ACE inhibitors and angiotensin receptor blockers

References

1. Regulator

   Upsher-Smith Laboratories, LLC. ZESTRIL (lisinopril) tablets, for oral use: full prescribing information US Food and Drug Administration-approved labelling, published in DailyMed (National Library of Medicine); structured product label version 2, effective 2 January 2025, label text revised 11/2024, 2025.

   https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=838c2d78-d2d8-4981-9ec9-e50ef9e1a5d8

   Funding and finding

   Funding

   not stated. The document is prescribing information approved by the US Food and Drug Administration and published by the labeller, Upsher-Smith Laboratories, LLC.

   Finding

   Initial US approval 1988. Indications: hypertension in adults and in children of 6 years and older, adjunct therapy for systolic heart failure, and reduction of mortality in haemodynamically stable patients within 24 hours of acute myocardial infarction. Boxed warning, fetal toxicity: when pregnancy is detected, discontinue as soon as possible; drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus; use during the second and third trimesters reduces fetal renal function and increases fetal and neonatal morbidity and death, and the resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations, including skull hypoplasia, anuria, hypotension and renal failure. Mechanism: ACE is a peptidyl dipeptidase that catalyses the conversion of angiotensin I to the vasoconstrictor angiotensin II, which also stimulates adrenal aldosterone secretion; inhibition lowers plasma angiotensin II, vasopressor activity and aldosterone secretion, which may raise serum potassium slightly; removal of angiotensin II negative feedback raises plasma renin activity; ACE is identical to kininase, the enzyme that degrades bradykinin, and whether raised bradykinin plays a part in the therapeutic effect remains to be elucidated; the drug is antihypertensive even in low-renin hypertension, and Black patients had a smaller average response to monotherapy. In hypertensive patients with normal renal function treated for up to 24 weeks, mean serum potassium rose by about 0.1 mEq/l, with increases above 0.5 mEq/l in about 15% and decreases above 0.5 mEq/l in about 6%. Hyperkalaemia (serum potassium above 5.7 mEq/l) occurred in 2.2% of treated patients with hypertension and 4.8% with heart failure; risk factors are renal insufficiency, diabetes mellitus and concomitant potassium-sparing diuretics, potassium supplements or potassium-containing salt substitutes. Pharmacokinetics: peak serum concentrations at about 7 hours; food does not alter bioavailability; mean extent of absorption about 25% from urinary recovery, with large intersubject variability of 6% to 60%; lisinopril does not undergo metabolism and is excreted unchanged entirely in the urine; effective half-life on multiple dosing 12 hours; the prolonged terminal phase probably represents saturable binding to ACE; absolute bioavailability falls to 16% in stable NYHA class II to IV heart failure; elimination is little changed above a glomerular filtration rate of 30 ml/min; removable by haemodialysis. Dosing in renal impairment: half the usual initial dose at creatinine clearance of 10 to 30 ml/min, and 2.5 mg once daily below 10 ml/min or on haemodialysis. Adverse reactions exceeding placebo by 2% in hypertension: headache by 3.8%, dizziness by 3.5%, cough by 2.5%; 5.7% of patients discontinued for adverse reactions. ATLAS trial, high against low dose: dizziness 19% against 12%, hypotension 11% against 7%, creatinine increased 10% against 7%, hyperkalaemia 6% against 4%, syncope 7% against 5%. Angio-oedema of the face, extremities, lips, tongue, glottis or larynx, including fatal reactions, has occurred at any time during treatment; ACE inhibitors have been associated with a higher rate of angio-oedema in Black than in non-Black patients; intestinal angio-oedema has occurred with normal C1 esterase levels; previous angio-oedema or hypersensitivity on an ACE inhibitor, and hereditary or idiopathic angio-oedema, are contraindications, as is combination with a neprilysin inhibitor such as sacubitril or, in diabetes, with aliskiren. GISSI-3: 19,394 patients within 24 hours of acute myocardial infarction, randomised in a 2 by 2 factorial design to six weeks of lisinopril, nitrates, both or open control; patients receiving lisinopril (n=9646) had an 11% lower risk of death at six weeks than those who did not (n=9672), 6.4% against 7.2% (p=0.04), with persistent hypotension in 9.0% against 3.7% and renal dysfunction in 2.4% against 1.1%. Dual blockade of the renin-angiotensin system with an angiotensin receptor blocker, an ACE inhibitor or aliskiren raises the risks of hypotension, hyperkalaemia and changes in renal function; in VA NEPHRON-D, 1448 patients with type 2 diabetes, raised urinary albumin-to-creatinine ratio and reduced estimated glomerular filtration rate were randomised to lisinopril or placebo on a background of losartan and followed for a median 2.2 years; the combination gave no additional benefit for decline in GFR, end-stage renal disease or death, and increased hyperkalaemia and acute kidney injury. Abrupt withdrawal has not been associated with a rapid increase in blood pressure or with a significant increase compared with pretreatment levels. Patients are told to report immediately any sign suggesting angio-oedema and to take no more of the drug until they have consulted the prescribing physician, and not to use potassium-containing salt substitutes without consulting their physician.

2. Regulator

   Organon LLC. COZAAR (losartan potassium) tablets, for oral use: full prescribing information US Food and Drug Administration-approved labelling, published in DailyMed (National Library of Medicine); structured product label version 9, effective 20 January 2026, label text revised 6/2021, 2026.

   https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=9949448f-c3b9-44ee-94ed-c1aca8c90f39

   Funding and finding

   Funding

   not stated. The document is prescribing information approved by the US Food and Drug Administration and published by the labeller, Organon LLC.

