Heart failure during the COVID-19 pandemic: clinical, diagnostic, management, and organizational dilemmas.

The coronavirus 2019 (COVID-19) infection pandemic has affected the care of patients with heart failure (HF). Several consensus documents describe the appropriate diagnostic algorithm and treatment approach for patients with HF and associated COVID-19 infection. However, few questions about the mechanisms by which COVID can exacerbate HF in patients with high-risk (Stage B) or symptomatic HF (Stage C) remain unanswered. Therefore, the type of HF occurring during infection is poorly investigated. The diagnostic differentiation and management should be focused on the identification of the HF phenotype, underlying causes, and subsequent tailored therapy. In this framework, the relationship existing between COVID and onset of acute decompensated HF, isolated right HF, and cardiogenic shock is questioned, and the specific management is mainly based on local hospital organization rather than a standardized model. Similarly, some specific populations such as advanced HF, heart transplant, patients with left ventricular assist device (LVAD), or valve disease remain under investigated. In this systematic review, we examine recent advances regarding the relationships between HF and COVID-19 pandemic with respect to epidemiology, pathogenetic mechanisms, and differential diagnosis. Also, according to the recent HF guidelines definition, we highlight different clinical profile identification, pointing out the main concerns in understudied HF populations.

Long-Term Cardiovascular Effects of COVID-19: Emerging Data Relevant to the Cardiovascular Clinician.

PURPOSE OF REVIEW: COVID-19 is now a global pandemic and the illness affects multiple organ systems, including the cardiovascular system. Long-term cardiovascular consequences of COVID-19 are not yet fully characterized. This review seeks to consolidate available data on long-term cardiovascular complications of COVID-19 infection. RECENT FINDINGS: Acute cardiovascular complications of COVID-19 infection include myocarditis, pericarditis, acute coronary syndrome, heart failure, pulmonary hypertension, right ventricular dysfunction, and arrhythmia. Long-term follow-up shows increased incidence of arrhythmia, heart failure, acute coronary syndrome, right ventricular dysfunction, myocardial fibrosis, hypertension, and diabetes mellitus. There is increased mortality in COVID-19 patients after hospital discharge, and initial myocardial injury is associated with increased mortality. Emerging data demonstrates increased incidence of cardiovascular illness and structural changes in recovered COVID-19 patients. Future research will be important in understanding the clinical significance of these structural abnormalities, and to determine the effect of vaccines on preventing long-term cardiovascular complications.

A randomized controlled trial of renin-angiotensin-aldosterone system inhibitor management in patients admitted in hospital with COVID-19.

BACKGROUND: Renin-angiotensin aldosterone system inhibitors (RAASi) are commonly used among patients hospitalized with a severe acute respiratory syndrome coronavirus 2 infection coronavirus disease 2019 (COVID-19). We evaluated whether continuation versus discontinuation of RAASi were associated with short term clinical or biochemical outcomes. METHODS: The RAAS-COVID-19 trial was a randomized, open label study in adult patients previously treated with RAASi who are hospitalized with COVID-19 (NCT04508985). Participants were randomized 1:1 to discontinue or continue RAASi. The primary outcome was a global rank score calculated from baseline to day 7 (or discharge) incorporating clinical events and biomarker changes. Global rank scores were compared between groups using the Wilcoxon test statistic and the negative binomial test (using incident rate ratio [IRR]) and the intention-to-treat principle. RESULTS: Overall, 46 participants were enrolled; 21 participants were randomized to discontinue RAASi and 25 to continue. Patients' mean age was 71.5 years and 43.5% were female. Discontinuation of RAASi, versus continuation, resulted in a non-statistically different mean global rank score (discontinuation 6 [standard deviation [SD] 6.3] vs continuation 3.8 (SD 2.5); P = .60). The negative binomial analysis identified that discontinuation increased the risk of adverse outcomes (IRR 1.67 [95% CI 1.06-2.62]; P = .027); RAASi discontinuation increased brain natriuretic peptide levels (% change from baseline: +16.7% vs -27.5%; P = .024) and the incidence of acute heart failure (33% vs 4.2%, P = .016). CONCLUSION: RAASi continuation in participants hospitalized with COVID-19 appears safe; discontinuation increased brain natriuretic peptide levels and may increase risk of acute heart failure; where possible, RAASi should be continued.

