Those are not glucoses. They are Sodiums. And, except for maybe an infant with congenital adrenal hyperplasia when I was a resident, those are the highest sodiums I have ever seen.
The primary management concern was the speed of correction. The first Na at 188 was drawn at 4:32 pm. Four hours later it was 177, a change of 11 mEq. Too fast. Here is the salient section from UpToDate:
Rate of correction in chronic hypernatremia — There are no definitive clinical trials, but data in children (particularly infants) suggest that the maximum safe rate at which the serum sodium concentration should be lowered in patients with chronic hypernatremia is 12 meq/L per day. To be safe, we suggest a maximum rate of correction of the serum sodium of 10 meq/L per day in patients who have had hypernatremia for at least 24 hours. The following findings provide support for this conclusion:
A retrospective case control study included 97 children with hypernatremia and dehydration; the mean baseline serum sodium was 165 meq/L. The rate of reduction in serum sodium was significantly faster in the children who developed cerebral edema compared with children who had no complications following correction of the hypernatremia (1.0 versus 0.5 meq/L per hour).
Similar findings were noted in another report in which the rate of reduction in serum sodium was 1.0 meq/L per hour in the nine infants who developed seizures compared with 0.6 meq/L per hour or less in 31 infants who did not develop seizures.
So Bud Rose, the dean of electrolytes, says 12 mEq per day.
My patient moves 11 mEq in 4 hours after receiving 500 mL of normal saline. Now what? I was convinced that continuing normal saline would perpetuate the overly rapid correction of the sodium and put the patient at risk of cerebral edema. But since the patient was still in hypovolemic shock, I couldn’t just stop the fluids.
I ordered 3% saline. I ran it at 100 mL/hour and 5 hours later the sodium was back up to 186. I was going in circles. I then changed back to normal saline and over the subsequent 48 hours we corrected the sodium at roughly 0.5 mEq/l/hr. The whole time I was going through this I was wondering is it all necessary? Is rapid correction of hypernatremia as dangerous as Rose said it was? Is half a miliequivalent/L/hr a real evidence based speed limit?
I put this question to a fourth year medical student and he did an excellent job diving into the evidence (or lack there of) on the topic. Here is his analysis:
I think he is a little hard on Rose’s guidelines. The student’s analysis criticizes one of 4 references that are provided in UpToDate (though his criticism is appropriate and is the sole reference in Rose’s landmark Clinical Physiology of Acid Bas Disorders) to support of the 0.5 mEq/L/hr speed limit.
The section in Rose’s text is very similar to the UpToDate card. The relevant paragraph is on page 777 in my 5th edition (black cover). The sole reference in this paragraph, is the 1986 Blum article (number 4 from the above list).
iPhone, a surprisingly effective photocopier.
Kahn retrospectively looked at the care of infants. They used half normal saline and gave it at 160 mL/kg/day (6.7 mL/kg/hr). All of the patients were 0-5 months, so maintenance fluids would have been 4 mL/kg/hr.
What book did this great page on maintenance fluids come from?
Nine of the first 47 patients developed seizures that could not be explained by other etiologies (fever, hypocalcemia, hypoglycemia) and so were ascribed to rapid fluid restoration, Group I. They matched these nine to 22 age-matched children who were treated contemporaneously but did not have a seizure, Group II. The investigators then changed the protocol for treating infants with hypernatremia to 120 mL/kg/day and included data on 9 patients under 5 months who were treated this way, Group III.
Here is the primary data on the three groups:
All three groups had similar sodiums but Group I had significantly higher BUNs than Group II, with I +II vs III and I vs III being non-signifigant.
The protocol called for patients in Group I and II to get only 160 mL/kg/day. Both groups significantly exceeded this. Group III hit its fluid goal nearly on the nose. They blamed the excess fluid on oral replacement and volume resuscitation with sodium bicarbonate.
