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Pharmacological therapy

TL;DR — For a given pressure reduction the major first-line classes deliver broadly similar outcome benefit, and the choices that matter most are how many drugs, started when, in one pill or several, not which molecule. ALLHAT randomised 33,357 people to chlorthalidone, amlodipine or lisinopril and found identical primary outcomes (RR 0.98 and 0.99 versus chlorthalidone), with chlorthalidone superior on heart failure versus amlodipine (RR 1.38 for amlodipine, 95% CI 1.25–1.52) and on several endpoints versus lisinopril (ALLHAT 2002, PMID 12479763). Cochrane's first-line review gives low-dose thiazides high-quality evidence for reducing mortality (RR 0.89, 95% CI 0.82–0.97), stroke (0.68, 0.60–0.77), coronary heart disease (0.72, 0.61–0.84) and total cardiovascular events (0.70, 0.64–0.76); β-blockers reduced stroke and total events but not mortality or coronary disease, and were inferior to low-dose thiazides (Wright 2018, PMID 29667175). Two departures from "any class will do" are well supported: ACCOMPLISH found an ACE-inhibitor-plus-amlodipine combination superior to ACE-inhibitor-plus-hydrochlorothiazide (HR 0.80, 95% CI 0.72–0.90) (Jamerson 2008, PMID 19052124), and starting with low-dose combination rather than monotherapy improves control substantially (Webster 2018, PMID 30120478; Chow 2021, PMID 34469767). Chronotherapy, once claimed to halve cardiovascular risk, was neutral in the 21,104-participant TIME trial (Mackenzie 2022, PMID 36240838).

First-line classes: what the evidence supports

Class Mortality Stroke CHD Total CV events Withdrawal for AEs vs control Certainty
Low-dose thiazide RR 0.89 (0.82–0.97) 0.68 (0.60–0.77) 0.72 (0.61–0.84) 0.70 (0.64–0.76) RR 2.38 (2.06–2.75) High
High-dose thiazide 0.90 (0.76–1.05), ns 0.47 (0.37–0.61) 1.01 (0.85–1.20), ns 0.72 (0.63–0.82) RR 4.48 (3.83–5.24) Low–moderate
β-blocker 0.96 (0.86–1.07), ns 0.83 (0.72–0.97) 0.90 (0.78–1.03), ns 0.89 (0.81–0.98) RR 4.59 (4.11–5.13) Low–moderate
ACE inhibitor 0.83 (0.72–0.95) 0.65 (0.52–0.82) 0.81 (0.70–0.94) 0.76 (0.67–0.85) Not reported Low–moderate
Calcium channel blocker 0.86 (0.68–1.09), ns 0.58 (0.41–0.84) 0.77 (0.55–1.09), ns 0.71 (0.57–0.87) Not reported Low
ARB No placebo-controlled first-line RCTs identified — — — — —

All values from (Wright 2018, PMID 29667175). Companion Cochrane reviews cover diuretics versus other classes (Reinhart 2023, PMID 37439548), calcium channel blockers versus other classes (Zhu 2022, PMID 35000192) and β-blockers specifically (Wiysonge 2017, PMID 28107561; Bradley 2006, PMID 17053529).

The β-blocker result is the field's clearest class-level demotion: they lower pressure but under-deliver on stroke relative to comparators, and are no longer recommended as routine first-line therapy without a compelling indication (Wiysonge 2017, PMID 28107561). LIFE gave the mechanism-agnostic version: for equal pressure reduction (30.2/16.6 vs 29.1/16.8 mm Hg), losartan beat atenolol on the composite (RR 0.87, 95% CI 0.77–0.98) driven almost entirely by stroke (0.75, 0.63–0.89), with no difference in myocardial infarction and less new-onset diabetes (Dahlöf 2002, PMID 11937178; Kjeldsen 2002, PMID 12243636; Okin 2003, PMID 12885747).

Head-to-head trials worth knowing

Trial n Comparison Result
ALLHAT (PMID 12479763) 33,357 Chlorthalidone vs amlodipine vs lisinopril Primary CHD outcome identical; amlodipine more heart failure (RR 1.38); lisinopril more combined CVD (1.10), stroke (1.15), heart failure (1.19)
ACCOMPLISH (PMID 19052124) 11,506 Benazepril+amlodipine vs benazepril+HCTZ Composite 9.6% vs 11.8%, HR 0.80 (0.72–0.90); stopped early
LIFE (PMID 11937178) 9,193 Losartan vs atenolol, with ECG LVH Composite RR 0.87 (0.77–0.98); stroke 0.75 (0.63–0.89)
VALUE (PMID 15207952) 15,245 Valsartan- vs amlodipine-based Composite HR 1.04 (0.94–1.15), ns; amlodipine lowered pressure faster early (4.0/2.1 mm Hg at 1 month)
ONTARGET (PMID 18378520) — Telmisartan vs ramipril vs both Dual RAS blockade added harm without benefit
Diuretic Comparison Project (PMID 36516076) 13,523 Chlorthalidone vs hydrochlorothiazide, pragmatic, age ≥65 Primary composite 10.4% vs 10.0%, HR 1.04 (0.94–1.16); hypokalaemia 6.0% vs 4.4%

VALUE is the clearest demonstration that "unequal blood-pressure reduction explains apparent class differences": amlodipine lowered pressure faster and the composite outcome did not differ, which the investigators interpreted as evidence for prompt control rather than for a superior class (Julius 2004, PMID 15207952).

