Tag: tolvaptan

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New hyponatremia data

In the last couple of months there has been an outpouring of new hyponatremia data and resources. The first I want to discuss is data on the speed of sodium correction with tolvaptan.

Juan Carlos lead a group who looked at the speed of sodium rise with tolvaptan. The primary endpoint was the change in sodium at 24-hours in patients given 15 mg of tolvaptan.

All patients had to have failed fluid restriction to be included in the analysis.

For the purpose of the study, SIADH was defined as:

  • serum sodium concentration ≤ 130 mEq/L
  • serum osmolality ≤ 280mOsm/kg
  • urine osmolality > 100 mOsm/ kg
  • urine sodium excretion > 20 mEq/L

CHF induced hyponatremia was defined as:

  • serum sodium concentration ≤ 130 mEq/L
  • serum osmolality ≤ 280mOsm/kg
  • echo- cardiographic evidence of systolic or diastolic dysfunction
  • urine sodium excretion < 20 mEq/L (if not on diuretics)

All patients had to start with a tolvaptan dose of 15 mg.

The only other concurrent therapy allowed was fluid restriction. Patients who subsequently were started on D5 water, diuretics or salt tablets, had their data censored at the point where the additional therapies were added.

Diuretics are listed as an exclusion criteria but the CHF group were allowed to use them (an exclusion to the exclusion criteria). This is not well described in the methods.

NO DIURETICS!
Except for the half of the cohort that has heart failure.

After restricting the patients by their pre-specified exclusion criteria they had 28 patients with SIADH and 39 with CHF.

Table 1.

Remember how the urine sodium is supposed to be low in heart failure. Take a look at the elevated level found in this study. Conclusion: diuretics work. Also take a look at the low Bun and low uric acid in the SIADH group. These are really helpful in my experience at differentiating the cause in tricky cases.

Tolvaptan was much more effective in SIADH with an average change sodium of 0.80 mmol/L/hr versus 0.17 mmol/L/hr in CHF

Sodium went up by more than 12 mEq/L in 25% of patients with SIADH and 3% of patients with CHF.

Using linear mixed-effects models to conduct multivariable repeated-measures analysis the investigators found:

  • In SIADH a lower serum sodium (<120 mmol/L) and lower serum urea (<6 mg/dL) were risk factors for rapid correction of sodium.
  • In CHF, only serum urea was a risk factor for rapid correction

This is what these variables look like when mixed together (data for SIADH patients)

The discussion includes this tidbit where the investigators try to explain why there is a more dramatic response in SIADH than in CHF.

As seen in Table 1, average kidney function of patients with SIADH was significantly greater than that of patients with CHF. As shown in Figures 4 and 5, a total of 8 of 39 patients with CHF and 1 of 28 patients with SIADH had serum creatinine concentrations > 1.5 mg/dL. Thus, difference in kidney function may account for the observed difference in therapeutic response between the SIADH and CHF groups.

I don’t find this argument convincing because kidney function was tested to see if it predicted response and though eGFR did correlate with response to tolvaptan in SIADH, it was not an independent predictor of response and was not a predictor of response at all in CHF.

In the SIADH cohort, age and baseline values for serum sodium, serum osmolality, SUN, serum creatinine, MDRD, and CKD-EPI significantly correlated with the magnitude of increase in serum sodium concentration during the first 24 hours of therapy. Unlike those parameters, no significant correlation was found between the initial 24-hour increase in serum sodium concentration and either body weight, body mass index, or baseline urine sodium, urine osmolality, serum uric acid, or serum potassium value. In the CHF cohort, baseline serum sodium, serum osmolality, SUN, serum creatinine, and serum potassium values significantly correlated with the 24-hour increase in serum sodium concentration. Conversely, no significant correlation was found between the initial 24-hour increase in serum sodium concentration and either age, body weight, body mass index, or baseline urine sodium, urine osmolality, MDRD, and CKD-EPI values.

This article is accompanied by an editorial by NephMadness Selection Committee member Richard Sterns. He does a nice job describing why this rapid increase in sodium in SIADH show in Morris’ paper was not also seen in Schrier’s SALT 1 and 2 paper. In that phase 3 trial that lead to the approval of tolvaptan, there were 51 patients patients with SIADH, and only 3 of them corrected too fast. This is 6%, well below the 25% found in Morris’ study. Sterns points out the relatively high sodiums found in SALT study (no one below 120 and only 30 had a sodium below 130) as a likely explanation.

