Clinical Research in Cardiology

, Volume 99, Issue 12, pp 787–794

Telmisartan improves absolute walking distance and endothelial function in patients with peripheral artery disease

Authors

    • Department of Cardiology and AngiologyUniversity of Heidelberg
  • B. Ivandic
    • Department of Cardiology and AngiologyUniversity of Heidelberg
  • M. Andrassy
    • Department of Cardiology and AngiologyUniversity of Heidelberg
  • H. C. Volz
    • Department of Cardiology and AngiologyUniversity of Heidelberg
  • U. Krumsdorf
    • Department of Cardiology and AngiologyUniversity of Heidelberg
  • E. Blessing
    • Department of Cardiology and AngiologyUniversity of Heidelberg
  • H. A. Katus
    • Department of Cardiology and AngiologyUniversity of Heidelberg
  • C. P. Tiefenbacher
    • Department of Cardiology and AngiologyUniversity of Heidelberg
Original Paper

DOI: 10.1007/s00392-010-0184-0

Cite this article as:
Zankl, A.R., Ivandic, B., Andrassy, M. et al. Clin Res Cardiol (2010) 99: 787. doi:10.1007/s00392-010-0184-0

Abstract

Background

Peripheral artery disease (PAD) is associated with high cardiovascular mortality and a poor quality of life. The AT1-receptor blocker telmisartan has been shown to have pleiotropic effects and it may also improve endothelial function. The aim of this study was to analyze the effects of telmisartan on absolute walking distance (WD) and endothelial function in patients with PAD.

Methods

In a single centre, single-blinded, prospective study, 36 patients with PAD at stage Fontaine II or higher and mild to moderate arterial hypertension were treated with telmisartan 40/80 mg once daily or placebo for 12 months. Primary endpoint was the improvement of the absolute treadmill WD. Flow-mediated vasodilation (FMD), carotid intima-media thickness (IMT), ankle-brachial index (ABI) and disease-related quality of life (DRQL) were examined as well.

Results

After 12 months, maximum WD increased by 26% in the telmisartan group (P < 0.001). However, in the placebo group it was comparable to baseline. FMD rose by 40% in the telmisartan group while it deteriorated in the placebo group (P < 0.001). IMT and ABI were comparable in both groups at baseline and did not change considerably after 12 months. In non-diabetic patients (72.2%), the ABI did not change in the placebo group, whereas it increased by 11% in the telmisartan group (P < 0.001). While the DRQL remained stable in the telmisartan group, placebo treatment was associated with a marked deterioration (P < 0.01).

Conclusion

Telmisartan improves WD and endothelial function, the ABI in non-diabetic patients and it may prevent further loss of quality of life in patients with advanced PAD.

Keywords

Endothelial dysfunctionPeripheral artery diseaseAngiotensin receptor blockadeAtherosclerosis

Introduction

Peripheral artery disease (PAD) is associated with a high risk for cardiovascular events and mortality and is considered as a coronary heart disease risk equivalent [1, 2]. One of the earliest atherosclerotic vascular changes is endothelial dysfunction which is known to predict cardiovascular prognosis. It is the result of an impairment of endothelium-derived NO synthesis by reduced NOS activity, lack of cofactors [2] or increased NO degradation. The availability of endothelium-derived NO is impaired by free radical generation promoting an inflammatory and prothrombotic process in the presence of cardiovascular risk factors, such as dyslipidemia, insulin resistance, arterial hypertension and hyperuricemia [3].

The principle mechanism of NO is vascular smooth-muscle relaxation via several NO signaling pathways. NO is the active principle of organic nitrates, which are widely used in therapy of ischemic heart disease. The therapeutic aim is to replace a compromised endothelial NO production. However, the chronic efficacy of organic nitrates is blunted due to the development of nitrate tolerance, a reduced nitrate-induced vasodilation, and endothelial dysfunction [4].

