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Robert Harrington, MD: Hi. This is Bob Harrington from Stanford University, here on theheart.org and Medscape Cardiology. Throughout the course of the last 2 years, we’ve been trying to bring to our listenership and our readership a series of topics on the intersection of COVID-19 and the heart — cardiovascular disease.
I’m really privileged today to have a colleague from the science community who is going to talk about a recent paper in Nature Medicine, but before I introduce him, but let’s go through a little bit of background.
We all remember the early reports of the pandemic coming out of China and Italy: There was this notion that patients with cardiovascular disease and in particular, interestingly, hypertension, might be at increased risk for infection and might be at increased risk for complications of COVID-19 infection. There was also an interesting tie into the potential use of angiotensin-converting enzyme (ACE) inhibitors. Well, quickly, researchers began to understand these relationships, and importantly, helped us understand that there was not, in fact, a relationship between ACE inhibitors and outcome that was causal in nature. That was an important observation.
Then we went into the summer of 2020 and we began to see these reports, particularly from the imaging community, on myocarditis. This was then seen in young athletes as sporting events were started and stopped, and recommendations from sports cardiologists had to be given. We’ve done some shows on that topic, including one with Manesh Patel.
The American Heart Association (AHA) COVID-19 Registry launched in the spring of 2020 and quickly began to show that, in fact, there was an increased risk for cardiovascular outcomes in the acute phase. The AHA registry was really concentrating on the hospital phase. And so those were important. The AHA, the National Institutes of Health, and others put a lot of money through rapid grant programs to try to understand some of these mechanistic links.
We started seeing papers that continue today on the intersection of endothelial dysfunction, vascular damage, thrombosis, and inflammation tying together in patients would have been exposed to COVID-19 leading at least to a pathobiology that might make sense for why we’re seeing this increased risk for cardiovascular disease or cardiovascular outcomes among our patients who are infected with COVID-19 that goes beyond just preexisting risk factors.
Now let’s take the next step, which I think is a really important one for us in the cardiovascular community to be aware of: What about in people who’ve survived COVID-19? What are their longer-term cardiovascular risks?
Well, I’m pleased to make a new friend and colleague today in Dr Ziyad Al-Aly, who is the chief of the Clinical Epidemiology Center at the Research and Development Service of the VA St. Louis Health Care System. Dr Al-Aly has done some really important work, most notably, a paper that appeared in Nature Medicine that I suspect many of you have read. If you have not, please take a look at it before you listen to this. This paper got into the long-term cardiovascular outcomes of COVID-19.
Dr Al-Aly, thank you for joining me here on theheart.org and Medscape Cardiology.
Ziyad Al-Aly, MD: Thank you for having me. I’m delighted to be with you and look forward to a wonderful conversation about heart disease in COVID-19.
Harrington: Terrific, thank you. First off, let’s go to the beginning. At some point in all research projects, somebody says, “I’ve got a question or idea that I want to explore.” Do you want to start by telling us about the thinking behind why you and your research group went after this problem?
Al-Aly: So early on in the pandemic, in March 2020, we had resolved as a group to do our best to identify knowledge gaps that were important to the public and address them. The conversation initially was on Zoom, when everybody was working from home. We convened around Zoom and said, “Okay, we’re in the middle of pandemic so what can we do to do our part.” Although we’re not virologists, we’ve never researched COVID-19, and none of us had been through a pandemic before, it was very clear to us that we need to marshal the resources we have and our intellect and energy to identify knowledge gaps that are important to advise the public.
In that journey, we started hearing from patients and patient-led research groups about them having a persistence of symptoms weeks and months after the initial infection. Those were initially anecdotes. Then, Fiona Lowenstein had a really wonderfully written op-ed piece in The New York Times saying that she was young and athletic and had no medical problems before getting COVID-19. She got COVID-19 and weeks after the initial infection, she was still having palpitations, heart problems, chest pain, and shortness of breath.
She was previously healthy and had no problems, so that really intrigued us and launched us on the pathway of identifying what’s happening with these people long-term and what’s happening with people who survive that acute phase of COVID-19. That initial step culminated in a paper in Nature in April 2021.
That paper was really a broad characterization of what we think of now as postacute sequela of COVID-19 and what it looks like. The major surprising finding was that it really can affect nearly every organ system, including the heart, but it was not limited to the heart. There were people with kidney problems, obviously neurocognitive or neurologic manifestations — what people referred to as brain fog, et cetera. There were manifestations or sequela in nearly every organ system.
