American Heart Association

American Heart Association

Perspective from Ajay J. Kirtane, MD, SM
Perspective from B. Hadley Wilson, MD, FACC
November 16, 2019
10 min read

ISCHEMIA: Invasive strategy, medical therapy yield similar CV outcomes in stable ischemia

Perspective from Ajay J. Kirtane, MD, SM
Perspective from B. Hadley Wilson, MD, FACC
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PHILADELPHIA — In stable patients with moderate or severe ischemia, an invasive strategy and a conservative strategy of optimal medical therapy yielded similar long-term CV outcomes, according to long-anticipated results of the ISCHEMIA and ISCHEMIA-CKD trials presented at the American Heart Association Scientific Sessions.

However, in the main ISCHEMIA trial, which excluded patients with renal disease, an invasive strategy was associated with improvements in angina control and quality of life in patients with angina compared with a conservative strategy. In patients without angina, the improvements in angina control and quality of life associated with an invasive strategy were minimal. In ISCHEMIA-CKD, which included only of patients with chronic kidney disease, results showed no difference in quality of life outcomes between the strategies.

Notably, in the main trial, an invasive strategy was linked with more procedural MI but less spontaneous MI compared with a conservative strategy, and the cohort had low rates of all-cause mortality and procedure-related stroke or death.

ISCHEMIA participants assigned the invasive strategy received optimal medical therapy plus diagnostic catheterization, and underwent PCI or CABG based on results of the catheterization. Patients assigned the conservative strategy received optimal medical therapy alone and diagnostic catheterization if they failed optimal medical therapy.

ISCHEMIA main results

Judith S. Hochman

The primary outcome of CV death, MI, hospitalization for unstable angina, HF or resuscitated cardiac arrest at 4 years occurred in 13.3% of the invasive group vs. 15.5% of the conservative group (absolute difference, –2.2%; 95% CI, –4.4 to 0; adjusted HR = 0.93; 95% CI, 0.8-1.08), Judith S. Hochman, MD, MA, Harold Snyder Family Professor of Cardiology and senior associate dean for clinical sciences at NYU Langone Health, said during a press conference.

The NHLBI-funded study included 5,179 patients (median age, 64 years; 23% women).

Initially, the primary outcome occurred more frequently in the invasive group (absolute difference at 6 months, 1.9%; 95% CI, 0.8-3), but at approximately 2 years, the curves crossed and the primary outcome occurred more frequently in the conservative group after that, she said.

The major secondary outcome of CV death or MI occurred in 11.7% of the invasive group vs. 13.9% of the conservative group at 4 years (absolute difference, –2.2%; 95% CI, –4.4 to –0.1; aHR = 0.9; 95% CI, 0.77-1.06), according to the researchers. Again, the outcome initially occurred more frequently in the invasive group (absolute difference at 6 months = 1.9; 95% CI, 0.9-3), but the curves crossed at approximately 2 years, Hochman said.


Net clinical benefit, defined as CV death, MI, unstable angina, HF, resuscitated cardiac arrest or stroke, was similar in both groups at 4 years (aHR = 0.95; 95% CI, 0.82-1.1) and the curves again crossed at approximately 2 years, she said.

Data presented here demonstrated no differences in CV death (aHR = 0.87; 95% CI, 0.66-1.15), all-cause death (aHR = 1.05; 95% CI, 0.83-1.32), resuscitated cardiac arrest (aHR = 1.01; 95% CI, 0.29-3.39), stroke (aHR = 1.22; 95% CI, 0.79-1.88) or overall MI (aHR = 0.92; 95% CI, 0.76-1.11).

“Stroke rates were quite low; this attests to the fact that we selected sites to be high-volume PCI sites and high-volume CABG sites,” Hochman said. “The sites had to have a low complication rate to even get in the trial. And they did very well, with very low stroke and death rates from the procedure.”

However, Hochman said, procedural MI (type 4a and 5) was higher in the invasive group (aHR = 2.98; 95% CI, 1.87-4.74), while spontaneous MI (types 1, 2, 4b and 4c) was higher in the conservative group (aHR = 0.67; 95% CI, 0.53-0.83).

In addition, she said, hospitalization for unstable angina was higher in the conservative group (aHR = 0.5; 95% CI, 0.27-0.91) and hospitalization for HF was higher in the invasive group (aHR = 2.23; 95% CI, 1.38-3.61), although event rates for both groups were low.

There was no heterogeneity of treatment effect in any of the prespecified subgroups, she said.

Among patients who had revascularization, approximately 80% underwent PCI and the rest underwent CABG. Newer stents and fractional flow reserve were used as needed, Hochman said.

In 13.8% of cases, the enrolling center deemed a patient had moderate ischemia, but the core lab determined the ischemia was mild or absent or could not confirm ischemia severity, she said.

“This is the largest trial of invasive vs. conservative strategy in stable ischemic heart disease,” Hochman said here. “The probability of at least a 10% benefit of the invasive strategy on all-cause mortality was low, at less than 10% based on prespecified Bayesian analysis.”

ISCHEMIA quality of life

John A. Spertus

For the angina control and quality of life analysis, participants were stratified by whether daily or weekly angina, angina several times per month or no angina, John A. Spertus, MD, MPH, FACC, director of health outcomes research at Saint Luke's Mid America Heart Institute, professor and Daniel J. Lauer Missouri Endowed Chair in Metabolism and Vascular Disease Research at the University of Missouri-Kansas City and adjunct professor of medicine at Washington University in St. Louis, said during the press conference.


