Amlodipine

References

1. Regulator

   US Food and Drug Administration. NORVASC (amlodipine besylate) tablets for oral administration: full prescribing information US Food and Drug Administration, NDA 019787 supplement 062, label revised October 2017, 2017.

   https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/019787s062lbl.pdf

   Funding and finding

   Funding

   US Food and Drug Administration

   Finding

   Indications: hypertension, chronic stable angina, vasospastic angina, and angiographically documented coronary artery disease without heart failure or an ejection fraction below 40%. Lowering blood pressure reduces the risk of fatal and non-fatal cardiovascular events, primarily strokes and myocardial infarctions, and the absolute risk increase per mm Hg is greater at higher blood pressures. Mechanism: a dihydropyridine calcium antagonist that inhibits the transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle, selectively and with a greater effect on vascular smooth muscle than on cardiac muscle; within the physiological pH range it is ionised (pKa 8.6) and its kinetic interaction with the calcium channel receptor is characterised by a gradual rate of association and dissociation, resulting in a gradual onset of effect; a peripheral arterial vasodilator that reduces peripheral vascular resistance; serum calcium concentration is not affected; sinoatrial nodal function and atrioventricular conduction are not changed. Dose: 5 mg once daily initially and 10 mg once daily at most; 2.5 mg once daily in small, fragile or elderly patients or in hepatic insufficiency; 7 to 14 days between titration steps. Pharmacokinetics: peak plasma concentrations 6 to 12 hours after a dose; absolute bioavailability 64 to 90%, unaltered by food; about 93% bound to plasma proteins; about 90% converted to inactive metabolites by hepatic metabolism, with 10% of the parent compound and 60% of the metabolites excreted in urine; terminal elimination half-life about 30 to 50 hours; steady state after 7 to 8 days of daily dosing; kinetics not significantly influenced by renal impairment; AUC about 40 to 60% higher in elderly patients, in hepatic insufficiency and in moderate to severe heart failure; half-life 56 hours with impaired hepatic function. Effect: in 15 double-blind placebo-controlled randomised studies in 800 patients on amlodipine and 538 on placebo, placebo-corrected reductions 24 hours after the dose averaged 12/6 mm Hg standing and 13/7 mm Hg supine in mild to moderate hypertension, with little difference between peak and trough. Oedema was dose related: 1.8% at 2.5 mg (n=275), 3.0% at 5 mg (n=296) and 10.8% at 10 mg (n=268) against 0.6% with placebo (n=520); oedema occurred in 14.6% of 512 women and 5.6% of 1218 men on amlodipine against 5.1% and 1.4% on placebo; discontinuation for adverse reactions about 1.5% against about 1% with placebo. Warnings: symptomatic hypotension is possible, particularly with severe aortic stenosis; worsening angina and acute myocardial infarction can develop after starting or increasing the dose, particularly with severe obstructive coronary artery disease. Interactions: diltiazem 180 mg daily raised amlodipine exposure by 60% in elderly hypertensive patients, and strong CYP3A inhibitors such as itraconazole and clarithromycin may raise plasma concentrations further, while cimetidine, antacids, sildenafil and grapefruit juice have no impact; amlodipine is a weak CYP3A inhibitor and 10 mg raised exposure to 80 mg simvastatin by 77%, so simvastatin is limited to 20 mg daily; trough cyclosporine rose by an average of 40% in 11 renal transplant recipients; tacrolimus exposure rose 2.5-fold to 4-fold in 9 healthy CYP3A5 expressers and did not change in 6 non-expressers. In the CAMELOT trial of 1318 patients with coronary artery disease followed for a mean 19 months, first events of the composite endpoint occurred in 110 of 663 (16.6%) on amlodipine against 151 of 655 (23.1%) on placebo, hazard ratio 0.691 (95% CI 0.540 to 0.884, p=0.003), driven by hospitalisation for angina (51, 7.7% against 84, 12.8%) and coronary revascularisation (78, 11.8% against 103, 15.7%).

2. Regulator

   US Food and Drug Administration (labelling submitted by Viatris Specialty LLC). NORVASC (amlodipine besylate) tablets for oral administration: full prescribing information US Food and Drug Administration-approved labelling, published in DailyMed (National Library of Medicine); structured product label version 10, published 10 December 2025, label text revised 2/2023, 2025.

   https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=7367289c-b0b0-466a-83e2-558e2985c29f

   Funding and finding

   Funding

   not stated; FDA-approved labelling carries no funding statement

   Finding

   Initial US approval 1992. Contraindication: known sensitivity to amlodipine only; the label carries no boxed warning. Warnings and precautions: symptomatic hypotension is possible, particularly with severe aortic stenosis, although acute hypotension is unlikely because of the gradual onset; worsening angina and acute myocardial infarction can develop after starting or increasing the dose, particularly with severe obstructive coronary artery disease; titrate slowly in severe hepatic impairment, because the plasma elimination half-life is 56 hours in patients with impaired hepatic function. Placebo-controlled trials (amlodipine n=1730, placebo n=1250): discontinuation for adverse reactions about 1.5% against about 1%; dose-related oedema 1.8% (2.5 mg, n=275), 3.0% (5 mg, n=296) and 10.8% (10 mg, n=268) against 0.6% (placebo, n=520); palpitation 0.7%, 1.4% and 4.5% against 0.6%; flushing 0.7%, 1.4% and 2.6% against 0.0%; oedema 14.6% of 512 women and 5.6% of 1218 men against 5.1% and 1.4% on placebo. Events in fewer than 1% but more than 0.1% of patients in controlled or open trials or marketing experience, causal relationship uncertain, include arrhythmia (including ventricular tachycardia and atrial fibrillation), bradycardia, syncope, vasculitis, peripheral neuropathy, tremor, constipation, dysphagia, pancreatitis, gingival hyperplasia, angioedema, erythema multiforme, depression, sexual dysfunction, nocturia, micturition frequency, hyperglycaemia, leukopenia, purpura and thrombocytopenia. Postmarketing: gynaecomastia; jaundice and hepatic enzyme elevations, mostly consistent with cholestasis or hepatitis, in some cases severe enough to require hospitalisation; a possible association with extrapyramidal disorder. Interactions: moderate and strong CYP3A inhibitors increase amlodipine exposure (diltiazem 180 mg raised it by 60% in elderly patients; erythromycin did not change it significantly in healthy volunteers; itraconazole and clarithromycin may raise it further); monitor for hypotension and oedema; no quantitative information on CYP3A inducers; monitor for hypotension with sildenafil; amlodipine is a weak CYP3A inhibitor, raised simvastatin exposure by 77% at 80 mg so simvastatin is limited to 20 mg daily, raised trough ciclosporin by an average 40% in 11 renal transplant patients and tacrolimus exposure 2.5-fold to 4-fold in 9 CYP3A5 expressers, with a 3-fold rise reported in one CYP3A5 non-expresser; cimetidine, antacids, sildenafil and grapefruit juice had no impact on amlodipine exposure. Pharmacodynamics: negative inotropic effects can be detected in vitro but have not been seen in intact animals at therapeutic doses; no change in sinoatrial nodal function or atrioventricular conduction in intact animals or man; serum calcium is not affected. Clinical studies of NORVASC did not include sufficient numbers of patients aged 65 or over to determine whether they respond differently; clearance falls in elderly patients, raising AUC by about 40 to 60%. Overdose may cause excessive peripheral vasodilation with marked hypotension and possibly reflex tachycardia; human experience with intentional overdose is limited; haemodialysis is not likely to help because the drug is highly protein bound. Pregnancy: post-marketing data insufficient to inform drug-associated risk; in rats a dose about 10 times the maximum human dose halved litter size, raised intrauterine deaths about 5-fold and prolonged gestation and labour. Lactation: median relative infant dose 4.2%. Heart failure: in a placebo-controlled study of 1153 patients with NYHA class III or IV heart failure (mean 13.8 months) the combined end point occurred in 222 of 571 (39%) on amlodipine and 246 of 583 (42%) on placebo; in PRAISE-2 (827 against 827 patients with non-ischaemic NYHA III or IV heart failure, mean 33 months) all-cause mortality did not differ (95% confidence limits from an 8% reduction to a 29% increase) and there were more reports of pulmonary oedema with amlodipine.

