Sripal Bangalore, MD, MHA, interprets the ISCHEMIA Trial and its use in clinical care.
Thank you for the invitation to present uh this talk. My talk is entitled ischemia trial interpretation and use in clinical care. My name is triple bangalore. I'm a professor of medicine at N. Y. U. School of Medicine. So these are some of my disclosures as it relates to this particular talk of grant support from N. H. L. B. I. For the ischemia ischemia CKD trials. So first let's start with the brief design. I'm sure most of you are familiar with the design of the schema trial in ischemia trial we enroll patients with stable patients. Typically outpatients who had moderate to severe ischemia on stress testing. This was determined by the site and read by the core lab and patients had a preserved E. G F. Are the fundamental blinded coronary ct and the blinded coronary cT was to um make sure that the patients had obstructive disease and also to make sure the patients did not have significant main disease. And if these criteria were satisfied, patients were randomized up front of the cath lab to an invasive strategy. We started with cardio cath and optimal revascularization. In addition to optimal medical therapy or to a conservative strategy of optimal medical therapy alone with kath reserved for failure of optimal medical therapy. If the patient had a. G. O. Far less than 30 or 40 on dialysis, they were enrolled in a panel trial called the ischemia CKD trial Where they underwent randomization. 1-1 to invest your conservative strategy. So ischemia addressed limitations of prior clinical trials. It included a higher risk patients with moderate or severe ischemia. As we know prior trials including courage, very two D. Or even the fame to trial did not select for uh threshold of unusable ischemia. And in fact observational studies have shown benefit in this group of patients who have at least 10% more ischemia in a non invasive stress testing. The other limitations that we addressed was we randomized patients without knowledge, the coronary artery anatomy. There has been criticisms of prior trials that uh knowledge of prior coronary anatomy could have biased towards enrolling only low risk subgroup of patients in those prior trials. So in ischemia, we randomized patients upstream of the cath lab. And unlike Origin barry today where mostly it was bare metal stents are first generation regulating stands to be. This trial was done with the latest generation regulating stents and also included patients who could undergo coronary artery bypass graft surgery. And this trial is larger than the two largest prior trials combined together, just like any trial. This the results apply to patients who were enrolled in the trial and the and the procedures that were followed in the trial. So it's important to recognize what which are the patients not enrolled in ischemia trial. And these were patients who had acute coronary syndromes within the prior to two months, patients who had E. F less than 35% since these were patients studied in the in the stitch trial, patients who had a class three or four heart failure patients were very symptomatic patients who had unacceptable engineer. Despite medical therapy and patients who had prior pcr cabbage within the last one year were also excluded. And of course the patients who had known severe left main disease were excluded to summarize uh scheme. In one slide we randomized 5179 patients who were randomized to invasive versus conservative strategy, making this the largest treatment strategy. Trial of stable ischemic heart disease. We have enrolled the highest substance patients. More than half of the patient at severe ischemia. Two thirds of the patients, 76% of patients at multi vessel coronary artery disease, with nearly half of the patients approximately lady disease and coronary ct. In patients who were randomized invasive strategy, 80% worry vascular Rised, 74% of those were by P. C. I. And 26% with cabbage. In patients who were randomized to conservative strategy, 28% underwent cat, 2033% underwent revascularization. At four years of follow up And most of these revascularization was for a primary endpoint event. In terms of medical therapy, 95% of patients were on a statin, two thirds of the patients were on a high intensity statin. The median achieved LDL was 64 mg per this leader and the median achieved systolic blood pressures were around 129 mm of mercury. The primary outcome was a composite of cardiovascular death. Eh my hospitalization for unstable angina heart failure, Resuscitated cardiac arrest and as can be seen on the slide, invasive isn't red. Conservative is in blue at the end of four years of follow up. No significant difference between invasive versus conservative strategy. However, the relationship is complex with an upfront hazard with an invasive strategy and potential late benefit with invasive and compared to conservative strategy. So the curves cross around the two year time point. If you look at the same major secondary endpoint, which is C. V. D. M. I. Again, a similar relationship with the up up front, a hazard potential benefit crossing of course around two years time point and overall no significant difference between the two strategies. So let's use this data and see how we can apply this into our clinical practice. So what are the potential reasons to revascularization? Patients who have stable cardiac disease? So, some of the reasons um potential reasons to consider revascularization are, can we improve survival in these group of patients? So what would it be learned from prior trials? So whether it's courage, barry Turia, even the uh fame to trial, which is generally considered a positive trial. One commonality of all of these trials are there has been no significant difference in debt between revascularization or the strategy of initial medical therapy alone. If you look at the schema and the schema CKD trials. Again, here is the curse for all cause mortality. No significant difference between invasive and conservative strategy in the ischemia trial. And also this is true in the schema CKd trial. In the schema CKD trial, the event rates were much higher when compared to that of ischemia trial. Um we published this meta analysis of randomized trials in the era of medical therapy. 