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A phase III trial presented at the European Society of Cardiology (ESC) Congress 2025, and published in The New England Journal of Medicine looks at the drug Baxdrostat for uncontrolled or treatment resistant high blood pressure.
Prof Morris J Brown, Professor of Endocrine Hypertension, Queen Mary University of London (QMUL), said:
Does the press release accurately reflect the science?
“Fair statement of results and interpretation. Full context and implications will depend on comparison of efficacy and tolerability of spironolactone (existing cheap therapy). It is always tricky to compare blood pressure (BP) reductions in different trials, but the efficacy of baxdrostat here looks similar to that of spironolactone in our PATHWAY-2 trial (Lancet 2015). Over 12 weeks (in that trial and this) there seems no difference in tolerability, but spironolactone problems develop over a longer period.”
Is this good quality research? Are the conclusions backed up by solid data?
“This is a very high quality study, and conclusions are reasonable. Findings are in line with those in the phase 2 study of baxdrostat in NEJM in 2023, and the phase 3 trial with lorundrostat in JAMA last month. It might have been nice to see ‘double-digit’ reduction in systolic BP, as we did in phase 2, but it’s common for a little regression to the mean when larger numbers are studied.
“Early results from the 32 week extension showed a fascinating persistence of BP reduction. I haven’t seen the aldosterone data in supplementary, which is said to remain suppressed. This fits what we saw in the recent Primary Aldosteronism trial (NEJM July 2025). My interpretation in that paper was a bit different from the authors’ here (which doesn’t seem to explain persistent reduction in aldosterone), and suggested the exciting possibility that ASIs (Aldosterone Synthase Inhibitors) reduce the number of aldosterone-producing cells (as in the animal models of AS enzyme deletion), and might therefore achieve remission of hypertension in patients where aldosterone was the sole cause.”
How does this work fit with the existing evidence?
“See above. Beyond the primary endpoint there are some interesting observations which the authors probably had no space to comment on.
“The term ‘aldosterone regulation’ seems to be catching on to indicate a spectrum of high blood pressure to which high aldosterone secretion contributes but not enough to qualify for a diagnosis of ‘Primary Aldosteronism’. I might prefer the term ‘Primarily Aldosteronism’ to concede a lot of uncertainty as to where the line between normal and abnormal really lies, and that in reality there is a continuous spectrum of patients who can benefit from ‘non-conventional’ drugs (i.e. those outside my AB/CD rule that underpins hypertension guidelines), of which spironolactone and now the ASIs are the main contenders. What BaxHTN and the recent Lorundrostat studies both show is that the patients with strictly defined Resistant Hypertension (BP above target despite 3 drugs including a diuretic) and ‘Uncontrolled Hypertension’ (above target despite 2 drugs) respond equally well to an ASI. This implies that the ‘reach’ of ‘Primarily Aldosteronism’ is broad, and that the class may come to be first line for the 20-25% of patients who do not reach target on a pair from each of the AB and CD categories of drugs. The actual (i.e. not placebo-corrected) falls in BP in BaxHTN were about 10 mmHg less than in the recent phase 2 trial of Baxdrostat in patients with proven Primary Aldosteronism (NEJM, July 27).”
Have the authors accounted for confounders? Are there important limitations to be aware of?
“I haven’t seen the supplementary appendix which gives the inclusion and exclusion criteria. Were patients with eGFR <45 excluded as in previous studies? The effects of ASI on eGFR are being studied in other studies by AZ.”
What are the implications in the real world? Is there any overspeculation?
“I think this is a landmark trial. Much of the impact on treatment will depend on whether ASIs are generally better tolerated than spironolactone, and whether the hints of progressive BP reduction over time, maybe even remission in some patients, are a unique feature of the new class. Hopefully this important efficacy and tolerability data will come out of the long-term extension. Meanwhile, together with PATHWAY-2, and the earlier ASI studies, it is clear that Resistant Hypertension as a concept could be usefully reconsidered so that it is not just accepted as the long-term consequence of poorly controlled ‘Essential Hypertension’. In a word, Resistant Hypertension is not essential, it is primarily Aldosteronism, and patients will benefit from much earlier recognition that they have a different mechanistic type of Hypertension from the polygenic condition in 75-80% of people with high blood pressure.”
Professor Paul Leeson, Professor of Cardiovascular Medicine and Cardiologist, University of Oxford, said:
“Patients with uncontrolled blood pressure often struggle to find the right tablets to reduce their risk of heart attacks or strokes. When new medicines are proven to lower blood pressure without causing significant rises in unwanted side effects, these are important to know about. Increased levels in the blood of a substance called aldosterone are known to be a cause of difficult to control blood pressure. For many years, we have had medications that are able to block aldosterone working but they do not actually lower levels of aldosterone, so patients may still experience adverse effects of the substance. Baxdrostat, the medicine used in this trial, is one version of a new range of medications that work differently, and directly reduce the levels of aldosterone.
“Importantly, the trial was performed across several countries and included both men and women, as well as patients with different ethnic backgrounds. This helps ensure the findings are relevant to the range of patients we see with blood pressure problems. The reduction in blood pressure of ~5 to 10mmHg is typically what we would expect for any drug or intervention we use to manage blood pressure. The medication also worked even when added on top of other tablets. The trial did not test whether the drug reduces your chance of a heart attack or stroke, but we would expect a benefit based on how it effects the blood pressure. This new type of medicine may therefore be a potentially valuable additional treatment to tackle high blood pressure.”
‘Efficacy and Safety of Baxdrostat in Uncontrolled and Resistant Hypertension’ by John M. Flack et al. was presented at the European Society of Cardiology (ESC) Congress 2025, and simultaneously published in The New England Journal of Medicine at 15:15 UK Time Saturday 30th August 2025.
DOI: 10.1056/NEJMoa2507109
Declared interests
Professor Paul Leeson: No conflicts relevant to this study.
Prof Morris J Brown: I was senior author of previous papers on baxdrostat (NEJM 2023, 2025, Hypertension 2017) and spironolactone (Lancet 2015). However I had no involvement in this trial, nor do I have any current connection with AZ.