3. Independent research

   Albasri A, Hattle M, Koshiaris C, Dunnigan A, Paxton B, Fox SE, et al.; STRATIFY investigators. Association between antihypertensive treatment and adverse events: systematic review and meta-analysis BMJ, 2021.

   doi:10.1136/bmj.n189PubMed 33568342

   Funding and finding

   Registration

   PROSPERO CRD42018116860

   Participants

   280,638

   Follow-up

   median 3 years (IQR 2 to 4)

   Funding

   This study was funded by the Wellcome Trust and Royal Society through a Sir Henry Dale fellowship held by JPS (ref 211182/Z/18/Z) and the National Institute for Health Research (NIHR) School for Primary Care (project 430), with further NIHR, Fonds de recherche du Québec - Santé and Cancer Research UK fellowships. The sponsor and funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

   Finding

   Antihypertensive treatment was associated with acute kidney injury (risk ratio 1.18, 95% CI 1.01 to 1.39; 15 trials), hyperkalaemia (1.89, 1.56 to 2.30; 26 trials), hypotension (1.97, 1.67 to 2.32; 35 trials) and syncope (1.28, 1.03 to 1.59; 16 trials); seven trials reporting falls showed no association (1.05, 0.89 to 1.24). Treatment was associated with lower all-cause mortality, cardiovascular death and stroke but not myocardial infarction. The authors state that adverse events such as fatigue or sexual dysfunction lack standardised definitions, that some events may be captured but not reported, that hazard ratios for harms were rarely reported, and that trials often select less frail, less multimorbid populations more likely to tolerate treatment, so fewer adverse events may be reported than would occur in the general population.

4. Regulator

   European Medicines Agency (marketing authorisation holder Novartis Europharm Limited). Exforge (amlodipine/valsartan): EPAR product information, Annex I summary of product characteristics European Medicines Agency, European public assessment report, product information; PDF created 16 September 2025, modified 12 November 2025, 2025.

   https://www.ema.europa.eu/en/documents/product-information/exforge-epar-product-information_en.pdf

   Funding and finding

   Funding

   not stated; EU product information carries no funding statement

   Finding

   Contraindications include hypersensitivity to dihydropyridine derivatives, severe hypotension, shock including cardiogenic shock, obstruction of the left ventricular outflow tract (for example hypertrophic obstructive cardiomyopathy and high-grade aortic stenosis) and haemodynamically unstable heart failure after acute myocardial infarction. Warnings: safety and efficacy of amlodipine in hypertensive crisis are not established; in PRAISE-2 amlodipine in NYHA III and IV heart failure of non-ischaemic aetiology was associated with increased reports of pulmonary oedema despite no significant difference in worsening heart failure; calcium channel blockers, including amlodipine, should be used with caution in congestive heart failure, as they may increase the risk of future cardiovascular events and mortality; special caution with mitral stenosis or significant aortic stenosis that is not high grade. Interactions linked to amlodipine: grapefruit or grapefruit juice is not recommended because bioavailability may increase in some patients; strong or moderate CYP3A4 inhibitors (protease inhibitors, azole antifungals, erythromycin, clarithromycin, verapamil, diltiazem) may significantly increase exposure, with clinical effects possibly more pronounced in the elderly; CYP3A4 inducers (carbamazepine, phenobarbital, phenytoin, fosphenytoin, primidone, rifampicin, Hypericum perforatum) may alter plasma concentration; simvastatin limited to 20 mg daily (77% exposure increase at 80 mg); risk of increased tacrolimus levels; in animals lethal ventricular fibrillation and cardiovascular collapse with hyperkalaemia followed verapamil and intravenous dantrolene, so co-administration of calcium channel blockers such as amlodipine is to be avoided in people susceptible to malignant hyperthermia and in its management. Pregnancy: safety not established; use only when no safer alternative exists. Breastfeeding: infant dose interquartile range 3 to 7% of the maternal dose, maximum 15%. Fertility: reversible biochemical changes in the head of spermatozoa reported in some patients treated with calcium channel blockers; in one rat study a dose comparable to the human dose for 30 days lowered follicle-stimulating hormone, testosterone, sperm density and mature spermatid and Sertoli cell numbers. Amlodipine adverse reactions by frequency: common somnolence, dizziness, headache, palpitations, flushing, abdominal pain, nausea, ankle swelling, oedema, fatigue; uncommon depression, mood changes, insomnia, syncope, hypotension, change of bowel habit, micturition disorder, impotence, gynaecomastia; rare confusion; very rare leukopenia, thrombocytopenia, hyperglycaemia, peripheral neuropathy, myocardial infarction, arrhythmia (including bradycardia, ventricular tachycardia and atrial fibrillation), vasculitis, pancreatitis, gastritis, gingival hyperplasia, hepatitis, intrahepatic cholestasis and jaundice, hepatic enzyme increase mostly consistent with cholestasis, angioedema, erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome, Quincke oedema; not known toxic epidermal necrolysis and extrapyramidal syndrome. Peripheral oedema in double-blind trials: amlodipine 10 mg alone 10.3%, with valsartan 160 mg 9.0% and 320 mg 9.5%; amlodipine 2.5 mg alone 8.0%; placebo 3.0%. Overdose: marked and potentially prolonged systemic hypotension including shock with fatal outcome has been reported; non-cardiogenic pulmonary oedema has rarely been reported after amlodipine overdose, may appear 24 to 48 hours after ingestion and require ventilatory support, and early resuscitative measures including fluid overload may be precipitating factors. Pharmacology: amlodipine does not change sinoatrial nodal function or atrioventricular conduction in intact animals or humans; bioavailability 64 to 80%, about 97.5% protein bound, terminal half-life 30 to 50 hours. ALLHAT (33,357 patients, mean 4.9 years): heart failure 10.2% with amlodipine against 7.7% with chlorthalidone (RR 1.38, 95% CI 1.25 to 1.52); all-cause mortality RR 0.96 (0.89 to 1.02).

5. Independent research

   Zhu J, Chen N, Zhou M, Guo J, Zhu C, Zhou J, et al. Calcium channel blockers versus other classes of drugs for hypertension Cochrane Database of Systematic Reviews, 2022.

   doi:10.1002/14651858.CD003654.pub6PubMed 35000192

   Funding and finding

   Participants

   153,849

   Follow-up

   2 to 5.3 years across the included trials

   Funding

   Internal sources: West China Hospital, Sichuan University, China; the project was supported by the National Key R&D program of China (2018YFC1311400 and 2018YFC1311401). External sources: none. All eight authors declare no competing interests.

   Finding

   All-cause mortality did not differ between first-line calcium channel blockers and any other class. Against diuretics: major cardiovascular events risk ratio 1.05 (95% CI 1.00 to 1.09, P = 0.03) and congestive heart failure 1.37 (1.25 to 1.51), 62 per 1000 against 45 per 1000 over 3 to 5 years, one additional case per 107 treated (71 to 213), 34,072 participants in 5 trials, moderate certainty; all-cause mortality 0.98 (0.92 to 1.04) and stroke 0.94 (0.84 to 1.05). Against beta blockers: major cardiovascular events 0.84 (0.77 to 0.92), stroke 0.77 (0.67 to 0.88), 32 against 41 per 1000, one stroke avoided per 104 treated (69 to 210), 22,249 participants in 3 trials, moderate certainty, and cardiovascular mortality 0.90 (0.81 to 0.99), low certainty. Against ACE inhibitors: stroke 0.90 (0.81 to 0.99), 47 against 52 per 1000, and congestive heart failure 1.16 (1.06 to 1.28), 73 against 63 per 1000, both low certainty. Against angiotensin receptor blockers: myocardial infarction 0.82 (0.72 to 0.94), 29 against 36 per 1000, moderate certainty, and congestive heart failure 1.20 (1.06 to 1.36), 45 against 38 per 1000, low certainty. The authors state that many of the differences are not robust and that further trials might change the conclusions.

6. Independent research

   Gandhi S, Fleet JL, Bailey DG, McArthur E, Wald R, Rehman F, et al. Calcium-channel blocker-clarithromycin drug interactions and acute kidney injury JAMA, 2013.

   doi:10.1001/jama.2013.282426PubMed 24346990

   Funding and finding

   Participants

   190,309

   Follow-up

   30 days after a new antibiotic prescription, 2003 to 2012

   Funding

   This project was conducted at the Institute for Clinical Evaluative Sciences (ICES) Western Site. ICES is funded by an annual grant from the Ontario Ministry of Health and Long-term Care. ICES Western is funded by an operating grant from the Academic Medical Organization of Southwestern Ontario. The project was conducted with members of the ICES Kidney, Dialysis, and Transplantation Research Program, which receives programmatic grant funding from the Canadian Institutes of Health Research. The sponsors had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

   In-kind support

   Brogan Inc provided its drug product and therapeutic class database; Gamma Dynacare its outpatient laboratory database.

