Effect of Angiotensin‐Converting Enzyme Inhibitors on Arterial Stiffness in Hypertension: Systematic Review and Meta‐Analysis

Abstract

Arterial stiffness is an independent cardiovascular prognostic factor and is modulated by angiotensin‐converting enzyme inhibitors (ACEIs). The authors performed a meta‐analysis of clinical trials investigating the effects of ACEIs on pulse wave velocity (PWV) or augmentation index. The search included randomized clinical trials as well as uncontrolled studies that measured in‐treatment changes in arterial stiffness. The authors performed separate analyses for carotid‐femoral PWV, brachioradial PWV, and augmentation index. Average absolute and relative reduction in mean arterial pressure and PWV were −15.4 mm Hg and −13.04% and −1.15 mis and ‐9.74% for carotid‐femoral PWV studies; and −11.2 mm Hg and ‐9.3% and −1.9 mis and −16.7% for brachioradial PWV studies. There was a greater reduction in augmentation index by ACEIs when compared with controls (—1.0% to −5.3%). The authors conclude that ACEIs have modest beneficial effects on arterial stiffness measured as PWV and augmentation index, and this effect is at least partly independent of changes in blood pressure.

Arterial stiffness has received increased attention due to its role as an independent prognostic factor for cardiovascular disease in hypertension, chronic kidney disease, diabetes, and heart failure. ¹ , ² Drugs that block the renin‐angiotensin‐aldosterone system, especially angiotensin II‐converting enzyme inhibitors (ACEIs), are of particular interest as the renin‐angiotensin‐aldosterone system contributes to the modulation of arterial stiffness. In fact, ACEIs have been recommended by recent Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines as the preferred agents to reduce arterial stiffness in patients with advanced chronic kidney disease. ³ Because of this increasing use of ACEIs as agents to reduce arterial stiffness independently of their anti‐hypertensive effects, we were interested in quantifying the blood pressure (BP)‐independent effects of ACEIs on arterial stiffness.

There are several methods available to assess arterial stiffness in clinical and research settings. These include direct measurements of arterial compliance or distensibility (usually ultrasound‐based), measurements of speed of pulse wave propagation (pulse wave velocity [PWV]) and reflection (augmented pressure and augmentation index [AI]), or evaluations of pulse wave contour (Windkessel models). ⁴ , ⁵ PWV and wave reflection (AI) are the two most commonly used indices with the most widely available prognostic data, and are also more readily comparable across studies. Hence, we chose to evaluate the impact of ACEIs on arterial stiffness by summarizing the effects on PWV and AI in published clinical trials.

METHODS

We searched three computerized databases: PubMed (through August 22, 2005), Ovid versions of MEDLINE (1966‐Week 32, 2005), and EMBASE (1980‐Week 31, 2005) to identify reports of clinical trials measuring PWV and AI in subjects receiving ACEIs. For PWV studies, the search strategy used the following approaches: 1) in PubMed, we used the terms “pulse wave velocity AND ACE inhibitors” (with limits to “Clinical trials, Humans”); 2) in Ovid and EMBASE, we used “pulse wave velocity” as keyword, and “ACE inhibitors” as keyword and MeSH term (with a limit to “Humans”). A similar strategy was used for AI, using the term “augmentation index” in place of “pulse wave velocity.” The search was not limited by language. Finally, after identification of all relevant articles (see below), we screened reference lists for any other studies not identified by the search strategy.

We screened each abstract to identify studies based on the following inclusion criteria: 1) prospective studies of adult hypertensive patients where an ACEI was administered with or without a control group; 2) studies wherein measurements of PWV and/or AI were available at baseline and end‐therapy (or end‐therapy in ACEI and placebo comparison groups); 3) duration of intervention with ACEIs of >4 weeks; 4) no other concomitant treatment with antihypertensive agents; and 5) sufficient data on BP and PWV/AI parameters either available in the paper or provided by the authors on request. We attempted to contact all authors for required supplemental information before excluding any study from analysis.

Trials were excluded if the study group was composed of patients with complex arterial structural and hemodynamic changes, such as end‐stage renal disease or transplantation, ⁶ , ⁷ , ⁸ , ⁹ or studies measuring PWV in territories of uncertain representation, such as the brachial‐ankle PWV method. ¹⁰ , ¹¹

Two of the investigators (MM, AJP) independently abstracted the data using a standard form. Any differences were resolved by consensus. Each article was scored using the Jadad score for quality and validity. ¹² We abstracted the following variables: characteristics of study population, study design and duration, BP parameters (systolic, diastolic, mean, and pulse pressure), and PWV and/or AI measurements. For BP, PWV, and AI, we determined the initial and end‐treatment values, and the respective in‐treatment change.

