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ISCHEMIA: Invasive strategy, medical therapy yield similar CV outcomes in stable ischemia
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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
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
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
References:
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.
Perspective
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Ajay J. Kirtane, MD, SM
The big question in the main ISCHEMIA trial was whether there could be a benefit or a harm to an invasive strategy in patients with stable ischemic heart disease. The answer is nuanced, because there is an early procedural harm. It’s probably from the revascularization. But that is offset by a small late benefit in terms of a reduction in MI. Over 4 years, there was a reduction in CV death and MI with the invasive approach. That suggests there are patients for whom the invasive approach can prevent heart events. The trial was not fully powered for to look at types of heart events, so we have to be circumspect about this. But there are other streams of data, from meta-analyses and FAME 2, showing a benefit in spontaneous MI. This is an important finding. But we have to be cognizant of the procedural risks for every patient.
I was impressed with the quality of life data. My feeling was that this is a population with a low number of symptoms and it would be hard to show benefits. But it seems there were enough patients in the trial who had symptoms that quality of life benefits were clearly demonstrated in favor of the invasive approach. Obviously, the worse your symptoms are, the better the results of the invasive approach, but even less symptomatic patients had a benefit as well. Importantly, that is on fewer medications. The invasive group were receiving on less calcium channel blockers and less anti-anginal medications than the conservative group. This is better quality of life on fewer medications, which is a win for patients.
Determining who would benefit from the invasive strategy includes taking account of how symptomatic the patients are at baseline. In clinical practice, if the patient does not have a lot of symptoms, I do CT angiography to rule out bad disease, and try medical therapy. But if the patient has a lot of symptoms, the invasive approach may be best.
The cardiology community needs to analyze and discuss the nuances of this trial. I don’t see how one could say there is no benefit to an invasive approach based upon the observations of reductions in spontaneous MI. On the other hand, anyone who says we’re going to be reducing death or preventing MIs with PCI would also be misstating the issue because of the periprocedural risk of the procedure.
Ultimately, if we are going to revascularize, we have to do it with the best quality and in the safest way. A lot of the data on revascularization will be presented subsequently. We’ll need to see how the procedures were done and what was treated. There is a lot more to come.
Perspective
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B. Hadley Wilson, MD, FACC
ISCHEMIA is the biggest news from the 2019 AHA Scientific Sessions and is the most important trial of medical therapy vs. coronary intervention since the COURAGE trial. I think we will see people on both sides — optimal medical therapy or PCI — saying it was positive. In the main study, there was no difference in clinical outcomes between optimal medical therapy and an invasive approach, but quality of life was significantly improved for patients with stable angina who had PCI. The win for the proponents of invasive therapy is that although over time, we cannot see a difference in clinical outcomes — for which there may be reasons such as people having natural progression of their atherosclerotic disease and people having disease in areas other than where they got their PCI — the people who had the invasive approach had significant improvement in their clinical quality of life, which had been challenged by ORBITA.
The win is on both sides and there will be those on either side, perhaps moreso among those who champion long-term medical management, that claim victory. The heart team approach and shared decision-making with the patient will help us arrive at a good decision. Patients with stable angina should be counseled that while PCI won’t necessarily make them live longer or improve their outcomes, they may well have better quality of life with less angina for the next few years.
The final caveat is that high-risk patients such as those with recent prior MI, those with low ejection fraction and those with left main disease were excluded. Therefore, these results cannot be generalized for the entire CAD population.
ISCHEMIA-CKD did not show the same difference in quality of life as the main study did. Patients with renal disease have a challenging set of problems and there are several reasons why the invasive approach may not have made a difference in quality of life. As with the main results, there was no difference in mortality or clinical outcomes. It is particularly important to employ shared decision-making and the heart team approach in these patients to let them know they may or may not achieve improvements in clinical outcomes and symptoms with an invasive approach.
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