the impact of cardiovascular disease...hypertension is also treated with ace inhibitors and arbs,...
TRANSCRIPT
The Impact of Cardiovascular Disease on COVID-19
Nihar R. Desai, MD, MPHAssociate Professor of Medicine, Yale School of Medicine
Associate Chief, Section of Cardiovascular MedicineMedical Director, Value Based Programs
Investigator, Center for Outcomes Research and Evaluation
Financial Disclosures
• Consulting– Amgen
– Boehringer Ingelheim
– Novartis
– Relypsa
– Cytokinetics
The Association of CV Disease and Outcomes in COVID-19
MR Mehra et al. N Engl J Med 2020. DOI: 10.1056/NEJMoa2007621
MR Mehra et al. N Engl J Med 2020. DOI: 10.1056/NEJMoa2007621
The Association of CV Disease and Outcomes in COVID-19
MR Mehra et al. N Engl J Med 2020. DOI: 10.1056/NEJMoa2007621
The Association of CV Disease and Outcomes in COVID-19
HR Reynolds et al. N Engl J Med 2020. DOI: 10.1056/NEJMoa2008975
NYU Langone Analysis of CV Pharmacotherapy and COVID-19 Outcomes
Telemedicine in the Era of COVID-19: Pearls for Success
Anandita Agarwala Kulkarni, MD
@AAgarwalaMD
Financial Disclosures
• Nothing to disclose
What is Telemedicine?
• Real-time, audio-video communication tools that connect physicians and patients.
• Store-and-forward technologies that collect images and data to be transmitted and interpreted later.
• Remote patient-monitoring tools i.e. blood pressure monitors, wearable devices that can communicate biometric data
• Verbal/Audio-only and virtual check-ins via patient portal and messaging technologies
Six Key Changes During COVID-19
1. Medicare will pay physicians for telehealth services at the same rate as in-person visits for all diagnoses
2. Patients can receive telehealth services in all areas of the country and in all settings i.e. at home
3. CMS will not enforce that patients have an established relationship with the physician providing telehealth.
4. Physicians can reduce or waive cost-sharing for telehealth visits.
5. Physicians licensed in one state can provide services to Medicare beneficiaries in another state. State licensure laws still apply.
6. HHS Office for Civil Rights offers temporary flexibility for telehealth via popular video chat applications, i.e. FaceTime and Skype
Disclaimers
The waivers are temporary and effective during the period of the
national health crisis. There is no guarantee that the waivers will
continue after the COIVD-19 crisis.
It may be advantageous to set up a telehealth practice that
incorporates the prior standards of care for telehealth to be
prepared for those changes.
Be informed
Separate entities make decisions on various aspects of Telehealth:
Federal vs. State regulations
CMS vs. State-run Medicaid Plans vs. Commercial Payers vs.
Self-funded Payers
Just because one payer allows something, does not mean that all
payers will.
Adopting Telemedicine into Practice
Be familiar with federal and state laws and regulations i.e. licensure, prescribing limitations. Stay up to date as these may change or be updated from time to time.
Choose a service model that works well for you and your patients i.e. providing direct care, triaging, providing consultative services to other practitioners
Assess your technology and tech support needs-peripheral devices (stethoscopes, otoscopes), data encryption
Understand and implement practice guidelines including clinical practice guidelines and state and federal regulatory guidelines
Inform patients about telemedicine
Educate and Encourage
This is an opportunity to emphasize cardiovascular
disease prevention
Duffy et al. Circ. 2020
References
• The American Medical Association Guide to Telemedicine in Practice : https://www.ama-assn.org/practice-management/digital/ama-quick-guide-telemedicine-practice?fbclid=IwAR2Nd1FMJnZsCaLUikyVDL76WOkpDNiFIAmDR1w-w6kNHo3qF3Yv2_F706U
• Centers for Medicare & Medicaid Services: https://www.cms.gov/newsroom/fact-sheets/medicare-telemedicine-health-care-provider-fact-sheet?fbclid=IwAR05mxbxAk7Nl7pwF14vHgtlERKzeRzon_A5zSjjDjvBRVEo86eZsF3CuAE
• National Lipid Association Telehealth Primer by Dr. Anne Liebeskind: https://www.lipid.org/sites/default/files/files/Telehealth%20Primer.pdf
ACEI/ARB, NSAIDs, and Aspirin Use in COVID-19:
A Real Concern or Just Nonsense?Dave Dixon, PharmD, FACC, FCCP, FNLA, CLS
Associate Professor and Vice-Chair of Clinical Services
Virginia Commonwealth University School of Pharmacy
Richmond, Virginia
Financial Disclosures
• Nothing to disclose
Renin-Angiotensin Aldosterone System (RAAS)
Nat Clin Pract Cardiovasc Med. 2004 Nov;1(1):42-7.
