A pause for HALT?

A momentary period of quiet to digest what the HALT studies mean for people with PKD. 

Nine months after the publication of the HALT-PKD trial results and the current news is relatively quiet, with few reviews or commentaries on the research and perhaps even a feeling of disappointment. Why disappointment? On the surface it seemed the results disproved the hypothesis – a negative result – but that is most definitely not the same as a non-result, so I don’t fully understand the restrained press.

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HALT

What was the HALT-PKD trial (answer with fewest possible sentences)
An 8 year study, US-based, multi-centre, with over 1000 participants; there were two hypotheses:

  1. That reducing blood pressure (BP) to very low levels would slow the disease progression during the early stages (558 patients, aged 15-49, eGFR>60, half to a BP below 110/75)
  2. That a combination of an ACE-inhibitor(ACEI) with an ARB would be better than an ACEI alone at reducing BP. (486 patients, aged 18-64, eGFR 25-60,BP 110/70 to 130/80)

Effectively there were two studies, one in early PKD and one later. The primary endpoint in the early PKD part was the percentage change in total kidney volume (TKV) over time and a second measure of change in eGFR compared with baseline. In the patients at later stages the primary endpoint was a composite one, time to death or end stage renal disease (ESRD) or a 50% reduction in eGFR. Both groups also had measurements made of urinary aldosterone and albumin, frequency of hospitalisations, pain and quality of life.

In the early study the results showed that a very low BP attenuated the progressive increase in TKV. This was not reflected by the change in eGFR, however.

The study at later stages showed that a combination of ACEI and ARB was NOT better than using ACEI alone at controlling BP.

Some background:

Blood pressure is, in part, controlled by the renin-angiotensin-aldosterone-system (RAAS).
Renin is secreted by the kidney.
Angiotensinogen is secreted by the liver.
Renin breaks down angiotensinogen into angiotensin-I.
Angiotensin-I is inactive but is changed by the angiotensin-converting-enzyme (ACE) into angiotensin-II, the active form.
Angiotensin II makes blood vessels constrict and also stimulate aldosterone secretion from the adrenal glands.
Aldosterone leads to retention of sodium and fluid in the body.
BP goes up when blood vessels tighten and blood volume is increased.

ACE-inhibitors stop this process at the A-I to A-II stage.
Angiotensin-receptor-blockers (ARBs) stop this process at the sites where angiotensin-II effect the blood vessel constriction.

Studies in mice had suggested that adding ACEI and ARB together would have a more profound effect on blood pressure in PKD.

Total Kidney Volume (TKV) has been shown to be a surrogate marker for progression of PKD.

eGFR is an estimate of the actually function of the kidneys, not just size, and thus presumed to be a better marker of progress of the disease.

Are they valid trials?

Validity in trials can mean different things but for the patients what we really need to know is “Does this mean me?
But there is no straightforward answer here either – on the surface these HALT trials don’t mean ME – they excluded people outside a specific age range, with co-morbidities and mental health diagnoses. But that is just because drawing conclusions when there are additional factors is difficult, so the trial population has to be standardised. They also excluded pregnancy, drug users, diabetics and immunosuppressed patients.

This trial population was huge – up until this study the largest group in a study of ADPKD was that in the CRISP trials, just 241 patients. It was undertaken in several centres, but all were in US, so while one might make comparisons with a UK or European population, the applicability to say a Chinese or Indian population is perhaps not so simple.

The treatments used were randomised, double-blind and placebo-controlled. These are all good things when looking at validity. One of my medical students commented that this really means “nobody knows what on earth was going on”, but in a study of therapeutics that, trust me, is a good thing.

Importantly, the pharmaceutical companies were not involved in the trial other than as suppliers of the drugs and matching placebo. Funding came from an unbiased source. The co-authors are all reputable experts who have many publications behind them and the clinicians involved are all practising nephrologists or relevant physicians.

This was a relatively long trial – a follow-up period of between 5 and 8 years. This is infinitely better than the pre-marketing drug trials of maybe just a few months.

8 years is a long time

8 years is a long time

Are the drugs used representative of the class?

In other words, do I have to take the exact same drugs to get the same effect or can I take an alternative from the same group and expect similar results?

The study used Lisinopril for an ACEI and Telmisartan as the ARB.

ACEI have been around since 1981 when captopril was first approved by the FDA. More than 10 “me-too” drugs followed during the 1980s and 90s, of which lisinopril was one of the earlier, approved in 1987, so it has been around a long time and has built up a significant safety profile.

