#NephJC Chat
Tuesday April 28th, 2020 at 9 pm Eastern Daylight Time
Wednesday April 29th, 2020 at 9 pm Indian Standard Time
Wednesday April 29th, 2020 at 9 pm BST
N Engl J Med. 2020 Apr 23;382(17):1608-1618. doi: 10.1056/NEJMoa1915925. Epub 2020 Mar 30.
Management of Coronary Disease in Patients With Advanced Kidney Disease
Sripal Bangalore, David J Maron, Sean M O'Brien , Jerome L Fleg, Evgeny I Kretov, Carlo Briguori, Upendra Kaul, Harmony R Reynolds, Tomasz Mazurek, Mandeep S Sidhu, Jeffrey S Berger, Roy O Mathew, Olga Bockeria, Samuel Broderick, Radoslaw Pracon, Charles A Herzog, Zhen Huang, Gregg W Stone, William E Boden, Jonathan D Newman, Ziad A Ali, Daniel B Mark, John A Spertus, Karen P Alexander, Bernard R Chaitman, Glenn M Chertow, Judith S Hochman, ISCHEMIA-CKD Research Group
PMID: 32227756 Full Text at NEJM
Study website (NIH)
ISCHEMIA-CKD Health Status Report (Spertus et al, NEJM 2020)
NEJM editorial (Antman and Braunwald, NEJM 2020)
Introduction
The mortality risk of a 20 year old person with end stage kidney disease (ESKD) is roughly similar to an 85 year old individual from the general population
In 1998, Foley and colleagues (Foley et al, AJKD supplements, 1998) reported findings from the USRDS dataset that jolted the nephrology community, with the image below becoming part of countless presentations since. They showed that the mortality risk of a 20 year old person with end stage kidney disease (ESKD) is roughly similar to an 85 year old individual from the general population. This was primarily driven by cardiovascular disease.
Figure 1 from Foley et al, AJKD Supplements, 1998
A decade and half later, using data from Kaiser Permanente, this increased mortality and cardiovascular risk was reported even in non-ESKD patients, with a graded association starting with GFR < 60 (Go et al, NEJM 2004) with an adjusted hazard ratio (HR) for cardiovascular events increasing from 1.4 at GFR 45-59, steadily to 3.4 at GFR < 15.
Figure 1b from Go et al, NEJM 2004
The big question has always been, “How can we decrease this risk?” In the general population, many interventions have been trialed, and have successfully become part of clinical practice.
…despite fulfilling criteria for angiography, CKD patients, under-went cardiac catheter-ization only half as often…
But a creatinine clearance < 30 ml/min remains a common exclusion criteria for these trials (and yes, the use of creatinine clearance clearly shows the age of this thinking). As a result, for most cardiovascular interventions, we do not know if they have any benefit in advanced CKD. Should we treat CKD as a special subgroup where all interventions need to be tested again? Do we repeat all the trials? We have already seen that in the case of statin how it plays out: 4D (Wanner et al, NEJM 2005) and AURORA (Fellstrom et al, NEJM 2008) reported no benefit of statins in dialysis patients, and a much larger SHARP trial (Baigent et al, Lancet 2011) had to be done to show that statins have a benefit in advanced CKD. The term ‘renalism’ was coined and refers to therapeutic nihilism for renal patients - patients with CKD not getting appropriate care. In 2004 Chertow et al, (JASN 2004), reported that despite fulfilling criteria for angiography, CKD patients, underwent cardiac catheterization only half as often, and had twice the mortality as patients with intact GFR.
The International Study of Comparative Health Effectiveness with Medical and Invasive Approaches in the CKD population (ISCHEMIA-CKD) was designed to provide answers in this understudied population. The trial was designed in parallel to the ‘main’ ISCHEMIA study (Maron et al, NEJM 2020), and was reported simultaneously. ISCHEMIA-CKD is supposed to answer if an invasive strategy is better or worse in managing stable coronary artery disease in patients with advanced chronic kidney disease (eGFR <30 or on dialysis).
The Study
Methods
Randomized controlled trial, international (30 countries), and investigator-initiated.
Study Population
Inclusion criteria
Advanced kidney disease (defined as an estimated glomerular filtration rate [eGFR] of <30 ml per minute per 1.73 m2 of body-surface area or dialysis) and
Moderate or severe myocardial ischemia
Age > 21 years
How was ischemia defined? Unlike the main ISCHEMIA trial, patients did not undergo coronary CT (perceived risk of contrast induced AKI) so they underwent stress tests based on any of these modalities with these criteria for moderate to severe ischemia.
Table 2 from Bangalore et al, Am H Journal 2018
Exclusion criteria
This list was much longer. Some of them are:
Recent CV event (ACS within 2 months, stroke within 6 months, PCI within 12 months)
Life expectancy < expected trial duration
Heart failure (EF < 35%; non-ischemic dilated or hypertrophic cardiomyopathy; NYHA class III or IV symptoms at entry, or hospitalization for heart failure within 6 months)
Unsuitable coronary anatomy or left main stenosis > 50%
Severe valvular heart disease
Interventions
Patients were randomized to one of two arms:
Invasive (INV) Strategy: Coronary angiography within 30 days of randomization, with revascularization (PCI or CABG) if clinically appropriate. All INV participants also received optimal medical therapy (OMT). Decision between PCI and CABG was according to local hospital standards and practices.