14 randomized trials, 15,000 patients followed for 4.5 years. And if you look at the endpoint of death, no significant difference between routine revascularization. Was initial medical therapy in patients with stable coronary artery disease. Of course, there have been other meta analysis which have included other trials, including trials where there was no medical therapy and including all of these trials, including trials done three or four decades ago. You see that the signal for cardiac mortality, there seems to be a 21% reduction in cardiac mortality with an absolute production of around 2.2% per year. But again, the caveat for some of these trials are for example, in this meta analysis to all of the studies were conducted more than a decade ago. And so whether this, the results apply to contemporary practice can be uh, is debatable in the ischemia trial. We did observe the reduction in CV data. Am I in the subgroup of patients with complete revascularization. So this was presented as a late breaker by Greg stone last year and the manuscript is in is under review. So here, in this group of patients who achieved an atomic complete revascularization in the invasive strategy. And compared to conservative strategy, there is a reduction in primary and point there is also a reduction in CV death. Am I driven by a reduction in CV debt with a similar signal for myocardial infarction? So going back to the drawing board potential reasons to revascularization. There hasn't been robust evidence to suggest that revascularization um Does that improve survival? And compared to medical therapy alone? But if you include all trials where there is hardly any medical therapy, there is a note to small reduction of around .2% per year in cardiac death with revascularization. And compared to medical therapy. What about revascularization to survive, improve survival and high risk subgroup of patients. Let's talk about patients with left main disease and dysfunction. Triple vessel disease. Approximately lady are patients who have extensive ischemia in patients with left main disease. The data from randomized trials is based on trials of bypass surgery versus no bypass was redone in the eighties, only 100 and 50 patients enrolling these trials and in this meta analysis of individual patient data, left Main was a subgroup of patients which had the best benefit of revascularization, an extension of survival of 20 months over a 10 year follow up period of time with bypass surgery when compared to no bypass surgery. Because of this data. Subsequent trials including the schema trial excluded patients with left Main disease and as such for left main disease. Revascularization is the standard of care to improve survival. What about patients with the LV systolic dysfunction? This was this was the question answered with the stitch trial and the long term follow stitches trial comparing cabbage to medical therapy alone. And in stitches stitches, bypass graft surgery um resulted in significant reduction in mortality when compared to medical therapy alone with the number needed to treat of only 14 to save one life. In the skimming trial, we excluded patients with with the EF less than 35 per se, But in the subgroup of patients who had in years between 35 and 45 or who had a history of heart failure or LV systolic dysfunction, that's only comprised of around 400 patients, 8% of the randomized cohort. You can see that the results mimic somewhat that of the stitch trial in the sense that invasive strategy was associated with significant reduction in primary and point also significant reduction in the video to my when compared to that of a conservative strategy. What about patient with triple vessel disease? Again, if you go back to the 1980s cabbage, which is no cabbage trials, patients who had triple vessel disease at an extension of survival of six months when compared to no cabbage or the follow up period of 10 years. Um However, if you move forward and now this is 2009 barry to the trial which enrolled patients with diabetes and in the cabbage stratum patient had multi vessel disease and they were randomized to cabbage or system medical therapy alone. You see that the curves are no longer statistically significant. No significant difference between bypass surgery were system medical therapy in the body to the cabbage stratum. Um in diabetic patients with multi vessel coronary heart disease. In the ischemia trial, we looked at some of this data based on an atomic complexity and this is an atomic complexity based on coronary cT. Given the fact that conservative strategy patients did not have a cardiac cath routinely. So what we saw in this analysis was in patients with the highest an atomic complexity patient with triple vessel disease or two vessel disease including proximity lady. There seems to be a signal that for reduction in CVD semi within Macy's strategy when compared to conservative strategy, it's important to recognize that this signal was driven by a decrease in myocardial infarction. There is no significant difference in all cause mortality. Even in this group of patients with an atomic complexity. What about patients approximately lady disease in the schema trial, whether patients at approximately lady disease or not did not matter, there is no heterogeneity of treatment effect based on approximately 30 stenosis status for the primary endpoint. And also this was true for all cause mortality. What about based on schema severity in the schema trial patients who had severe ischemia or moderate ischemia and even patients who have mild and no ischemia, there's no significant difference in mortality between invasive versus conservative strategy. So going back to the drawing board potential reasons for revascularization, stable coronary artery disease. In important subgroup of patients, we know that revascularization especially with bypass surgery reduces improves survival in those with left main disease. But this is based on older trials and also with bypass surgery. In patients with LV systolic dysfunction. From the stitch stitches Trial. What about to prevent other cardiovascular