   Finding

   Initial US approval 1995. Indications: hypertension in adults and children older than 6 years; reduction of the risk of stroke in patients with hypertension and left ventricular hypertrophy, with the statement that there is evidence that this benefit does not apply to Black patients; and treatment of diabetic nephropathy with raised serum creatinine and proteinuria (urinary albumin-to-creatinine ratio of 300 mg/g or more) in patients with type 2 diabetes and a history of hypertension. Boxed warning, fetal toxicity: when pregnancy is detected, discontinue as soon as possible; drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus; second- and third-trimester use reduces fetal renal function and increases fetal and neonatal morbidity and death, with oligohydramnios, fetal lung hypoplasia, skeletal deformations including skull hypoplasia, hypotension, anuria, renal failure and death. Mechanism: losartan and its principal active metabolite block the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively blocking its binding to the AT1 receptor found in many tissues, for example vascular smooth muscle and adrenal gland; neither shows partial agonist activity at AT1, and both have about 1000-fold greater affinity for AT1 than for AT2; losartan is a reversible competitive inhibitor of AT1 in vitro and the active metabolite, 10 to 40 times more potent by weight, appears to be a reversible non-competitive inhibitor; neither inhibits ACE (kininase II, the enzyme that converts angiotensin I to angiotensin II and degrades bradykinin), nor binds or blocks other hormone receptors or ion channels important in cardiovascular regulation. Pharmacodynamics: a 100 mg dose inhibits the pressor effect of angiotensin II by about 85% at peak, with 25% to 40% inhibition persisting for 24 hours; removal of angiotensin II negative feedback causes a doubling to tripling of plasma renin activity; losartan does not affect the response to bradykinin, whereas ACE inhibitors increase the response to bradykinin; aldosterone plasma concentrations fall, yet very little effect on serum potassium was observed; no apparent rebound effect follows abrupt withdrawal. Pharmacokinetics: systemic bioavailability about 33%; peak concentrations of losartan at 1 hour and of the active metabolite at 3 to 4 hours, with the metabolite AUC about 4 times that of losartan; terminal half-life about 2 hours for losartan and 6 to 9 hours for the metabolite; about 14% of an oral dose is converted to the active metabolite; in vitro studies indicate that cytochrome P450 2C9 and 3A4 are involved in the biotransformation of losartan, and the data suggest that conversion to the active metabolite is mediated primarily by P450 2C9 and not P450 3A4; subjects who do not metabolise losartan to the active metabolite have been shown to have a specific, rare defect in cytochrome P450 2C9; fluconazole, an inhibitor of P450 2C9, decreased the AUC of the active metabolite by approximately 40% and increased the AUC of losartan by approximately 70% after multiple doses, rifampicin decreased the AUC of losartan and of the active metabolite by 30% and 40%, and conversion after intravenous administration was not affected by the P450 3A4 inhibitor ketoconazole; the pharmacodynamic consequences of concomitant use of losartan and inhibitors of P450 2C9 have not been examined; plasma concentrations and AUCs of losartan and the metabolite are 50% to 90% higher in mild or moderate renal insufficiency and neither is removed by haemodialysis; in mild-to-moderate hepatic impairment concentrations of losartan and of the metabolite were about 5 times and 1.7 times those in healthy volunteers, so the recommended starting dose is 25 mg. Hyperkalaemia: monitor serum potassium periodically and treat appropriately; dosage reduction or discontinuation may be required; concomitant drugs that raise serum potassium may lead to hyperkalaemia. Cough: in two prospective, parallel-group, double-blind randomised trials in hypertensive patients who had had typical ACE-inhibitor cough on challenge with lisinopril and whose cough disappeared on placebo, the incidence of cough during up to 8 weeks of double-blind treatment was, in study 1 (n=135; 89% Caucasian, 64% female), 25% with hydrochlorothiazide 25 mg, 17% with losartan 50 mg and 69% with lisinopril 20 mg, and in study 2 (n=97; 90% Caucasian, 51% female), 35% with placebo, 29% with losartan and 62% with lisinopril; cases of cough, including positive re-challenges, have been reported with losartan after marketing. Angio-oedema, including swelling of the larynx and glottis causing airway obstruction, swelling of the face, lips, pharynx or tongue and swelling of the intestine, has been reported after marketing; some of these patients had previously experienced angio-oedema with other drugs, including ACE inhibitors. LIFE study: 9193 hypertensive patients with electrocardiographic left ventricular hypertrophy randomised to losartan 50 mg or atenolol 50 mg once daily, with hydrochlorothiazide added and the dose doubled as needed; mean age 67 years, 54% female, 533 (6%) Black, baseline blood pressure 174/98 mmHg in both groups, mean follow-up 4.8 years; the primary composite of cardiovascular death, non-fatal stroke or non-fatal myocardial infarction occurred in 508 (11%; 23.8 per 1000 patient-years) on losartan against 588 (13%; 27.9 per 1000 patient-years) on atenolol, a 13% risk reduction (95% CI 2% to 23%, p=0.021) adjusted for baseline Framingham risk score and degree of left ventricular hypertrophy; fatal or non-fatal stroke 232 (5%; 10.8 per 1000 patient-years) against 309 (7%; 14.5), a 25% reduction (11% to 37%, p=0.001); fatal or non-fatal myocardial infarction 198 (4%) against 188 (4%), risk reduction -7% (p=0.491); end-of-study mean blood pressure 144.1/81.3 against 145.4/80.9 mmHg. In the subgroup of 533 Black patients there were 46 primary endpoints among 270 patients (17%; 42 per 1000 patient-years) on losartan and 29 among 263 (11%; 26 per 1000 patient-years) on atenolol; the label states that this finding could not be explained by differences other than race or by imbalance between treatment groups, that blood-pressure reductions were consistent between Black and non-Black patients, that it cannot be known whether the observed difference is the result of chance, and that the LIFE study provides no evidence that the benefit applies to Black patients. RENAAL study: 1513 patients with type 2 diabetes and nephropathy randomised to losartan 50 mg once daily, titrated to 100 mg, or placebo on a background of conventional antihypertensive therapy excluding ACE inhibitors and angiotensin II antagonists; mean follow-up 3.4 years; the primary composite of doubling of serum creatinine, end-stage renal disease or death occurred in 43.5% against 47.1%, a 16.1% risk reduction (95% CI 2.3% to 27.9%, p=0.022); overall incidence of doubling of serum creatinine 21.6% against 26.0% (25.3% reduction, 7.8% to 39.4%, p=0.006), end-stage renal disease 19.6% against 25.5% (28.6% reduction, 11.5% to 42.4%, p=0.002) and death 21.0% against 20.3% (p=0.884); end-of-study mean blood pressure 143/76 against 146/77 mmHg; adverse events reported in 4% or more of treated patients and with a 2% or greater difference against placebo included asthenia or fatigue, chest pain, hypotension, orthostatic hypotension, diarrhoea, anaemia, hyperkalaemia, hypoglycaemia, back pain, muscular weakness and urinary tract infection. Dual blockade: in VA NEPHRON-D, 1448 patients with type 2 diabetes, raised urinary albumin-to-creatinine ratio and estimated glomerular filtration rate of 30 to 89.9 ml/min were randomised to lisinopril or placebo on a background of losartan and followed for a median 2.2 years; the combination gave no additional benefit for the composite of decline in GFR, end-stage renal disease or death and increased hyperkalaemia and acute kidney injury. In four placebo-controlled monotherapy trials of 10 to 150 mg per day, doses of 50, 100 and 150 mg once daily lowered blood pressure by 5.5 to 10.5 mmHg systolic and 3.5 to 7.5 mmHg diastolic more than placebo, with no greater effect at 150 mg; the effect was somewhat less in Black patients, usually a low-renin population.

3. Regulator

   Toh D, Reichman ME, Houstoun M, Ross Southworth M, Ding X, Hernandez A, et al. Signal refinement of angioedema events in association with use of drugs that act on the renin-angiotensin-aldosterone system: report Mini-Sentinel Medical Product Assessment, US Food and Drug Administration Sentinel Initiative, 15 October 2012, 2012.

   https://www.sentinelinitiative.org/sites/default/files/Drugs/Assessments/Mini-Sentinel_Angioedema-and-RAAS_Final-Report.pdf

   Funding and finding

   Participants

   3,909,596

   Follow-up

   up to 365 days after the first prescription; mean 149 days for ACE inhibitor initiators, 136 for angiotensin receptor blocker initiators and 126 for beta-blocker initiators

   Funding

   Mini-Sentinel is a pilot project sponsored by the U.S. Food and Drug Administration. The Mini-Sentinel Coordinating Center is funded by the FDA through the Department of Health and Human Services Contract number HHSF223200910006I. Nine of the thirteen authors are FDA staff. The analysis was also published as Toh S et al., Arch Intern Med 2012;172:1582-9 (PMID 23147456).

   Finding

   Angio-oedema arose at 4.38 per 1000 person-years (95% CI 4.24 to 4.54) with ACE inhibitors, 1.66 (1.47 to 1.86) with angiotensin receptor blockers, 4.67 (1.88 to 9.63) with aliskiren and 1.67 (1.56 to 1.78) with beta-blockers; cumulative incidence 1.79 per 1000 ACE inhibitor initiators. Serious angio-oedema, with airway obstruction requiring inpatient care, arose at 0.43 per 1000 person-years with ACE inhibitors against 0.06 with angiotensin receptor blockers and 0.09 with beta-blockers. Against beta-blockers, propensity-score-adjusted hazard ratios were 3.04 (2.81 to 3.27) for ACE inhibitors, 1.16 (1.00 to 1.34) for angiotensin receptor blockers and 2.85 (1.34 to 6.04) for aliskiren, and 4.91 (3.62 to 6.65) for serious angio-oedema with ACE inhibitors. With ACE inhibitors the rate was 9.68 per 1000 person-years in the first 30 days and 2.59 at days 271 to 365, which remained above beta-blockers (adjusted hazard ratio 2.10, 1.60 to 2.76); 66% of cases arose within 90 days. Rates with ACE inhibitors were 5.64 per 1000 person-years in women against 3.30 in men, and 4.92 at age 65 or over. Race was missing for most patients and was not adjusted for.

4. Regulator

   Bausch Health US, LLC. VASOTEC (enalapril maleate) tablets: prescribing information US Food and Drug Administration-approved labelling, published in DailyMed (National Library of Medicine); structured product label version 15, effective 23 January 2026, label text Rev. 11/2025, 2026.

   https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=39631f1f-5d19-43c1-b504-bf56d991ed97

   Funding and finding

   Funding

   not stated. The document is prescribing information approved by the US Food and Drug Administration and published by the labeller, Bausch Health US, LLC.

