Angiotensin‐Converting Enzyme Inhibitors in the Treatment of Hypertension: An Update

Abstract

Angiotensin‐converting enzyme inhibitors are an important treatment option for hypertension, especially when elevated blood pressure exists in the presence of diabetes mellitus, chronic kidney disease, or congestive heart failure. This article reviews some of the pathophysiologic mechanisms involved in patients with hypertension and these comorbidities and how they relate to the renin‐angiotensin system (RAS). Inhibition of the RAS when utilized along with other antihypertensive medications has been particularly effective in hypertensive patients with type 2 diabetes, chronic kidney disease, and vascular disorders; consensus group guidelines have reflected this in their treatment recommendations. Clinical trial data demonstrate that the effectiveness of RAS blockers is enhanced by maximizing the daily dose and combining these medications with thiazide diuretics.

Patients with hypertension in addition to other cardiovascular (CV) risk factors, such as diabetes mellitus, previous myocardial infarction (MI) or stroke, or proven vascular disease, are at a substantial risk for future CV events. These patients are seen frequently in general medical practice, accounting for about two‐thirds of patients with hypertension. ¹ , ² Guidelines recommend the use of diuretics, angiotensin‐converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), calcium channel blockers (CCBs), and β‐blockers for the treatment of hypertension in patients who are at increased risk for coronary and stroke events based on numerous outcome studies over the past 30 years.

There are a number of controversies related to initial drug regimens to treat hypertension, despite abundant data that have been derived from large‐scale clinical trials. For example, compared with the long‐acting diuretic chlorthalidone in the Antihypertensive and Lipid‐Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), ³ the relatively long‐acting ACE inhibitor lisinopril was associated with a similar coronary heart disease (CHD) outcome but an increased risk of stroke (probably due to lesser systolic blood pressure (BP) control especially in black patients); the long‐acting dihydropyridine CCB amlodipine was associated with a CHD outcome similar to that of chlorthalidone but an increased risk of heart failure. In several other large, long‐term clinical trials in hypertensive patients with at least 1 additional CV risk factor, a CCB‐based regimen reduced the overall risk of CHD events to a degree similar to that of a diuretic and/or β‐blocker treatment program. ⁴ , ⁵ , ⁶ Some differences were noted in the International Nifedipine GITS study: Intervention as a Goal in Hypertension Treatment (INSIGHT), ⁴ however. Rates of fatal MI and congestive heart failure (CHF) were higher in the CCB‐treated group than in the diuretic‐treated patients.

There has been a long history of the evaluation of ACE inhibitors in CV outcomes in patients with hypertension and vascular disease. The ACE inhibitors ramipril in the Heart Outcomes Prevention Evaluation (HOPE) trial ⁷ and perindopril in the European Trial on Reduction of Cardiac Events With Perindopril in Stable Coronary Artery Disease (EUROPA) trial ⁸ were evaluated and compared with therapy that did not include an ACE inhibitor in high‐risk populations without a clinical history of CHF. In the HOPE trial (47% had hypertension at baseline), ramipril dosed at night significantly reduced the risk of MI, stroke, and coronary revascularization. ⁷ In the EUROPA study (27% had hypertension at baseline), perindopril significantly reduced the composite CV end point as well as the secondary end point of nonfatal MI. ⁸ These studies have demonstrated benefits of ACE inhibition in preventing cardiac events in patients with hypertension. It should be noted that in both of these trials, the ACE inhibitor was given along with other antihypertensive medications.

Since the publication of The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) ¹ in 2003, several new studies have also reported that ARBs improve CV outcomes by reducing rates of MI and stroke in high‐risk populations. For example, in the Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity (CHARM‐Preserved) trial ⁹ in which >60% of patients were hypertensive and had preserved systolic function, candesartan (plus other medications) significantly reduced the composite end point of CV death or hospital admission for CHF, stroke, or MI compared with a group of patients who did not receive an ARB (adjusted P=.04).