Conservative (CON) strategy: OMT alone with lifestyle and pharmacologic interventions recommended. Coronary angiography was restricted to patients that failed OMT. Failure was defined as acute coronary syndrome heart failure, resuscitated cardiac arrest, or angina refractory to medical therapy.
All patients (regardless of arm assignment) received OMT which included intensive secondary prevention with lifestyle and pharmacologic therapy. The goals of medical therapy included the following:
Smoking cessation
Physical activity ≥30 minutes of moderate intensity for ≥5days per week
<7% of calories from saturated fats
BP <130/80mmHg
LDL-C <70mg/dl
BMI<25 if initial BMI 25-27.5 and 10% relative weight loss if initial BMI >27.5
HbA1c <8%
Medications as listed in figure below
Antiplatelet therapy with Aspirin (P2Y12 receptor antagonist in patients with contraindication to aspirin)
To reduce the risk of kidney injury, there was a customized hydration protocol and a contrast-volume threshold (based on eGFR and body weight) and protocols involving the use of ultralow contrast volume. Patients were followed at months 1.5, 3, 6, 12 and then every 6 months thereafter.
Outcomes
Primary outcome: Composite of death or nonfatal myocardial infarction.
Secondary outcome: Composite of death, non fatal MI, hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest, angina-related quality of life (Seattle Angina Questionnaire and the Canadian Cardiovascular Society angina class).
Safety outcomes: Initiation of dialysis and a composite of initiation of dialysis or death.
Statistical analysis
The original sample size was 1000 patients, with a 80-95% power to detect a 15-19% reduction in events in the INV arm compared to control (Bangalore et al Am Heart Jour, 2018). Recruitment was slower than anticipated, so the the sample size was reduced to 500 - 700. Ultimately 777 patients were recruited (as seen below in results). What follows is what we presume to be a post hoc calculation.
A sample size of 777 provides power of approximately 80% to detect a 22 to 24% reduction in incidence of the primary outcome with the invasive-strategy group. This assumed a 4-year event rate of 41 to 48% in the conservative-strategy group and an accrual of 240 to 270 outcomes.
Outcomes were analyzed according to intention to treat principle. KM method to estimate event rates for outcomes. They used Cox proportional hazards model to estimate average effect sizes for each treatment. The Cox model was adjusted for age, sex, kidney function (dialysis status and eGFR), left ventricular ejection fraction, and diabetes.
Funding
The trial was funded by the NHLBI arm of the NIH. In addition, the investigators acknowledge donation of stents and wires from Abbott Vascular, Medtronic, St. Jude’s and Volcano. From the supplement, it also seems that medications were supplied by various drug companies, which differed from country to country.
Results
Between April 2014 and Jan 2018, 802 pts were enrolled and 777 underwent randomization (389 in CON and 388 in INV strategy group) at 118 sites in 30 countries. See modified figure 1 from the NephJC team below. It is not clear how many patients were screened and/or were eligible. It is also not stated how patients were identified: did CKD patients with GFR < 30 and not fitting into the exclusion criteria undergo stress tests regardless of symptoms? We know from the accompanying paper (Spertus et al, NEJM 2020) that nearly half the patients did not have angina in the month before randomization.
The median age of patients was 63 years; 57% had diabetes; 92% had hypertension; and 53% were receiving dialysis (84% on hemodialysis). Among those not on dialysis, the median eGFR was 23 ml/min/1.73m2. Qualifying stress tests included various types of stress imaging in 82% and exercise stress testing in 18%. Severe ischemia was present in 38%. 64% were white and 25% were Asian.
Medical therapy and attainment of risk-factor goals: lipids and blood pressures were similar in both groups. Antianginal medications were used more frequently in CON group compared to dual antiplatelet medications in INV group.
Invasive Procedures
Only 85% if patients in the INV group underwent coronary angiography. Just under a third of the conservative group underwent angiography. Death and illness (5%) and patient preference (6%) were some of the reasons why patients in the invasive group did not undergo angiography. Of these, about half underwent revascularization, mostly (85%) PCI with the remainder getting bypass surgery. About 20% of patients in the CON group went for revascularization, though the timing was different from the INV group, as seen in the figures below.
Clinical outcomes
At a median follow-up of 2.2 years, a primary outcome event occurred in 123 patients in the invasive-strategy group and in 129 patients in the conservative-strategy group (estimated 3-year event rate, 36% vs. 37%; adjusted hazard ratio, 1.01; 95% confidence interval [CI], 0.79 to 1.29; P=0.95).
Figure 1A from Bangalore et al, NEJM 2020
Results for the key secondary outcome were similar 132 vs 138 patients (39% vs. 40%; hazard ratio, 1.01; 95% CI, 0.79 to 1.29). The invasive strategy was associated with a higher incidence of stroke than the conservative strategy (hazard ratio, 3.76; 95% CI, 1.52 to 9.32; P=0.004) and with a higher incidence of death or initiation of dialysis (hazard ratio, 1.48; 95% CI, 1.04 to 2.11; P=0.03).