   Finding

   Boxed warning, fetal toxicity: discontinue as soon as pregnancy is detected; oligohydramnios may not appear until after the fetus has sustained irreversible injury; most epidemiological studies of first-trimester exposure have not distinguished renin-angiotensin drugs from other antihypertensives. Warnings: anaphylactoid and related reactions, presumably because ACE inhibitors affect the metabolism of eicosanoids and polypeptides including endogenous bradykinin; head and neck angio-oedema at any time during treatment, which with laryngeal oedema may be fatal, with higher incidence in Black than non-Black patients and increased risk with mTOR inhibitors (temsirolimus, sirolimus, everolimus) or a neprilysin inhibitor; intestinal angio-oedema presenting as abdominal pain with normal C1 esterase levels, resolving after stopping; life-threatening anaphylactoid reactions during hymenoptera venom desensitisation, and anaphylactoid reactions during dialysis with high-flux membranes and during LDL apheresis with dextran sulfate; excessive hypotension, sometimes with oliguria, progressive azotaemia and rarely acute renal failure or death, in heart failure, hyponatraemia, high-dose diuretic therapy, dialysis or volume depletion, and myocardial infarction or stroke from an excessive fall in pressure in ischaemic heart or cerebrovascular disease; neutropenia or agranulocytosis, for which trial data are insufficient to exclude a captopril-like rate; rarely a syndrome beginning with cholestatic jaundice that progresses to fulminant hepatic necrosis and sometimes death, by an unknown mechanism. In hypertensive patients with unilateral or bilateral renal artery stenosis, blood urea nitrogen and serum creatinine rose in 20%, almost always reversibly on discontinuation. Hyperkalaemia above 5.7 mEq/l in about 1% of hypertensive patients (discontinuation in 0.28%) and 3.8% in heart failure. NSAIDs including COX-2 inhibitors given with ACE inhibitors to elderly, volume-depleted or renally impaired patients may cause deterioration of renal function including acute renal failure, usually reversible. Dual blockade with ACE inhibitors, angiotensin receptor blockers or aliskiren raises the risks of hypotension, hyperkalaemia and acute renal failure without additional benefit for most patients. Lithium toxicity has been reported, and nitritoid reactions (flushing, nausea, vomiting, hypotension) with injectable gold. Post-marketing and uncommon trial reports include cardiac arrest, pancreatitis, hepatitis, hepatic failure, neutropenia, thrombocytopenia, bone marrow depression, exfoliative dermatitis, toxic epidermal necrolysis, Stevens-Johnson syndrome, pemphigus, renal failure and hyponatraemia. Hypotension in heart failure 6.7% and syncope 2.2%; in hypertension 0.9% and 0.5%. Discontinuation for adverse experiences 3.3% in hypertension and 5.7% in heart failure. Mean haemoglobin fell by about 0.3 g/dl; haemolytic anaemia, including in G6PD deficiency, has been reported. Cough is presumed to follow inhibition of bradykinin degradation and always resolves after discontinuation. SOLVD-Treatment: 2569 patients with symptomatic heart failure and ejection fraction of 35% or less followed for up to 55 months; enalapril was associated with an 11% reduction in all-cause mortality and a 30% reduction in heart-failure hospitalisation. SOLVD-Prevention: 4228 patients with ejection fraction of 35% or less without symptomatic heart failure followed for up to 5 years; no statistically significant mortality effect, 32% fewer first heart-failure hospitalisations; the trial was not designed to show whether treating asymptomatic patients is superior to close follow-up with enalapril at the earliest sign of heart failure. CONSENSUS, NYHA class IV heart failure: one-year survival 64% with enalapril (n=127) against 48% with placebo (n=126). Abrupt withdrawal has not been associated with a rapid increase in blood pressure.

5. Regulator

   Aurobindo Pharma Limited. RAMIPRIL capsules, for oral use: full prescribing information US Food and Drug Administration-approved labelling, published in DailyMed (National Library of Medicine); structured product label version 19, effective 18 September 2026, label text revised 09/2026, 2026.

   https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d6d57158-e8f9-4c91-8317-0374e0c87d33

   Funding and finding

   Funding

   not stated. The document is prescribing information approved by the US Food and Drug Administration and published by the labeller, Aurobindo Pharma Limited.

   Finding

   Initial US approval 1991. Indications: hypertension; reduction of the risk of myocardial infarction, stroke or death from cardiovascular causes in patients of 55 years or older at high risk; and heart failure after myocardial infarction. Boxed warning, fetal toxicity: when pregnancy is detected, discontinue as soon as possible; drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus. Chemistry and metabolism: ramiprilat, the diacid metabolite, is a non-sulfhydryl ACE inhibitor; ramipril is converted to ramiprilat by hepatic cleavage of the ester group; ramipril is almost completely metabolised to ramiprilat, which has about 6 times the ACE inhibitory activity of ramipril, and to the inactive diketopiperazine ester, diketopiperazine acid and glucuronides. Pharmacokinetics: peak plasma concentrations of ramipril within 1 hour and of ramiprilat 2 to 4 hours after intake; extent of absorption at least 50% to 60%; absolute bioavailability 28% for ramipril and 44% for ramiprilat; serum protein binding about 73% and 56%; plasma ramiprilat declines triphasically, the initial distribution phase with a half-life of 2 to 4 hours, the apparent elimination phase of free ramiprilat 9 to 18 hours and a terminal phase above 50 hours that probably represents the binding and dissociation kinetics of the ramiprilat-ACE complex and does not contribute to accumulation; after multiple daily doses of 5 to 10 mg the half-life within the therapeutic range was 13 to 17 hours; steady state by the fourth dose; about 60% of parent drug and metabolites is eliminated in urine and about 40% recovered in faeces, with less than 2% of the dose recovered in urine as unchanged ramipril. Single doses of 2.5 to 20 mg inhibit plasma ACE activity by about 60% to 80% at 4 hours and 40% to 60% at 24 hours; multiple doses of 2 mg or more lower plasma ACE activity by more than 90% at 4 hours with over 80% inhibition remaining at 24 hours. Renal impairment: in a single-dose study the AUC(0-24h) for ramiprilat was about 1.7-fold, 3-fold and 3.2-fold higher with mild (creatinine clearance 40 to 80 ml/min), moderate (15 to 40 ml/min) and severe (below 15 ml/min) impairment than with normal renal function; in multiple-dose regimens total exposure to ramiprilat below 40 ml/min/1.73 m2 is 3 to 4 times as large as with normal renal function, and 25% of the usual dose is expected to produce full therapeutic levels of ramiprilat; in hepatic impairment metabolism to ramiprilat appears slowed and plasma ramipril levels are about 3-fold increased, while peak ramiprilat concentrations are unchanged. Mechanism: ACE, a peptidyl dipeptidase, catalyses the conversion of angiotensin I to the vasoconstrictor angiotensin II, which also stimulates adrenal aldosterone secretion; the enzyme is identical to kininase, which degrades bradykinin, and whether raised bradykinin plays a part in the therapeutic effect remains to be elucidated; removal of angiotensin II negative feedback raises plasma renin activity; the drug is antihypertensive even in low-renin hypertension, with a smaller average response in Black than in non-Black patients. Hyperkalaemia (serum potassium above 5.7 mEq/l) occurred in approximately 1% of hypertensive patients; in most cases these were isolated values that resolved despite continued therapy, and no patient was withdrawn for hyperkalaemia; risk factors are renal insufficiency, diabetes mellitus and concomitant drugs that raise serum potassium. Cough: persistent nonproductive cough has been reported with all ACE inhibitors, presumably caused by inhibition of the degradation of endogenous bradykinin, always resolving after discontinuation of therapy. In a later 1-year study increased cough was seen in almost 12% of patients, with about 4% requiring discontinuation. Angio-oedema is presumed to follow effects on the metabolism of eicosanoids and polypeptides, including endogenous bradykinin; in a large US post-marketing study angio-oedema was reported in 3 of 1523 (0.2%) Black and 8 of 8680 (0.09%) non-Black patients, rates that were not statistically different; angioneurotic oedema was reported in 0.3% of patients in US clinical trials. HOPE study, as described in this label: 9541 patients of 55 years or older at high cardiovascular risk, 4645 on ramipril 10 mg once daily, mean follow-up 5 years; the two group sizes given in the label's own table sum to 9297, the number randomised in the HOPE publication; myocardial infarction, stroke or death from cardiovascular causes in 651 of 4645 (14.0%) against 826 of 4652 (17.8%) on placebo (relative risk 0.78, 95% CI 0.70 to 0.86); death from cardiovascular causes 282 (6.1%) against 377 (8.1%) (0.74, 0.64 to 0.87); myocardial infarction 459 (9.9%) against 570 (12.3%) (0.80, 0.70 to 0.90); stroke 156 (3.4%) against 226 (4.9%) (0.68, 0.56 to 0.84); death from any cause 482 (10.4%) against 569 (12.2%) (0.84, 0.75 to 0.95). Reasons for stopping or interrupting treatment in HOPE, ramipril against placebo: cough 7% against 2%, hypotension or dizziness 1.9% against 1.5%, angio-oedema 0.3% against 0.1%. AIRE study: 2006 patients with clinical signs of heart failure 2 to 9 days after acute myocardial infarction, average follow-up 15 months (range 6 to 46 months); ramipril was associated with a 27% reduction in the risk of death from any cause (p=0.002), a 23% reduction in progression to severe heart failure (p=0.017) and a 26% reduction in heart failure-related hospitalisation (p=0.011); adverse reactions more frequent on ramipril included hypotension 11% against 5% and increased cough 8% against 4%. Dual blockade: in ONTARGET, 25,620 patients older than 55 years with atherosclerotic disease or diabetes with end-organ damage were randomised to telmisartan, ramipril or the combination and followed for a median 56 months; the combination gave no benefit for the composite of cardiovascular death, myocardial infarction, stroke and heart failure hospitalisation and increased clinically important renal dysfunction, so concomitant use is not recommended. Abrupt withdrawal of ramipril has not resulted in a rapid increase in blood pressure. Patients are advised to report immediately any sign suggesting angio-oedema and to temporarily discontinue the drug until they have consulted the prescribing physician, and not to use potassium-containing salt substitutes without consulting their physician.

