ISCHEMIA-CKD: No Gain From Initial Invasive Strategy for Ischemia in Patients With CKD

November 17, 2019

PHILADELPHIA — Most patients with advanced chronic kidney disease (CKD) and moderate to severe ischemia at stress testing won't live longer or be any more protected from myocardial infarction (MI) if they go straight to the cath lab for possible revascularization, suggests a rare randomized trial focusing on this high-risk group.

That conclusion from the ISCHEMIA-CKD trial applies only to such patients who are mostly unbothered by symptoms on contemporary guideline-based optimal medical therapy (OMT), a requirement for patients in the study reported November 16 at the American Heart Association (AHA) Scientific Sessions 2019.

ISCHEMIA-CKD was designed similarly and run in parallel to its larger, splashier sibling trial ISCHEMIA, also presented here at the sessions, but in a classically much higher-risk population.  

It randomly assigned 777 adults with CKD and moderate or severe ischemia according to exercise or pharmacologic stress testing to either an initial invasive strategy of OMT plus diagnostic cardiac cath, with revascularization as appropriate, or a conservative strategy that turns invasive only if symptoms occur despite OMT.

Ultimately, about 85% of the 388 patients assigned to the initial invasive strategy actually underwent angiography during the study's 3 years, and as a result, 50% of the group had percutaneous coronary intervention (PCI) or coronary bypass grafting (CABG). Corresponding rates for the 389 conservatively managed patients were 22% and 12%, respectively.

Importantly, interventional personnel at the investigator sites around the world were trained in techniques for customized hydration and low- or zero-contrast-agent procedures to minimize the risk for acute kidney injury (AKI) from contrast exposure.

But the invasive strategy didn't make a significant difference to the primary endpoint of death or nonfatal MI. Over 3 years, the hazard ratio (HR) was 1.01 (95% CI, 0.79 - 1.29; P = .95). Nor, in a prospectively defined secondary analysis, did the strategy make much difference to angina severity and frequency or in other quality-of-life (QoL) issues.

Procedural complications were few, "especially procedural stroke and AKI," the study's principal Investigator, Sripal Bangalore, MD, MHA, New York University Langone Health, New York City, told | Medscape Cardiology.

Even so, "an overall initial invasive strategy did not demonstrate a reduced risk of clinical outcomes compared to an initial conservative strategy," he said.

He cautioned that the findings apply only to patients with CKD like those entered into the study: those without a recent acute coronary syndrome who are not highly symptomatic or who have a left ventricular ejection fraction less than 30%, treated at centers experienced in the low-contrast and no-contrast interventional techniques.

"The ability of those centers to use no- or incredibly low-contrast was very impressive," observed C. Michael Valentine, MD, from Stroobants Cardiovascular Center, Centra Health, Lynchburg, Virginia, who was not part of ISCHEMIA-CKD.

"They went to great efforts to limit any potential complications in a high-risk patient group," he said. "The concern is, would centers all across the United States and the world have this advanced ability to limit the risk — are they knowledgeable enough? Many centers may not be."

Most patients like those enrolled in the trial "can be safely treated with medical therapy," Alice K. Jacobs, MD, Boston University School of Medicine, Massachusetts, told | Medscape Cardiology. The initial strategy of invasive management offered "really no clinical benefit, and there was no quality-of-life benefit either."

Jacobs, also not with the trial, said ISCHEMIA-CKD "gives me the confidence not to proceed with the invasive strategy in patients with CKD. You're always balancing benefit and risk, and there's always added risk from a procedure." Now she can confidently recommend the conservative approach — usually.

"If their symptoms are controlled, if they really are stable, if they fit the trial entry criteria, I think we can feel safe at least initially pursuing a strategy of medical therapy," Jacobs said.

"This was as well designed and executed a trial as one could practically do in the real world," said Glenn N. Levine, MD, Baylor College of Medicine, Houston, Texas, the invited discussant after Bangalore's formal trial presentation.

It was adequately powered for its outcomes, "and the results are generally internally consistent," he said.

"I would think, without any inside knowledge, that ISCHEMIA and ISCHEMIA CKD will be key studies that are incorporated into American College of Cardiology/AHA revascularization guidelines," he said.

"Based on the results of ISCHEMIA-CKD, I will generally not go searching for ischemia and CAD in most severe and end-stage CKD patients, absent marked or unacceptable angina, and will treat them with medical therapy alone."

Explaining further for | Medscape Cardiology, Levine agreed that the ISCHEMIA-CKD results "probably apply to the vast majority of patients who we see who [are like those] enrolled in this study." In general, they could be initially managed with meds only; others should probably be assessed further, perhaps with CT angiography.

"Certainly, if someone had profound ischemia, or if someone on a treadmill dropped their ST segment by 5 mm 2 minutes into the test, and they dropped their systolic blood pressure, I think it's still reasonable to make certain this person does not have severe left main disease."

Table 1. Hazard Ratios for Outcomes at 3 Years: Invasive vs Conservative Strategies in Patients With CKDa

Endpoints HR (95% CI) P Value
Primary: Death or nonfatal MI 1.01 (0.79 - 1.29) .95
Death 1.02 (0.76 - 1.35) .91
Cardiovascular death 0.97 (0.71 - 1.33) .84
MI 0.84 (0.57 - 1.25) .39
Death, MI, hospitalization for unstable angina or heart failure, resuscitated cardiac arrest 1.02 (0.79 - 1.29) .93
a CKD defined as an estimated glomerular filtration rate less than 30 mL/min/1.73 m² or end-stage renal disease or on dialysis.