In a group of elderly hypertensive patients in the Study on Cognition and Prognosis in the Elderly (SCOPE), ¹⁰ a regimen that included candesartan also reduced the risk of all stroke by 24% (P=.056) and of nonfatal stroke by 28% (P=.04) compared with a treatment program that did not include this medication. The results from these 2 studies confirm earlier findings from the Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) study, ¹¹ which demonstrated that a losartan‐based treatment program significantly reduced stroke event rates compared with an atenolol treatment group in hypertensive patients with left ventricular hypertrophy. In the Valsartan Antihypertensive Long‐term Use Evaluation (VALUE) trial, ¹² the use of valsartan, another ARB, reduced composite cardiac events to a degree similar to amlodipine, although higher incidences of MI and stroke occurred in the valsartan treatment arm; this finding has been associated with the fact that systolic BP was lower with amlodipine in the first year of the trial. When examined in their totality, these trials have provided evidence for the use of ARBs in hypertensive patients at high risk for coronary artery disease.

THE RENIN‐ANGIOTENSIN SYSTEM

The renin‐angiotensin system (RAS) is an integral part of the hypertensive and vascular disease process. Renin is a proteolytic enzyme that cleaves angiotensinogen to produce an inactive peptide (angiotensin I), which is converted by ACE and other enzyme systems to angiotensin II (AII), a potent vasoconstrictor. ¹³ In addition to its well‐known effects on vascular resistance, AI induces vascular and cardiac myocyte growth, increases oxidative stress in CV and renal tissues, and is prothrombotic.

Besides its mediation of AI production, ACE inactivates bradykinin, a peptide that stimulates the release of nitric oxide (NO), which promotes vascular smooth muscle relaxation. Thus, ACE inhibitors have 2 effects: reducing the production of AII, a potent vasoconstrictor, and preserving bradykinin, which has vasodilating biologic actions that oppose those of AII.

The sympathetic nervous system strongly influences the renin‐angiotensin‐aldosterone system (RAAS). This is activated by many common comorbidities of hypertension including type 2 diabetes, hyperinsulinemia, excess weight, and a carbohydrate‐ and fat‐enriched diet. Numerous investigators have shown that obese patients have elevated sympathetic nervous system activity, measured both directly and indirectly. ¹⁴ , ¹⁵ Both human and animal studies have also shown that food intake increases sympathetic nervous system activity, whereas fasting and weight loss decrease the activity. ¹⁴ , ¹⁵ Insulin is believed to partially mediate the effect of diet by stimulating glucose uptake and metabolism and ultimately disinhibiting sympathetic neurotransmission from the brain stem. ¹⁶ Several investigators have found that numerous other mechanisms and mediators are thought to cause sympathetic nervous system activation in the insulin‐resistant state, including renal afferent nerve stimulation by increased intrarenal pressure, plasma free fatty acids, and AII. ¹⁴ , ¹⁵ , ¹⁶ The RAS has been shown to play an important role in insulin sensitivity, and 2 large clinical trials of ACE inhibitors (HOPE and the Captopril Prevention Project [CAPPP]) showed that these drugs decreased the risk of developing type 2 diabetes in patients with hypertension and/or vascular disease. ⁷ , ¹⁷ These actions may be related to the interaction of the sympathetic system and the and RAS.

ENDOTHELIAL DYSFUNCTION AND THE RAS

The endothelium is responsible for maintaining the balance between vasoconstriction and vasodilation by producing compounds that regulate vascular homeostasis, among them AII and NO. The endothelium also helps to maintain normal blood viscosity by balancing clotting factors. ¹⁸ Endothelial dysfunction involves impaired vasomotor response (reduced vasodilation and increased endothelium dependent contraction), cell proliferation, platelet adhesion and aggregation, vascular permeability, and vascular inflammation by stimulating production of vascular adhesion molecules, growth factors, and vasoconstrictive agents. ¹⁹ , ²⁰ NO is a ubiquitous vasodilator produced via an intact endothelium. Reactive oxygen species, created during inflammation, impair vascular relaxation by reducing NO and increasing vascular contractile responses. ²¹

Activation of the RAS leads to endothelial dysfunction and inflammation, by promoting production of AII, which then induces vascular injury through several mechanisms, including vasoconstriction, cell growth, oxidative stress, and inflammation (inducing release of cytokines release and proinflammatory transcription factors). These mechanisms contribute to a prothrombotic state and plaque buildup and instability and, ultimately, plaque rupture. ²⁰ , ²¹ AII is also one of the key mediators of the RAS system, so as it is generated and utilized, a continuous feedback loop is promoted.