events in the schema trial, invasive strategy was associated with significant increase in procedural um I but a significant decrease in spontaneous semi. So here you see the curves for spontaneous my 33% reduction in spontaneous semi. With invasive compared to the conservative strategy. It's important to also note that the curves continue to diverge um In and we also looked at the prognostic value of procedural versus spontaneous M. I. And in the schema trial, the procedural um M. I. Seems to be less strongly associated with death and the cardiovascular death when compared to spontaneous semi. So here you see, Type one of my more strongly associated with both death and cardiovascular death when compared to procedural M. I. And in our meta analysis of randomized trial, we see a similar signal revascularization reduces spontaneous M. I also reduces unstable angina but this is at the expense of increasing procedural M. I. In the schema trial, we also looked at whether revascularization can introduce cardiovascular hospital stays and if you look at the proportion of patients who are alive and out of hospital overall there was no significant difference between invasive and conservative strategy, especially if you exclude invasive protocol assignment procedures. However invasive strategy reduced cardiovascular stays. And this reduction was mainly to run by lower states or spontaneous semi and lower states for unstable angina. So going back to the drawing board potential reason to do vascular stable coronary artery disease invasive strategy that uses spontaneous semi and stable engine and although also lowers cardiovascular state. And finally, what about implementing quality of life? This is the results from the ischemia trials. So unlike prior trials, what we showed was in major strategy results in an immediate and also sustained implementing agenda related quality of life. Uh this is durable, up to four years of follow up in the ischemia trial and completely conservative strategy. And in the schema trial, the benefit of angina relief depends on baseline angina status. So if you have a patient with a daily or weekly angina, you only need to treat three patients to make them free of angina. However, if the patient is asymptomatic, there is no difference between invasive and conservative strategy for the probability of no angina. So revascularization improves and generated quality of life, but this is not in the asymptomatic patients. And finally in this key mia trial although we had a threshold for entry. So in other words we only mainly in patients with moderate or severe ischemia. Ischemia severity was not independently associated primary outcomes. So here you see all cause mortality, my korean function, primary outcome divided by patients with severe moderate noise, keamy. And you can see the relationship between ischemia severity. Um And uh each of these cardiovascular endpoints. However, if you look at an atomic severity, patients with the more complex disease, three vessel um disease greater than equal to 70% to vessel with proximal L. A. D. Clearly um an atomic severity was more associated with all cause mortality. Myocardial infarction and primary endpoint when compared to ischemia severity. Just to summarize what revascularization to improve survival. I mean we didn't talk about acute coronary syndromes but clearly multiple randomized drones have clearly shown revascularization improve survival in patients who present with acute coronary syndromes in stable coronary artery disease. There is there are data for patients who have left main disease but no contemporary data, clearly for cabbage, there is data from stitch and stitch is for an improvement in survival. Um But for patients with triple triple vessel disease, proximity and extensive ischemia. There isn't a significant difference in survival between revascularization and medical therapy alone. Um So um when and why should we revascularization based on the skinny trial. Clearly for patients is symptomatic implemented, imagine related quality of life that is faster and more durable relief of angina in symptomatic patients if you're looking for implementing clinical outcomes. There is a reduction in spontaneous semi and unstable angina but of course this is at the expense of procedural in my and it's important to recognize that it's not just an ischemia. We see this in um other trials also and in the meta analysis of randomized trials um in the schema trial, we showed that there is reduction in primary outcome with complete revascularization but this is hypothesis generating and also it seems to uh the benefit seems to extend in the subgroup of patients with a history of heart failure, a year of 35 to 45%. Um and um as was shown, there seems to be a reduction in CV death am I in the subgroup of patients with higher an atomic atomic risk such as those the Duke uh six category. And as was shown, there is also a reduction in CV stays um mainly driven by a reduction in hospitalization for an M. I. And unstable angina. So just to summarize um revascularization, corner coronary disease, I feel like there should be um based on the ef, we know data from stitch that there is data for benefit of cabbage in patients with the f 35% are less in patients with the f 35 to 50 scheme trial shows that the strategy potentially reduces primary composite and also see the death of my patients with preserved ef strategy that uses spontaneous semi unstable angina but the best benefit is for greater angina relief. Um, and finally, I want to live with these two slides in the schema trial. We saw that for CVD AM I, the curves cross around two years and we also saw that there was a separation of course was spontaneous semi and the curse seems to separate. Um, so we are following the patients who are randomizing the schema trial for a longer term follow up up to 10 years of follow up. This is called ischemia extend trial. This will assess long term CV death within his conservative strategy and also assisted all cause death within the conservative strategy. Um the interim results of this ischemia extent will be presented as a late breaker at age 8 2022. Please stay tuned and thank you for your attention.
