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1.
Lancet Respir Med ; 9(3): 275-284, 2021 03.
Article in English | MEDLINE | ID: covidwho-1117266

ABSTRACT

BACKGROUND: Biological considerations suggest that renin-angiotensin system inhibitors might influence the severity of COVID-19. We aimed to evaluate whether continuing versus discontinuing renin-angiotensin system inhibitors (angiotensin-converting enzyme inhibitors or angiotensin receptor blockers) affects outcomes in patients admitted to hospital with COVID-19. METHODS: The REPLACE COVID trial was a prospective, randomised, open-label trial done at 20 large referral hospitals in seven countries worldwide. Eligible participants were aged 18 years and older who were admitted to hospital with COVID-19 and were receiving a renin-angiotensin system inhibitor before admission. Individuals with contraindications to continuation or discontinuation of renin-angiotensin system inhibitor therapy were excluded. Participants were randomly assigned (1:1) to continuation or discontinuation of their renin-angiotensin system inhibitor using permuted block randomisation, with allocation concealed using a secure web-based randomisation system. The primary outcome was a global rank score in which participants were ranked across four hierarchical tiers incorporating time to death, duration of mechanical ventilation, time on renal replacement or vasopressor therapy, and multiorgan dysfunction during the hospitalisation. Primary analyses were done in the intention-to-treat population. The REPLACE COVID trial is registered with ClinicalTrials.gov, NCT04338009. FINDINGS: Between March 31 and Aug 20, 2020, 152 participants were enrolled and randomly assigned to either continue or discontinue renin-angiotensin system inhibitor therapy (continuation group n=75; discontinuation group n=77). Mean age of participants was 62 years (SD 12), 68 (45%) were female, mean body-mass index was 33 kg/m2 (SD 8), and 79 (52%) had diabetes. Compared with discontinuation of renin-angiotensin system inhibitors, continuation had no effect on the global rank score (median rank 73 [IQR 40-110] for continuation vs 81 [38-117] for discontinuation; ß-coefficient 8 [95% CI -13 to 29]). There were 16 (21%) of 75 participants in the continuation arm versus 14 (18%) of 77 in the discontinuation arm who required intensive care unit admission or invasive mechanical ventilation, and 11 (15%) of 75 participants in the continuation group versus ten (13%) of 77 in the discontinuation group died. 29 (39%) participants in the continuation group and 28 (36%) participants in the discontinuation group had at least one adverse event (χ2 test of adverse events between treatment groups p=0·77). There was no difference in blood pressure, serum potassium, or creatinine during follow-up across the two groups. INTERPRETATION: Consistent with international society recommendations, renin-angiotensin system inhibitors can be safely continued in patients admitted to hospital with COVID-19. FUNDING: REPLACE COVID Investigators, REPLACE COVID Trial Social Fundraising Campaign, and FastGrants.


Subject(s)
Angiotensin Receptor Antagonists/therapeutic use , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , COVID-19/therapy , Cardiovascular Diseases/drug therapy , Withholding Treatment/statistics & numerical data , Aged , COVID-19/complications , COVID-19/mortality , Cardiovascular Diseases/mortality , Cardiovascular Diseases/virology , Female , Hospitalization/statistics & numerical data , Humans , Male , Middle Aged , Prospective Studies , Respiration, Artificial/statistics & numerical data , SARS-CoV-2 , Treatment Outcome
2.
Am J Kidney Dis ; 77(2): 190-203.e1, 2021 02.
Article in English | MEDLINE | ID: covidwho-780044

ABSTRACT

RATIONALE & OBJECTIVE: Underlying kidney disease is an emerging risk factor for more severe coronavirus disease 2019 (COVID-19) illness. We examined the clinical courses of critically ill COVID-19 patients with and without pre-existing chronic kidney disease (CKD) and investigated the association between the degree of underlying kidney disease and in-hospital outcomes. STUDY DESIGN: Retrospective cohort study. SETTINGS & PARTICIPANTS: 4,264 critically ill patients with COVID-19 (143 patients with pre-existing kidney failure receiving maintenance dialysis; 521 patients with pre-existing non-dialysis-dependent CKD; and 3,600 patients without pre-existing CKD) admitted to intensive care units (ICUs) at 68 hospitals across the United States. PREDICTOR(S): Presence (vs absence) of pre-existing kidney disease. OUTCOME(S): In-hospital mortality (primary); respiratory failure, shock, ventricular arrhythmia/cardiac arrest, thromboembolic events, major bleeds, and acute liver injury (secondary). ANALYTICAL APPROACH: We used standardized differences to compare patient characteristics (values>0.10 indicate a meaningful difference between groups) and multivariable-adjusted Fine and Gray survival models to examine outcome associations. RESULTS: Dialysis patients had a shorter time from symptom onset to ICU admission compared to other groups (median of 4 [IQR, 2-9] days for maintenance dialysis patients; 7 [IQR, 3-10] days for non-dialysis-dependent CKD patients; and 7 [IQR, 4-10] days for patients without pre-existing CKD). More dialysis patients (25%) reported altered mental status than those with non-dialysis-dependent CKD (20%; standardized difference=0.12) and those without pre-existing CKD (12%; standardized difference=0.36). Half of dialysis and non-dialysis-dependent CKD patients died within 28 days of ICU admission versus 35% of patients without pre-existing CKD. Compared to patients without pre-existing CKD, dialysis patients had higher risk for 28-day in-hospital death (adjusted HR, 1.41 [95% CI, 1.09-1.81]), while patients with non-dialysis-dependent CKD had an intermediate risk (adjusted HR, 1.25 [95% CI, 1.08-1.44]). LIMITATIONS: Potential residual confounding. CONCLUSIONS: Findings highlight the high mortality of individuals with underlying kidney disease and severe COVID-19, underscoring the importance of identifying safe and effective COVID-19 therapies in this vulnerable population.


