Publications by authors named "Peter A McCullough"

587 Publications

Inpatient hospitalisation and mortality rate trends from 2004 to 2014 in the USA: a propensity score-matched case-control study of hyperkalaemia.

BMJ Open 2022 May 19;12(5):e059324. Epub 2022 May 19.

Cardiorenal Society of America, Phoenix, Arizona, USA.

Objective: To study the trends of hyperkalaemia in USA inpatient hospitalisation records with heart failure (HF), chronic kidney disease (CKD), acute kidney injury (AKI) and/or type II diabetes mellitus (T2DM) from 2004 to 2014 with respect to prevalence and inpatient mortality.

Design: Observational cross-sectional and propensity score-matched case-control study.

Setting: The National Inpatient Sample (representing up to 97% of inpatient hospital discharge records in the USA) from 2004 to 2014 PARTICIPANTS: 120 513 483 (±2 312 391) adult inpatient hospitalisation records with HF, CKD/end-stage renal disease (ESRD), AKI and/or T2DM.

Exposure: Hyperkalaemia, defined as the presence of an International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) code of '276.7' in any of the first 15 diagnostic codes.

Primary And Secondary Outcome Measures: The outcomes of interest are the annual rates of hyperkalaemia prevalence and inpatient mortality.

Results: Among 120 513 483 (±2 312 391) adult inpatient hospitalisations with HF, CKD/ESRD, AKI and/or T2DM, we found a 28.9% relative increase of hyperkalaemia prevalence from 4.94% in 2004 to 6.37% in 2014 (p<0.001). Hyperkalaemia was associated with an average of 4 percentage points higher rate of inpatient mortality (1.71 post-matching, p<0.0001). Inpatient mortality rates decreased from 11.49%±0.17% to 6.43%±0.08% and 9.67%±0.13% to 5.05%±0.07% for matched cases with and without hyperkalaemia, respectively (p<0.001).

Conclusions: Hyperkalaemia prevalence increased over time and was associated with greater inpatient mortality, even after accounting for presentation characteristics. We detected a decreasing trend in inpatient mortality risk, regardless of hyperkalaemia presence.
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http://dx.doi.org/10.1136/bmjopen-2021-059324DOI Listing
May 2022

Innate immune suppression by SARS-CoV-2 mRNA vaccinations: The role of G-quadruplexes, exosomes, and MicroRNAs.

Food Chem Toxicol 2022 Apr 15;164:113008. Epub 2022 Apr 15.

Truth for Health Foundation, Tucson, AZ, USA. Electronic address:

The mRNA SARS-CoV-2 vaccines were brought to market in response to the public health crises of Covid-19. The utilization of mRNA vaccines in the context of infectious disease has no precedent. The many alterations in the vaccine mRNA hide the mRNA from cellular defenses and promote a longer biological half-life and high production of spike protein. However, the immune response to the vaccine is very different from that to a SARS-CoV-2 infection. In this paper, we present evidence that vaccination induces a profound impairment in type I interferon signaling, which has diverse adverse consequences to human health. Immune cells that have taken up the vaccine nanoparticles release into circulation large numbers of exosomes containing spike protein along with critical microRNAs that induce a signaling response in recipient cells at distant sites. We also identify potential profound disturbances in regulatory control of protein synthesis and cancer surveillance. These disturbances potentially have a causal link to neurodegenerative disease, myocarditis, immune thrombocytopenia, Bell's palsy, liver disease, impaired adaptive immunity, impaired DNA damage response and tumorigenesis. We show evidence from the VAERS database supporting our hypothesis. We believe a comprehensive risk/benefit assessment of the mRNA vaccines questions them as positive contributors to public health.
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http://dx.doi.org/10.1016/j.fct.2022.113008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9012513PMC
April 2022

Effectiveness of ivermectin-based multidrug therapy in severely hypoxic, ambulatory COVID-19 patients.

Future Microbiol 2022 03 9;17:339-350. Epub 2022 Feb 9.

Centre for Digestive Diseases, 229 Great North Road, Five Dock, NSW, 2046, Australia.

Ivermectin is a safe, inexpensive and effective early COVID-19 treatment validated in 20+ random, controlled trials. Having developed combination therapies for , the authors present a highly effective COVID-19 therapeutic combination, stemming from clinical observations. In 24 COVID-19 subjects refusing hospitalization with high-risk features, hypoxia and untreated moderate to severe symptoms averaging 9 days, the authors administered this novel combination of ivermectin, doxycycline, zinc and vitamins D and C. All subjects resolved symptoms (in 11 days on average), and oxygen saturation improved in 24 h (87.4% to 93.1%; p = 0.001). There were no hospitalizations or deaths, less than (p < 0.002 or 0.05, respectively) background-matched CDC database controls. Triple combination therapy is safe and effective even when used in outpatients with moderate to severe symptoms. NCT04482686 (ClinicalTrial.gov).
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http://dx.doi.org/10.2217/fmb-2022-0014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8826831PMC
March 2022

Clinical Utility of a Biomarker to Detect Contrast-Induced Acute Kidney Injury during Percutaneous Cardiovascular Procedures.

Cardiorenal Med 2022 14;12(1):11-19. Epub 2022 Jan 14.

Hikari Dx, Inc., San Diego, California, USA.

Introduction: Contrast-induced acute kidney injury (CI-AKI) is a major clinical complication of percutaneous cardiovascular procedures requiring iodinated contrast. Despite its relative frequency, practicing physicians are unlikely to identify or treat this condition.

Methods: In a 2-round clinical trial of simulated patients, we examined the clinical utility of a urine-based assay that measures liver-type fatty acid-binding protein (L-FABP), a novel marker of CI-AKI. We sought to determine if interventional cardiologists' ability to diagnose and treat potential CI-AKI improved using the biomarker assay for 3 different patient types: pre-procedure, peri-procedure, and post-procedure patients.