Chlorthalidone versus hydrochlorothiazide was the longest-running unsettled question in this space. Observational and network meta-analytic work favoured chlorthalidone on pressure, left ventricular mass and events (Roush 2012, PMID 22526259; Roush 2015, PMID 25733245; Roush 2021, PMID 33470735; Dhalla 2013, PMID 23552325). The Diuretic Comparison Project — a pragmatic randomised trial embedded in the electronic health record, 13,523 veterans aged ≥65 already on hydrochlorothiazide — found no difference (HR 1.04, 95% CI 0.94–1.16) with more hypokalaemia on chlorthalidone (Ishani 2022, PMID 36516076). Per-protocol, kidney-outcome and post-MI/stroke secondary analyses are consistent (Anand 2026, PMID 41614323; Ishani 2024, PMID 39656458; Ishani 2024, PMID 38743423), though the trial's design — switching people already tolerating hydrochlorothiazide — limits inference about de novo choice. Observational comparisons continue (Lim 2025, PMID 39957722; Song 2024, PMID 39484134).

Combination-first strategy

The strongest recent evidence is about strategy, not molecule.

  • TRIUMPH. 700 adults in Sri Lanka randomised to a once-daily triple pill (telmisartan 20 mg, amlodipine 2.5 mg, chlorthalidone 12.5 mg) versus usual care: target attainment at 6 months 70% vs 55% (risk difference 12.7%, 95% CI 3.2–22.0); mean pressure 125/76 vs 134/81 mm Hg; withdrawal for adverse events 6.6% vs 6.8% (Webster 2018, PMID 30120478). Secondary analyses show reduced therapeutic inertia and more time at target (Wang 2020, PMID 32717045; Gnanenthiran 2022, PMID 35416909).
  • QUARTET. 591 Australian adults randomised to a quarter-dose quadpill (irbesartan 37.5, amlodipine 1.25, indapamide 0.625, bisoprolol 2.5 mg) versus irbesartan 150 mg: systolic pressure 6.9 mm Hg lower at 12 weeks (95% CI 4.9–8.9), control 76% vs 58% (RR 1.30, 1.15–1.47), and at 52 weeks still 7.7 mm Hg lower with control 81% vs 62%; no difference in withdrawal for adverse events (Chow 2021, PMID 34469767). The concept was established in a placebo-controlled crossover trial (Chow 2017, PMID 28190578), replicated in the US (Huffman 2024, PMID 38584159), confirmed on ambulatory monitoring (Nolde 2024, PMID 38501351) and pooled (Marschner 2025, PMID 41419232). Meta-analyses of ultra-low-dose quadruple and low-dose triple combinations agree (Abuelazm 2023, PMID 37902939; Elgendy 2025, PMID 39912900), and participants' own views have been studied (Kovoor 2024, PMID 38744907).
  • Single-pill combinations more generally improve adherence and control versus free combinations, and head-to-head single-pill comparisons exist (Mancia 2015, PMID 25380149; Jadhav 2014, PMID 24714044; Ahn 2026, PMID 41717679; Kim 2026, PMID 41915114).

Chronotherapy — a corrected literature

The Hygia Chronotherapy Trial reported that bedtime dosing nearly halved cardiovascular risk (Hermida 2020, PMID 31641769), a result that would have been the largest single effect in modern hypertension therapeutics. The European Heart Journal issued an Expression of Concern about the paper (PMID 32318736), and the investigators published rebuttals (Crespo 2020, PMID 32684071; Hermida 2020, PMID 32684008; Fernández 2020, PMID 32684004). The definitive test came from TIME: 21,104 UK adults randomised to evening versus morning dosing of usual antihypertensives, median 5.2 years, primary endpoint 3.4% vs 3.7% (unadjusted HR 0.95, 95% CI 0.83–1.10, p=0.53), with no safety signal (Mackenzie 2022, PMID 36240838). The practical conclusion is that timing can be chosen for tolerability and adherence. This sequence is a useful case study in how a large single-centre effect estimate should be handled before practice changes.