The net result was a wide spread in the rate of correction of sodium:
The kids that seized: 1.02 mEq/L/hr
The kids that did not seize but were on the same treatment protocol: 0.62 mEq/L/hr
The kids on the conservative protocol, also without seizures: 0.35 mEq/L/hr
Fang looked at 97 children with hypernatremia. Mean sodium was 164.5. Mean age 13 months. He performed a case-control study with the cases being patients who developed cerebral edema. Manifestations included seizures, eyelid edema, papilledema in all the patients and bulging fontanel in 36 and pupillary abnormalities in 9 cases.
The data shows cerebral edema was more common with bolus therapy, especially when the bolus was faster, higher sodiums were associated with cerebral edema but much of that disappeared in multivariate analysis as higher sodiums were also associated with increased rate of correction and ind increased bolus rates. Using ROC the investigators found a rate of fluid administration of 6.8 ml/kg/hr was safest. And the average decrease in serum sodium in the cerebral edema group was 1 mEq/L/hr and 0.5 mEq/L/hr without cerebral edema.
The final reference is Blum’s study of oral rehydration, this is the reference my med student was upset with. As he outlined, this was a study of oral rehydration rather than a study of rates of treatment. The cohort was composed of eighteen infants, 6 months or younger admitted with hypernatremia (Na > 150) and treated with oral fluid resuscitation. They compared the hypernatremia outcomes to a second cohort of 26 infants who received IV rehydration for hypernatremia. Average sodium for both groups was 160.
In both groups the reduction of sodium was slow (0.3 mEq/L/hr) and no patient developed seizures.
In Burton Rose’s Clinical Physiology of Acid-Base and Electrolyte Disorders this observational study with no seizures is the sole reference behind the recommendation for a slow restoration of normal sodium. Weak sauce. Of note Androgue’s review of hypernatremia in the NEJM from 2000 references the same Blum and Khan articles to support its recommendation of slow treatment.
So in the end, the recommendation for slow normalization of sodium is based on a handful of studies in infants with no randomized or even prospective studies. What is unbelievable to me is no one references a study that reviews the functional/neurological outcomes of patients with the highest sodiums admitted to a large hospital based on the speed of correction. Seems like an easy study and in its absence we are left to trust in the physiology of babies.
A year ago, a slender, 40 year old, white female presented to my clinic with new onset elevated blood pressure. The hypertension was discovered during a routine visit for a minor injury. The family practitioner refused to believe the vitals and kept having the patient return for follow-up visits before resigning himself to the diagnosis. Surprisingly, this otherwise healthy woman, was resistant to multiple medications. He began to suspect a more sinister diagnosis and initiated a work-up for secondary hypertension and referred her to me.
The initial work-up showed a aldosterone of 16 but the renin was not done. She also had modestly elevated metanephrines, but not high enough to suggest a pheochromacytoma. Her blood pressure typically ran 140-160/100 with labetalol 100 mg bid, but she admitted to being forgetful regarding her medications.
One of the findings that stood out for me was the hypokalemia on the initial labs
We repeated the renin-aldo ratio and did a EKG. Unfortunately she had LVH. For me, this ruled out white coat syndrome. The demonstration of end-organ damage also helped the patient see that this condition was “real” and after that she was compliant with the medical therapy.
The repeat Aldo was only 3 with a fully suppressed renin at 0.15. This is an aldosterone-renin ratio (ARR) of 20, however, I was taught a low total aldosterone ruled this diagnosis out. In other words, one needs an elevated aldosterone, not just a suppressed renin to make the diagnosis of primary hyperaldosteonism. This always made sense to me but the Endocrine Society states that this is not always true and questions the requirement for a high aldosterone:
Against a formal cutoff level for aldosterone are the findings of several studies. In one study, seated plasma aldosterone levels were less than 15 ng/dl in 36% of 74 patients diagnosed with PA after screening positive by ARR defined as more than 30 and showing failure of aldosterone to suppress during fludrocortisone suppression testing (FST), and in four of 21 patients found by AVS to have unilateral, surgically correctable PA.