   Finding

   Within 30 days, hospitalisation with acute kidney injury occurred in 420 of 96,226 (0.44%) given clarithromycin against 208 of 94,083 (0.22%) given azithromycin: absolute risk increase 0.22% (95% CI 0.16% to 0.27%), odds ratio 1.98 (1.68 to 2.34). Hospitalisation with hypotension 111 (0.12%) against 68 (0.07%), absolute increase 0.04%, OR 1.60 (1.18 to 2.16); all-cause mortality 984 (1.02%) against 555 (0.59%), absolute increase 0.43% (0.35% to 0.51%), OR 1.74 (1.57 to 1.93). By calcium channel blocker, the risk of acute kidney injury was highest with nifedipine (OR 5.33, 3.39 to 8.38; absolute increase 0.63%; number needed to harm 160). The number needed to harm for acute kidney injury was 95 with chronic kidney disease against 723 without. Clarithromycin is a CYP3A4 inhibitor and azithromycin is not.

7. Regulator

   European Medicines Agency, Pharmacovigilance Risk Assessment Committee (PRAC) and Coordination Group for Mutual Recognition and Decentralised Procedures (CMDh). Amlodipine/rosuvastatin, perindopril/amlodipine/rosuvastatin: CMDh scientific conclusions and grounds for variation, amendments to the product information and timetable for the implementation (PSUSA/00010434/202107) European Medicines Agency; CMDh position adopted at the March 2022 meeting, 2022.

   https://www.ema.europa.eu/en/documents/psusa/amlodipine/rosuvastatin-perindopril/amlodipine/rosuvastatin-cmdh-scientific-conclusions-grounds-variation-amendments-product-information-timetable/00010434/202107_en-0.pdf

   Funding and finding

   Funding

   not stated; a regulatory assessment carries no funding statement

   Finding

   In view of literature data on non-cardiogenic pulmonary oedema, spontaneous reports including cases with a compatible temporal relationship and a plausible mechanism of action, the PRAC considers a causal relationship between amlodipine and non-cardiogenic pulmonary oedema at least a reasonable possibility, and the CMDh agrees. New text for section 4.9 of the summary of product characteristics: gross overdosage could result in excessive peripheral vasodilatation and possibly reflex tachycardia; marked and probably prolonged systemic hypotension up to and including shock with fatal outcome has been reported; non-cardiogenic pulmonary oedema has rarely been reported as a consequence of amlodipine overdose, may manifest with a delayed onset 24 to 48 hours after ingestion and require ventilatory support, and early resuscitative measures, including fluid overload, to maintain perfusion and cardiac output may be precipitating factors. The package leaflet is to state that fluid may accumulate in the lungs up to 24 to 48 hours after an overdose. Translations were transmitted on 8 May 2022 and implementation by member states was set for 7 July 2022.

8. Industry-funded

   Packer M, O'Connor CM, Ghali JK, Pressler ML, Carson PE, Belkin RN, et al.; Prospective Randomized Amlodipine Survival Evaluation Study Group. Effect of amlodipine on morbidity and mortality in severe chronic heart failure New England Journal of Medicine, 1996.

   doi:10.1056/NEJM199610103351504PubMed 8813041

   Funding and finding

   Participants

   1,153

   Follow-up

   6 to 33 months

   Funding

   Supported by a grant from Pfizer Central Research. One author (A.B.C.) is listed at Pfizer Central Research, Groton, Connecticut.

   Finding

   Double-blind amlodipine (n=571) against placebo (n=582). The primary end point of death from any cause or hospitalisation for major cardiovascular events occurred in 39% against 42% (9% risk reduction, 95% CI 24% reduction to 10% increase, P=0.31); death in 33% against 38% (16% reduction, 31% reduction to 2% increase, P=0.07). In non-ischaemic cardiomyopathy amlodipine reduced the combined risk by 31% (P=0.04) and death by 46% (P<0.001); no difference in ischaemic heart disease. Peripheral oedema (P<0.001) and pulmonary oedema (P=0.01) occurred more often with amlodipine, the authors putting the risk of pulmonary oedema attributable to amlodipine at 5 percent; worsening renal function 7.7% against 3.6% (P=0.002). Hospitalisation for worsening heart failure 36% against 39%. The authors propose dilatation of pulmonary arterioles, rather than an adverse effect on the heart, as the cause of the pulmonary oedema.

9. Industry-funded

   Packer M, Carson P, Elkayam U, Konstam MA, Moe G, O'Connor C, et al.; PRAISE-2 Study Group. Effect of amlodipine on the survival of patients with severe chronic heart failure due to a nonischemic cardiomyopathy: results of the PRAISE-2 study (Prospective Randomized Amlodipine Survival Evaluation 2) JACC: Heart Failure, 2013.

   doi:10.1016/j.jchf.2013.04.004PubMed 24621933

   Funding and finding

   Participants

   1,654

   Follow-up

   median 33 months

   Funding

   This research was supported by a grant from Pfizer, Inc.

   Finding

   Amlodipine (target 10 mg daily) against placebo: 278 against 262 deaths (hazard ratio 1.09, 95% CI 0.92 to 1.29, p=0.33); cardiovascular death and hospitalisation did not differ significantly. Combined with the non-ischaemic patients of PRAISE, the hazard ratio for death was 0.97 (0.83 to 1.13). Both trials observed more peripheral and pulmonary oedema and less uncontrolled hypertension and chest pain with amlodipine. The authors conclude that amlodipine does not exert favourable effects in heart failure and that striking subgroup benefits call for great caution.

10. Industry-funded

    Agodoa LY, Appel L, Bakris GL, Beck G, Bourgoignie J, Briggs JP, et al.; African American Study of Kidney Disease and Hypertension (AASK) Study Group. Effect of ramipril vs amlodipine on renal outcomes in hypertensive nephrosclerosis: a randomized controlled trial JAMA, 2001.

    doi:10.1001/jama.285.21.2719PubMed 11386927

    Funding and finding

    Participants

    1,094

    Follow-up

    interim analysis at 3 years; enrolment February 1995 to September 1998

    Funding

    Study drugs and some financial support were provided by Pfizer Inc, Astra-Zeneca Pharmaceuticals, and King Pharmaceuticals Inc. In addition to funding under a cooperative agreement from National Institute of Diabetes and Digestive and Kidney Diseases, this study was supported in part by the following general clinical research center grants from the National Institutes of Health: M01 RR-00080, 5M01 RR-00071, M01 00032, P20-RR11145, M01 RR00827, and 2P20 RR11104.

    In-kind support

    Study drugs provided by Pfizer, AstraZeneca and King Pharmaceuticals.

    Finding

    The amlodipine arm was terminated in September 2000 on the recommendation of the data and safety monitoring board, on safety concerns from interim analyses showing slower GFR decline and fewer clinical end points with ramipril and metoprolol than with amlodipine in proteinuric participants. With urinary protein to creatinine ratio above 0.22 (about 300 mg/day, one third of participants), ramipril slowed mean GFR decline by 36% (2.02 ml/min per 1.73 m2 per year, P=0.006) and reduced the composite of GFR decline over 50% or 25 ml/min, end-stage renal disease or death by 48% (95% CI 20% to 66%) against amlodipine. In the whole cohort, mean GFR decline from baseline to 3 years did not differ (P=0.38), but the composite occurred in 87 of 436 on ramipril (0.058 per person-year) against 56 of 217 on amlodipine (0.077 per person-year), a 38% reduction (13% to 56%); ramipril also slowed GFR decline after 3 months by 36% (P=0.002) and lowered proteinuria (P<0.001). Termination of the entire amlodipine arm was recommended partly because protein excretion increased significantly in participants with and without proteinuria. The proteinuria cut-point of 0.22 was chosen post hoc.