Food security, diet quality, nutritional knowledge, and attitudes towards research in adults with heart failure during the COVID-19 pandemic.

BACKGROUND: The impact of the novel coronavirus disease 2019 (COVID-19) pandemic on diet and nutrition among older adults with chronic medical conditions have not been well-described. METHODS: We conducted a survey addressing (1) food access, (2) diet quality and composition, (3) nutritional understanding, and (4) attitudes towards research among adults with heart failure (HF) within an integrated health system. Adults (≥18 years) with diagnosed HF and at least one prior hospitalization for HF within the last 12 months were approached to complete the survey electronically or by mail. Outcomes included all-cause and HF-specific hospitalizations and all-cause death was ascertained via the electronic health record. RESULTS: Among 1212 survey respondents (32.5% of eligible patients) between May 18, 2020 and September 30, 2020, mean ± SD age was 77.9 ± 11.4 years, 50.1% were women, and median (25th-75th) left ventricular ejection fraction was 55% (40%-60%). Overall, 15.1% of respondents were food insecure, and only 65% of participants answered correctly more than half of the items assessing nutritional knowledge. Although most respondents were willing to participate in future research, that number largely declined for studies requiring blood draws (32.2%), study medication (14.4%), and/or behavior change (27.1%). Food security, diet quality, and nutritional knowledge were not independently associated with outcomes at 90 or 180 days. CONCLUSION: In a cohort of older adults with HF and multiple comorbidities, a significant proportion reported issues with food access, diet quality, and nutritional knowledge during the COVID-19 pandemic. Future research should evaluate interventions targeting these domains in at-risk individuals.

Timing of AKI after urgent percutaneous coronary intervention and clinical outcomes: a high-dimensional propensity score analysis.

INTRODUCTION: Acute kidney injury is a common complication of percutaneous coronary intervention and has been associated with an increased risk of death and progressive chronic kidney disease. However, whether the timing of acute kidney injury after urgent percutaneous coronary intervention could be used to improve patient risk stratification is not known. METHODS: We conducted a retrospective cohort study in adults surviving an urgent percutaneous coronary intervention between 2008 and 2013 within Kaiser Permanente Northern California, a large integrated healthcare delivery system, to evaluate the impact of acute kidney injury during hospitalization at 12 (±6), 24 (±6) and 48 (±6) hours after urgent percutaneous coronary intervention and subsequent risks of adverse outcomes within the first year after discharge. We used multivariable Cox proportional hazards models with adjustment for a high-dimensional propensity score for developing acute kidney injury after percutaneous coronary intervention to examine the associations between acute kidney injury timing and all-cause death and worsening chronic kidney disease. RESULTS: Among 7250 eligible adults undergoing urgent percutaneous coronary intervention, 306 (4.2%) had acute kidney injury at one or more of the examined time periods after percutaneous coronary intervention. After adjustment, acute kidney injury at 12 (±6) hours was independently associated with higher risks of death (adjusted hazard ratio [aHR] 3.55, 95% confidence interval [CI] 2.19-5.75) and worsening kidney function (aHR 2.40, 95% CI:1.24-4.63). Similar results were observed for acute kidney injury at 24 (±6) hours and death (aHR 3.90, 95% CI:2.29-6.66) and worsening chronic kidney disease (aHR 4.77, 95% CI:2.46-9.23). Acute kidney injury at 48 (±6) hours was associated with excess mortality (aHR 1.97, 95% CI:1.19-3.26) but was not significantly associated with worsening kidney function (aHR 0.91, 95% CI:0.42-1.98). CONCLUSIONS: Timing of acute kidney injury after urgent percutaneous coronary intervention may be differentially associated with subsequent risk of worsening kidney function but not death.

