Benazepril

What it is

Benazepril is a prescription tablet taken by mouth, first approved in the United States in 1991 and sold as Lotensin and as generics. It is a prodrug: the body cleaves it in the liver to benazeprilat, which is the active ACE-inhibiting molecule. It is cleared mainly by the kidneys, with an effective half-life of about 10 to 11 hours on once-daily dosing. It is also sold in fixed combinations with hydrochlorothiazide and with amlodipine. Its label carries a boxed warning about fetal toxicity.

What the research says

Benazepril blocks the enzyme that makes angiotensin II, so blood vessels relax and the kidneys retain less salt and water; blood pressure falls. In randomised outcome trials it slowed the loss of kidney function in people with chronic kidney disease that was not caused by diabetes, including advanced disease, and it was the backbone drug in a large hypertension outcome trial. The harms that matter most are a dry cough in a minority of users, rare but potentially fatal angioedema, a rise in blood potassium, and harm to a developing fetus.

Evidence grade: Well established.

How it works

Drug class: Angiotensin-converting enzyme (ACE) inhibitor

Benazepril is converted in the liver to benazeprilat, which blocks angiotensin-converting enzyme. That enzyme normally turns angiotensin I into angiotensin II, a powerful blood-vessel constrictor that also tells the adrenal gland to release aldosterone. With less angiotensin II, blood vessels relax and less aldosterone is made, so blood pressure falls and potassium rises slightly. The same enzyme also breaks down bradykinin, and the build-up of bradykinin is the usual explanation for the dry cough and for angioedema. (Source 1)

Boxed warning

When pregnancy is detected, discontinue benazepril hydrochloride as soon as possible.

(Source 2)

What it is used for

• Benazepril lowers blood pressure by about 6 to 12 mmHg systolic and 4 to 7 mmHg diastolic at 24 hours after a dose in the manufacturer’s multiple-dose studies. In the 11,506-patient ACCOMPLISH trial, benazepril combined with amlodipine reduced the composite cardiovascular endpoint from 11.8% to 9.6% over a mean of 36 months compared with benazepril plus hydrochlorothiazide, an absolute risk reduction of 2.2%. ACCOMPLISH compared two benazepril-based regimens against each other, so it establishes the choice of partner drug rather than benazepril against placebo. Evidence: established. (Source 3)
• Two placebo-controlled randomised trials tested benazepril in chronic renal insufficiency. In AIPRI (583 patients, three years) 31 patients on benazepril versus 57 on placebo reached the endpoint of doubled creatinine or dialysis, a 53% risk reduction. In advanced disease (serum creatinine 3.1 to 5.0 mg/dL), 41% on benazepril versus 60% on placebo reached the composite endpoint over a mean 3.4 years, a 43% reduction and an absolute difference of about 19 percentage points. The approved US indication for benazepril is hypertension only, so this use is off-label in the United States. Evidence: established. (Source 4)
• A randomised withdrawal study in 107 children aged 7 to 16 found that blood pressure in children switched to placebo rose 4 to 6 mmHg more than in those kept on benazepril over two weeks, with no dose-response seen. This is a blood-pressure endpoint over two weeks, not an outcome trial. Evidence: limited. (Source 5)
• In the 25,620-patient ONTARGET trial, adding an angiotensin receptor blocker to an ACE inhibitor produced no reduction in the primary outcome (16.3% versus 16.5%) but more hypotensive symptoms, more syncope and more renal dysfunction. The label states that most patients on two RAS inhibitors obtain no additional benefit. Evidence: not-supported. (Source 6)