After that paper was published in Nature, it led us to do a deeper dive into all these different organ systems that could be affected. One of them, obviously, is the heart. We have done some other work on diabetes that will be coming out soon and we have recent publications on mental health disorders and the kidney. The paper we’re discussing today is primarily focused on the cardiovascular system and the vascular systems.
Harrington: I really like several things about your explanation, one of which is that I love how excited you are about having had these conversations that then led you to do what you do, which is epidemiology. I love the passion associated with that.
The second thing is —that I always tell the residents and the fellows — that all good research questions originate from a keen observation by clinicians or by patients that ask, “Well, why does this happen? Why are we seeing this?” I enjoyed hearing that you had those conversations with your research group about what you were reading in the lay press. It’s that circle of science wherein somebody is going to make the initial observation and ask, “What is it that we should use our tools and skills to explore?”
You are an epidemiologist. You run a large research group in the Veterans Affairs (VA) system in St. Louis and you have access to a large amount of data. The VA dataset, as we talked about this before we started recording, is a fabulous national resource.
What were the design issues that your group was thinking about? What did you have available to you that you thought you could answer this question or at least could add some insights? What were the methods you employed? As I said to you off camera, we have a lot of listeners who are quite experienced methodologists who will be interested in why you picked the methods that you did.
Al-Aly: I do think the VA system is a national treasure. The VA was a pioneer in adopting electronic health record systems and it runs the largest integrated healthcare system in the US. There are many states, areas, or regions, for example, Kaiser in northern Southern California and Sutter and so on, but they tend to be regional and they’re not really an integrated national network. The VA is almost a unique example in the US of an integrated system that admits anybody who is eligible for care and provides outpatient care, inpatient care, rehab — a really broad spectrum of care from A to Z.
The VA electronic health record system is a unique national resource to address questions, especially in an ongoing pandemic where hundreds and thousands of people, now millions of people, are infected with COVID-19, and we can track them over time to better characterize or understand their outcomes.
We knew from our prior work in people who had COVID-19 and especially people who needed to be hospitalized or admitted to the intensive care unit (ICU) for acute COVID-19, that it was not uncommon to see heart attacks or stroke in that population, that’s not really novel. That should not be a surprise to anybody in the audience. It was established previously that some of the people who got very sick during the acute phase ended up in the ICU; and some get stroke, deep vein thrombosis (DVT), and pulmonary embolism (PE).
But what we didn’t really know is what happens in the long-term. What happens after people survive the first 30 days and long-term, and especially in the segment of the population that didn’t need hospital care or didn’t need to be admitted to ICU. They didn’t have disease that was severe enough to need hospitalization. We wanted to leave no stone unturned. At the VA, we know the exposure date and we know who got COVID-19 and who didn’t get COVID-19 and we have that data for people who were not hospitalized people and those who were hospitalized or who were admitted to the ICU.
We built a cohort primarily of people who got COVID-19 and compared them with two control groups. We chose two controls. First, we used a contemporary control of people who would have the same exposure to the broad or contextual characteristics of the pandemic. Those are people who were also exposed to the stress of lockdowns and all the disturbances that happen in our environment that touched nearly every aspect of our life — the school, your children. People couldn’t go to the gym because the gyms were closed, you couldn’t even go to Starbucks early on. We wanted a contemporary control that was exposed to the same broader conditions.
Because of all of the disruption in care, we wanted to make sure that if we found something that it wasn’t just because of the disruption caused by the pandemic. We also built a historical control of what standard baseline care looked like, with rates of heart conditions and rates of atrial fibrillation (AF), atrial flutter, stroke, DVT, and PE in the VA population in 2017, in an era that preceded the pandemic. These people were not exposed to COVID-19 (this was before anybody on Earth knew about COVID-19).
Then we did the analysis both ways. The criticism always is, Well, the people who get COVID-19 are different from the people who don’t get COVID-19 and how do you ensure that it’s truly an apples-to-apples comparison? The statisticians or people who really are into methods who are listening know that there are many methods available to us to balance the characteristics of the exposure groups, so to speak.
As our primary method, we selected a weighting method to try to weight people in the cohort so they have the same demographic and nondemographic health characteristics at baseline to kind of even the playing field so that the only difference between the COVID-19 group and control one or control two is the fact that the COVID-19 group got COVID-19. It should be the only difference, theoretically, and then we run the analysis to look at a prespecified set of outcomes.