6. Independent research

   Fralick M, Macdonald EM, Gomes T, Antoniou T, Hollands S, Mamdani MM, et al. Co-trimoxazole and sudden death in patients receiving inhibitors of renin-angiotensin system: population based study BMJ, 2014.

   doi:10.1136/bmj.g6196PubMed 25359996

   Funding and finding

   Follow-up

   1 April 1994 to 1 January 2012; exposure windows of 7 and 14 days after an antibiotic prescription

   Funding

   This study was supported in part by a grant from the Canadian Drug Safety and Effectiveness Research Network (CDSERN) and by the Institute for Clinical Evaluative Sciences (ICES), a non-profit research institute sponsored by the Ontario Ministry of Health and Long-Term Care (MOHLTC). The opinions, results and conclusions reported in this paper are those of the authors and are independent from the funding sources.

   Finding

   Of 39,879 sudden deaths, 1027 occurred within 7 days of an antibiotic prescription and were matched to 3733 controls. Against amoxicillin, co-trimoxazole was associated with sudden death, adjusted odds ratio 1.38 (95% CI 1.09 to 1.76) within 7 days and 1.54 (1.29 to 1.84) within 14 days, corresponding to approximately three sudden deaths within 14 days per 1000 co-trimoxazole prescriptions. Ciprofloxacin, which prolongs the QT interval, gave 1.29 (1.03 to 1.62); nitrofurantoin and norfloxacin showed no such risk. The authors propose unrecognised severe hyperkalaemia as the mechanism.

7. Independent research

   Lapi F, Azoulay L, Yin H, Nessim SJ, Suissa S. Concurrent use of diuretics, angiotensin converting enzyme inhibitors, and angiotensin receptor blockers with non-steroidal anti-inflammatory drugs and risk of acute kidney injury: nested case-control study BMJ, 2013.

   doi:10.1136/bmj.e8525PubMed 23299844

   Funding and finding

   Participants

   487,372

   Follow-up

   mean 5.9 years (SD 3.4)

   Funding

   This study was funded in part by infrastructure grants from the Drug Safety and Effectiveness Network (DSEN), the Canadian Institute of Health Research (CIHR), and the Canada Foundation for Innovation. The funding sources had no role in the design, analysis, or interpretation of the results, and thus the authors were independent from the funding sources.

   Finding

   2215 cases of acute kidney injury requiring hospital admission arose during follow-up, an incidence of 7 per 10,000 person-years. Current use of a double combination of a diuretic, an ACE inhibitor or an angiotensin receptor blocker with a non-steroidal anti-inflammatory drug was not associated with an increased rate. Current use of a triple combination of a diuretic with an ACE inhibitor or angiotensin receptor blocker and a non-steroidal anti-inflammatory drug was associated with a rate ratio of 1.31 (95% CI 1.12 to 1.53), highest in the first 30 days of combined use (1.82, 1.35 to 2.46).

8. Regulator

   Hikma Pharmaceuticals USA Inc. Captopril tablets, USP: prescribing information US Food and Drug Administration-approved labelling, published in DailyMed (National Library of Medicine); structured product label version 29, effective 27 December 2024, label text Rev. 08/24, 2024.

   https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=607687f4-63cf-411c-a20b-21d238a6b7a7

   Funding and finding

   Funding

   not stated. The document is prescribing information approved by the US Food and Drug Administration and published by the labeller, Hikma Pharmaceuticals USA Inc.

   Finding

   Neutropenia below 1000/mm3 with myeloid hypoplasia: one patient of over 8600 hypertensive patients with normal renal function in clinical trials; about 1 per 500 with serum creatinine of 1.6 mg/dl or more without collagen vascular disease; 3.7% with collagen vascular disease (for example systemic lupus erythematosus or scleroderma) and impaired renal function. About half of neutropenic patients developed infections or other features of agranulocytosis; neutropenia was usually detected within three months of starting; neutrophils usually returned to normal about two weeks after discontinuation; about 13% of cases ended fatally, almost all in patients with collagen vascular disease, renal failure, heart failure or immunosuppressant therapy; more than 75% of reported heart-failure cases also received procainamide. Proteinuria above 1 g/day in about 0.7%, mostly with prior renal disease or doses above 150 mg/day; nephrotic syndrome in about one-fifth of these. Cholestatic jaundice progressing to fulminant hepatic necrosis and sometimes death has occurred rarely with ACE inhibitors. Angio-oedema in approximately 1 in 1000 patients, with fatal upper-airway obstruction reported; intestinal angio-oedema reported. Cough reported in 0.5 to 2% of captopril-treated patients in clinical trials. Rash in about 4 to 7 of 100, taste loss in 2 to 4 of 100. SAVE: 2231 patients with ejection fraction of 40% or less 3 to 16 days after myocardial infarction, average follow-up 3.5 years; risk reduction 19% for all-cause mortality and 21% for cardiovascular death. Type 1 diabetic nephropathy: 409 patients aged 18 to 49 with proteinuria of 500 mg/day or more, median follow-up 3 years; 51% reduction in risk of doubling of serum creatinine and of end-stage renal disease or death. In 235 normotensive type 1 diabetic patients with microalbuminuria followed up to 2 years, captopril delayed progression to overt nephropathy, but the long-term clinical benefit of reducing progression from microalbuminuria to proteinuria has not been established. Withdrawal of treatment for hyperkalaemia in 4 of 207 type 1 diabetic patients with proteinuria. Abrupt withdrawal has not been associated with a rapid increase in blood pressure.

9. Regulator

   Cosette Pharmaceuticals, Inc. BENICAR (olmesartan medoxomil) tablets, for oral use: full prescribing information US Food and Drug Administration-approved labelling, published in DailyMed (National Library of Medicine); structured product label version 1, effective 23 September 2025, 2025.

   https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=dc3f1fd4-5578-4c5d-be7b-12e3f8f3e7df

   Funding and finding

   Funding

   not stated. The document is prescribing information approved by the US Food and Drug Administration and published by the labeller, Cosette Pharmaceuticals, Inc.

   Finding

   Warning 5.5, sprue-like enteropathy: severe, chronic diarrhoea with substantial weight loss has been reported months to years after starting olmesartan; intestinal biopsies often showed villous atrophy; if no other cause is found, alternative antihypertensive therapy is to be considered. Post-marketing reports include angio-oedema, anaphylactic reactions, hyperkalaemia, rhabdomyolysis and acute renal failure. In the placebo-controlled ROADMAP trial (n=4447) of olmesartan 40 mg daily in type 2 diabetes with normoalbuminuria, onset of microalbuminuria was delayed but decline in GFR was not slowed, and adjudicated cardiovascular death occurred in 15 on olmesartan against 3 on placebo (hazard ratio 4.9, 95% CI 1.4 to 17). In an epidemiological study of patients aged 65 or older with over 300,000 patient-years of exposure, diabetic patients taking 40 mg/day for more than 6 months had a higher risk of death than those on other angiotensin receptor blockers (hazard ratio 2.0, 1.1 to 3.8), whereas non-diabetic patients had a lower risk (0.46, 0.24 to 0.86); the label states that the data raise a concern of possible increased cardiovascular risk with high-dose olmesartan in diabetes but are not conclusive.

10. Independent research

    Hicks BM, Filion KB, Yin H, Sakr L, Udell JA, Azoulay L. Angiotensin converting enzyme inhibitors and risk of lung cancer: population based cohort study BMJ, 2018.

    doi:10.1136/bmj.k4209PubMed 30355745

    Funding and finding

    Participants

    992,061

    Follow-up

    mean 6.4 years (SD 4.7), to 31 December 2016

    Funding

    This study was funded by a Foundation Scheme grant from the Canadian Institutes of Health Research. BMH holds a Cancer Research UK population research fellowship; KBF and LA hold awards from the Fonds de recherche du Québec – Santé and McGill University; JAU holds a Heart and Stroke Foundation of Canada award. The funding source had no influence on the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or the decision to submit the manuscript for publication.

    Finding

    7952 incident lung cancers (crude incidence 1.3 per 1000 person-years). Against angiotensin receptor blockers, use of ACE inhibitors was associated with lung cancer, incidence 1.6 against 1.2 per 1000 person-years, hazard ratio 1.14 (95% CI 1.01 to 1.29); the association appeared after five years of use (1.22, 1.06 to 1.40) and peaked after more than ten years (1.31, 1.08 to 1.59). The authors cite accumulation of bradykinin and substance P in the lung as a possible mechanism and state that randomised trials of ACE inhibitors had median follow-up of 3.5 years.

