Stable CAD With High-Risk Anatomy Warrants PCI or CABG, APPROACH Suggests

Patients with stable ischemic heart disease fare better when treated invasively with PCI or CABG surgery as opposed to medical therapy, provided they have high-risk coronary anatomic features, according to a new observational analysis of a large Canadian database.  

Overall, revascularization in patients with triple-vessel or left main coronary artery disease was associated with a significantly lower risk of all-cause mortality or myocardial infarction, which was the study’s primary endpoint, when compared with conservative medical management, Kevin Bainey, MD (Canadian VIGOUR Center/University of Alberta, Canada), and colleagues reported recently in the Journal of the American Heart Association.

“Within this ultra-high-risk patient population, albeit in a stable ischemic heart disease environment, we found that revascularization, whether it was done with PCI or CABG, led to an improvement in clinical outcomes compared with conservative management,” Bainey told TCTMD. “What was striking was that despite all the different ways of adjustment to correct for selection bias, we found that not only was the primary endpoint reduced, but the reduction in all-cause mortality and cardiovascular mortality was particularly impressive.”

The researchers say these results open a small window where revascularization may yield a treatment benefit, including improved survival, in the setting of stable ischemic heart disease—despite the results from the ISCHEMIA trial. Bainey stressed that he believes the findings from ISCHEMIA, a landmark study that showed the invasive strategy on top of optimal medical therapy yielded no benefit beyond medical therapy alone in preventing a range of major cardiovascular events in patients with stable heart disease.

The reduction in all-cause mortality and cardiovascular mortality was particularly impressive. Kevin Bainey

“The ISCHEMIA trial is very intriguing and very important in how it will change practice for patients,” said Bainey. “We enrolled quite a few patients in the trial, and I saw those patients treated with a conservative approach do very well. When you look into the intricacies of the trial, it’s interesting to see the curves cross at about 2 years. And we will need to wait for long-term follow-up, but the trial made us ask if there was a subgroup within [stable ischemic heart disease] patients who may benefit from revascularization or an invasive approach.”

Notably, patients with unprotected left main CAD (> 50% stenosis) were excluded from ISCHEMIA, with blinded CT angiography performed in 73% to exclude such patients.  

The Impact of Anatomy

To address the influence of coronary anatomy on outcomes with revascularization versus medical therapy, Bainey and colleagues turned to the Alberta Provincial Project for Outcomes Assessment in Coronary Heart Disease (APPROACH) registry. They identified 9,016 patients with high-risk coronary anatomy, defined as angiographically significant three-vessel disease (> 70% stenosis in all three epicardial vessels) or left main disease (> 50% stenosis), either alone or in combination with other CAD. Of these, 3,529 were treated with medical therapy and 5,487 underwent revascularization, including 3,312 treated surgically and 2,175 who had PCI.

Revascularization patients tended to be younger, were more likely to be male, and had a slightly higher body mass index. Prior MI and congestive heart failure also were less common in those who underwent revascularization and impaired ejection fraction was less likely.

During a median follow-up of 6.2 years, coronary revascularization was associated with a lower risk of death/MI (inverse probability weighted [IPW]-HR 0.62; 95% CI 0.58-0.69). Revascularization was also linked to lower risks of all-cause mortality (IPW-HR 0.60; 95% CI 0.54-0.67), cardiovascular mortality (IPW-HR 0.41; 95% CI 0.32-0.52), and MI (IPW-HR 0.77; 0.62-0.96). With respect to the primary endpoint of death/MI, similar reductions in risk were observed with both PCI and CABG surgery.

Across different subgroups, such as those with left main disease alone, severe left main disease (> 95% stenosis), or triple-vessel with disease with at least one artery more than 95% occluded, revascularization was associated with a lower risk of death/MI. In patients with triple-vessel disease with a proximal LAD more than 70% occluded, revascularization was only showed a trend toward benefit, although the reduction in risk was significant for those with a proximal LAD with a stenosis > 95%. The test for interaction of the treatment effect in these subgroups was significant, “suggesting that the relative risk reduction benefit of revascularization varies according to the subtypes of coronary anatomy,” say researchers.   

Based on their findings, Bainey and colleagues urge that the coronary anatomical profile should be considered when revascularization is contemplated in stable ischemic heart disease. Bainey said that at his institution, they will bring select patients to the cath lab to define the coronary anatomy (CT angiography is infrequently used in Canada and difficult to have reimbursed, he noted). In those with high-risk anatomical features, they will recommend revascularization.