Her potassium remained low at 3.1 despite potassium supplementation. She was breast feeding at the time so we did not use an ACEi or ARB and were successfully treating her blood pressure with a combination of nifedipine XL and labetalol.
The low aldosterone appeared to rule-out primary hyperaldo but with the unexplained hypokalemia I ordered a third ARR and hit pay-dirt
An ARR of close to 300 with a sky-high aldosterone of 29. Remember, when you calculate the aldosterone-renin ratio make sure the units are correct:
aldosterone in nanograms per deciliter
renin measured as plasma renin activity (PRA) in nanograms per milliliter per hour
With a positive ARR, the endocrine society recommends a confirmatory test. There are four recommended tests, all of which are variations on attempts to suppress endogenous aldosterone via sodium loading or fludrocortisone suppression. I did not do this. I feel that the critical diagnosis to make is the functional adenoma that is surgically curative. Whether the patient has bilateral hyperplasia or simply aldosterone driven hypertension that doesn’t meet the criteria for primary aldosterone is not important to me because I’m going to treat both of those conditions identically, with spironolactone or eplerenone.
So we proceeded with the work-up for a functional adenoma and sent her for a CT scan. We found a 1 x 2 cm left adrenal mass.
Here is where it gets tricky. This sounds like a functional adenoma, however functional adrenal adenomas are rare diagnosis, and even in the presence of documented hyperaldosteronism, non-functional incidentalomas are too common (0.35-5%) to assure that a CT finding of an adrenal mass represents a functional adenoma. Following a CT scan, you can neither rule-out nor rule-in the diagnosis of a surgically correctible functional adenoma. Patients still need to get adrenal vein sampling. Here is the experience from University of Texas Southwestern:
Twenty patients had unilateral CT abnormalities, and 14 (70%) of them lateralized to the same side (concordant). Of the remaining 6 patients with unilateral CT abnormalities (3 left and 3 right), 1 patient each lateralized to the opposite side and 2 patients each had bilateral hypersecretion. Only 5 of 15 patients (33%) with bilateral CT abnormalities showed concordant bilateral aldosterone hypersecretion. The other 10 patients (67%) demonstrated unilateral hypersecretion. Of the 5 patients with normal-appearing adrenal glands on CT, 1 patient each lateralized to 1 side, and the other 3 patients had bilateral hypersecretion.
The authors did not provide a 2×2 table to determine sensitivity or specificity (insert rant regarding surgical literature here) so I put one together. This is how I interpreted the data above:
Positive test: 20 with unilateral findings, 14 true positives and 6 false positives (I considered the CT scan identifying the wrong affected adrenal as being a fail)
Negative test: 15 patients with bilateral findings, 5 were true negatives and 10 were false negatives
Negative test: 5 patients with normal adrenals, 2 lateralized, false negatives and 3 true negatives
The two-way table looks like this:
What? You’re still using Epocrates’ medical calculator? Don’t be a tool, get a tool, MedCalc
It should be apparent that a CT scan looks truly terrible at diagnosing a functional adenoma. A negative predictive value of only 40%. Ughh! Note: these numbers assume the adrenal vein sampling is a valid gold-standard.
We sent her for adrenal vein sampling to see if the aldosterone secretion lateralizes. It did with a 20-fold increase in aldosterone on the left side. Because aldosterone levels can be unreliable due to dilution and technique, it is recommended that an adjusted aldosterone (aldo/cotisol) exceed the contralateral adrenal by three fold. In our case, it was 10-fold.
She went for an laparoscopic left adrenalectomy and is now normotensive off all medications.
The endocrine society had published consensus recommendations on screening, diagnosis and treatment of primary hyperaldosteronism. I love it when important articles are available in PDF for free.