Sterns wraps up his editorial with a neat description of the pharmacokinetics of tolvaptan and arguing for dosing the drug at 3.75 mg and then repeating the dose as needed every 6 hours to titrate the change in the sodium level.  Clever.

The minimally effective tolvaptan plasma concentration to increase urine output is approx. 25 ng/mL, and maximal increases in output occur when tolvaptan concentrations exceed 100 ng/mL. Levels > 25 ng/mL are achieved by doses as low as 3.75 mg, but do not remain at this level for long because the half-life for this dose is a little more than 4 hours. A 15-mg dose achieves peak plasma concentra- tions well above 100 ng/mL in patients with SIADH, enough to sustain a maximum water diuresis for more than 4 hours. A maximum water diuresis can increase the serum sodium concentration by >2.5 mEq/L per hour, yet it is not clear why this would be desired.

The standard practice in the United States is to administer 15 mg of tolvaptan and then encourage water intake to offset the resulting variable (and often large) water losses. Considering the high price of the drug in the United States (w$300 per tablet), this practice is basically flushing money down the toilet…

…A much more desirable outcome in patients with severe hyponatremia would be a modest but sustained increase in urine volume with a resulting slow steady increase in serum sodium concentration. If urine volumes were less massive, free-water restriction could be continued to avoid unwanted exacerbation of hypona- tremia. Theoretically, the desired response could be achieved with initial doses of 3.75 mg, repeating or increasing the dose every 6 hours if necessary, based on results of urine output and/or serum sodium levels measured before each dose, until the target increase in serum sodium level for the day is achieved.

Another source of additional insight on the study is an interview by Tim Yau of Juan Carlos at AJKDbog.org.

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It’s summer, make sure to warn all of your SIADH patients about sun sensitivity

This came into my office on Friday.

Demeclocycline induced sun-sensitivity
Demeclocycline is minimally effective for SIADH and has a bad side-effect profile to boot. This patient has heart failure in addition to idiopathic SIADH. So salt tablets are poorly tolerated, and he needs chronic loop diuretics to stay out of the hospital. This makes managing his water metabolism pretty tricky. The only reason I use demeclocycline as opposed to the highly-effective and safer tolvaptan is cost. Tolvaptan is $300/day wholesale, and not one of my patients has been able to get it covered by insurance.
From the University of Utah New Drug Bulletin
Way to price that drug Otsuka, such that even well insured patients can’t use it. I’ll never understand drug pricing.
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Lowest sodium I have ever seen

I’m not sure if it is really the lowest sodium but it definately was among the lowest.

I received a call regarding a consult for a patient with a sodium of 105.

The patient is a 60 year old caucasian woman who had been started on chlorthalidone 3 days prior to admission. Her physician had been wrestling with hypertension and changed her from 25 mg of hydrochorothiazide to 50 mg of chlorthalidone. (The internist was keeping up with her American Journal of Hypertension. Though 50 mg is a whole lotta chlorthalidone.)

Both figures are from Ernst Et al. Hypertension 2006

After one or two days of the new diuretic the patient started vomiting and developed diarrhea. The only thing she was able to keep down was water. When she came to the ER she hadn’t eaten anything solid for two days.

She was admitted with hypovolemic hyponatremia. She was given a bolus of 500 mL of normal saline in the ER and the sodium went up to 108. Additionally her potassium was 2.7 and her magnesium and phosphorous were low. She was started on potassium chloride and sodium phosphate prior to being transferred to the ICU. When I called the nurse I was told the intensivist  planned on starting her on 3% saline.
I was immediately worried about overcorrecting her sodium and developing osmotic demyelination syndrome from 3% saline and aggressive correction of her potassium. Tom Berl had come and spoken to our fellow and had put the fear of potassium in me by discussing a case that was triggered by potassium repletion. From the case report:

This patient was at risk of overcorrection because she had two of the most common clinical settings in which such overcorrection occurs: thiazide use and hypovolemia.

Patients with hypovolemic hyponatremia send conflicting signals to the hypothalamus regarding ADH release. The volume deficiency stimulates ADH (if the body volume deficient, let’s not lose any water via the kidneys) and low osmolality surpresses ADH (the body is too diluted so let’s lose some water to bring the concentration up). In the case of this conflict, volume rules. As I tell my medical students,

Remember the ABC’s, Airway, breathing and circulation. O for osmoregulation is way down in the alphabet.

