Aloke Finn, MD
Medical Director and Chief Scientific Officer
CVPath Institute Inc.
Gaithersburg, Maryland
afinn@cvpath.org
Disclosures: CVPath has received sponsored research grants from CeloNova BioSciences, Inc.; Dr. Finn received consulting/lecture fees from CeloNova BioSciences, Inc.

Rajiv Jauhar, MD, FACC, FSCAI
Chief of Cardiology
Northwell Health System
Manhasset, New York
rjauhar@northwell.edu
Disclosures: Speaker for CeloNova BioSciences, Inc.

S. Jay Mathews, MD, MS, FACC
Director, Cardiac Catheterization Laboratory,
Structural Heart, and PERT
Manatee Memorial Hospital
Bradenton, Florida
sjaymathewsmd@gmail.com
Disclosure: Speaker for CeloNova BioSciences, Inc.

What have you learned about your cardiovascular patients who have contracted COVID-19?

Dr. Finn: Because I split my time between clinical duties as an interventionalist and research at CVPath, I have a distinct perspective on the effects of COVID-19 on the heart that combines both clinical experience and pathologic analysis. From the pathology angle, we are learning more every day about how COVID-19 can cause heart damage. First, it is clear that some patients become hypercoagulable during a COVID-19–induced cytokine storm, which may result in cardiac injury through three major mechanisms: (1) epicardial coronary thrombosis; (2) intracardiac thrombus (or even venous thrombosis), which may embolize into the coronary arteries causing myocardial infarction (MI); and (3) microthrombi in small intramyocardial vessels, which is difficult if not impossible to detect clinically. Our own experience has shown that direct infection of the heart (i.e., myocarditis) is less common during SARS-CoV-2 infection. Translating these findings directly to the clinic is challenging, especially when we are only beginning to explore different therapeutic options.

Dr. Jauhar: We know from several epidemiological studies that cardiac risk factors such as hypertension and diabetes, along with cardiovascular diseases such as cardiomyopathy or troponin leak, worsen the prognosis in patients who develop COVID-19. We have also seen a dramatic increase in COVID-19 patients developing arterial and venous thrombi requiring short and long-term anticoagulation. Long-term anticoagulation with direct-acting oral anticoagulants (DOACs) or vitamin K antagonists makes the management of coronary artery disease (CAD) with intracoronary stenting more challenging.

We also know that heart disease has not gone away during this pandemic. We learned from our colleagues in Europe and China that the volume of acute MI dramatically decreased. Clearly, patient fears of coming to the hospital led to patients staying home with symptoms. Data from our institution showed that there was a dramatic increase in patients with out-of-hospital cardiac arrests.1 As the pandemic waned in New York, the volume of patients coming in with acute coronary syndrome (ACS) dramatically increased.

Dr. Mathews: Since the start of the pandemic, we have seen a multitude of cardiovascular disease presentations. For those without COVID-19, we are seeing delayed presentation for MI and increased mechanical complications (i.e., papillary muscle rupture, ventricular septal defect, ventricular aneurysm). We have also seen several presentations among patients with COVID-19. A number of our patients are “asymptomatic,” meaning they test positive incidentally as part of our routine pretesting protocols prior to elective or urgent cardiovascular procedures. Among the patients with ACS, a microvascular thrombosis/myocarditis picture has been seen with open epicardial vessels at the time of catheterization. In addition, we are seeing COVID-19–related ST-segment elevation MI (STEMI) and non–ST segment elevation MI (NSTEMI). These patients tend to have dense thrombus that can be challenging to treat and potentially require advanced therapies.

Cardiac involvement may be common in COVID-19 infection, and elevation of B-type natriuretic peptide seems more frequent than troponin elevation among patients in the ICU.2 However, elevated troponin levels seem to be associated with increased mortality.3 Among ICU patients, a > 30% risk of thrombotic complications (both arterial and venous) has been reported.4 We have also seen an increased risk of venous thromboembolism (VTE), with both symptomatic/asymptomatic events and acute/subacute arterial thrombosis in non–critically ill patients. Because we have been unable to determine the true frequency of COVID-19 involvement with our cardiovascular patients, we have treated them all as potential COVID-19 patients until confirmatory testing is performed.