11. Industry-funded

    Wright JT Jr, Bakris G, Greene T, Agodoa LY, Appel LJ, Charleston J, et al.; African American Study of Kidney Disease and Hypertension Study Group. Effect of blood pressure lowering and antihypertensive drug class on progression of hypertensive kidney disease: results from the AASK trial JAMA, 2002.

    doi:10.1001/jama.288.19.2421PubMed 12435255

    Funding and finding

    Participants

    1,094

    Follow-up

    3 to 6.4 years

    Funding

    In addition to funding under a cooperative agreement from National Institute of Diabetes and Digestive and Kidney Diseases, this work was supported in part by the following institutional General Clinical Research Center and other National Institutes of Health grants: M01 RR-00080, 5M01 RR-00071, M01 00032, P20-RR11145, M01 RR00827, M01 RR00052, 2P20 RR11104, and DK 2818-02. We gratefully acknowledge support from the Office of Research in Minority Health and the donation of drug and some financial support to NIDDK by Pfizer Inc, AstraZeneca Pharmaceuticals, and King Pharmaceuticals Inc.

    In-kind support

    Drugs donated by Pfizer, AstraZeneca and King Pharmaceuticals.

    Finding

    3 by 2 factorial trial of two blood-pressure goals and initial ramipril (n=436), metoprolol (n=441) or amlodipine (n=217). The lower goal (achieved 128/78 against 141/85 mm Hg) did not slow GFR decline (-2.21 against -1.95 ml/min/1.73 m2 per year) or reduce the composite of 50% GFR decline, end-stage renal disease or death (risk reduction 2%, 95% CI -22% to 21%). GFR slope did not differ consistently between drugs, but ramipril reduced the composite outcome by 22% (1% to 38%) against metoprolol and 38% (14% to 56%) against amlodipine.

12. Textbook or database

    UniProt Consortium. UniProt: the Universal Protein Knowledgebase in 2025 Nucleic Acids Research, 2025.

    doi:10.1093/nar/gkae1010PubMed 39552041

    Funding and finding

    Funding

    National Human Genome Research Institute [HG002273]; Office of the Director, NIH OD [U24HG007822]; NIAID; NIA; NIGMS [R35GM141873]; NIDDK; NEI; NCI; NHLBI; Biotechnology and Biological Sciences Research Council [BB/T015608/1]; National Science Foundation's Directorate for Biological Sciences [BB/X002179/1]; Open Targets; Horizon 2020 [825575]; State Secretariat for Education, Research and Innovation; EMBL Australia. Funding for open access charge: National Institutes of Health.

    Finding

    Reviewed UniProtKB entries read on 2026-10-22 through rest.uniprot.org, annotation update 2026-09-02. CACNA1C (Q13936, entry version 255): pore-forming alpha-1C subunit giving rise to L-type calcium currents; plays an important role in excitation-contraction coupling in the heart and is required for normal heart development and regulation of heart rhythm; required for normal contraction of smooth muscle in blood vessels and in the intestine; essential for blood pressure regulation through arterial smooth muscle contraction; inhibited by dihydropyridines such as isradipine and by nifedipine; shear stress and pressure increase channel activity. Tissue specificity: detected throughout the brain (hippocampus, cerebellum, amygdala), heart and vascular system including the ductus arteriosus, urinary bladder, retina and sclera; expressed in brain, heart, jejunum, ovary, pancreatic beta cells and vascular smooth muscle, with reduced expression in atherosclerotic vascular smooth muscle. Variants cause Timothy syndrome (multiorgan dysfunction with lethal arrhythmias, webbing of fingers and toes, congenital heart disease, immune deficiency, intermittent hypoglycaemia, cognitive abnormalities and autism), long QT syndrome 8 and a neurodevelopmental disorder with hypotonia, language delay and skeletal defects with or without seizures, and may be involved in Brugada syndrome 3. CACNA1D (Q01668, entry version 232): alpha-1D subunit giving rise to L-type calcium currents, which are blocked by dihydropyridines, phenylalkylamines and benzothiazepines; voltage-sensitive calcium channels take part in muscle contraction, hormone or neurotransmitter release, gene expression, cell motility, cell division and cell death; expressed in pancreatic islets and in brain (cerebral cortex, hippocampus, basal ganglia, habenula, thalamus), not in skeletal muscle. CACNA1D variants cause sinoatrial node dysfunction and deafness (congenital deafness with episodic syncope from intermittent pronounced bradycardia) and primary aldosteronism with seizures and neurological abnormalities (hypertension, hypokalaemia, high aldosterone with low renin).

13. Independent research

    Parkinson Study Group STEADY-PD III Investigators. Isradipine versus placebo in early Parkinson disease: a randomized trial Annals of Internal Medicine, 2020.

    doi:10.7326/M19-2534PubMed 32227247

    Funding and finding

    Registration

    NCT02168842

    Participants

    336

    Follow-up

    36 months

    Funding

    By grants U01NS080818 and U01NS080840 from NINDS. Research officers at NINDS were involved in the study design and interpretation of results, reviewed the manuscript and took part in the decision to submit; there was no industry involvement in the trial.

    In-kind support

    None: isradipine was purchased through a wholesale pharmacy and matching placebo manufactured by the University of Rochester Clinical Materials Services Unit.

    Finding

    Immediate-release isradipine 5 mg twice daily, a dihydropyridine, against placebo: adjusted mean change in UPDRS parts I to III over 36 months 2.99 against 3.26 points, treatment effect -0.27 (95% CI -3.02 to 2.48; P=0.85); secondary outcomes showed no effect. Oedema occurred in 31 of 170 (18.2%) on isradipine against 9 of 166 (5.4%) on placebo. The trial was based on studies suggesting that dihydropyridines may be associated with reduced Parkinson disease risk; the authors note the dose may have been insufficient to engage the targeted calcium channels.

14. Independent research

    Nazarzadeh M, Bidel Z, Canoy D, Copland E, Wamil M, Majert J, et al.; on behalf of the Blood Pressure Lowering Treatment Trialists' Collaboration. Blood pressure lowering and risk of new-onset type 2 diabetes: an individual participant data meta-analysis Lancet, 2021.

    doi:10.1016/S0140-6736(21)01920-6PubMed 34774144

    Funding and finding

    Participants

    145,939

    Follow-up

    median 4.5 years (IQR 2.0)

    Funding

    British Heart Foundation (MN, grant FS/19/36/34346; KR and DC, grant PG/18/65/33872), the National Institute for Health Research Oxford Biomedical Research Centre, the Oxford Martin School and the UKRI Global Challenge Research Fund (ES/P011055/1). The funders of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report.

    Finding

    Of 145,939 participants followed for a median 4.5 years, 9883 were diagnosed with new-onset type 2 diabetes; the incidence per 1000 person-years was 16.44 (95% CI 16.01 to 16.87) in the comparator group and 15.94 (15.47 to 16.42) in the intervention group. A 5 mm Hg reduction in systolic blood pressure reduced the risk of type 2 diabetes by 11% (hazard ratio 0.89, 95% CI 0.84 to 0.95). In a network meta-analysis of 22 trials, compared with placebo, calcium channel blockers had no material effect (relative risk 1.02, 95% CI 0.92 to 1.13, 11% direct evidence), angiotensin-converting enzyme inhibitors (0.84, 0.76 to 0.93) and angiotensin II receptor blockers (0.84, 0.76 to 0.92) reduced the risk, and beta blockers (1.48, 1.27 to 1.72) and thiazide diuretics (1.20, 1.07 to 1.35) raised it. In a complementary mendelian randomisation analysis, each 5 mm Hg genetically influenced lower systolic blood pressure was associated with a 12% lower risk of type 2 diabetes (0.88, 0.84 to 0.92), and the pattern across drug classes was reproduced except for thiazide diuretics, for which the genetic evidence lacked power.

15. Independent research

    Savage RD, Visentin JD, Bronskill SE, Wang X, Gruneir A, Giannakeas V, et al. Evaluation of a common prescribing cascade of calcium channel blockers and diuretics in older adults with hypertension JAMA Internal Medicine, 2020.

    doi:10.1001/jamainternmed.2019.7087PubMed 32091538

    Funding and finding

    Participants

    339,019

    Follow-up

    90 days, with analyses up to 1 year

    Funding

    This research was supported by project grant PJT-153060 from the Canadian Institutes of Health Research. This study was supported by ICES, which is funded by an annual grant from the Ontario Ministry of Health and Long-Term Care. The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

    In-kind support

    IMS Brogan Inc provided use of its Drug Information Database.

