Time Stamps

  • 00:50 Question REVIVED addressed
  • 01:44 Revascularication in HFrEF
  • 06:32 Revascularization in stable CAD
  • 10:02 REVIVED trial
  • 12:20 Summary and takeaways

Show Notes

  • Question REVIVED addressed:
    • Does percutaneous coronary intervention (PCI) with stents help patients with severe coronary artery disease (CAD) and heart failure with reduced ejection fraction (HFrEF) live longer and experience fewer heart failure hospitalizations?
      • Patient population: Severe CAD and HFrEF
      • Intervention: PCI
      • Outcome: Survival and future hospitalizations
  • The story behind of revascularization in HFrEF
    • “Stitching” up a case for (surgical) revascularization in HFrEF
    • Previous trials:
      • STICH Trial
        • Patients enrolled:
          • Extensive multivessel disease (majority had 2- or 3-vessel disease) 
          • 40% had diabetes
          • Most were symptomatic
        • Findings: coronary artery bypass grafting (CABG) + medical therapy reduced all-cause mortality in patients with multivessel CAD and HFrEF compared to medical therapy alone
          • Number needed to treat (NNT) = 14 over 10-years
          • Breaking down the causes of mortality that were reduced:
            • Cardiovascular deaths 
            • Fatal arrhythmias 
            • Heart failure deaths

          • As an aside, the STICH viability substudy demonstrating viability didn’t predict improved outcome with revascularization in the STICH trial
        • Established surgical revascularization as standard of care for those with HFrEF and severe CAD with anatomy suitable for bypassing
          • “Hibernating myocardium” = idea that myocardial cells may have chronic contractile dysfunction due to ischemia AND that reperfusion can restore the function of these cells
      • FREEDOM Trial
        • Is PCI equivalent to CABG?
        • Showed us that in those with diabetes and anatomy amenable to either intervention:
          • CABG was superior to PCI terms of:
            • Deaths and MIs
  • The story behind revascularization in stable CAD
    • Definition of stable CAD: no current or recent acute coronary syndrome (unstable angina, NSTEMI, STEMI)
      • COURAGE Trial
        • Foray into PCI for stable CAD (2007)
        • Findings: stenting patients with stable CAD via PCI does NOT improve mortality or non-fatal MIs compared to medical therapy alone, but may help improve short-term anginal symptoms, with no difference at 5 years
      • ISCHEMIA Trial
        • Is stable ischemia worth stenting in those with more severe CAD? (2020)
        • Compared to COURAGE, enrollment required moderate or severe ischemia on imaging or exercise tests, selecting a population with more severe CAD
        • Findings: stenting patients with stable CAD and moderate-severe ischemia via PCI did NOT reduce the incidence of ischemic cardiovascular events or death over 3.2 years
        • Important to note:
          • Long-term follow-up data currently being collected
          • Incidence of spontaneous type 1 MI was reduced in ISCHEMIA, and the Kaplan Meier curve for the composite endpoint looks very similar to the STICH curve:

  • Now, back to the REVIVED Trial!
    • REVIVED Trial
      • PCI for ischemic cardiomyopathy? (2022)
      • Patient population: severe but stable CAD + HFrEF
      • Majority had 2- or 3-vessel disease
        • Less severe CAD than the STICH population
      • Majority had no anginal symptoms
        • Less symptoms than the STICH population
      • Risk factors: 
        • ~50% had HTN 
        • ~40% had diabetes 
        • ~70% were smokers
      • Conducted in the UK (so most patients were White)
      • Many were not optimized on guideline-directed medical therapy that would be the standard of care currently (e.g. ARNIs, SGLT2is):

      • Exclusion criteria: recent MI or HF exacerbation or ventricular arrhythmia, or if they had no residual viability in their myocardium
      • Caveat: not known whether viable myocardium had corresponding vascularized anatomy
      • Findings: PCI did NOT improve mortality or hospitalization for heart failure over 3 years compared to medical therapy alone
      • Secondary endpoints were also all negative:
        • LVEF at 6 and 12 months
        • QOL scores at 24 months
        • No indication for PCI to reduce mortality or HF exacerbations in those with ischemic cardiomyopathy, but there remains a role for PCI to reduce refractory symptoms, and a role for revascularization with CABG if indicated
    • Medical management has improved dramatically over the past few decades, and many patients have not optimized medical management yet
    • Potential reasons there was no difference in the two arms:
      • CABG may be better than PCI
      • Follow-up may not be long enough to detect small differences in outcomes
      • Medical arm of trial received more ICDs and had more unplanned PCI
      • Role of revascularization in stable ischemic heart disease is less in patients on contemporary medical therapy

Access to Rotation Prep Cardiology guide on NEJM Resident 360 is free for August 2023. View the relevant sections on ACS and CHF.

