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…