How are these COVID-19 positive cardiovascular patients presenting in your clinical practice?

Dr. Mathews: The vast majority of our COVID-19 consultations have been for those hospitalized for cardiopulmonary issues related to infection. We certainly have a number of patients with symptomatic infection who do not reach the threshold for hospitalization, and we have managed them remotely via our outpatient telemedicine practice. Asymptomatic positive patients have been discovered as part of our routine pretesting protocols prior to elective/urgent procedures. In general, these patients have been deferred when possible, until the infectious risk has passed as per Centers for Disease Control and Prevention guidelines. A small number of patients at our institution have presented with ACS and are generally treated with primary percutaneous coronary intervention (PCI) rather than conservative medical therapy.

Dr. Jauhar: Early in the pandemic, we saw very few patients with ACS (STEMI or NSTEMI). As the number of hospitalized patients with COVID-19 decreased, we saw a significant increase in both elective and urgent cases. The significant decrease in volume during the peak of the pandemic quickly reverted back to pre-COVID-19 days (Figure 1).

Figure 1. The significant decrease in volume during the peak of the pandemic quickly reverted back to pre-COVID days.

Dr. Finn: Most patients presenting with urgent issues such as thrombotic occlusion of coronary arteries usually present to the emergency room. In the absence of rapid testing, it is always uncertain which STEMI patients have COVID-19. Decisions on taking COVID-19 patients to the lab should be done on an individual basis because one must consider the risks versus benefits, including exposure of cath lab personnel. All elective patients at my center are required to have COVID-19 testing before the procedure, which makes everything a bit easier.

What should interventional cardiologists consider in terms of treatment choice for their PCI patients if they have tested positive for COVID-19, or given the potential risk of contracting COVID-19 in the future?

Dr. Jauhar: Interventional cardiologists should treat COVID-19 and non-COVID-19 patients the same in terms of STEMI management. Fibrinolytics have a 50% to 60% success rate and should not be used in STEMI patients. Also, studies have shown that COVID-19 patients presenting with ST-segment elevations have a 40% rate of nonobstructive disease. Appropriate personal protective equipment (PPE) should be used for all staff and patients. The management of COVID-19 patients and the risk of thrombus and eventual DOAC or warfarin use make minimizing dual antiplatelet therapy (DAPT) of paramount importance. The COBRA PzF Nanocoated Coronary Stent (NCS) (CeloNova BioSciences, Inc.) is being studied with 14-day DAPT in patients at high bleeding risk (HBR), and may be useful in patients with COVID-19 who require anticoagulation.

Dr. Mathews: In the beginning of the pandemic, we had several meetings regarding the optimal treatment for patients with active COVID-19 infection, considering thrombolytics for those with true STEMI, medical therapy for those with NSTEMI, and bailout intervention for those who fail these therapies. This strategy came from the Chinese experience early in the pandemic. However, this presented a number of logistical issues, including a shortage of thrombolytics and a general unwillingness to defer intervention in our primary PCI-capable hospitals. Moreover, many of the patients initially treated medically ended up requiring intervention due to failure of therapy.

Fortunately, the American College of Cardiology and Society for Cardiovascular Angiography & Intervention provided guidance suggesting that a primary PCI strategy for patients with STEMI should be pursued regardless of COVID-19 status.5 For patients with active COVID-19 infection and NSTEMI, treatment may be delayed to allow for testing, with interventional therapy reserved for high-risk patients. Moreover, as most hospitals have resumed elective procedures, patients can be pretested for COVID-19 in close proximity to their procedure.