Results: 154 participating cardiologists were randomly divided into either control or intervention. At baseline, we found no difference in the demographics or how they identified and treated potential complications of AKI, with both groups providing less than half the necessary care to their patients (46.4% for control vs. 47.6% for intervention, p = 0.250). The introduction of L-FABP into patient care resulted in a statistically significant improvement of 4.6% (p = 0.001). Compared to controls, physicians receiving L-FABP results were 2.9 times more likely to correctly identify their patients' risk for AKI (95% CI 2.1-4.0) and were more than twice as likely to treat for AKI by providing volume expansion and withholding nephrotoxic medications. We found the greatest clinical utility in the pre-procedure and peri-procedure settings but limited value in the post-procedure setting.

Conclusion: This study suggests L-FABP as a clinical marker for assessing the risk of potential CI-AKI, has clinical utility, and can lead to more accurate diagnosis and treatment.
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http://dx.doi.org/10.1159/000520820DOI Listing
May 2022

Usefulness of Combined Renin-Angiotensin System Inhibitors and Diuretic Treatment In Patients Hospitalized with COVID-19.

Am J Cardiol 2022 03 10;167:133-138. Epub 2022 Jan 10.

Cardiorenal Society of America, Phoenix, AZ.

Antecedent use of renin-angiotensin system inhibitors (RASi) prevents clinical deterioration and protects against cardiovascular/thrombotic complications of COVID-19, for indicated patients. Uncertainty exists regarding treatment continuation throughout infection and doing so with concomitant medications. Hence, the purpose of this study is to evaluate the differential effect of RASi continuation in patients hospitalized with COVID-19 according to diuretic use. We used the Coracle registry, which contains data of hospitalized patients with COVID-19 from 4 regions of Italy. We used Firth logistic regression for adult (>50 years) cases with admission on/after February 22, 2020, with a known discharge status as of April 1, 2020. There were 286 patients in this analysis; 100 patients (35.0%) continued RASi and 186 (65%) discontinued. There were 98 patients treated with a diuretic; 51 (52%) of those continued RASi. The in-hospital mortality rates in patients treated with a diuretic and continued versus discontinued RASi were 8% versus 26% (p = 0.0179). There were 188 patients not treated with a diuretic; 49 (26%) of those continued RASi. The in-hospital mortality rates in patients not treated with a diuretic and continued versus discontinued RASi were 16% versus 9% (p = 0.1827). After accounting for age, cardiovascular disease, and laboratory values, continuing RASi decreased the risk of mortality by approximately 77% (odds ratio 0.23, 95% confidence interval 0.06 to 0.95, p = 0.0419) for patients treated with diuretics, but did not alter the risk in patients treated with RASi alone. Continuing RASi in patients concomitantly treated with diuretics was associated with reduced in-hospital mortality.
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http://dx.doi.org/10.1016/j.amjcard.2021.12.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8744009PMC
March 2022

Retrospective Study of Outcomes and Hospitalization Rates of Patients in Italy with a Confirmed Diagnosis of Early COVID-19 and Treated at Home Within 3 Days or After 3 Days of Symptom Onset with Prescribed and Non-Prescribed Treatments Between November 2020 and August 2021.

Med Sci Monit 2021 Dec 30;27:e935379. Epub 2021 Dec 30.

Independent Researcher, Gallipoli, Italy.

BACKGROUND This retrospective study aimed to investigate outcomes and hospitalization rates in patients with a confirmed diagnosis of early COVID-19 treated at home with prescribed and non-prescribed treatments. MATERIAL AND METHODS The medical records of a cohort of 158 Italian patients with early COVID-19 treated at home were analyzed. Treatments consisted of indomethacin, low-dose aspirin, omeprazole, and a flavonoid-based food supplement, plus azithromycin, low-molecular-weight heparin, and betamethasone as needed. The association of treatment timeliness and of clinical variables with the duration of symptoms and with the risk of hospitalization was evaluated by logistic regression. RESULTS Patients were divided into 2 groups: group 1 (n=85) was treated at the earliest possible time (<72 h from onset of symptoms), and group 2 (n=73) was treated >72 h after the onset of symptoms. Clinical severity at the beginning of treatment was similar in the 2 groups. In group 1, symptom duration was shorter than in group 2 (median 6.0 days vs 13.0 days, P<0.001) and no hospitalizations occurred, compared with 19.18% hospitalizations in group 2. One patient in group 1 developed chest X-ray alterations and 2 patients experienced an increase in D-dimer levels, compared with 30 and 22 patients, respectively, in group 2. The main factor determining the duration of symptoms and the risk of hospitalization was the delay in starting therapy (P<0.001). CONCLUSIONS This real-world study of patients in the community showed that early diagnosis and early supportive patient management reduced the severity of COVID-19 and reduced the rate of hospitalization.
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http://dx.doi.org/10.12659/MSM.935379DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8725339PMC
December 2021

Discordance between estimated and measured changes in plasma volume among patients with acute heart failure.

ESC Heart Fail 2022 02 8;9(1):66-76. Epub 2021 Dec 8.

Department of Nephrology and Medical Intensive Care, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Hindenburgdamm 30, Berlin, 12203, Germany.

Aims: In acute heart failure (AHF), changes of venous haemoglobin (Hb) concentrations, haematocrit (Hct), and estimated plasma volume (ePV) have been proposed as surrogates of decongestion. These estimates are based on the theoretical assumptions that changes of Hb concentrations and Hct are driven by the intravascular volume status and that the intravascular Hb pool remains stable. The objective of this study was to assess the relationship of changes of measured plasma volume (mPV) with changes of Hb, Hct, and ePV in AHF.

Methods And Results: We studied 36 AHF patients, who received two sequential assessments of mPV, measured red cell volume (mRCV) and measured total blood volume (mTBV) (48 h apart), during the course of diuretic therapy using a novel visible fluorescent injectate (VFI) technique based on the indicator dilution principle. Changes of ePV were calculated based on the Kaplan-Hakim or Strauss formula. AHF patients receiving diuretics (median intravenous furosemide equivalent 160 mg/48 h) displayed a wide range of changes of mPV (-25.4% to +37.0%). Changes in mPV were not significantly correlated with changes of Hb concentration [Pearson's r (r) = -0.241, P = 0.157], Hct (r = -0.307, P = 0.069), ePV (r = 0.228, P = 0.182), or ePV (r = 0.237, P = 0.163). In contrast to theoretical assumptions, changes of mTBV were poorly correlated with changes of Hb concentrations and some patients displayed unanticipated variability of mRCV, suggesting an unstable intravascular red cell pool.

