Ileana L. Piña, MD, MPH; Eric J. Velazquez, MD

Disclosures

September 08, 2016

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Ileana L. Piña, MD, MPH: Hello. This is Ileana Piña from Montefiore Medical Center in the Bronx, New York, and Albert Einstein College of Medicine, and this is my blog. I am here at the European Society of Cardiology (ESC) Congress. It is a huge congress with 34,000 attendees, which makes it the largest cardiology venue in the world.

I'm thrilled today to have my good friend Eric Velazquez with me. Eric is the principal investigator of the STICH trial, which we're going to talk about. And he is the director of imaging at Duke, professor of medicine, cardiology. Eric, congratulations on all these years of a very hard trial to do; our audience includes general cardiologists and internists. So, why don't you give us a broad view of STICH and then go into STICHES?

STICH: State-of-the-Art Medical Therapy for the Time

Eric J. Velazquez, MD: Thank you for the introduction, and it's wonderful to be here with you. I know how much effort you put into the STICH program over these years. The Surgical Treatment for Ischemic Heart Failure program, or STICH, started as a National Institutes of Health–led investigation that began enrolling in 2002. We finished follow-up in 2015, so you can imagine the extent of time and effort across many different centers (over 100 centers in nearly 25 countries), with two main hypotheses. We are going to focus our discussion today on the revascularization hypothesis.[1] But, just to remind people, the STICH program was two trials embedded—one that looked at the effect of reconstruction of the ventricles surgically versus coronary artery bypass grafting (CABG) alone, and the other which looked at whether CABG added to guideline-directed medical therapy for ischemic cardiomyopathy patients was better than medical therapy alone.

Dr Piña: We had a medical therapy committee that looked very carefully at the background medical therapies. I remember that the first beta-blocker trial came out in 1998, '99, and so by 2002, we already had beta-blockers as part of our standard armamentarium.

Dr Velazquez: We were very fortunate. It's an important point to highlight that we benefited from the wonderful work that had come before us on guideline-directed medical therapy. There were very high rates of beta blockade, angiotensin-converting enzyme (ACE) inhibition, or angiotensin II receptor blocker (ARB) use if not a candidate for ACE inhibitors, and mineralocorticoid receptor antagonists.

Dr Piña: Yes, even before the mineralocorticoids [were widely used].

Dr Velazquez: Before, 50%-plus magnetic resonance angiogram (MRA) usage was standard. Our rates of implantable cardioverter-defibrillator (ICD) use were relatively low at baseline but progressed to over 20% by the time of the last follow-up period because of, frankly, the fact that those data lag behind the medical therapy data.

Dr Piña: Yes. SCD-HeFT came after this trial.[2]

Dr Velazquez: Really, the point to highlight is that we wanted to test guideline-directed medical therapy for all patients, including those who were randomized to CABG versus those who continued only on medical therapy.

Dr Piña: What was the ejection fraction (EF) at entry?

Dr Velazquez: The median EF was 28%; these patients had very large ventricles. The end systolic volume index on average was about 80.

Dr Piña: That's huge.

Dr Velazquez: Remember, normal is 25, so these are very large ventricles. All patients had coronary disease that was amenable to cardiac surgery, and the majority had two- or three-vessel disease. About 70% had proximal left anterior descending artery (LAD) involvement, 40% were diabetic.

Dr Piña: That's a good number of diabetics.

Dr Velazquez: As we've discussed before, we didn't do as well enrolling women, which is a challenge in all clinical trials, particularly in coronary disease and heart failure.

Dr Piña: And you've all heard it from me a million times.

Dr Velazquez: About 12% were women. And this may be important to our discussion: The mean age was 60 years. As you mentioned, this was a global trial with 99 clinical centers for revascularization, involving 22 countries. Because you didn't have equipoise in the data, we actually took advantage of having a large spectrum of sites across different countries. What may have been standard of care based on no data but a lot of belief, say, in Canada, was very different in Poland. A patient whom a group of clinicians may not have felt comfortable enrolling in Canada may have been opposite to the patients who may have been randomized in Poland.

