The “High-Impact Clinical Trials” session was held at the ASN KidneyWk on Oct 26, 2018.

National meetings are the time when you re-establish contact with old friends and create new collaborations. They are to show off your latest work and appreciate the progress of mentees. But the reason everyone gets time off to travel across the country (or around the globe) is the presentation of new and, hopefully, practice-changing research. Some of this happens in the daily poster and oral sessions, but the biggest studies with the brightest potential impact are reserved for one session: The Late-Breaking and High-Impact Clinical Trials session.

This year, ASN put 8 studies on that rarified stage and in the process reopened some old wounds, planted a flag in some new areas, and brought attention to progress in patient-oriented outcomes.

Back to anemia

The Anemia Wars are reheating up. Anemia used to be the biggest topic at Kidney Week but ever since normalization of hemoglobin in CKD was soundly rejected by the TREAT trial in 2009, anemia has been absent from the big stage. This is changing. The HIF-stabilizers are racing through phase-3 trials and the clinical trialists are limbering up their presentation skills. The late-breaking trials session had three anemia trials:

1. PIVOTAL on IV iron
2. CERA vs ESA for cardiovascular safety
3. Transfusion protocols and AKI (The TRiCS-III trial)

PIVOTAL had simultaneous publication in the New England Journal of Medicine. When this happens it always ratchets up the excitement in the High-Impact trials session. It feels like the medical world’s attention is locked on Kidney Week.

PIVOTAL was a randomized controlled trial of two strategies for iron therapy: the control arm administered IV iron in response to low TSAT (<20%) or ferritin (< 200 µg/L) while the experimental arm gave the patient 400 mg of IV iron a month every month (unless the ferritin went over 700 µg/L or the TSAT went over 40%). The primary outcome was a composite of nonfatal myocardial infarction, nonfatal stroke, hospitalization for heart failure, or death. Scheduled use iron meant that patients got a lot more iron, had higher TSATs, and ferritin. The study met its non-inferiority primary outcome. Importantly, while not reducing the primary outcome, it did reveal a number of intriguing secondary outcomes:

• Reduced ESA dose 19.4%
• Reduced transfusion rate 21%
• No increased risk of infection or hospitalization
• Reduced risk of hospitalization for heart failure
• Reduced risk for recurrent events

The next trial was a randomized controlled trial of methoxy polyethylene glycol-epoetin beta (AKA CERA) versus a reference ESA. This was a cardiovascular safety study and so was designed around a non-inferiority study design. Interestingly (or strangely) the study population was not exclusively on dialysis population but included roughly 16% of patients with non-dialysis-dependent CKD. CERA was just as safe as the reference ESA for cardiovascular outcomes.

I was not a fan of this study and wrote more about why at PBFluids.

The last anemia trial of the session was TRiCS III. This was a re-analysis of a previously published trial that compared two different protocols for providing blood transfusions during cardiac surgery. Apparently something close to 20% of all blood is used during cardiac surgery, so changing practice here can have a profound impact on the blood supply. The liberal transfusion arm transfused patients when hemoglobin went below 9.5 in the ICU or 8.5 on the wards. The conservative policy did not transfuse patients until their hemoglobin fell below 7.5. The primary outcome was development of KDIGO-defined acute kidney injury (AKI), i.e. an increase in creatinine of 0.3 mg/dL or a 50% bump within 7 days of surgery.

Compared to the liberal protocol, the restrictive group consumed 38% less blood and was not associated with any additional risk of AKI.

Diabetes continues to impress

Diabetes is showing continued progress after repeatedly depressing signals from ACCORD, BEACON, and VA-NEPHRON D where aggressive reductions in A_1c, use of bardoxolone, and dual RAAS blockade not only failed to improve patient outcomes but caused harm. Two agents for diabetes were presented: Linagliptn, a DPP-4 inhibitor, and bexagliflozin, a new SGLT2i-inhibitor.

