Join us Tuesday August 25 at 9 Eastern and August 26 at 8 PM GMT for the #NephJC chat on the delivery of iron.

Blog posts about this chat:


A randomized trial of intravenous and oral iron in chronic kidney disease.

Agarwal RKusek JWPappas MK.

PMID: 26083656

The study looks at patients with CKD stages 3 and 4. According to the introduction, only half of the studies which have looked at IV versus PO iron have reported adverse affects. This comes from this Cochrane Review. Shameful.

The authors hypothesized that IV iron may accelerate kidney dysfunction via oxidative stress and endothelial damage.

The trial is called REVOKE: Randomized trial to Evaluate intraVenous and Oral iron in chronic KidnEy disease.


Open-label, parallel-group, single-center RCT.

Patients had GFRs by 4 variable MDRD of 20-60 mL/min, anemia (hemoglobin < 12 g/dL) and iron deficiency ( ferritin < 100 ng/mL or TSAT of < 25%).

Intervention: IV iron patients received 200 mg of iron sucrose over two hours at week 0, 2, 3, 6, and 8. One gram of IV iron. Oral iron patients were instructed to take 325 mg of ferrous sulfate three times a day for 8 weeks.

GFR was measured by iothalamate clearance at baseline, 8 weeks, 6 months, 12 months and 24 months after randomization.

The primary outcome was the slope of GFR deterioration.

Power analysis called for 100 patients in each group.


They only enrolled 136 of the 200 required in the power analysis. Under enrollment may have been the reason there were differences in the baseline characteristics in the groups:

  • IV iron group was younger
  • IV iron group had less cardiovascular disease
  • IV iron group had less history of infection

There was no difference between hemoglobin levels between the groups. There was some off protocol use of IV and oral iron that resulted in some cross over.

  • 2 patients in the oral group received IV iron after the 8-week intervention
  • 9 patients in the IV iron group received additional IV iron outside of the 8-week intervention period
  • 7 patients in the IV iron group received oral iron outside of the 8-week intervention period
  • 36 patients in the oral iron groups likewise were treated with oral iron after the 8-week intervention period

The trial was stopped early due to excess serious adverse events. At the time of terminating the study there was no signal that GFR might decrease faster with IV iron. Likewise there was no difference in proteinuria or quality of life.

Overall serious adverse events were similar, but when the data was adjusted for baseline:

age, sex, black race, stratum of proteinuria, baseline estimated glomerular filtration rate (GFR), diabetes, cardiovascular disease, tobacco use, systolic blood pressure (BP), statin use, antiplatelet therapy, angiotensin-converting enzyme (ACE) or angiotensin receptor blocker (ARB) use.

The data show increased risk with IV iron:

Cardiovascular events in the oral iron group occurred 36 times in 19 subjects (34.4/100 PY); in the IV iron group they occurred 55 times in 17 subjects (54.4/100 PY; IRR 1.58 (95% CI 1.04–2.41, P = 0.033). Adjusted IRR was 2.51 (1.56–4.04), Po0.001. Compared with the oral iron group, the incidence of hospitalized heart failure was increased approximately twofold in the IV iron group. Supplementary Figures S3–S5 online show that the distribution of the events was such that it was not one or two subjects in one group who influenced the outcomes. 

The discussion mentions an interesting finding:

REVOKE counted each event as a separate serious adverse event. In fact, the number of patients who had serious adverse events in REVOKE were similar between oral and IV iron groups. Indeed in our study, we found that exposure to IV iron increased the frequency—not the number of participants—with serious adverse events.

The final conclusions of the study:

However, among patients with IDA and moderate-to-advanced CKD, compared with oral iron, IV iron sucrose appears to result in a higher risk for infections and cardiovascular complications over the long term. Oral iron may be the preferred initial mode of treatment for IDA in stage 3 and 4 CKD.
Taken together, our findings raise the urgent need for long-term safety of IV iron in vulnerable populations such as CKD.