The primary outcome of benefit of invasive therapy on Seattle Angina Questionnaire (SAQ) summary score favored the invasive group in the overall population at 3 months (posterior mean = 4.1; 95% CI, 3.2-5), 1 year (posterior mean = 4.2; 95% CI, 3.3-5.1) and 3 years (posterior mean = 2.9; 95% CI, 2.2-3.7), Spertus said.

“We are 100% confident that there is a treatment benefit associated with the invasive strategy early after randomization and later,” he said.

Compared with the overall cohort, the SAQ summary score measure more heavily favored the ischemia group in those with daily or weekly angina (posterior mean at 3 months = 8.5; 95% CI, 5.8-11.1; posterior mean at 1 year = 7.3; 95% CI, 4.8-9.9; posterior mean at 3 years = 5.3; 95% CI, 3.4-7.5), and in those with angina at least once per month (posterior mean at 3 months = 5.5; 95% CI, 4.3-6.9; posterior mean at 1 year = 4.8; 95% CI, 3.4-6.1; posterior mean at 3 years = 3.1; 95% CI, 2-4.2), he said.

However, in patients with no angina, the SAQ summary score benefit favored neither group at 3 months (posterior mean = 0.1; 95% CI, –1.2 to 1.4) and minimally favored the invasive group at 1 year (posterior mean = 1.7; 95% CI, 0.4-2.9) and 3 years (posterior mean = 1.2; 95% CI, 0.2-2.2), Spertus said.

At 3 months, for every three patients with angina treated with the invasive approach, one would be angina-free, he said, noting those results were sustained out to 3 years.

ISCHEMIA-CKD main results

ISCHEMIA-CKD comprised a separate patient population of 777 patients (median age, 63 years; 31% women) who had CKD alongside stable ischemia heart disease, Cardiology Today Editorial Board Member Sripal Bangalore, MD, MHA, professor of medicine at NYU Langone Health, said in an interview.

“We started with the ISCHEMIA trial and, like almost every other cardiovascular trial, it excluded patients with impaired kidney function,” Bangalore told Healio. “We decided we needed a dedicated trial to address this question in the CKD population. If ISCHEMIA did not have that exclusion, I don’t think it would have enrolled many patients with CKD. That’s what happened in the COURAGE trial. This way, we made sure there is focus on the CKD population. The upfront risk is higher and the results may have been diluted if the populations were combined.”


The primary endpoint of death or MI at 3 years occurred in 36.4% of the invasive group vs. 36.7% of the conservative group (aHR = 1.01; 95% CI, 0.79-1.29), according to Bangalore.

Major secondary endpoint of death, MI, hospitalization for HF or unstable angina or resuscitated cardiac arrest also did not differ between the groups at 3 years (invasive, 38.5%; conservative, 39.7%; aHR = 1.01; 95% CI, 0.79-1.29), according to the researchers.

Results showed no difference in all-cause death, CV death, overall MI, procedural MI, spontaneous MI, unstable angina, HF or new dialysis.

However, stroke was higher at 3 years in the invasive group (aHR = 3.76; 95% CI, 1.52-9.32), as was death or new dialysis at 3 years (aHR = 1.48; 95% CI, 1.04-2.11), Bangalore said, noting there was no difference in procedural stroke.

The treatment effect differed according to degree of ischemia. For patients with severe baseline ischemia, the primary endpoint and key secondary endpoint favored the invasive group. For those with moderate baseline ischemia, the primary endpoint and key secondary endpoint favored the conservative group (P for interaction for both = .02), according to the results.

Approximately 85% of those who had revascularization underwent PCI, with the remainder having CABG.

“If you do not have the right expertise, there is a high risk of upfront harm from the invasive approach with these patients,” Bangalore told Healio. “Since there is not a survival benefit, the conservative strategy is potentially the way to move forward, unless the patient has modest symptoms. We trained our operators to do ultra-low-contrast and zero-contrast PCIs, so you need to go to a center that can do that.”

ISCHEMIA-CKD quality of life

The ISCHEMIA-CKD quality of life study was structured similarly to the quality of life study from the main ISCHEMIA trial, Spertus said at the press conference.

In the overall cohort, the treatment effect on SAQ summary score did not favor either group (posterior mean at 3 months = 2.1; 95% CI, –0.4 to 4.6; posterior mean at 1 year = 0.1; 95% CI, –3 to 3.1; posterior mean at 3 years = 0.5; 95% CI, –3.6 to 4.5), he said.

The results were consistent regardless of whether patients had frequent angina, infrequent angina or no angina, he said.

“Unlike in the main trial, we did not see a lot of quality of life improvement with the invasive approach,” Bangalore told Healio. “If we are revascularizing these patients, the study shows that we are not going to prolong their survival, and if the patient is less symptomatic, they likely will not have a quality of life or angina benefit.” – by Erik Swain



Bangalore S, et al.

Hochman JS, et al.

Spertus JA, et al. Late Breaking Science II: Results for the ISCHEMIA Trials: To Intervene or Not to Intervene. All presented at: American Heart Association Scientific Sessions; Nov. 16-18, 2019; Philadelphia.

Disclosures: Hochman reports she received research support from Abbott, Amgen, Arbor Pharmaceuticals, AstraZeneca, Medtronic, Merck Sharpe and Dohme, Omron and Volcano. Spertus reports he received honoraria from AstraZeneca, Bayer, Cytokinetics, Janssen, Myokardia, Novartis and United Healthcare, serves on the board for Blue Cross Blue Shield of Kansas City and has ownership interest in Health Outcomes Sciences. Bangalore reports he received honoraria from Abbott Vascular, Amgen, Biotronik and Pfizer and research grants from Abbott Vascular.