"You have mentioned that the evidence for Hb targets of
10 to 12 g/dl of NICE was weak. You have then proposed that "In fact, the
RCT's would support a Hb range of 9 to 11 g/dL.". Does this statement have
enough strong evidence or is it a simple projection after observing the dangers
of higher (usually above 13 g/dl) targets in RCTs. (Anon Jan 25, 2012)”
 |
| Source: FDA CDRAC Briefing Document 2007 |
 |
| Source: FDA CDRAC Briefing Document 2007 |
The other study is the “Trial to Reduce Cardiovascular Events with Aranesp Therapy” (TREAT). In TREAT 4,038 subjects were treated
with darbepoetin or placebo, with a goal Hb of 13g/dL in the active treatment
arm. Rescue darbepoetin treatment was given to those with a Hb below 9 g/dL in
the placebo arm. The median achieved Hb in the intervention
arm was 12.6 g/dL (IQR of 12.0-12.8 g/dL) and in the placebo arm 10.6 g/dL (IQR
of 9.9-11.3).
TREAT was neutral for its
primary composite endpoints: death or a cardiovascular event or death or
end-stage renal disease. For the primary composite of death or a cardiovascular
event (hazard ratio for darbepoetin versus placebo, 1.05; P = 0.41), but, there
was a significantly higher rate of strokes in patients treated with
darbepoetin. Fatal or nonfatal strokes occurred in 101 patients assigned to
darbepoetin and 53 patients assigned to placebo (hazard ratio, 1.92;
P<0.001). Death or end-stage renal disease occurred in 652
patients in the darbepoetin alfa group (32.4%) and in 618 patients in the
placebo group (30.5%) (Hazard ratio for darbepoetin alfa vs. placebo, 1.06; 95%
CI, 0.95 to 1.19; P = 0.29). A higher rate of both thromboembolism in the darbepoetin-treated
patients was also observed.
The bottom-line? Normal Hematocrit demonstrates that a
target of 9 to 11 g/dL is better than a higher target in dialysis patients,
and TREAT demonstrates that patients randomized to placebo (keeping the Hb
above 9 g/dL) did better with respect to stroke and no worse with respect to
mortality and cardiovascular and renal complications.
The evidence to support a target Hb range of 10 to 12 g/dL is illusory and pharma-industry driven. Pushing a target of 10-to-12 g/dL is more dogma than science. The best evidence is for a Hb target of 9 to 11 g/dL.
Notwithstanding all of this, the goal should be tailoring anemia management by developing an individualized Hb trigger and using the lowest possible dose of ESA. The hemoglobin trigger is defined as the Hb concentration at which patients become symptomatic. The intervention could be ESA, iron, blood or a combination thereof. This would mean that some patients who become symptomatic at 10 g/dL would require treatment, whereas others who are asymptomatic at lower Hb concentrations will need no intervention.
The evidence to support a target Hb range of 10 to 12 g/dL is illusory and pharma-industry driven. Pushing a target of 10-to-12 g/dL is more dogma than science. The best evidence is for a Hb target of 9 to 11 g/dL.
Notwithstanding all of this, the goal should be tailoring anemia management by developing an individualized Hb trigger and using the lowest possible dose of ESA. The hemoglobin trigger is defined as the Hb concentration at which patients become symptomatic. The intervention could be ESA, iron, blood or a combination thereof. This would mean that some patients who become symptomatic at 10 g/dL would require treatment, whereas others who are asymptomatic at lower Hb concentrations will need no intervention.
Ok, so let's assume that keeping above 9 g/dL is better than not treating at all. We still don't know the upper target. NHCT showed that 9-11 is better than 13-15, but perhaps 9-10 is better than 10-11? I realize that you can only slice and dice so much and this all becomes impractical to test, but each 1 g/dL higher target is billions of dollars, right?
ReplyDeleteJust to add one patient's experience. I am not influenced by Pharma but by my own body experience. When my hgb is less than 12.0 I feel exhausted and sick and too tired to exercise or do much else. I also experience angina when my hgb is too low. I am a Type 1 diabetic, CKD5, currently doing home hemodialysis 6 days/wk. I use 4000 units of EPO three times a week. I realize that it is possible my risks for stroke/MI may be higher but I will take the quality of life I have with a higher hemoglobin over the misery of forced anemia any day.
ReplyDeleteThis is why I feel that each patient needs an individualized Hb trigger - the Hb below which one feels symptomatic and then use epo, iron and blood to keep you above that threshold. For most patient's 9 to 11 should be fine but probably not for all - and it sounds like you should be keeping your Hb above 12 g/dL. Others don't have significant symptoms at a Hb of 9.0 g/dL. One-size-doesn't-fit-all. Ajay Singh
ReplyDeleteIt really shouldn't be so hard to understand this. In asymptomatic patients, high doses of ESA's are more dangerous than low Hb.
DeleteTreat based on actual symptoms, rather than a laboratory Hb number. There is no obvious "upper bound" because it depends on individual response. Is FDA supposed to just spoon feed?
Yet ASN fights the FDA for trying to protect patient safety.
http://www.asn-online.org/policy_and_public_affairs/docs/ASN%20Letter%20to%20FDA%20re.%20ESAs%2011.8.18.pdf
The unintended consequence of imposing ANY target range is that whenever Hgb exceeds one of the bounds it may lead to aggressive dose adjustments in the hope of quick correction (for example, dose hold when Hgb > 12 g/dL or too large increase when Hgb < 10 g/dL). Furthermore, if the range is too narrow, the adjustments could be due to non-ESA related Hgb variability (assay error, volume status, etc.).
ReplyDelete