Figure S8 from Bangalore et al, NEJM 2020
Patients in the invasive-strategy group had a higher incidence of stroke than those in the conservative-strategy group
Incidence of death from any cause and cardiovascular death were high and similar in two groups (fig 2A). There were no significant between-group differences in the incidence of myocardial infarction (Fig. 2B), hospitalization for unstable angina (Fig. 2C), or hospitalization for heart failure (Fig. 2D). Patients in the invasive-strategy group had a higher incidence of stroke than those in the conservative-strategy group (adjusted hazard ratio, 3.76; 95% CI, 1.52 to 9.32; P = 0.004), a difference that was driven by a higher incidence of nonprocedural strokes (i.e., those that occurred more than 30 days after the procedure) (Fig. S8).
The incidence of death or initiation of dialysis in patients who were not receiving dialysis at baseline was higher in the invasive-strategy group, a difference that was driven by a higher incidence of newly initiated dialysis (Figs. S9 and S10).
Figure S9 from Bangalore et al, NEJM 2020
The risk of contrast induced acute kidney injury (CI-AKI) in non dialysis patients who underwent coronary angiography or PCI that was not preceded by a clinical event was low (8% in the invasive-strategy group vs. 0% in the conservative-strategy group).
Possible heterogeneity of treatment effect was noted according to the degree of ischemia (severe or moderate), the ejection fraction (lower or higher), and the eGFR (lower or higher) (Fig. 3, and figures S12 and S13)
Figure 3 from Bangalore et al, NEJM 2020
Figures S12 and S13 from Bangalore et al, NEJM 2020
Change in Angina
From the accompanying paper (Spertus et al, NEJM 2020), there was a small non-significant change at 3 months - mostly driven by the patients who had daily or weekly angina. By 12 months, however, even this effect had dissipated, as seen below.
Table 2 from Spertus et al, NEJM 2020
Discussion
Among patients with stable coronary artery disease, advanced kidney disease, and moderate or severe ischemia, there was no difference in primary (composite of death or nonfatal myocardial infarction) and secondary (composite of death, nonfatal myocardial infarction, or hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest) outcomes between patients that received an initial invasive strategy, as compared with an initial conservative strategy.
The invasive strategy was associated with a higher risk of stroke, as well as a higher risk of the safety outcome (death or dialysis), mostly driven by a small increase for dialysis after angiography and/or revascularization. There was some heterogeneity of effects: possible benefit of invasive strategy with severe ischemia, lower eGFR and lower ejection fraction (though no statistics reported).
Angina associated health status (secondary outcome) was assessed (Spertus et al NEJM 2020) via Seattle Angina Questionnaire (SAQ) score. Though there was some difference (2.1 points) in favor of the invasive strategy group at 3 months post intervention, it was nullified at 6 months post intervention. This is similar to results seen in COURAGE (Boden Cardio Vasc Med 2009) Trial that included 16 patients with ESKD.
Is there a study error that masked the difference in outcome?
One possible explanation is that study might have ended too soon. In the first 6 months patients there were more myocardial infarctions in the invasive strategy group. By the end of 4 years, death due to MI or cardiovascular events was higher in the conservative strategy group (13.9% vs. 11.7%).
Strengths:
ISCHEMIA-CKD RCT was run concomitantly with ISCHEMIA (excluded CKD) RCT, for comparable results.
This is the largest study thus far and more patients underwent randomization in each trial than in previous trials addressing this issue
Limitations of the study:
Only 777 of the initially planned 1000 patients were enrolled, and the number of events was only half of what was anticipated reducing the power of the study to detect a differnce between the two strategies.
Very symptomatic patients (heart failure or recent acute coronary syndromes, or had an ejection fraction of less than 35%) were excluded from the trial. This may account for many patients with CKD. Having information on the number of patients screened and the reasons they were excluded would help adjudicate this.
Conclusion
Though the risk of IHD whether stable or acute, increased with CKD, invasive strategy of treatment does not seem to improve angina or event rates (though the larger Ischemia trial did show a short term reduction in angina with the invasive-therapy group). The conservative strategy, with invasive management as a rescue option seems to be good. Optimal medical therapy should be a mainstay for every CKD patient.
Additionally, roughly half the patients entering the trial didn’t even have angina - so the ‘stable’ ischemic heart disease component was a finding on stress tests. Perhaps we should do less of those unless the patient is having severe angina, or ACS? The exception where many programs do otherwise - i.e. screen asymptomatic patients, is for when working up for a kidney transplant. An argument has been made in the past (Sharif A, AM J Kidney Dis 2019) for abolishing this practice, and the findings of this trial bolster that argument.
Summary by
Anju Yadav MD FASN,
Thomas Jefferson University, Philadelphia, PA
Sai Sudha Mannemuddhu MD FAAP,
University of Florida- College of Medicine, Gainesville, FL
NSMC interns, class of 2020