ISCHEMIA results consistent across subgroups; invasive strategy may be harmful in advanced CKD
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New analyses of the ISCHEMIA trials of patients with stable ischemic heart disease presented at the virtual American College of Cardiology Scientific Session showed that results from the main trial were consistent across all anatomic and ischemia subgroups, but an invasive strategy raised death and stroke risk in patients with advanced chronic kidney disease.
As Healio previously reported, in the main results of ISCHEMIA and ISCHEMIA-CKD, an invasive strategy and a conservative strategy of optimal medical therapy yielded similar 4-year CV outcomes, while the invasive strategy improved quality of life in people with frequent angina in the ISCHEMIA cohort but not the ISCHEMIA-CKD cohort.
Ischemia, anatomic severity
David J. Maron, MD, clinical professor of medicine and director of preventive cardiology at Stanford University, presented on behalf of Harmony R. Reynolds, MD, associate professor of medicine and associate director of the Cardiovascular Clinical Research Center at NYU Langone Health, an analysis of the relationship between ischemia severity and CAD extent and clinical outcomes in ISCHEMIA.
Among the 5,179 patients randomized, 5,105 were stratified by ischemia severity — severe, moderate, mild or none — and 2,936 with coronary CT angiography data were stratified by anatomic CAD severity score — 3 (one-vessel stenosis of at least 50%), 4 (two-vessel stenosis of at least 50% or one-vessel stenosis of at least 70% if not the proximal left anterior descending artery), 5 (two-vessel stenosis of at least 70% or proximal LAD stenosis of at least 70%) or 6 (three-vessel stenosis of at least 70% or two-vessel stenosis of at least 70% including the proximal LAD). Patients with left main disease or no obstructive CAD were excluded.
Outcomes of interest included all-cause death, MI and the main trial primary outcome of CV death, MI or hospitalization for unstable angina, HF or resuscitated cardiac arrest.
Degree of ischemia did not correlate with all-cause mortality (P for trend = .33), but degree of anatomic CAD severity did. Patients with a score of 3 had the lowest risk and those with a score of 6 had the highest risk (P for trend < .001), Maron said.
Both ischemia degree (P for trend = .04) and anatomic CAD severity (P for trend < .001) correlated with MI, he said.
“Coronary anatomy was more predictive of outcomes than ischemia,” Maron said. “There was no association between core laboratory-determined ischemia severity and death, but there was a marginal association between ischemia severity and MI. There was a strong association between anatomic burden and risk of all-cause death and MI.”
There was no interaction between ischemia severity and assignment to the invasive or conservative strategy for the main trial primary outcome (P for interaction = .28), MI (P for interaction = .15) or all-cause mortality (P for interaction = .23), according to the researchers.
Similarly, Maron said, there was no interaction between anatomic severity and assignment to the invasive or conservative strategy for the main trial primary outcome (P for interaction = .17), MI (P for interaction = .26) or all-cause mortality (P for interaction = .83).
“The ISCHEMIA main trial results apply to all ischemia and anatomic subgroups,” Maron said. “There was no statistically significant evidence of a benefit from the invasive strategy on 4-year event rates for any level of ischemic or anatomic burden. Although more severe and extensive coronary disease increased risk for death and MI, an invasive strategy did not significantly lower that risk at 4 years.”
Chronic kidney disease
Cardiology Today Editorial Board Member Sripal Bangalore, MD, MHA, professor of medicine at the NYU Grossman School of Medicine, presented an analysis of clinical and quality of life outcomes according to baseline kidney function in patients from the ISCHEMIA and ISCHEMIA-CKD trials.
The primary outcome was time to death or MI. Secondary outcomes included time to the first event from the primary endpoint of ISCHEMIA, quality of life, procedural complications and death or initiation of dialysis.
The 6,146 patients were stratified according to kidney function: stage 1 (estimated glomerular filtration rate of at least 90 mL/min/1.73 m2), stage 2 (eGFR 60 to < 90 mL/min/1.73 m2), stage 3 (eGFR 30 to < 60 mL/min/1.73 m2), stage 4 (eGFR 15 to < 30 mL/min/1.73 m2) and stage 5/dialysis (eGFR < 15 mL/min/1.73 m2). Those with stage 4 CKD or stage 5 CKD/dialysis were enrolled in ISCHEMIA-CKD, and the others were enrolled in ISCHEMIA, Bangalore said.
The worse the kidney function, the greater the risk for death/MI, the primary endpoint of ISCHEMIA-CKD, all-cause death or MI (P < .001 for all), Bangalore said during a presentation.
“There was an exponential increase in cardiovascular events, including all-cause death and myocardial infarction, with lower kidney function,” he said.
Bleeding events and procedure-related complications were more frequent with worsening kidney function, he said.
The treatment effect of the invasive vs. the conservative strategy did not vary by kidney function for death/MI (P for interaction = .47), the primary endpoint of ISCHEMIA (P for interaction = .41), all-cause death (P for interaction = .08) = any MI (P for interaction = .46), procedural MI (P for interaction = .74), nonprocedural MI (P for interaction = .79), stroke (P for interaction = .08) or death/new dialysis (P for interaction = .29), according to the researchers.
“The invasive strategy increased procedural MI and significantly reduced nonprocedural MI, and this was consistent across CKD stages,” Bangalore said.
However, Bangalore said, risk for death was elevated in patients with stage 4 CKD assigned the invasive strategy (HR = 1.74; 95% CI, 1.08-2.82) and risk for stroke was elevated in the invasive-strategy group with stage 4 CKD (HR = 5.65; 95% CI, 1.23-25.87) or stage 5 CKD (HR = 3.23; 95% CI, 1.04-10.02).
The invasive strategy conferred a “significant and durable benefit at improving angina-related quality of life,” but the effect was attenuated in patients at lower CV risk and in those with lower eGFR levels, Bangalore said. – by Erik Swain
References:
Bangalore S, et al.
Reynolds HR, et al. Featured Clinical Research II: Interventional. Both presented at: American College of Cardiology Scientific Session; March 28-30, 2020 (virtual meeting).
Disclosures: Devices used in the trial were donated by Abbott Vascular, Medtronic, Omron Healthcare, St. Jude Medical, Volcano, and Omron Healthcare and medications were provided by Arbor Pharmaceuticals, AstraZeneca Pharmaceuticals and Merck Sharp & Dohme. Maron reports he has financial ties with Medscape. Bangalore reports he received a research grant from Abbott and consultant fees/honoraria from Abbott, Amgen, Biotronik, Meril, Pfizer, Reata and SMT. Reynolds reports she has received donated products for research from Abbott and BioTel.
Perspective
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Ashish Pershad, MD
The main take-home message of the analysis of kidney function is that patients with underlying bad kidney disease have incredibly high 3-year rates of death and MI, almost approaching 40%. That was eye-opening, because most studies in the past excluded these types of patients.
Another point of interest is that lasting quality-of-life benefits are accrued from the invasive strategy, but the effect is attenuated in patients with end-stage renal disease and in patients with fewer baseline symptoms.
The invasive strategy comes with a penalty in bleeding, stroke and periprocedural MI rates, but that was offset but a one-third reduction in the likelihood of having a spontaneous MI at 3 years, which is an even-keeled way of looking at this problem.
I do not think these findings will change how we manage patients with stable ischemic heart disease. It is sobering to realize that if you perform surgery or choose another option, the outcomes of patients with CKD and stable ischemic heart disease are bad no matter what.
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