A randomized trial of icosapent ethyl in ambulatory patients with COVID-19.

The coronavirus disease 2019 (COVID-19) pandemic remains a source of considerable morbidity and mortality throughout the world. Therapeutic options to reduce symptoms, inflammatory response, or disease progression are limited. This randomized open-label trial enrolled 100 ambulatory patients with symptomatic COVID-19 in Toronto, Canada. Results indicate that icosapent ethyl (8 g daily for 3 days followed by 4 g daily for 11 days) significantly reduced high-sensitivity C-reactive protein (hs-CRP) and improved symptomatology compared with patients assigned to usual care. Specifically, the primary biomarker endpoint, change in hs-CRP, was significantly reduced by 25% among treated patients (-0.5 mg/L, interquartile range [IQR] [-6.9,0.4], within-group p = 0.011). Conversely, a non-significant 5.6% reduction was observed among usual care patients (-0.1 mg/L, IQR [-3.2,1.7], within-group p = 0.51). An unadjusted between-group primary biomarker analysis was non-significant (p = 0.082). Overall, this report provides evidence of an early anti-inflammatory effect of icosapent ethyl in a modest sample, including an initial well-tolerated loading dose, in symptomatic outpatients with COVID-19. ClinicalTrials.gov Identifier: NCT04412018.

Management of Renin-Angiotensin-Aldosterone System blockade in patients admitted to hospital with confirmed coronavirus disease (COVID-19) infection (The McGill RAAS-COVID- 19): A structured summary of a study protocol for a randomized controlled trial.