ARBs
ACE-I
ACE2 (2002)
ACE2 lowers BP by catalyzing the
hydrolysis of AT-2 into Ang(1-7). ACE2 counters the activity of the related (ACE)
by reducing the amount of AT-2 and increasing Ang(1-7).
Angiotensin-converting enzyme 2 (ACE2) mediates influenza H7N9 virus-induced acute lung injury
Scientific Reports. 2014;4:7027. DOI: 10.1038/srep07027
ACEI/ARB Use Associated with Lower Risk of Pneumonia: Systematic Review and Meta-Analysis
N=37 studies
BMJ. 2012; 345: e4260.
SARS-CoV-2 and RAAS
N Engl J Med. 2020;382;17
• SARS-CoV-2 uses ACE2 to gain host entry, but as the virus replicates, ACE2 is downregulated.
• The reduction of ACE2 during the infection leads to hyperactive AT-II activity, which may contribute to inflammation and lung injury.
• Thus, inhibiting AT-II through either ACE inhibition or ARB, may reduce inflammation and risk of lung injury.
Conflicting Information • “The expression of ACE2 is substantially
increased in patients with type 1 or type
2 diabetes, who are treated with ACE
inhibitors and ARBSs. Hypertension is
also treated with ACE inhibitors and
ARBs, which results in an upregulation
of ACE2.”
• “Additionally, the activity and action of
ACE2 are not affected by ACE
inhibitors, further distinguishing ACE2
from the classic ACE.”
• “Olmesartan significantly increased the
cardiac ACE2 expression level.”
Circ Res. 2000; 87(5):E1– E9. J Biol Chem. 2000; 275(43):33238–33243.
Lancet Respir Med. 2020 Apr;8(4):e21.
Clinical, Immunological, Inflammatory,
and Viral Findings: ACEI/ARB vs. no
ACEI/ARB
Retrospective studyShenzhen Hospital, China
N=42 patients admitted with COVID-19
Emerging Microbes & Infections. 2020;9:1:757-760. DOI: 10.1080/22221751.2020.1746200
ACEI/ARB Use Not Associated with Severity or Risk of Death in Patients with Hypertension
Central Hospital,Wuhan, China
JAMA Cardiol. 2020. doi:10.1001/jamacardio.2020.1624
Population-based Case–control Study in the Lombardy region of Italy
N Engl J Med. 2020. DOI: 10.1056/NEJMoa2006923
Cases (n=6272) Controls (n=30,759)
Ongoing Clinical Trials
Clinical Trial Name Reference
Study of Open Label Losartan in COVID-19 https://clinicaltrials.gov/ct2/show/NCT04335123
Losartan for Patients With COVID-19 Requiring Hospitalization
https://clinicaltrials.gov/ct2/show/NCT04312009
Losartan for Patients With COVID-19 Not Requiring Hospitalization
https://clinicaltrials.gov/ct2/show/NCT04311177
Elimination or Prolongation of ACE Inhibitors and ARB in Coronavirus Disease 2019 (REPLACECOVID)
https://clinicaltrials.gov/ct2/show/NCT04338009
LIBERATE Trial in COVID-19 (LIBERATE) https://clinicaltrials.gov/ct2/show/NCT04334629
Protective Effect of Aspirin on COVID-19 Patients (PEAC) https://clinicaltrials.gov/ct2/show/NCT04365309
Current Recommendations: ACEI/ARBs
• Patients with cardiovascular disease are at increased risk for severe illness due to COVID-19.