Given the frequency of increased thrombogenicity in COVID-19 patients, some patients may require therapeutic parenteral or OACs. As such, long-term DAPT could become problematic in this population due to elevated bleeding risk. Bare-metal stents (BMS), which typically do not require long-term antiplatelets, trade off this benefit at the expense of increased target lesion revascularization (TLR). Moreover, because they are polymer uncoated, data suggest an increased risk of stent thrombosis, especially at < 30 days.6,7 With COVID-19 infection, this risk could be increased. A durable polymer stent with low thrombogenicity and that does not require long-term antiplatelets could be beneficial in this scenario.

Dr. Finn: We really need to think about the need for long-term anticoagulation and antiplatelet therapies when treating COVID-19 patients with thrombotic complications. In my opinion, this type of cocktail will likely be needed to prevent excess risk of thrombotic complications, including stent thrombosis. What exactly those specific anticoagulants are needs to be determined in clinical trials. We do need to be aware of excess bleeding risks if patients receive drug-eluting stents (DES) along with antiplatelets and anticoagulants for prolonged periods of time (i.e., months). The COBRA REDUCE trial, which is looking at the best combination of stent and drug therapies in patients requiring OACs, may be especially relevant. In this trial (which will be released at Transcatheter Cardiovascular Therapeutics [TCT] Connect 2020 Late Breaking Trials Session IV), the treatment regimen of COBRA PzF NCS along with 14-days of DAPT and OACs is compared with a regimen of DES combined with DAPT and OACs for 3 or 6 months. The results of this trial may be very relevant to our COVID-19 patients, especially if long-term OACs are found to be effective in these patients. This trial may even help guide stent choice in these patients.

Should treatment choice differ for PCI patients who are critically ill from COVID-19 and on anticoagulation versus HBR patients who have mild symptoms from COVID-19 versus otherwise healthy patients who may contract COVID-19 in the future?

Dr. Mathews: Bleeding risk plays a role in stent choice. Modern-generation DES offer low rates of TLR but still carry a risk of stent thrombosis while off antiplatelets. There are data suggesting that short-duration antiplatelet therapy (< 6 months) may be feasible with less bleeding risk over standard (6-12 months) and long-term (> 12-month duration) therapy but at the expense of stent thrombosis, which can be catastrophic.8 BMS are still thrombogenic early on and carry increased stent thrombosis risk, thus requiring at least 1 month of antiplatelets.6

Patients with COVID-19, including those that are not critically ill, carry increased risk of thrombogenicity, sometimes as evidenced by increased D-dimer levels.9 Simultaneously, they may also be at elevated bleeding risk, with reported increased cases of coagulopathy ranging from mild thrombocytopenia and elevated prothrombin times to frank disseminated intravascular coagulation.9 There is evidence that the cytokine storm in some of the most critically ill patients with COVID-19 may predispose them to some of the thrombotic complications that have been seen. These patients will often require systemic anticoagulation. Similarly, patients with increased risk or known VTE may be placed on OACs.9 Although controversial, we have started doing this for all of our patients with elevated D-dimers and COVID-19 infection, even if they have concomitant ACS requiring stenting. Triple therapy with aspirin, a P2Y12 inhibitor, and OAC increases the bleeding risk 2 to 3 times more than DAPT alone.6 As such, stent choice may be important in these patients, even among those at increased risk for contracting COVID-19 with cardiovascular complications (men, elderly patients, patients with diabetes, patients with chronic kidney disease, etc.).10

Fluorinated durable polymers may be thromboresistant. As seen in in vitro testing, the fluorinated Polyzene-F coating seen with the COBRA PzF NCS offers a unique combination of both thromboresistance due to the coating and low rates of TLR without drug-elution.11-13 In COVID-19 patients where increased thrombogenicity is common, this stent may perform better than an uncoated BMS, without the trade-offs of long-term antiplatelet requirements with a DES.