I was searching PBFluids and could not find any posts about ACCOMPLISH which surprised me. I then went to the Renal Fellow Network and found a similar lack of commentary. Dito for Nephron Power, and Nephrology on Demand. Even The Kidney Doctor with 100+ posts (and in the process putting the rest of the nephrology blogosphere to shame) in the last 2 months comes up empty handed.
Now some of this may be due to faulty blog search and some of this may be due to the fact that the study is approaching 3 years of age, but regardless ACCOMPLISH is important enough that it should get higher profile coverage.
From the title, if not the acronym, the point of the study should be clear: The study pits benazepril and amlodipine (Lotrel) against benazepril and hydrochlorothiazide (Lotensin).
The politics of this fight are interesting as this study tries to right one of the possible mis-steps in the wake of ALLHAT. ACCOMPLISH used the thiazide diuretic that is actually most often used in the U.S. and the only thiazide that is used in combination pills, hydrochlorothiazide (yes I know I’m ignoring Tenoretic, atenolol and chlorthalidone, but every other combination pill uses hydrochlorothiazide). ALLHAT used chlorthalidone as its diuretic and when this largest-ever hypertension study concluded that there was no difference among chlorthalidone, amlodipine and lisinopril on fatal coronary heart disease and non-fatal heart attacks, thiazides became institutionalized as the primary agent to treat hypertension.
The money shot from JNC7 (pdf) institutionalizing thiazide-type diuretics
The problem stems from the fact that hydrochlorothiazide and chlorthalidone are unique molecules with significant biologic and pharmacokinetic differences.
This year Dorsch et al re-analyzed data from the MRFIT trial. This was a long-term primary prevention trial from the 70’s that changed protocols mid-stream and converted patients from HCTZ to chlorthalidone. This allowed Dorsch’s team to look for differential effects of the two diuretics. They found a 21% reduction in cardiovascular events with chlorthalidone:
So ACCOMPLISH set out to show that the ACEi CCB combination is superior to the ACEi HCT combination. They randomized 11,506 patients to one of these two arms. The dosing titration seems fair:
20 benazepril and either 5 of amlodipine or 12.5 of dydrochlorothiazide
if BP is not < 140/90 (130/80 in CKD and DM) increase to 40 mg of benazepril
if BP is not < 140/90 (130/80 in CKD and DM) increase to 10 of amlodipine or 25 of hydrochlorothiazide
if BP is not < 140/90 (130/80 in CKD and DM) add additional agents as needed
The cohort was rather sick with previously diagnosed hypertension and an additional history of at least one of the following:
Impaired renal function
Peripheral artery disease
The end point was time to first cardiovascular event, or death from cardiovascular disease.
The study was well run but the blood pressures were not perfectly equal between groups with a small but statistically signifigant difference in the blood pressures between the two groups:
131.6/73.3 in the Benazepril-Amlodipine group
132.5/74.4 in the Benazepril-Hydrochlorothiazide group
A difference of 0.9/1.1 in favor of the Benazepril-Amlodipine group
The study was terminated early because the data and safety monitoring committee observed a difference between the two groups that exceeded the pre-specified stopping rule. They found a 20% risk reduction in only 30 months. This represented an absolute risk reduction of 2.2% which translates into a Number Needed to Treat of only 45.
Entering EBM free zone:
To my eyes, ACCOMPLISH better represents the patients I see than ALLHAT. All of the patients that come to my CKD clinic have high blood pressure and almost all also have the additional co-morbidities needed for enrollment. After fully digesting ACCOMPLISH I have made two changes in my practice pattern:
I am starting patients with ACEi + CCB or ARB + CCB. I have been impressed by the effectiveness of Lotrel and Exforge as single pill solutions to a lot of hypertension.
I avoiding hydrochlorothiazide where ever possible. This usually requires re-jiggering a number of medications but a common switch will be to move patients from a list that looks like this:
To a list that looks like this:
ACEi CCB combination pill
This results in significant improvement in blood pressure control. I have to thank ACCOMPLISH to opening my eyes to this change.