For PWV, our search strategy identified 34 citations on PubMed, 58 on MEDLINE, and 105 on EMBASE. For AI, we identified 20 citations on PubMed, 21 on MEDLINE, and 46 on EMBASE. Search results were screened and unrelated studies or review articles were eliminated on the basis of title and abstract. After appropriate exclusions, we identified 12 trials using carotid‐femoral PWV, four trials using brachioradial PWV, one trial using femorotibial PWV, and six trials using AI as potentially appropriate. Three of the carotid‐femoral PWV studies, ¹³ , ¹⁴ , ¹⁵ two of the brachioradial PWV studies, ¹⁶ , ¹⁷ and the only femorotibial PWV study ¹⁶ were excluded because of insufficient data. Two of the AI trials were also excluded—one due to an unknown duration of intervention ¹⁸ and another because of additional antihypertensives administered in the ACEI group. ¹⁹

We performed separate analyses for PWV and AI. PWV was further analyzed based on territories of PWV measurement, as we were interested in discerning effects on predominantly elastic (aorta) and muscular arteries. The final analysis included nine trials using carotid‐femoral PWV ¹⁶ , ¹⁷ , ²⁰ , ²¹ , ²² , ²³ , ²⁴ , ²⁵ (two of which were randomized clinical trials ²³ , ²⁴ ), two brachioradial PWV trials ²⁶ , ²⁷ (one randomized clinical trial), and four AI studies, ²³ , ²⁸ , ²⁹ , ³⁰ all of which were randomized clinical trials.

Statistical Analyses

We calculated absolute and relative (percent) change in mean arterial pressure ([MAP], the estimate of distending pressure) and PWV from baseline to end‐treatment in uncontrolled trials. We included the ACEI arm of controlled trials as part of this observational analysis. In addition, we calculated these changes for both ACEI and control groups in the controlled clinical trials. We calculated weighted averages (with standard errors) to establish treatment effect adjusted for sample size. We performed sensitivity analyses by eliminating studies with markedly different (larger) sample sizes that could alter the results. Metaregression analysis was done to determine the correlation between change in MAP and change in PWV.

With respect to AI, we calculated absolute and percent change in MAP and PWV from baseline to end‐treatment in parallel studies. For crossover studies, the change in MAP and PWV was calculated as the difference between end‐treatment values of ACEI and control groups.

RESULTS

Carotid‐Femoral PWV

Out of a total of nine clinical trials, seven were uncontrolled studies with no placebo group, and two were randomized clinical trials (one crossover and one parallel group). Jadad validity scores ranged from zero to two (out of a maximum score of five), with a median score of zero. All trials were conducted in patients with essential hypertension. Tables I and II summarize the data for studies using carotid‐femoral PWV.

All trials showed significant reductions in MAP and PWV with ACEIs. Metaregression analysis between absolute ΔMAP and ΔPWV showed that only 12% of variance in absolute ΔPWV is explained by ΔMAP (r ²=0.12; r=0.36; p=0.34), and 26% of relative ΔPWV is explained by relative ΔMAP (r ²=0.26; r=0.51; p=0.15). Multiple sensitivity analyses were performed to explore the variations in our summary results. Exclusion of the study of Asmar et al. ²⁰ (N=1371) showed similar results (weighted averages for ΔPWV were −2.26 m/s and −18.11%, and −17.2 mm Hg and −14.5% for ΔMAP. Also, results were unchanged when analyses were done with or without randomized trials or without the study of Toblli et al., ²⁵ wherein a very large ΔPWV was observed. Results from the two randomized clinical trials are summarized in Table II. As the two results compiled from Rajzer et al. ²⁴ involve the same ACEI subjects, we did not calculate the average weighted values.

Table II.

 Effects of Angiotensin‐Converting Enzyme Inhibitors (ACEIs) on Carotid—Femoral Pulse Wave Velocity (PWV) in Randomized Clinical Trials

						ΔMAP (mm Hg)		ΔMAP (%)		ΔPWV (m/s)		ΔPWV (%)
Study	Design	Duration (wk)	N	ACEI	C	ACEI	C	ACEI	C	ACEI	C	ACEI	C
Mahmud et al., 2002 23	Crossover	4	12	Captopril	Valsartan	−15	−16.3	−12.7	−14	−0.8	−0.8	−7.2	−7.2
Rajzer et al., 2003 24	Parallel	24	62	Quinapril	Losartan	−21	−14.7	−18.1	−13.1	−1.7	−0.2	−15	−2
Rajzer et al., 2003 24	Parallel	24	75	Quinapril	Amlodipine	−21	−15	−18.1	−13.4	−1.7	−0.6	−15	−5.1
C=control drug; Δ=change; MAp=mean arterial pressure

Overall, ACEI administration uniformly resulted in a substantial decrease in carotid‐femoral PWV.

Brachioradial PWV

Of the two clinical trials, one was an uncontrolled, “observational” study and one was a randomized clinical trial. The mean Jadad validity score was two. All trials were conducted in patients with essential hypertension.

The effects of ACEI use on brachioradial PWV are summarized in Table III. Consistent with the effects observed in the carotid‐femoral territory, ACEIs induced a significant fall in brachioradial PWV. In this territory, the only randomized trial (Armentano et al. ²⁶ ) showed that the improvement in PWV was independent of BP, as the control group achieved greater BP reductions without improvement in brachioradial PWV. Although there are fewer studies of the brachioradial territory, the effects of ACEIs appear to be independent of BP.