Interactions

• Potassium supplements and potassium-containing salt substitutes (label): Benazepril itself pushes potassium up, and adding potassium from a supplement or a "low-sodium" salt substitute (usually potassium chloride) pushes it up further. High potassium can disturb the heart rhythm. The risk is greater with impaired kidney function or diabetes. (Source 7)
• Potassium-sparing diuretics (spironolactone, amiloride, triamterene) (label): These raise potassium by a different route, so combining them with benazepril compounds the effect and the label calls for frequent potassium monitoring. (Source 8)
• NSAIDs including ibuprofen, naproxen and COX-2 inhibitors (case reports): In older, volume-depleted or already kidney-impaired people, adding an NSAID to an ACE inhibitor can make kidney function deteriorate, sometimes to acute kidney failure, and it also blunts the blood-pressure-lowering effect. Adding an NSAID to an ACE inhibitor plus a diuretic (the "triple whammy") was linked to a 31% higher rate of acute kidney injury in UK primary care data, and 82% higher in the first 30 days. (Source 9)
• Food (pharmacokinetic study): Food does not change how much benazepril gets into the blood, although it delays the peak level of the active metabolite from 1 to 2 hours out to 2 to 4 hours. No food restriction follows from the pharmacokinetics. (Source 10)
• A high-salt or low-salt diet (label): The blood-pressure effect of benazepril itself was not appreciably different between high- and low-sodium diets in the manufacturer’s studies, so the drug keeps working on either. Salt intake still matters for blood pressure in its own right. (Source 5)
• Another drug that blocks the same system (an ARB such as valsartan, or aliskiren) (clinical trial): Doubling up on renin-angiotensin blockade increases low blood pressure, high potassium and kidney problems without adding benefit for most people. (Source 11)
• Sacubitril (a neprilysin inhibitor, in sacubitril/valsartan) (label): Combining them raises the risk of angioedema; the label contraindicates the combination and requires a 36-hour gap when switching. (Source 12)
• Insulin and oral diabetes medicines (label): ACE inhibitors can increase the risk of low blood sugar when taken with insulin or oral hypoglycaemic agents. (Source 13)
• Lithium (case reports): Lithium toxicity has been reported when lithium and benazepril are taken together, and reversed when one was stopped; serum lithium should be monitored. (Source 14)
• mTOR inhibitors (sirolimus, everolimus, temsirolimus) (label): Taking an mTOR inhibitor with an ACE inhibitor raises the risk of angioedema. (Source 15)
• Alcohol (theoretical): We found no documented pharmacokinetic interaction between benazepril and alcohol in the sources we reached. The relevant overlap is that alcohol can itself lower blood pressure and cause light-headedness, and benazepril can cause symptomatic hypotension, particularly in the first two weeks and in people who are volume-depleted. (Source 16)

Stopping it

• There is no withdrawal syndrome described for benazepril and no taper requirement in the label. The one situation where the label requires stopping promptly is pregnancy: the boxed warning says to discontinue as soon as pregnancy is detected. (Source 2)
• The label also directs prompt and permanent discontinuation if angioedema occurs, with monitoring continued until signs and symptoms have fully resolved. (Source 17)
• Stopping is also considered when kidney function falls meaningfully on treatment; the label says to consider withholding or discontinuing therapy in that situation. (Source 18)
• Benazepril is only slightly removed by dialysis, so dialysis is not an effective way to clear it after an overdose, though it may be used to support someone with severely impaired kidney function. (Source 10)

What goes wrong

Dry cough is the characteristic ACE inhibitor adverse effect, occurring roughly twice as often as on placebo across the class. (Source 19)

• Meta-analysis, Moderate certainty.
• Size: 135 randomised controlled trials, 45,420 patients treated with eleven ACE inhibitors.
• Who: adults in randomised trials of ACE inhibitors.
• How long: varied across trials.
• Result: pooled RR for cough, ACE inhibitor versus placebo 2.21 (95% CI 2.05 to 2.39); versus ARB 3.2 (2.91 to 3.51); versus calcium channel blocker 5.30 (4.32 to 6.50); benazepril SUCRA 58.6%.
• Funding: not stated in the abstract.

Limit of this finding: This review contradicts itself about the individual drugs. It ranks eleven ACE inhibitors against each other for cough, from moexipril at 80.4% down to spirapril at 12.3% — benazepril sits at 58.6% — and then states in the same abstract that all ACE inhibitors carry a similar risk of cough. Both statements cannot be taken at face value. The dependable part is the comparison of the class as a whole against placebo and against other blood pressure drug classes; benazepril's position in the ranking should not be read as a real difference from the other ACE inhibitors.

