Tag: anemia

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The state of anemia research

When we last left the anemia wars, the erythropoietin stimulating agents (ESA, which is Epo, Darbe, and CERA) were in full retreat. The ESAs had conquered ESKD and were (and still are) the standard of care to treat anemia. From that position they made a strategic strike on pre-dialysis CKD, targeting anemia in a larger slice of the world. There are 30 million patients with CKD, the market is big but relatively few of them have hemoglobin that is really low. Only 15% of patients with CKD have anemia, and that is using <12 g/dl in woman an < 13 g/dl in men.

One of the prominent theories at the time was to increase the hemoglobin to around 13 to reduce the cardiovascular disease that is so prevalent in CKD (remember the vast majority of these CKD 3 patients will die of heart disease long before they are even smelling a dialysis center).

This strategy was actually not a new idea. We had already tried this is dialysis patients. Besarab’s Normalization of Hematocrit was published in 1998. This showed that bringing the hemoglobin to 13 was bad in hemodialysis. It increased access failure, it nearly increased total mortality, and there was no signal of any benefit.

Despite Besarab’s red flag three randomized controlled trials were done to show that a high hemoglobin was beneficial in CKD, CHOIR, CREATE, and TREAT. All of them failed to show a benefit from the high hemogbin and all of them showed various, and not always consistent safety signals. The bottom line lesson of these three studies (four, if you include Besarab’s) was not to target a high (or even normal) hemoglobin with these drugs. The FDA recommended only using these drugs to avoid transfusions. KDIGO guidelines suggest a hemoglobin from 10 to 11.5 g/dl.

Nobody missed the top line result but the failure of normalization of hemoglobin also shined a light on the remainder of the ESA data. Erythropoietin was approved in the late 80’s for its ability to reduce the need for transfusions. But look as hard as you can you won’t find any data showing that treating anemia improved mortality. This is why the FDA limited use of the drug to prevent transfusion.

  • Those are quarterly transfusion rates, not annual.
  • The transfusion rate fell by two-thirds in the first year of widespread ESA use.

So that is how we left the anemia wars. ESAs retreated back to dialysis and there was a smaller amount of anemia treatment in pre-dialysis CKD to much more modest targets.

Since publishing TREAT and the revised FDA and KDIGO guidelines, anemia has slipped from the forefront of nephrology. The science has continued to mature and there is a new target, HIF-stabilizers (Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitors). he HIF-stabilizers have been winding their way from the bench to the bedside for the last 20 years and are currently in the midst of large, long phase three trials. These trials are different than the approval trials for CERA, Darbe and Epo. Those drugs needed to show the ability to correct and maintane a stable hemoglobin. The HIF-stabilizers have to be at least as safe as erythropoietin. Just like diabetes drugs after Rosiglitazone, the FDA is no longer satisfied with an improved number. the drugs need to show cardiovascular safety.

That was the landscape in which two high impact trials on anemia were announced at Kidney Week 2018.

The first was Cardiovascular Safety of Methoxy Polyethylene Glycol-Epoetin Beta in Treatment of Anemia of CKD by Francesco Locatelli. This is a cardiovascular safety study of Mircera. It looks like the same type of trial the HIF-stabilizers are now undergoing to demonstrate CV safety. This is clearly a government request and so my criticism about the study may need to be directed at the FDA/EMA. What makes me uncomfortable with this study is the choice of control. Remember these are cardiovascular safety studies, but the epoetin was originally approved not based on cardiovascular safety but on the ability to avoid transfusion. In the only placebo controlled, cardiovascular trial of ESAs, darbepoetin alfa fell short of placebo.

In this latest Locatelli trial, Mircera was found to be as safe as ESAs that were previously shown to be inferior to placebo (at least at high hemoglobin and in diabetics, with pre-dialysis CKD). It is essential, if we are going to do studies assessing cardiovascular safety that they are compared to appropriate controls. 

We should not be having patients spend years in a randomized trial trying to show non-inferiority to a drug that looks pretty inferior.

This is in opposition to the Intravenous Iron in Patients Undergoing Maintenance Hemodialysis study by Iain C. Macdougall. They showed that  an aggressive iron schedule resulted in fewer transfusions, no safety signal and some real patient oriented outcome advantages (mainly hospitalization for heart failure and transfusions, which are especially important for patients waiting on a transplant list, i.e. almost everyone on dialysis). 