Hypertension and insulin resistance both contribute to endothelial dysfunction and inflammation in the vascular wall as well as smooth muscle cell proliferation, extracellular matrix deposition, cell adhesion, and thrombus formation: all processes that lead to atherosclerosis. ¹⁹ Thus, continued promotion of endothelial dysfunction increases hypertension and elevated vascular resistance, and activation of the RAS exacerbates endothelial dysfunction.

UTILITY OF RAS BLOCKADE EARLIER IN PATIENTS WITH CV RISK

The trend toward more aggressive detection and management of hypertension is consistent with consensus guidelines from virtually every country, including the United States (Figure 1). ¹ In patients with type 2 diabetes, chronic kidney disease, or heart disease, drug therapy is warranted to achieve a target BP level of <130/80 mm Hg because of the high CV and renal risk seen in these patients. ²² A joint statement from the American Diabetes Association (ADA) and the American Heart Association (AHA) concurs with this progressive approach to treating hypertension in patients with type 2 diabetes, noting that rigorous control of BP is mandatory for reducing the progression of diabetic nephropathy to end‐stage renal disease. Diabetic patients found to have systolic BP levels >130 mm Hg or diastolic BP levels >80 mm Hg should have their BP level confirmed on a separate day and treated accordingly. ²³ The National Kidney Foundation has issued similar guidelines for the management of hypertension in patients with diabetes and chronic kidney disease (CKD) and recommends a target BP level of <130/80 mm Hg in patients with diabetes and CKD stages 1 through 4. ²⁴

Figure 1.

Composite of recommendations for management of patients with hypertension according to level of blood pressure and comorbid risks. SBP indicates systolic blood pressure; DBP, diastolic blood pressure; T2DM, type 2 diabetes mellitus; ACE, angiotensin‐converting enzyme inhibitor; ARB, angiotensin receptor blocker; CCB, calcium channel blocker.

Patients with both diabetes and hypertension should be treated with an ACE inhibitor or an ARB as part of a treatment regimen. ²¹ , ²² , ²³ If one class is not tolerated, the other may be substituted. Other drug classes that might be added to achieve BP targets and reduce CV events include thiazide diuretics, β‐blockers, and CCBs. ²³ The ADA and AHA also recommend that if ACE inhibitors, ARBs, or diuretics are used, renal function and serum potassium levels should be monitored within the first 3 months. If these values are stable over a minimum of 2 visits, follow‐up should occur every 6 months thereafter. In addition, measurement of BP in the standing position should be performed in persons with diabetes and hypertension when clinically indicated. For patients in whom target BP is not achieved despite multiple‐drug therapy, it is valuable to consider referral to a physician specializing in the care of patients with hypertension. ²³