The pooled estimated relative risk (RR) between ACEI and placebo was 2.21 (95% CI: 2.05-2.39). ACEI had more incidences of cough than ARB (RR 3.2; 95% CI: 2.91, 3.51), and pooled estimated of RR between ACEI and CCB was 5.30 (95% CI: 4.32-6.50) Moexipril ranked as number one for inducing cough (SUCRA 80.4%) and spirapril ranked the least (SUCRA 12.3%). The order for the rest of the ACEIs are as follows: ramipril (SUCRA 76.4%), fosinopril (SUCRA 72.5%), lisinopril (SUCRA 64.7%), benazepril (SUCRA 58.6%), quinapril (SUCRA 56.5%), perindopril (SUCRA 54.1%), enalapril (SUCRA 49.7%), trandolapril (SUCRA 44.6%) and, captopril (SUCRA 13.7%). All ACEI has the similar risk of developing a cough.

Angioedema is uncommon in absolute terms but about three times more likely on an ACE inhibitor than on a beta blocker. (Source 20)

• Cohort study, Moderate certainty.
• Size: 1,845,138 ACE inhibitor initiators, 467,313 ARB, 4,867 aliskiren, 1,592,278 beta blocker.
• Who: adults aged 18 and over in 17 US health plans, 2001 to 2010.
• How long: up to 365 days of follow-up per person.
• Result: cumulative incidence 1.79 per 1,000 persons (95% CI 1.73 to 1.85) for ACE inhibitors versus 0.58 (0.54 to 0.61) for beta blockers; incidence rate 4.38 versus 1.67 per 1,000 person-years; adjusted HR 3.04 (2.81 to 3.27)
• Funding: US FDA Mini-Sentinel programme (independent)

The cumulative incidences per 1000 persons were 1.79 (95% CI, 1.73-1.85) cases for ACEIs, 0.62 (95% CI, 0.55-0.69) cases for ARBs, 1.44 (95% CI, 0.58-2.96) cases for aliskiren, and 0.58 (95% CI, 0.54-0.61) cases for β-blockers. The incidence rates per 1000 person-years were 4.38 (95% CI, 4.24-4.54) cases for ACEIs, 1.66 (95% CI, 1.47-1.86) cases for ARBs, 4.67 (95% CI, 1.88-9.63) cases for aliskiren, and 1.67 (95% CI, 1.56-1.78) cases for β-blockers. Compared with the use of β-blockers, the adjusted hazard ratios were 3.04 (95% CI, 2.81-3.27) for ACEIs, 1.16 (95% CI, 1.00-1.34) for ARBs, and 2.85 (95% CI, 1.34-6.04) for aliskiren.

In the manufacturer’s own trial programme, side effects more common on benazepril than placebo were headache, dizziness and sleepiness, and about 5% of people stopped because of a side effect versus 3% on placebo. (Source 13)

• Official position, Moderate certainty.
• Size: over 6,000 patients with hypertension, of whom over 700 were treated for at least a year.
• Who: adults with hypertension in the registration programme.
• How long: up to and beyond one year.
• Result: discontinuation for a side effect 5% versus 3% on placebo; headache 6% versus 4%; dizziness 4% versus 2%; somnolence 2% versus 0%; postural dizziness 2% versus 0%; commonest reasons for stopping were headache (0.6%) and cough (0.5%)
• Funding: manufacturer labeling (Amneal Pharmaceuticals)

Discontinuation of therapy because of a side effect was required in approximately 5% of U.S. patients treated with benazepril hydrochloride and in 3% of patients treated with placebo. The most common reasons for discontinuation were headache (0.6%) and cough (0.5%). Adverse reactions seen in at least 1% greater frequency in patients treated with benazepril hydrochloride than placebo were headache (6% versus 4%), dizziness (4% versus 2%), somnolence (2% versus 0%) and postural dizziness (2% versus 0%).

