Circulation April 2, 2019 Issue

 Dr Carolyn Lam:               Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to The Journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center, and Duke National University of Singapore.

Dr Greg Hundley:             And I'm Greg Hundley, also associate editor in Richmond, Virginia at VCU Health.

 Dr Carolyn Lam:               So, PCI or no PCI for chronic total occlusion. That is a perennial question, and we have the results of the decision CTO trial reported in this week's Journal. In fact, we're going to discuss it right after our little chat here.

                                                So, Greg, why don't you kick us off? What paper did you choose?

 Dr Greg Hundley:            Yeah, thanks so much Carolyn. My first paper is from Laura Benschop from the Department of Obstetrics and Gynecology at Erasmus Medical Center in Rotterdam, the Netherlands. It's going to focus on placental growth factor as an indicator of maternal cardiovascular risk after pregnancy.

                                                So, as we all know, pregnancy is accompanied by extensive maternal hemodynamic changes that allow for proper placental implantation, growth, profusion, and fetal development and this process requires a tight balance between pro-angiogenic factors like placental growth factor, and anti-angiogenic factors like soluble FMS like tyrosine kinase factors. So, in response to stress, the syncytiotrophoblast will decrease the production of placental growth factor and women with reduced placental growth factor and increased FLT-1, are more at risk of a complicated pregnancy. For example, like preeclampsia and spontaneous preterm birth.

                                                So, angiogenic placental growth factor concentrations can rise during pregnancy, peaking at the end of the mid-pregnancy. And low placental growth factor concentrations during pregnancy are associated with pregnancy complications with recognized later life cardiovascular risk. So here, the authors hypothesize that low placental growth factor concentrations, especially in mid pregnancy, identify not only a subset of women at risk for pregnancy complications, but also women with greater cardiovascular risk factor burden after pregnancy, regardless of their outcome.

                                                So, among 5,529 women, the authors computed gestational age adjusted and mid-pregnancy placental growth factor concentrations and pregnancy complications, like preeclampsia, small for gestational age, spontaneous preterm birth, was obtained from hospital registries.

 Dr Carolyn Lam:               Cool, and what did they find?

 Dr Greg Hundley:            So six years after pregnancy, the authors found that women with mid pregnancy low placental growth factors, in the lowest quartile, had larger aortic diameters, left atrial diameters, and LV mass, and a higher systolic blood pressure by an average of 2.3 millimeters of mercury. High mid-pregnancy placental growth factor concentrations were the opposite. They were associated with smaller aortic diameters, smaller left atrial diameters, lower LV mass by 3.9 grams, and lower systolic blood pressure. And these differences persisted after exclusion of women with complicated pregnancies.

                                                So, the results suggest that a woman's response to the cardiovascular changes of pregnancy, measured by pre-mid-pregnancy placental growth factor levels could provide insight into the path of physiological mechanisms leading to future cardiovascular disease in multiparous women.

 Dr Carolyn Lam:               Wow. That is really interesting. Well, the paper I chose really answers the question, are there racial differences in sudden cardiac death, and why? And this is from corresponding author Dr Guallar from Welch Center for Prevention, Epidemiology, and Clinical Research in Johns Hopkins Bloomberg School of Public Health and Colleagues.

                                                What they did is they compared the lifetime cumulative risk of sudden cardiac death among blacks and whites in the atherosclerosis risk in community study, or ARIC. They evaluated the risk factors that may explain racial differences in sudden cardiac death risk in this general population.

                                                What they found was that blacks had a much higher risk of sudden cardiac death in comparison with whites, with a sex adjusted hazards ratio of 2.12. Known factors explained 65% of the axis risk of sudden cardiac death in blacks compared to whites. The single most important factor explaining this difference was income, followed by education, hypertension, and diabetes. These racial differences were evident in both genders, but stronger in women than men.

 Dr Greg Hundley:            Hmm. So are there implications, and are there potential strategies that could help reduce this risk in African Americans?

 Dr Carolyn Lam:               Yeah, this is a really interesting study, and it really implies that efforts to reduce the sudden cardiac risk in blacks should perhaps focus on improving CPR outreach, medical care engagement in response to cardiac arrest, the quality of treatment in medical institutions in predominantly black neighborhoods, and factors such as that. Because remember the single most important factor explaining the difference was actually income and education.