ASSESSMENT OF THE ACE INHIBITOR RAMIPRIL IN PATIENTS WITH HYPERTENSION

BP Control

Ramipril, an ACE inhibitor, has been extensively studied in the treatment of hypertension, including in special populations ²⁵ , ²⁶ , ²⁷ , ²⁸ and the evaluation of renal effects, ²⁹ vascular effects, ³⁰ , ³¹ , ³² and CV outcomes. ⁷ , ³³ In most trials, the dosage of ramipril that has been used is 5 mg twice daily or a fixed dosage of 10 mg once daily. There has been some controversy regarding the appropriate dosage and dosing interval of the drug for optimal treatment of hypertension. In a recent study by Goyal and colleagues ²⁶ with ramipril 5 mg bid compared with ramipril 10 mg each morning, reductions from baseline in 24‐hour BP were similar and significantly larger than what was observed in the clinic (Table). In contrast, in a more severely hypertensive population that included nearly equal numbers of black and nonblack patients, Moran and colleagues ²⁷ found larger reductions in clinic BP (−9/−4 to −12/−7 mm Hg) following a fixed dose of ramipril 10 mg compared with the daytime ambulatory BP (−5/−3 to −11/−7 mm Hg) and nighttime ambulatory BP (−6/−5 to −9/−5 mm Hg). Not surprisingly, the reductions from baseline in the black patients were less than what was observed in the nonblack population. It is well known that an ACE inhibitor as monotherapy is not as effective in reducing BP in black patients as in white patients. The authors pointed out that in an assessment of individual responses, 72% of the patients in both ethnic groups had similar ambulatory BP responses.

Table.

Differential Findings for Changes in Blood Pressure Using Clinic vs Ambulatory Monitoring After ACE Inhibitor Therapy

Parameter	Baseline	Ramipril 5 mg bid	Ramipril 10 mg qd
Office SBP, mm Hg	132.8±11	129±17.9	131.2±15.3
Office DBP, mm Hg	80.8±9.5	79.1±11.2	77.7±8.2
24‐hour SBP, mm Hg	123.7±14.7	116.9±13.2a	115.1±11.1a
24‐hour DBP, mm Hg	73.3±9.1	69.3±9.6a	68.3±7.3a
Abbreviations: ACE, angiotensin‐converting enzyme; bid, twice daily; DBP, diastolic blood pressure; qd, once daily; SBP, systolic blood pressure. a P<.001.

In a recently conducted double‐blind, randomized trial involving 340 patients with stage 2 hypertension (clinic BP >160/100 mm Hg and <180/110 mm Hg), ³⁴ we assessed the highest approved dose of ramipril (20 mg total daily dose) and compared a 10 mg twice daily regimen and a 20 mg once daily regimen compared with hydrochlorothiazide 25 mg once daily as monotherapy. The study utilized seated, clinic, and 24‐hour ambulatory BP at baseline and following 8 weeks of therapy. As shown in Figure 2, reductions from baseline 24‐hour ambulatory systolic BP were similar for both regimens. Of interest in this study was the finding that changes from baseline in clinic and ambulatory BP were nearly the same (−10 and −11 mm Hg, respectively). The study used semiautomatic devices to record office BP levels instead of mercury sphygmomanometers. While adaptation to the medical care environment is still likely to occur in this sort of trial, the observer bias is substantially removed. ³⁵ Hence, this method may be more appropriate for double‐blind clinical trials in hypertension in the future.

Figure 2.

Changes from baseline in clinic and 24‐hour ambulatory systolic blood pressure (BP) after 8 weeks of treatment with ramipril 20 mg once daily (qd) or 10 mg twice daily (bid) and hydrochlorothiazide 25 mg qd. There were no significant differences among the treatment groups. ³⁴

Thus, once‐daily dosing at higher doses with this medication, as well as with many other ACE inhibitors and ARBs, is appropriate considering the improved compliance that is seen with once‐daily dosing compared with twice‐daily dosing in patients with hypertension. ³⁶

CV and Renal Effects of RAAS Inhibitors

The Irbesartan in the Management of Proteinuric Patients at High Risk for Vascular Events (IMPROVE) study ²⁹ was designed to evaluate the impact of combining an ARB (irbesartan) with an ACE inhibitor (ramipril) on BP control and microalbuminuria in hypertensive patients with elevated CV risk. Following 20 weeks of double‐blind therapy, BP was reduced to a small but significantly greater extent with irbesartan plus ramipril (−23/−11 mm Hg) than with ramipril plus placebo (−20/−9 mm Hg). Reductions in albuminuria were virtually the same in each treatment group, however (Figure 3). This suggests that the effect of combining the ARB irbesartan (150–300 mg/d) with the ACE inhibitor ramipril (10 mg/d) was not additive. The authors pointed out that there was substantial variability in the study results and that the patient population had relatively low albumin excretion rates at baseline. ²⁹ It may not be necessary to use more than 1 RAS‐blocking agent in hypertensive patients with low excretion rates of albumin, although some data suggest that combining an ACE inhibitor and an ARB may reduce albuminuria when the baseline levels are high.