Daniel Coyne, Author of the DRIVE and DRIVE II trials had a nice series of tweets about this trial:

https://twitter.com/i/moments/edit/1059278971030921216
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Crazy numbers: largest drop in hemoglobin without a transfusion

A drop in hemoglobin on 9 grams brings to mind the old surgical maxim “all bleeding stops” but I just had a case of a drop that big that includes three other confounding factors:

    1. He is a dialysis patient
    2. He didn’t died 
    3. He didn’t required a transfusion
He is a 58 year old patient with ADPKD, as part of this disease he had polycythemia and the day he was admitted with a chief complaint of dyspnea he had a hemoglobin of 19 g/dL. He had been advised that this was dangerous and he should go for phlebotomy. Sure enough he had a bilateral PE and multiple DVTs.


We started unfractionated heparin and ordered phlebotomy. So the next morning when we saw the decrease in the hemoglobin from 19 to 14 I was satisfied that he had a good response to phlebotomy. In reality, he never received the phlebotomy.

On that next hospital day he reported worsening flank pain. We ordered a CT to evaluate this and to help evaluate why his PD was failing. Turns out the pain and falling hemoglobin were due to a large bleeding renal cyst and renal hematoma. We stopped the heparin. The hemoglobin fell to 10 g/dL, a tidy 9 gram drop. We transferred him to the MICU. The initial plan was to embolise the bleeding kidney but the hemoglobin stabilized after stopping the heparin. After a few days of expectant testing and nervous observation we resumed the heparin and the hemoglobin held.
While we initially attributed the DVT solely to the erythrocytosis, he has a troubling family history (in addition to the ADPKD) that suggests thrombophilia.
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Crazy numbers: the lowest hemoglobin I have ever seen

When I was a resident I saw a really low hemoglobin. I don’t remember what the number was but I remember the circumstances. I was working the ER at Riley Children’s hospital and EMS pulled up with a infant who was short of breath. The family had been feeding him cows milk instead of formula and as a result he had severe iron deficiency anemia. Great case and after a few transfusions and some parental education, everyone lived happily ever after.

Last week I saw another lowest hemoglobin. Since I wasn’t blogging when I was a resident I don’t know if this hemoglobin is lower than that poor kid but here it is:

Hemoglobin of 3.6 g/dL. The hematocrit is still a double digit number, but still that’s a really low hemoglobin.

This is a dialysis patient who started having some vomiting that looked a little “dark” but didn’t really bother him. A day or so later he developed some dark colored diarrhea. Still didn’t bother him. Then he found himself short of breath, like he missed a treatment and got volume overloaded. This kept getting worse so he finally decided to get in his car and drive to the ER. The admitting hemoglobin was 3.7 followed by a repeat by I’m sure a disbelieving ER doc.

Diagnosis duodenal ulcer and after a half dozen transfusions and a prescription for BID omeprazole he was discharged home to lived happily ever after.

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New kid on the block: The Kidney Doctor

I first met Ajay Singh when he came to St John Hospital as part of a symposium on chronic kidney disease in 2004 or 2005. It was a great meeting and Singh gave two memorable lectures.

The first was a dismantling of the MDRD equation as an accurate measure of GFR. He was speaking against an equation that was way better than a simple creatinine but had some real problems, especially when used in patients without kidney disease. It was a inflammatory and a bit wonky for a conference directed to primary care doctors. Here we, the local nephrologists, were trying to get our doctors to recognize occult CKD by abandoning serum creatinine in favor of the superior eGFR and then the invited expert comes in and tells them how stupid this is.

His second lecture was the correction of anemia dog-and-pony show. He gave an amazing and persuasive presentation in favor of correcting of anemia in renal disease. Though the data was all retrospective and observational it was clear that Dr. Singh was personally a few steps past equipoise. At the time CHOIR was in full swing recruiting and retaining patients and my group was part of that process as a research site for CHOIR.

Five or so years later he returned to talk with our fellows and staff regarding anemia. This was after the publication of CHOIR, but I believe before the release of TREAT, though my memory is a bit hazy on the timing.