Some people will ask why we selected these outcomes. Why not something else? Our outcomes were primarily selected on the basis of the work we did previously on a broader characterization of the postacute sequela of COVID-19 and the literature that we had at the time.
This suggested that COVID-19 might increase the risk for myocarditis, pericarditis, DVT, PE, and stroke. We took bits and pieces from much smaller studies and we put them all together. We leveraged all of the information that was available at the time to say, “Okay, well, let’s examine the association between COVID-19 and all these outcomes 1 year out.” That’s the broad outline of what we did.
Harrington: I’d ask people to read the paper and look at the methods because you also did some clever sensitivity analyses to make sure that, in fact, your weighting was appropriate. You looked at some other methods and you did some work looking at people exposed to flu. For the methodologists listening, please look into it. This was elegant work.
Please describe the primary outcomes and your key findings, which I thought were not just interesting, but extremely consistent.
Al-Aly: The main finding was that, even a year later, people who had COVID-19 have higher risk for stroke; cerebrovascular disease, including strokes and transient ischemic attack (TIA); and even a bunch of arrhythmias and dysrhythmias, including AF. Some people had tachycardia or bradycardia.
The cardiologists listening probably won’t be surprised by that, but it was a bit surprising to us that there would be this diversity of outcomes. There were also signals related to increased risk for myocarditis, pericarditis, and heart failure. It was interesting to us to see these increases with thromboembolic disease, including DVT and PE.
Harrington: I thought the figures in the paper were beautiful — those in the main paper and in the supplements. People should take a look at it. One of the striking things to me was just how consistent the message was across all these different diseases.
Talk a little bit about the limitations. These data obviously have some important strengths to them — it’s a nationwide survey with a diverse patient population, but it’s also mainly a White, male, veteran population. Let’s talk about the limitations that you see.
Al-Aly: Sure. Absolutely. Like any scientific work, there are limitations, and as you described, this is within the VA system. We may not generalize to people outside the VA system because in the VA system, you have different behavioral characteristics and differences between the VA population and the general population and the delivery of care, etc., etc. That needs to be taken into account.
As for the demographics of the VA population, yes, they are older, White, and males. That’s important, but it’s also important to put it in perspective: While most of our population was White, 20% of our people are Black participants, and because the study is big — about 154,000 people with COVID-19 and nearly 11 million controls — that 20% is 2 million people.
That is not a small number of Black people. Most veterans are males, but 10% of the population nowadays is females and 10% out of the 11 million, that’s 1 million female veterans. If we do a substudy on them, it will be the largest study to date on cardiovascular outcomes in female veterans. I think you need to take into consideration that this is a large study.
The third important limitation is that, however we try to do the weighting and controlling for confounding and try to even the playing field, we have to be cognizant that we cannot fully eliminate the possibility that there may be confounding out there that is unknown or unmeasured and something that we couldn’t account for. Having a negative control and doing the negative exposure control reduces but does not eliminate this concern about confounding. It lessens the probability of confounding but it doesn’t eliminate it, it doesn’t make it zero. I think people need to understand that.
The counter argument to that is that it wouldn’t be feasible for us to randomize people to COVID-19 or no COVID-19. When people say, “Oh, observational work in causal inference isn’t really going to add to our understanding,” well, the counter argument is that it is probably the only thing that’s going to add to our understanding here because it wouldn’t be feasible for us to do a randomized trial.
You can’t take people and say we’re going to give you COVID-19 or we’re going to give you a placebo and then follow you for a year or two and see what happens to your heart.
The better approach is to see how we can work more intensively and rigorously on the science to elevate confidence in the rigor of the approach and also understand the limitations so when we interpret the evidence, we interpret the strength and also the limitation in each study, including ours.
Harrington: You should choose the right research methods for the question that is at hand. In this particular case, the observational data are what we have to look at for this particular question. I thought you were very careful in both the number of analyses that you did, including sensitivity analyses, but also in how you presented your results. You were the same way today.
As we get to the end here, I’m going to ask you quickly to give me the implications. I’m a cardiologist. What should I be thinking about with these data? What should my patients be thinking about with these data? For someone like you, who advises policymakers, etc., what should the policymakers be thinking?
Al-Aly: For cardiologists, it’s still in the hypothetical realm, but we need to start thinking about COVID-19 as potentially a cardiovascular risk factor and how does it stack up vis-à-vis hyperlipidemia and hypertension or diabetes? I don’t know the answer, but I think we as a community of scientists and physicians need to start thinking about it.