Several experimental and clinical studies have identified a pivotal role of the renin–angiotensin system in the development of endothelial dysfunction in animal models [5] and in patients with coronary heart disease [6, 7]. Treatment with angiotensin-converting enzyme (ACE) inhibitors or Angiotensin II type 1 (AT1) receptor blockers have been shown to improve endothelial function. The mechanisms underlying the beneficial vascular effects of ACE inhibitors include the inhibition of formation of angiotensin II but also the inhibition of kininase II leading to increased endothelial concentrations of the endothelium-dependent vasodilator bradykinin. AT1-receptor blockers (ARBs) inhibit the coupling of angiotensin II with the AT1-receptor. Suppression of the renin–angiotensin system via ACE-inhibitors or ARBs have been shown to reduce microalbuminuria in diabetic and non-diabetic patients, which is recognized as a marker of endothelial dysfunction [8]. Furthermore, ACE inhibitors and AT1-blockers have been characterized to improve cardiovascular outcome in patients with cardiovascular risk [8].

Telmisartan has been shown to improve endothelial dysfunction more effectively than the calcium antagonist amlodipine over a period of 24 weeks in patients with essential hypertension [9]. In diabetic hypertensive patients, telmisartan significantly increased NO activity of the renal endothelium during a study period of 9 weeks [10].

Studies evaluating long-term effects of telmisartan on endothelial dysfunction and absolute walking distance (WD) in patients with PAD are still lacking. We hypothesized that telmisartan improves endothelial function, which may even translate into longer maximum WDs over a period of 12 months. Flow-mediated vasodilation (FMD), ankle-brachial index (ABI), intima-media-thickness (IMT) and disease-related quality of life (DRQL) were also determined.

Methods

Study design

The primary endpoint examined the change of maximum WD after 12 months of treatment with telmisartan or placebo compared to baseline. Secondary endpoints were changes of FMD, IMT, ABI and quality of life in the two treatment arms.

Thirty-six patients between 18 and 80 years of age with documented PAD at least stage Fontaine IIa were included. They were recruited from April 2004 to February 2006. Exclusion criteria were pre-treatment with angiotensin-converting-enzyme inhibitors or ARBs, uncontrolled hypertension (systolic blood pressure ≥ 170 mmHg and/or diastolic blood pressure ≥ 95 mmHg), poorly regulated diabetes mellitus (HbA1c ≥ 7.5%), renal insufficiency (creatinine > 1.3 mg/dl, blood urea nitrogen (BUN) > 60 mg/dl), and severe haematological and hepatic disorders. Furthermore patients with invasive revascularization procedures, intravenous alprostadil application and supervised exercise training 1 month before and/or during study period were excluded.

Written informed consent was obtained. The study protocol was approved by the local Ethics Committee. Investigations were undertaken in accordance with the Declaration of Helsinki.

The study design was prospective and single-blind. Patients were randomized to take the oral AT1-receptor blocker telmisartan (n = 18) or placebo (n = 18). The study course consisted of four visits: at visit 1 baseline clinical chemistry and blood pressure were obtained and maximum WD, FMD, IMT, ABI and DRQL were measured. Study medication was initiated at visit 1. The initial standard dose of telmisartan was 40 mg/day. Visit 2 was after 4 weeks for clinical follow-up in order to detect side effects of the study drugs (blood pressure measurement and clinical chemistry). Study medication was up-titrated to two capsules containing 40 mg telmisartan or two capsules placebo in case of persistent hypertensive blood pressure (≥150 mmHg systolic blood pressure). Visits 3 and 4 were held after 6 and 12 months following the same protocol as at visit 1.

Blood pressure measurement

Systolic and diastolic blood pressure of both brachial arteries were measured at baseline visit, after 4 weeks and after 6 and 12 months of treatment with placebo versus telmisartan. Measurements were performed in the supine position after 10 min rest using a manual sphygmomanometer. Values of the left and right arm were averaged.

Determination of the maximum treadmill WD

Absolute WD was measured at baseline visit and after 6 and 12 months by standard treadmill exercise test. Patients walked at a speed of 3 km/h and a gradient of 12% for 5 min or until claudication symptoms forced to stop the exercise.

