PIVOTAL trial confirms long-term safety and efficacy of IV iron dosing

Detailed results from the Proactive IV irOn Therapy in haemodiALysis patients (PIVOTAL) trial were announced yesterday as a late-breaking oral presentation at ASN Kidney Week 2018 in San Diego, California, US. PIVOTAL is a randomised controlled trial designed to investigate the effects of two IV iron dosing strategies among patients on maintenance haemodialysis.⁵ The reactive, low-dose IV iron arm was intended to maintain patients near the lowest acceptable iron limits (serum ferritin of 200 µg/L and TSAT of 20%). In contrast, the proactive, high-dose IV iron regimen encouraged more liberal iron dosing and permitted higher ferritin and TSAT levels (up to 700 µg/L and 40%, respectively), as has been observed in the US.^6,7 Although liberal IV iron dosing is known to improve ESA response and to allow for reduced ESA doses, the effect of this strategy on other objective outcomes was previously unclear.⁸

The PIVOTAL trial followed 2,141 patients from 50 sites in the United Kingdom for up to 4.4 years (median follow-up after 2.1 years). The trial met its primary endpoint by demonstrating noninferiority of the proactive dosing regimen as assessed by the risk of death, nonfatal myocardial infarction, nonfatal stroke, or hospitalisation for heart failure (HR=0.88, 95% CI: 0.76-1.03, P<0.001). Additionally, the proactive iron dosing regimen was associated with a significant 22% reduced risk of death or cardiovascular events when analysed as recurrent events. As suggested by prior data, higher doses of iron allowed for a significant, nearly 20% reduction in monthly median ESA dose. Notably, the proactive dosing strategy, and attendant increases in serum ferritin concentrations and TSAT, was not associated with any increase in the risk of hospitalisation, infection, or vascular access thrombosis. The results of the PIVOTAL trial were simultaneously published online in The New England Journal of Medicine (available online at NEJM.org).

Key information about PIVOTAL:

• Results from the PIVOTAL trial were presented during the High-Impact Clinical Trials session at American Society of Nephrology (ASN) Kidney Week 2018.
• The trial met its primary endpoint of noninferiority as assessed by a composite of death and cardiovascular events, demonstrating that a liberal, proactive intravenous (IV) iron dosing regimen did not expose patients to an increased level of harm.
• Treatment with greater doses of iron, allowing for higher ferritin and transferrin saturation (TSAT) levels, was associated with significantly reduced rates of the primary outcome when the components were analysed as recurrent events and was less likely to result in hospitalisation for heart failure.
• Among patients on maintenance haemodialysis, a proactive, high-dose regimen of IV iron significantly reduced dose requirements for erythropoiesis-stimulating agents (ESAs) and the need for blood transfusions, without adversely impacting mortality or safety endpoints such as hospitalisation or infection.
• Across Europe and the United States, more than 70% of patients on maintenance haemodialysis receive IV iron1-4.

Stefan Schulze, President of the Executive Committee and COO of Vifor Pharma Group said: "These robust data add a wealth of information to the evidence base supporting an optimal IV iron dose for the management of anaemia in this patient population. As the market leader for IV iron, we are committed to ensuring safe therapy for patients. With this study, a knowledge gap in the anaemia treatment of HD patients can be closed."

The trial was supported by an unrestricted research grant from Vifor Fresenius Medical Care Renal Pharma Ltd. (VFMCRP) to Kidney Research UK. In addition to financial support, VFMCRP also provided Venofer (iron sucrose) free of charge for the duration of the trial.

Initiated in 2013, PIVOTAL represents the largest prospective, controlled clinical trial of IV iron in patients with CKD. It also stands as the largest nephrology clinical trial ever conducted exclusively in the UK. "This is the first trial of its kind and size to have taken place in the UK and we are immensely proud of everyone who took part. There was a gap in the understanding of intravenous iron therapy which needed to be addressed and we now believe the results will lead to improved treatments and better outcomes for patients," said Sandra Currie, Chief Executive of Kidney Research UK.

1. G.R. Bailie, et al., "Variation in intravenous iron use internationally and over time: the Dialysis Outcomes and Practice Patterns Study (DOPPS)," Nephrol Dial Transplant. 28:2570-2579 (2003).

2. US-DOPPS (Dialysis Outcomes and Practice Patterns Study) Practice Monitor. IV iron use, last 3 months. April 2018; https://www.dopps.org htm. Accessed October 10, 2018.

3. Germany-DOPPS (Dialysis Outcomes and Practice Patterns Study) Practice Monitor. IV iron use, last 3 months. June 2016; https://www.dopps.org Accessed October 10, 2018.

4. B.M. Robinson, et al., "Evaluating the effectiveness of IV iron dosing for anemia management in common clinical practice: results from the Dialysis Outcomes and Practice Patterns Study (DOPPS)," BMC Nephrol 18:330 (2017).

5. I.C. Macdougall, et al., "Randomized trial comparing proactive, high-dose versus reactive, low-dose intravenous iron supplementation in hemodialysis (PIVOTAL): study design and baseline data," Am J Nephrol 48:260-268 (2018).

6. US-DOPPS (Dialysis Outcomes and Practice Patterns Study) Practice Monitor. Monthly IV iron dose received (90 day average), continuous (mg). April 2018; https://www.dopps.org/DPM/Files/sum_IVIRON90DAY_overallTAB.htm. Accessed October 10, 2018.

7. US-DOPPS (Dialysis Outcomes and Practice Patterns Study) Practice Monitor. Serum ferritin (3 month average), continuous (ng/mL). April 2018; https://www.dopps.org/DPM/Files/meanferritinngml1_overallTAB.htm. Accessed October 10, 2018.

8. I.C. Macdougall, et al., "Iron management in chronic kidney disease: conclusions from a 'Kidney Disease: Improving Global Outcomes' (KDIGO) Controversies Conference," Kidney Int 89:28-39 (2016.

9. World Health Organization. Preventing and controlling iron deficiency anaemia through primary health care. 1989; http://www.who.int/nutrition/publications/micronutrients/anaemia_iron_ deficiency/ida_preventng_control_primary_healthcare.pdf Accessed October 17, 2018.