Transcript

Dr. Shreya Trivedi: Welcome to Beyond Journal Club, a new collaboration with NEJM group where we take landmark trials and put them into context.

Dr. Greg Katz: Too often with journal club, it’s easy to get lost in the details of an article, struggling to figure out the clinical relevance through the tsunami of p-values, confidence intervals, and long table ones.

Dr. Shreya Trivedi: Except today, we will try to go beyond our typical journal clubs. And instead tell a story of how we got to where we are. To really appreciate the clinical question of the trial at hand, and then get into what these findings mean for our patients. I’m Dr. Shreya Trivedi, an internist at Beth Israel Deaconess Medical Center.

Dr. Greg Katz: I’m Dr. Greg Katz, cardiologist at NYU.

Dr. Clement Lee: And I’m Dr. Clement Lee, a senior editorial fellow at the New England Journal of Medicine, which is a part of  NEJM group.

Dr. Shreya Trivedi: Yes, we are so excited to launch this new collaboration between Core IM and NEJM group.

Dr. Clement Lee: So today we are talking the REVIVED trial, which was published in the October 13th, 2022 issue of the New England Journal of Medicine. It’s a really relevant trial to me because it lives at the intersection of two diseases that I see so frequently – heart failure and coronary artery disease.

Dr. Greg Katz: REVIVED asked a very simple question. Does putting stents into patients with severe coronary artery disease and a reduced ejection fraction make them live longer or reduce heart failure hospitalizations?

Dr. Shreya Trivedi: Uh, this is a great question because I can’t tell you the number of times I’ve taken care of patients with a new drop in ejection fraction. The knee jerk reflex is to send them for a quote unquote ischemic evaluation. Go to the cath lab, look at their coronary anatomy. But you know, now that we’re bringing this up, what’s a thought behind this ischemic evaluation and why are we just cathing these patients who aren’t actually having myocardial infarctions and may not even be having angina?

Dr. Greg Katz: You can’t understand the decision about doing an ischemic evaluation if you don’t understand the history of revascularization and heart failure.

Dr. Clement Lee: Exactly. So today, first, we’re gonna go through the story of revascularization in heart failure.

Dr. Shreya Trivedi: And then we’ll paint the story of revascularization in stable ischemic heart disease.

Dr. Greg Katz: And finally we’re gonna talk about how these two tales become intertwined with the REVIVED trial and the implications when you look at its results.

Dr. Shreya Trivedi: So let’s start with a story behind revascularization and heart failure, and just so we’re all on the same page, when we use a term quote unquote revascularization, we basically mean putting in stents or doing bypass surgery for someone who has severe coronary artery disease. So someone with at least 70% blockage.

Dr. Greg Katz: Yeah! So the landmark trial that established the role of revascularization in ischemic cardiomyopathy is the STICH Trial published in the New England Journal in 2011. Or to be a bit more precise the long-term follow up of STICH called STICHES published in 2016. STICH took patients with a reduced ejection fraction and ischemic heart’s disease and randomized them to CABG plus medical therapy versus medical therapy alone. They found that CABG carried an upfront risk of dying but that when you follow these patients for a long time there’s a reduction in death about a 7% absolute risk reduction in all cause mortality over 10-year follow up.

Dr. Shreya Trivedi: Wow, that’s like a number needed a treat of like 14 to save one life with bypass. That is pretty impressive.

Dr. Greg Katz: Yeah and looking at all cause death is a pretty important endpoint I would argue.

Dr. Clement Lee: Yeah, me too. Although Greg, I think it’s worth noting that in STICH, these patients were really sick. They had multi-vessel coronary disease that’s amenable to bypass. 40% had diabetes, they had low EFs, and most of them had symptoms of both heart failure and angina. I think it’s pretty telling just how sick they were, that when you look at the long-term follow-up data for these patients, for the ones who didn’t get bypassed, two-thirds of them had died.

Dr. Greg Katz: Yeah, numbers like that put in real perspective just how sick these patients are. So, why did STICH have such a mortality benefit? Well the patients who had bypass surgery ultimately had fewer deaths from fatal arrhythmias fewer deaths from pump failure and fewer deaths from acute MIs. So bypass surgery kind of makes everything better.