Dr. Finn: I think critically ill COVID-19 patients should be treated similar to HBR patients simply because of the risk of future procedures and increased bleeding risk in critically ill patients. The more we can do to lessen bleeding risk in both of these patient types, the better. For these patients, stents (which require very short-term DAPT) are preferred to minimize the risk of both thrombotic complications and bleeding. Critically ill patients with COVID-19 often experience a cytokine storm that is a result of their immune system trying to fight off the virus. Unfortunately, this storm may be more detrimental than beneficial because of the damage it may do to organs, including the heart, through mechanisms such as hypercoagulability.

Recently, I have studied the effect of the cytokine storm on stent thrombosis in my lab. We simulated such a storm by using human blood from volunteers and spiking it with cytokines such as interleukin-6 and tumor necrosis factor-α, which are typically seen in COVID-19 cytokine storm patients. We examined its effect on platelet accumulation in various stents using a flop loop model. Metallic stents, as well as DES with metallic surfaces, performed poorly in terms of platelet accumulation, whereas stents with fluoropolymer coatings such as COBRA PzF NCS performed very well and did not show a difference in platelet accumulation between storm and no storm conditions. Currently, we do not have clinical data to suggest which type of stent is better, however, our preclinical data suggest that stents with greater thromboresistance characteristics may fare better in the cytokine storm conditions of COVID-19. I think COBRA PzF NCS is a good choice for this category of patient because it has demonstrated thromboresistant and rapid healing properties in nonclinical studies.

The last category (i.e., healthy patients who may contract COVID-19 in the future) should be offered more choices in terms of stent types, especially if they are practicing social distancing and are at low risk of contracting COVID-19.

Dr. Jauhar: A DES is my stent of choice for healthy patients despite the potential for COVID-19 in the future. However, critically ill COVID-19 patients on anti­coagulation may benefit from DAPT therapy that is shorter than recommended for DES, and in that situation, a nanocoated stent (e.g., the COBRA PzF NCS) may be beneficial.

What medical therapy is ideal for treating patients at increased thrombotic risk?

Dr. Jauhar: Patients with increased arterial or venous thrombotic risk would benefit from OACs. If they develop CAD or have ACS, then triple therapy may be necessary, and therefore, limiting DAPT would decrease the bleeding risk.

Dr. Finn: It is a moving target in terms of what will be the ideal therapies for COVID-19 patients. I still believe patients who are at excess risk of thrombotic complications (both venous and arterial) should be treated with a combination of antiplatelet and anticoagulant therapies. The best choice is probably to choose one antiplatelet agent along with one OAC. If these patients undergo PCI, stents that only need very short-term DAPT (i.e., 14 days) along with OAC are preferred. The COBRA REDUCE trial will lend important insights in terms of stent choice and antiplatelet/OAC regimen, which may also help inform strategies in COVID-19 patients.

Dr. Mathews: Guidance for triple therapy comes from the cardiovascular literature regarding patients with DES requiring OACs.6 Efforts have been made to reduce the risk of bleeding by using P2Y12 monotherapy in combination with OACs at 1 month post-PCI, but large studies have not yet been performed nor are there consistent guidelines. Existing literature supports safety and efficacy with a minimum of 1-month DAPT with COBRA PzF NCS.12 The COBRA REDUCE 14-day DAPT trial results will hopefully reassure physicians looking toward shorter duration DAPT in the setting of patients with increased thrombotic risk needing OACs. If positive, this strategy can potentially be applied to patients with COVID-19 who require coronary intervention and OACs.

How do you personally plan to navigate the year ahead?

Dr. Finn: Carefully! It is going to be a challenging fall season, but we will prevail over this virus!

Dr. Mathews: The pandemic significantly curtailed our office visits and cardiovascular procedural volume. We do not believe that these patients or their pathologies disappeared but rather that they are presenting in a delayed fashion. As we reopen and see an influx of patients, it will be important to mitigate the complications associated with postponed care. I am hopeful that with increased patient and physician education and awareness, we can recognize these conditions and still have a meaningful impact.