Determination of FMD

FMD involves the determination of the diameter of a conduit artery before and after an increase in shear stress induced by reactive hyperemia [11]. FMD occurs predominantly as a result of local endothelial release of NO [12]. All studies were performed in a temperature-controlled room (at 23°C) with patients resting at least 30 min in supine position to establish a stable baseline. A blood pressure cuff was placed around the right upper arm. Diameter measurements of the right brachial artery were performed in longitudinal section between 5 and 10 cm above the elbow. After a baseline recording of 4 min, ischemia was induced by inflating the cuff for 4.5 min to 50 mmHg above the patient’s systolic blood pressure and then deflated to induce reactive hyperemia (RH) [13]. Immediately after cuff deflation, the maximal diameter of brachial artery was measured and continuously monitored for another 2 min. Vascular ultrasound scans were performed with the Phillips EnVisor scanner, using a 7.5 MHz linear array transducer.

Determination of ABI

Systolic blood pressures of the brachial, anterior and posterior tibial arteries were measured using inflatable cuffs and a Doppler probe [14, 15]. The maximum ankle arterial pressures were divided by the maximum of the brachial arterial pressures to calculate the ABI. Measurement of ABI was performed according to the Transatlantic Inter Society Consensus (TASC II) guidelines for the management of PAD [16]. The measurements were performed at least 5 min of rest using a standard cw Doppler probe (8 MHz).

Determination of IMT

Ultrasound scans of carotid arteries were performed at baseline visit, after 6 and 12 months using a Phillips EnVisor scanner equipped with a 7.5 MHz linear array transducer. IMT was measured on the far wall of the left and right common carotid artery (CCA). A minimum of three measurements on different localizations of each side of CCA were performed. IMT values were averaged. All study sonographers underwent a standardized training and used a common and extensively validated imaging protocol [17].

Assessment of DRQL

Quality of life was assessed using the Peripheral Arterial Occlusive Disease 86 Questionnaire developed by Bullinger et al. [18]. It contains 86 items of the following dimensions: functional status, pain, symptoms, mood, disease-related anxiety, social life and treatment evaluation. The global DRQL score ranged between 0 (no limitation) and 10 (maximum limitation in quality of life).

Clinical chemistry

Electrolytes, serum creatinine and blood urea nitrogen (BUN), alanine aminotransferase (ALT) and γ-glutamyltransferase (GGT), blood counts and C-reactive protein were examined in a centralized hospital laboratory at baseline, after 6 and 12 months. If dose of telmisartan was up-titrated to two capsules containing telmisartan 40 mg/2 capsules placebo after 4 weeks, there was an additional laboratory control at week 8. Willebrand factor antigen (vWf) was determined by immunoturbidometry (Dade Behring, Deerfield, USA) at baseline.

Statistical analysis

The primary objective was to determine whether treatment with telmisartan increases maximum WD. The study was designed to have 80% power to demonstrate a difference of 1.5% points in WD with a sample size of n = 18 per group. The secondary objective was to compare the two treatment arms telmisartan and placebo with respect to their effect on the FMD, ABI, IMT and DRQL.

Comparisons of changes in variables between the treatment groups were performed relative to baseline using the Mann–Whitney U test. The primary endpoint WD was additionally examined using the two-way analysis of variance with time and treatment being the two factors. Clinical characteristics of the two study groups were compared using Fisher’s exact test or the Student’s t test as appropriate. All data are presented as median and 95% confidence interval (CI) unless stated otherwise. P values <0.05 were considered statistically significant. All statistical analyses were carried out using the SPSS software package version 15.00 (SPSS Inc, Chicago, IL, USA).