We know it increases risk, but how does it stack up against other things? When we’re evaluating patients in clinic, we need to keep that knowledge in mind and really ask people about whether they are having chest pain or having palpitations or new swelling in the leg, shortness of breath, or manifestations that could actually be symptoms of a much larger problem that, if detected early, would lead to better outcomes than later.
For the patient community, we didn’t touch upon this, but the risk, overall, is only important because there are so many people with COVID-19. The relative risk for major adverse cardiovascular events (MACE) — which is arguably the most consequential outcome, it’s not just minor chest pain, MACE is a major outcome — is 4%. That means 96 out of 100 will do fine.
It’s certainly not a cause for panic or a reason for people to lose sleep, but I think it’s important because if you multiply 4% by the larger number of people who got COVID-19 in the US and globally, you end up with a trend that fuels a surge in the burden of noncommunicable diseases more broadly and specifically in cardiovascular disease in the US. I think it needs to be taken into consideration and not muted as being too small but also not exaggerated. I think it needs to be contextualized for what it is.
My advice to patients is to take things seriously. If they’re having problems with their heart or chest pain, definitely seek help earlier rather than later because we know that that COVID-19 leads to potentially long-term consequences of the heart and identifying those earlier is absolutely the right approach.
For policymakers, the broader message is that in March 2020, we all thought that SARS-CoV-2 or COVID-19 was a respiratory illness that involves the respiratory system and goes away in 1, 2, or 3 weeks. It is clearly evident to me — it’s as clear as the sun — that COVID-19 or SARS-CoV-2 is more like a systemic virus that can in some people (not everybody) leave its marks on extrapulmonary systems.
Because of the huge number of people infected with COVID-19, even a risk of 4% will translate into millions of new people hitting the clinics with cardiovascular disease. I worry that, as a nation and globally, we are not prepared for this.
Without assigning blame to anybody, we collectively dropped the ball on COVID-19. I feel like we could have done better with COVID-19, but we didn’t, and now I worry that long COVID-19 is a complex problem and we’re really not prepared to deal with it. I don’t think that there are enough conversations nationally, internationally in different governments, and in the World Health Organization (WHO) about long COVID. Those conversations are not totally muted, but they’re not as vibrant and as front and center as they should be.
I worry that now the conversation is around moving on from a pandemic to an endemic stage and lifting mask mandates, while totally ignoring that this virus could leave some people literally with scars that will mark them for a lifetime. This, in my view, is not the best calibrated approach.
I urge people and policymakers to consider the long-term consequences of COVID-19 in policy discussions and decisions that affect public health. That’s very important for planning for the aftereffects of the pandemic. People are going to be flooding our clinics. We’re already seeing this and it’s playing out in slow motion now, but soon enough, it’s going to be quite staggering. Our health systems are already strained after 2 years of COVID-19. We are all exhausted and strained. It will need a more concerted effort to help us to be able to deal with the challenge of long COVID-19.
Harrington: You summarized that really beautifully. As you point out, it’s a 4% absolute risk. In cardiovascular disease, I’m used to dealing with 1%-5% absolute risk differences because that’s where we play in terms of the risk for myocardial infarction, where a new therapy might lower that risk by 1% or 2%. For us, as cardiologists, 4% is real, particularly, as you’ve said, given the magnitude and that fact that we’re talking about millions of people exposed; 4% is a big deal.
Well, Dr Al-Aly, I could talk with you all afternoon. This has been fabulous. I want to thank you, number one, for doing what you do, which is contributing to our scientific knowledge of the long-term effects of COVID-19. Keep it up. Second, I want to thank you for coming on and diving into what I think is a pretty important paper for our readership to take note of.
I also want to thank you for the honesty and the clarity of what you did and what’s good about what you did and where there are some limitations. I applaud that as a fellow researcher.
It has been my pleasure to talk with Dr Ziyad Al-Aly, who is the chief of the Clinical Epidemiology Center at the VA St. Louis Health Care System. I’m Bob Harrington from Stanford University. Thanks for joining us.
Al-Aly: Well, thank you. Thank you for having me. This was great.
Robert A. Harrington, MD, is chair of medicine at Stanford University and former president of the American Heart Association. (The opinions expressed here are his and not those of the American Heart Association.) He cares deeply about the generation of evidence to guide clinical practice. He’s also an over-the-top Boston Red Sox fan.
Créditos: Comité científico Covid