ISCHEMIA: No Clinical Event Reduction With Invasive Strategy in CTO Patients

For stable patients with chronic total occlusion (CTOs), treatment with an invasive strategy that includes coronary revascularization does not reduce the risk of cardiovascular death or myocardial infarction when compared with a conservative strategy using optimal medical therapy (OMT), an analysis of the ISCHEMIA trial shows.

Just as in the main trial, coronary revascularization was associated with a higher risk of procedural infarction but a lower risk of spontaneous MI and improved quality of life during follow-up, report investigators.

In addition, the new data showed that if coronary revascularization was successful, there was a lower likelihood of cardiovascular death or MI, as well as MI, unstable angina, and heart failure, when compared with those treated conservatively.

Sripal Bangalore, MD (New York University Grossman School of Medicine, New York, NY), who led the analysis published this week in the Journal of the American College of Cardiology, said there is a misconception around the treatment of CTOs in that many clinicians assume there is no benefit to revascularization. While there was no reduction in the primary composite endpoint in ISCHEMIA (cardiovascular mortality, MI, hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest) or the stricter composite of cardiovascular mortality or MI, there was a reduction in spontaneous MI and a long-term reduction in cardiovascular death.

“Ideally, the interpretation should be that those benefits will also apply to patients with CTOs,” he told TCTMD. 

Dedicated randomized trials investigating the potential role of PCI in patients with CTOs have not demonstrated a benefit on hard clinical endpoints. The studies to date have either been underpowered for clinical outcomes or weakened by a large number of patients crossing over from medical therapy to revascularization. While observational studies have suggested that revascularization lowers the risk of major adverse cardiovascular events in patients with CTOs, experts say those analyses are limited by selection bias and unmeasured confounding.

Emil Holck, MD, PhD (Aarhus University Hospital, Denmark), one of the study leaders of the ongoing ISCHEMIA-CTO trial investigating PCI in asymptomatic and symptomatic patients with CTO, said he’d been awaiting this analysis from the ISCHEMIA group, noting the intention-to-treat analysis lines up with the main results. The observational finding that successful revascularization of CTOs was associated with a reduction in hard clinical endpoints aligns with the observational data.

Still, Holck said there are important caveats to this new analysis. In Europe, 10% to 20% of patients who present with CTOs have had prior CABG surgery, a percentage that is even higher in the US, but less than 4% of ISCHEMIA patients had previous surgery. 

“The population they have investigated is not as diseased as our usual CTO population,” he told TCTMD. “Secondly, the majority of the CTO patients in this ISCHEMIA substudy have two- or three-vessel disease. This means that they have had other lesions revascularized as well. So, the prognostic benefit that we see could just as well be from the other lesions.”

Jaikirshan Khatri, MD (NewYork-Presbyterian/Weill Cornell Medical Center, New York), who wasn’t involved in the study, said the ISCHEMIA analysis raises a lot of interesting questions about whether there might be longer-term benefits of revascularization in CTO patients. Nonetheless, the improved clinical outcomes seen among those who were successfully revascularized should be interpreted cautiously, urged Khatri.

“The summation of data that we have today from observational registry information versus randomized clinical trial data is that there isn’t a lot of benefit on hard clinical endpoints,” he told TCTMD. “It seems to be really effective at reducing symptom burden, whether it’s chest pain or dyspnea. Quality of life clearly improves, in both the randomized data as well as the observational data, but beyond that, I don’t know that there’s a lot of other reasons to revascularize somebody with a CTO.”

Revascularization also carries risks, said Khatri, noting that procedural success with PCI in ISCHEMIA was just 54% in those with CTOs. Even with advances in CTO PCI, procedural success has not really changed much over the past decade, he said.

“So, that’s something that you need to take into account when you’re advising patients,” said Khatri. If revascularization is recommended for symptomatic patients, “it really behooves them to be sent to a center where there’s truly a level of expertise.”

Randomization Prior to Blinded CCTA

The National Institutes of Health-funded ISCHEMIA study, which was published in 2020, enrolled 5,179 patients with stable CAD, preserved ejection fraction, and moderate-to-severe ischemia and randomized them 1:1 to a strategy of invasive coronary angiography followed by revascularization, if needed, on top of OMT or to an initial conservative strategy of OMT alone.

Over a median follow-up of 3.3 years, there was no significant difference in the study’s primary composite endpoint or in the risk of cardiovascular mortality or MI between the two strategies. Patients randomized to the invasive strategy had a larger improvement in angina-related health status than those assigned to conservative therapy with OMT alone, a benefit that was largely driven by those with angina at baseline.

