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HYPERTENSION affects around one-third of the adult population in Australia and represents the leading modifiable risk factor for major adverse outcomes, accounting for 10.8 million deaths per year globally. In Australia, elevated blood pressure (BP) alone is responsible for 43% of coronary heart disease, 41% of stroke, 65% of the burden of hypertensive heart disease, 38% of chronic kidney disease, and 32% of atrial fibrillation (here and here).
To make things worse, patients with “resistant hypertension” — commonly defined as office BP that remains uncontrolled (systolic BP ≥ 140 mmHg or diastolic BP ≥ 90 mmHg) despite adherence to three or more different antihypertensive drug classes, including a diuretic, at maximally tolerated doses — are at even higher risk of cardiovascular and renal diseases compared with those with uncomplicated hypertension. If ambulatory BP measurements are used to confirm the diagnosis of resistant hypertension, around 10–12% of patients with hypertension are identified as treatment resistant.
As for the treatment of hypertension in general, lifestyle modification remains a major pillar of the therapeutic approach to resistant hypertension, in particular, keeping a healthy weight. While often difficult to achieve, patients should always be encouraged to improve their lifestyle where possible. Effective weight loss drugs such as glucagon-like peptide 1 (GLP1) agonists have become very popular and have a significant impact on BP.
Antihypertensive pharmacotherapy is the second pillar of BP management. A major principle of effective combination therapy is to combine drugs with a different mode of action initially at moderate doses and ideally as single pill combinations where available. This has been shown to be more effective and to result in better adherence with prescribed medication. Non-adherence is a substantial issue in clinical practice, with studies showing an average rate of around 44% with partial or complete non-adherence among patients with resistant hypertension. Interventional approaches, the third pillar of BP management, may be a good alternative for these patients.
The 2016 Heart Foundation guidelines recommend three major drug classes as first line therapies, including blockers of the renin-angiotensin system (either angiotensin-converting enzyme inhibitors or angiotensin receptor blockers), long-acting calcium channel blockers, and diuretics.
Two single pill triple combinations containing each of the three drug classes mentioned above in a variety of doses are available in Australia. These help to simplify treatment strategies and reduce the pill burden for patients, keeping in mind that many have multiple comorbid conditions such as diabetes, dyslipidaemia, chronic kidney disease, and others, requiring additional medications. If secondary causes and pseudo-resistance (incorrect BP measurement technique, non-adherence etc) has been excluded and BP remains above target despite maximally tolerated doses, ideally confirmed by ambulatory BP monitoring, a diagnosis of resistant hypertension can be made.
Discussion around the preferred fourth line treatment has been addressed in the seminal PATHWAY-2 study, which compared the effects of the mineralocorticoid receptor antagonists spironolactone, the β-blocker bisoprololol, and the α-blocker doxasozin as add-on therapy in patients with resistant hypertension uncontrolled on concomitant therapy with the three major drug classes. Spironolactone achieved placebo-controlled mean systolic home BP reductions of –8.7 mmHg (95% confidence interval [CI], –9.72 to –7.69 mmHg), which was more pronounced than the effects of doxazosin and bisoprolol (–4.03 mmHg [95% CI, –5.04 to –3.02 mmHg] and –4.48 mmHg [95% CI, –5.50 to –3.46] respectively). It is therefore considered by many as the preferred fourth line therapy.
More recently, the ReHOT trial showed that spironolactone was comparable to clonidine, a centrally acting sympatholytic agent, in achieving treatment target BP (20.8% v 20.5%), but promoted greater absolute BP reductions in 24-hour systolic and diastolic BP. Drugs targeting sympathetic overactivity, a characteristic feature of resistant hypertension, indeed appear as a valuable option.
It has been a long time since drugs with a novel mode of action have been introduced to the hypertension field. At a clinical trial session at the 2022 American Heart Association (AHA) Conference in Chicago, the main findings from three novel pharmacological approaches to improve BP control in patients with resistant hypertension were presented.
Centrally acting aminopeptidase inhibitors
Aminopeptidases promote peripheral vasoconstriction and consequently elevate BP. The aminopeptidase A inhibitor QGC001 was shown to be safe and well tolerated in 56 healthy normotensive volunteers.
Encouragingly, in a phase 2 open-label uncontrolled multicentre study, which enrolled 256 ethnically diverse overweight hypertensive patients (54% Hispanic or black), QGC001 (renamed firibastat) lowered ambulatory systolic BP and diastolic BP by 9.5 mmHg and 4.3 mmHg respectively. Ambulatory systolic BP decreased by 10.2 mmHg in the obese subgroup of patients. No angioedema was reported.