A patient, on Friday, explained that doctors are like the pyromaniac fireman who when he’s not putting out fires is secretly setting them so he can fight them.
Well, on that same day I saw a patient who previously had uncontrolled blood pressure. I had gotten her blood pressure under control with a combination of torsemide, spironolactone, carvedilol and amlodipine. Her office blood pressure was 123/72 with a heart rate 86. During the visit she told me that she had fallen three times in the last few weeks. Her standing blood pressure was 96/53 with a heart rate of 96. On her previous visit I had extinguished and set a new fire at the same time. Her previous blood pressure had been in the 150s. Controlling her blood pressure was the right thing to do medically but undoubtably it was the cause of her recent falls and my attempt to trim long term morbidity resulted in her being exposed to increased short term morbidity.
Another patient I saw has advanced diabetic nephropathy, CKD stage 4. He needs an ACE inhibitor or an angiotensin receptor blocker to stave off dialysis, unfortunately he cannot tolerate them because of recurrent of hyperkalemia. A few months ago I added a loop diuretic to control edema and hypertension and a couple of weeks ago he returned for a follow-up. His potassium was 4.6 mmol/L. The loop diuretic had increased kaluresis enough that I felt that I had some room to give another trial of renin-angiotensin blockade. Yesterday I received a call informing me of a critically high potassium in this patient.
These cases are not limited to clinical medicine, the ACCORD trial tried to determine if normalizing the Hgb a1c in diabetics reduced cardiovascular mortality. Better diabetic control caused increased total mortality.
In OnTarget the combination of an ACE inhibitor and an angiotensin receptor blocker was tested to see if it could reduce cardiovascular events. The combination was a favorite among nephrologists as a way to stave off dialysis in patients with persistant proteinruia despite single drug renin-angiotensin blockade. Dual blockade was the fashion mostly in response to the subsequently retracted COOPERATE trial. In OnTarget there was significant increase in renal dysfunction with dual ACEi/ARB and a trend toward increased dialysis:
“…whereas the rate was increased in the combination-therapy group, with 65 patients (0.8%) undergoing dialysis”
Pyro fireman, academic style.
It’s what makes medicine so difficult, the more you try to help your patients the more you expose them to unintended, adverse reactions. I feel that so little of medical education prepares us to balance these competing end-points, how do you judge what is an acceptable risk of hyperkalemia, how do you balance the risk of hypertension versus the risk of orthostatic hypotension?
Managing secondary hyperparathyroidism in dialysis patients should be a rewarding aspect of nephrology. I thrive on complex management that involves balancing various numbers with clever treatment strategies. It is exactly what I find so exhilarating about a juicy electrolyte case in the ICU.
The principle variables in secondary hyperparathyroidism are:
And I use one additional lab that is generally ignored in the guidelines, alkaline phosphatase.
To bend these numbers we have a variety of tools with interesting effects, mechanisms of action and side-effects. The principle therapeutics:
low phosphorous diet
calcium containing binders
paricalcitol and doxercalciferol
And additional therapeutics that can be brought to bear in difficult cases or in unusual circumstances
dialysate calcium concentration
And K/DOQI provided cleanly laid out treatment goals:
Calcium x phosphorous product < 55
Patients that achieve those targets have a lower mortality risk than patients that miss these targets:
The numbers (0 of 3, 1 of 3, etc) refer to the number of months a patient is at the K/DOQI target in the quarter, PTH was measured only once a quarter
The problem is that no one has performed a prospective randomized controlled trial showing these targets improve outcomes. We want to believe that the retrospective data showing a survival advantage with cinacalcet and paricalcitol are real and that the observational data showing better calcium and phosphorous (and to a smaller degree, PTH) results in better patient outcomes.