Dr. Shreya Trivedi: Yeah. And then from a pathophysiology perspective, the thought is that if you open up the blocked arteries in a patient with a low ejection fraction, then better blood flow is gonna help that ejection fraction recover and improve. Greg, I’m curious, have you seen this actually pan out though?

Dr. Greg Katz: So, I’ve, I’ve definitely seen cases where the ejection fraction improves in a patient after they get revascularized but that certainly doesn’t happen all the time. This is the so-called hibernating myocardium theory where better blood flow means better pump function.

Dr. Clement Lee: So it sounds like STICH really put surgical revascularization in heart disease on the map as something that has mortality benefit and those with symptoms and multi-vessel coronary disease, but you know what’s bugging me?

Dr. Shreya Trivedi: What? What’s that?

Dr. Clement Lee: That STICH looked at bypass surgery, but REVIVED, the trial that we’re talking about today, is looking at stents.

Dr. Shreya Trivedi: Yeah. And now that you bring this up, we do have data that stents are not as good as bypass when it comes to patients who have complex coronary disease or patients with diabetes, right? There was a FREEDOM trial in the New England Journal that showed that in those with diabetes, an anatomy that was amenable to bypass or a percutaneous intervention, bypass was better in preventing death, myocardial infections, stroke.

Dr. Greg Katz: It’s a really important point and to that I’d add we have to keep in mind STICH published their 10 year follow up in 2015, which means they started enrolling patients in the early 2000s. The role of stents in general has changed quite a bit over that time. There was a time when we used to put stents in for every abnormal stress test. Not to mention all of the asymptomatic patients who we would just send for regular stress testing.

Dr. Shreya Trivedi: Painful to hear. Low value care, indeed.

Dr. Greg Katz: Yeah, it was low value, but times have changed and indications for stents aren’t the same as they were when STICH was designed.

Dr. Shreya Trivedi: Yeah, So then why don’t we move on to stents and the other disease of interest in the REVIVED trial. Stable ischemic heart disease. I feel like this is gonna be bedtime story time with Papa Greg. I can only imagine alphabet soup of landmark trials that is gonna help us tell the story of how our understanding of stents have changed. I am kind of excited for this!

Dr. Clement Lee: Yeah, but I think you should be careful what you wish for when you give the cardiologist an open invitation to discuss clinical trials.

Dr. Shreya Trivedi: Yeah, that is true. I feel like it’s gonna be like my toddler being like, okay. One more story! One more story!

Dr. Greg Katz: At the same time that the story of revascularization and heart failure was evolving, the overall management of all stable ischemic heart disease was evolving too.

Dr. Shreya Trivedi: Wait, speaking of stable ischemic heart disease, before we get into story time with the trials of stents, can we make sure we’re on the same page on what we mean by the word stable in stable ischemic heart disease?

Dr. Greg Katz: Stable in this context means no recent acute coronary syndrome. No recent STEMI, NSTEMI, unstable angina. No progressive anginal syndrome. No chest pain at rest.

Dr. Shreya Trivedi: So if we’re talking about the patient who has significant coronary disease who may or may not have stable chest pain, right? So chest pain pain that comes on predictably with exertion and improves with rest.

Dr. Clement Lee: Great. And now that we have that squared away, if I remember correctly, there are two big trials in the story of stents and stable ischemic heart disease – COURAGE and ISCHEMIA. Both also published in the journal in the last two decades.

Dr. Greg Katz: Yes. COURAGE is the landmark trial published in 2007 asking whether putting stents in for patients with stable coronary artery disease reduces death and non-fatal MI. And the answer is that it really only reduces angina in the short term. It doesn’t make patients live longer and it doesn’t make patients feel better over the long haul.

Dr. Clement Lee: Hmm. So COURAGE makes us feel pretty comfortable not putting in stents in stable patients.

Dr. Shreya Trivedi: Oh, I did not expect that! You’d think that fewer blockages the better. So I’m curious, do we see the same thing then with even sicker patients with even more coronary disease?

Dr. Greg Katz: That’s where the ISCHEMIA trial comes in. The ISCHEMIA trial is fascinating. It was published in 2019 in the journal, but ISCHEMIA enrolled patients with moderate or severe ischemia on stress tests and we’re talking the kind of stress tests that often get outpatients sent directly from the stress lab to the emergency room. ISCHEMIA showed us that putting stents in these patients may reduce MIs, but it doesn’t save lives and it takes a pretty long time to show that MI benefit.

