Hello, everybody. I've been given the topic of discussing the issue of survival and revascularization in stable coronary artery disease, which has become quite a bit of a debate in recent times. So these are my disclosures as it relates to this particular talk. I have grant support from NHLBI for the ischemia and ischemia CKD trial. Let's start with the question whether there is a survival benefit of revascularization in patients with stable coronary artery disease. I mean, we clearly know in patients who present with ACS, revascularization improves survival. So here we are specifically focusing on patients with stable coronary artery disease. If you look back at the trials done back in the day in the 70s and 80s, these trials of cabbage versus no cabbage, where there was hardly any medical therapy, suggest that there is a survival benefit. And this is a meta-analysis of randomized trials put together by Youssef et al., published in 1994, where they showed that there was a survival benefit of cabbage compared to no cabbage at five years. And at 10 years, the curves start to converge and absolute reduction decreases, but there is still a statistically significant difference in mortality at 10 years with cabbage compared to no cabbage. And if you look at the three major trials that went into this meta-analysis, you can see that two of the studies by themselves did not show a significant difference in mortality, and only the European study showed a difference in survival with cabbage when compared to no cabbage in stable coronary artery disease. So this was in the pre-guideline-directed medical therapy era. So more contemporary trials seem to suggest that there is no more difference in mortality when compared with modern medical therapy. For example, in the COURAGE trial of PCI versus medical therapy, there was no difference in death. BADDI 2D trial, which included both PCI and cabbage, also showed no difference in death. And in FAME 2 trial, a strategy of ischemia-driven revascularization using physiological guidelines also did not show a significant difference in death when compared to medical therapy alone. In the ISCHEMIA trial, where we enrolled over 5,000 patients and randomized them to invasive versus conservative strategy, for the endpoint of all-cause mortality, again, we have two overlapped curves, no significant difference in mortality in the ISCHEMIA trial, and the same was also true for in the ISCHEMIA CKD trial. We put together a meta-analysis of randomized trials, 14 randomized trials, 15,000 patients followed up for around 4.5 years with 65,000 patients years of follow-up. And the trials we chose here were trials where there was some amount of medical therapy. And the medical therapy, we defined it as being on an antiplatelet and also being on statins. And in this meta-analysis of randomized trials, again, the result is consistent, no significant difference in mortality between a revascularization when compared to a medical therapy. And in fact, if you're restricted to more modern trials where stents were used, the point estimate falls in the line of unity, 0.99 with a confidence interval, which is pretty tight, suggesting no significant difference in mortality with revascularization compared to medical therapy. Other meta-analysis, this is a meta-analysis by Navarese, looking at 25 trials, 19,000 patients followed up for 5.7 years. And in this meta-analysis, they showed cardiac mortality reduction of 21% with revascularization when compared to medical therapy. Of note, the 20 trials included in this analysis span between 1979 and 2020, 12 of these studies were actually conducted more than 10 years ago. So one can question the applicability of these trials where there was hardly any medical therapy to modern day management of patients with stable coronary artery disease. Even in this analysis, even though the relative reduction was 21%, the absolute reduction was around 0.2% per year. So a small difference in absolute risk reduction per year with the revascularization when compared to medical therapy. Others have looked at the mortality signal, cardiac mortality signal seen in the Navarese analysis. This is an interesting way of looking at the same data. They use the same number of trials and they pooled trials in chronological order, starting from older trials to newer trials, and then also pulling them in the reverse chronological order from newer trials to older trials. What they found was very interesting that if you start from older to newer trials, you only need to add two trials to have a significant difference in cardiac mortality. But as if you do the reverse, start from the more recent trials, such as ischemia trial, you had to add 17 trials to achieve statistical significance. This suggests that the difference in cardiac mortality is largely driven by older trials and not much seen in the more recent trials. They also assessed the impact of optimum medical therapy and found that there was a significant interaction such that in trials where there was a use of OMT, there is no significant difference between revascularization versus medical therapy, whereas the cardiac mortality signal was mainly seen in trials where there was not much use of medical therapy. So let's move away from looking at overall stable coronary artery disease to focusing on subgroup of patients where we think that there may be a benefit in terms of improvement in survival with revascularization. Some of these subgroups are those with left main disease, those with LV systolic dysfunction, patients with triple vessel disease, patients with proximal LAD disease, and those with extensive ischemia. In patients with left main disease, this is the data from the same CELIM use of meta-analysis showing that CABG at 10 years when compared to no CABG extended survival by 20 months. This is the subgroup