The results were consistent across subgroups, Bangalore reported, except for a suggestion of a possible benefit from invasive management in patients with more severe ischemia at baseline.

The primary-endpoint HR was 1.30 (95% CI, 0.94 - 1.79) for the 61.9% of patients with moderate baseline ischemia and 0.70 (95% CI, 0.46 - 1.05) when it was severe, in 38.1%. The interaction between ischemia severity and outcomes was significant at P = .02.

The risk for stroke was increased more than threefold in the invasive vs conservative strategy group, Bangalore observed. Only one patient in each group experienced a procedural stroke (that is, within 30 days of intervention), "so it appears that stroke is driven by non–procedural-related stroke."

Also, the combined endpoint of death or initiation of dialysis was significantly higher for the invasive group. And because mortality was similar in both groups, "this difference was driven by differences in dialysis." The HRs for invasive vs conservative management were as follows:

  • 3.76 (95% CI, 1.52 - 9.32; P = .004) for stroke

  • 1.48 (95% CI, 1.04 - 2.11; P = .02) for death or new dialysis

  • 0.15 (95% CI, 0.02 - 1.37; P = .09) for unstable angina

Not unexpectedly, the need for first-time dialysis jumped soon after intervention in the invasive strategy group, but the rate was statistically similar to that of the conservative group at 3 years: HR, 1.47 (95% CI, 0.88 - 2.44; P = .13).

Although the interventional centers were trained in the use of contrast-sparing techniques, data on volume of contrast agent used during invasive procedures were not collected, Bangalore observed. So there is no direct way to assess how compliant the centers were, or how successful, at the AKI-prevention measures.

However, he noted, rates of AKI at the different centers were consistently low. Overall, the rate of AKI after PCI or CABG was 7.8% in the invasive group and 5.4% for conservatively managed patients who crossed over at some point. Correspondingly, the rates of new need for dialysis within 30 days of the procedure were only 2.1% and 0.6%, respectively.

"Those rates, in a group of patients who are on the verge of dialysis, are pretty low," Bangalore said, compared to the usual expected rate of 30% to 60% in such a high-risk group. "So it means that when the procedures were done, they were likely done the way we trained them."

The prospectively defined QoL analysis called for patients to self-assess angina frequency and disease-specific QoL as measured by the Seattle Angina Questionnaire (SAQ) Angina Frequency and Quality of Life scales. However, it was the SAQ Summary Score that served as the primary QoL yardstick in the study.

Completed baseline and follow-up QoL forms were available for 358 patients in the invasive group and 347 in the conservative management group.

Table 2. SAQ-7 Summary Score Odds Ratios: Invasive vs Conservative Management

Follow-up Time (mo) SAQ-7 Summary Score, Odds Ratio (95% CI)
1.5 1.20 (0.76 - 1.66)
3 1.48 (0.90 - 2.16)
6 1.13 (0.61 - 1.69)
12 1.06 (0.55 - 1.62)
24 1.59 (0.77 - 2.49)
36 1.16 (0.45 - 2.03)


"In patients with stable coronary art disease and advanced CKD and moderate to severe ischemia, we did not observe a substantial treatment benefit in angina control or quality of life over time," John A. Spertus, MD, Saint Luke's Mid America Heart Institute, Kansas City, Missouri, who formally presented the QoL analysis here at the sessions, told | Medscape Cardiology.

However, because a high proportion of patients—50% of invasively managed patients and 48% of conservative-management patients—were symptom-free at baseline, "we can't exclude a possibility of a small benefit in symptomatic patients, especially up to 3 months."

The SAQ-7 odds ratios and CIs are fairly small, Spertus said, so there may be a "high probability for an early benefit from an invasive strategy. But we have very low confidence of any benefit beyond 3 months."

The findings support "a classic shared-decision making model," Valentine said. "If you have a patient with advanced CKD who is not symptomatic or minimally symptomatic, then I think the data in this trial support continuing, conservative, but optimal medical therapy."

Important for shared decision making is to "tell your patient the data shows that long-term outcomes are not going to be any different" with use of the invasive approach, he said. "Yes, it will help your angina but potentially at the cost of more complications."

Because of that, he said, early invasive management should be reserved "for the very symptomatic patient who is struggling with frequent angina."

Bangalore discloses serving as a c onsultant or on an advisory board for Abbott Vascular, Biotronik, Pfizer, Amgen, and Reata; receiving honoraria from Abbott Vascular, Biotronik, Pfizer, and Amgen; and receiving research grants from Abbott Vascular. Spertus discloses receiving honoraria from AstraZeneca, Bayer, Novartis, Janssen, Cytokinetics, Myokardia, and United Healthcare; serving as a board member for Blue Cross Blue Shield of Kansas City; and holding ownership interest in Health Outcomes Sciences and copyrights to the KCCQ and SAQ instruments. Levine and Valentine had no disclosures. Jacobs discloses receiving research support from Abbott Vascular.

American Heart Association (AHA) Scientific Sessions 2019. Presented November 16, 2019.

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