Table 1: Main Trials on Classical and Novel Pharmacological Agents as Fourth-line Treatment in Patients with Resistant Hypertension.
| Drug Class | Trial Name and Phase | Drug(s) and Comparator(s) | Trial Duration (Weeks) | Main Endpoint | Main Results | Reported Side-effects |
|---|---|---|---|---|---|---|
| MRAs | PATHWAY-2[92] Phase IIII | Spironolactone 25–50 mg versus bisoprolol 5–10 mg versus doxazosin modified release (4–8 mg) versus placebo | 12 | Office SBP change | Spironolactone versus placebo -8.70 mmHg (95% CI [-9.72, -7.69]; p<0.0001), versus doxazosin and bisoprolol -4.26 [-5.13, -3.38]; p<0.0001), and versus doxazosin -4.03 [-5.04, -3.02]; p<0.0001) and versus bisoprolol -4.48 [-5.50, -3.46]; p<0.0001) | Hyperkalaemia (particularly when combined with ACEI/ARB) Anti-androgen effects (gynaecomastia, erectile dysfunction in men; menstrual irregularities in women) |
| Centrally acting drugs | FRESH Phase III | Firibastat 500 mg twice daily versus placebo | 12 | Office SBP change | Firibistat -7.82 mmHg; placebo -7.85 mmHg | Skin allergic reactions: firibistat 5.1%; placebo 0.004% |
| Dual endothelin receptor antagonists | PRECISION[110] Phase III | Aprocitentan 12.5 or 25 mg for 4 weeks → 25 mg for 32 weeks versus placebo | 36 | Office SBP change | Aprocitentan -3.7 (SE 1.3) mmHg (97.5% CI [-6.8, -0.8]; p=0.0042) versus placebo both at the 12.5 and 25 mg doses | Mild to moderate fluid retention in the aprocitentan 25 mg arm leading 7 patients to discontinue treatment |
| Inhibitors of aldosterone synthase | BrigHTN[113] Phase II | Baxdrostat 0.5, 1, or 2 mg versus placebo | 12 | Office SBP change | Baxdrostat 0.5 mg -12.1 mmHg; baxdrostat 1.0 mg -17.5 mmHg; baxdrostat 2 mg -20.3 mmHg; placebo -9.4 mmHg | Hyperkalaemia in 2 patients on baxdrostat (not recurring after stopping the drug) |
| Target-HTN[116] Phase II | Lorundrostat 12.5, 50, or 100 mg once daily, or 12.5 or 25 mg twice daily versus placebo | 8 | Office SBP change | Lorundrostat 100 mg once daily -14.1 mmHg; 50 mg once daily -13.2 mmHg; 25 mg twice daily -10.1 mmHg; 12.5 mg twice daily 13.8 mmHg; 12.5 mg once daily -6.9 mmHg; placebo -4.1 mmHg | Hyperkalaemia in 6 patients on lorundrostat (not recurring after stopping the drug) | |
| RNA interference therapeutic agent inhibiting hepatic angiotensinogen synthesis | KARDIO-1[117] Phase I | Zilebesiran 150, 300 or 600 mg every 6 months versus Zilebesiran 300 mg every 3 months versus placebo | 24 | Mean 24 h BP change | -14.1 mmHg with the 150 mg dose, -16.7 mmHg with the 300 mg dose, and -15.7 mmHg with the 600 mg dose | Transient local injection site reactions Transient rise in serum potassium levels |
ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin receptor blocker; BP = blood pressure; MRA = mineralocorticoid receptor antagonist; SBP = systolic blood pressure.