• Multiple professional societies (AHA/ACC/HFSA/ESC...and others) recommend to continue ACEI/ARBs in patients currently being prescribed these therapies.• NIH Panel does not recommend initiating ACEI/ARBs for the sole purpose of
treating COVID-19 unless enrolling the patient in a clinical trial
• Abrupt withdrawal in high-risk patients (e.g., heart failure, prior myocardial infarction) may lead to clinical instability and adverse health outcomes.
N Engl J Med. 2020;382;17. DOI: 10.1056/NEJMsr2005760.NIH COVID-19 Treatment Guidelines. https://www.covid19treatmentguidelines.nih.gov/. Accessed 2020 May 1.
NSAIDs Controversy
Lancet Respir Med. 2020 Apr;8(4):e21.
Reference?
Impact of NSAID Use in other Viral Illnesses
Jpn J Infect Dis. 2016;69: 248–251.
Potential Antiviral Activity of Indomethacin
• In vitro, indomethacin has potent antiviral activity against SARS-CoV infection
• Indomethacin does not affect binding or entry into host cells.
• Possible MOA:
• Blocks viral RNA synthesis
• Independent of COX inhibition
• A parallel experiment did not find aspirin to have antiviral activity
Antivir Ther. 2006;11(8):1021-30.
Current Recommendations: NSAIDs
• Both the WHO and FDA agree there is no evidence that NSAIDs worsen outcomes in patients with COVID-19• https://www.who.int/news-room/commentaries/detail/the-use-of-non-steroidal-
anti-inflammatory-drugs-(nsaids)-in-patients-with-covid-19
• https://www.fda.gov/drugs/drug-safety-and-availability/fda-advises-patients-use-non-steroidal-anti-inflammatory-drugs-nsaids-covid-19
• However, remember that NSAID use remains ill advised in patients with cardiovascular disease, heart failure, or chronic kidney disease.
Take Home Points
• There is conflicting evidence regarding the presence, and significance, of an interaction between ACEI/ARBs and ACE2.
• The available evidence, although of generally low quality, shows continued use of ACEI/ARBs does not appear to increase the risk of severe illness due to COVID-19.
• There is no evidence to support that NSAIDs have any effect on SARS-CoV-2 infection.
The Role of Hydroxychloroquine in COVID-19 Management
Nihar R. Desai, MD, MPHAssociate Professor of Medicine, Yale School of Medicine
Associate Chief, Section of Cardiovascular MedicineMedical Director, Value Based Programs
Investigator, Center for Outcomes Research and Evaluation
Hydroxychloroquine and COVID-19
Hydroxychloroquine and COVID-19 Outcomes
J Geleris et al. N Engl J Med 2020. DOI: 10.1056/NEJMoa2012410
Association of Treatment With Hydroxychloroquine or Azithromycin With In-Hospital Mortality in Patients With
COVID-19 in New York State
JAMA. Published online May 11, 2020. doi:10.1001/jama.2020.8630
QTc Prolongation with Hydroxychloroquine +/- Azithromycin
JAMA Cardiol. Published online May 01, 2020. doi:10.1001/jamacardio.2020.1834
Still An Open Question (Sort Of)
Conclusions• Not only is there a growing recognition of the CV
manifestations of COVID-19 but also a growing appreciation of the serious consequences of COVID-19 infection in patients with CV disease.
• At this point, there does not appear to be significant concern regarding the use of ACE inhibitors or ARBs.
• Hydroxychloroquine, with or without azithromycin, does not appear to meaningfully mitigate the risk of adverse events in hospitalized patients with COVID-19.
• Its role in individuals with mild to moderate disease remains unclear.
STATINS IN VIRAL PANDEMICS
IMMUNOMODULATORY and
CARDIOPROTECTIVE ROLE IN
LUNG INJURY/SEPSIS/MYOCARDIAL
INJURY
Sudha Ravilla, MD, Diplomate ABCL, FNLA
Medical Director, Lipid Center
TMH Metabolic Health Center
Tallahassee, Florida
Financial Disclosures
Nothing to disclose
Host responseVIRAL EPI/PANDEMICS IN THE 21ST Century: caused by Coronaviruses:
SARS- CoV (2003) , MERS- CoV (2013) and SARS-CoV2 (2019)
A lesson in history from the 1918 Influenza pandemic….