Angioedema of the face, lips, tongue, glottis or larynx has occurred with benazepril including fatal cases, and is more common in Black patients. (Source 17)

• Official position, Moderate certainty.
• Size: not a trial; labeling statement drawn from trials and post-marketing reports.
• Who: people treated with benazepril.
• How long: can occur at any time during treatment.
• Result: no rate given in this section; the Mini-Sentinel cohort puts the absolute cumulative incidence at 1.79 per 1,000 ACE inhibitor initiators within a year.
• Funding: manufacturer labeling (Amneal Pharmaceuticals)

Angioedema of the face, extremities, lips, tongue, glottis, and/or larynx including some fatal reactions, have occured in patients treated with benazepril hydrochloride. Patients with involvement of the tongue, glottis or larynx are likely to experience airway obstruction, especially those with a history of airway surgery. Benazepril hydrochloride should be promptly discontinued and appropriate therapy and monitoring should be provided until complete and sustained resolution of signs and symptoms of angioedema has occurred. Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at increased risk of angioedema while receiving an ACE inhibitor [see Contraindications (4)]. ACE inhibitors have been associated with a higher rate of angioedema in Black than in non-Black patients.

Benazepril raises blood potassium, and the risk is higher with potassium-sparing diuretics, potassium supplements or potassium-containing salt substitutes. (Source 7)

• Official position, Moderate certainty.
• Size: not a trial; labeling statement.
• Who: people taking benazepril, particularly with kidney impairment or diabetes.
• How long: throughout treatment.
• Result: no rate given in the label; a 2024 network meta-analysis of 36 trials and 45,120 participants in diabetic kidney disease ranked ACE inhibitor or ARB plus a mineralocorticoid antagonist as the combination most likely to cause hyperkalaemia.
• Funding: manufacturer labeling (Amneal Pharmaceuticals)

Serum potassium should be monitored periodically in patients receiving benazepril hydrochloride. Drugs that inhibit the renin-angiotensin system can cause hyperkalemia. Risk factors for the development of hyperkalemia include renal insufficiency, diabetes mellitus, and the concomitant use of potassium-sparing diuretics, potassium supplements and/or potassium-containing salt substitutes

Adding an NSAID on top of an ACE inhibitor and a diuretic was associated with a higher rate of acute kidney injury, with the risk concentrated in the first month. (Source 21)

• Case-control study, Moderate certainty.
• Size: cohort of 487,372 users of antihypertensive drugs; 2,215 cases of acute kidney injury.
• Who: UK primary care patients taking antihypertensive drugs.
• How long: mean follow-up 5.9 years (SD 3.4)
• Result: triple therapy rate ratio 1.31 (95% CI 1.12 to 1.53); first 30 days of use rate ratio 1.82 (1.35 to 2.46); background incidence 7 per 10,000 person-years; double therapy was not associated with increased risk.
• Funding: not stated in the abstract.

Overall, current use of a double therapy combination containing either diuretics or angiotensin converting enzyme inhibitors or angiotensin receptor blockers with NSAIDs was not associated with an increased rate of acute kidney injury. In contrast, current use of a triple therapy combination was associated with an increased rate of acute kidney injury (rate ratio 1.31, 95% confidence interval 1.12 to 1.53). In secondary analyses, the highest risk was observed in the first 30 days of use (rate ratio 1.82, 1.35 to 2.46).

First-trimester exposure to an ACE inhibitor was associated with nearly three times the risk of major congenital malformations in a Medicaid cohort. (Source 22)

• Cohort study, Low certainty.
• Size: 29,507 infants, including 209 exposed to ACE inhibitors in the first trimester alone.
• Who: infants in Tennessee Medicaid born 1985 to 2000, without maternal diabetes.
• How long: malformations ascertained in the first year of life.
• Result: risk ratio 2.71 (95% CI 1.72 to 4.27) versus no antihypertensive exposure; cardiovascular malformations RR 3.72 (1.89 to 7.30); central nervous system RR 4.39 (1.37 to 14.02); other antihypertensives RR 0.66 (0.25 to 1.75)
• Funding: not stated in the abstract.

Infants with only first-trimester exposure to ACE inhibitors had an increased risk of major congenital malformations (risk ratio, 2.71; 95 percent confidence interval, 1.72 to 4.27) as compared with infants who had no exposure to antihypertensive medications. In contrast, fetal exposure to other antihypertensive medications during only the first trimester did not confer an increased risk (risk ratio, 0.66; 95 percent confidence interval, 0.25 to 1.75). Infants exposed to ACE inhibitors were at increased risk for malformations of the cardiovascular system (risk ratio, 3.72; 95 percent confidence interval, 1.89 to 7.30) and the central nervous system (risk ratio, 4.39; 95 percent confidence interval, 1.37 to 14.02).