Conclusions: Changes of Hb or Hct were not reflective of directly measured changes of intravascular volume status in AHF patients. Basing clinical assessment of decongestion on changes of Hb or Hct may misguide clinical decision-making on an individual patient level.
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http://dx.doi.org/10.1002/ehf2.13739DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8788058PMC
February 2022

WITHDRAWN: A Report on Myocarditis Adverse Events in the U.S. Vaccine Adverse Events Reporting System (VAERS) in Association with COVID-19 Injectable Biological Products.

Curr Probl Cardiol 2021 09 30:101011. Epub 2021 Sep 30.

Institute of Pure and Applied Knowledge, Public Health Policy Initiative (PHPI), Texas A & M College of Medicine, Baylor Dallas Campus, Dallas TX USA.

The Publisher regrets that this article has been temporarily removed. A replacement will appear as soon as possible in which the reason for the removal of the article will be specified, or the article will be reinstated.
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http://dx.doi.org/10.1016/j.cpcardiol.2021.101011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8483988PMC
September 2021

Role of hydroxychloroquine in multidrug treatment of COVID-19.

Rev Cardiovasc Med 2021 09;22(3):545-546

Yale School of Public Health, New Haven, CT 06510, USA.

No abstract present.
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http://dx.doi.org/10.31083/j.rcm2203063DOI Listing
September 2021

Editorial.

Cardiorenal Med 2021 3;11(5-6):252-253. Epub 2021 Sep 3.

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http://dx.doi.org/10.1159/000517876DOI Listing
December 2021

Cardionephrology from the point of view of the cardiologist: no more agree to disagree-getting to 'yes' for every patient.

Clin Kidney J 2021 Sep 18;14(9):1995-1999. Epub 2021 May 18.

Internal Medicine Department, 'Grigore T. Popa' University of Medicine, Iasi, Romania.

Whether one wants to or not, interactions between the heart and the kidneys exist and manifest nevertheless. Both from theoretical and clinical perspectives, it seems the need for a subspecialty of cardionephrology seems justified. Our editorial is a cardiologist perspective on the article by Diez and Ortiz published in related to the 'need for a cardionephrology subspecialty'. We analysed the historical similarities of the emergence of already ingrained clinical fields with the current needs in the cardionephrology sector. We motivated our approach based on novel cardiovascular diagnostic and therapeutic developments and significant pathophysiological differences from a cardiological perspective, accounting for the foundation of a novel sustainable medical field. One of the sensitive issues we also addressed was the operationality and applicability of the principles. We answered with some examples from high-risk debatable contexts the question of where a cardionephrologist should be integrated. Clarifying the operationality aspects would be a positive shift towards improving guidelines adherence in managing complex patients. In conclusion, we underline that the necessity of a cardionephrologist must be addressed from an operational and scientific perspective, with the ultimate goal of reducing mortality and complications in cardiorenal patients.
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http://dx.doi.org/10.1093/ckj/sfab092DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8406057PMC
September 2021

Synthetic mRNAs; Their Analogue Caps and Contribution to Disease.

Diseases 2021 Aug 23;9(3). Epub 2021 Aug 23.

Department of Internal Medicine, Division of Cardiology, Baylor University Medical Center, Dallas, TX 75246, USA.

The structure of synthetic mRNAs as used in vaccination against cancer and infectious diseases contain specifically designed caps followed by sequences of the 5' untranslated repeats of -globin gene. The strategy for successful design of synthetic mRNAs by chemically modifying their caps aims to increase resistance to the enzymatic deccapping complex, offer a higher affinity for binding to the eukaryotic translation initiation factor 4E (elF4E) protein and enforce increased translation of their encoded proteins. However, the cellular homeostasis is finely balanced and obeys to specific laws of thermodynamics conferring balance between complexity and growth rate in evolution. An overwhelming and forced translation even under alarming conditions of the cell during a concurrent viral infection, or when molecular pathways are trying to circumvent precursor events that lead to autoimmunity and cancer, may cause the recipient cells to ignore their differential sensitivities which are essential for keeping normal conditions. The elF4E which is a powerful RNA regulon and a potent oncogene governing cell cycle progression and proliferation at a post-transcriptional level, may then be a great contributor to disease development. The mechanistic target of rapamycin (mTOR) axis manly inhibits the elF4E to proceed with mRNA translation but disturbance in fine balances between mTOR and elF4E action may provide a premature step towards oncogenesis, ignite pre-causal mechanisms of immune deregulation and cause maturation (aging) defects.
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http://dx.doi.org/10.3390/diseases9030057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8395722PMC
August 2021

Mortality and guideline-directed medical therapy in real-world heart failure patients with reduced ejection fraction.

Clin Cardiol 2021 Sep 3;44(9):1192-1198. Epub 2021 Aug 3.

Scripps Clinic, La Jolla, California, USA.

Objective: To estimate the prevalence of guideline-directed medical therapy (GDMT) in commercially insured US patients with heart failure with reduced ejection fraction (HFrEF) and examine the effect of GDMT on all-cause mortality. GDMT for HFrEF includes pharmacologic therapies such as β-blockers (BB), angiotensin-converting enzyme inhibitors (ACE-I), angiotensin receptor blockers (ARB), angiotensin receptor-neprilysin (ARNI), mineralocorticoid receptor antagonists (MRA), and sodium-glucose cotransporter inhibitors to reduce morbidity and mortality.

Methods: Patients in the Optum Integrated File from 2007 to 2019Q3, ≥18 years, with history of HFrEF, were identified. Patients prescribed both a BB and either an ACE-I, ARB, or ARNI during 6-month post-diagnosis were assigned to the GDMT cohort. All others were assigned to the not on GDMT cohort. The GDMT cohort was further classified by those patients with a record of prescription fills for both classes of medications concurrently (GDMT concurrent medication fills). Mortality at 2 years was assessed with a Cox regression model accounting for baseline demographics, comorbidities, and diuretic use.