In ISCHEMIA, randomization was done prior to angiography, and blinded coronary CT angiography (CCTA) was performed in approximately two-thirds of the enrolled patients to exclude life-threatening left main disease and other acute problems.

“Since the investigators are blinded to coronary anatomy, the crossover will be reduced,” said Bangalore. “We felt like this would be a good opportunity to look at invasive versus conservative [strategies] in CTOs and see the effect on cardiovascular and quality-of-life outcomes.”

This trial emphasizes that if you’re faced with the patient with [multiple] lesions, including CTO, maybe you should consider a complete revascularization with the best modality you have available. Sripal Bangalore

Overall, 1,470 of the 3,113 patients who underwent CCTA had at least a single CTO, a group that was younger, more often male, and more likely to have a history of MI or heart failure. They were also less likely to have angina in the 3 months prior to randomization but more likely to have ischemia and three-vessel coronary disease. There was no significant difference in baseline characteristics between the invasive and conservative randomized groups with and without CTOs.

In the CTO group randomized to invasive therapy, 95.3% underwent angiography and 83.5% coronary revascularization (66.8% with PCI and 33.2% with surgery). For those with CTOs randomized to conservative therapy, 26.2% underwent angiography and 27.7% coronary revascularization by 4 years, with the majority of revascularization procedures for primary events. 

In those with CTOs, the invasive strategy did not lower the risk of cardiovascular death or MI, cardiovascular death, or all-cause mortality in the intention-to-treat analysis. The invasive approach was associated with a significantly higher risk of procedural MIs compared with the conservative strategy (5-year difference of 2.5%; 95% CI 1.0% to 4.0%), but a lower risk of spontaneous MIs (5-year difference of -6.3%; 95% CI -9.7% to -3.2%). Quality-of-life outcomes were improved with invasive management.

In a secondary Bayesian analysis focused on successful CTO revascularization versus OMT, the invasive strategy was associated with a greater than 90% probability of lower cardiovascular death or MI, MI, spontaneous MI, unstable angina, and heart failure, but a high probability of more procedural MIs. There was also a significant improvement in the Seattle Angina Questionnaire summary, quality-of-life, angina frequency, and physical limitation scores, as well as other quality-of-life metrics.

“I think this trial emphasizes that if you’re faced with the patient with [multiple] lesions, including CTO, maybe you should consider a complete revascularization with the best modality you have available,” said Bangalore. “It can either be CABG or PCI, including the revascularization of the CTO, if it can be safely done and if you have the expertise in that center. I think, for me, that’s the critical message.”   

Successful Revascularization’s Benefits

Holck believes the reason the few randomized CTO trials to date have not shown a benefit on hard clinical endpoints is because studies have been underpowered.

Their ongoing study, ISCHEMIA-CTO, will include roughly 1,200 asymptomatic patients with CTO lesions and significant myocardial ischemia randomized to PCI or conservative medical therapy. The primary endpoint is a composite of major adverse cardiovascular and cerebrovascular events. Another 300 patients with symptoms will also be randomized to investigate whether PCI improves quality of life versus medical therapy.

In an editorial, Ziad Ali, MD, DPhil (St. Francis Hospital, Roslyn NY), Rasha Al-Lamee, MD (Imperial College London, England), and John Bittl, MD (Journal of the American College of Cardiology, Washington, DC), wonder if the bar should be raised for CTO PCI because of the procedural risks or lowered because of its potential benefit, acknowledging that revascularization in chronic coronary syndromes is primarily for symptomatic relief. 

They also wonder whether the reduction in spontaneous MI seen among patients successfully revascularized makes CTO PCI a more appealing treatment option.

“Any suggestion of a causal relation between successful revascularization and reduced spontaneous MI needs to consider the accuracy of invasive angiography used in dedicated CTO trials, as compared with CCTA in the present study, which could have misclassified some subtotal occlusions as CTOs,” they write. “It is possible that participants with subtotal occlusions undergoing successful revascularization experienced fewer spontaneous MIs over 5 years than those treated conservatively, similar to what was reported for the entire cohort in the original trial.”

Regarding the reduction in spontaneous MI, Holck said it’s difficult to know if this is attributable to revascularization of the CTO or other lesions. He also noted that some observational studies have shown that the rate of spontaneous MI is higher after successful CTO revascularization.

“We don’t know—it’s observational data—but it could be because you now have one more vessel where there could be plaque rupture,” said Holck. 

In addition to ISCHEMIA-CTO, there are more randomized trials in CTO patients coming, including the planned ORBITA-CTO pilot study investigating the feasibility of a placebo-controlled study arm.