The problem of rapid correction occurs when you correct the volume deficiency and all of the sudden the hypothalamus asks itself, why am I releasing any ADH with an osmolality of 260?

Then the kidney starts producing urine that you could probably bottle and sell as organically filtered water. Electrolyte free water clearance begins to approach the urine output and the sodium also starts to climb and climb fast.

To protect this patient I told the nurse to decrease the normal saline to 100 mL per hour and to call me if the urine output goes over 200 per hour. We also started checking the sodium every six hours and I ordered urine osmolality, sodium and potassium.

Her sodium started to rise slowly, the urine output increased but never resembled Niagra. After two days her sodium was in the 120s her urine still appeared volume depleted and volume status began to look wet. She developed wheezes and she had a few rales. We had to abandon the normal saline. We started tolvaptan. She received 30 mg once and then 15 mg the next day after she had a brisk response. After that her urine electrolytes resembled SIADH.

Once the sodium crossed 130 I stopped the tolvaptan, restricted her free water, and added a gram of sodium chloride twice a day. Her sodium stabilized around 130.

Around this time I sent a renin aldo ratio. I usually order these before I start a patient on aldactone, because after you start it you need to wash them out for weeks prior to checking for primary hyperaldosteronism. Our patient had difficult to treat hypertension and hypokalemia on admission, so I checked it. I just found out that it came back positive. The high aldosterone was after we had corrected her volume deficiency. I think it is primary, and this may explain why she had persistently low urine sodiums despite successful volume resuscitation.

We looked for a cause of the SIADH, but couldn’t find anything. No narcotics, no pulmonary disease, no malignancy, normal TSH and cortisol, no anti-depressants. She had a normal non-contrast head CT scan on admission. I even ordered a contrasted CT scan of the chest to make sure she didn’t have a cancer in there. Nothing. Idiopathic SIADH hiding behind, at least initially, volume depletion and in the background of primary hyperaldosteronism. Strange case.

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Pharma and Medical Education

Jose Arruda, Chief of Nephrology, UIC Medical Center
I was excited to see Dr. Arruda on the schedule to speak at our fellowship. This is one of the best aspects of being an academic nephrologist; we get prominent nephrologists from around the country to speak to our department.
When I saw the title of his lecture was A New Approach to Hyponatremia, I knew we were going to get the vaptan story (PDF).

Otsuka is pushing tolvaptan (Scamsca™) hard. We are getting detailed a lot, and I hear that the cardiologists are also getting an earful. Honestly, the data looks a little thin to me. The drug is the most reliable method for tackling persistent SIADH. But that’s rare. In my experience, usual care fixes almost every case of hyponatremia within a day or two. There are a minority of cases that don’t respond quickly. These episodes of persistent hyponatremia worry me. Unfortunately, tolvaptan doesn’t feel like a good option for these patients. We know from the SALT studies that a week after you stop the drug the sodium equals the control group and the drug costs $300 per day (average wholesale price (PDF), retail price). I find it hard to prescribe a $9,000 per month drug for chronic therapy. I’ll stick with salt tablets, furosemide and water restriction.

Arruda’s lecture was on tolvaptan and the first slide was giving some background on hyponatremia and he commented that “I hate this slide.” I can’t imagine putting together a presentation and flying 500 miles to present it and loathing the very first slide.
It is illustrative of what is wrong with academic nephrology. Dr. Arruda hates the first slide in his deck. Why doesn’t he remove/fix/change the slide? Because the slide deck has been vetted by the FDA and Otsuka’s lawyers. He can’t change it. He has signed a contract saying he won’t change it. Dr. Arruda gave a solid, thoughtful lecture to our department, but he did that in spite of the materials he was using. He spent considerable time just talking about the pathophysiology of sodium and did a better job than most at avoiding being a mere shill for Otsuka.
Our nephrology program, and I suspect others (most?) rely on the generosity of pharma companies to bring scientists to our program but we pay by letting the drug companies supply the slides. Tragically, those slides are vetted by people uninterested in education and devoted to meeting the conflicting demands of both the marketing and legal departments.
Dr. Arruda seems like a good guy and is a highly respected nephrologist but the only way we could get him to come to Detroit was on Otsuka’s dime and they were able to control the message.