    Finding

    Cumulative incidence of a loop diuretic dispensed within 90 days: 1.4% after a new calcium channel blocker against 0.7% after a new ACE inhibitor or angiotensin receptor blocker and 0.5% after an unrelated drug (P<0.001). Adjusted hazard ratios against ACE inhibitor or receptor blocker: 1.68 (95% CI 1.38 to 2.05) for days 1 to 30, 2.26 (1.76 to 2.92) for days 31 to 60 and 2.40 (1.84 to 3.13) for days 61 to 90; against unrelated drugs 2.51, 2.99 and 3.89. The association persisted, slightly attenuated, up to 1 year and in the subgroup newly dispensed amlodipine. The authors describe the cascade as oedema misinterpreted as a new condition and treated with a diuretic.

16. Independent research

    Copland E, Canoy D, Nazarzadeh M, Bidel Z, Ramakrishnan R, Woodward M, et al.; Blood Pressure Lowering Treatment Trialists' Collaboration. Antihypertensive treatment and risk of cancer: an individual participant data meta-analysis Lancet Oncology, 2021.

    doi:10.1016/S1470-2045(21)00033-4PubMed 33794209

    Funding and finding

    Registration

    PROSPERO CRD42018099283

    Participants

    260,447

    Follow-up

    median 4.2 years (IQR 3.0 to 5.0)

    Funding

    British Heart Foundation, National Institute for Health Research, Oxford Martin School. The funder of the study had no role in study design, data collection, data analysis, data interpretation or writing of the report.

    Finding

    15,012 cancer events. Comparing each class with all other comparators, no class was associated with any cancer except calcium channel blockers (hazard ratio 1.06, 95% CI 1.01 to 1.11); ACE inhibitors 0.99 (0.95 to 1.04), angiotensin receptor blockers 0.96 (0.92 to 1.01), beta blockers 0.98 (0.89 to 1.07), thiazides 1.01 (0.95 to 1.07). Against placebo in the network analysis, calcium channel blockers 1.04 (0.96 to 1.13). The authors state that evidence was insufficient to rule out excess risk entirely, in particular for calcium channel blockers.

17. Textbook or database

    UniProt Consortium. UniProt: the Universal Protein Knowledgebase in 2025 Nucleic Acids Research, 2025.

    doi:10.1093/nar/gkae1010PubMed 39552041

    Funding and finding

    Funding

    National Human Genome Research Institute [HG002273]; Office of the Director, NIH OD [U24HG007822]; NIAID; NIA; NIGMS [R35GM141873]; NIDDK; NEI; NCI; NHLBI; Biotechnology and Biological Sciences Research Council [BB/T015608/1]; National Science Foundation's Directorate for Biological Sciences [BB/X002179/1]; Open Targets; Horizon 2020 [825575]; State Secretariat for Education, Research and Innovation; EMBL Australia. Funding for open access charge: National Institutes of Health.

    Finding

    Reviewed UniProtKB entries read on 2026-10-21 through rest.uniprot.org, annotation update 2026-09-02. CACNA1C (Q13936, entry version 255): pore-forming alpha-1C subunit of the voltage-gated calcium channel that gives rise to L-type calcium currents, required for normal contraction of smooth muscle cells in blood vessels and in the intestine and essential for normal blood pressure regulation through contraction of arterial smooth muscle cells; expressed in vascular smooth muscle; inhibited by dihydropyridines such as isradipine and by nifedipine; the channel complex contains one each of alpha, beta, gamma and delta subunits and is modulated by CACNB1, CACNB2, CACNB3, CACNA2D1 and CACNA2D4; activity is regulated by calcium and calmodulin, and phosphorylation by protein kinase A at Ser1981 activates the channel. The selectivity-filter motifs of the four repeats are TMEG at 361-364, TGED at 704-707, TFEG at 1133-1136 and TGEA at 1462-1465, each containing one glutamate, and Glu363, Glu1135 and Glu1464 are annotated as sites of calcium ion selectivity and permeability; dihydropyridine-binding regions span residues 1109-1198 and 1478-1546, and the phenylalkylamine-binding region spans 1492-1534. CACNA1C variants cause Timothy syndrome, long QT syndrome 8 and, with Brugada syndrome 3, loss of ion selectivity: Gly406Arg causes a nearly complete loss of voltage-dependent channel inactivation, Ile1186Thr shifts the voltage dependence of activation to a more negative potential with increased window and steady-state current, and Glu1135Lys, in the repeat III selectivity filter, causes loss of selectivity for calcium and other divalent cations over monovalent cations with increased sodium-mediated inward and potassium-mediated outward currents. CALM1 (P0DP23, version 62): calcium binding activates calmodulin, which stimulates myosin light-chain kinases among other enzymes, and mediates calcium-dependent inactivation of CACNA1C. MYLK (Q15746, version 244): calcium/calmodulin-dependent myosin light chain kinase that phosphorylates myosin light chains (EC 2.7.11.18) with Mg2+ and Ca2+ as cofactors; all catalytically active isoforms require binding to calcium and calmodulin for activation; variants cause familial thoracic aortic aneurysm 7, some of them decreasing kinase activity or calmodulin affinity, and megacystis-microcolon-intestinal hypoperistalsis syndrome, a visceral myopathy with loss of smooth muscle contraction in the bladder and intestine. MYL9 (P24844, version 211): myosin regulatory light polypeptide 9 of smooth muscle; phosphorylation by MLCK/MYLK increases the actin-activated myosin ATPase activity and thereby regulates contractile activity; the 172-residue entry sequence begins with the initiator methionine and carries phosphothreonine at position 19 and phosphoserine at position 20, the residues numbered Thr18 and Ser19 when the initiator methionine is excluded. PPP1CB (P62140, version 213): protein phosphatase 1 beta catalytic subunit, which hydrolyses O-phospho-L-seryl-[myosin light chain] and O-phospho-L-threonyl-[myosin light chain] (EC 3.1.3.53) with Mn2+ as cofactor; PPP1R12A, PPP1R12B and PPP1R12C mediate its binding to myosin. PPP1R12A (O14974, version 223): protein phosphatase 1 regulatory subunit 12A, also called MYPT1, a key regulator of protein phosphatase 1C that mediates binding to myosin. CYP3A4 (P08684, version 254): a cytochrome P450 monooxygenase that metabolises the majority of administered drugs, inserting one oxygen atom into a substrate with two electrons provided by NADPH through cytochrome P450 reductase, and induced by drugs such as rifampicin.

18. Independent research

    Rognstad S, Soraas CL, Brunborg C, Halvorsen LV, Brobak KM, Olsen E, et al. Pharmacokinetic variability of amlodipine serum concentration and effect on blood pressure in patients treated for hypertension Pharmacology Research & Perspectives, 2025.

    doi:10.1002/prp2.70140PubMed 40616336

    Funding and finding

    Registration

    NCT03209154

    Participants

    471

    Funding

    This work was supported by the Research Council of Norway (grant 273563). The authors declare no conflicts of interest.

    Finding

    Mean serum amlodipine concentration was 46 (SD 26) nmol/l on a mean daily dose of 8.0 (SD 2.6) mg; the ratio of mean concentration at peak to the 24-hour value was 1.4. Median dose-adjusted concentration was 6.7 nmol/l per mg in women against 4.9 in men (p < 0.001), rose with age (p < 0.001) and was higher below an absolute eGFR of 60 ml/min (7.3 against 5.1 nmol/l per mg, p < 0.001). Of 258 patients genotyped, 16 (6.2%) carried CYP3A4*1/*22 or *22/*22: dose-adjusted concentration in that group exceeded the CYP3A4*1/*1 group by about 30% (unadjusted coefficient 1.89 nmol/l per mg, 95% CI 0.40 to 3.39, p = 0.013; adjusted for nine covariates 1.94, 0.56 to 3.32, p = 0.006), with medians of 6.0 against 5.1 nmol/l per mg (p = 0.062). CYP3A5 genotype showed no association with dose-adjusted concentration (adjusted coefficient 0.66, 95% CI -0.22 to 1.54, p = 0.138); 215 of 258 carried CYP3A5*3/*3. Nine covariates with the dose explained 41% of the variance in serum concentration, of which genotype accounted for 3%. The report states that hepatic metabolism, mainly by CYP3A4 and CYP3A5, accounts for elimination, with 5% to 10% of the parent drug and 60% of the metabolites excreted in urine, and the half-life is 35 to 50 hours.