Results

Baseline characteristics

In total, 40 patients were randomized to treatment, but only 36 completed the study and were analyzed. Premature discontinuation was due to incompliance of medication intake in four patients. No serious adverse events were seen. Basal demographic, hemodynamic and laboratory parameters were comparable between both treatment groups (Table 1). vWf is released from endothelial cells in response to stress and can be regarded as an indirect marker of endothelial dysfunction. Plasma concentrations of vWf were increased above 120% in 31 of 36 patients (86.1%). The median of vWf was 146.0% (95% CI 134.7–161.2). PAD was newly diagnosed in 5 (27.8%) patients of the telmisartan group and in 7 patients (38.9%) of the placebo group. At baseline, 17 patients (94.4%) took statins in the telmisartan group and 18 patients (100%) of the placebo group.
Table 1

Patient baseline characteristics

 

Placebo (n = 18)

Telmisartan (n = 18)

P

Age (years)

63 (56–75)

57 (53–64)

ns

Male, n (%)

13 (72.2)

13 (72.2)

ns

SBP (mmHg)

150.0 (140.0–159.3)

150.0 (145.0–155.0)

ns

DBP (mmHg)

80.0 (80.0–90.0)

80.0 (80.0–90.0)

ns

Cardiovascular risk factors

  

ns

 Current smokers, n (%)

4 (22.2)

8 (44.4)

ns

 Hyperlipoproteinemia, n (%)

17 (94.4)

18 (100.0)

ns

 Arterial hypertension, n (%)

18 (100)

18 (100)

ns

 BMI (kg/m2)

26.5 (25.3–28.1)

26.7 (25.5–28.3)

ns

 Diabetes mellitus, n (%)

5 (27.8)

5 (27.8)

ns

 HbA1c (%)

5.7 (5.6–6.3)

6.0 (5.8–6.4)

ns

 Carotid artery stenosis ≥ 70%, n (%)

2 (11.1)

2 (11.1)

ns

 Hx of peripheral bypass grafting, n (%)

2 (11.1)

1 (5.6)

ns

 Hx of percutaneous angioplasty, n (%)

7 (38.9)

10 (55.6)

ns

Concomitant therapy

  

ns

 Beta-blockers, n (%)

8 (44.4)

9 (50.0)

ns

 Calcium channel blockers, n (%)

7 (38.9)

5 (27.8)

ns

 Platelet inhibition, n (%)

16 (88.9)

17 (94.4)

ns

 Statin use, n (%)

17 (94.4)

18 (100.0)

ns

Creatinine (mg/dl)

0.80 (0.67–0.92)

0.86 (0.76–0.89)

ns

Serum urea (mg/dl)

37.0 (22.0–42.3)

30.0 (21.2–41.2)

ns

Total cholesterol (mg/dl)

200.0 (176.1–228.3)

218.0 (172.4–234.9)

ns

HDL (mg/dl)

41.0 (33.0–44.9)

43.0 (36.0–49.0)

ns

LDL (mg/dl)

149.0 (99.7–171.8)

142.8 (97.2–182.6)

ns

CRP (mg/l)

6.9 (3.1–9.2)

5.7 (2.4–9.7)

ns

ALT (U/l)

36.0 (25.2–38.9)

32.0 (25.0–42.9)

ns

GGT (U/l)

33.0 (27.4–42.7)

43 (22–65.2)

ns

von Willebrand factor (%)

144.0 (121.1–167.1)

154.0 (134.1–167.9)

ns

Data are expressed as median with the 95% CI for the median or n (%). P values <0.05 were considered significant

SBP systolic blood pressure, DBP diastolic blood pressure, BMI body mass index, HDL high-density lipoprotein, LDL low-density lipoprotein, CRP C-reactive protein, ALT alanin-aminotransferase, GGT γ-glutamyltransferase. ns not significant

Resting blood pressure

There were no significant differences in systolic, diastolic and mean arterial pressure (MAD) at baseline (systolic RR P = 0.51, diastolic RR P = 0.97, MAP P = 0.55, Table 1). After 12 months, the telmisartan group showed a significant reduction of systolic and diastolic blood pressures: 150 (95% CI 145–155)/90 (95% CI 80–90 mmHg) at baseline versus 135 (95% CI 130–140)/80 (95% CI 80–85 mmHg) after 12 months (P each <0.001, Table 2). In the placebo group, blood pressure decreased from 150 (95% CI 140–159)/90 (95% CI 80–90 mmHg) at baseline to 145 (95% CI 140–150)/90 (95% CI 80–90 mmHg, Table 2) after 1 year. There were significant differences between the two treatment groups in systolic (P < 0.001) and diastolic blood pressure (P < 0.01) and in MAP (P < 0.001) after 1 year of treatment (Table 2).
Table 2

