value was 100%. CONCLUSION: We found that a simple combination of ECG and echocardiographic parameters used in clinical settings was able to differentiate ATTR-CA from other aetiologies of HF with increased interventricular septum thickness. The high sensitivity and negative predictive value render the algorithm useful for selection of patients for further diagnostic procedures for ATTR-CA.

Recurrent heart failure hospitalizations increase the risk of cardiovascular and all-cause mortality in patients with heart failure in Sweden: a real-world study.

AIMS: Heart failure (HF) is a leading cause of hospitalization and is associated with high morbidity and mortality. We examined the impact of recurrent HF hospitalizations (HFHs) on cardiovascular (CV) mortality among patients with HF in Sweden. METHODS AND RESULTS: Adults with incident HF were identified from linked national health registers and electronic medical records from 01 January 2005 to 31 December 2013 for Uppsala and until 31 December 2014 for Västerbotten. CV mortality and all-cause mortality were evaluated. A time-dependent Cox regression model was used to estimate relative CV mortality rates for recurrent HFHs. Assessment was also done for ejection fraction-based HF phenotypes and for comorbid atrial fibrillation, diabetes, or chronic renal impairment. Overall, 3878 patients with HF having an index hospitalization were included, providing 9691.9 patient-years of follow-up. Patients were relatively old (median age: 80 years) and were more frequently male (55.5%). Compared with patients without recurrent HFHs, the adjusted hazard ratio (HR [95% confidence interval; CI]) for CV mortality and all-cause mortality were statistically significant for patients with one, two, three, and four or more recurrent HFHs. The risk of CV mortality and all-cause mortality increased approximately six-fold in patients with four or more recurrent HFHs vs. those without any HFHs (HR [95% CI]: 6.26 [5.24-7.48] and 5.59 [4.70-6.64], respectively). Similar patterns were observed across the HF phenotypes and patients with comorbidities. CONCLUSIONS: There is a strong association between recurrent HFHs and CV and all-cause mortality, with the risk increasing progressively with each recurrent HFH.

Eligibility of Dapagliflozin and Empagliflozin in a Real-World Heart Failure Population.

AIMS: This study is aimed at investigating the eligibility in a real-world heart failure population for the DAPA-HF (testing dapagliflozin) and EMPEROR-reduced (testing empagliflozin) trials, comparing the eligible real-world patients to trial participants and to characterize the noneligible patients. METHODS: Medical records of all heart failure patients who had a diagnosis of heart failure from the Heart Centre or Department of Internal Medicine at Umeå University Hospital were reviewed. RESULTS: 2433 of the hospital's uptake population of 150 000 had a diagnosis of heart failure. 681 patients had left ventricle ejection fraction ≤ 40%, and of these 352 (52%) and 268 (39%) patients met eligibility criteria for DAPA-HF and EMPEROR-reduced, respectively. Comparing eligible patients in our population with the DAPA-HF- and EMPEROR-reduced trial populations, we found that eligible real-world patients were older (79.0 vs. 66.2 years and 80.3 vs. 67.2 years, respectively), had worse renal function (eGFR 54.4 vs. 66.0 ml/min/1.73m2 and 49.5 vs. 61.8 ml/min/1.73m2, respectively), higher prevalence of atrial fibrillation (56.0% vs. 36.1% and 53.0% vs. 35.6%, respectively), and lower prevalence of diabetes mellitus (21.0% vs. 41.8% and 26.1% vs. 49.8%, respectively). The main reasons for ineligibility were low NT-proBNP or low eGFR. Noneligible patients differed according to reason for ineligibility, where patients with low NT-proBNP were generally younger and healthier, and patients with low eGFR were older and had more comorbidities. CONCLUSIONS: 39-52% of patients with heart failure and reduced ejection fraction in this real-world heart failure population were eligible for SGLT2-inhibitor treatment, corresponding to 11-14% of all heart failure patients. Compared to trial participants, eligible real-world patients were significantly older with worse renal function, more atrial fibrillation, and less diabetes mellitus. Trial entry criteria exclude comparatively young and healthy patients, as well as comparatively old patients with more comorbid conditions.

Prevalence of wild type transtyrethin cardiac amyloidosis in a heart failure clinic.

AIMS: Wild type transthyretin amyloidosis (ATTRwt) has gained interest during recent years due to better diagnostic tools and the emergence of treatment options. Little is known about the prevalence of the disease. We aimed to investigate the prevalence in a heart failure population with myocardial hypertrophy. METHODS AND RESULTS: All patients with an ICD code of heart failure living within the catchment area of Umeå University hospital and intraventricular septum >14 mm were offered screening with 3,3-diphosphono-1,2-propanodicarboxylic acid (DPD) scan and a clinical work up. Out of 2238 patients with heart failure, 174 patients were found to have a septum >14 mm. Ten patients were already diagnosed with hereditary ATTR cardiomyopathy, 12 patients had ATTRwt cardiomyopathy, 12 patients had known HCM, one patient had AL amyloidosis, and four patients had already undergone a negative DPD scan (DPD uptake grade 0 and 1) within the last 3 years. This left 134 patients who we tried to contact for screening, but 48 patients had either died or declined to participate. Out of 86 screened patients, 13 had a DPD uptake of grade 2 or 3 without other amyloid disease making the total number of patients with ATTRwt in this population 25. CONCLUSIONS: Approximately 20% of investigated patients in a cohort with heart failure and increased myocardial wall thickness has ATTRwt. Calculated for the whole population of heart failure patients, the prevalence is just over 1.1%. Comparing this number to the total population would give an estimated prevalence of 1:6000.