Please note that the text below has been copyedited.

Dr Schlaich:
-Hello, my name is Professor Markus Schlaich. I'm the Dobney Chair in Clinical Research at the University of Western Australia and the Royal Perth Hospital.

What are the unmet needs in patients with RHT? What is the rationale for PRECISION?

Dr Schlaich:
Resistant hypertension (RHT) is defined as uncontrolled blood pressure despite taking three antihypertensive drugs at maximally tolerated doses including a diuretic. And it is reasonably common, around 10 to 12% of patients with hypertension have resistant hypertension. The problem is that it is associated with a significantly increased cardiovascular risk.

The reason and the rationale for this specific study was our belief that in a lot of patients a very important pathophysiologic mechanism that plays a role in elevating blood pressure is not targeted therapeutically.
This pathophysiologic mechanism is the endothelin pathway with its two receptors, the endothelin A and B receptor. The PRECISION study was conducted to assess whether targeting the endothelin system with a dual endothelin-receptor antagonist, aprocitentan, helps to improve blood pressure control in patients with RHT.

What is the study design, outcome measures and eligibility criteria?

Dr Schlaich:
PRECISION was a randomised, controlled, blinded phase 3 trial and its design was quite sophisticated.
What is very important in the context of resistant hypertension is to ensure that these patients have true resistant hypertension: For this reason we had a run-in phase and then we swapped these patients to a standard background therapy consisting of what guidelines would recommend; a single pill triple combination of an angiotensin receptor blocker, calcium channel blocker, and a diuretic. Only patients who maintained a sitting blood pressure above 140 over 90 millimetres of mercury made it into the trial.
After this run-in phase, patients with true RHT were initially randomised in a double blind four-week phase during which they were either randomised to placebo or to the dual endothelin antagonist, aprocitentan, at 12.5 or 25 milligrammes. The primary endpoint was the change from baseline after these four weeks of double-blind treatment.

We then wanted also to see whether aprocitentan can reduce blood pressure in the long term, so the part 1 double-blind phase was followed by a 32-week single blind period. In this part 2 phase all patients were swapped to 25 milligrammes aprocitentan. At the end of this part 2, single-blind 32 weeks we checked blood pressure again.

And a clue of this study is really we had a withdrawal phase; a re-randomization where these patients either remained on the high dose of aprocitentan or were switched to placebo. In this part 3 phase we looked at blood pressure changes is with placebo and assessed whether the changes are maintained with aprocitentan. And after this part 3 phase, as usual, we had a 30 days safety follow-up phase.

The primary endpoint was the change from baseline to week 4 in the double blind 4-week phase in mean trough sitting office systolic blood pressure (SBP).
Key secondary endpoints were the change from the withdrawal baseline, which occurred at week 36 to week 40, again in sitting office blood pressure and as is standard these days also changes in 24 ambulatory blood pressure monitoring.

What are the key results?

Dr Schlaich:
First off, primary endpoint, the change from baseline in the double blind 4-week phase, there was around 15 millimetre of mercury blood pressure reduction from the baseline of around 153 millimetres of mercury measured by unattended automated office blood pressures.
This blood pressure reduction was significantly more pronounced with both doses of aprocitentan compared to placebo. There was a placebo effect of around 11 millimetres of mercury, which is quite substantial. But again, aprocitentan significantly more efficacious in terms of lowering blood pressure.
During the single blind phase on the 25 milligrammes, blood pressure was maintained at that level. So throughout that period, aprocitentan at 25 milligrammes worked perfectly in and kept blood pressure at bay.
As expected, once patients were re-randomized after 36 weeks to either maintain 25 milligrammes of aprocitentan or receiving placebo, there was a significant rise in the placebo group of 5.8 millimetres of mercury. Highlighting again that the aprocitentan continued to work and maintained excellent blood pressure control as opposed to placebo.

The 24-hour blood pressure monitoring results were also quite important because we know that ambulatory blood pressure monitoring is more reliable and gives us a better indication across the 24 hours. There was a very clear-cut distinction between placebo and both doses of aprocitentan. And interestingly, particularly night-time blood pressure was reduced significantly by around 10 millimetres of mercury with the higher dose of aprocitentan.
This is relevant because we know that night-time blood pressure is the best predictor of cardiovascular outcomes and reducing night-time blood pressure very likely has significant benefits.

I think this is a very exciting study in that it is proof of principle and shows the safety and the efficacy of a novel pathophysiological approach to treat resistant hypertension by targeting the endothelin pathway with a dual endothelin antagonist aprocitentan. It worked both at the moderate and the higher dose.

We have seen as expected as a common side effect, fluid retention and peripheral oedema. This was usually easily treated with additional diuretic therapy. It is important to acknowledge that fluid retention can be seen in these patients and needs to be looked after.
We are very excited about the study and we feel that we have a new weapon in our armamentarium to combat and to treat resistant hypertension which is a high risk condition. Treating resistant hypertension by targeting the endothelin pathway with a dual endothelin antagonist may help many patients to reduce their cardiovascular risk.

What are the take home messages for practice and research?

Dr Schlaich:
PRECISION was a phase 3 trial with a decent enrolment and a very sophisticated trial design. During the study we also looked at several different subgroups and throughout it appeared that this endothelin antagonist, aprocitentan works quite well. And there are signals that particularly in patients who are traditionally difficult to treat: Patients with with proteinuria, with a low renal function or a low eGFR, and the elderly seem to benefit specifically.
We believe that this is a new opportunity for those very high-risk subjects whose blood pressure is traditionally difficult to control, to have a new treatment that will help to improve their blood pressure control.

What are the next steps?

Dr Schlaich:
The key now will be to move forward to see how this drug performs, of course after regulatory processes have been gone through and hopefully make this drug available for clinical use in the not-too-distant future and then see in a real world how the drug actually performs.