Blood pressure during study period

RR

Placebo, n = 18

Telmisartan, n = 18

P

Systolic

Diastolic

MAD

Systolic

Diastolic

MAD

Systolic

Diastolic

MAD

Baseline

150 (140–160)

90 (80–90)

118 (110–125)

150 (145–155)

90 (80–90)

120 (115–120)

ns

ns

ns

Twelve months

145 (140–150)

90 (80–90)

115 (110–120)

135 (130–140)

80 (80–85)

108 (104–110)

<0.01

ns

<0.01

P

ns

ns

<0.01

<0.001

<0.001

<0.001

 

Data are expressed as median with the 95% CI for the median. P values <0.05 were considered significant

ns not significant

Primary endpoint

The maximum treadmill WD increased by 26% in the telmisartan group: from 132 m (95% CI 103–192) at baseline to 191 m (95% CI 157–226) after 12 months (P < 0.001, Fig. 1; Table 3). An improvement of WD was noted in 15 of 18 subjects. In comparison, total WD was comparable to baseline in the placebo group after 12 months: 100 m (95% CI 74–169) at baseline and 103 m (95% CI 76–164) after 1 year (P = 0.37, Fig. 1; Table 3). The telmisartan and placebo group did not differ significantly at baseline (P = 0.21). Patients treated with telmisartan showed a significant increase of WD after 12 months in comparison to the placebo group (P < 0.001, Fig. 1; Table 3).
https://static-content.springer.com/image/art%3A10.1007%2Fs00392-010-0184-0/MediaObjects/392_2010_184_Fig1_HTML.gif
Fig. 1

The maximum treadmill walking distance significantly increased in the telmisartan group (n = 18, *P < 0.001) whereas the placebo group (n = 18) did not show any significant difference at the end of the study relative to baseline baseline (P = ns). The two groups differed significantly after 12 months (P < 0.001). Median values ± 95% CI

Table 3

Primary endpoint and secondary endpoints at baseline and after 12 months of treatment with telmisartan versus placebo in patients with peripheral artery disease

Placebo, n = 18

Telmisartan, n = 18

P

Maximum walking distance (m)

 Baseline

100 (74–169)

132 (103–192)

ns

 Twelve months

103 (76–164)

191 (157–226)

<0.001

 P

ns

<0.001

 

Flow-mediated vasodilation (mm)

 Baseline

0.05 (0.04–0.07)

0.06 (0.04–0.09)

ns

 Twelve months

0.04 (0.04–0.06)

0.08 (0.05–0.12)

0.01

 P

0.02

<0.001

<0.001

Intima-media thickness (cm)

 Baseline

0.08 (0.08–0.1)

0.09 (0.08–0.09)

ns

 Twelve months

0.09 (0.08–0.1)

0.08 (0.07–0.09)

ns

 P

ns

ns

ns

Ankle brachial index

 All patients

  Baseline

0.52 (0.50–0.72)

0.60 (0.56–0.77)

ns

  Twelve months

0.52 (0.48–0.67)

0.60 (0.60–0.77)

0.01

  P

0.01

ns

<0.05

 Non-diabetic patients

(n = 13)

(n = 13)

 

  Baseline

0.50 (0.46–0.72)

0.57 (0.50–0.77)

ns

  Twelve months

0.50 (0.45–0.67)

0.69 (0.58–0.80)

<0.01

  P

ns

<0.001

< 0.001

Disease-related quality of life (score between 0 and 10)

 Baseline

5.0 (4.0–6.0)

4.0 (3.0–5.0)

0.01

 Twelve months

6.5 (6.0–7.0)

4.0 (3.0–5.0)

<0.001

 P

<0.001

ns

<0.01

Data are expressed as median and the 95% CI for the median. P values <0.05 were considered significant

ns Not significant

The choice of treatment had a significant influence on maximum WD (two-way ANOVA, P < 0.001). The effect of the treatment group on the WD was independent of treatment time.

