Who needs Tolvaptan?

Who needs Tolvaptan?

I am not being sarcastic in phrasing this question, it is a genuine dilemma in the management of ADPKD for both clinicians and patients.  
Before my US readers skip this post (Tolvaptan has not yet been licensed for ADPKD use in US) I’d suggest that it won’t be long before US follows Japan, Canada, Europe and UK and watching how these other countries “ration” the treatment will be helpful. Perhaps my use of the word “ration” is a little unfair, but from the patient perspective that is really what it feels like and I have read several forum posts where people feel they are being denied the treatment rather than told it is not in their best interests. And why does it need rationing? The cost of course – annually at around £15,750 per person (or £43.15 per day, £1208.20 for 28 days). To put some perspective on that, the most expensive statins (cholesterol lowering drugs) in UK cost around £5,000 per person per year and aside from the specialised immunological cancer treatments almost all other regularly prescribed drugs are less expensive per person than the statins. 
Of course, compared to dialysis and transplant, this sum barely reaches significance, but it is not easy to make any direct comparison. The Scottish Medicine’s Consortium, in their supporting papers published December 2015, used estimates provided by the pharmaceutical company, Otsuka, that treatment with Tolvaptan was associated with 0.5 years less on dialysis / 20% fewer transplants / a reduction of 2 years time spent in end stage renal disease (ESRD). For the population this matters, but for the individual patient it could literally be the difference between life and death. 
Healthcare costs are managed with such fundamentally different approaches in different countries that the above figures may not be transferable to non-UK countries. UK has specifically stated in its guidance for prescribing that Tolvaptan can only be used for as long as a patient access scheme exists – essentially a discount offered on the price by the drug company to the NHS. Details of this discount are clearly too sensitive to be published, but it does mean that it is a bit unfair for consultants to use specific costs when they decide on an individual’s treatment – doing so definitely reeks of rationing and generalised justifications rather than the patient’s best interests. 

So what are the clinical criteria for prescribing Tolvaptan? 

In UK there are just two rules: 

•  CKD 2 or 3 at the start of treatment
• evidence of rapidly progressing disease

As a reminder, CKD stages are defined by estimated renal function (eGFR) and stages 2 and 3 means an eGFR between 90 and 30 (while I know a scientist should always use units, typing out “millilitres per minute per 1.73 metres squared” each time – well it just isn’t going to happen!). The European Medicines Agency (EMA) has approved Tolvaptan for stage 1 CKD as well, on the basis that the TEMPO3:4 trial, the main one involving Tolvaptan, used patients in stage 1. Actually, to be pedantic, TEMPO3:4 used the Cockcroft-Gault creatinine clearance as a measure of renal function and this tends to overestimate GFR by up to 20%, due to tubular creatinine secretion. Because of the patient selection criteria in that trial there is very limited information about using Tolvaptan in stage 3 but there is an ongoing study, REPRISE, looking at patients with an eGFR between 25 and 65 – stage 3b is eGFR 30-44. 
NICE excluded CKD stage 1 on a cost effectiveness basis, though their guidance does note that if you use total kidney volume (TKV) rather than eGFR then there is evidence of efficacy in CKD stage 1 as much as CKD stages 2 and 3.

“Evidence of rapidly progressing disease” 

What, exactly, does that mean? 
The reason this clause is in the guidance is simply because the benefit to risk ratio is highest in such patients. Slow progression would lead to longer exposures to the drug with increased risks of adverse effects. But there is no accepted definition of “early onset end stage renal disease” and at the moment there are no agreed markers for predicting rapid progression.  
The ERA-EDTA has tackled this question. From studies the most useful markers in predicting progression are high total kidney volume, early onset of hypertension, gross haematuria and an early decline in eGFR. This places higher import on imaging and clinical features than environmental, genetic or laboratory results. A paper published early this year (Cornec-Le Gall et al) devised a prognostic score, PRO-PKD, that aims to predict whether a patient will reach ESRD before the age of 60. This includes gender, onset of high BP before 35, urological symptoms before 35 and the genetic mutation (see previous post). The barrier to using this score is the limited availability of genetic testing.  
So assessing progression really boils down to the documented change in eGFR. The Mayo clinic has used data from its own patients (n=590), plotted the height-adjusted TKV against age, resulting in 5 classifications, 1A to 1E, with increasing likelihood of ESRD in 10 years time. So patients in group 1A have just 2.4% chance of developing ESRD in the next 10 years and those in group 1E a 66.9% chance. The Mayo data was confirmed using data from the CRISP cohort of patients, so groups 1C, 1D and 1E have rapidly progressive disease and, according to the ERA-EDTA, would qualify for Tolvaptan treatment. 
You may have noticed that they have brought age into the equation, a factor that is not specified in NICE guidance. The European algorithm recommends it only for people under the age of 50. I was indignant when reading this, but I can follow their reasoning that if you are over 50 years with an eGFR above 45 then you have not progressed rapidly. Similarly if aged 40-50 and in CKD stages 1-2 or aged 30-40 with an eGFR above 90 – these people have less to gain from treatment with Tolvaptan. 
The TEMPO3:4 trial only included patient between 18 and 50, so it is a lack of information concerning patients older than 50 rather than specific contra-indications. Proponents of the biological concept of age rather than chronological might have something to say about this. 
So what are the actual figures for falling eGFR that will trigger consideration for Tolvaptan? Whilst not specifically defined in NICE guidance, the ERA-EDTA have stated a fall greater than 5 in one year, or an average annual decline of 2.5 if measured over 5 years. By this, I would qualify for consideration, except I am over 50 …. I await my next clinic appointment! Interestingly, in the study placebo group the average annual decline was 3.7, so there is an argument for using that for a cut-off point, but 5 is a nice round number!
The issue of “Who shouldn’t have Tolvaptan” really needs a whole post of its own. I will tackle side effects and contra-indications later.  
My conclusions are that for patients in countries where Tolvaptan has a licence for treating ADPKD then the simplified NICE criteria (CKD2-3 with eGFR fall greater than 5 in the last year) should be enough to trigger the discussion with your nephrologist. There is no point in asking your GP because it is a consultant only initiation. And when you have this discussion, make sure it is focused around you and whether you will benefit – good luck! 

Assessing rapid progression isnt always easy!