CARMELINA was presented by Twitter star @VladoPerkovic of the George Institute. CARMELINA pitted the DPP-4 inhibitor linagliptin against placebo to look for cardiovascular safety. This is a familiar study design as the FDA has required them since the rosiglitazone disaster. These studies are required as regulatory hurdles but have provided the most remarkable advances in medicine as they are directly responsible for revealing the almost magical cardio- and reno-protection of SGLT2i. CARMELINA is unique in that it enrolled patients down to an eGFR of 15 mL/min. The study showed no cardiovascular signal, either positive or negative.

The second diabetes study was on the SGLT2i, bexagliflozin. While this is YASI (“Yet Another SGLT2 Inhibitor”), this short study had an interesting twist. All previous SGLT2i are only recommended for patients with eGFRs over 45 ml/min. In this study, they exclusively recruited patients with CKD stage 3 and notably included patients with eGFRs down to 30 mL/min. They randomized 314 patients, half with CKD 3a and half with CKD 3b. Beyond this twist, the study was pretty typical of what we have seen in previous trials of SGLT2i. The A_1c, blood pressure, body weight, albuminuria, and eGFR all fell with study drug, and all then returned to pre-treatment levels after the drug was stopped. The study was only 24 weeks long, so there was no time to see improvement in CV or renal outcomes.

The important finding here is that SGLT2i seem to work in eGFRs all the way down to 30 mL/min. This will be especially important as the renal protective effects seen in the first wave of cardiovascular trials are verified in the renal outcome trials now being conducted.

After anemia and diabetes, we got a smattering of other concepts.

There was the LANDMARK study which is another round of calcium versus non-calcium based binders. This time the featured non-calcium based binder was lanthium which faced off against calcium carbonate. The study was done in Japan on prevalent hemodialysis patients with elevated PTH (for Japan). The primary outcome was cardiovascular survival defined as absence of cardiovascular death, non-fatal MI, stroke, unstable angina, hospitalization for heart failure, or ventricular arrhythmia. As has been seen in most studies with this design, after four years of exposure there was no cardiovascular signal. Look for the updated meta-analysis in an upcoming issue of…AJKD? Lancet?

The Editor-in-Chief of CJASN, Raj Mehotra presented the results of the ASCEND Trial. This trial looked at the management of major depression in hemodialysis and compared 12 weeks of cognitive behavioral therapy (CBT) to sertraline. As discussed in NephMadness 2017, 20% of patients treated with dialysis have major depression. Both arms of the trial showed benefits with improved depression scores (Beck Depression Index) by the end of the trial; however, the sertraline group did statistically better than the CBT group.

The last presentation of the session was by Navdeep Tangri. It was an ambitious attempt to see if an intervention could dissuade nephrologists from initiating dialysis at high eGFR. The inspiration for the trial comes from the finding that between the years 2000-2010, the number of patients who started dialysis with an eGFR over 10 mL/min doubled. For the purpose of the trial, early dialysis was defined as initiation with eGFR > 10.5 mL/min. They did a clustered randomized controlled trial of 55 advanced CKD clinics, representing 80% of the dialysis patients in Canada. The intervention consisted of multifaceted knowledge translation. What this meant was the following resources were applied:

• Audit and feedback
• Academic detailing
• Patient and physician facing infographics
• Ongoing support through a Knowledge Translation broker

It did not work. The rate of early initiation of dialysis fell in both groups without any difference between the experiment and control groups. Tangri suggested that the intervention may have failed because the results of the IDEAL trial moved the whole country toward delayed dialysis and overwhelmed the intervention.

Overall, the Late-Breaking and High-Impact Trial session had solid results that will inspire and intrigue nephrologists for another year, but no earth-shattering moments.

– Post prepared by Joel Topf, AJKD Social Media Advisory Board member. Follow him @kidney_boy.

Check out more AJKDBlog coverage of Kidney Week 2018!