19. Independent research

    Wright AJ, Gomes T, Mamdani MM, Horn JR, Juurlink DN. The risk of hypotension following co-prescription of macrolide antibiotics and calcium-channel blockers CMAJ, 2011.

    doi:10.1503/cmaj.100702PubMed 21242274

    Funding and finding

    Participants

    7,100

    Follow-up

    prescriptions between 1 April 1994 and 31 March 2009

    Funding

    This study was supported by the Institute for Clinical Evaluative Sciences (ICES), which is funded by an annual grant from the Ontario Ministry of Health and Long-Term Care. The study was supported in part by the Ontario Drug Innovation Fund, which had no role in the design, analysis, conduct or reporting of the study.

    Finding

    Of 7100 patients admitted with hypotension while taking a calcium channel blocker, 176 had a macrolide in the risk or control interval. Erythromycin, the strongest CYP3A4 inhibitor of the three, was associated with hypotension or shock (odds ratio 5.8, 95% CI 2.3 to 15.0), followed by clarithromycin (3.7, 2.3 to 6.1); azithromycin, which does not inhibit CYP3A4, was not (1.5, 0.8 to 2.8). Results were similar in patients taking only dihydropyridines (nifedipine, amlodipine or felodipine).

20. Independent research

    Wright JM, Musini VM, Gill R. First-line drugs for hypertension Cochrane Database of Systematic Reviews, 2018.

    doi:10.1002/14651858.CD001841.pub3PubMed 29667175

    Funding and finding

    Participants

    58,040

    Follow-up

    weighted average 4.9 years for the ACE inhibitor trials; 3 to 5 years across the review

    Funding

    Internal sources: Faculty of Medicine, University of British Columbia, Canada (salary, space and infrastructure). External sources: CIHR grant to the Hypertension Review Group, Canada (infrastructure support to the Cochrane Hypertension Group).

    Finding

    Trials were available for four first-line classes: thiazides (19 trials, 39,713 patients), beta-blockers (5 trials, 19,313), ACE inhibitors (3 trials, 6002) and calcium channel blockers (1 trial, 4695). No randomised trial of a first-line angiotensin receptor blocker or alpha-blocker against placebo or no treatment was identified. First-line ACE inhibitors reduced total mortality (13.6% with control against 11.3% with treatment; RR 0.83, 95% CI 0.72 to 0.95; 6002 patients, 3 trials, I2 0%), stroke (6.0% against 3.9%; RR 0.65, 0.52 to 0.82; 6002 patients, 3 trials), coronary heart disease (13.5% against 11.0%; RR 0.81, 0.70 to 0.94; 5145 patients, 2 trials) and total cardiovascular events (20.1% against 15.3%; RR 0.76, 0.67 to 0.85; 5145 patients, 2 trials). The quality of this evidence was graded moderate for mortality and total cardiovascular events and low for stroke and coronary heart disease. First-line low-dose thiazides reduced mortality (11.0% against 9.8%; RR 0.89, 0.82 to 0.97), total cardiovascular events (12.9% against 9.0%; RR 0.70, 0.64 to 0.76), stroke (6.2% against 4.2%; RR 0.68, 0.60 to 0.77) and coronary heart disease (3.9% against 2.8%; RR 0.72, 0.61 to 0.84) on high-quality evidence. Withdrawals due to adverse effects could not be calculated for first-line ACE inhibitors, because the only trial reporting them had an unblinded untreated control group. Risk of bias assessment treated funding by the manufacturer with a conflict of interest as high risk; of the three ACE inhibitor trials, the HOPE trial is recorded as partially funded by the manufacturer. The authors concluded that first-line ACE inhibitors and calcium channel blockers may be as effective as first-line low-dose thiazides, on evidence of lower quality.

21. Independent research

    Wang D, Wright JM, Adams SP, Cundiff DK, Gueyffier F, Grenet G, et al. Pharmacotherapy for mild hypertension Cochrane Database of Systematic Reviews, 2026.

    doi:10.1002/14651858.CD006742.pub4PubMed 41925078

    Funding and finding

    Participants

    9,124

    Follow-up

    trials of at least one year

    Funding

    CIHR Grant to the Hypertension Review Group and British Columbia Ministry of Health Grant to the Therapeutics Initiative.

    Finding

    Treatment may make little or no difference to all-cause mortality (RR 0.85, 95% CI 0.64 to 1.14; 5 trials, 9124 participants), total cardiovascular events (0.93, 0.69 to 1.24; 4 trials, 7292) or coronary heart disease (1.12, 0.80 to 1.57; 3 trials, 7080), and may reduce stroke (0.41, 0.20 to 0.84; 4 trials, 7292), all low certainty. Withdrawal for adverse effects was reported by one trial only, without individual data for the mild-hypertension subgroup, so all 17,354 of its participants were analysed: RR 4.80 (4.14 to 5.57). One stroke-reducing trial enrolled people with kidney disease. The 2012 version of the review found no difference in mortality, cardiovascular events, stroke, coronary disease or withdrawals.

22. Independent research

    Sheppard JP, Stevens S, Stevens R, Martin U, Mant J, Hobbs FDR, et al. Benefits and harms of antihypertensive treatment in low-risk patients with mild hypertension JAMA Internal Medicine, 2018.

    doi:10.1001/jamainternmed.2018.4684PubMed 30383082

    Funding and finding

    Participants

    38,286

    Follow-up

    median 5.8 years (IQR 2.6 to 9.0)

    Funding

    This work was funded by Medical Research Council (MRC) Strategic Skills Postdoctoral Fellowship MR/K022032/1 (Dr Sheppard), a National Institute for Health Research (NIHR) professorship (Dr Sheppard and Mr McManus), and grant NIHR-RP-R2-12-015 from the NIHR, with further NIHR support. The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

    Finding

    Treatment was not associated with mortality (hazard ratio 1.02, 95% CI 0.88 to 1.17) or cardiovascular disease (1.09, 0.95 to 1.25). It was associated with hypotension (1.69, 1.30 to 2.20; number needed to harm over 10 years 41), syncope (1.28, 1.10 to 1.50; 35), electrolyte abnormalities (1.72, 1.12 to 2.65; 111) and acute kidney injury (1.37, 1.00 to 1.88; 91). The authors advise caution in generalising trial findings in high-risk individuals to people at lower risk.

23. Independent research

    Musini VM, Tejani AM, Bassett K, Puil L, Thompson W, Wright JM. Pharmacotherapy for hypertension in adults 60 years or older Cochrane Database of Systematic Reviews, 2025.

    doi:10.1002/14651858.CD000028.pub4PubMed 41065416

    Funding and finding

    Participants

    26,795

    Follow-up

    mean treatment duration 3.8 years

    Funding

    Internal sources: Department of Anesthesiology, Pharmacology & Therapeutics, University of British Columbia (office space). External sources: BC Ministry of Health grant to the Therapeutics Initiative (infrastructure).

    Finding

    All-cause mortality 10% with treatment against 11% with control (RR 0.91, 95% CI 0.85 to 0.97; 13 trials, 25,932; high certainty); cardiovascular morbidity and mortality 10% against 14% (0.72, 0.68 to 0.77); cerebrovascular 3.4% against 5.2% (0.66, 0.59 to 0.74); coronary heart disease 3.7% against 4.8% (0.78, 0.69 to 0.88); withdrawals for adverse effects 16% against 5.4% (2.91, 2.56 to 3.30; 4 trials, 11,310; low certainty). Mortality RR 0.86 (0.79 to 0.95) at ages 60 to 79 against 0.97 (0.87 to 1.10) at 80 or older, without a significant subgroup difference. Downgrading was mainly for incomplete outcome data and selective outcome reporting.

24. Independent research

    Blood Pressure Lowering Treatment Trialists' Collaboration. Blood pressure-lowering treatment based on cardiovascular risk: a meta-analysis of individual patient data Lancet, 2014.

    doi:10.1016/S0140-6736(14)61212-5PubMed 25131978

    Funding and finding

    Participants

    51,917

    Follow-up

    median 4.0 years (IQR 3.4 to 4.4)

    Funding

    Funding: None (as stated in the published summary; the full text with the role and declaration sections is behind a subscription).