Be Cautious When Interpreting Results, Says COURAGE PI

William Boden, MD (Boston University School of Medicine/VA New England Healthcare System, MA), who led the COURAGE trial in patients with stable ischemic heart disease and was an ISCHEMIA investigator, praised the new analysis, adding that he believes anatomy is a better predictor of clinical outcomes than the amount of myocardial ischemia, as demonstrated in the ISCHEMIA trial. “If anything, ISCHEMIA basically destroyed the ischemia hypothesis,” he told TCTMD. “There’s not a great deal of appeal to look for ischemia as a modifier of risk.”

In one analysis of the COURAGE trial, anatomic burden was a consistent predictor of death, MI, and NTSE-ACS whereas ischemic burden was not, added Boden. “When we looked at this, we also showed that anatomic severity and complexity—that is to say patients with multivessel disease or other high-risk anatomic features—was a better predictor of events,” he said. “Even though COURAGE only had one-third of patients with moderate-to-severe ischemia, that didn’t show anything at all. So yes, I do think that, as the APPROACH registry shows, coronary anatomy does appear to be associated with worse outcomes.” 

Nonetheless, Boden was cautious interpreting the reduction in clinical outcomes with revascularization in patients with more-severe and complex coronary anatomy. As the authors acknowledge, the analysis is observational, and even though they attempted to offset potential confounding with the use of inverse probability weighting, the study has limitations, said Boden. 

He noted that the researchers censored events occurring in the first 3 months after revascularization. In doing so, MIs classified as type 4b (related to stent thrombosis) and 4c (related to restenosis in PCI) are not captured. In the ISCHEMIA trial, these events occurred less frequently than type 4a MIs but were particularly lethal when they did occur, said Boden. “I think this could also offset some of the benefits we see in this study,” he said. He also noted that optimal medical therapy was significantly better in patients treated with an invasive strategy and said this might have influenced the outcomes, too.

“We’re back to where to we always seem to come with this, which is to say that randomized trials so far have not shown a benefit of revascularization, particularly with PCI, in patients with significant multivessel disease,” he said. On the other hand, revascularization with CABG surgery has been shown to be beneficial in patients with left main disease and those with triple-vessel disease, particularly if they also have multivessel disease and diabetes as they did in the FREEDOM trial, he added. Contemporary data comparing revascularization against optimal medical therapy in patients with left main disease are lacking, he acknowledged, noting that such a trial is worth pursuing.  

Bainey agreed that a study randomizing stable ischemic heart disease patients with high-risk coronary anatomy to revascularization or medical therapy is warranted. Such a trial might be difficult, Bainey and Boden both pointed out, because many physicians wouldn’t feel entirely comfortable randomizing a patient with left main disease to medical management as some already have their minds made up that revascularization is the best approach. Then again, Boden noted, many physicians had their minds made up about revascularization before COURAGE and ISCHEMIA, too.  

Patients Not Represented in Clinical Trials

In an editorial, Brian Bergmark, MD, and David Morrow, MD (Brigham and Women’s Hospital, Boston, MA), say the new study addresses a timely topic central to the management of patients with stable ischemic heart disease, particularly since some of the subgroups included in the analysis are not represented well in randomized clinical trials. They point out that the aggregate rate of death/MI for these APPROACH registry patients was roughly 4% at 1 year, which reinforces the high-risk nature of those studied. 

In ISCHEMIA, the editorialists point out, there were trends toward a benefit with revascularization in those with triple-vessel disease or proximal LAD disease, although there was no statistically significant interaction between treatment strategy and the extent of coronary disease. Still, “for some experts, uncertainty remains about the potential benefits of initial revascularization in the population with left main disease or severe three-vessel disease, as defined by Bainey and colleagues, a cohort who had a higher absolute mortality rate at 1 year in the APPROACH registry (3%) than that seen in the ISCHEMIA trial (1%),” write Bergmark and Morrow.  

The editorialists also note some of the aforementioned limitations. They add that many patients in the analysis had a clinical indication for revascularization according to the European Society of Cardiology guidelines relevant during the study, meaning there must have been significant clinical reasons for deferring PCI or CABG.