Furthermore, in a phase 2a double-blind placebo-controlled proof-of-concept study — a 4-week treatment with firibastat as monotherapy for hypertensive patients with ambulatory BP > 135/85 mmHg and < 170/105 mmHg — ambulatory daytime systolic BP was lowered 2.7 mmHg versus placebo.
The main results from the first-in-class aminopeptidase A inhibitor Firibastat in Treatment-Resistant Hypertension (FRESH) phase 3 study were presented at AHA 2022. It was a multicentre double-blind, placebo-controlled trial that enrolled 515 patients with uncontrolled hypertension despite at least two different classes of antihypertensive drugs. After a 4-week run-in period, adherent patients who remained uncontrolled were randomly allocated (1:1) to firibastat 500 mg twice a day or placebo in addition to their background treatment for 3 months. The primary endpoint was the change from baseline in unattended clinic systolic BP. The study failed to demonstrate significantly greater efficacy than placebo in the phase 3 FRESH study. This has caused the company to prematurely discontinue the second phase 3 study, REFRESH, for ethical reasons concerning the patients. For the same reason, in view of these results, it was decided to stop the development of firibastat in the cardiovascular field.
Aldosterone synthase inhibitors
Attention turned to reducing the production of aldosterone, and a new class of anti-aldosterone agents, so-called aldosterone synthase inhibitors, were developed.
A challenge with this drug class was the co-inhibition of the almost homologous encoding genes for aldosterone synthase (CYP11B2) and 11 b-hydroxylase (CYP11B1) which causes a near tenfold increase in mineralocorticoid receptor-activating 11-deoxycorticosterone, consequently offsetting the potential benefits of reduction in aldosterone synthesis.
This problem may have been overcome with baxdrostat, a highly selective aldosterone synthase inhibitor tested in a phase 2, randomised, double-blind, placebo-controlled study evaluating the efficacy and safety of baxdrostat in patients with resistant hypertension (BrigHTN study). Patients on a stable regimen of ≥ 3 antihypertensives, with seated BP ≥ 130/80 mmHg, and ≥ 70% adherence to dosing during a 2-week run-in period were randomised to receive placebo or 0.5 mg, 1 mg or 2 mg baxdrostat once daily for 12 weeks. The primary endpoint used a hierarchical analysis of the change from baseline in office systolic BP comparing active drug with placebo, starting with the highest dose (2 mg). Safety was assessed by adverse events, clinical laboratory evaluations, electrocardiography, and physical examinations. A total of 275 subjects were randomised, with 248 completing the trial.
The trial was stopped early by an independent data review committee due to overwhelming efficacy determined at a prespecified interim analysis. Mean systolic BP for all cohorts ranged from 147.3 mmHg to 148.9 mmHg.
Baxdrostat demonstrated dose-dependent, placebo-corrected decreases in systolic BP and diastolic BP of 11.0 mmHg and 5.2 mmHg at the 2 mg dose respectively, with an 8.1 mmHg systolic BP reduction at 1 mg. Baxdrostat reduced serum and urine aldosterone levels by > 50%, producing a reciprocal increase in plasma renin activity of up to threefold without reducing serum cortisol levels.
Treatment-emergent adverse events were mostly mild, with two instances of elevated potassium > 6.0 mEq/mL, which rapidly corrected, and these subjects completed the study on baxdrostat with normal potassium.
The authors concluded that baxdrostat is the first aldosterone synthase inhibitor to demonstrate substantial lowering of BP without reducing serum cortisol levels and that it was safe to use in combination with other inhibitors of the renin-angiotensin-aldosterone system. The selective action of baxdrostat may avert the risk of inducing adrenal insufficiency and the loss of BP-lowering efficacy that can result from the accumulation of mineralocorticoid receptor-activating steroid precursors seen with first generation aldosterone synthase inhibitors.
These advantages will need to be confirmed in phase 3 trials involving more patients over a longer period.
Endothelin receptor antagonists
Endothelin-1 (ET1), via its receptors (ETA and/or ETB), triggers arterial vasoconstriction, promotes inflammation, oxidative damage, fibrinogenesis, and atherosclerosis, and is involved in salt and water regulation. The ET pathway has been implicated in the pathogenesis of hypertension, but it is currently not targeted therapeutically.
Yet, this pathway is activated in patients prone to developing resistant hypertension, such as black patients, patients with obesity or obstructive sleep apnoea (here, here and here), and in comorbid conditions frequently associated with resistant hypertension, such as diabetes and chronic kidney disease.
Aprocitentan is a once-daily, orally active, dual ETA/ETB receptor antagonist, with a half-life of 44 hours and low drug–drug interaction potential. In a phase 2 dose-finding study in patients with hypertension, aprocitentan, administered as monotherapy, in the range of 10–25 mg provided the most favorable profile combining effective BP lowering with low rates of fluid retention.