    Finding

    4167 participants (8%) had a cardiovascular event. Mean predicted 5-year risks in the four groups were 6.0%, 12.1%, 17.7% and 26.8%. Relative reductions in cardiovascular events were 18% (95% CI 7 to 27), 15% (4 to 25), 13% (2 to 22) and 15% (5 to 24) (p for trend 0.30). Treating 1000 patients for 5 years would prevent 14 (8 to 21), 20 (8 to 31), 24 (8 to 40) and 38 (16 to 61) cardiovascular events respectively (p for trend 0.04).

25. Industry-funded

    Jamerson K, Weber MA, Bakris GL, Dahlöf B, Pitt B, Shi V, et al.; ACCOMPLISH Trial Investigators. Benazepril plus amlodipine or hydrochlorothiazide for hypertension in high-risk patients New England Journal of Medicine, 2008.

    doi:10.1056/NEJMoa0806182PubMed 19052124

    Funding and finding

    Registration

    NCT00170950

    Participants

    11,506

    Follow-up

    mean 36 months; stopped early when the prespecified stopping boundary was exceeded

    Funding

    Supported by Novartis. Representative members of the executive committee and the sponsor met regularly and oversaw coordination and data gathering; investigators entered data into an electronic database maintained by Novartis, and data analysis was carried out by the Clinical Information Sciences statistical group at Novartis according to a plan devised by the executive committee.

    Finding

    Double-blind benazepril with amlodipine against benazepril with hydrochlorothiazide in single capsules. Mean pressures after titration 131.6/73.3 against 132.5/74.4 mm Hg. The primary composite (cardiovascular death, non-fatal myocardial infarction or stroke, hospitalisation for angina, resuscitated cardiac arrest, coronary revascularisation) occurred in 552 (9.6%) against 679 (11.8%): absolute risk reduction 2.2 percentage points, hazard ratio 0.80 (95% CI 0.72 to 0.90); 32.3 against 39.7 events per 1000 patient-years. Cardiovascular death, non-fatal myocardial infarction or stroke 288 (5.0%) against 364 (6.3%), hazard ratio 0.79. Hospitalisation for heart failure 1.7% in both groups. Discontinuation for adverse events 13.4% against 14.3%.

26. Independent research

    Neal B, Wu Y, Feng X, Zhang R, Zhang Y, Shi J, et al. Effect of salt substitution on cardiovascular events and death New England Journal of Medicine, 2021.

    doi:10.1056/NEJMoa2105675PubMed 34459569

    Funding and finding

    Registration

    NCT02092090

    Participants

    20,995

    Follow-up

    mean 4.74 years, median 5.12 years

    Funding

    Supported by research grants (APP1164206 and APP1049417) and an investigator grant (APP1197709, to Dr. Neal) from the National Health and Medical Research Council of Australia. The trial was sponsored by the George Institute for Global Health, where the analyses were performed; the first author wrote the first draft and all authors took the decision to submit. Registry lead sponsor: The George Institute; collaborators were universities and the Chinese Center for Disease Control and Prevention.

    In-kind support

    The salt substitute (75% sodium chloride, 25% potassium chloride) was purchased by the investigators from local manufacturers in each province for years 1, 2 and 5 and donated by Jiangsu Sinokone Technology for years 3 to 4.

    Finding

    Stroke 29.14 versus 33.65 events per 1000 person-years with salt substitute versus regular salt (rate ratio 0.86, 95% CI 0.77 to 0.96); fatal stroke 6.78 versus 8.79 (0.77, 0.65 to 0.91); haemorrhagic 4.37 versus 6.30 (0.69, 0.56 to 0.85); ischaemic 21.36 versus 22.90 (0.93, 0.82 to 1.05); major adverse cardiovascular events 49.09 versus 56.29 (0.87, 0.80 to 0.94); death 39.28 versus 44.61 (0.88, 0.82 to 0.95); serious adverse events attributed to hyperkalaemia 3.35 versus 3.30 (1.04, 0.80 to 1.37). Mean differences: 24-hour urinary sodium -350 mg, potassium +803 mg, systolic blood pressure -3.34 mm Hg. Exclusions: potassium-sparing diuretic, potassium supplement or known serious kidney disease in the household; no routine kidney function or serum potassium measurement; 22.8% used an ACE inhibitor or angiotensin-receptor blocker.

27. Independent research

    Edwards JJ, Deenmamode AHP, Griffiths M, Arnold O, Cooper NJ, Wiles JD, et al. Exercise training and resting blood pressure: a large-scale pairwise and network meta-analysis of randomised controlled trials British Journal of Sports Medicine, 2023.

    doi:10.1136/bjsports-2022-106503PubMed 37491419

    Funding and finding

    Participants

    15,827

    Follow-up

    interventions of 2 weeks or longer

    Funding

    No sources of funding were used to assist in the preparation of this article. NJC is supported by the National Institute for Health and Care Research (NIHR) Complex Reviews Support Unit (project number 14/178/29) and NIHR Applied Research Collaboration East Midlands (ARC EM).

    Finding

    Resting systolic/diastolic blood pressure fell by 4.49/2.53 mm Hg with aerobic training, 4.55/3.04 with dynamic resistance training, 6.04/2.54 with combined training, 4.08/2.50 with high-intensity interval training and 8.24/4.00 with isometric training (all p<0.001). The outcomes analysed were resting systolic and diastolic blood pressure.

28. Independent research

    Semlitsch T, Krenn C, Jeitler K, Berghold A, Horvath K, Siebenhofer A. Long-term effects of weight-reducing diets in people with hypertension Cochrane Database of Systematic Reviews, 2021.

    doi:10.1002/14651858.CD008274.pub4PubMed 33555049

    Funding and finding

    Participants

    2,100

    Follow-up

    mean treatment duration 6 to 36 months

    Funding

    Internal sources: Medical University of Graz, Austria (salary, office space, computer support, library resources); Institute of General Practice, Goethe University Frankfurt, Germany (salary). External sources: no sources of support supplied.

    Finding

    No trial included mortality as a predefined outcome and none evaluated adverse events as defined in the protocol. One trial found a lower risk of a combined end point of reinstated antihypertensive therapy and severe cardiovascular complications (hazard ratio 0.70, 95% CI 0.57 to 0.87). Systolic pressure -4.5 mm Hg (-7.2 to -1.8) and diastolic -3.2 mm Hg (-4.8 to -1.5) (3 trials, 731 participants; low certainty); body weight -4.0 kg (-4.8 to -3.2; 5 trials, 880; high certainty). The authors conclude that whether weight loss reduces mortality and morbidity is unknown.

29. Independent research

    Moynihan RN, Cooke GP, Doust JA, Bero L, Hill S, Glasziou PP. Expanding disease definitions in guidelines and expert panel ties to industry: a cross-sectional study of common conditions in the United States PLoS Medicine, 2013.

    doi:10.1371/journal.pmed.1001500PubMed 23966841

    Funding and finding

    Funding

    NHMRC Screening and Test Evaluation Program Grant. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

    Finding

    Ten of 16 publications widened disease definitions, one narrowed them and five had unclear impact; none rigorously assessed the potential harms of widening. Among 14 panels with disclosures, on average 75% of members had industry ties, 12 were chaired or led by people with ties, and members with ties had a median of seven companies. The JNC 7 hypertension panel created the category of pre-hypertension; 9 of its 11 members (82%) disclosed industry ties, to a median of 12 companies (IQR 11 to 13), its chair had ties, and 8 of 11 (73%) each had ties to Bristol-Myers Squibb, Merck and Novartis, whose products include irbesartan, losartan and amlodipine besylate/benazepril.

30. Independent research

    Muntner P, Carey RM, Gidding S, Jones DW, Taler SJ, Wright JT Jr, et al. Potential US Population Impact of the 2017 ACC/AHA High Blood Pressure Guideline Circulation, 2018.

    doi:10.1161/CIRCULATIONAHA.117.032582PubMed 29133599

    Funding and finding

    Participants

    9,623

    Funding

    Paul Muntner receives research support through grant 15SFRN2390002 from the American Heart Association.

    Finding

    The crude prevalence of hypertension among US adults was 45.6% (95% CI 43.6% to 47.6%) by the 2017 ACC/AHA definition (130/80 mm Hg) against 31.9% (30.1% to 33.7%) by JNC7 (140/90 mm Hg); antihypertensive medication was recommended for 36.2% against 34.3%. Among adults taking antihypertensive medication, 53.4% were above the 2017 goal against 39.0% above the JNC7 goal. 103.3 million US adults had hypertension by the 2017 guideline, of whom 81.9 million were recommended medication.