Flu Orphans and the “W” curve in the 1918 Pandemic, Nature Immunology 8 (11)
Common pathways in
PANDEMICS…COVID-19
• Common signaling pathways to death: Dysregulated immune response and late immunosuppression—targeting the lungs and then become systemic—HOST RESPONSE. So, there is scope for targeting– with anti-inflammatory and/or immunomodulatory agents.
• With delays in vaccine development/antiviral agents, we need established/time tested/safe agents that can be REPURPOSED: cost/efficacy/safety are the cardinal aspects of therapeutic agents in Pandemics that would merit consideration for study.
WHY STATINS?? WHY NOT STATINS??
How about a drug that can influence the host response and the
common pathways to mortality?
Statins have been studied in:
Pneumonia/ALI/ARDS/Sepsis/Cardiac injury
STATINS IN LUNG INJURY:
PNEUMONIA, ALI AND ARDS
• Basic injury pattern at molecular level: LPS →Pulm
macrophages→ROS→OxPLs→TLR4/MYD88→ NF-kB→ CYTOKINE
STORM → ALI (Acute Lung Injury)
Fedson, Influenza and other Respiratory viruses 3 (4), 129-142
Statins and BROAD Immunomodulatory effects via blockade of Mevalonate pathway
Jain, M., Ridker, P. Anti-
Inflammatory Effects of
Statins: Clinical Evidence
and Basic Mechanisms.
Nat Rev Drug Discov 4,
977–987 (2005).
Statins and BROAD Immunomodulatory effects via blockade of Mevalonate pathway
Jain, M., Ridker, P. Anti-
Inflammatory Effects of
Statins: Clinical Evidence
and Basic Mechanisms.
Nat Rev Drug Discov 4,
977–987 (2005).
STATINS AND Community Acquired Pneumonia (CAP)
• MA of 13 studies > 250,000 pts with CAP, Rx with statins improved survival BUT
prior Statin users in the community had the most benefit in terms of survival//Exp
data also shows that “Pre-Rx” with Simvastatin attenuated the inflammatory
response to LPS in healthy human subjects. (Ref: McAuley,Int Care med 2017; 43)
• Fascinating RCT study 2019: 62/ Older pts with CAP + Sepsis /non-ICU/ High
dose Simvastatin 80 mg explored the ability of statins to improve Neutrophil Fn:
Prim end point: NETosis : +ve and Post hoc: Hosp-free survival / Safe!
Who did well?:Older pts/ Milder dx/ High dose/ Rx started Early
(Ref: Sapey,Amer J of Resp and Crit care med, 2019; 200;10)
STATINS and
Ventilator Associated Pneumonia (VAP)
• RCT :150 ICU pts/on ventilator/Pravastatin 40/pts on prior Statin Rx
excluded / VAP frequency and ICU mortality: Positive
( Ref: Makris, Crit Care Med 2011; 39; No.11)
• RCT: 300 pts with VAP/Simvastatin 60 mg/ 28 day mortality:
Negative
(Ref: Papazian L, JAMA; 310 (16))
• Other RCTs: mixed results-but overall safety data was Positive
Statins and Pneumonia: take away
• So, positive Obs. studies (Epidemiological and Experimental)
• BUT negative in most RCTs…caveat : these RCTs done in
Heterogenous clinical phenotypes which may explain the
discordance.
• De novo vs continued Statin therapy which fares better?
• Answer: depends on Type of popln (Clinical and Biochemical
phenotype)?/Severity of illness/Type of Statin?/Dose?/Duration of
Rx/ Timing of Rx ?
ALI/ARDS
• ALI/ARDS : spectrum characterized by acute Hypoxemic Resp. Failure in response to a pulmonary or systemic injury.
• Central process: Alveolar epithelial and Vasc endothelial injury: Neutrophils/Alvmacrophage induced cytokines/Proteases/ROS, followed by the late Fibroproliferative phase-organization of the alveolar exudate orchestrated by lymphocyte and fibroblasts.