11. Regulator

    European Medicines Agency. Sartan medicines: companies to review manufacturing processes to avoid presence of nitrosamine impurities European Medicines Agency, EMA/248364/2019 Rev 1, 17 April 2019; Article 31 referral EMEA/H/A-31/1471, 2019.

    https://www.ema.europa.eu/en/documents/referral/angiotensin-ii-receptor-antagonists-sartans-article-31-referral-sartan-medicines-companies-review-manufacturing-processes-avoid-presence-nitrosamine-impurities_en.pdf

    Funding and finding

    Funding

    European Medicines Agency

    Finding

    N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA), classified as probable human carcinogens, were detected in some sartan medicines; before June 2018 they were not among the impurities identified in sartans and were not detected by routine tests. They can form during synthesis of sartans containing a tetrazole ring (candesartan, irbesartan, losartan, olmesartan, valsartan), NDMA from dimethylamine in the presence of nitrites under acidic conditions, or from contaminated equipment or reagents. The highest possible risk was estimated from animal studies: if 100,000 patients took valsartan from Zhejiang Huahai at the highest dose every day for 6 years, NDMA could cause 22 extra cancers over their lifetimes, and NDEA 8 extra cancers per 100,000 over 4 years. Interim limits of 96.0 ng/day for NDMA and 26.5 ng/day for NDEA applied for a 2-year transition, after which products must contain less than 0.03 ppm. Some medicines were recalled. The EMA page for the referral states that in November 2020 limits were aligned with those for other medicines so that excess lifetime cancer risk stays below 1 in 100,000.

12. Independent research

    Mansouri I, Botton J, Semenzato L, Haddy N, Zureik M. N-nitrosodimethylamine-Contaminated Valsartan and Risk of Cancer: A Nationwide Study of 1.4 Million Valsartan Users Journal of the American Heart Association, 2022.

    doi:10.1161/JAHA.122.026739PubMed 36533625

    Funding and finding

    Follow-up

    median 4.0 years exposed (4,253,623 person-years) and 3.5 years unexposed (2,565,339 person-years)

    Funding

    Sources of Funding: None. Disclosures: None.

    Finding

    986,126 patients exposed to NDMA-contaminated and 670,388 to uncontaminated valsartan. Overall cancer: adjusted hazard ratio 0.99 (95% CI 0.98 to 1.0). Liver cancer 1.12 (1.04 to 1.22) and melanoma 1.10 (1.03 to 1.18), estimated at a mean of 3.7 and 5.8 extra cases per 100,000 person-years respectively.

13. Regulator

    EFSA Panel on Nutrition, Novel Foods and Food Allergens (NDA), Turck D, Castenmiller J, de Henauw S, Hirsch-Ernst KI, Kearney J, et al. Dietary reference values for sodium EFSA Journal, 2019.

    doi:10.2903/j.efsa.2019.5778PubMed 32626425

    Funding and finding

    Funding

    European Food Safety Authority, on request from the European Commission (question number EFSA-Q-2011-01224).

    Finding

    Sodium chloride is the main constituent of table salt; 1 g of sodium chloride provides 0.4 g of sodium and 0.6 g of chloride. In healthy people almost all dietary sodium is absorbed, along most of the small and large intestine; apical co-transporters couple sodium entry to the uptake of solutes, the basolateral Na+/K+-ATPase exchanges three intracellular Na+ for two extracellular K+, net sodium and water absorption occurs in the distal ileum and colon, and distal absorption responds to aldosterone. Renin is released from the juxtaglomerular apparatus in response to reduced afferent arteriolar pressure, increased sympathetic activity and decreased distal tubular NaCl; renin hydrolyses angiotensinogen to angiotensin I, which angiotensin-converting enzyme converts to angiotensin II; angiotensin II stimulates proximal sodium reabsorption, arteriolar constriction and adrenal aldosterone release; aldosterone stimulates sodium recovery in exchange for potassium in distal tubule, collecting ducts and distal colon. Genotypes with increased ENaC function cause volume expansion, hypertension and hypokalaemia (e.g. Liddle's syndrome). A sodium intake of 2.0 g/day is considered safe and adequate for adults, including pregnant and lactating women.

14. Regulator

    Novartis Pharmaceuticals Corporation. ENTRESTO (sacubitril and valsartan) tablets and ENTRESTO SPRINKLE oral pellets: full prescribing information US Food and Drug Administration-approved labelling, published in DailyMed (National Library of Medicine); structured product label version 25, effective 6 July 2026, 2026.

    https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=000dc81d-ab91-450c-8eae-8eb74e72296f

    Funding and finding

    Funding

    not stated. The document is prescribing information approved by the US Food and Drug Administration and published by the labeller, Novartis Pharmaceuticals Corporation.

    Finding

    A combination of a neprilysin inhibitor, sacubitril (metabolised to LBQ657), and the angiotensin receptor blocker valsartan; contraindicated with ACE inhibitors, within 36 hours of switching, because of increased angio-oedema risk, and after angio-oedema on an ACE inhibitor or angiotensin receptor blocker. PARADIGM-HF required sequential enalapril and sacubitril-valsartan run-in periods (median 15 and 29 days): 1102 patients (10.5%) left during the enalapril run-in, 5.6% for adverse events (renal dysfunction 1.7%, hyperkalaemia 1.7%, hypotension 1.4%), and a further 10.4% during the sacubitril-valsartan run-in; the label states that because of this run-in design the adverse reaction rates are lower than expected in practice. In the double-blind period (4203 against 4229 patients, median exposure 24 months), angio-oedema occurred in 0.5% on sacubitril-valsartan against 0.2% on enalapril, and in Black patients 2.4% against 0.5%; hypotension 18% against 12%, hyperkalaemia 12% against 14%, cough 9% against 13%, renal failure 5% against 5%; potassium above 5.5 mEq/l in about 16% and creatinine rise above 50% in about 16% of both groups. In cynomolgus monkeys, two weeks of treatment raised cerebrospinal fluid amyloid-beta 1-40, 1-42 and 1-38 without a rise in brain amyloid-beta.

15. Industry-funded

    ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) JAMA, 2002.

    doi:10.1001/jama.288.23.2981PubMed 12479763

    Funding and finding

    Registration

    NCT00000542

    Participants

    33,357

    Follow-up

    mean 4.9 years; outcome rates reported at 6 years

    Funding

    This study was supported by contract NO1-HC-35130 with the National Heart, Lung, and Blood Institute (NHLBI). ALLHAT investigators received contributions of study medications supplied by Pfizer (amlodipine and doxazosin), AstraZeneca (atenolol and lisinopril), and Bristol-Myers Squibb (pravastatin), and financial support provided by Pfizer. Role of the Sponsor: the NHLBI sponsored the study and was involved in all aspects other than direct operations of the study centres, including collection, analysis and interpretation of the data and the decision to submit the manuscript for publication. Partial industry funding sets the class to industry; a role of Pfizer in design, analysis or publication is not stated.

    In-kind support

    Study medications supplied by Pfizer (amlodipine and doxazosin), AstraZeneca (atenolol and lisinopril) and Bristol-Myers Squibb (pravastatin).

    Finding

    Chlorthalidone 12.5 to 25 mg/day (n=15,255), amlodipine 2.5 to 10 mg/day (n=9048) or lisinopril 10 to 40 mg/day (n=9054), double-blind. Six-year rates, lisinopril versus chlorthalidone: fatal coronary heart disease or non-fatal myocardial infarction 11.4% versus 11.5% (relative risk 0.99, 95% CI 0.91 to 1.08); all-cause mortality 17.2% versus 17.3% (1.00, 0.94 to 1.08); stroke 6.3% versus 5.6% (1.15, 1.02 to 1.30); heart failure 8.7% versus 7.7% (1.19, 1.07 to 1.31); combined cardiovascular disease 33.3% versus 30.9% (1.10, 1.05 to 1.16). Stroke relative risk 1.40 (1.17 to 1.68) in Black and 1.00 (0.85 to 1.17) in non-Black participants. Mean follow-up systolic pressure was 2 mm Hg higher with lisinopril overall and 4 mm Hg higher in Black participants. Angio-oedema in 38 of 9054 (0.4%) on lisinopril versus 8 of 15,255 (0.1%) on chlorthalidone, with one fatal case in the lisinopril group. Serum potassium at 4 years 4.5 versus 4.1 mEq/l, with values below 3.5 mEq/l in 0.8% versus 8.5%; new fasting glucose of 126 mg/dl or more at 4 years in 8.1% versus 11.6% of participants without diabetes at baseline.

16. Funding unknown

    Nussberger J, Cugno M, Amstutz C, Cicardi M, Pellacani A, Agostoni A. Plasma bradykinin in angio-oedema Lancet, 1998.

    doi:10.1016/S0140-6736(97)09137-XPubMed 9734886

    Funding and finding

    Participants

    49

    Funding

    not read: the publisher page is not accessible and the PubMed abstract carries no funding statement.

    Finding

    With a specific assay (liquid-phase extraction, HPLC and radioimmunoassay), plasma bradykinin rose to two to twelve times the upper limit of normal during attacks of hereditary and acquired angio-oedema. In the single patient treated with captopril, plasma bradykinin was 47 fmol/ml during an acute attack and 3.2 fmol/ml in remission after withdrawal of the drug, against a geometric mean of 2.2 fmol/ml in healthy volunteers.