Results: This study identified 14 880 HFrEF patients, of which 70% had a record of GDMT, and 57% had a record of concurrent prescriptions. Patients in the not on GDMT cohort had 29% increased risk of mortality versus GDMT (hazard ratio 1.29; 95% CI (1.19-1.40); p < .0001). As a sensitivity analysis, the effect of patients not on GDMT compared to GDMT with concurrent medication fills was more pronounced, with a 37% increased mortality risk.

Conclusion: In a real-world population of HFrEF patients, inadequate GDMT confers a 29% excess mortality risk over the 2-year follow-up.
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http://dx.doi.org/10.1002/clc.23664DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8427999PMC
September 2021

The Reply.

Am J Med 2021 08;134(8):e464

Department of Internal Medicine, Division of Cardiology, Texas A & M University College of Medicine, Dallas. Electronic address:

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http://dx.doi.org/10.1016/j.amjmed.2021.02.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8324249PMC
August 2021

Healthcare utilization and guideline-directed medical therapy in heart failure patients with reduced ejection fraction.

J Comp Eff Res 2021 10 6;10(14):1055-1063. Epub 2021 Jul 6.

Scripps Clinic, La Jolla, CA, USA.

This study examines the effect of guideline-directed medical therapy (GDMT) on healthcare utilization in patients with heart failure with reduced ejection fraction from Optum Integrated File from 1 January 2007 to 30 June 2020. Patients with both a beta blocker and either an ACE inhibitor (ACE-I), angiotensin receptor blocker (ARB) or angiotensin receptor neprilysin inhibitor were assigned to the GDMT cohort. All others were not on GDMT. Estimated annual all cause hospitalizations and emergency department visits per 100 patients was 29% (80 vs 62 patients) and 26% higher (54 vs 43 patients; p < 0.0001) and annualized hospital days were longer (1.88 vs 1.64; p = 0.0020) for patients not on GDMT. In a real-world population, heart failure with reduced ejection fraction, patients not optimally managed on GDMT had higher annualized healthcare utilization when compared with patients on GDMT.
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http://dx.doi.org/10.2217/cer-2021-0118DOI Listing
October 2021

Screening for SARS-CoV-2 via PCR and serological testing in asymptomatic healthcare workers.

Proc (Bayl Univ Med Cent) 2021 Mar 30;34(4):437-441. Epub 2021 Mar 30.

Baylor University Medical Center, Dallas, Texas.

The prevalence and seroconversion rate of SARS-CoV-2 infection among asymptomatic health care workers in the US is unclear. Our study utilized real-time polymerase chain reaction (RT-PCR) SARS-CoV-2 testing and serological evaluation to detect IgG antibodies specific to SARS-CoV-2 antigens in asymptomatic health care workers. A total of 197 subjects with a mean age of 35 years were recruited into the study. While most (67%) reported prolonged contact with known COVID-19 patients, only 8 (4.2%) tested positive on RT-PCR and 23 (11.7%) had detectable levels of IgG antibody to SARS-CoV-2. Out of 19 subjects with detectable IgG antibody at week 1, 11 (57.9%) lost their antibody response by week 3. No statistically significant difference was found in baseline characteristics or exposure status between subjects with positive and negative results on RT-PCR or antibody positivity. In conclusion, we found a low incidence of PCR positivity for SARS-CoV-2 in a high-risk group. This likely demonstrates the effectiveness of proper personal protective equipment use and low transmission risk in health care settings. The detectable IgG antibody titer was low, and a significant portion of subjects lost their antibody response on repeat testing. This may mean that antibody response in asymptomatic patients is categorically different than in symptomatic hospitalized patients with COVID-19.
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http://dx.doi.org/10.1080/08998280.2021.1895959DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8224198PMC
March 2021

Impact of renin-angiotensin-aldosterone system inhibitor continuation on outcomes for patients with severe coronavirus disease 2019 manifestations.

J Hypertens 2021 08;39(8):1725-1726

Baylor University Medical Center, Baylor Heart and Vascular Institute, Texas A&M College of Medicine Health Science Center, Dallas, Texas, USA.

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http://dx.doi.org/10.1097/HJH.0000000000002876DOI Listing
August 2021

The Reply.

Am J Med 2021 07;134(7):e440-e441

Texas A & M University College of Medicine, Department of Internal Medicine, Division of Cardiology, Dallas. Electronic address:

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http://dx.doi.org/10.1016/j.amjmed.2021.02.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8229557PMC
July 2021

Early multidrug treatment of SARS-CoV-2 infection (COVID-19) and reduced mortality among nursing home (or outpatient/ambulatory) residents.

Med Hypotheses 2021 Aug 5;153:110622. Epub 2021 Jun 5.

Concerned Ontario Doctors, Toronto, ON, Canada. Electronic address:

The outbreak of COVID-19 from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread all over the world with tremendous morbidity and mortality in the elderly. In-hospital treatment addresses the multifaceted nature of the illness including initial viral replication, cytokine storm, and endothelial injury with thrombosis. We identified nine reports of early treatment outcomes in COVID-19 nursing home patients. Multi-drug therapy including hydroxychloroquine with one or more anti-infectives, corticosteroids, and antithrombotic anti-blood clotting agents can be extended to seniors in the nursing home setting without hospitalization. Data from nine studies found hydroxychloroquine-based multidrug regimens were associated with a statistically significant > 60% reduction in mortality. Going forward, we conclude that early empiric treatment for the elderly with COVID-19 in the nursing home setting (or similar congregated settings with elderly residents/patients e.g. LTF or ALF) has a reasonable probability of success and acceptable safety. This group remains our highest at-risk group and warrants acute treatment focus prior to symptoms worsening. Given the rapidity and severity of SARS-CoV-2 outbreaks in nursing homes, in-center treatment of acute COVID-19 patients is a reasonable strategy to reduce the risks of hospitalization and death. If elderly high-risk patients in such congregated nursing home type settings are allowed to worsen with no early treatment, they may be too sick and fragile to benefit from in-hospital therapeutics and are at risk for pulmonary failure, life-ending micro-thrombi of the lungs, kidneys etc. The issue is timing of therapeutics, and we argue that early treatment before hospitalization, is the right time and can potentially save lives, especially among our higher-risk elderly populations hit hardest by severe illness and death from COVID-19. We must reiterate, we are talking about 'early' treatment before the disease is far along in the disease sequelae where the patient then needs hospitalization and aggressive interventions. We are referring to the initial days e.g. day one, post infection when symptoms emerge or there is strong clinical suspicion. This early therapeutic option deserves serious and urgent consideration by the medical establishment and respective decision-makers. Doctors must be allowed their clinical discretion in how they optimally treat their patients. Doctors must be brave and trust their skilled judgements and do all to save the lives of their patients. We therefore hypothesize that early outpatient ambulatory treatment, once initiated as soon as symptoms begin in high-risk positive persons, would significantly reduce hospitalizations and prevent deaths. Specifically, the provision of early multi-drug sequenced therapy with repurposed drugs will reduce hospitalization and death in elderly patients being cared for in long-term-care facilities. The most important implications of our hypothesis are: 1) hospitalizations and deaths would be reduced 2) transmission would be reduced due to the mitigation of symptoms and 3) recovery following infection and treatment provides for natural exposure immunity that is broad based, durable, and robust (helping towards natural immunity within the population). The end result is reduced strain on hospitals and systems that would allow for other non-COVID illnesses to receive care.
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http://dx.doi.org/10.1016/j.mehy.2021.110622DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8178530PMC
August 2021

Phosphate Control: The Next Frontier in Dialysis Cardiovascular Mortality.

Cardiorenal Med 2021 11;11(3):123-132. Epub 2021 Jun 11.

Baylor University Medical Center, Dallas, Texas, USA.

Background: Cardiovascular disease (CVD) is a major cause of death in patients with chronic kidney disease (CKD) on dialysis. Mortality rates are still unacceptably high even though they have fallen in the past 2 decades. Hyperphosphatemia (elevated serum phosphate levels) is seen in almost all patients with advanced CKD and is by far the largest remaining modifiable contributor to CKD mortality.

Summary: Phosphate retention drives multiple physiological mechanisms linked to increased risk of CVD. Fibroblast growth factor 23 and parathyroid hormone (PTH) levels, both of which have been suggested to have direct pathogenic CV effects, increase in response to phosphate retention. Phosphate, calcium, and PTH levels are linked in a progressively worsening cycle. Maladaptive upregulation of phosphate absorption is also likely to occur further exacerbating hyperphosphatemia. Even higher phosphate levels within the normal range may be a risk factor for vascular calcification and, thus, CV morbidity and mortality. A greater degree of phosphate control is important to reduce the risk of CV morbidity and mortality. Improved phosphate control and regular monitoring of phosphate levels are guideline-recommended, established clinical practices. There are several challenges with the current phosphate management approaches in patients with CKD on dialysis. Dietary restriction of phosphate and thrice-weekly dialysis alone are insufficient/unreliable to reduce phosphate to <5.5 mg/dL. Even with the addition of phosphate binders, the only pharmacological treatment currently indicated for hyperphosphatemia, the majority of patients are unable to achieve and maintain phosphate levels <5.5 mg/dL (or more normal levels) [PhosLo® gelcaps (calcium acetate): 667 mg (prescribing information), 2011, VELPHORO®: (Sucroferric oxyhydroxide) (prescribing information), 2013, FOSRENAL®: (Lanthanum carbonate) (prescribing information), 2016, AURYXIA®: (Ferric citrate) tablets (prescribing information), 2017, RENVELA®: (Sevelamer carbonate) (prescribing information), 2020, RealWorld dynamix. Dialysis US: Spherix Global Insights, 2019]. Phosphate binders do not target the primary pathway of phosphate absorption (paracellular), have limited binding capacity, and bind nonspecifically [PhosLo® gelcaps (calcium acetate): 667 mg (prescribing information). 2013, VELPHORO®: (Sucroferric oxyhydroxide) (prescribing information), 2013, FOSRENAL®: (Lanthanum carbonate) (prescribing information), 2016, AURYXIA®: (Ferric citrate) tablets (prescribing information), 2017, RENVELA®: (Sevelamer carbonate) (prescribing information) 2020]. Key Messages: Despite current phosphate management strategies, most patients on dialysis are unable to consistently achieve target phosphate levels, indicating a need for therapeutic innovations [RealWorld dynamix. Dialysis US: Spherix Global Insights, 2019]. Given a growing evidence base that the dominant mechanism of phosphate absorption is the intestinal paracellular pathway, new therapies are investigating ways to reduce phosphate levels by blocking absorption through the paracellular pathway.
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http://dx.doi.org/10.1159/000516286DOI Listing
October 2021

Nomenclature for Kidney Function from KDIGO: Shortcomings of Terminology Oversimplification.

Cardiorenal Med 2021 4;11(3):119-122. Epub 2021 Jun 4.

Department of Internal Medicine, Texas A&M University Health Science Center College of Medicine, Dallas, Texas, USA.

The recent Kidney Disease: Improving Global Outcomes (KDIGO) consensus conference proposed a universal nomenclature calling for "Kidney Disease" (KD) to be applied to every form of kidney dysfunction, regardless of etiology. We recognize that the estimated glomerular filtration rate and urine albumin:creatinine ratio are limited in their application to the broad spectrum of KD. However, there are additional in vitro and advanced diagnostic options that can help identify the underlying cause of KD and inform about prognosis and management. While the overarching benefit of generalizing KD as a medical problem lies with screening and detection, the downsides attributable to a nonexact diagnosis (i.e., unclear prognosis and management strategy) are considerable. Finally, the terms "acute kidney injury" and "worsening renal function" are currently used interchangeably by nephrologists and cardiologists alike, and a universal adoption of one term will likely be a sizeable challenge. To be of greater benefit, we propose KD be used as a starting point and that the etiology and other epigenetic determinants of illness continue to be evaluated and characterized.
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http://dx.doi.org/10.1159/000516615DOI Listing
October 2021

Measuring the Variation in the Prevention and Treatment of CI-AKI Among Interventional Cardiologists.