Craig T., O’Kane C., McAuley D. (2007) Potential Mechanisms by which Statins Modulate the Development of Acute Lung Injury.
In: Intensive Care Medicine. Yearbook of Intensive Care and Emergency Medicine, vol 2007. Springer, Berlin, Heidelberg
STATINS in ALI/ARDS
Broad immunomodulatory effects
*Induce eNOS expression: End.Dysfn is central to ALI
*Also downregulate T cell stimulation//reduces VCAM and ICAM
expression and hence less T cell influx; LFA-1<->ICAM;
*Inhibit induction of NF-kB/upregulating the inhibitor of this pathway
*Activate PPARs → inhibition of Inflammatory pathways
*Inhibits MMP→ aid alveolar epithelial barrier function/Key in ARDS
*Coagulopathy/COVID 19 : Statins inhibit PAI-1(asstd with mortality)
*Statins ACE2 levels via epigenetic modification…this is beneficial
as SARS- Cov2 virus can downregulate ACE2!
STATINS AND ALI/ARDS: Clinical studies• Two Negative RCT trials : one with Simvastatin 80mg and ARDS of
any-cause (HARP-2) and Rosuvastatin and ARDS from sepsis
(SAILS). But a subgroup analysis of HARP-2 however showed Risk
reduction in the Hyperinflammatory phenotype , Whereas
retrospective analysis of SAILS showed Statin group had a RISE in
IL-18 levels which tracked with mortality…
(Ref: NEJM; 371; 18, Oct 2014) & (Ref: NEJM, 370; 23,June 2015)
• So, a Phenotype/Biomarker dependent Rx response is possible–
“Predictive enrichment” strategies may help design RCTs in the
future...
Statins and ALI/ARDS: take away
Game over??
• Two major Negative interventional RCTs in critically ill patients
with ARDS and mixed results in Preclinical models (more positive)
& Observational studies for ARDS prevention in pre-Rxed context.
• Personal opinion: there is hope: “Precision medicine”: identify
subgroups/specific Clinical and Biomarker phenotypes and
formulate highly targeted RCTs in Homogenous populations.
SEPSIS
• Sepsis: Infection induced inflammatory syndrome:
Uncontrolled systemic inflammatory response, multi organ
failure…precipitous death.
• Sepsis develops when the initial appropriate host response
becomes amplified and aberrant.
Sepsis
Cohen, J. The immunopathogenesis of sepsis. Nature 420, 885–891 (2002). https://doi.org/10.1038/nature01326
Molecular mechanisms “Unique” to Corona viruses
• TLR-3 and TLR-4 are protective against Corona viruses- help clear the virus ! Most Use MYD88
• MYD88 signaling → NF-kB
• MYD88: INDUCED by SARS-CoV !
• MYD88: >> or < < mortality in mice models
• MYD88 antagonist: Statins happen to “stabilize” MYD88 under Hypoxia (in vitro study).
• Atorva 40 mg NF-kB via MYD88 pathway.
(Ref: mBio, 2015, Vol 6, Issue 4)
Statins in Sepsis: Clinical trial evidence ?
• ANZ-STATInS trial: MC/Prospective RCT stratified by PRIOR STATIN USE/
Atorvastatin 20 mg/Primary outcome: IL-6 levels and secondary outcome included
28-day mortality. Results: Negative study ; But the subgroup of PRIOR STATIN
USERS had lower IL-6 baseline level AND improved survival (Ref:Am J Respir Crit
Care Med; Vol 187; issue:7, April 2013)
• ASEPSIS trial: RCT/ Atorvastatin 40 mg (x 28) days in Statin Naive pts/ Primary
outcome: progression to severe Sepsis: Positive study (Ref: Critical care 2012; 16)
• *Population based/Retro Study: Cohort: One million ppl! Over 10 yrs->50,000 pts
with Sepsis identified /~ 3600 on Statins at the time of Sepsis/Prim outcome:
Simvastatin and Atorvastatin lowered 30 day mortality while Rosuvastatin did NOT !