Benazepril can cause symptomatic hypotension that may be complicated by reduced urine output, worsening kidney function or death, and acute kidney injury can occur in people whose kidney blood flow depends on the renin-angiotensin system. (Source 16)

• Official position, Moderate certainty.
• Size: not a trial; labeling statement.
• Who: people with heart failure and low systolic pressure, ischaemic or cerebrovascular disease, low sodium, high-dose diuretics, dialysis, or volume or salt depletion.
• How long: highest in the first two weeks and after each dose increase.
• Result: no rate given in the label.
• Funding: manufacturer labeling (Amneal Pharmaceuticals)

Benazepril hydrochloride can cause symptomatic hypotension, sometimes complicated by oliguria, progressive azotemia, acute renal failure, or death. Patients at risk of excessive hypotension include those with the following conditions or characteristics: heart failure with systolic blood pressure below 100 mm Hg, ischemic heart disease, cerebrovascular disease, hyponatremia, high dose diuretic therapy, renal dialysis, or severe volume and/or salt depletion of any etiology.

What the evidence supports

Benazepril slowed progression of chronic renal insufficiency from a range of causes in a three-year placebo-controlled trial. (Source 4)

• Randomized trial, Moderate certainty.
• Size: 583 patients (300 benazepril, 283 placebo)
• Who: adults with renal insufficiency from glomerulopathies, interstitial nephritis, nephrosclerosis, polycystic kidney disease, diabetic nephropathy and other causes; baseline creatinine clearance 30 to 60 mL/min.
• How long: three years.
• Result: 31 patients on benazepril versus 57 on placebo reached doubling of baseline creatinine or dialysis (P<0.001); risk reduction 53% (95% CI 27 to 70); 71% (21 to 90) in mild and 46% (12 to 67) in moderate insufficiency.
• Funding: not stated in the abstract.

At three years. 31 patients in the benazepril group and 57 in the placebo group had reached the primary end point (P<0.001). In the benazepril group, the reduction in the risk of reaching the end point was 53 percent overall (95 percent confidence interval, 27 to 70 percent), 71 percent (95 percent confidence interval, 21 to 90 percent) among the patients with mild renal insufficiency, and 46 percent (95 percent confidence interval, 12 to 67 percent) among those with moderate renal insufficiency.

Benazepril also slowed progression in people with advanced non-diabetic kidney disease, where ACE inhibitors had previously been avoided. (Source 23)

• Randomized trial, Moderate certainty.
• Size: 422 patients enrolled; the randomised comparison was 112 benazepril versus 112 placebo in the advanced group.
• Who: adults without diabetes; group 2 had serum creatinine 3.1 to 5.0 mg per decilitre.
• How long: mean 3.4 years.
• Result: 44 of 108 on benazepril (41%) versus 65 of 107 on placebo (60%) reached the composite of doubled creatinine, end-stage renal disease or death; 43% relative risk reduction (P=0.005); proteinuria fell 52%.
• Funding: registered NCT00270426; funding not stated in the abstract.

Limit of this finding: The patient numbers in this abstract do not add up. It says 422 people were enrolled, then describes 104 in group 1 and 224 in group 2 (112 on benazepril and 112 on placebo), which comes to 328, and then reports results for 102, 108 and 107 people. The abstract never reconciles those figures or says how many people left the study. The direction and size of the benefit are the authors' own, but treat the exact percentages as approximate.

Of 102 patients in group 1, 22 (22 percent) reached the primary end point, as compared with 44 of 108 patients given benazepril in group 2 (41 percent) and 65 of 107 patients given placebo in group 2 (60 percent). As compared with placebo, benazepril was associated with a 43 percent reduction in the risk of the primary end point in group 2 (P=0.005). This benefit did not appear to be attributable to blood-pressure control. Benazepril therapy was associated with a 52 percent reduction in the level of proteinuria and a reduction of 23 percent in the rate of decline in renal function.