Subject(s)
COVID-19 , Critical Illness , Intensive Care Units/statistics & numerical data , Renal Insufficiency, Chronic , Aged , COVID-19/mortality , COVID-19/physiopathology , COVID-19/therapy , Comorbidity , Critical Illness/mortality , Critical Illness/therapy , Female , Hospital Mortality , Humans , Kidney Function Tests/methods , Kidney Function Tests/statistics & numerical data , Male , Renal Dialysis , Renal Insufficiency, Chronic/diagnosis , Renal Insufficiency, Chronic/epidemiology , Renal Insufficiency, Chronic/physiopathology , Retrospective Studies , Risk Factors , SARS-CoV-2/isolation & purification , Treatment Outcome , United States/epidemiology
3.
J Clin Hypertens (Greenwich) ; 22(10): 1780-1788, 2020 10.
Article in English | MEDLINE | ID: covidwho-767484

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for coronavirus disease 2019 (COVID-19), is associated with high incidence of multiorgan dysfunction and death. Angiotensin-converting enzyme 2 (ACE2), which facilitates SARS-CoV-2 host cell entry, may be impacted by angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), two commonly used antihypertensive classes. In a multicenter, international randomized controlled trial that began enrollment on March 31, 2020, participants are randomized to continuation vs withdrawal of their long-term outpatient ACEI or ARB upon hospitalization with COVID-19. The primary outcome is a hierarchical global rank score incorporating time to death, duration of mechanical ventilation, duration of renal replacement or vasopressor therapy, and multiorgan dysfunction severity. Approval for the study has been obtained from the Institutional Review Board of each participating institution, and all participants will provide informed consent. A data safety monitoring board has been assembled to provide independent oversight of the project.


Subject(s)
Angiotensin Receptor Antagonists/pharmacology , Angiotensin-Converting Enzyme Inhibitors/pharmacology , COVID-19/complications , Multiple Organ Failure/epidemiology , SARS-CoV-2/drug effects , Adult , Angiotensin Receptor Antagonists/adverse effects , Angiotensin-Converting Enzyme Inhibitors/adverse effects , COVID-19/epidemiology , COVID-19/virology , Case-Control Studies , Female , Hospitalization/statistics & numerical data , Humans , Incidence , Male , Multiple Organ Failure/mortality , Prospective Studies , Renal Replacement Therapy/statistics & numerical data , Respiration, Artificial/statistics & numerical data , SARS-CoV-2/genetics , Severity of Illness Index , Vasoconstrictor Agents/therapeutic use , Withholding Treatment/statistics & numerical data
4.
Adv Chronic Kidney Dis ; 27(5): 404-411, 2020 09.
Article in English | MEDLINE | ID: covidwho-722379

ABSTRACT

Hypertension emerged from early reports as a potential risk factor for worse outcomes for persons with coronavirus disease 2019 (COVID-19). Among the putative links between hypertension and COVID-19 is a key counter-regulatory component of the renin-angiotensin system (RAS): angiotensin-converting enzyme 2 (ACE2). ACE2 facilitates entry of severe acute respiratory syndrome coronavirus 2, the virus responsible for COVID-19, into host cells. Because RAS inhibitors have been suggested to increase ACE2 expression, health-care providers and patients have grappled with the decision of whether to discontinue these medications during the COVID-19 pandemic. However, experimental models of analogous viral pneumonias suggest RAS inhibitors may exert protective effects against acute lung injury. We review how RAS and ACE2 biology may affect outcomes in COVID-19 through pulmonary and other systemic effects. In addition, we briefly detail the data for and against continuation of RAS inhibitors in persons with COVID-19 and summarize the current consensus recommendations from select specialty organizations.


Subject(s)
Acute Lung Injury/metabolism , Angiotensin Receptor Antagonists/therapeutic use , Angiotensin-Converting Enzyme 2/metabolism , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , COVID-19/metabolism , Hypertension/drug therapy , Acute Lung Injury/epidemiology , Acute Lung Injury/immunology , Angiotensin I/immunology , Angiotensin I/metabolism , Angiotensin II/immunology , Angiotensin II/metabolism , Angiotensin-Converting Enzyme 2/immunology , COVID-19/epidemiology , COVID-19/immunology , Comorbidity , Humans , Hypertension/epidemiology , Hypertension/metabolism , JNK Mitogen-Activated Protein Kinases/immunology , JNK Mitogen-Activated Protein Kinases/metabolism , Lung/immunology , Lung/metabolism , MAP Kinase Signaling System , Peptide Fragments/immunology , Peptide Fragments/metabolism , Protective Factors , Receptors, Coronavirus/immunology , Receptors, Coronavirus/metabolism , Renin-Angiotensin System , Risk Factors , SARS-CoV-2 , Up-Regulation
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