Figure 3.

Changes in albumin excretion rates from baseline after 20 weeks' treatment with ramipril plus irbesartan and ramipril plus placebo. While both therapies significantly reduced albumin excretion rate (AER) from baseline, there were no differences between the 2 treatment groups. ²⁹

Recently, investigators have studied the effects of ACE inhibitors such as ramipril on vascular function, using flow‐mediated dilation after inhibition of NO synthase. ³⁰ , ³¹ In the first study by Schmieder and colleagues, ³⁰ ramipril and telmisartan, an ARB, were compared in 96 patients with both hypertension and type 2 diabetes mellitus. The vascular bed targeted was the kidney, and renal plasma flow was evaluated following an infusion of the NO synthase inhibitor, N‐monomethyl‐l‐arginine (L‐NMMA) (thus, the generation of the vasodilator NO was reduced). Changes from baseline in renal plasma flow increased similarly in the 2 treatment groups after 9 weeks of treatment. In another study, the radial artery diameter response was evaluated before and after intra‐arterial infusion of L‐NMMA using sublingual nitroglycerin to enhance flow‐mediated dilation. As shown in Figure 4, ramipril significantly increased NO‐dependent flow‐mediated dilation. ³¹

Figure 4.

Nitric oxide‐dependent flow‐mediated dilation (FMD) as the percentage FMD inhibited by N‐monomethyl‐l‐arginine (L‐NMMA) in normotensive and hypertensive patients at baseline and after 3 months of ramipril at either 5 or 10 mg/d. ^aP<.001 vs baseline. In addition, the percent change in the group given the 5‐mg dose was significantly higher than baseline (P<.001) and the percent change in the group given the 10‐mg dose was significantly greater than that in the 5‐mg dose group (P<.001). ³²

Recent secondary studies from the HOPE trial ⁷ have focused on outcomes in older patients. ³⁶ , ³⁷ In an analysis by Salehian and associates, ³⁶ the impact of ACE inhibition with ramipril 10 mg dosed at night on the incidence of atrial fibrillation was evaluated. The risk of developing new‐onset atrial fibrillation was 86/4291 (2.0%) with ramipril and 91/4044 (2.3%) in patients not receiving this ACE inhibitor. No significant difference was noted between treatment groups (odds ratio, 0.92; P=.57).A new analysis from the HOPE study involving 2755 patients older than aged 70 years ³⁷ reported that patients assigned to ramipril had a lower major vascular event rate (18.6%) over 4.5 years than those assigned to a regimen that did not include this agent (24.0%) for a relative reduction in risk of 25% (P=.0006). Data from numerous trials in the elderly have reported significant reductions in CV events in hypertensive patients treated with diuretics/β‐blockers, CCBs plus other agents, and ACE inhibitors plus other medications. Preliminary data for the Hypertension in the Very Old Trial (HYVET) report that incidence of stroke and mortality are reduced with a diuretic/ACE inhibitor regimen even in persons older than 80 years.

CONCLUSIONS

The RAS plays an important role in mediating hypertension through increased vascular resistance and mediating vascular disease through promotion of vascular and cardiac cell growth, oxidative stress, and inflammatory substances that can lead to cell death and fibrosis. ACE inhibitors, such as ramipril, have demonstrated the importance of blockade of the RAS in improving CV outcome. Utility of ACE inhibitors for hypertension management is enhanced by paying careful attention to dose response and dose escalation to achieve better BP control and using ACE inhibitors in conjunction with classes of antihypertensive therapies that are additive (eg, diuretics and CCBs) rather than those classes which may yield only modest BP benefits (eg, ARBs and β‐blockers).