Curr Probl Cardiol 2021 Sep 3;46(9):100851. Epub 2021 Apr 3.

QURE Healthcare, San Francisco, CA; University of California, School of Medicine, San Francisco, CA; University of California, Fielding School of Public Health, Los Angeles, CA. Electronic address:

Contrast-induced acute kidney injury (CI-AKI) occurs in up to 10% of cardiac catheterizations and coronary interventions, resulting in increased morbidity, mortality, and cost. One main reason for these complications and costs is under-recognition of CI-AKI risk and under-treatment of patients with impaired renal status. 157 interventional cardiologists each cared for three simulated patients with common conditions requiring intravascular contrast media in three typical settings: pre-procedurally, during the procedure, and post-procedure. We evaluated their ability to assess the risk of developing CI-AKI, make the diagnosis, and treat CI-AKI, including proper volume expansion and withholding nephrotoxic medications. Overall, the quality-of-care scores averaged 46.0% ± 10.5, varying between 18% to 78%. The diagnostic scores for accurately assessing risk of CI-AKI were low at 57.1% ± 21.2% and the accuracy of diagnosis pre-existing chronic kidney disease was 50.2%. Poor diagnostic accuracy led to poor treatment: proper volume expansion done in only 30.7% of cases, in-hospital repeat creatinine evaluation performed in 32.1%, and avoiding nephrotoxic medications occurred in 14.2%. While volume expansion was relatively similar across the three settings (P = 0.287), the cardiologists were less likely to discontinue nephrotoxic medications in pre-procedurally (9.7%) compared to the other settings (27.0%), and to order in-hospital creatinine testing in peri-procedurally (18.8%) compared to post-procedure (57.8%) (P < 0.05 for both). The overall care of patients at risk for contrast-induced acute kidney injury varied widely and showed room for improvement. Improving care for this condition will require greater awareness by cardiologists and better diagnostic tools to guide them.
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http://dx.doi.org/10.1016/j.cpcardiol.2021.100851DOI Listing
September 2021

The Reply.

Am J Med 2021 05;134(5):e346-e347

Baylor University Medical Center, Dallas, Tex; Baylor Heart and Vascular Institute, Dallas, Tex; Baylor Jack and Jane Hamilton Heart and Vascular Hospital, Dallas, Tex. Electronic address:

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http://dx.doi.org/10.1016/j.amjmed.2021.01.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8095728PMC
May 2021

The Reply.

Am J Med 2021 05;134(5):e343-e344

Baylor Heart and Vascular Institute, Dallas, Tex. Electronic address:

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http://dx.doi.org/10.1016/j.amjmed.2021.01.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8095713PMC
May 2021

Serum creatinine and cystatin C-based estimates of glomerular filtration rate are misleading in acute heart failure.

ESC Heart Fail 2021 08 6;8(4):3070-3081. Epub 2021 May 6.

Department of Nephrology and Medical Intensive Care, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.

Aims: We aimed to test whether the endogenous filtration markers serum creatinine or cystatin C and equation-based estimates of glomerular filtration rate (GFR) based on these markers appropriately reflect changes of measured GFR in patients with acute heart failure.

Methods: In this prospective cohort study of 50 hospitalized acute heart failure patients undergoing decongestive therapy, we applied an intravenous visible fluorescent injectate (VFI), consisting of a low molecular weight component to measure GFR and a high molecular weight component to correct for measured plasma volume. Thirty-eight patients had two sequential GFR measurements 48 h apart. The co-primary endpoints of the study were safety of VFI and plasma stability of the high molecular weight component. A key secondary endpoint was to compare changes in measured GFR (mGFR) to changes of serum creatinine, cystatin C and estimated GFR.

Results: VFI-based GFR measurements were safe and consistent with plasma stability of the high molecular weight component and glomerular filtration of the low molecular weight component. Filtration marker-based point estimates of GFR, when compared with mGFR, provided only moderate correlation (Pearson's r, range 0.80-0.88, depending on equation used), precision (r , range 0.65-0.78) and accuracy (56%-74% of estimates scored within 30% of mGFR). Correlations of 48-h changes GFR estimates and changes of mGFR were significant (P < 0.05) but weak (Pearson's r, range 0.35-0.39). Observed decreases of eGFR by more than 15% had a low sensitivity (range 38%-46%, depending on equation used) in detecting true worsening mGFR, defined by a >15% decrease in mGFR.

Conclusions: In patients hospitalized for acute heart failure, serum creatinine- and cystatin C-based predictions performed poorly in detecting actual changes of GFR. These data challenge current clinical strategies to evaluate dynamics of kidney function in acute heart failure.
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http://dx.doi.org/10.1002/ehf2.13404DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8318462PMC
August 2021

Safety and Efficacy of Vadadustat for Anemia in Patients Undergoing Dialysis.

