Can angiotensin converting enzyme (ACE) inhibitors lower my chances of blood pressure-related problems like heart disease and stroke?

The risk for heart attack, stroke and other high blood pressure complications begins to increase around 115/75 mm Hg.^1-5 The risk doubles for each 20 mm Hg increase in the systolic pressure and each 10 mm Hg increase in the diastolic pressure.^1-5

Evidence shows that lowering blood pressure (BP) decreases the risk of adverse cardiovascular outcomes such as heart disease, stroke, and death.^1,6-9 It may also slow the progression of kidney damage in people with chronic kidney disease (CKD).10 Further, meta-analyses as well as national and international guidelines suggest that lowering BP decreases risk of these outcomes regardless of which agent is used.^1,6-9,11

Angiotensin Converting Enzyme Inhibitors Antihypertensive Effects 

Angiotensin converting enzyme (ACE) inhibitors are a first-line treatment for all stages of hypertension as a monotherapy or in combination with one or more other antihypertensive agents.^1,6-9,12 Studies have found no significant efficacy differences between the individual ACE inhibitors.^12,13

Monotherapy trials show the BP lowering efficacy of ACE inhibitors.^14-19 A 2008 Cochrane Review meta-analysis found 92 randomized controlled trials (RCTs) that studied the dose-related trough BP lowering efficacy of 14 ACEIs in 12 954 participants.¹² The baseline BP was 157/101 mm Hg across the trials. ACE inhibitors lowered BP measured 1 to 12 hours after the dose by about 11/6 mm Hg (systolic/diastolic). The best estimate of trough BP lowering effect for ACEIs based on the largest trials was -8 mm Hg for systolic blood pressure and -5 mm Hg for diastolic blood pressure. The analysis also found that a dose of 50% of the maximum (max) daily dose had a BP lowering effect that was 90% of max and that ACE inhibitor doses above the max dose did not lower BP significantly any more than the max dose did.

A 2015 meta-analysis of 5 major antihypertensive drug classes found 12 RCTs and 13 randomized comparisons (35 707 patients) in which an ACE inhibitor was the active treatment drug.²⁰ The review found a systolic BP/diastolic BP difference of about -4/-2 mmHg between ACE inhibitor therapy versus placebo. The average baseline BP of these studies was 157/91, with an average follow up of 3.8 years. The BP reduction was associated with significant reductions in the relative risk of all outcomes, except cardiovascular and all-cause mortalities. The analysis found a reduction of coronary heart disease (CHD) by –13% (–3 to –21%), stroke by –20% (–7 to –31%), heart failure by –21% (–7 to –34%), and major cardiovascular events (composite of stroke, CHD and heart failure) by –17% (–8 to 25%). Statistical significance was not achieved by cardiovascular mortality (11% reduction) and all-cause mortality (8% reduction).

Cardiovascular Disease Risk Reduction 

Bangalore et al. performed a meta-analysis¹¹ of 106 randomized trials of 254 301 patients without heart failure (including placebo-controlled, active-controlled, and head-to-head trials) that compared two first-line antihypertensive monotherapies, ACE inhibitors and angiotensin receptor blockers (ARBs). One important conclusion was that ACE inhibitors compared to placebo significantly reduce the outcomes of myocardial infarction (MI) (relative risk [RR] 0.83, 95% confidence interval [CI] [0.78 – 0.90]), heart failure (RR 0.77, 95% CI [0.71 – 0.84]), stroke (RR 0.85, 95% CI [0.76 – 0.94]), end-stage renal disease (ESRD) (RR 0.81, 95% CI [0.70 – 0.94), new-onset diabetes (RR 0.89, 95% CI [0.84 – 0.95]), cardiovascular death (RR 0.85, 95% CI [0.79 – 0.92]), and all-cause mortality (RR 0.91, 95% CI [0.86 – 0.96]).

A 1993 multicenter randomized clinical trial of 19 394 patients assessed the efficacy of lisinopril, transdermal glyceryl trinitrate, and their combination on ventricular function and survival for 6 weeks following an acute MI.²¹ The study found that lisinopril started within 24 hours of the acute MI significantly reduced overall mortality compared to usual care (odds ratio [OR] 0.88, 95% CI [0.79 – 0.99]) and the combined outcome measure of mortality and severe ventricular dysfunction (OR 0.90, 95% CI [0.84 – 0.98]).

A 1987 double-blind randomized controlled trial of enalapril with 253 patients with severe heart failure, found a 27% (p=0.003) reduction in total mortality in the treated group versus the placebo group, at 6 months average follow up.²² A significant improvement with reduction of heart size and reduced need for other heart failure medication was seen in the enalapril group.