Table III.

 Effects of Angiotensin‐Converting Enzyme Inhibitors (ACEIs) on Brachioradial Pulse Wave Velocity (PWV)

Study	Design	Duration (wk)	N	ACEI		ΔMAP (mm Hg)		ΔMAP (mm Hg)	ΔMAP (%)	ΔPWV (m/.s)	ΔPWV (%)
Longitudal studies
Asmar et al., 1988 27	Longitudinal	12	14	Perindoprill	−16.5	−12.8	−1.3	−13.3
Armentano et al., 2001 26	RCT, ACEI arm	12	14	Perindopril	−9	−7.8	−2.1	−18.1
Weighted average					ACEI	C	ACEI	C
RCT					ACEI	C	ACEI	C
Armentano et al., 2001 26	Parallel	12	34	Ramipril*	−9	−19	−7.8	−16.1	−2.1	−1.3	−18.1	−11.1
Δ=change; MAp=mean arterial pressure; RCT=randomized clinical trial; *control (C)=atenolol

Augmentation Index

All studies were randomized clinical trials with Jadad validity scores ranging from one to three (median, 2.5). ACEIs reduced Al uniformly in all four trials, but in only one trial was it statistically significant in comparison to placebo (Morgan et al. ³⁰ ). These results are summarized in Table IV. Overall, it appears that ACEIs have a beneficial effect on Al that is independent of BP reduction.

Table IV.

Effects of Angiotensin‐Converting Enzyme Inhibitors (ACEIs) on the Aortic Augmentation Index (Al)

Study	Duration	Duration (wk)	N	ACEI	Control	ΔMAP (ACEI—Control) (mm Hg)	ΔAI (ACEI—Control)(%)
Mahmud et al., 2002 23	Crossover	4	12	Captopril	Valsartan	1.3	−5.3
Deary et al.,2002 29	Crossover	6	30	Lisinopril	Placebo
			22 M			−12.3 M	−5M
			8F			−13 F	−1 F
Dart et al., 2001 28	Parallel	4	111	Perindopril Usual treatment	−0.9	−4.7
Morgan et al., 2004 30	Crossover	8	32	Perindopril	Placebo	−5.3	−3.3*
Δ=change; MAp=mean arterial pressure; M=males; F=females; */<0.05

DISCUSSION

The results of this analysis show that ACEIs reduce arterial stiffness in patients with hypertension independently of BP reduction. Stiffness is reduced in both muscular and elastic territories, although there appears to be a greater effect on the muscular arteries (average A brachioradial PWV, ‐17% vs. −0% for A carotid‐femoral PWV). We are unable to determine, however, whether ACEI effects are different from other antihypertensive agents, given the limited number of available studies.

We did not include studies of end‐stage renal disease patients due to the complex nature of arterial structure and function in this population. In hemodialysis patients, Tycho Vuurmans et al. ³¹ showed that ACEIs combined with volume reduction cause significant reduction in PWV and AL More importantly, Guerin et al. ³² showed that the use of ACEIs has a favorable effect on survival independent of BP changes. ³² Therefore, it is possible that the favorable effects on arterial stiffness noted in patients with hypertension may result in improved outcomes. This issue has not yet been formally addressed.

We did not include studies using other measures of stiffness such as arterial compliance, distensibility, or elastic modulus, as there is significant diversity in the methodologies and values for these measures. The measures we used (PWV and AI) have validated and accepted methods of measurement and are comparable across studies. A review of other trials using arterial distensibility or compliance as a measure of stiffness also indicates that ACEIs uniformly reduce arterial stiffness. ^33–35 Aging and hypertension contribute to increasing arterial stiffness, particularly through an increase in collagen deposition. In animal models of hypertension, ACEIs decrease collagen deposition, an effect that is independent of BP changes and more closely related to decreased angiotensin II production. ³⁶ Aortic stiffness in human hypertension has also been linked to angiotensin II type 1 receptor gene polymorphism. ²¹ , ³⁶

Arterial stiffness is an independent prognostic indicator in cardiovascular disease. ¹ , ² Therefore, there is potential value to identifying effective treatments to decrease arterial stiffness, particularly among antihypertensive medications. Our results show that ACEIs are effective, but the data are certainly limited by the number and quality of studies, and the fact that several of the studies were conducted by the same investigative group. Our impression is that ACEIs uniformly decrease PWV and AI, and it seems that these effects are only partly related to BP lowering. It is not clear, however, that ACEIs are better than other antihypertensive agents, although it appears that ACEIs are consistently better than β blockers.

In summary, ACEIs have a modest beneficial effect in reducing arterial stiffness measured as PWV and AI, and this effect is at least partly independent of BP. Given the limited methodologic quality of studies available to date, further trials are needed to validate this effect, examine its durability over longer periods of follow‐up, and compare it with that obtained with other antihypertensive agents commonly used in clinical practice.