17. Industry-funded

    Baş M, Greve J, Stelter K, Havel M, Strassen U, Rotter N, et al. A randomized trial of icatibant in ACE-inhibitor-induced angioedema New England Journal of Medicine, 2015.

    doi:10.1056/NEJMoa1312524PubMed 25629740

    Funding and finding

    Registration

    NCT01154361

    Participants

    27

    Funding

    Funded by Shire and the Federal Ministry of Education and Research of Germany (statement in the published abstract). The registry names the Technical University of Munich as lead sponsor.

    Finding

    Phase 2, double-blind, double-dummy trial of icatibant 30 mg subcutaneously, a bradykinin B2 receptor antagonist, against intravenous prednisolone 500 mg plus clemastine 2 mg. Median time to complete resolution of oedema 8.0 hours against 27.1 hours (P=0.002); complete resolution within 4 hours in 5 of 13 against 0 of 14. Three patients on standard therapy required rescue treatment and one required tracheotomy.

18. Industry-funded

    Sinert R, Levy P, Bernstein JA, Body R, Sivilotti MLA, Moellman J, et al.; CAMEO study group. Randomized Trial of Icatibant for Angiotensin-Converting Enzyme Inhibitor-Induced Upper Airway Angioedema Journal of Allergy and Clinical Immunology: In Practice, 2017.

    doi:10.1016/j.jaip.2017.03.003PubMed 28552382

    Funding and finding

    Registration

    NCT01919801

    Participants

    121

    Funding

    The registry entry names Shire as lead sponsor, with PPD Development as collaborator; four authors are Shire employees in clinical development and biostatistics. The funding statement of the article was not read.

    Finding

    Icatibant 30 mg (n=61) against placebo (n=60), given a median 7.8 hours after symptom onset. Median time to meeting discharge criteria 4.0 hours in each group (P=0.63); median time to onset of symptom relief 2.0 against 1.6 hours (P=0.57); no difference in any secondary end point or subgroup.

19. Funding unknown

    Cooper WO, Hernandez-Diaz S, Arbogast PG, Dudley JA, Dyer S, Gideon PS, et al. Major congenital malformations after first-trimester exposure to ACE inhibitors New England Journal of Medicine, 2006.

    doi:10.1056/NEJMoa055202PubMed 16760444

    Funding and finding

    Participants

    29,507

    Follow-up

    first year of life

    Funding

    not read: the publisher page is not accessible. PubMed lists grants HS10384 (Agency for Healthcare Research and Quality) and 223-02-3003 (US Public Health Service).

    Finding

    Against infants without antihypertensive exposure, first-trimester ACE inhibitor exposure was associated with major congenital malformations (risk ratio 2.71, 95% CI 1.72 to 4.27), cardiovascular malformations (3.72, 1.89 to 7.30) and central nervous system malformations (4.39, 1.37 to 14.02); first-trimester exposure to other antihypertensives was not (0.66, 0.25 to 1.75). Malformations were confirmed by medical record review.

20. Independent research

    Li DK, Yang C, Andrade S, Tavares V, Ferber JR. Maternal exposure to angiotensin converting enzyme inhibitors in the first trimester and risk of malformations in offspring: a retrospective cohort study BMJ, 2011.

    doi:10.1136/bmj.d5931PubMed 22010128

    Funding and finding

    Participants

    465,754

    Funding

    This project was funded under Contract No 290050033I from the Agency for Healthcare Research and Quality, US Department of Health and Human Services as part of the Developing Evidence to Inform Decisions about Effectiveness (DEcIDE) programme. The Food and Drug Administration, Office of Women's Health also contributed funds. The authors of this report are responsible for its content.

    Finding

    First-trimester-only ACE inhibitor use 0.9 per 1000 pregnancies. Against women with neither hypertension nor antihypertensives, congenital heart defects occurred in 15 of 381 (3.9%) exposed to ACE inhibitors against 6232 of 400,021 (1.6%), odds ratio 1.54 (95% CI 0.90 to 2.62), and other antihypertensives gave 1.52 (1.04 to 2.21). Against women with untreated hypertension (708 of 29,735, 2.4%), neither ACE inhibitors (1.14, 0.65 to 1.98) nor other antihypertensives (1.12, 0.76 to 1.64) were associated with congenital heart defects; the authors attribute the apparent excess to the underlying hypertension.

21. Independent research

    Bateman BT, Patorno E, Desai RJ, Seely EW, Mogun H, Dejene SZ, et al. Angiotensin-Converting Enzyme Inhibitors and the Risk of Congenital Malformations Obstetrics and Gynecology, 2017.

    doi:10.1097/AOG.0000000000001775PubMed 27926639

    Funding and finding

    Participants

    1,333,624

    Funding

    Research reported in this publication was supported by the Eunice Kennedy Shriver National Institute of Child Health & Human Development of the NIH under Award Number K08HD075831 (BTB), the National Heart Lung and Blood Institute under grant number K24HL096141 (EWS), and the National Institute of Mental Health under grant number K01MH099141 (KH). The content is solely the responsibility of the authors.

    Finding

    Unadjusted, malformations occurred in 5.9% of ACE-inhibitor-exposed against 3.3% of unexposed pregnancies (relative risk 1.82, 95% CI 1.61 to 2.06) and cardiac malformations in 3.4% against 1.2% (2.95, 2.50 to 3.47). Restricted to pregnancies with chronic hypertension and adjusted for confounders, relative risks were 0.89 (0.75 to 1.06) for any malformation, 0.95 (0.75 to 1.21) for cardiac and 0.54 (0.26 to 1.11) for central nervous system malformations.

22. Regulator

    European Medicines Agency; marketing authorisation holder Sanofi Winthrop Industrie. Aprovel (irbesartan): EPAR product information, summary of product characteristics European Medicines Agency, European public assessment report product information, read October 2026, 2026.

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

    Funding and finding

    Funding

    not stated. The document is product information approved by the European Commission on the opinion of the European Medicines Agency and supplied by the marketing authorisation holder.

    Finding

    Section 4.4: hypoglycaemia may be induced, particularly in diabetic patients, and insulin or antidiabetic doses may need adjustment; intestinal angio-oedema with abdominal pain, nausea, vomiting and diarrhoea has been reported with angiotensin II receptor antagonists and resolves on discontinuation; increased risk of severe hypotension and renal insufficiency with bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney; dual blockade with ACE inhibitors, angiotensin receptor blockers or aliskiren increases hypotension, hyperkalaemia and acute renal failure and is not recommended; primary aldosteronism generally does not respond; less blood-pressure-lowering effect in Black people, possibly from low-renin states. Section 4.6: first-trimester epidemiology for ACE inhibitors is not conclusive but a small increase in risk cannot be excluded; second- and third-trimester exposure is known to cause fetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia). Section 4.8: hyperkalaemia of 5.5 mEq/l or more in 29.4% on irbesartan 300 mg against 22% on placebo in diabetic hypertensive patients with microalbuminuria (IRMA 2), and 46.3% against 26.3% with chronic renal insufficiency and overt proteinuria (IDNT). Section 5.1, IDNT (1715 patients, mean 2.6 years): the renal composite was reached by about 33% on irbesartan against 39% on placebo and 41% on amlodipine, without effect on all-cause mortality; renal benefit was not evident in women (32%) or Black patients (26%), and non-fatal myocardial infarction was more frequent in women on irbesartan than on placebo. IRMA 2 (590 patients, 2 years): overt proteinuria in 5.2% on irbesartan 300 mg against 14.9% on placebo. ALTITUDE (aliskiren added to ACE inhibitor or angiotensin receptor blocker in type 2 diabetes) was terminated early for increased adverse outcomes.

23. 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]; NIH Office of the Director [U24HG007822]; NIAID; NIA; NIGMS [R35GM141873]; NIDDK; NEI; NCI; NHLBI; BBSRC [BB/T015608/1]; National Science Foundation Directorate for Biological Sciences [BB/X002179/1]; Open Targets; Horizon 2020 [825575]; Swiss State Secretariat for Education, Research and Innovation; EMBL Australia.