In our recently published phase 3 PRECISION trial, patients with resistant hypertension were randomly allocated to aprocitentan 12.5 mg (n = 243), 25 mg (n = 243), or placebo (n = 244) for 4 weeks. Subsequently, all patients received aprocitentan 25 mg for 32 weeks followed by a 12-week double-blind withdrawal phase on aprocitentan 25 mg (n = 307) or placebo (n = 307). The primary and key secondary endpoints were changes in unattended office systolic BP from baseline to week 4 and from withdrawal baseline to week 40 respectively. Secondary endpoints included 24-hour ambulatory BP changes.
The mean (± standard error) change in office systolic BP at 4 weeks was –15.3 ± 0.9 mmHg for aprocitentan 12.5 mg, –15.2 ± 0.9 mmHg for 25 mg, and –11.5 ± 0.9 mmHg for placebo, for a difference versus placebo of –3.8 ± 1.3 mmHg (97.5% CI, –6.8 to –0.8; P = 0.004) and –3.7 ± 1.3 mmHg (97.5% CI, –6.7 to –0.8; P = 0.005) respectively. The respective difference for 24-hour ambulatory systolic BP was –4.2 mmHg (95% CI, –6.2 to –2.1) and –5.9 mmHg (95% CI, –7.9 to –3.8). After 4 weeks of withdrawal, office systolic BP significantly increased with placebo versus aprocitentan (+5.8 mmHg; 95% CI, +3.7 to +7.9; P < 0.0001).
The most frequent adverse event was mild-to-moderate fluid retention, occurring in 9%, 18%, and 2% for patients receiving aprocitentan 12.5 mg, 25 mg and placebo during the 4-week double-blind part respectively. This event led to discontinuation in seven aprocitentan-treated patients.
Importantly, night-time BP, which has been shown to be the most accurate predictor of averse cardiovascular outcomes was particularly reduced. My colleagues and I concluded that aprocitentan, by targeting a currently unopposed pathophysiologic pathway, provided clinically meaningful lowering of systolic BP and diastolic BP in patients with treatment-resistant hypertension over 48 weeks with manageable adverse effects.
Aprocitentan represents a novel, effective, and well tolerated treatment for resistant hypertension.
Summary
Resistant hypertension is common and requires additional therapeutic approaches beyond the three major drug classes.
We are fortunate to have several options, the preferred choice currently being spironolactone, although caution is required particularly in patients with impaired kidney function and tendency to hyperkalaemia. Long term tolerability can also be an issue.
α-Blockers, β-blockers, centrally acting sympatholytic agents and peripheral vasodilators can also be effective in improving BP control in these high risk patients.
Recent studies highlight substantial potential for the novel aldosterone synthase inhibitors baxdrostat (phase 2 trial) and, currently most advanced, the dual endothelin antagonist aprocitentan (phase 3 trial). Their availability, once approved, will enrich our armamentarium to treat resistant hypertension effectively in the future.
Professor Markus Schlaich is the Dobney Chair in Clinical Research at the University of Western Australia, and Head of the Dobney Hypertension Centre. He is a renal physician and hypertension specialist.
The statements or opinions expressed in this article reflect the views of the authors and do not necessarily represent the official policy of the AMA, the MJA or InSight+ unless so stated.
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Re 1: Estimates suggest that around 70% of incident hypertension is associated with overweight/obesity and average BMI in most studies in patients with resistant hypertension is around 32-33kg/m2. Weight loss by any means would likely have a substantial impact on resistant hypertension.
Re 2: Eplerenone indeed has advantages, is however less effective in terms of BP lowering and associated with costs for patients.
Re 3: Indeed, the findings from the HYGIA trial, which suggested enormous reduction in CV events with night-time dosing could not be reproduced in the very recent TIME study (Lancet 2022; 400: 1417–25): Evening dosing of usual antihypertensive medication was not different from morning dosing in terms
of major cardiovascular outcomes. The authors concluded that patients can be advised that they can take their regular antihypertensive medications at a convenient time that minimises any undesirable effects.
Wonder what the effect of having accessible treatment for obesity (GLP-1 agonists, surgery) would be on the prevalence of resistant h/t
Often spironolactone is given to older males resulting in a drastic reduction in testosterone levels hence it’s “use” as a puberty blocker. Eplerenone is better in this respect. Older males need as much testosterone as they can make!
I was interested to see in prof. Schlaich’s article on resistant hypertension that there was no mention of studies showing better end results taking BP meds at night rather than morning. Is that because there have been contradictory studies?