Dr Piña: That is the beauty of randomization and doing it right. And so, the overall results, if you can just review them briefly for us.

Dr Velazquez: Sure. I'll speak mostly to the 10-year follow-up.[3] We did present initial results at 5 years,[1] and then, a priori before publication or understanding those results, we had decided to continue follow-up out to 10 years. We had a median follow-up of 9.8 years, and we are very proud that 98% of patients were followed up through the last 6 months of the follow-up period. We enrolled 1212 patients; 610 were randomly assigned to CABG and 602 to medical therapy. These patients were sick; 62% were dead at 10 years. These were high-risk patients.

Dr Piña: That shows you how bad ischemic heart failure is.

Dr Velazquez: The end results were very gratifying for us and are guideline-modifying in a way. We showed an 8% absolute risk reduction in all-cause mortality in favor of CABG, a 9% absolute risk reduction in terms of cardiovascular mortality, and an almost 11% reduction in the combination endpoint of all-cause mortality plus cardiac hospitalization. So these are relative risk reductions of 16%, 20%, and nearly 30% for these three main endpoints.

Dr Piña: And it held out at10 years.

Dr Velazquez: It continued to diverge a little bit over the period of study. To put it in other terms, we were able to show that the median survival was extended by about 18 months in patients who were randomized to CABG compared with those who remained only on guideline-directed medical therapy.

Viability Testing Not Needed Anymore

Dr Piña: And this was CABG in a lot of different countries where techniques may be a bit different, and compared against good background therapy. That's an important point to make for the general cardiologist who has the patient in front of them with an ischemic heart failure picture—to think about surgery in the long term. Our surgeons still ask, "Well, did you do a viability study?" So tell us about that.

 
Viability [testing] in this era of great surgery, great medical therapy... it's only being used to disqualify someone who might benefit from CABG.
 

Dr Velazquez: I'd like to introduce that concept, because it's an important one, by just saying that because we had limited data on the benefits of CABG, there was clearly a need, particularly when we didn't have the evidence for medical therapy 20-plus years ago. For viability testing, you try to use imaging studies to help select those patients who might have the most benefit. I give credit to my mentors who developed these tests, which were very important in that era. But the question was, should these viability tests be used to select patients who may or may not benefit from CABG?

Dr Piña: Right—the yes-or-no decision.

Dr Velazquez: Many physicians feel very strongly about this because that's how they've learned how to select patients.

Dr Piña: Oh, I know, and they still do.

Dr Velazquez: To be very upfront, this was not the primary analysis; this was a subgroup of 600-plus patients who had viability testing by either nuclear or echo, and we found that there was no difference whether patients were deemed to have viable or nonviable tissue.[4] These images were reviewed closely by the leaders in the field in a blinded core lab without knowledge of how the patients were being treated or what the results and outcomes were. There really was not a hint of benefit. I think it tells us a few things. One is that we have to be careful about applying pathophysiologic constructs that might be old and may not be relevant as medical therapy changes.

Dr Piña: And even surgical therapy has advanced tremendously.

Dr Velazquez: Right. It's been a lesson for all of us. We went into it with a hypothesis that perhaps the patients who had the most viability would have the most to gain. In fact, what we've seen is the opposite: The point estimates in favor of CABG actually are larger for those who have less viability.

Dr Piña: That's interesting.

Dr Velazquez: An important paper by one of our colleagues, Julio Panza,[5] in JACC a few years back really tried to divine some structural and functional definitions to understand whether high-risk patients do differently from low-risk patients. Patients who have the worst EFs, the largest ventricles, and the most extensive coronary disease have the most to gain from CABG, but those are also the highest-risk patients for the operation. This idea of using a test like viability to try to eliminate those high-risk patients—it's actually not consistent.

Dr Piña: That is very interesting. You may want to save the test.

Dr Velazquez: My personal belief, which has evolved, is that these tests become a crutch. If you have good vessels and you have the right patient who is willing to take a risk, because there is a risk up front of any procedure including surgery... Then the only reason, I believe, to do viability testing is to try to disqualify them from receiving CABG. That's a little strongly worded, but I do think that viability [testing] in this era of great surgery, great medical therapy, and with these data now available, really it's only being used to disqualify someone who might benefit from CABG.