Dr. Jauhar: The year ahead is unclear in regard to COVID-19. My goal is to continue to use PPE in procedures where COVID-19 status is unknown. I hope to educate the community that CAD prevalence has not changed during the pandemic and to take symptoms seriously. The management of CAD will not change except for trying to limit DAPT in patients with COVID-19 given the increased risk of thrombosis.

1. Moutantonakis S, Moussa S, Kuvin J, et al. Out-of-hospital cardiac arrest and acute coronary syndrome hospitalizations during the COVID-19 surge. J Am Coll Cardiol. 2020;76:1271-1273. doi: 10.1016/j.jacc.2020.07.021

2. Akhmerov A, Marbán E. COVID-19 and the heart. Circulation Research. 2020;126:144-1455. doi: 10.1161/CIRCRESAHA.120.317055

3. Shi S, Qin M, Shen B, et al. Association of cardiac injury with mortality in hospitalized patients with COVID-19 in Wuhan, China. JAMA Cardiol. 2020;5:802-810. doi: 10.1001/jamacardio.2020.0950

4. Kloka FA, Kruip MJHA, van der Meer NJM, et al. Incidence of thrombotic complications in critically ill ICU patients with COVID-19. Thrombosis Research. 2020;191:145-147. doi: 10.1016/j.thromres.2020.04.013

5. Welt FGP, Shah PB, Aronow HD, et al. Catheterization laboratory considerations during the coronavirus (COVID-19) pandemic: From ACC’s Interventional Council and SCAI. J Am Coll Cardiol. 2020;75:2372-2375. doi: 10.1016/j.jacc.2020.03.021

6. Levine G, Bates E, Bittl J, et al. 2016 ACC/AHA guideline focused update on duration of dual antiplatelet therapy in patients with coronary artery disease. Circulation. 2016;134:e123-e155. doi: 10.1161/CIR.0000000000000404

7. Kolandaivelu K, Swaminathan R, Gibson WJ, et al. Stent thrombogenicity early in high-risk interventional settings is driven by stent design and deployment and protected by polymer-drug coatings. Circulation. 2011;123:1400-1409. doi: 10.1161/CIRCULATIONAHA.110.003210

8. Yin SHL, Xu P, Wang B, et al. Duration of dual antiplatelet therapy after percutaneous coronary intervention with drug-eluting stent: systematic review and network meta-analysis. BMJ. 2019;365:l2222. doi: 10.1136/bmj.l2222

9. Bikdeli B, Mahesh MV, Jimenez D, et al. COVID-19 and thrombotic or thromboembolic disease: implications for prevention, antithrombotic therapy, and follow-up. J Am Coll Cardiol. 2020;75:2950-2973. doi: 10.1016/j.jacc.2020.04.031

10. Madjid M, Safavi-Naeini P, Solomon SD, et al. Potential effects of coronaviruses on the cardiovascular system: a review. JAMA Cardiol. 2020;5:831-840. doi: 10.1001/jamacardio.2020.1286

11. Jinnouchi H, Mori H, Cheng Q, et al. Thromboresistance and functional healing in the COBRA PzF stent versus competitor DES: implications for dual anti-platelet therapy. EuroIntervention. 2019;15:e342-e353. doi: 10.4244/EIJ-D-18-00740

12. Cutlip D, Garrat K, Novack V, et al. 9-month clinical and angiographic outcomes of the COBRA Polyzene-F nanocoated coronary stent system. JACC Cardiovasc Interv. 2017;10:160-167. doi: 10.1016/j.jcin.2016.10.037

13. Maillard L, de Labriolle A, Brasselet C, et al. Evaluation of the safety and efficacy of the Cobra PzF NanoCoated coronary stent in routine, consecutive, prospective, and high-risk patients: the e-Cobra study. Catheter Cardiovasc Interv. 2020 Jun 17. doi: 10.1002/ccd.29065