But given nephrology’s previous relationships with retrospective data (see anemia, Kt/V, and statins, and homocysteine) I can’t accept that data. I can’t take these treatment goals seriously. I appreciate that the fresh KDIGO guidelines readily admit that the emperor has no clothes and that the best they can recommend is to generally keep the calcium and phosphorous close to normal (evidence level 2D) and the PTH anywhere from 150 to 600 (evidence level 2c) or roughly wherever the hell you want it.
I love this figure from KDIGO, essentially once the PTH rises over 150 it provides no information. PTH > 300 has a positive predictive value of only 65% for high turnover disease. And don’t miss the laughably small numbers. We are basing global guidelines off of a study of less than 100 patients. From Barreto and Barreto.
It is shameful that Abbott has not done an RCT with survival as an endpoint on Zemplar or Calcijex. They have had 20+ years to do this. Both of the other players in CKD-MBD have taken a chance at building RCT data to support there products:
Genzyme took a poke with DCOR (RCT of sevelamer versus calcium based binders)
Amgen is in the final countdown of EVOLVE (RCT of sensipar + usual care vs usual care)
Abbott the oldest player is sitting on the sidelines.
The lack of data, the lack of clarity, and the reliance on observational data muddles the issue enough that I don’t enjoy taking care of secondary hyperparathyroidism. But recently I had a great case, a situation where treating secondary hyperparathyroidism did more than loaded the dice in my patients favor but actually really made a difference.
I have a young dialysis patient who suffers from a horrific trauma a number of years ago. As a result he has profound chronic pain. Much of the pain is back pain but he also complained of diffuse body aches. Earlier this year his PTHs were consistently over a thousand with some over two thousand.
We added 90 mg of cinacalcet daily and the the PTH plummeted to goal. This was in a patient who had not responded to doxercalciferol 10 mcg three times a week. It was nice to see the PTH come down but what made this case standout was that his body aches melted away. We had been sending him to pain clinics and switching narcotics trying to get his pain tolerable and all of a sudden, done. Pain dramatically improved with a log reduction in PTH.
Sometimes I get so carried away worrying about total mortality that I forget about the direct toxicity of high PTH.
The blog post claims that the data on treating pulmonary embolism is shaky, a randomized study from 1960 with a few handfuls of patients that was terminated early after 6 end-points.
The author then goes on to point out that since our methods of diagnosis are so much more sensitive than they were in the 1960s we should be skeptical of using old treatments for this modern concept of pulmonary embolism.
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.
There has been some greatarticles regarding the expensive, waste of a decade induced by nesiritide.
I like this article the most because it’s written by someone who is not in medicine. It tackles many of the same issues I looked at in my post, The problems with numbers, namely when drugs are approved based on intermediate end-points bad things can happen.
The best thing we can say about niseritide is that when the definitive trial was finally done, the previous concerns about renal failure, were shown to be merely illusions created by the smoke and mirrors of meta-analysis.
Acute renal failure was an early concern regarding Nesiritide…
…but when the right placebo controlled trial was done, no renal failure.
So go and read Carolyn Thomas’ view of nesiritide and see how we have failed the people we are entrusted to care for.
By a mistake of communication I was scheduled to give the anemia talk at a recent chronic kidney disease symposium. I would have never selected this topic on my own. I work with Robert Provenzano, one of the Gods of Anemia. Fortunately, this was a happy accident. I loved researching and writing this presentation. The whole experience was an important lesson on the value of working out of your comfort areas.
The anemia saga is well known to all nephrologists and is covered in depth in my presentation but let me recap my version of the story.
Life before Epo was pretty bad. the average dialysis patient received a transfusion more years than not. On the Eve of Epo the transfusion was rate was 16% per quarter!
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 is 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.
I was in college when this happened and it’s a little hard to imagine how exciting that must have been. The introduction of Epo launched a million observational trials that all pointed in the same direction:
Where you found higher hemoglobins you found better patient outcomes.