Secondary endpoints

In the telmisartan group (n = 18), FMD significantly increased by 40% from 0.06 mm (95% CI 0.04–0.09) to 0.08 mm (95% CI 0.05–0.12) after 12 months of treatment (P < 0.01, Fig. 2; Table 3). Endothelial function deteriorated in the placebo group: FMD decreased from 0.05 mm (95% CI 0.04–0.07) at baseline to 0.04 mm (95% CI 0.04–0.06) (P = 0.02, Fig. 2; Table 3). FMD was similar in both treatment groups at baseline (P = 0.73). Telmisartan showed a considerable improvement of FMD after 12 months compared to the placebo group (P < 0.001, Fig. 2; Table 3).
https://static-content.springer.com/image/art%3A10.1007%2Fs00392-010-0184-0/MediaObjects/392_2010_184_Fig2_HTML.gif
Fig. 2

Telmisartan significantly improves FMD of brachial artery during the study period of 1 year in patients with PAD (*P < 0.001). In patients treated with placebo FMD deteriorated (P < 0.05), with a significant difference between the two groups after 12 months of treatment (P < 0.001). Median values ± 95% CI

The ankle brachial indexes (ABI) of all patients were similar in both groups and were unaffected by either treatment (Table 3). In non-diabetic patients (72.2%), telmisartan therapy led to an increased ABI by 11%, whereas it did not change in the placebo group (P < 0.001, Table 3).

The carotid IMT remained unchanged during 1 year within groups. There were no significant differences between groups, neither at baseline nor after 1 year (Table 3).

The DRQL scores did not change during the entire study period in the telmisartan group: 4.0 (3.5–5.0) at baseline and end. There was, however, a significant decrease of DRQL in the placebo group by 30% from 5.0 (95% CI 4.0–6.0) at baseline to 6.5 (95% CI 6.0–7.0) at study end (P < 0.001). Both treatment groups differed already at baseline (P = 0.01), with a drastic increase of difference after 12 months (P < 0.01, Table 3).

Discussion

This is a pilot study to obtain estimates of the impact of telmisartan on endothelial function and clinical parameters, such as maximum WD, brachial endothelial function, ABI, carotid IMT and DRQL in patients with PAD over a long-term study period of 12 months. Long-term treatment with telmisartan improved maximum WD, endothelial function and stabilized DRQL. IMT remained unchanged in both treatment arms. ABI significantly increased in non-diabetic patients in the telmisartan group while it did not change in the placebo group.

There are only few reports about the influence of telmisartan on endothelial function. Treatment periods were limited to 24 weeks, sufficient to demonstrate a significant improvement of endothelial function [19]. This observation was consistent with beneficial effects of other ARBs on brachial endothelial function [20, 21]. An enhancement of endothelial function has been related to improved cardiovascular prognosis [22, 23]. Our data extended the benefit of AT1-blockade with telmisartan to PAD patients.

Up to now, it was not clear whether the improvement of endothelial function would also translate into clinical advantages from which patients would benefit: walking capacity and quality of life. Improvements in both parameters may promote patient’s compliance in terms of cardiovascular therapy in general. This is important because PAD patients carry a high risk for cardiovascular events. In the present trial patients treated with telmisartan showed a significant improvement of the maximum WD, which was determined in a highly standardized fashion. For comparison, a recent study on patients with PAD focused on the endpoint pain-free WD after stent angioplasty comparing candesartan with quinapril treatment for 6 months [24]. Here candesartan treatment led to a significant extended pain-free WD [24].

We examined several clinical parameters that might be implicated in the observed improvement of endothelial function. There was no significant change in carotid IMT in both treatment groups after 12 months. Present reports on the effects of ARBs on the IMT are controversial. Petrovic et al. [25] showed a significant reduction in carotid IMT in hypertensive patients after treatment with telmisartan, ramipril or the combination of both for 6 months. Furthermore, Ariff et al. [26] showed a reduction of IMT in both treatment regimens with candesartan or atenolol after 1 year. These observations are in contrast to the results of Ichihara et al. [27] who were not able to detect changes in IMT after 12 months of candesartan therapy. Although an increased IMT may predict myocardial infarction and stroke [28], carotid IMT is not an appropriate parameter to reflect the ability of the endothelium to react directly to increase NO activity.