A 1993 double-blind randomized controlled trial of enalapril on 108 patients with left ventricular ejection fraction ≤0.35 but without clinical heart failure found that enalapril slows or reverses left ventricular dilatation in asymptomatic patients.²³ Radionuclide end-diastolic volume decreased in enalapril patients (120 ± 25 to 113 ± 25 mL/m2, mean ± SD) but increased in placebo patients (119 ± 28 to 124 ± 33 mL/m2) at 25 months.

Heart failure management guidelines recommend the inhibition of angiotensin by an ACE inhibitor or an ARB as a key component of the treatment plan for people with hypertension and heart failure with reduced ejection fraction (HFrEF).^24-26 Studies have shown that ACE inhibitors may reduce heart failure hospitalizations and death in people with HFrEF.^27-31

Kidney Disease Risk Reduction 

Studies have shown that the progression of kidney disease may be slowed by ACE inhibitors by reducing blood pressure, reducing proteinuria, improving renal blood flow, and improving intraglomerular pressure due to the vasodilatory effects of ACE inhibitors.^32-35

A 2015 network meta-analysis of randomized trials examined the effect of antihypertensives on all-cause mortality and end-stage renal disease (ESRD) in adults with diabetic kidney disease.³⁵ It found ARB monotherapy reduced progression to end-stage renal disease in people with diabetes compared to placebo (OR 0.77, 95% CI [0.65 – 0.92]), but ACE inhibitor monotherapy just barely missed statistical significance (OR 0.71, 95% CI [0.51-1.01]). Combination therapy with ARB and ACE inhibitor was superior (OR 0.62, 95% CI [0.43-0.90]), but this combination has some risk of increased hyperkalemia and acute kidney injury.

A 1999 double-blind placebo controlled trial of 186 patients with chronic non-diabetic nephropathy and persistent proteinuria found that progression to ESRD was significantly less in the ramipril group than placebo group (9.1% vs 20.7%, risk ratio [RR] 2.72, 95% CI [1.22 – 6.08]).³⁴ Progression to overt proteinuria was also less in the ramipril group (15/99 vs 27/87, RR 2.40, 95% CI [1.27–4.52]).

A 1996 randomized controlled trial of 583 patients with renal insufficiency from a variety of underlying diseases including glomerulopathies, interstitial nephritis, and diabetes found that benazepril slowed the progression of renal insufficiency except in patients with polycystic kidney disease.³³ Overall unadjusted risk reduction of progressive renal insufficiency was 53% in the benazepril group (71% in those with mild insufficiency and 46% with moderate).

A prospective randomized, double-blind, placebo-controlled trial of captopril on 147 normotensive patients with type 1 diabetes with persistent albumin excretion 20 to 200 mcg/min over 24 months found that 6.0% (4/67) of patients on captopril and 18.6% (13/70) of patients on placebo progressed to clinical proteinuria.³² The albumin excretion rate decreased annually by 17.9% (95% CI [-29.6% – -4.3%]) for people taking captopril, while it increased 11.8% (95% CI [-3.3% –  29.1%]) in the placebo group (p=0.004).

Type 2 Diabetes Risk Reduction

A 2007 network meta-analysis³⁶ of 22 clinical trials (n=143 153) looked at the incidence of new-onset diabetes in patients treated with different antihypertensive class agents or placebo. It showed the lowest incidence of new-onset diabetes occurred in those who were treated with an ACE inhibitor (OR 0.67, 95% CI [0.56 – 0.80], p<0.0001) or an ARB (OR 0.57, 95% CI [0.46 – 0.72], p<0.0001).

Roy J et al. compared a cohort of 25 035 patients with hypertension who were newly prescribed an ACE inhibitor or an ARB.³⁷ They found no significant differences for either group for the risk of stroke, CHD, CKD, or death. They did find ARBS had a higher rate of new-onset diabetes than patients on ACE inhibitors (hazard ratio 1.28, 95% CI [1.08 – 1.52]).

Dementia 

A 2016 meta-analysis³⁸ was performed on ten randomized controlled trials and observational studies that reported the effects of either ARBs or ACE inhibitors on the development of Alzheimer disease (AD) or the cognitive impairment of aging in hypertensive patients with no pre-existing neurological deficits. The use of any renin-angiotensin system blocker (RASB) was significantly associated with a reduced risk of AD (risk ratio 0.80; 95% CI [0.68–0.92) and cognitive impairment of aging (RR, 0.65;95%CI [0.35–0.94]) compared to no use of RASB. The follow up periods of the individual studies ranged from 3-8 years.

A 2016 cohort study³⁹ compared the dementia risk in patients with type 2 diabetes and hypertension between these cohorts: receiving ARBs (n=1780) versus an equal cohort of patients not receiving ARBs and receiving ACE inhibitors (n=2377) versus an equal cohort of patients not receiving ACE inhibitors. The authors found a reduction in all-cause dementia and vascular dementia for ACE inhibitor treatment (HR 0.74, 95% CI [0.74 – 0.96]) as well as for ARBs.

References

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