Usually the earlier drugs of a class will have better scientific documentation but the later drugs can be made with lower financial investment. This means some later drugs can be marketed at lower cost and might be more popular in the cost-conscious world. I was bemused to read that ramipril is the most-prescribed ACEI in UK and recall days back in General Practice during the early 2000s when we had drives to change patients onto ramipril because it was significantly cheaper than other ACEIs – of course it will be commonly prescribed.

All ACEI will share the effect of inhibiting the conversion of angiotensin-I to angiotensin-II. But each has a slightly different structure and so will have variable “other” or extra effects. They are not, therefore clinically interchangeable. But what we are asking is whether a different ACEI will also be effective in keeping BP low in PKD. Unfortunately the answer can be stated no more firmly than “probably”. Of the studies and reviews I have read the efficacy has only been considered for patients with primary cardiovascular diagnoses such as heart failure and there have been very few “head-to-head” studies comparing the use of one particular ACEI with another.

As for telmisartan, although one particular irritating drug-rep comes to mind when I hear the word “Micardis” (original trade name for telmisartan), I have to say that it is a long-acting ARB providing 24 hour cover and with what is described as a “preferential pharmacodynamic profile”, meaning: it works, and it works well, with few side effects. There seems little to choose between the ARBs and one can for now at least, assume that they will all have a similar effect. This is lightly less relevant given that the study outcome was that adding an ARB to an ACEI was not more beneficial. But I felt it worth looking at anyway because I am actually one of those who couldn’t tolerate an ACEI and so am on an ARB alone.
What are the risks I should know about?

Here there is not really an option of doing nothing as high blood pressure exacerbates cyst enlargement and leads to more rapid deterioration in kidney function. So the “risks” to consider are side effects of the medications and any effects of having a very low blood pressure.

Importantly, very few people withdrew from the trial because of adverse drug reactions – both active drugs are commonly prescribed and the side effect profiles are well documented. Some 12% people taking an ACEI will develop a repetitive dry cough, usually resulting in them being changed onto an ARB since these drugs are more selective in the receptors they block and tend not to cause a cough.

Curiously one other listed “side effect” of both drugs, lisonopril and telmisartan, is “hypotension” or low blood pressure – isn’t that what we are trying to achieve, not an incidental effect at all!

But sometimes a lowering of blood pressure can lead to light-headedness and dizziness and specifically a postural drop that might lead to fainting or falling down. This was noted in the trials.  It is often just an annoyance and not dangerous. It requires getting up slowly and pausing before storming off – something my family have grown used to, waiting while Mother’s brain catches up!  Rarely, low blood pressure could lead to a damaging loss of pressure to a part of the brain, or a stroke – I will not attempt to quantify this risk.

The frequencies of significant events did not differ between the group treated to a standard BP and those treated more aggressively.
What do the results of the HALT trials mean?

Firstly these huge trials justify the use of an ACE-inhibitor as first line treatment for ADPKD patients with hypertension. Around 70% of patients in the trial achieved adequate BP control using just an ACEI.

Secondly they show clearly that stricter control of BP, down to levels between 95/60 to 110/75mmHg, delay progression in younger patients. This is progression as measured by total kidney volume and separate studies have shown that increased kidney volume equates to increased cyst dimensions. The inverse relationship of BP to eGFR could not be confirmed. There are possible reasons for this, maybe there is a time lag between kidney volume and stabilisation of GFR. Maybe eGFR is not always the best measure to use in clinical decision making regarding ADPKD.

Closer analysis showed that the patients who benefitted most from strict BP control were those under 30, those who had larger kidneys and men. One can only postulate reasons for that. Secondary analyses are ongoing and more outcomes will be discussed in future papers from the investigators.
What is the take-home message of the HALT-PKD trials?

The main positive lesson from HALT is that stricter BP control delays progression of the disease. It underlines the importance of early detection and early treatment of high blood pressure. That is quite an attitude change from how ADPKD has been managed in the past 30 years as many of us would have been perhaps seen by a specialist on diagnosis and effectively told to “come back when you have renal failure”. Now the message should be “come and see me often, we can manage this, and maybe you won’t get renal failure”.

HALT, then make decisions

HALT, then make decisions

Of note: 

HALT-PKD trials cost some $32 million

Renal replacement therapy in US costs $4billion each year.

References:

HALT-PKD studies can be read in full here:

http://www.pkdiet.com/pdf/halt/HALTresults.pdf
http://www.nejm.org/doi/pdf/10.1056/NEJMoa1402685
http://www.pkdiet.com/pdf/halt/HALTangiotensin.pdf

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