In a large hypertension outcome trial, benazepril combined with amlodipine prevented more cardiovascular events than benazepril combined with a thiazide diuretic. (Source 3)

• Randomized trial, High certainty.
• Size: 11,506 patients.
• Who: adults with hypertension at high risk for cardiovascular events.
• How long: mean 36 months (trial stopped early)
• Result: 552 primary events on benazepril-amlodipine (9.6%) versus 679 on benazepril-hydrochlorothiazide (11.8%); absolute risk reduction 2.2%, relative risk reduction 19.6%, HR 0.80 (95% CI 0.72 to 0.90), P<0.001.
• Funding: industry-sponsored (Novartis); registered NCT00170950.

There were 552 primary-outcome events in the benazepril-amlodipine group (9.6%) and 679 in the benazepril-hydrochlorothiazide group (11.8%), representing an absolute risk reduction with benazepril-amlodipine therapy of 2.2% and a relative risk reduction of 19.6% (hazard ratio, 0.80, 95% confidence interval [CI], 0.72 to 0.90; P<0.001).

What the evidence does not support

In the same trial benazepril did not work in people whose kidney disease was polycystic kidney disease. (Source 4)

• Randomized trial, Low certainty.
• Size: 64 of the 583 patients had polycystic kidney disease.
• Who: adults with polycystic kidney disease and renal insufficiency.
• How long: three years.
• Result: no benefit reported in this subgroup; the trial reports the subgroup result without a separate effect estimate.
• Funding: not stated in the abstract.

Benazepril was not effective in patients with polycystic disease. Diastolic pressure decreased by 3.5 to 5.0 mm Hg in the benazepril group and increased by 0.2 to 1.5 mm Hg in the placebo group.

Adding a second drug that blocks the renin-angiotensin system to an ACE inhibitor gave no extra benefit and caused more harm. (Source 6)

• Randomized trial, High certainty.
• Size: 25,620 patients randomised (8,576 ramipril, 8,542 telmisartan, 8,502 combination)
• Who: adults with vascular disease or high-risk diabetes without heart failure.
• How long: median 56 months.
• Result: primary outcome 16.3% on combination versus 16.5% on ramipril alone, relative risk 0.99 (95% CI 0.92 to 1.07); hypotensive symptoms 4.8% versus 1.7% (P<0.001), syncope 0.3% versus 0.2% (P=0.03), renal dysfunction 13.5% versus 10.2% (P<0.001)
• Funding: industry-sponsored (Boehringer Ingelheim); registered NCT00153101.

In the combination-therapy group, the primary outcome occurred in 1386 patients (16.3%; relative risk, 0.99; 95% CI, 0.92 to 1.07); as compared with the ramipril group, there was an increased risk of hypotensive symptoms (4.8% vs. 1.7%, P<0.001), syncope (0.3% vs. 0.2%, P=0.03), and renal dysfunction (13.5% vs. 10.2%, P<0.001).

A larger cohort that compared against untreated hypertensive women found no ACE-inhibitor-specific first-trimester malformation risk, attributing the earlier signal to the underlying hypertension. (Source 24)

• Cohort study, Moderate certainty.
• Size: 465,754 mother-infant pairs.
• Who: pregnant women and live-born offspring in Kaiser Permanente Northern California, 1995 to 2008.
• How long: congenital malformation in live births.
• Result: versus normal controls, ACE inhibitor OR 1.54 (95% CI 0.90 to 2.62) for congenital heart defects; versus hypertension controls, OR 1.14 (0.65 to 1.98) for ACE inhibitors and 1.12 (0.76 to 1.64) for other antihypertensives.
• Funding: not stated in the abstract.

Limit of this finding: One figure in this paper is easy to misread. The authors write that first-trimester ACE inhibitor use "seemed to be associated" with more congenital heart defects while giving odds of 1.54 with a range of 0.90 to 2.62 — a range that includes 1, meaning no difference, so that comparison does not establish a raised risk. The comparison this finding rests on is the one against women who had hypertension but took no medicine, where the odds were 1.14 (0.65 to 1.98). This is about first-trimester exposure only and says nothing about the established fetal harm from ACE inhibitors later in pregnancy.