OBJECTIVES: The aim of the RAAS-COVID-19 randomized control trial is to evaluate whether an upfront strategy of temporary discontinuation of renin angiotensin aldosterone system (RAAS) inhibition versus continuation of RAAS inhibition among patients admitted with established COVID-19 infection has an impact on short term clinical and biomarker outcomes. We hypothesize that continuation of RAAS inhibition will be superior to temporary discontinuation with regards to the primary endpoint of a global rank sum score. The global rank sum score has been successfully used in previous cardiovascular clinical trials. TRIAL DESIGN: This is an open label parallel two arm (1,1 ratio) randomized control superiority trial of approximately 40 COVID-19 patients who are on chronic RAAS inhibitor therapy. PARTICIPANTS: Adults who are admitted to hospital within the McGill University Health Centre systems (MUHC) including Royal Victoria Hospital (RVH), Montreal General Hospital (MGH) and Jewish General Hospital (JGH) and who are within 96 hours of COVID-19 diagnosis (confirmed via PCR on any biological sample) will be considered for the trial. Of note, the initial protocol to screen and enrol within 48 hours of COVID-19 diagnosis was extended through an amendment, to 96 hours to increase feasibility. Participants have to be 18 years or older and would have to be on RAAS inhibitors for at least a month to be considered eligible for the study. Additionally, RAAS inhibitors should not have been held for more than 48 hours before randomization. A list of inclusion and exclusion criteria can be found in the full protocol document. In order to prevent heart failure exacerbation, patients with reduced ejection fraction were excluded from the trial. Once a patient is admitted on the ward with a diagnosis of COVID-19, we will confirm with the treating physician if the participant is suitable for the RAAS-COVID trial and meets all the inclusion and exclusion criteria. If the patient is eligible and informed consent has been obtained we will collect data on sex, age, ethnicity, past medical history and list of medications (e.g. other anti-hypertensives or anticoagulants), for further analysis. INTERVENTION AND COMPARATOR: All the study participants will be randomized to a strategy of temporarily holding the RAAS inhibitor [intervention] versus continuing the RAAS inhibitor [continued standard of care]. Among participants who are randomized to the intervention arm, alternative guide-line directed anti-hypertensive medication will be provided to the treating physician team (detail in study protocol). In the intervention arm RAAS inhibitor will be withheld for a total of 7 days with the possibility of the withdrawn medication being initiated at any point after day 7 or on the day of discharge. The recommendation for re-initiating the withdrawn medication will be made to the treating physician. The re-initiation of these therapies are according to standard convention and follow-up as per Canadian guidelines. Additionally, the date of restarting the withdrawn medication or whether the medication was re-prescribed on discharge or not, will be collected. This will be used to conduct a sensitivity analysis. Furthermore, biomarkers such as troponin, c-reactive protein (CRP) and lymphocyte count will be assessed during the same time period. Samples will be collected on randomization, day 4 and day 7. MAIN OUTCOMES: PRIMARY ENDPOINT: In this study the primary end point is a global rank score calculated for all participants, regardless of treatment assignment ( score from 0 to 7). Please refer to table 4 in the full protocol. In the context of the current trial, it is estimated that death is the most meaningful endpoint, and therefore has the highest score ( score of 7). This is followed by admission to ICU, the need for mechanical ventilation etc. The lowest scores ( score of 1) are assigned to biomarker changes (e.g. change in troponin, change in CRP). This strategy has been used successfully in cardiovascular disease trials and therefore is applicable to the current trial. The primary endpoint for the present trial is assessed from baseline to day 7 (or discharge). Participants are ranked across the clinical and biomarker domains. Lower values indicate better health (or stability). Participants who died during the 7th day of the study will be ranked based on all events occurring before their death and also including the fatal event in the score. Next, participants who did not die but were transferred to ICU for invasive ventilation will be ranked based on all the events occurring before the ICU entry and also including the ICU admission in the score. Those participants who did not die were not transferred to ICU for invasive ventilation, will be ranked based on the subsequent outcomes. The mean rank score will then be compared between groups. In this scheme, a lower mean rank score indicates greater overall stability for participants. Secondary endpoints : The key secondary endpoints are the individual components of the primary components and include the following: death, transfer to ICU primarily for invasive ventilation, transfer to ICU for other indication, non-fatal MACE ( any of following, MI, stroke, acute HF, new onset Afib), length of stay > 4 days, development of acute kidney injury ( > 40% decline in eGFR or doubling of serum creatinine), urgent intravenous treatment for high blood pressure, 30% increase in baseline high sensitivity troponin, 30% increase in baseline BNP, increase in CRP to > 30% in 48 hours and lymphocyte count drop> 30%. We will also look at the World Health Organization (WHO) ordinal scale for clinical improvement (in COVID-19) in our data. In this scale death will be assigned the highest score of 8. Patients with no limitation of activity will be assigned a score of 1 which indicates overall more stability (3). Additionally, we will evaluate the potential effects of discontinuing RAAS inhibition on alternative schedules (longer/shorter than 7 days, intermittent discontinuation) using a mechanistic mathematical model of COVID-19 immunopathology calibrated to data collected from our patient cohort. In particular, we will assess the impact of alternative schedules on primary and secondary endpoints including increases to baseline CRP and lymphocyte counts. RANDOMIZATION: Participants will be randomized in a 1:1 ratio. Randomization will be performed within an electronic database system at the time of enrolment using a random number generator, an approach that has been successfully used in other clinical trials. Neither participant, study team, or treating team will be blinded to the intervention arm. BLINDING: This is an open label study with no blinding. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): The approximate number of participants required for this trial is 40 patients (randomized 1:1 to continuation versus discontinuation of RAAS inhibitors). This number was calculated based on previous rates of outcomes for COVID-19 in the literature (e.g. death, ICU transfer) and statistical power calculations. TRIAL STATUS: Protocol number: MP-37-2021-6641, Version 4: 01-10-2020. Trial start date September 1st 2020 and currently enrolling participants. Estimated end date for recruitment of participants : July 2021. Estimated end date for study completion: September 1st 2021. TRIAL REGISTRATION: Trial registration: ClincalTrials.gov : NCT04508985 , date of registration: August 11th , 2020 FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

Rationale and design of the pragmatic randomized trial of icosapent ethyl for high cardiovascular risk adults (MITIGATE).