(Ref: Chest 2018; 153)
Statins in Sepsis- take away?
• Observational/Retrosp.studies: Mixed results: > Positive but
“healthy user” bias and heterogeneity plagued the analyses….safety
reassuring.
• RCTs and MA: Largely NULL/NEGATIVE in an interventional
setting ! Again, safety reassuring.
• We need very large Pros. RCTs to establish mortality benefit…not
feasible…..but there IS hope if we identify subjects with
comparable Clinical and Biological phenotypes…as our
understanding of Sepsis evolves…
• Continuation seems safe and potentially beneficial !
• Discontinuation— seems to track with worse outcomes
Effects of VIRAL infections on CVS
JAMA Cardiology, March 2020
Myocardial injury in COVID-19• Presentation patterns: a) Troponin elevations/associated with elevations in
D-dimer, Ferritin, IL-6, LDH……Cytokine storm! b)Viral
Myocarditis/Stress CM c) Fulminant Myocarditis/shock
• Histology: Interstitial Lymphocytic infiltrate in Autopsy/EMB(Ref : Xu, The Lancet Resp Med, vol:8, issue:4, April 2020)
(Ref: European Heart Journal, Volume 41, Issue 19, 14 May 2020, Pages 1861–1862 )
• Mechanism: ACE2 related ? Cytokine storm? Hypoxemia-ischemia ?
Could there be a unique mechanism???
• Myocardial injury: Key prognostic factor in COVID-19
Myocarditis: Immunopathology
• Experimental models show 3 phases: ACUTE: injury to
cardiomyocytes from Viral replication; SUBACUTE: T cell immune
response to myocyte injury and CHRONIC: Myocardial
repair/remodeling→ DCM
• Th1 and Th17 T-helper cells: key players in immunopathogenesis
(Ref: Lazzerini, Cardiovasc Drugs Ther 2013; 27)
Immunomodulatory effects of Statins in
Myocarditis
• Statins can affect T cell function at many levels: Cell
activation, cell proliferation, Th1 and Th17 polarization
and reduce cross talk with APCs→ myocyte apoptosis in
animal models.
Ref: Lazzerini, Cardiovasc Drugs Ther 2013; 27
Statins in animal models of Myocarditis
Lazzareni, Cardiovasc Drugs Ther 2013;27
Statins in Lymphocytic Myocarditis:
Preclinical and Clinical studies • So, based on Preclinical studies, there is rather CONSISTENT
evidence for the therapeutic benefits of Statins as cardioprotective &
immunomodulatory agents: suppressing the Th1 induced
autoimmune process as well as Th-17 driven post-myocarditis
cardiac remodeling in the chronic phase.
• Unfortunately no major dedicated clinical studies: One small study
in Bx proven Lymphocytic Myocarditis and EF< 40%, Atorvastatin
40mg improved EF and NYHA functional class.
Am J Cardiol 2006; 97
Statins in COVID-19
WHY NOT?
Castiglione V, European Heart Journal- CV Pharmacotherapy, https://doi.org/10.1093/ehjcvp/pvaa042
Statins in Pneumonia/ALI/ARDS/Sepsis/Myocardial injury
Final take-away?
❖Reasonable and potentially beneficial to continue statin therapy…
❖ ???Consider de novo statin initiation - we need to conduct RCTs in
Clinically & Biologically classified phenotypes for definitive answers.
Reasonable to start if there is a Pre-existing guideline-based indication,
early in the disease process in patients with hepatic/renal reserve, where
the risk of harm is low....since overall, there were no major serious safety
concerns in clinical trials...but monitor CK/Transaminases closely as
needed.
❖Discontinuation of Statin not a good choice given the CV comorbidity in
this population-stopping can lead to worse outcomes in Sepsis but also in
ACS/Stroke conditions
Before the next pandemic hits…
• Hope we have some answers before the next pandemic hits,
or some protocols at the very least, that can be applied
globally. This certainly has implications in developing
countries as well, given the wide availability and cost
profile. Explore I.V Statins more? Lastly, perhaps consider
adding a section for “Statins in Viral Pandemics” in future
guidelines…