PIVOTAL – A pioneering trial of worldwide importance
We have co-ordinated a pioneering clinical trial investigating the optimum amount of intravenous iron that can be given to patients on dialysis to treat anaemia effectively and safely.
A complication of being treated for kidney failure using haemodialysis is that patients develop anaemia and iron deficiency. This is a condition that leaves people feeling exhausted and seriously reduces their quality of life. Intravenous iron is a routine part of anaemia management in haemodialysis patients worldwide. However, there has been little evidence to guide optimum dosing and no consistency in approach across the UK or globally.
About the trial
PIVOTAL was a randomised controlled trial which ran from November 2013 to July 2018, and was designed to address this shortfall in the evidence base.
The trial gathered evidence from two different clinical approaches. Some patients were given high doses of iron to increase the levels of iron in their body (proactive high-dose) whilst another group received lower doses of iron only as per normal routine treatment when their iron levels got too low (reactive low-dose).
Led by King’s College Hospital in collaboration with Glasgow Clinical Trials Unit, the trial involved 2,141 patients in their first year on haemodialysis and clinicians and research nurses from 50 hospital renal units.
It is one of the largest renal clinical trials ever undertaken exclusively in the UK.
An update of the highly anticipated results has now been published in the New England Journal of Medicine (N Engl J Med 2019; 380:447-458).
Publication in this peer-reviewed medical journal signifies the importance of the PIVOTAL trial not just in the UK, but globally.
- The trial demonstrated that a higher-dose of intravenous iron reduced the risk of death, hospitalisation for heart failure, and other major cardiovascular events.
- There was also no increased infection risk in those receiving a higher dose of iron which is important, given previous research has suggested that iron might increase bacterial growth and infection.
There were also other benefits in the higher dose group:
- a reduction in the dose of erythropoetin (EPO) required - this could be beneficial because high doses of EPO have been associated with an increased risk of cardiovascular events, such as strokes
- fewer blood transfusions - this reduces the risk of developing antibodies which can affect the chance of a successful transplant in the future.
What the results mean
Elizabeth Clarke, a research nurse from Canterbury, explains the results:
Professor David Wheeler, steering committee member for the trial, said: “PIVOTAL shows that patients treated with higher iron doses (who also received less EPO) experienced fewer cardiovascular events and no increase in serious adverse events when compared to those receiving lower doses.”
“Clinicians use both EPO and iron to treat anaemia in haemodialysis patients. Giving more iron allows us to use less EPO. High doses of EPO have been associated with an increased risk of cardiovascular events, such as strokes. This is why clinicians like to minimise the EPO dose by giving more iron. The PIVOTAL trial provides reassurance that this is a good approach.
”PIVOTAL has demonstrated the UK renal community can successfully deliver a large, randomised trial. The on-going enthusiasm, commitment and support shown by the participating sites has been a key factor in ensuring the success of this important study. We also need to thank all the patients who have taken part in the trial for many years. Their dedication to and participation in this landmark study will help answer important questions about the treatment of haemodialysis patients with anaemia.”
Sandra Currie, Kidney Research UK chief executive said: “This is the first trial of its kind and size, one of the largest to have taken place in the UK dialysis population and we are immensely proud of everyone who took part and helped to make it happen.
"It brought together patients, and clinical staff from right across the country to understand how we can improve the clinical care of patients on dialysis.
“This has been a huge project for the charity to facilitate and we are delighted to see it has yielded positive results. 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.”
The charity was supported by an unrestricted grant of just under £3.5million from Vifor Fresenius Medical Care Renal Pharma Ltd. The company also provided all the iron for the study, free of charge.
An Advisory and Dissemination Board, led by the charity, with representation from a range of stakeholders provided assurance to and accountability from the trial steering committee.
These results supersede those published on The New England Journal of Medicine website on 26 October 2018. View the updated results.
Patients have played a key part in the development of PIVOTAL through a patient and carer support group. The group provided the ‘patient voice’ and awareness about the ongoing trial throughout all stages, including profiling, evaluation and analysis.
Derek took part in the trial. It formed part of his regular four-hour haemodialysis sessions which are held three times a week in the dialysis unit at Kent and Canterbury Hospital.
Derek said “This is the first clinical trial I’ve been involved in and I would definitely recommend it to others. I consider myself fortunate. I’ve lived my life and don’t have to rush around anymore, but some of the younger people on dialysis have got school work, jobs or young families to think of. Hopefully their lives will improve as a result of this trial.”
Paul was one of the 2,141 people across 50 UK centres who took part in the trial. He was in the group who were proactively given high doses of iron, while another group were given low doses, and only when their iron levels got too low.
Paul said: “I felt like I was contributing to medical evidence for the future, aimed at trying to help make decisions about what is best for patients going forwards. I was doing my bit really, doing my duty to help other haemodialysis patients.”
Reviewed April 2018