Is Just Being NICE the secret answer to anemia management in CKD patients?

About 1 year ago, the National Institute of Health and Clinical Excellence (NICE) in the United Kingdom published their “Rapid Update” anemia guidelines". They are available open access.

NICE represents the the main source of guidelines in kidney disease in the United Kingdom (a paper in CJASN provides background on these guidelines).

The guidelines were previously published in 2006, but a lot has happened since then and an update is timely, especially after the publication of 3 randomized controlled trials – CHOIR, CREATE, and TREAT.

The guideline has been produced using standard NICE methodology, and according to the head of NICE “explicitly evidence-linked”. The guideline development group includes “clinical experts and patient and carer representatives”, and NICE does take pains to publish their conflicts of interest.

The guideline is an exhaustive review and have now been implemented in the UK, but with no clear data on compliance. 

My first impression: good but not great. I was disappointed by the Pollyannaish tone, and the wholly inadequate consideration of the safety signals that have emerged from the 4 large randomized trials (Normal Hematocrit, CHOIR, CREATE, and TREAT) published so far.

The specific NICE guideline recommendations are available here.

The most important strength of the guideline is the emphasis on individualization of treatment and of clinically monitoring the patient. 

“The pros and cons of a trial of anaemia management should be discussed between the clinician, the person with anaemia of CKD and their families and carers if applicable” (#10).

 “ESAs need not be administered where the presence of comorbidities, or the prognosis, is likely to negate the benefits of correcting the anaemia” (#12).

“All people started on ESA therapy should be reviewed after an agreed interval in order to decide whether or not to continue using ESAs. [D (GPP)]” (#14).

People offered ESA therapy, and their GPs, should be given information about why ESA therapy is required, how it works, and what benefits and side effects may be experienced (#18).

There are some aspects of the guideline that I vigorously disagree with (I will focus on ESAs and discuss my problems with the iron guidelines another time).

First, there is only a cursory consideration of the risks of anemia treatment with ESAs. 

For example, the stroke risk reported in TREAT? The increased risk of progression to ESRD in CREATE, and the higher rate of death and cardiovascular complications in CHOIR. Lastly, what about the higher rate of cancer related deaths in TREAT? The higher rate of thromboembolic events in TREAT? The higher rate of MI and deaths and vascular thrombosis in Normal Hematocrit?

Second, the guidelines keep stating - yes repeatedly - the quality of life benefit of which the good evidence is limited or non-existent. (For example, there is no benefit in quality of life in correcting anemia in CHOIR and TREAT. The evidence from CREATE is questionable and the Normal Hematocrit study didn't perform a detailed quality of life analysis). 

Third, the NICE guidelines adopt a target (NICE terms it “aspirational”) Hb concentration of 10 to 12 g/dL while stating that the evidence to support this is weak. In fact, the RCT's would support a Hb range of 9 to 11 g/dL. (It’s notable that the FDA has adopted a HB <11 g/dL as a target or aspiration Hb, contrary to the NICE recommendations).

Typically maintain the aspirational Hb range between 10 and 12 g/dl for adults, young people and children aged 2 years and older, and between 9.5 and 11.5 g/dl for children younger than 2 years of age, reflecting the lower normal range in that age group.

To keep the Hb level within the aspirational range, do not wait until Hb levels are outside the aspirational range before adjusting treatment (for example, take action when Hb levels are within 0.5 g/dl of the range’s limits). [new 2011]

Where is the evidence for the above recommendations from the RCTs?

Fourth, when to begin treating the anaemia?

The NICE guidelines state: "Consider investigating and managing anaemia in people with CKD if their Hb level falls to 11 g/dl or less (or 10.5 g/dl or less if younger than 2 years) or they develop symptoms attributable to anaemia (such as tiredness, shortness of breath, lethargy and palpitations). [new 2011] (recommendation #35)

The NICE guideline says “The evidence showed no contraindication to early correction of anaemia.”(6.4.4).

TREAT would suggest that most patients with mild anemia do not require treatment, but rescuing patients who drift down to <9 g/dL is reasonable.

Recall that in the TREAT patients randomized to the placebo arm did very well – maintaining their median hemoglobin concentration at around 10 g/dL and with better outcomes for stroke and essentially equivalent quality of life and cardiovascular, renal and mortality outcomes compared to those patients randomized to the darbepoetin treatment arm who were targeted for a higher Hb concentration.

Lastly, I also did not like the lack of focus on the risks of exposing patients to high dosages of ESA, especially when they are not responding to ESA therapy. Where is the emphasis on "first do no harm"?

The NICE guideline states: "The correction to normal levels of Hb with ESAs is not usually recommended in people with anaemia of CKD". Why? Could it be because of exposure to high dosages of ESA?

While there is a passing reference to this issue it is poorly examined. For example:

NICE states in recommendation #36

Consider accepting Hb levels below the agreed aspirational range if:

- high doses of ESAs are required to achieve the aspirational range or

- the aspirational range is not achieved despite escalating ESA doses. [new 2011]

And in recommendation #29:

ESA therapy should be clinically effective, consistent and safe in people with anaemia of CKD. To achieve this, the prescriber and patient should agree a plan that is patient-centred and includes: [D (GPP)]

- continuity of drug supply

- flexibility of where the drug is delivered and administered

- the lifestyle and preferences of the patient

- cost of drug supply

- desire for self-care where appropriate

- regular review of the plan in light of changing needs.

In recommendation #36, it might have been useful to have added “Avoid or use low ESA dosages in patients with an active cancer” and “Avoid ESA or use low ESA dosages in patients with a prior stroke especially if they are diabetic”

Bottom-line: Is Just Being NICE the secret answer to anemia management in CKD patients? Truthfully, NICE is being too nice.