 Dr Greg Hundley:            Oh, wow. Well, I'm going to switch gears a little bit here Carolyn, and we're going to talk about pulmonary hypertension. And this next paper is going to focus on pericytes. We'll learn a little bit about what pericytes are. So, the paper is from Vinicio de Jesus Perez, who's an assistant professor of medicine and pulmonary critical care at Stanford University Medical Center in California.

                                                What are pericytes? So, pericytes are specialized perivascular cells embedded in the basement membrane of blood vessels, where in conjunction with neighboring and endothelial cells, they support vessel maturation and stability. In the lung, pericytes are mostly found associated with small precapillary arteries, the capillaries, and then those post capillary venules. And it's thought that pericytes are responsible for regulation of vasomotor tone and structural support of these micro-vessels. When the vessels become muscularized, pulmonary vascular resistance increases, resulting in pulmonary artery hypertension.

                                                So recent studies have focused on pericytes in addition to pulmonary endothelial cells, smooth muscle cells, and fiberglass, but not much is known about the contribution of pulmonary pericytes to pulmonary arterial hypertension. Two genes are involved in Wnt planar cell polarity pathway that is responsible for coordinating complex cell movements during tissue morphogenesis. So, in this group, they have produced prior results that show that restoration of the Wnt planar cell polarity in pulmonary arterial hypertension, pericytes could partially restore recruitment to PNVECs and increase vessel stability.

 Dr Carolyn Lam:               Interesting, and so that was their past research, and what did the current paper show?

 Dr Greg Hundley:            Right. So Carolyn, what they found is that pulmonary microvascular endothelial cells isolated from pulmonary arterial hypertension patients, and endothelium from pulmonary arterial hypertension tissue have reduced expression of Wnt-5a. Healthy PMVECs produce and package Wnt-5a in the form of exosomes which regulate pericyte recruitment, motility, and polarity.

                                                And so, the overall implication is that promising therapeutic strategies that help can restore the Wnt/PCP, or planar cell polarity pathway, and endothelial pericyte communication could help prevent micro-vessel loss in patients with pulmonary artery hypertension.

 Dr Carolyn Lam:               Thanks, Greg. So, I'm going to take us to the cath lab for this next paper. And it's the results of the CANTIC study, which aimed to answer the question, does intravenous P2Y12 inhibitor Cangrelor have a role in bridging the gap in platelet inhibition in patients with STEMI undergoing primary PCI. And this is from corresponding author Dr Angiolillo from the University of Florida College of Medicine Jacksonville and Colleagues.

                                                Now, CANTIC was a prospective randomized double-blind placebo control parallel design investigation of the pharmacal dynamic effects of Cangrelor versus placebo in patients undergoing primary PCI, who were also treated with crushed Ticagrelor. So, after diagnostic angiography, patients were randomized to a blinded two-hour infusion of either Cangrelor or placebo. At the same time, 180 milligrams of crushed Ticagrelor was administered to both groups. Platelet reactivity was measured with Verify Now P2Y12 point of care testing, and with vasodilator-stimulated phosphoprotein, or VASP.

 Dr Greg Hundley:            So what did the trial show, Carolyn?

 Dr Carolyn Lam:               They found that addition of Cangrelor led to more prompt and potent platelet inhibitory effects, compared with crushed Ticagrelor alone in patients undergoing primary PCI. The significant differences were observed as early as five minutes post bolus administration, and persisted until the end of its two-hour infusion.

                                                Furthermore, after discontinuation of Cangrelor or the placebo infusion, there were no differences in levels of platelet reactivity between groups. And this importantly rules out a drug/drug interaction when Cangrelor and Ticagrelor are concomitantly administered. This lack of drug-drug interaction is important, as it supports a more versatile use of Ticagrelor with respect to timing of its administration in patients treated concurrently with Cangrelor.

                                                Overall, the results are reassuring and demonstrate reduced platelet reactivity, and no high on treatment platelet reactivity with Cangrelor in combination with Ticagrelor in primary PCI patients. Of course, the implications of these pharmacal dynamic findings really warrant investigation in an adequately powered clinical trial.

                                                And that brings us to the end of our summaries. Let's go to our featured discussion.

                                                So PCI, or no PCI for chronic total occlusion, that is a perennial question isn't it? Especially nowadays when procedural results for PCI and CTO have improved in recent years, and PCI strategies have moved towards more complete revascularization. Yet the evidence is clearly lagging behind for us to make decisions on this. And that's why we're so happy that our featured paper today is the DECISION-CTO trial from Korea, and so happy to have the first author, Dr Seung-Whan Lee from ASA Medical Center to tell us about this, as well as our associate editor, Dr Manos Brilakis from UT Southwestern.

