How is Baxdrostat used in treating resistant hypertension?

Baxdrostat in Resistant Hypertension Management

Baxdrostat is a novel aldosterone synthase inhibitor that significantly reduces blood pressure in patients with resistant hypertension, with recent phase 3 trial data showing placebo-corrected systolic blood pressure reductions of 8.7-9.8 mmHg when added to existing antihypertensive regimens. 1

Mechanism and Clinical Evidence

Baxdrostat works by selectively inhibiting aldosterone synthase, the enzyme that controls aldosterone production. This selectivity is crucial as it:

• Demonstrates 100:1 selectivity for aldosterone synthase over similar enzymes involved in cortisol synthesis 2
• Reduces plasma aldosterone levels without affecting cortisol levels 2
• Targets a key pathophysiological mechanism in resistant hypertension, as aldosterone dysregulation plays an important role in hard-to-control hypertension 1

Efficacy Data

The most recent and highest quality evidence comes from a phase 3 multinational trial (BaxHTN) that demonstrated:

• At 12 weeks, 1mg baxdrostat reduced systolic BP by 14.5 mmHg and 2mg baxdrostat reduced it by 15.7 mmHg (versus 5.8 mmHg with placebo) 1
• Placebo-corrected differences were -8.7 mmHg with 1mg and -9.8 mmHg with 2mg (p<0.001 for both) 1

This builds on earlier phase 2 data (BrigHTN trial) that showed dose-dependent reductions in systolic blood pressure:

• 2mg: -20.3 mmHg
• 1mg: -17.5 mmHg
• 0.5mg: -12.1 mmHg
• Placebo: -9.4 mmHg 2

Clinical Application in Resistant Hypertension

When to Consider Baxdrostat

According to the 2024 ESC Guidelines, baxdrostat should be considered in the context of resistant hypertension management when:

1. Blood pressure remains uncontrolled despite:

   • Appropriate lifestyle modifications
   • Concurrent use of at least three antihypertensive agents from different classes at optimal doses, including a diuretic 3, 4

2. After mineralocorticoid receptor antagonists (MRAs) like spironolactone have been tried, as these remain the recommended fourth-line agents 3, 4, 5

Treatment Algorithm for Resistant Hypertension

1. First ensure true resistant hypertension:

   • Exclude medication nonadherence, white coat hypertension, secondary hypertension
   • Confirm with out-of-office BP measurements
   • Rule out interfering substances (especially NSAIDs) 4

2. Optimize current therapy:

   • Ensure patient is on maximum tolerated doses of:
     • ACE inhibitor or ARB
     • Long-acting calcium channel blocker
     • Thiazide-like diuretic 4, 5
   • Consider single-pill combinations to improve adherence

3. Add fourth-line agent:

   • Spironolactone remains the preferred fourth agent (Class IIa recommendation) 3, 4, 5
   • If spironolactone is not tolerated or contraindicated:
     • Consider eplerenone, amiloride, doxazosin, or beta-blockers 4, 5

4. Consider newer agents like baxdrostat:

   • When conventional options fail to achieve target BP
   • Particularly in patients with evidence of aldosterone dysregulation 3

Safety Considerations

Baxdrostat has shown a generally favorable safety profile:

• No deaths or serious adverse events attributed to baxdrostat in clinical trials 2
• No instances of adrenocortical insufficiency 2
• Main safety concern is hyperkalemia:
  • Potassium levels >6.0 mmol/L occurred in 2.3% of patients on 1mg and 3.0% on 2mg (versus 0.4% with placebo) 1
  • Monitor serum potassium levels, particularly when adding to regimens containing RAS blockers 4

Current Status and Future Directions

Baxdrostat is still investigational and awaits supportive evidence from cardiovascular outcomes trials for guideline endorsement and routine use in hypertension 3. The 2024 ESC guidelines specifically mention baxdrostat as a novel aldosterone synthase inhibitor that has "significantly lowered BP in patients with uncontrolled hypertension in phase 2 trials" 3.

It's worth noting that while the BrigHTN trial showed promising results, another trial (HALO) did not demonstrate blood pressure-lowering benefits compared to placebo 6, 7. However, the most recent phase 3 BaxHTN trial has shown significant efficacy 1.

Conclusion

Baxdrostat represents a promising new approach for resistant hypertension through selective aldosterone synthase inhibition. While not yet approved for routine clinical use, recent phase 3 data supports its efficacy in reducing blood pressure in patients with resistant hypertension. As with any new agent, careful patient selection and monitoring will be essential when this medication becomes available for clinical use.