It almost didn’t matter what outcome you were interested in: hospitalizations, mortality, regression of left ventricular hypertrophy, quality of life, fatigue score. It didn’t matter, everything was better with higher hemoglobins. I suspect the community was seduced by the observational results but for what ever reason the amount of randomized controlled trial data that emerged was laughably small. By 2007, Epo was eating up 1.8 billion Medicare dollars. It should have been the best studied drug and instead it was among the least studied.
I tried to find Henry Paulson’s signature but had to settle for George Bush’s.
Here is the table from K/DOQI anemia recommendations where they summarized all of the RCT data from the birth of Epo through May 2006 (apparently it omits a single 2005 study).
8 Epo vs Epo studies and 3 placebo controlled trials, 1 placebo controlled trials in pediatrics
The paucity of placebo controlled trials is shocking. No one demonstrated that higher hemoglobin targets had a mortality benefit or regressed LVH compared to placebo. This would not be so problematic if the Epo vs Epo studies had been positive, but those too were negative trials. So we are in the awkward position, a quarter century after the introduction of EPO we cannot conclusively state that the drug does any more than reduce transfusions and improve quality of life. All the mortality reductions, cardiovascular disease protection amount to observational-backed hype (one small rct (N=38) study did show a reduction in LVH).
Favorite slide from the deck
Part of me is outraged but another part understands how difficult it would be randomize dialysis patients to placebo. I couldn’t, in good faith, expose trial subjects to the transfusions, fatigue and weakness that being randomized to the placebo-arm would entail. It fails my personal “Grandma test” (i.e. Would you feel comfortable enrolling your grandma in a placebo controlled trial of Epo? No). I understand that and forgive the dialysis researchers; however I am a little disturbed to witness how in the pre-dialysis CKD population the same pattern of relying on observational data. In CKD these is no transfusion epidemic that needed to be derailed, there is no profound fatigue turning patients to zombies. We had an opportunity to do the right studies to figure out if this expensive Nectar of Thousand Oaks really helped. The paucity of placebo controlled and randomized controlled trials in pre-dialysis patients is embarrassing.
Reading this editorial by Marc Pfeffer crystalized this critical mistake. I spent a fair proportion of the presentation laying out how statins evolved from being used in only the sickest patients to larger and larger populations and how at each step placebo controlled trials were used to prove efficacy. Not every step was a win, statins for heart failure failed, but the key is that cardiologists know that statins don’t improve heart failure because they tested it with two (1, 2) placebo-controlled trials.
Why is nephrology lacking the randomized controlled trials that have defined the huge advancement in cardiovascular disease over the last 25 years?
It isn’t due to the severity of illness, the first placebo controlled trial of ACEi in heart failure used a cohort with 40% mortality at 6 months.
It isn’t timing, ACEi for heart failure was developed and proven at the same time as the introduction of Epo.
I don’t know the why but I have a couple of theories. One is the richness of the retrospective data in nephrology, brought to us by the USRDS, blinds us to the importance of prospective data. This could explain why are repeatedly burned by observational studies, see: kT/V, vitamin D, and binders.
The other theory is that, unlike statins and ACEi where there are many vendors producing drugs in the class of interest, there is a total monopoly in the field of ESA. You want to increase the hemoglobin you need to buy Epogen. No generic, no competing ESA. In the ACEi market, having enalepril as the drug studied in the CONSENSUS and SOLVD trials paid huge dividends to Merck. Having in-class competition lead to commercial support of critical research. Amgen had no need for this because the US Patent Office gave them a monopoly. A monopoly that seems to last forever. Why is it that every other drug from the late 80’s is generic: omeprazole, captopril, enalepril, benazepril, metformin, simvastatin, etc. Even drugs from the 90’s are now generic: losartan, lansoprazole.
Epogen stands alone without generic competition. And unfortunately, largely without placebo controlled trials to back-up mountains of hype.