                                                So Dr Lee, could you tell us about the DECISION-CTO trial?

Dr Seung-Whan Lee:       Yeah, in our trial our multicenter, randomized, noninferiority trial, PCI-eligible patients were assigned to receive either one of two strategies; PCI or no PCI or CTO. We did the option for PCI of the other. The primary endpoint as you know the composite outcome of deaths, myocardial infraction, stroke, or any revascularization. As related to quality of life was assessed up to three years. However, because of the slow recruitment, the trial was stopped before completion. We started 208 planned enrollments. For six years 834 patients there were randomly assigned to the CTO PCI versus no CTO PCI strategy.

                                                Among the patients assigned to the no CTO PCI strategy, nearly 20 percent of patient cross over to the CTO PCI. That is our big limitation, as you know. Anyways, the primary end point was assessed per year, and then, finally, we founded the per year risk of the major adverse cardiac events there’s no difference in contributor composite outcome, MI, revascularization, and stroke.

                                                However, in our trial, in some detail, in CTO PCI was success rate around 91 percent. However, complication is very low, .6 percent of patient is complication. Very surprisingly the coheir is up to the three, and no difference between CTO PCI versus no CTO PCI.  

                                                I think our main message is our patient is a relatively low-risk population, including the syntax score 20 and the score 22%. The majority of patient preserved LV function and single-vessel disease 25%. The relative low risk population CTO PCI versus no CTO PCI clinical outcome is no difference of the per year from the two groups.

                                                I think that our trial is make the reposition with the medical law in the CTO patient. That’s my summary.

Dr Carolyn Lam:                Thank you. Manos, could you maybe paint the background and let us know why this was so important for us to publish in Circulation? Why is it so difficult to do these trials?

 Dr Manos Brilakis:           This is the largest study on CTO PCI so congratulations on getting this accomplished. I know it was many years and a lot of effort.

                                                I think a couple of things on the background. As Dr Lee said as well, CTO PCI success rates have been improved, and now at experienced centers you can get 85 to 90 percent success fairly consistently.

                                                The complication rates are low. .5 to 3 percent is the average rate. We do have a tool right now. The procedure is mature, and it's time test in the randomized trials.

                                                The question has always been for CTO PCI, "How does it help?" Does it improve symptoms? Does it improve the heart outcomes? Myocardial Infarction?  This is what DECISION CTO was trying to answer.

                                                Couple of I think limitations that we should take into account when interpreting the results. The first one is that these were notations with an isolated CTO, but a significant proportion had also multi-vessel disease. They were enrolled before treating the other vessels, which were subsequently treated.

                                                Sometimes it's hard to know how much the residual ischemia or symptoms would be present after the other lesions were treated. That's one thing.

                                                The second is that there was a significant crossover for about 1 in 5 patients that randomized to medical therapy immediately crossed over to the CTO PCI group. And that always uses the power and creates difficulty in interpreting the results.

                                                In my mind, the question still remains, in low risk populations it's possible that CTO PCI doesn't improve symptoms, but the ones that were expected to improve, the heart outcomes dec-MI, would be the high-risk patients with significant ischemia. Ideally, studies in the future should actually look specifically at patients who have high ischemia, significant symptoms when looking at heart outcomes.

 Dr Carolyn Lam:               Dr Lee, I think you did mention as well in your manuscript that a viability test was not mandatory for patient enrollment. I mean, clearly it was such as work of labor enrolling such patients. If you put even more criteria it would have been impossible, I suppose. Do you have some thoughts there on maybe future studies?

Dr Seung-Whan Lee:       Yeah, as you know, the currently ongoing CTO PCI process medical treatment is nobel CTO and ischemia CTO is assessed at the reduction of the ischemia burden in CTO PCI. I think there maybe two studies that give us some answer for the low level of the CTO PCI for the reduction of the ischemia.

                                                So, I think the larger ischemic burden the patient is maybe high risk to make the however we don’t know exactly the cut off… ischemic burden in CTO patient. Usually instable angina any kind…coronary disease…3 years circulation showed more than 10 percent of ischemic burden is really predictive of future cardiac event. However, we don't know exactly the can be applied to CTO patient. We don't know exactly.