    Finding

    Reviewed UniProtKB entries, release 2026_03, read through rest.uniprot.org. REN (P00797), renin: a highly specific endopeptidase whose only known function is to generate angiotensin I from angiotensinogen in the plasma; cleavage of the Leu-|-Xaa bond in angiotensinogen (EC 3.4.23.15); secreted; interaction with ATP6AP2 gives a 5-fold higher efficiency of angiotensinogen processing; variants cause renal tubular dysgenesis and autosomal dominant tubulointerstitial kidney disease 4. AGT (P01019), angiotensinogen: expressed by the liver and secreted in plasma; renin cleaves it to angiotensin-1, from which ACE removes a dipeptide to yield angiotensin-2; angiotensin-2 acts on AGTR1 and AGTR2, constricts vascular smooth muscle and stimulates aldosterone release; angiotensin 1-7 has been proposed to be cleaved from angiotensin-2 by ACE2 or from angiotensin-1 by neprilysin (MME) and has vasodilator and antidiuretic effects through MAS1; variants are associated with susceptibility to essential hypertension and cause renal tubular dysgenesis. ACE (P12821): a dipeptidyl carboxypeptidase (EC 3.4.15.1) composed of two similar catalytic domains, each with a functional active site and different substrate selectivity; angiotensin I + H2O = L-histidyl-L-leucine + angiotensin II; bradykinin + H2O = L-Phe-L-Arg + bradykinin(1-7); binds 2 Zn2+ and 3 chloride ions per subunit; the dipeptidyl carboxypeptidase activity is strongly activated by chloride and specifically inhibited by lisinopril, captopril and enalaprilat; cleavage of angiotensin I and cholecystokinin is mediated by the C-terminal catalytic region, degradation of N-acetyl-SDKP and of amyloid-beta peptides by the N-terminal domain; also degrades substance P, neurotensin and enkephalins; ubiquitously expressed, with highest levels in lung, kidney, heart, gastrointestinal system and prostate; a soluble form is released after cleavage in the juxtamembrane stalk; the testis-specific isoform contains only one catalytic domain and is required for male fertility; genetic variants in ACE are associated with interindividual variability of plasma ACE levels; variants cause renal tubular dysgenesis. AGTR1 (P30556), type-1 angiotensin II receptor: receptor for angiotensin II; the activated receptor couples to G-alpha proteins G(q) (GNAQ, GNA11, GNA14 or GNA15), activates phospholipase C and raises cytosolic Ca2+, which stimulates protein kinase C; cell membrane; variants cause renal tubular dysgenesis. ACE2 (Q9BYF1): counter-regulatory carboxypeptidase of the renin-angiotensin system; angiotensin II + H2O = angiotensin-(1-7) + L-phenylalanine (EC 3.4.17.23) and angiotensin I + H2O = angiotensin-(1-9) + L-leucine; binds 1 Zn2+ and 1 chloride ion per subunit; not inhibited by the ACE inhibitors lisinopril, captopril and enalaprilat. CYP2C9 (P11712): a cytochrome P450 monooxygenase of the endoplasmic reticulum membrane that inserts one oxygen atom into a substrate and reduces the second to water, with two electrons provided by NADPH through cytochrome P450 reductase; contributes to the wide pharmacokinetic variability of the metabolism of S-warfarin, diclofenac, phenytoin, tolbutamide and losartan.

24. Independent research

    Li EC, Heran BS, Wright JM. Angiotensin converting enzyme (ACE) inhibitors versus angiotensin receptor blockers for primary hypertension Cochrane Database of Systematic Reviews, 2014.

    doi:10.1002/14651858.CD009096.pub2PubMed 25148386

    Funding and finding

    Participants

    11,007

    Follow-up

    mean 4.3 years for total mortality, 4.5 years for total cardiovascular events and 4.1 years for withdrawals due to adverse effects

    Funding

    Internal sources: University of British Columbia, Canada (office space and salary of JMW). External sources: no sources of support supplied.

    Finding

    No evidence of a difference between ACE inhibitors and angiotensin receptor blockers for total mortality (RR 0.98, 95% CI 0.88 to 1.10; 10,248 participants, 5 studies, 3 with events; assumed risk 116 per 1000 on ACE inhibitors), total cardiovascular events (RR 1.07, 0.96 to 1.19; 5499 participants, 3 studies, 1 with events; 179 per 1000) or cardiovascular mortality (RR 0.98, 0.85 to 1.13; 9747 participants, 4 studies, 2 with events). High-quality evidence showed a lower incidence of withdrawal due to adverse effects with the blockers (RR 0.83, 0.74 to 0.93; absolute risk reduction 1.8%, number needed to treat 55 over a mean 4.1 years; 10,963 participants, 8 studies; 113 per 1000 on ACE inhibitors against a corresponding 94 per 1000). Among withdrawals for which a reason was stated, cough accounted for 22 of 51 events (43%) in the ACE inhibitor arms and 2 of 49 (4%) in the blocker arms, and removing cough from the analysis made the difference in withdrawals non-significant. The evidence for mortality was graded moderate and for cardiovascular events low, because at least 9 initially eligible studies may hold unpublished mortality or morbidity data and at least 14 may hold unpublished subgroup data for people with hypertension. The authors state that placebo-controlled trials of angiotensin receptor blockers in hypertension do not exist to their knowledge and are unlikely to be conducted for ethical reasons, so the benefit ACE inhibitors have shown over placebo cannot be extrapolated directly to the blockers.

25. Independent research

    Schmidt M, Mansfield KE, Bhaskaran K, Nitsch D, Sørensen HT, Smeeth L, et al. Serum creatinine elevation after renin-angiotensin system blockade and long term cardiorenal risks: cohort study BMJ, 2017.

    doi:10.1136/bmj.j791PubMed 28279964

    Funding and finding

    Participants

    122,363

    Follow-up

    1997 to 2014; risks reported at 1, 5 and 10 years

    Funding

    MS was supported by Aarhus University Hospital, the A.P. Møller Foundation for the Advancement of Medical Science, Snedkermester Sophus Jacobsen and Hustru Astrid Jacobsens Fond, and Christian og Ottilia Brorsons Rejselegat; HTS by the Program for Clinical Research Infrastructure established by the Lundbeck Foundation and the Novo Nordisk Foundation; KB by a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society; LAT and KEM by a Wellcome Trust intermediate clinical fellowship. None of these funding sources had a role in the design, conduct, analysis, or reporting of the study.

    Finding

    The authors attribute the creatinine rise after starting these drugs to antagonism of angiotensin II-mediated efferent arteriolar constriction, and cite data that only 10% of patients receive the recommended monitoring and only 20% of those with a rise of 30% or more discontinue. 2078 patients (1.7%) had a creatinine increase of 30% or more after starting treatment; they were more often women, aged 80 or over, with heart failure, and using non-steroidal anti-inflammatory drugs, loop or potassium-sparing diuretics. Against increases below 30%, adjusted incidence rate ratios were 3.43 (95% CI 2.40 to 4.91) for end-stage renal disease, 1.46 (1.16 to 1.84) for myocardial infarction, 1.37 (1.14 to 1.65) for heart failure and 1.84 (1.65 to 2.05) for death; 10-year mortality was 49.2% against 22.5%. The relation was graded: against increases below 10%, increases of 10 to 19% gave a mortality rate ratio of 1.15 (1.09 to 1.22) and 20 to 29% gave 1.35 (1.23 to 1.49). The authors state that the 30% stopping threshold lacks a clear rationale, and that the results identify a high-risk group but do not necessarily support discontinuation.

26. Independent research

    Choi HK, Soriano LC, Zhang Y, Rodríguez LA. Antihypertensive drugs and risk of incident gout among patients with hypertension: population based case-control study BMJ, 2012.

    doi:10.1136/bmj.d8190PubMed 22240117

    Funding and finding

    Participants

    74,768

    Follow-up

    UK general practice records, 2000 to 2007

    Funding

    This work was supported in part by grants from the National Institutes of Health (AR056291 and P60AR047785). The Spanish Centre for Pharmacoepidemiological Research has received an unrestricted research grant from Novartis to work on other projects related to gout. The funding sources had no role in the design, conduct, or reporting of the study or in the decision to submit the manuscript for publication.

    Finding

    Among people with hypertension, multivariable relative risks of incident gout with current use were 0.81 (95% CI 0.70 to 0.94) for losartan, 1.29 (1.16 to 1.43) for other angiotensin receptor blockers, 1.24 (1.17 to 1.32) for ACE inhibitors, 0.87 (0.82 to 0.93) for calcium channel blockers, 2.36 (2.21 to 2.52) for diuretics and 1.48 (1.40 to 1.57) for beta blockers. With losartan the relative risk fell from 0.98 below one year of use to 0.87 at 1 to 1.9 years and 0.71 at two years or more (P<0.05 for trend).

27. 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.

28. Funding unknown

    Bangalore S, Kumar S, Messerli FH. Angiotensin-converting enzyme inhibitor associated cough: deceptive information from the Physicians' Desk Reference American Journal of Medicine, 2010.

    doi:10.1016/j.amjmed.2010.06.014PubMed 21035591

    Funding and finding

    Participants

    198,130

    Follow-up

    at least 3 months in each included trial

    Funding

    not read: the publisher page is not accessible and the PubMed abstract carries no funding statement.

    Finding

    Pooled weighted incidence of cough with enalapril 11.48% (95% CI 9.54% to 13.41%), nine times the 1.3% in the Physicians' Desk Reference and drug label; pooled withdrawal for cough with enalapril 2.57% (2.40% to 2.74%), 31 times the 0.1% in the label. Reported incidence rose over two decades but stayed several-fold below the trial data in the label; results were similar for most other ACE inhibitors. The authors expect real-world rates to exceed trial rates.