Dr. Clement Lee: Although, to be fair, we don’t have tenure outcomes data for ISCHEMIA like we do with STICH or COURAGE, right. Greg?

Dr. Greg Katz: That’s totally accurate, but when you’re presenting someone with a decision to make right now, the ISCHEMIA trial certainly makes me feel comfortable that there’s no rush in these patients to do anything other than treat them medically.

Dr. Clement Lee: That’s a fair point, and if a cardiologist is comfortable, so am I.

Dr. Shreya Trivedi: Yes. All right. So maybe if I can take a stab at summarizing the big picture. It seems like in the story of stents, in the early days, we were asking the question, what can we do with stents? But I think as more data came in with these trials, the questions started to become, what should we do with stents?

Dr. Greg Katz: That’s such a great way to frame the way that the field has changed. Most cardiologists today are way less aggressive about putting in stents and way more aggressive about using medical therapy to treat heart disease. But for our patients with ischemic cardiomyopathies, it’s pretty hard to ignore that STICH data when the mortality from the disease is just so high.

Dr. Shreya Trivedi: Yeah, and this is where the REVIVED trial comes in, right? Again, asking the question, does putting in stents into patients with severe coronary disease and a reduced ejection fraction, make them live longer and prevent heart failure hospitalizations?

Dr. Greg Katz: In other words, for those patients with ischemic cardiomyopathy that would’ve qualified for bypass, wouldn’t it be amazing if we could get the benefit of STICH without cracking open their chests?!

Dr. Shreya Trivedi: That is a great question, very patient-centered. Let’s get into it. Let’s get started with who was enrolled in the REVIVED trial.

Dr. Clement Lee: Yeah, let’s take a look. These were patients with a reduced ejection fraction and extensive coronary disease. So about half of the patients had a prior MI and about half had two vessel disease. From a symptom perspective, most had minimal heart failure symptoms and no angina. There was a fair amount of these standard risk factors, like half had hypertension, 40% had diabetes, and 70% were smokers. And of note, this trial was done in the UK, so most of the patients were white.

Dr. Greg Katz: And I wanna emphasize these were stable coronary artery disease patients. People were excluded with an acute coronary syndrome in the past four weeks, or a heart failure exacerbation in the past three days. Its also worth noting that they all had viability established to ensure that the myocardium reading revascularized wasn’t fully scarred, which suggests that there won’t be a benefit from improving blood flow to dead tissue. This basically means that all the patients had viable myocardium and some potential to have at least some degree of cardiac recovery if we improve blood flow to the myocardium.

Dr. Shreya Trivedi: Right. One critique of the study that we should probably point out specifically about that viability is that the PIs did not submit the data regarding if those viable portions of the heart matched up with portions of the heart anatomy that actually got revascularized. And if you wanna get into the weeds of this, there’s a whole editorial on it that we will link in the show.

Dr. Clement Lee: Yep. And now back out of the weeds into the grass or the lawn. Let’s look at the methods of the trial. Um, it all seems pretty rigorous to me. They had a blinded core lab that verified the endpoints and they used standardized questionnaires for patient reported outcomes.

Dr. Shreya Trivedi: Right? So they took this group of patients and they randomized them to medical therapy alone or medical therapy with stents. And drum roll please. Thank you, Clem. What they found was, pretty disappointing. Uh, after about three and a half years, the patients who got stents did not have any differences in mortality or heart failure exacerbations than medical therapy alone.

Dr. Greg Katz: And it doesn’t really matter how you slice that data. You can look at subgroups, you can look at each individual element of the composite outcome. You can look at quality of life. Everything basically showed no difference between putting in stents or just treating people with medicines.

Dr. Shreya Trivedi: Okay. What an adventure this has been. Can you walk us through one more time that journey?

Dr. Greg Katz: Absolutely. So STICH showed us that patients with a low ejection fraction and multivessel coronary artery disease live longer after bypass surgery. COURAGE showed us that patients with stable coronary artery disease don’t live longer or have fewer MIs from getting stents. But stents do relieve angina better in the short term than medications alone. ISCHEMIA cemented that story in stable ischemic heart disease. Even patients with a more extensive CAD burden and very abnormal stress tests don’t have their lives saved or less hospitalizations for unstable angina, heart failure or cardiac arrest by putting in stents.

Dr. Clement Lee: Yeah, and then the REVIVED trial looked at both heart failure with reduced ejection fraction and severe coronary artery disease, and found that stents did not change mortality or heart failure hospitalizations.