What I do remember is that he talked about the dangers of correcting anemia and the lack of data supporting its use. I remember being so angry. I felt that for the last half dozen years I had worked to convince my CKD patients that they needed to enroll in our anemia clinic, needed to come to our office for EPO shots and iron infusions, and that all this would make them feel better, protect their heart and prolong their life, all purported advantages of ESA therapy. And now Mr. Harvard returns and tells us that this is wrong, without ever apologizing, without even mentioning how he’d jumped the fence.

I stopped him mid-lecture and told him that the last time he’d been in Detroit he’d been telling us how important it was to treat anemia and now he had completely changed positions. Dr. Singh paused, looked at me, and gave the best answer possible. I can’t remember his exact words, so I’m paraphrasing here,

“The data has changed. Now we know more and what I’m telling you is what is currently correct. In medicine, there is no room for intellectual loyalty. We must be loyal to our patients not our theories. The reason my position has changed is that I am following the data. Would you want me to do anything else?”

His answer completly satisfied me and it extuinguished my rage. I was better able to deal with my regret and embarrassment at having to abandon a long held belief and practice pattern at the feet of new data.

His new blog is off to a flying start with a productivity that hasn’t been seen since Nate Hellman and quality that, to my eyes, no one can match.

Thanks Ajay, I’m looking forward to following your blog.

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Calling all nephrologists! If you care about anemia, you have until August 30th

The Centers for Medicare and Medicaid Services has proposed changes in the Quality Incentive Program (QIP) for 2013. The changes specifically involve anemia. The QIP was created to assure that even though the costs of providing dialysis care are born exclusively by the dialysis provider, there are specific quality goals that if not met result in financial penalties. The quality goals currently place are:

  • Percentage of Medicare patients with an average Hemoglobin < 10.0g/dL (Hemoglobin Less Than 10g/dL Measure)
  • Percentage of Medicare patients with an average Hemoglobin > 12.0g/dL (Hemoglobin Greater Than 12g/dL Measure)
  • Percentage of Medicare patients with an average Urea Reduction Ratio (URR) ≥ 65 percent (URR Hemodialysis Adequacy Measure).

Dialysis units that fail to hit the goals perscribed by the quality score receive a reduction in the Medicare payment by 0.5-2%. It should be apparent that the required hemoglobin targets ares problematic, especially given the recent action by the FDA (see my recent post Between a rock and a hard place). CMS is proposing the elimination of the floor on hemoglobin targets:

…Therefore, for the PY 2013 ESRD QIP, we propose to continue to use the following two measures previously adopted for the PY 2012 ESRD QIP:

  • Hemoglobin Greater Than 12g/dL Measure.
  • URR Hemodialysis Adequacy Measure.

This feels wrong to me. Creating an economic incentive that puts the cost of treating anemia on the provider but doesn’t provide any minimal goals may result in a race to the lowest hemoglobin. What’s to stop a rogue dialysis unit from removing ESAs from their formulary. We can all freely admit that ESAs have some previously under appreciated risks and that our enthusiasm for treating anemia was not entirely evidence-based, but our response to should not be to turn back the calendar to 1988.

After the release of Epo, the transfusion rate plummets. It falls by two thirds in a year and continues to fall so that the current rate of 0.3% per quarter represents a 98% reduction in transfusions. Revolutionary. And this doesn’t even begin to address the quality of life brought to dialysis patients by higher hemoglobins.

CMS states that they cannot add another unique quality indicator for 2013 and are looking toward 2014 to do this. In the absence of new quality guidelines they should keep the goal to maintain a hemoglobin over 10 g/dl but lower the target to 9 g/dL for 2013.

Patients deserve an incentive that keeps providers conscious of anemia. In study after study, low hemoglobins walk hand in hand with poor outcomes. The concern regarding anemia has been driven by attempts to normalize hemoglobin. It is clear that normalization is hazardous and without scientific support; however a failure of the experimental group does not mean we should abandon the therapy given to the control group. In every study the control group received ESA to maintain hemoglobins at least 9 g/dL.  Removing the hemoglobin floor from the quality measures would be giving a de facto license to withhold an important medication from dialysis patients.

The TREAT trial is the best study every done on outcomes in CKD with an ESA.
These dosing groups resulted in an effective separation in hgb with little profound anemia

I have copied this post to Regulations.gov as my comment on the latest guidelines.

The deadline for comments is August 30th.