Dr Piña: The other beauty of this type of trial is that it spits out papers that are helpful to the clinician on other things, like exercise testing. You presented an important paper at ESC. Tell us about that one.

Age Analysis: Not Quite What You'd Expect

Dr Velazquez: The benefit of a clinical trial like this is not only the main results but also to explore the disease state. We are very proud of the 30 papers that are already published from STICH and the many to come now, that we have closed the dataset with the long-term follow-up. I was honored to present, at a clinical trial update hotline session, data looking at the interaction between the effect of CABG on medical therapy and age.[6] We all recognize that the older you are, the more comorbidities you have and the higher your risk for mortality. I wish we could change that, but that's a biological fact.

Dr Piña: Not an option.

Dr Velazquez: Therefore, it becomes important to understand the interaction between the effect of CABG versus medical therapy by different age groups. We looked at the STICH population through the entirety of the follow-up.

Dr Piña: So you did it as a continuous variable.

Dr Velazquez: We used age as a continuous variable and presented these data for descriptive purposes in quartiles of age groups. It is important to recognize that this is a randomized trial, that this analysis is selected patients who were randomized; it is not an observational analysis, per se, of a larger cohort.

One limitation that we have to recognize is that the median age was 60 years at baseline. Only about a third of the patients were over the age of 65 years, and about 6% were over the age of 75 years. It's informative, but we have to recognize its limitations.

Dr Piña: Yeah, there's a limitation to this.

Dr Velazquez: What we were able to show is that regardless of age, cardiovascular mortality is by far the most common cause of mortality in these patients.

Dr Piña: Isn't that interesting.

Dr Velazquez: It's an important, important point that gets lost.

Dr Piña: It parallels all of the epidemiologic data that we know.

Dr Velazquez: And it really doesn't change across age. What happens is that as you get older, competing risk for noncardiovascular causes increases.

Dr Piña: Like cancer, for example.

Dr Velazquez: Now, that's not to say that cardiovascular mortality becomes less important; it actually remains twice as common a cause of mortality than noncardiovascular causes.

Dr Piña: Fascinating.

Dr Velazquez: But by the time you're in the oldest quartile, your noncardiovascular cause—and these again were adjudicated events by yours truly and a wonderful clinical events group blinded to trial—the result was about 20% versus 6% in those who were in the youngest quartile.

Dr Piña: There you go.

Dr Velazquez: You get an increase in all-cause mortality as you age, but cardiovascular mortality remains the same. Now, what was really interesting was that as a percentage, the frequency of cardiovascular mortality as the cause of mortality in the younger quartile was greater: 79% versus 62% in older patients. We were able to show that the effect of CABG versus medical therapy was consistent across all of the ages. There was an interaction that wasn't statistically significant but certainly trended towards being so.

Dr Piña: And you have some graphs that are really very informative on that.

Dr Velazquez: The graphs show that the effect on the younger patients, in terms of all-cause mortality, is greater than on the older patients. That is an important lesson: When you have a patient in front of you, don't avoid pursuing CABG and medical therapy, even early. And in the elderly, don't avoid using CABG; the upfront surgical risk wasn't substantially different. But be aware of the competing noncardiovascular risks. With your heart team, evaluate the impact of those noncardiovascular potential causes of mortality down the road and make that part of your equations. But always remember that cardiovascular mortality is by far the leading cause of death, regardless of age.

Dr Piña: And I think with that statement we will wrap it up today. I want to thank you for joining me, wish you luck on your presentation, and I look forward to seeing the paper. Where are you going to send it?

Dr Velazquez: It's simultaneously published in Circulation.

Dr Piña: Fabulous. I want to thank my audience. I hope that this discussion is helpful to you as you see the patients in front of you. There are so many patients with coronary disease that now we do all of these interventions to try to save myocardium, but these are patients who already have hurting myocardium. And it's particularly those large ventricles, where things like end-systolic volume index become very important parameters, that I want this audience to think about.

This is Ileana Piña. Thank you for joining me today. Have a great day.

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