Dr. Shreya Trivedi: You know, I’m thinking about where these results leave us now, and I think maybe the most optimistic read of REVIVED is that we probably don’t need to rush to open up blocked arteries with stents in our patients with stable coronary disease who have heart failure.

Dr. Greg Katz: That’s exactly right. Stable coronary artery disease is just that. It’s stable. no signal in any of the revascularization data from COURAGE to ISCHEMIA to REVIVED. There’s no signal that we get any immediate benefit from studying patients who are not having heart attacks, except for the fact that we’re better able to treat angina.

Dr. Shreya Trivedi: You know, this is pretty striking when we compare, uh, these results to STICH, right? Both STICH and REVIVED looked at patients with pretty extensive coronary disease. Their ejection fractions had taken a hit, although I, I will make the big caveat that these populations don’t match up exactly. But there is overlap, right? But we saw a pretty big difference in the outcomes. STICH had pretty significant mortality benefit, over, but with REVIVED, we did not see any benefit at all. So what gives here, how do we explain this discrepancy?

Dr. Greg Katz: There’s a lot of possible explanations here. Maybe stents are inferior to bypass surgery or maybe we haven’t followed these patients long enough in REVIVED to see a mortality benefit. Or maybe because in REVIVED the medically treated patients were more likely to get defibrillators, so they didn’t die of sudden cardiac death. And they were also more likely to have an unplanned trip to the cath lab, so they didn’t dive an untreated MI. Or maybe the most boring explanation is the right one. Medical therapy in the era of REVIVED is different and better than medical therapy in the era of STICH.

Dr. Clement Lee: Yeah, I was thinking about that as well. The world of heart failure is so different now with SGLT-2 inhibitors, angiotensin and neprilysin inhibitors, and cardiac resynchronization therapy.

Dr. Shreya Trivedi: An ischemic heart disease management is also different, right? We now have ezetimibe, we have PSCK-9 inhibitors on top of statins, and now we also have changed the game of how we treat cardio-metabolic disease. We, we have GLP-1 agonists, SGLT-2 inhibitors. The ballgames very different.

Dr. Greg Katz: Right? And as medical therapy for any disease gets better, the role that procedures play is necessarily going to decrease, but, but you wanna know what the kicker here is? If you look at the tables from the REVIVED supplementary appendix where they discussed the medical therapy, it’s pretty striking that these patients weren’t even optimally treated for either coronary disease or for heart failure.

Dr. Clement Lee: Hmm. Yeah, you’re totally right. Only half were on mineral0corticoid receptor antagonists, and only 20 to 30% were on an ARNI. Although I will say that enrollments started in 2013, so that’s before the data for ARNI and SGLT-2 inhibitors had come out.

Dr. Greg Katz: And so we can only imagine just how well the patients in the medical therapy are may have done if they have been on contemporary guideline directed therapy for heart failure. And so I think it’s safe to say that the routine revascularization of every single patient with an ischemic cardiomyopathy certainly isn’t urgent and may not even be necessary. But we shouldn’t throw out the whole idea of putting in stents or doing bypass surgery. It still plays a really important role in how we manage lots of patients. Keep in mind, patients with persistent or progressive angina still have a huge benefit from going to the cath lab.

Dr. Clement Lee: Yeah, it’s important to keep emphasizing that we’re talking about stable coronary disease. Now that we have the results of the REVIVED trial, what do you think the next steps are, Greg?

Dr. Greg Katz: So the most important conclusion here is medical therapy is really, really good and we should do it, and we should do it better. But maybe the next investigation step is to redo the STICH trial in the era of contemporary medical therapy and see if bypass surgery still makes these patients live any longer, which I know may make my cardiac surgery colleagues a bit frustrated with me.

Dr. Clement Lee: Yeah, but maybe on the other hand, they’ll be happy. We’re not calling them at 5:00 PM on Friday.

Dr. Shreya Trivedi: That will make anyone happy! All right. So there you have it, the first edition of Beyond Journal Club with NEJM Group discussing the way the REVIVED trial adds to the body of literature on the way we manage coronary artery disease and heart failure with a low ejection fraction.

Dr. Greg Katz: And that is a wrap for today. If you found this episode helpful, please share with your team and colleagues and give us a rating on Apple Podcasts or whatever podcast app you use. It really does help people find us!

Dr. Clement Lee: And if you have any feedback, please email us at hello@coreimpodcast.com. The opinions express are our own and do not represent the opinions of any affiliated institutions.

References

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