 Dr Manos Brilakis:           Can I ask Dr Lee a question regarding the study and his interpretation as well. Now the study was borrowed for hard end points dec MI. What his is perception, based on the DECISION CTO, and, of course, everything else in the literature and the CTO study with symptomatic benefit...Dr Lee, what is your conclusion about, or your kind of thoughts about, the effect of CTO PCI on improving symptoms, which is a more accepted indication for the procedure right now?

Dr Seung-Whan Lee:       As you know, the university trials symptom assessment was done after the no CTO PCI. However, our trial is a pragmatic trial, initial approach to the CTO vessel and the vessels that is patient.

                                                At this moment, I think the other vessel, other no CTO vessel intervention and OMT may improve the patient symptom and then CTO vessel is the intervention including the CI patient completely…improve the symptom status. However, analysis showed up to the 3 year, maybe no difference between two groups in the CTO PCI versus medical treatment.

                                                Our trials of the CTO PCI symptom, we don't exactly the role of the after no CTO PCI. We don't know exactly the CTO based symptom assessment was not done, because of the symptom assessment was done before the intervention.

                                                I think that our trials are more practical, because of the initial…multivessel… CTO. Our trials, maybe, completely vascularization including CTO and no CTO vessel revascularization without the CTO intervention. Sometimes the patient to complain of symptom multivessel with the CTO I think we can wait if we continue the patient symptom…

                                                However, in this trial showed CTO specific intervention trial, because of the symptom assessment was done after no CTO vessel intervention. There is some improvement of the… receptor treatment satisfaction of the angina stability. I think that the CTO intervention is maybe reserved for the symptom control after the medical treatment failure of patient.

                                                I fully agree the symptom control is possible with the CTO PCI.

 Dr Manos Brilakis:           Wonderful. Thank you. I think that's a critical differentiation that the DECISION CTO is not specific for CTO, but it's multi-vessel disease plus CTO. Thanks for clarifying. That's very important for the leaders and the entire community to understand that part.

                                                One more question, if it's okay. I know that in Asian countries bypass patients are relatively less. I think in the U.S. 50 percent. Any comment on that? I know people get less bypass in Asia than they do in the United States. How may that affect the interpretation of the DECISION CTO?

Dr Seung-Whan Lee:       Initially, I introduced my studies to our patients syntax score under 20. As you know, the U.S. Registry shows the syntax score more than I think the 20, and the tester score around 46. Quite different in population, because the risk factor is quite different. U.S. patient is hypertension and diabetic are more prevalent than the Asian patient. Bypass surgery is 40 percent in Asian patients. Bypass surgery is around 102 percent in CTO registry. Quite big difference of the base rank, risk factor, and morbidity.

                                                I cannot apply to U.S. population exactly the same ... Not same situation. We cannot apply directly to the U.S. population. I fully agree with your suggestion, though. Lowest population is maybe ... Our trial is maybe lowest population. We agree.

 Dr Carolyn Lam:               I'm just learning so much listening to both of your interventionists. What do you think are the take-home messages from this? Maybe, could I start with Dr Lee, and then give Manos the last word?

Dr Seung-Whan Lee:       CTO PCI critical outcome, it should be tested as a large random trial. Maybe Manos already mentioned about the high-risk population, because our population is the lowest population. However, in some large random trial with a high-risk population we have consider some random trial because they are not easy.

                                                Maybe not easy to test in high-risk population. However, you must do that, because of the two established CTO PCI law in the current practice.

 Dr Carolyn Lam:               Manos?

 Dr Manos Brilakis:           Yeah, I would agree with that. I think the main conclusion regarding the field of CTO PCI is that still right now, the key indication remains symptom improvement. We do have the trials at this point showing that you do CTO PCI in terms of improving mortality. However, CTO PCI is a tool. It's a revascularization tool. Patients who have severe, complex, coronary disease, multi-vessel disease, may be best served with bypass in the first place. Those who have multi-vessel disease that's less complex and don't have significant symptoms after fixing the non-CTO lesions, then they may not benefit from CTO PCI as well. But those who have CTO lesions and have significant symptoms, this is the population for which I think there is general agreement, and I the decision that CTO is good with that, that those patients could benefit from CTO intervention.

 Dr Carolyn Lam:               Thank you so much for sharing your insights.

                                                Thank you, listeners, for joining us today. You've been listening to Circulation on the Run. Don't forget to tune in again next week.

                                                This program is copyright American Heart Association 2019.