Optimizing Hypertension Treatment: Evidence-Based Approaches & New Drugs
Optimizing Hypertension Treatment: Evidence-Based Approaches & New Drugs
Source: Cleveland Clinic Journal of Medicine — Review
Date: September 2025 •
1. Big picture
• BP control is still poor worldwide (~21% controlled).
• Main causes: weak prevention policies, non-adherence, and therapeutic inertia (not intensifying when BP stays high).
• Start with single-pill combinations when possible; they hit targets faster and keep BP controlled longer.
2. First-line strategy (most adults)
• Begin combination therapy:
• ACEi/ARB + CCB (preferred combo), or
• *ACEi/ARB + thiazide/thiazide-like diuretic.
• Use single-pill formats to improve adherence.
3. Case 1 (new HTN, high CV risk: T2D, obesity) — What to start?
• Best: ACEi/ARB + CCB (amlodipine) in one pill + lifestyle.
• Why not ACEi + thiazide as first choice?
• ACCOMPLISH trial: benazepril+amlodipine reduced CV events more than benazepril+HCTZ despite similar BP.
• Message: in high-risk patients, ACEi/ARB + CCB is a strong, evidence-based start.
4. Combination vs monotherapy
• No head-to-head RCTs of “start mono then up-titrate” vs “start combo,” but multiple studies show:
• Faster target attainment, better long-term control, greater BP fall with initial combo.
5. Guideline harmony (US vs Europe)
• Both: support initial combinations (low/moderate doses).
• US: especially for stage 2 HTN, BP ≥20/10 above target, and many Black adults.
• Europe: combo for most patients.
• Practical nuance for many Black patients: thiazide/CCB respond well; ACEi/ARB monotherapy is often less effective.
6. Case 2 (well-controlled on ACEi+HCTZ, post-MI) — Change anything?
• No change: stay on current regimen if BP and risk are controlled.
• Diuretic Comparison Project: switching HCTZ→chlorthalidone did not improve major outcomes in already-controlled patients.
7. Case 3 (uncontrolled on ARB+CCB) — What to add?
• Add chlorthalidone (more potent and longer half-life than HCTZ).
• Why not low-dose HCTZ? Less BP-lowering than chlorthalidone at comparable doses.
• Monitor K+ and renal function (risk of hypokalaemia).
8. Chlorthalidone vs HCTZ — quick facts
• Half-life: chlorthalidone 40–60 h vs HCTZ 6–9 h.
• Potency: chlorthalidone roughly 1.5–2× HCTZ.
• Safety: both can lower K+; chlorthalidone may do so more → monitor electrolytes.
9. Case 4 (apparent resistant HTN on ACEi/CCB/thiazide) — First step
• Tackle lifestyle + confirm adherence (salt restriction, weight, activity, simplify to single-pill combos, reminders).
• Screen for obstructive sleep apnoea if suggested by history.
• “Apparent” resistance is often pseudo-resistance (non-adherence, white-coat, suboptimal regimen).
10. Case 4 (true resistant HTN after optimisation) — Fourth drug
• Add spironolactone (best 4th drug per PATHWAY-2; superior to doxazosin/bisoprolol/placebo).
• If side effects or concern: consider eplerenone or indapamide as alternatives (clinical judgement).
11. Case 5 (uncontrolled + hypokalaemia) — Think primary aldosteronism
• Clues: HTN + low K+, sometimes metabolic alkalosis, even if on ACEi/CCB/thiazide.
• Next step: measure plasma aldosterone and renin (or direct renin) → ARR screening.
• If positive, confirm (e.g., saline infusion) and consider targeted therapy.
12. Adherence — the quiet giant
• Up to ~46% non-adherence in apparent resistant HTN (objective testing).
• Improve by: single-pill combos, once-daily dosing, minimise cost, manage side effects, and use reminders/pillboxes.
13. New/emerging therapies (for difficult HTN)
• Aprocitentan (endothelin receptor antagonist): modest SBP reduction in resistant HTN; benefit sustained, relapse on withdrawal.
• Aldosterone synthase inhibitors:
• Lorundrostat: phase 2 shows ~8–11 mmHg SBP drop (dose-dependent).
• Baxdrostat: dose-related SBP fall up to ~20 mmHg at 12 weeks; no adrenal insufficiency signals reported.
• Zilebesiran (siRNA vs angiotensinogen): single SC injection; durable BP lowering (up to 24 weeks in early data); KARDIA-2 shows add-on benefit to standard drugs.
• Tirzepatide (dual GIP/GLP-1 RA): in obesity, weight loss drove ~7–8 mmHg SBP reduction; useful for metabolic syndrome–related HTN.
14. Practical “how-to” for the clinic
• Start combo therapy early; prefer single-pill formats.
• If uncontrolled on ARB/ACEi + CCB, add chlorthalidone (or indapamide).
• If still uncontrolled (true resistance): add spironolactone.
• If hypokalaemia or resistant features: screen for primary aldosteronism.
• Always address lifestyle + adherence before escalating.
15. Safety & monitoring
• Check K+ and creatinine after starting or changing ACEi/ARB/MRA (1–2 weeks), then every 3–6 months when stable.
• Watch for hypokalaemia with thiazides/chlorthalidone; hyperkalaemia with MRAs/RAAS blockade.
• Reassess every 3–6 months; escalate promptly if above target.