29. Independent research

    Makani H, Bangalore S, Desouza KA, Shah A, Messerli FH. Efficacy and safety of dual blockade of the renin-angiotensin system: meta-analysis of randomised trials BMJ, 2013.

    doi:10.1136/bmj.f360PubMed 23358488

    Funding and finding

    Participants

    68,405

    Follow-up

    mean trial duration 52 weeks

    Funding

    This research received no specific grant from any funding agency in the public, commercial, or not for profit sectors. None of the authors received any compensation for their work on this manuscript.

    Finding

    Against monotherapy, dual blockade did not reduce all-cause mortality (relative risk 0.97, 95% CI 0.89 to 1.06) or cardiovascular mortality (0.96, 0.88 to 1.05) and reduced admissions for heart failure (0.82, 0.74 to 0.92). Hyperkalaemia (potassium above 5.5 mmol/l) occurred in 2188 of 22,717 (9.6%) on dual therapy against 1887 of 37,921 (4.9%) on monotherapy (1.55, 1.32 to 1.82); hypotension rose by 66%, renal failure by 41% and withdrawal for adverse events by 27%. The authors note that the COOPERATE trial of dual blockade for nephroprotection was retracted by the Lancet after inconsistencies were found.

30. 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.

31. 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.

32. Funding unknown

    PEACE Trial Investigators; writing committee Braunwald E, Domanski MJ, Fowler SE, Geller NL, Gersh BJ, Hsia J, et al. Angiotensin-converting-enzyme inhibition in stable coronary artery disease New England Journal of Medicine, 2004.

    doi:10.1056/NEJMoa042739PubMed 15531767

    Funding and finding

    Participants

    8,290

    Follow-up

    median 4.8 years

    Funding

    not read: the author manuscript in PubMed Central lacks the funding section and the publisher page is not accessible. Three writing-committee members are National Heart, Lung, and Blood Institute staff; PubMed indexes US Public Health Service and non-US-government support.

    Finding

    Double-blind trandolapril, target 4 mg/day (n=4158), against placebo (n=4132). Cardiovascular death, myocardial infarction or coronary revascularisation in 21.9% against 22.5% (hazard ratio 0.96, 95% CI 0.88 to 1.06). The authors conclude that in patients with stable coronary disease and preserved left ventricular function on current therapy, in whom event rates are lower than in earlier ACE inhibitor trials, there is no evidence that adding an ACE inhibitor provides further benefit.

33. 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.

34. 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.

35. Expert consensus

    National Institute for Health and Care Excellence. Hypertension in adults: diagnosis and management. NICE guideline NG136 National Institute for Health and Care Excellence, published 28 August 2019, last updated 26 February 2026, 2026.

    https://www.nice.org.uk/guidance/ng136/chapter/recommendations

    Funding and finding

    Funding

    not stated

    Finding

    Step 1 treatment, recommendations marked 2019: offer a calcium channel blocker to adults starting step 1 antihypertensive treatment who are aged 55 or over and do not have type 2 diabetes, or who are of Black African or African-Caribbean family origin and do not have type 2 diabetes, of any age (1.4.35); if a calcium channel blocker is not tolerated, for example because of oedema, offer a thiazide-like diuretic (1.4.36); if there is evidence of heart failure, offer a thiazide-like diuretic (1.4.37). Step 2: if hypertension is not controlled on a calcium channel blocker, offer the choice of an ACE inhibitor, an angiotensin receptor blocker or a thiazide-like diuretic in addition (1.4.42); if it is not controlled on an ACE inhibitor or angiotensin receptor blocker, offer the choice of a calcium channel blocker or a thiazide-like diuretic in addition (1.4.41). Step 3: offer an ACE inhibitor or angiotensin receptor blocker with a calcium channel blocker and a thiazide-like diuretic (1.4.45). Step 4: patients whose hypertension is not controlled on optimal tolerated doses of those three drugs are regarded as having resistant hypertension (1.4.46).

36. Funding unknown

    Hinton J, Reeves T, Shah BN. Analysis of conflicts of interest among authors and researchers of European clinical guidelines in cardiovascular medicine Clinical Medicine (London), 2021.

    doi:10.7861/clinmed.2020-0552PubMed 33762382

    Funding and finding

    Funding

    not stated: the full text on PubMed Central carries no funding or competing-interest statement.

    Finding

    Of 603 recommendations, 271 (45%) concerned pharmaceutical agents, 72 of 169 in the heart failure guideline. In every guideline except pericardial diseases, at least 80% of committee authors had a relevant financial conflict of interest, most often a direct personal payment (68 to 82%). Industry support of cited studies ranged from 5% to 65% across guidelines, and when a cited study was industry-funded its authors were conflicted with the sponsor in 55 to 90% of cases. The authors propose that guideline writers be free of such conflicts.

37. Independent research

    Legrand M, Falcone J, Cholley B, Charbonneau H, Delaporte A, Lemoine A, et al.; Stop-or-Not Trial Group. Continuation vs Discontinuation of Renin-Angiotensin System Inhibitors Before Major Noncardiac Surgery: The Stop-or-Not Randomized Clinical Trial JAMA, 2024.

    doi:10.1001/jama.2024.17123PubMed 39212270

    Funding and finding

    Registration

    NCT03374449

    Participants

    2,222

    Follow-up

    28 days after surgery

    Funding

    This study was supported by a grant from the French Ministry of Health (Programme Hospitalier de Recherche Clinique National). The French Ministry of Health 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

    Continuation until the day of surgery (n=1107) against discontinuation 48 hours before surgery (n=1115). Death from any cause or major postoperative complications within 28 days: 247 of 1107 (22%) with continuation against 245 of 1115 (22%) with discontinuation (risk ratio 1.02, 95% CI 0.87 to 1.19). Intraoperative hypotension occurred in 54% with continuation against 41% with discontinuation (risk ratio 1.31, 1.19 to 1.44). Acute kidney injury, organ failure and length of stay did not differ.

38. Independent research

    Bhandari S, Mehta S, Khwaja A, Cleland JGF, Ives N, Brettell E, et al.; STOP ACEi Trial Investigators. Renin-Angiotensin System Inhibition in Advanced Chronic Kidney Disease New England Journal of Medicine, 2022.

    doi:10.1056/NEJMoa2210639PubMed 36326117

    Funding and finding

    Registration

    ISRCTN62869767; EudraCT 2013-003798-82

    Participants

    411

    Follow-up

    3 years

    Funding

    Funded by the National Institute for Health Research and the Medical Research Council (statement in the published abstract). A post hoc analysis of the same trial gives the grant as NIHR-HTA 11/30/07 from the National Institute for Health Research and the Medical Research Council. The role of the funders is not stated in a readable source.

    Finding

    Open-label trial of discontinuing against continuing renin-angiotensin system inhibitors. At 3 years the least-squares mean eGFR was 12.6 against 13.3 ml/min/1.73 m2 (difference -0.7, 95% CI -2.5 to 1.0), with no heterogeneity across prespecified subgroups. End-stage kidney disease or kidney replacement therapy occurred in 128 (62%) after discontinuation and 115 (56%) with continuation (hazard ratio 1.28, 0.99 to 1.65). Cardiovascular events 108 against 88 and deaths 20 against 22.

39. Independent research

    Halliday BP, Wassall R, Lota AS, Khalique Z, Gregson J, Newsome S, et al. Withdrawal of pharmacological treatment for heart failure in patients with recovered dilated cardiomyopathy (TRED-HF): an open-label, pilot, randomised trial Lancet, 2019.

    doi:10.1016/S0140-6736(18)32484-XPubMed 30429050

    Funding and finding

    Registration

    NCT02859311

    Participants

    51

    Follow-up

    6 months randomised, then 6 months single-arm crossover

    Funding

    The study was funded by a Clinical Research Training Fellowship from the British Heart Foundation (FS/15/29/31492) and received additional support from the Alexander Jansons Foundation, the Cardiovascular Research Centre and NIHR Biomedical Research Unit at Royal Brompton Hospital, the NIHR Imperial College Biomedical Research Centre, the Wellcome Trust and Rosetrees Trust. The British Heart Foundation provided peer review of the grant proposal and had no other role; the other funders had no role in study design, data collection, analysis, interpretation or writing.

    Finding

    All 51 patients took an ACE inhibitor or angiotensin receptor blocker at enrolment. Phased withdrawal (loop diuretic, then mineralocorticoid receptor antagonist, then beta-blocker, finally ACE inhibitor or angiotensin receptor blocker) against continuation. Relapse within 6 months in 11 of 25 (44%) after withdrawal against none of 26 with continuation (Kaplan-Meier event rate 45.7%, 95% CI 28.5 to 67.2). In the crossover phase, 9 of 25 who then withdrew relapsed within 6 months (36.0%, 20.6 to 57.8). No deaths; three serious adverse events in the withdrawal group. Anonymised participant data are available on request.

40. 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.