with the biggest benefit in terms of extension of survival in the analysis done back in the day from the 1970s and 80s trials. So in this particular analysis, the patient with left main disease, there were 150 patients and clearly showed a significant survival benefit of CABG when compared to no CABG in this group of patients. Subsequently, all trials have excluded patients with significant left main disease and as such, for patients with left main disease, the standard of care is revascularization when compared to no revascularization. What about patients with LV systolic dysfunction? This was studied in the STITCHES trial and for patients with EF, 35% are lower, randomized to CABG versus medical therapy alone. And at 10 years, there's a significant 16% reduction in all-cause mortality with CABG when compared to medical therapy alone with the number needed to treat a 14. In the ISCHEMIA trial, we excluded patients with EF less than 35% and as such, based on this data, revascularization with CABG is the standard of care for patients who have LV systolic dysfunction to improve survival. In the ISCHEMIA trial, we had patients with moderate LV systolic dysfunction. So if you look at the subgroup of patients with EF, 35 to 45% are those who had a prior history of heart failure. Interestingly, in this subgroup of patients, invasive strategy reduced both the primary endpoint and also CV death or MI when compared to conservative strategy, almost as an extension of the STITCHES trial. Of note, this was based off of a small subgroup of close to 400 patients, comprising only 8% of participants enrolled in the ISCHEMIA trial and should therefore be viewed as hypothesis generating. What about patients with triple vessel disease? In the Salim Youssef analysis of older trials, triple vessel disease patients also derived benefit from CABG extension of survival by six months. But if you fast forward and look at BADD-E2D trial of patients with diabetes and multi-vessel disease, even in the CABG stratum, when you compare CABG with medical therapy, we no longer see a significant mortality advantage of CABG when compared to medical therapy, attesting to the fact that medical therapy likely has advanced since the older trials of CABG versus no CABG. In the ISCHEMIA trial, if you look at the triple vessel subgroup of patients looking at Duke score 6, which includes triple vessel disease and also two vessel with proxal AD, there is no significant difference between revascularization, invasive strategy and conservative strategy for all-cause mortality. In the ISCHEMIA trial, however, in this subgroup of patients, we saw a significant difference in cardiovascular mortality with invasive strategy when compared to conservative strategy, but this has to be interpreted in the light of a non-significant interaction p-value of 0.33. This difference in CV dethyramide, as shown in this curves, was largely driven by reduction in myocardial infarction. There was no significant difference in all-cause mortality. What about patients with proximal LAD disease? In ISCHEMIA trial, there is proximal LAD disease was not an effect modifier. There is no heterogeneity of treatment effect based on proximal LAD disease status for the primary endpoint, and this is also true for based on the degree of ISCHEMIA. So whether patients had severe ISCHEMIA, moderate ISCHEMIA, mild or no ISCHEMIA, there is no significant difference in survival between invasive and a conservative strategy. So in conclusion, revascularization to improve survival in SAHD and high-risk subgroup of patients, we do have data for left main disease, but this is not based off of contemporary trials. For LV systolic dysfunction, STITCH's trial, especially for CABG, clearly shows a benefit of CABG at improving survival compared to medical therapy alone. For triple universal disease patients, there is not much robust data. I mean, ISCHEMIA trial does point to a benefit of reduction in CV dethyramide, but all-cause mortality reduction has not been clearly shown, and the same applies for proximal LAD and also for patients with extensive ISCHEMIA. So let's quickly look at the guidelines, the 2021 ACCHA guidelines, and what do we recommend in terms of revascularization to improve survival. For left main disease, it's a class 1 indication to consider CABG to improve survival, and it's a class 2a to consider PCI if it can provide equivalent revascularization to that of CABG to improve survival in left main disease. In patients with multivessel disease, as we discussed, the data is rather fragile for survival benefit, and therefore it is a class 2b for CABG to improve survival. Again, important to recognize it's not a class 3, it's 2b, and CABG may be reasonable to consider to improve survival in this group of patients. For PCI, we are less certain, and therefore it's, even though it's 2b, the wording is that the usefulness of PCI to improve survival is uncertain in patients with triple vascular disease. The other subgroup of patients to improve survival, if you have patients with LV systolic dysfunction, it's a class 1 to consider CABG to improve survival, and if you have patients with mild to moderate left ventricular dysfunction, 35 to 50, again, CABG is a 2a indication to improve survival. In patients with proximal LAD, it's a class 2b to consider revascularization to improve survival, and if you have less severe disease, single or double vessel disease, it's a class 3, no benefit to consider a routine revascularization in these patients, and as such, for these group of patients, you should consider other reasons that could include improvement in quality of life by improving angina, and also consideration for reduction in spontaneous MI in these group of patients. Thank you for your attention.

survival

revascularization

coronary artery disease

medical therapy

mortality