OBJECTIVE: The MITIGATE study aims to evaluate the real-world clinical effectiveness of pre-treatment with icosapent ethyl (IPE), compared with usual care, on laboratory-confirmed viral upper respiratory infection (URI)-related morbidity and mortality in adults with established atherosclerotic cardiovascular disease (ASCVD). BACKGROUND: IPE is a highly purified and stable omega-3 fatty acid prescription medication that is approved for cardiovascular risk reduction in high-risk adults on statin therapy with elevated triglycerides. Preclinical data and clinical observations suggest that IPE may have pleiotropic effects including antiviral and anti-inflammatory properties that may prevent or reduce the downstream sequelae and cardiopulmonary consequences of viral URIs. METHODS: MITIGATE is a virtual, electronic health record-based, open-label, randomized, pragmatic clinical trial enrolling ∼16,500 participants within Kaiser Permanente Northern California - a fully integrated and learning health care delivery system with 21 hospitals and >255 ambulatory clinics serving ∼4.5 million members. Adults ≥50 years with established ASCVD and no prior history of coronavirus disease 2019 (COVID-19) will be prospectively identified and pre-randomized in a 1:10 allocation ratio (∼ 1,500 IPE: ∼15,000 usual care) stratified by age and previous respiratory health status to the intervention (IPE 2 grams by mouth twice daily with meals) vs the control group (usual care) for a minimum follow-up duration of 6 months. The co-primary endpoints are moderate-to-severe laboratory-confirmed viral URI and worst clinical status due to a viral URI at any point in time. CONCLUSION: The MITIGATE study will inform clinical practice by providing evidence on the real-world clinical effectiveness of pretreatment with IPE to prevent and/or reduce the sequelae of laboratory-confirmed viral URIs in a high-risk cohort of patients with established ASCVD.

Sacubitril/Valsartan in Advanced Heart Failure With Reduced Ejection Fraction: Rationale and Design of the LIFE Trial.

The PARADIGM-HF (Prospective Comparison of Angiotensin II Receptor Blocker Neprilysin Inhibitor With Angiotensin-Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial reported that sacubitril/valsartan (S/V), an angiotensin receptor-neprilysin inhibitor, significantly reduced mortality and heart failure (HF) hospitalization in HF patients with a reduced ejection fraction (HFrEF). However, fewer than 1% of patients in the PARADIGM-HF study had New York Heart Association (NYHA) functional class IV symptoms. Accordingly, data that informed the use of S/V among patients with advanced HF were limited. The LIFE (LCZ696 in Hospitalized Advanced Heart Failure) study was a 24-week prospective, multicenter, double-blinded, double-dummy, active comparator trial that compared the safety, efficacy, and tolerability of S/V with those of valsartan in patients with advanced HFrEF. The trial planned to randomize 400 patients ≥18 years of age with advanced HF, defined as an EF ≤35%, New York Heart Association functional class IV symptoms, elevated natriuretic peptide concentration (B-type natriuretic peptide [BNP] ≥250 pg/ml or N-terminal pro-B-type natriuretic peptide [NT-proBNP] ≥800 pg/ml), and ≥1 objective finding of advanced HF. Following a 3- to 7-day open label run-in period with S/V (24 mg/26 mg twice daily), patients were randomized 1:1 to S/V titrated to 97 mg/103 mg twice daily versus 160 mg of V twice daily. The primary endpoint was the proportional change from baseline in the area under the curve for NT-proBNP levels measured through week 24. Secondary and tertiary endpoints included clinical outcomes and safety and tolerability. Because of the COVID-19 pandemic, enrollment in the LIFE trial was stopped prematurely to ensure patient safety and data integrity. The primary analysis consists of the first 335 randomized patients whose clinical follow-up examination results were not severely impacted by COVID-19. (Entresto [LCZ696] in Advanced Heart Failure [LIFE STUDY] [HFN-LIFE]; NCT02816736).