A science liaison at Amgen told me that Amgen was advocating for a hemoglobin floor of 10 g/dl. The Renal Physician Association is also supporting a hemoglobin of 10 g/dL. [This paragraph was updated 8/22/11, after a complaint that I mis-interpreted Amgen’s position. My apologies.]

I have heard that CMS has received few comments from physicians. Embarrassing. Anemia is important and nephrologists should care how the governments crafts incentives that will change how our patients are treated. Go now and comment. Tell CMS what you think.

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Davita: is the vial half empty or half full

Early Tuesday, I caught half a headline about drugs being wasted at the expense of Medicare and to the benefit of some dialysis company. A few hours later I saw the first caustic tweets:

Just some of the angry tweets

Then I started getting direct messages asking for my thoughts. Recently, Davita has been getting more than its share of bad press recently and this seemed like more of the same. The facts of the news story, as far as I can tell, are as follows

  • A former medical director and nurse brought a whistle blower suit against Davita
  • They accuse Davita of using large vials to administer IV drugs during dialysis. The large vials resulted in excess medication being wasted
  • Medicare pays for the entire vial regardless of how much is wasted
  • The Justice department investigated this claim for more than two years and decided not to join the lawsuit
My first reaction was Davita had done a bad, bad deed here but the more I thought about it, the more that seemed to be a rush to judgment. The fact that the Justice Department, after investigating  for two years, did not join the lawsuit became the itch I could not ignore. My interpretation, is that the Feds looked into how Davita was handling the drugs and they did not find any unlawful activity.

So I was satisfied with the assumption that the way Davita was handling the drugs was legal. However, even when things are within the letter of the law we want our medical institutions to use resources efficiently. Clearly, intensionally pouring drugs down the biohazard drain, as the whistle blowers contend, is not the most efficient use of medical resources. The problem was the Medicare reimbursement system. For years, Medicare underpaid for the dialysis procedure so that dialysis providers had to turn themselves into high-end retail pharmacies that peddled Epo, and Zemplar in order to keep the lights on. With this type of system the providers were incentivized to use as much drug as possible. This perversion of fee-for-service has been at the root of almost all of the recent scandals in dialysis units. The recent anemia controversies were driven to the forefront largely because dialysis companies were payed for giving drugs not for patient oriented outcomes.

Its clear to me that retail pharmacy system was not the system we wanted. The laws need to change and you know what? This system is no longer the law. Bundling began earlier this year and removes these perverted incentives in order to better align provider and patient goals. In response to the new incentives you know what happened? The vials became right sized and Epo use plummeted. It’s too early to see how bundling effects patient outcomes but Davita and the other Large Dialysis Organizations are responding to the new incentives.

The lesson here is that incentives drive medical decision making. Incentives need to be implemented thoughtfully because small, seemingly minor holes can be blown wide open and introduce major distortions in the delivery of care. In terms of this whistle blower case, I think we shouldn’t dwell on the cows leaving the old barn that has been replaced by one with automatic and secure doors. The old reimbursement system was broken and has been fixed (or at least changed) and I don’t think there is much to be gained by dwelling on the previous system’s inefficiencies and errors.

So as I see it:
  • Davita administered and wasted dialysis drugs in a way that is uncomfortable, and inefficient but legal.
  • The Government realized the incentives were not aligned with better outcomes and changed the incentives
  • Davita and the other large dialysis organizations have changed their purchasing and administration procedures in response to the new incentives
  • A couple of former employees want to sue Davita for its legal, but opportunistic, drug handling behavior under the old incentives
Transparency: I am a part owner of a dialysis joint venture with Davita and one of my partners, Robert Provenzano, is Davita’s VP of Medical Affairs.
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The problem with numbers, the curse of intermediate end-points

The curse of treating chronic kidney disease is that one is always treating patients to the numbers:

  • Blood pressure. I need to get my patients below 130/80
  • Cholesterol. I need to get their LDL below 100
  • Metabolic bone disease. I need to keep their PTH
    • KDOQI 
      • Stage 3: 35-70
      • Stage 4: 70-110
      • Stage 5: 150-300
    • KDIGO
      • In patients with CKD stages 3–5 not on dialysis, in whom serum PTH is progressively rising and remains persistently above the upper limit of normal for the assay despite correction of modifiable factors, treatment with calcitriol or vitamin D analogs is suggested. (hey KDIGO, thanks for the guideline)
  • Diabetes. I need to keep their Hgb A1c less than 7
  • Anemia. I need to keep their hemoglobin
But these numbers are all intermediate, and from a patient perspective, pretty abstract. Patients don’t get PTH angina. Targetting the numbers is a way to shift the odds toward better patient outcomes, to load the dice in the patient’s favor. However we cannot allow the numbers to substitute for the real goals of care. I don’t really care about your blood pressure, I just want to prevent the heart failure, dementia, kidney failure, stroke and erectile dysfunction that result from the high blood pressure. If you give me a pill that magically improves the blood pressure but doesn’t avoid those end-points I’m not interested.
But as the number game has become a larger part of medicine we are getting medications that are pursued and approved only for their ability to fix the numbers. Some have been super successful, statins have repeatedly and reliably shown their ability to reduce events in lockstep with reducing the cholesterol. Lately however, it is feeling like success of the statins to reduce LDL and also reduce cardiovascular events maybe more the exception than the rule.
The recent experience with ESAs and hemoglobin have been beat to death in the nephrology community. See this post for a deep dive. The core issue, is that low hemoglobins are bad for patients, but using ESAs to improve the hemoglobin does not mitigate the risk. And not only does it not mitigate the risk, it appears that the current agents bring with them novel arterial and venous thrombotic risks.
The experience with A1c seems to be playing out using a similar script. Glitazones were approved based on their ability to reduce blood sugars. They effectively lower blood sugar but Rosiglitazone increased the risk of cardiovascular death by 64% and was associated with increased composite outcome of stroke, heart failure and total mortality compared to pioglitazone.
And June 9th pioglitazone was pulled from the shelves in France for increased risk of bladder cancer. A position validated by the FDA on June 15th.
This comes on the heals of three studies in 2008 and 2009 that question the notion of very tight (less than 7%) hemoglobin a1c targets to improve patient outcomes.
In cardiology, following the stunning success of statins and LDL we have a string of failures, Ezetimibe (Zetia/Vytorin) for LDL and niacin/torcetripib for HDL
I often feel the only reason we still treat PTH is that no one has done the study to show that it helps and when we get around to that trial, I’m looking at you Abbott, we will find that it too, has been a waste of money and attention.
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The new definition of a rock and a hard place–Updated

The rock would be Amgen with their newest prescribing information for Epogen and Aranesp. The recommendations for dialysis patients can be summarized as:

Specifically, for patients on dialysis, the label advises physicians to initiate ESA therapy when the hemoglobin level is less than 10 g/dL and guides physicians to reduce or interrupt the dose when the hemoglobin approaches or exceeds 11 g/dL.  So target a hemoglobin higher than needed to prevent transfusions and no higher than 11 g/dL.

The hard place would be the federal government whose Quality Improvement Plan (QIP) for dialysis units states:

The intent is to control anemia and maintain optimum hemoglobin levels within the range of 10-12 g/dL (grams per deciliter).  Anemia management will be assessed by two separate measures: 

  1. CMS will assess the percentage of patients whose hemoglobin levels dipped under 10 g/dL.  The program assigns this measure the greatest weight in facility performance calculation, because numbers under 10 g/dL are highly undesirable.  (Weight = 50%)
  2. CMS will assess the percentage of patients whose hemoglobin levels exceeded 12 g/dL. Numbers greater than 12 g/dL could suggest unnecessary or excessive administration of certain drugs.  (Weight = 25%)

There is little air to breathe between 10 and 11 g/dL. Something has got to change and my guess is by the end of the year QIP will be suggesting hemoglobins between 9 and 10.

UPDATE: CMS has proposed new rules that remove the lower limit for hemoglobin as a quality measure. Here is some news coverage and here is the PDF.

I think its crazy to remove the lower hemoglobin limit. When CMS introduced the bundled payment system they turned anemia management from a profit center to a cost center for dialysis units. The Quality Incentive Plan was designed to prevent dialysis units from minimizing costs by denying patients adequate treatment. It seems that with the 2013 proposal, a Machiavellian dialysis unit could eliminate anemia management completely and reap financial rewards without penalty.

This can’t be right, at the least CMS should add minimizing transfusions as a quality measure, that would reconcile the prescribing information and the quality goals.

Hat tip to the anonymous first poster.