In overall patients, the ABI remained unchanged in both treatment groups. There was a significant increase in ABI during the study period in non-diabetic patients of the telmisartan group. The ABI measurements in diabetic patients were excluded in a second analysis because of the inconsistent results due to media-sclerosis.

Only few studies examined the influence of ARBs on the ABI. Two recent studies with candesartan/losartan did not show any improvement of ABI after 1 year of therapy [23, 27].

A limited DRQL is common in patients with PAD and contributes to morbidity resulting in loss of economic productivity. In the present study, self-reporting by questionnaire demonstrated a significant decrease in DRQL in the placebo group. This deterioration correlated to decreases in the maximum WD and in endothelial function consistent with a progression of PAD. In contrast, telmisartan was able to prevent impairment of WD and stabilized the DRQL. The maintenance of quality of life is particularly important to motivate the patients for exercise training, which is a cornerstone of non-invasive treatment of PAD. Conversely, previous studies have shown that continuous exercising maintains a higher quality of life and a greater daily functional status [29]. Interestingly, patients treated with telmisartan showed a significant improvement of maximum WD, but the DRQL did not improve significantly. This might be explained by the fact that chronic claudication pain in PAD patients is not completely abolished by telmisartan treatment [30].

Recently, the ongoing telmisartan alone in combination with ramipril global endpoint trial (ONTARGET) demonstrated an equivalence of 80 mg telmisartan and 10 mg ramipril with respect to primary endpoints outcome of cardiovascular death, stroke, heart attack or hospitalization for new-onset heart failure. Only 13% of the subjects qualified as PAD patients and clinical endpoints comparable to those described here, were not reported [31]. Therefore, the results of ONTARGET do not overlap with our data.

The impact of baseline values on treatment was evaluated using an ANCOVA analysis. There was a significant difference in DRQL at baseline between both treatment groups, but a confounding effect on treatment was excluded. Furthermore, statin use did not show any confounding effects on endpoint outcomes of WD, EF, IMT, ABI and quality of life.

Limitations

The present study is a small pilot study without a double-blinded design.

There were, in part, significant differences in values at baseline between the two treatment groups. It is due to a small study group, in spite of randomization. Therefore, ANCOVA testing was performed. It revealed no confounding effects of differences in baseline values on the treatment. Subgroup analysis could not be evaluated since the design of the study did not provide a statistically sufficient number of test subjects.

Further studies are required to confirm our observations. Long-term follow-up monitoring of large clinical trials such as ONTARGET will provide more information about prognostic benefits (including clinical measures) of AT1-receptor blockade.

FMD is a widely used, non-invasive tool for the determination of endothelial function [11, 20], and may serve as a surrogate marker for clinical endpoints [32]. However, there are certain limitations of this method including local endothelium-independent factors contributing to vasodilatation after ischemia and an operator-dependent variability which can be minimized by training. Finally, the improvement of endothelial function might also be related to improved blood pressure therapy with telmisartan and not due to the improvement of endothelial function. These results provide further justification for large trials investigating the relation between blood pressure-dependent and -independent effects on the improvement of endothelial dysfunction in PAD.

Conclusions

In summary, our study demonstrates for the first time that a long-term treatment with telmisartan improves endothelial function and functional capacity in patients with PAD. Moreover, telmisartan was able to stabilize the quality of life in these patients. In non-diabetic patients, treatment with telmisartan improved ankle-brachial-index. The improvement of endothelial function may also improve cardiovascular prognosis because a low FMD has been associated with a high cardiovascular event rate. This remains to be confirmed in larger clinical trials.

Acknowledgments

This pilot study was supported by Bayer, Leverkusen, Germany. We thank Thomas Wienbrandt for critically reading the manuscript.

Copyright information

© Springer-Verlag 2010