N Engl J Med 2021 04;384(17):1601-1612

From the Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, Berlin (K.-U.E.); the Department of Medicine, Division of Nephrology, Indiana University School of Medicine, Indianapolis (R.A.); Gonzalez M.D. and Aswad M.D. Health Care Services, Miami (A. Aswad); Clinical Research Consultants, Kansas City, MO (A. Awad); U.S. Renal Care, Plano (G.A.B.), Baylor University Medical Center, Baylor Heart and Vascular Hospital, Baylor Heart and Vascular Institute, Dallas (P.A.M.), Renal Associates, Division of Nephrology, University of Texas Health Science Center at San Antonio, San Antonio (P.P.), and the Section of Nephrology, Baylor College of Medicine, Houston (W.C.W.) - all in Texas; Praxis Medical Research, and the Department of Medicine, Division of General Practice, Faculdade de Medicina do ABC, São Paulo (M.R.B.); Akebia Therapeutics, Cambridge (Y.M.K.F., Z.K., B.J.M., W.L., D.L.V.), and the Division of Nephrology, Tufts Medical Center, Tufts University School of Medicine, Boston (M.J.S.) - both in Massachusetts; the Division of Nephrology, Department of Medicine, Hofstra Northwell School of Medicine, Great Neck (S.F.), and the Division of Nephrology, New York Presbyterian, Queens (B.S.) - both in New York; Nephrology Associates, Augusta (H.H.), and Emory University School of Medicine, Atlanta (J.T.) - both in Georgia; the Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom (A.J.); the Department of Medicine, Vanderbilt University Medical Center, Nashville (M.J.K.); the Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore (K.M.); Stanford University School of Medicine, Palo Alto, CA (E.F.L., G.M.C.); the Department of Medicine, Memorial University, St. John's, NL, Canada (P.S.P.); Statistics Collaborative, Washington, DC (K.A.W., J.W.); and the Department of Kidney Transplantation-Dialysis Department, Barlicki Memorial Teaching Hospital No. 1, Medical University of Lodz, Lodz, Poland (R.Z.).

Background: Vadadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor, a class of compounds that stimulate endogenous erythropoietin production.

Methods: We conducted two randomized, open-label, noninferiority phase 3 trials to evaluate the safety and efficacy of vadadustat, as compared with darbepoetin alfa, in patients with anemia and incident or prevalent dialysis-dependent chronic kidney disease (DD-CKD). The primary safety end point, assessed in a time-to-event analysis, was the first occurrence of a major adverse cardiovascular event (MACE, a composite of death from any cause, a nonfatal myocardial infarction, or a nonfatal stroke), pooled across the trials (noninferiority margin, 1.25). A key secondary safety end point was the first occurrence of a MACE plus hospitalization for either heart failure or a thromboembolic event. The primary and key secondary efficacy end points were the mean change in hemoglobin from baseline to weeks 24 to 36 and from baseline to weeks 40 to 52, respectively, in each trial (noninferiority margin, -0.75 g per deciliter).

Results: A total of 3923 patients were randomly assigned in a 1:1 ratio to receive vadadustat or darbepoetin alfa: 369 in the incident DD-CKD trial and 3554 in the prevalent DD-CKD trial. In the pooled analysis, a first MACE occurred in 355 patients (18.2%) in the vadadustat group and in 377 patients (19.3%) in the darbepoetin alfa group (hazard ratio, 0.96; 95% confidence interval [CI], 0.83 to 1.11). The mean differences between the groups in the change in hemoglobin concentration were -0.31 g per deciliter (95% CI, -0.53 to -0.10) at weeks 24 to 36 and -0.07 g per deciliter (95% CI, -0.34 to 0.19) at weeks 40 to 52 in the incident DD-CKD trial and -0.17 g per deciliter (95% CI, -0.23 to -0.10) and -0.18 g per deciliter (95% CI, -0.25 to -0.12), respectively, in the prevalent DD-CKD trial. The incidence of serious adverse events in the vadadustat group was 49.7% in the incident DD-CKD trial and 55.0% in the prevalent DD-CKD trial, and the incidences in the darbepoetin alfa group were 56.5% and 58.3%, respectively.

Conclusions: Among patients with anemia and CKD who were undergoing dialysis, vadadustat was noninferior to darbepoetin alfa with respect to cardiovascular safety and correction and maintenance of hemoglobin concentrations. (Funded by Akebia Therapeutics and Otsuka Pharmaceutical; INNOVATE ClinicalTrials.gov numbers, NCT02865850 and NCT02892149.).
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http://dx.doi.org/10.1056/NEJMoa2025956DOI Listing
April 2021

Vadadustat in Patients with Anemia and Non-Dialysis-Dependent CKD.

N Engl J Med 2021 04;384(17):1589-1600

From Stanford University School of Medicine, Palo Alto, CA (G.M.C., E.F.L.); Renal Associates, San Antonio (P.E.P.), U.S. Renal Care, Plano (G.A.B.), Baylor University Medical Center, Baylor Heart and Vascular Hospital, Baylor Heart and Vascular Institute, Dallas (P.A.M.), and the Section of Nephrology, Baylor College of Medicine, Houston (W.C.W.) - all in Texas; Akebia Therapeutics, Cambridge (Y.M.K.F., S.B., Z.K., W.L., B.J.M., A.S., D.L.V.), and the Division of Nephrology, Tufts Medical Center, Tufts University School of Medicine, Boston (M.J.S.) - both in Massachusetts; the Department of Medicine, Division of Nephrology, Indiana University School of Medicine, Indianapolis (R.A.); Excellentis Clinical Trial Consultants, George, South Africa (S.A.); Bihor County Hospital Oradea, Oradea, Romania (G.B.); Qway Research, Hialeah, FL (F.P.C.); the Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom (A.G.J.); the Department of Medicine, Vanderbilt University Medical Center, Nashville (M.J.K.); Firma Clinical Research, Hunt Valley (T.L.), and the Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore (K.M.) - both in Maryland; the Department of Medicine, Memorial University of Newfoundland, St. John's, Canada (P.S.P.); the Division of Nephrology and Hypertension, University of North Carolina Kidney Center, Chapel Hill, and the W.G. (Bill) Hefner Veterans Affairs Medical Center, Salisbury - both in North Carolina (P.R.-C.); the Division of Nephrology, New York-Presbyterian Queens, Flushing (B.S.); Firma Clinical Research, Chicago (C.T.); Emory University School of Medicine, Atlanta (J.T.); Statistics Collaborative, Washington, DC (K.A.W., J.W.); and the Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, Berlin (K.-U.E.).

Background: Vadadustat is an oral hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor, a class of drugs that stabilize HIF and stimulate erythropoietin and red-cell production.