Beyond first-line: fourth-drug and new mechanisms

  • Spironolactone is the evidence-based fourth agent: in PATHWAY-2's double-blind crossover of 335 patients with resistant hypertension, home systolic pressure fell 8.70 mm Hg (95% CI 7.69–9.72) more than placebo and 4.26 mm Hg (3.38–5.13) more than the average of bisoprolol and doxazosin; superiority was greatest at low plasma renin, and potassium exceeded 6.0 mmol/L on one occasion in 6 of 285 (Williams 2015, PMID 26414968; mechanisms substudy Williams 2018, PMID 29655877). See resistant and refractory hypertension.
  • Aldosterone synthase inhibitors. Baxdrostat reduced pressure in phase 2 (Freeman 2023, PMID 36342143) and phase 3 in uncontrolled and resistant hypertension (Flack 2025, PMID 40888730), with ambulatory confirmation (Azizi 2026, PMID 41794437), CKD data (Dwyer 2026, PMID 40913594) and a first approval (Blair 2026, PMID 42625106). Lorundrostat has phase 2 and phase 3 data (Laffin 2023, PMID 37690061; Laffin 2025, PMID 40267417; Saxena 2025, PMID 40587141).
  • Endothelin antagonism. Aprocitentan lowered pressure in PRECISION, a phase 3 trial in resistant hypertension (Schlaich 2022, PMID 36356632), with subsequent data in Black patients (Flack 2025, PMID 39840441) and in chronic kidney disease (Rossignol 2026, PMID 41363010); it received its first approval in 2024 (Dhillon 2024, PMID 38833193).
  • RNA interference. Zilebesiran, a hepatocyte-targeted siRNA against angiotensinogen, produced dose-dependent, months-long pressure reduction after a single dose in phase 1 (Desai 2023, PMID 37467498), confirmed in KARDIA-1 (Bakris 2024, PMID 38363577) and as add-on therapy in KARDIA-2 (Desai 2025, PMID 40434761).
  • RAAS modulators generally have been compared in network meta-analysis (Yi 2024, PMID 39312177).

See clinical trials landscape for registered trials and phases.

Adverse effects that change practice

Class Principal issues
Thiazide-type diuretics Hypokalaemia (6.0% vs 4.4% chlorthalidone vs HCTZ) (Ishani 2022, PMID 36516076), hyponatraemia, hyperuricaemia, glucose intolerance (Black 2008, PMID 18000186); high withdrawal rate versus placebo (Wright 2018, PMID 29667175)
ACE inhibitors Cough, angio-oedema, hyperkalaemia, acute eGFR fall; contraindicated in pregnancy
ARBs As ACE inhibitors without cough; contraindicated in pregnancy
Calcium channel blockers Peripheral oedema, more heart failure than chlorthalidone in ALLHAT (RR 1.38) (ALLHAT 2002, PMID 12479763)
β-blockers Fatigue, high withdrawal rate, new-onset diabetes (more than losartan in LIFE) (Dahlöf 2002, PMID 11937178)
Dual RAS blockade Hypotension, syncope, renal dysfunction without outcome benefit (ONTARGET 2008, PMID 18378520)
Mineralocorticoid receptor antagonists Hyperkalaemia; gynaecomastia with spironolactone (Manolis 2019, PMID 30826898)

A systematic review and meta-analysis of antihypertensive treatment and adverse events puts the overall harm profile in context (Albasri 2021, PMID 33568342). See red flags and safety concerns.

Special-population modifiers

Effect and choice change by population — Black patients (ALLHAT subgroup: Wright 2005, PMID 15811979; review: Sulaica 2020, PMID 32276785), chronic kidney disease and diabetes (Wu 2013, PMID 24157497; Burnier 2023, PMID 37053276), older and frail people, and pregnancy where most classes are contraindicated. These are covered in special populations and hypertension in pregnancy. Sub-Saharan African drug evidence has been assembled separately because it is thin (Seeley 2020, PMID 32216794).

Open questions

  • The Diuretic Comparison Project randomised people already tolerating hydrochlorothiazide. Does chlorthalidone remain preferable as an initial choice, where the pharmacology arguments still apply? (Ishani 2022, PMID 36516076; Roush 2021, PMID 33470735)
  • ACCOMPLISH's superiority of amlodipine over hydrochlorothiazide as the ACE-inhibitor partner has not been replicated with chlorthalidone as the diuretic comparator; the 2026-09-01 PubMed and ClinicalTrials.gov searches located no benazepril–amlodipine versus benazepril–chlorthalidone outcome trial (Jamerson 2008, PMID 19052124).
  • Quarter-dose quadruple therapy improves control substantially — does it improve hard outcomes, and does the fourth (β-blocker) component earn its place given class-level evidence? (Chow 2021, PMID 34469767; Wiysonge 2017, PMID 28107561)
  • No placebo-controlled first-line trial of ARBs exists, so their first-line status rests entirely on indirect comparison (Wright 2018, PMID 29667175).
  • Will aldosterone synthase inhibitors and angiotensinogen siRNA show outcome benefit proportional to their pressure effect, or does mechanism matter beyond pressure? (Flack 2025, PMID 40888730; Desai 2025, PMID 40434761)

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