31. Expert consensus

    James PA, Oparil S, Carter BL, Cushman WC, Dennison-Himmelfarb C, Handler J, et al. 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8) JAMA, 2014.

    doi:10.1001/jama.2013.284427PubMed 24352797

    Funding and finding

    Funding

    The evidence review for this project was funded by the National Heart, Lung, and Blood Institute (NHLBI).

    Finding

    In the general population aged 60 or older, start drug treatment at systolic 150 mm Hg or diastolic 90 mm Hg or higher and treat to below 150/90 (strong recommendation, grade A). Below age 60, start at diastolic 90 or higher (grade A for ages 30 to 59, expert opinion for 18 to 29) and at systolic 140 or higher (expert opinion), with goals below 90 and 140. With chronic kidney disease or diabetes, start at 140/90 and treat to below 140/90 (expert opinion). Initial drugs in the non-black population: thiazide-type diuretic, calcium channel blocker, ACE inhibitor or angiotensin receptor blocker; in the black population a thiazide-type diuretic or calcium channel blocker. The panel was unable to reach unanimity on the systolic goal below 150 mm Hg; some members recommended continuing the JNC 7 goal below 140 mm Hg for people older than 60.

32. Expert consensus

    McEvoy JW, McCarthy CP, Bruno RM, Brouwers S, Canavan MD, Ceconi C, et al.; ESC Scientific Document Group. 2024 ESC Guidelines for the management of elevated blood pressure and hypertension European Heart Journal, 2024.

    doi:10.1093/eurheartj/ehae178PubMed 39210715

    Funding and finding

    Funding

    Funding for the development of ESC Guidelines is derived entirely from the ESC with no involvement of the healthcare industry.

    Finding

    Office blood pressure categories: non-elevated below 120/70 mm Hg; elevated 120 to 139 systolic or 70 to 89 diastolic; hypertension 140 or above systolic or 90 or above diastolic, unchanged as a definition. In elevated blood pressure, a 10-year predicted cardiovascular risk of 10% or more is considered sufficiently high to warrant lowering by lifestyle or drug treatment, with lifestyle measures for 3 months first and drugs recommended for confirmed pressure of 130/80 mm Hg or more; confirmed hypertension is recommended for treatment without further risk stratification. Adults receiving blood-pressure-lowering drugs should pursue a systolic target of 120 to 129 mm Hg if well tolerated, with more lenient targets for some patients and out-of-office confirmation. ACE inhibitors, angiotensin receptor blockers, dihydropyridine calcium channel blockers and diuretics are recommended as first-line options; beta-blockers can be added preferentially for angina, heart failure, after myocardial infarction or for heart-rate control, are less effective at preventing stroke, have a higher discontinuation rate due to side effects, are associated with new-onset diabetes in predisposed patients, especially with diuretics, and should be avoided in isolated systolic hypertension or arterial stiffness; in resistant hypertension a beta-blocker, preferably vasodilating, is an alternative to a mineralocorticoid receptor antagonist as fourth-line treatment.

33. Independent research

    Sheppard JP, Burt J, Lown M, Temple E, Lowe R, Fraser R, et al.; OPTIMISE Investigators. Effect of Antihypertensive Medication Reduction vs Usual Care on Short-term Blood Pressure Control in Patients With Hypertension Aged 80 Years and Older: The OPTIMISE Randomized Clinical Trial JAMA, 2020.

    doi:10.1001/jama.2020.4871PubMed 32453368

    Funding and finding

    Registration

    EudraCT 2016-004236-38; ISRCTN97503221

    Participants

    569

    Follow-up

    12 weeks

    Funding

    This work received joint funding from NIHR CLAHRC at Oxford Health NHS Foundation Trust (P2-501) and the NIHR School for Primary Care Research (335). Drs Sheppard and McManus were funded by an NIHR professorship (NIHR-RP-R2-12-015); further fellowships from the Wellcome Trust/Royal Society and NIHR. The University of Oxford had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

    Finding

    Unblinded non-inferiority trial: removal of one antihypertensive drug (n=282) against usual care (n=287). Systolic pressure below 150 mm Hg at 12 weeks in 229 (86.4%) against 236 (87.7%), adjusted relative risk 0.98 (97.5% one-sided CI 0.92 to infinity), meeting the non-inferiority margin of 0.90. Medication reduction was sustained in 187 (66.3%). Mean systolic pressure rose 3.4 mm Hg (95% CI 1.1 to 5.8) more than with usual care. At least one serious adverse event in 12 (4.3%) against 7 (2.4%), adjusted relative risk 1.72 (0.7 to 4.3). The authors call for research on long-term clinical outcomes.

34. Independent research

    Sheppard JP, Lown M, Burt J, Ford GA, Hobbs FDR, Little P, et al. Blood pressure changes following antihypertensive medication reduction, by drug class and dose chosen for withdrawal: exploratory analysis of data from the OPTiMISE trial Frontiers in Pharmacology, 2021.

    doi:10.3389/fphar.2021.619088PubMed 33959004

    Funding and finding

    Participants

    569

    Follow-up

    12 weeks

    Funding

    Joint funding from the National Institute for Health Research (NIHR) Oxford Collaboration for Leadership in Applied Health Research and Care at Oxford Health NHS Foundation Trust (P2-501) and the NIHR School for Primary Care Research (335); Sheppard and McManus were funded by an NIHR Professorship (NIHR-RP-R2-12-015); Sheppard now receives funding from the Wellcome Trust and Royal Society through a Sir Henry Dale Fellowship (211182/Z/18/Z) and an NIHR Oxford Biomedical Research Centre Senior Fellowship.

    Finding

    Exploratory analysis of a randomised non-inferiority trial in which physicians removed one antihypertensive drug or continued usual care. Among patients prescribed calcium channel blockers, the drug selected for withdrawal was a higher dose in 118 of 131 instances (90%). Withdrawal of a calcium channel blocker was followed by a rise in systolic blood pressure of 5 mm Hg (95% CI 0 to 10) and by reduced systolic blood pressure control at 12 weeks, adjusted relative risk 0.89 (95% CI 0.80 to 0.998), against usual care. Withdrawal of a beta blocker, usually at low dose (87%), was followed by no change in systolic pressure (-4 mm Hg, 95% CI -10 to 2) and no difference in control (1.15, 0.96 to 1.37). Withdrawal of specific drug classes showed no association with adverse events. Calcium channel blockers were the most commonly prescribed class at baseline, in 390 of 569 participants (68.5%).

35. Independent research

    Gnjidic D, Langford AV, Jordan V, Sawan M, Sheppard JP, Thompson W, et al. Withdrawal of antihypertensive drugs in older people Cochrane Database of Systematic Reviews, 2025.

    doi:10.1002/14651858.CD012572.pub3PubMed 40162571

    Funding and finding

    Participants

    1,073

    Follow-up

    4 to 56 weeks

    Funding

    Sources of support, read on the PubMed Central article page: internal sources, Faculty of Pharmacy and Pharmaceutical Sciences, Monash University; School of Pharmacy, University of Sydney; Royal North Shore Hospital, University of Sydney; Department of Obstetrics and Gynaecology, University of Auckland; Department of Epidemiology and Preventive Medicine, Monash University. External sources: National Health and Medical Research Council (NHMRC) Investigator Grant fellowship for Emily Reeve (GNT1195460); NHMRC-Australian Research Council Dementia Research Leadership Fellowship for Danijela Gnjidic; Wellcome Trust/Royal Society Sir Henry Dale Fellowship for James Sheppard (211182/Z/18/Z/WT).

    Finding

    Discontinuation against continuation: all-cause mortality OR 2.08 (95% CI 0.79 to 5.46; 4 studies, 630 participants; low certainty), myocardial infarction 1.86 (0.19 to 17.98; very low certainty), hospitalisation 0.83 (0.33 to 2.10; 1 study, 385), stroke 1.44 (0.25 to 8.35; 3 studies, 524); systolic pressure 9.75 mm Hg higher (7.33 to 12.18) and diastolic 3.5 mm Hg higher. Adverse drug reactions could not be meta-analysed, withdrawal reactions were not assessed and no study reported falls. The authors conclude that firm conclusions cannot be drawn and call for trials in frail, older and polymedicated people measuring adverse drug events, falls and quality of life.