Methods: In two phase 3, randomized, open-label, active-controlled, noninferiority trials, we compared vadadustat with the erythropoiesis-stimulating agent (ESA) darbepoetin alfa in patients with non-dialysis-dependent chronic kidney disease (NDD-CKD) not previously treated with an ESA who had a hemoglobin concentration of less than 10 g per deciliter and in patients with ESA-treated NDD-CKD and a hemoglobin concentration of 8 to 11 g per deciliter (in the United States) or 9 to 12 g per deciliter (in other countries). The primary safety end point, assessed in a time-to-event analysis, was the first major adverse cardiovascular event (MACE; a composite of death from any cause, nonfatal myocardial infarction, or nonfatal stroke), pooled across the two trials. Secondary safety end points included expanded MACE (MACE plus hospitalization for either heart failure or a thromboembolic event). The primary and key secondary efficacy end points in each trial were the mean change in hemoglobin concentration from baseline during two evaluation periods: weeks 24 through 36 and weeks 40 through 52.

Results: A total of 1751 patients with ESA-untreated NDD-CKD and 1725 with ESA-treated NDD-CKD underwent randomization in the two trials. In the pooled analysis, in which 1739 patients received vadadustat and 1732 received darbepoetin alfa, the hazard ratio for MACE was 1.17 (95% confidence interval [CI], 1.01 to 1.36), which did not meet the prespecified noninferiority margin of 1.25. The mean between-group differences in the change in the hemoglobin concentration at weeks 24 through 36 were 0.05 g per deciliter (95% CI, -0.04 to 0.15) in the trial involving ESA-untreated patients and -0.01 g per deciliter (95% CI, -0.09 to 0.07) in the trial involving ESA-treated patients, which met the prespecified noninferiority margin of -0.75 g per deciliter.

Conclusions: Vadadustat, as compared with darbepoetin alfa, met the prespecified noninferiority criterion for hematologic efficacy but not the prespecified noninferiority criterion for cardiovascular safety in patients with NDD-CKD. (Funded by Akebia Therapeutics and Otsuka Pharmaceutical; PROTECT ClinicalTrials.gov numbers, NCT02648347 and NCT02680574.).
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http://dx.doi.org/10.1056/NEJMoa2035938DOI Listing
April 2021

Understanding and Overcoming the Challenges Related to Cardiovascular Trials Involving Patients with Kidney Disease.

Clin J Am Soc Nephrol 2021 09 23;16(9):1435-1444. Epub 2021 Apr 23.

Department of Medicine, Division of Cardiology, Hennepin Healthcare, University of Minnesota, Minneapolis, Minnesota

Cardiovascular disease is a prevalent and prognostically important comorbidity among patients with kidney disease, and individuals with kidney disease make up a sizeable proportion (30%-60%) of patients with cardiovascular disease. However, several systematic reviews of cardiovascular trials have observed that patients with kidney disease, particularly those with advanced kidney disease, are often excluded from trial participation. Thus, currently available trial data for cardiovascular interventions in patients with kidney disease may be insufficient to make recommendations on the optimal approach for many therapies. The Kidney Health Initiative, a public-private partnership between the American Society of Nephrology and the US Food and Drug Administration, convened a multidisciplinary, international work group and hosted a stakeholder workshop intended to understand and develop strategies for overcoming the challenges with involving patients with kidney disease in cardiovascular clinical trials, with a particular focus on those with advanced disease. These efforts considered perspectives from stakeholders, including academia, industry, contract research organizations, regulatory agencies, patients, and care partners. This article outlines the key challenges and potential solutions discussed during the workshop centered on the following areas for improvement: building the business case, re-examining study design and implementation, and changing the clinical trial culture in nephrology. Regulatory and financial incentives could serve to mitigate financial concerns with involving patients with kidney disease in cardiovascular trials. Concerns that their inclusion could affect efficacy or safety results could be addressed through thoughtful approaches to study design and risk mitigation strategies. Finally, there is a need for closer collaboration between nephrologists and cardiologists and systemic change within the nephrology community such that participation of patients with kidney disease in clinical trials is prioritized. Ultimately, greater participation of patients with kidney disease in cardiovascular trials will help build the evidence base to guide optimal management of cardiovascular disease for this population.
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http://dx.doi.org/10.2215/CJN.17561120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8729590PMC
September 2021

The Reply.

Am J Med 2021 04;134(4):e298

Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas, Tex. Electronic address:

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http://dx.doi.org/10.1016/j.amjmed.2020.11.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8054639PMC
April 2021

Angiotensin converting enzyme inhibitors and angiotensin receptor blockers in acute heart failure: invasive hemodynamic parameters and clinical outcomes.

Rev Cardiovasc Med 2021 Mar;22(1):199-206

Department of Medicine, Division of Nephrology, Einstein Medical Center, 19141 Philadelphia, USA.

There are limited data regarding the use of angiotensin converting enzyme inhibitors/angiotensin receptor blockers (ACEi/ARBs) in acute heart failure (AHF). The purpose is to determine the patterns of ACEi/ARB use at the time of admission and discharge in relation to invasive hemodynamic data, mortality, and heart failure (HF) readmissions. This is a retrospective single-center study in patients with AHF who underwent right heart catheterization between January 2010 and December 2016. Patients on dialysis, evidence of shock, or incomplete follow up were excluded. Multivariate logistic regression analysis was used to analyze the factors associated with continuation of ACEi/ARB use on discharge and its relation to mortality and HF readmissions. The final sample was 626 patients. Patients on ACEi/ARB on admission were most likely continued on discharge. The most common reasons for stopping ACEi/ARB were worsening renal function (WRF), hypotension, and hyperkalemia. Patients with ACEi/ARB use on admission had a significantly higher systemic vascular resistance (SVR) and mean arterial pressure (MAP), but lower cardiac index (CI). Patients with RA pressures above the median received less ACEi/ARB ( = 0.025) and had significantly higher inpatient mortality ( = 0.048). After multivariate logistic regression, ACEi/ARB use at admission was associated with less inpatient mortality; OR 0.32 95% CI (0.11 to 0.93), and this effect extended to the subgroup of patients with HFpEF. Patients discharged on ACEi/ARB had significantly less 6-month HF readmissions OR 0.69 95% CI (0.48 to 0.98). ACEi/ARB use on admission for AHF was associated with less inpatient mortality including in those with HFpEF.
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http://dx.doi.org/10.31083/j.rcm.2021.01.216DOI Listing
March 2021
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