However, compared with hypertension controls (those with a diagnosis of hypertension but without use of antihypertensives) (708/29,735 (2.4%) cases of congenital heart defects), neither use of ACE inhibitors or of other antihypertensives in the first trimester was associated with increased congenital heart defects risk (odds ratios 1.14 (0.65 to 1.98) and 1.12 (0.76 to 1.64) respectively).

Where the evidence is mixed

A cluster-randomised trial of a 25% potassium chloride salt substitute reduced stroke and death and did not significantly increase serious hyperkalaemia, but it was not run in people selected for ACE inhibitor use or kidney disease. (Source 25)

• Randomized trial, Moderate certainty.
• Size: 20,995 people in 600 villages.
• Who: people in rural China with a history of stroke, or aged 60 and over with high blood pressure.
• How long: mean 4.74 years.
• Result: stroke 29.14 versus 33.65 per 1,000 person-years, rate ratio 0.86 (95% CI 0.77 to 0.96, P=0.006); death 39.28 versus 44.61, rate ratio 0.88 (0.82 to 0.95); serious adverse events attributed to hyperkalaemia 3.35 versus 3.30 per 1,000 person-years, rate ratio 1.04 (0.80 to 1.37, P=0.76)
• Funding: National Health and Medical Research Council of Australia; registered NCT02092090.

The rate of serious adverse events attributed to hyperkalemia was not significantly higher with the salt substitute than with regular salt (3.35 events vs. 3.30 events per 1000 person-years; rate ratio, 1.04; 95% CI, 0.80 to 1.37;

Where the research disagrees

Whether taking an ACE inhibitor in the first trimester of pregnancy itself causes birth defects, or whether the signal comes from the underlying hypertension

• Cooper and colleagues, Tennessee Medicaid cohort (New England Journal of Medicine, 2006), retrospective cohort of 29,507 infants with 209 first-trimester ACE inhibitor exposures; comparator was women on no antihypertensive at all: Exposure to ACE inhibitors during the first trimester cannot be considered safe and should be avoided. (Source 22)
• Li and colleagues, Kaiser Permanente Northern California cohort (BMJ, 2011), retrospective cohort of 465,754 mother-infant pairs that added an untreated-hypertension comparison group; the ACE inhibitor association disappeared against that group: The apparent increased risk of malformations associated with use of ACE inhibitors (and other antihypertensives) in the first trimester is likely due to the underlying hypertension rather than the medications. (Source 24)

How much

• Reference intake: Dosing is set by the prescriber, not by the reader. The label records as a position that the usual starting dose in an adult not taking a diuretic is 10 mg once a day, with a usual maintenance range of 20 to 40 mg a day as a single dose or in two divided doses, and 5 mg once daily as the starting dose in someone already on a diuretic (Amneal Pharmaceuticals labeling, SPL version 5, effective 3 August 2026). Section 2.2 of the same label separately records a starting dose of 5 mg once daily for adults with a GFR below 30 mL/min/1.73 m2 (serum creatinine above 3 mg/dL), titrated to a maximum total daily dose of 40 mg. (Source 26)
• Upper limit: The label records as a position that a dose of 80 mg gives an increased response but that experience with that dose is limited; in children, doses above 0.6 mg/kg or more than 40 mg daily have not been studied. (Source 26)
• Studied: The AIPRI kidney trial gave benazepril to 300 patients and placebo to 283, all with renal insufficiency from a range of causes and a baseline creatinine clearance of 30 to 60 mL per minute, over three years; the published abstract does not state the daily dose used. (Source 4)
• Studied: The advanced kidney disease trial gave 20 mg of benazepril per day to patients with serum creatinine 1.5 to 3.0 mg/dL and 20 mg per day to those with 3.1 to 5.0 mg/dL. (Source 23)
• Studied: The ACCOMPLISH hypertension outcome trial used benazepril as the backbone in both arms, combined with either amlodipine or hydrochlorothiazide, in 11,506 high-risk patients. (Source 3)

A common belief, and what the research shows

The belief: An ACE inhibitor cough is a sign of an allergy, and a "low-sodium" salt substitute is a safe swap for anyone on blood pressure tablets.

What the research shows: The cough is not allergic; it is a class effect attributed to bradykinin build-up, it occurs about twice as often as on placebo across 135 trials and 45,420 patients, and switching to an angiotensin receptor blocker reduces it roughly threefold. Separately, most "low-sodium" salt substitutes replace sodium chloride with potassium chloride, and benazepril already raises potassium: the label names "potassium-containing salt substitutes" as a hyperkalaemia risk factor alongside potassium supplements and potassium-sparing diuretics. The large salt-substitute trial that found a stroke benefit without a significant hyperkalaemia excess was not run in people selected for kidney disease or ACE inhibitor use, so it does not clear the combination for them.

Questions and answers

What is it?

Benazepril is a prescription tablet in the ACE inhibitor class, approved in the United States in 1991 and sold as Lotensin and as generics. It is a prodrug: the liver converts it to benazeprilat, the active molecule. Its approved use in the United States is to lower blood pressure. (Source 1)

What does it do in the body?

It blocks the enzyme that converts angiotensin I into angiotensin II. Angiotensin II narrows blood vessels and triggers aldosterone release, so blocking it relaxes vessels, reduces aldosterone and lowers blood pressure, with a small rise in potassium as a side consequence. The same enzyme also breaks down bradykinin, which is the usual explanation for the cough. (Source 1)

Is it good or bad for you?

For people who need their blood pressure lowered or who have progressive non-diabetic kidney disease, the randomised evidence is favourable: in one trial 41% on benazepril reached the kidney endpoint versus 60% on placebo. It is harmful in pregnancy, which is why there is a boxed warning. It is unsuitable for anyone who has had angioedema, and it is a poor choice combined with another drug blocking the same system, which in ONTARGET added harm without benefit. (Source 23)

How do you get more of it?

Benazepril is prescription-only and no dose is suggested here. The label records as a position that the usual adult starting dose without a diuretic is 10 mg once a day, that the maintenance range is 20 to 40 mg a day, and that 80 mg gives a greater response but with limited experience. Dividing the same daily dose into two was more effective at controlling blood pressure just before the next dose. Section 2.2 of the same label records a separate, lower starting dose for adults whose kidneys are significantly impaired: 5 mg once daily when GFR is below 30 mL/min/1.73 m2 (serum creatinine above 3 mg/dL), titrated upward to a maximum total daily dose of 40 mg. (Source 26)

If it is harmful, what reduces it?

It is cleared mainly by the kidneys, with an effective half-life of about 10 to 11 hours, so blood levels fall over a day or so after the last dose. Dialysis removes very little of it, around 6% of the active metabolite in four hours. Where it is causing harm, the response described in the label is to stop it: immediately and permanently for angioedema, as soon as pregnancy is detected, and to consider withholding it if kidney function falls significantly. (Source 10)

Why might someone be low in it or missing it?

This is a medicine rather than a nutrient, so "low" means it has been stopped, reduced or never started. The label names the situations where it is contraindicated or has to come off: previous angioedema with or without ACE inhibitor exposure, hypersensitivity to any ACE inhibitor, combination with sacubitril, and combination with aliskiren in people with diabetes. Pregnancy and angioedema are the two reasons for stopping it immediately. (Source 12)

Which whole foods contain it or feed it?

No food contains benazepril. Food does not change the amount absorbed, only delaying the peak of the active metabolite from 1 to 2 hours to 2 to 4 hours. The foods that matter are potassium-rich ones and especially potassium-chloride salt substitutes, because the drug already pushes potassium up and the label lists potassium-containing salt substitutes among the hyperkalaemia risk factors. (Source 10)

What happens if you do not have it?

Nobody needs benazepril physiologically. For someone who was taking it for hypertension or proteinuric kidney disease, stopping removes the blood-pressure and kidney-protective effect: in the childhood hypertension study, children withdrawn to placebo had blood pressure rise 4 to 6 mmHg more than those kept on it within two weeks, and in the kidney trials more people on placebo reached doubled creatinine or dialysis. (Source 5)

How can you test for it?

There is no routine blood test for benazepril itself. What is monitored instead is its effects: blood pressure, serum potassium and kidney function. The label says serum potassium should be monitored periodically, and that renal function should be monitored periodically because drugs inhibiting the renin-angiotensin system can cause changes in renal function including acute renal failure. These are standard, well-validated laboratory tests, not drug assays. (Source 18)

References

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