Introduction

Increased left ventricular mass (LVM) is an independent risk factor for cardiovascular morbidity and mortality in patients with hypertension.¹ Therefore, left ventricular hypertrophy (LVH) regression is a key objective when managing hypertensive patients, the risk of cardiovascular disease being reduced in patients with LVH regression compared with those with none.²

According to a meta-analysis published in 1992,³ ACE inhibitors produced the greatest reduction in LVM, despite the blood pressure reductions produced by other classes of antihypertensive agents — beta-blockers, calcium channel blockers and diuretics — being equivalent to those of ACE inhibitors. As a class, ACE inhibitors are well recognised as being effective in the treatment of hypertension and relatively well tolerated. In their presence, alternative enzymatic pathways of angiotensin II formation (eg, cardiac chymase) may become activated resulting in the so-called 'ACE escape'.⁴ Also, the low substrate specificity of ACE means that breakdown of other peptides, such as bradykinin and substance P, that are implicated in such side effects as cough and angioedema may be inhibited.⁵ Another class of antihypertensive agents introduced more recently into the clinical arena — the angiotensin II receptor blockers (ARBs) — also target the RAA system. Their mode of action involves the specific and selective antagonism of the angiotensin II type 1 (AT₁) receptors, which mediate most of the adverse cardiovascular effects of angiotensin II.⁶ The selectivity of this action allows the available angiotensin II, whether produced via ACE or other enzymatic pathways, to stimulate the AT₂ receptors that may confer target-organ protection.⁶ The ARBs, which have side effect profiles similar to placebo, overcome the limitations of ACE inhibitors without sacrificing their effectiveness in reducing blood pressure or LVM.⁷ The Losartan Intervention For Endpoint reduction in hypertension (LIFE) study demonstrated the long-term benefit on the ARB losartan in terms of LVH regression.^8,9

The ARB telmisartan binds insurmountably to and dissociates slowly from the AT₁ receptor.¹⁰ Other distinguishing features of telmisartan are its almost exclusive biliary excretion and terminal elimination half-life of about 24 h.¹¹ Clinical studies have shown the ability of once-daily telmisartan to provide effective control of blood pressure.¹¹ Preclinical studies suggest that telmisartan is highly effective in reducing LVH,^12,13,14,15 and preliminary observations provide evidence for the clinical efficacy of telmisartan in the treatment of LVH at doses that confer effective blood pressure control.^16,17

The purpose of the present study was to compare the effect of the standard therapeutic dose of telmisartan 80 mg with that of the thiazide diuretic hydrochlorothiazide (HCTZ) 25 mg on blood pressure, LVM and tolerability in hypertensive subjects after 12 months of treatment. Clinical studies have shown that, in the long term, HCTZ in addition to reducing blood pressure brings about LVH regression in hypertensive patients.¹⁸ Other data suggest that HCTZ is inferior to ACE inhibitors in the regression of LVH.¹⁹ Discrepancy in findings on the effects of antihypertensives on LVH may be due to the LVM quantification method. M-mode and two-dimensional echocardiography, although widely used and generally regarded as reliable, involve geometrical assumptions that may decrease the accuracy.²⁰ The problem is greatest in subjects with abnormally shaped left ventricles, as often occurs in hypertensive patients.²¹ Three-dimensional echocardiography avoids any such assumptions.²² Dynamic freehand precordial three-dimensional echocardiography, as used in the present study, allows easy and fast determination of the ventricular volume by using a magnetic sensor device attached to the ultrasound probe.^23,24

Materials and methods

Patient selection

Patients (age >18 years) with mild-to-moderate essential hypertension (DBP 90–114 mmHg at the end of a 2-week washout period) were eligible for inclusion. All patients were required to display sinus rhythm, but the presence of LVH was not an inclusion criterion. Only patients with an optimal acoustic window, evaluated by two-dimensional echocardiography, were selected. The exclusion criteria were previous myocardial infarction or stroke, renal failure, chronic severe liver disease, congestive heart failure, pregnancy or breast-feeding, electrolyte imbalance and gout. Patients provided informed consent before entering the study.

Study design

Enrolment and follow-up of patients was carried out at four institutions. During an initial 2-week washout period, the patients underwent twice-weekly physical examinations at an out-patient clinic. The mean of three supine blood pressures, measured using a manual cuff sphygmomanometer, was recorded to establish eligibility. Thereafter, eligible subjects received the first dose of the randomly allocated double-blind, once-daily telmisartan 80 mg or HCTZ 25 mg given for a total of 12 months. Patients were instructed to take the medication in the early morning. For the first 3 months of active treatment, cuff blood pressure was measured at 1-month intervals and then every 3 months. No other antihypertensive treatment was allowed for the duration of the study; any patient failing to respond sufficiently to treatment was withdrawn from the study. At baseline and after completion of the 12 months' treatment, standard blood tests, electrocardiography, two- and three-dimensional echocardiography and 24-h ABPM were performed. Routine blood tests were also conducted after 6 months' treatment.

ABPM

An oscillometric SpaceLab 90207 monitor (SpaceLab Inc., Redmond, WA, USA) programmed to take measurements every 15 min for 24 h was used, with recording starting between 0900 and 1100. In cases of an arm circumference of >32 cm, a broad cuff was used. The device was checked against a mercury sphygmomanometer by a Y-tube.

Echocardiography

Echocardiography was performed at the Three-Dimensional Echocardiography Laboratory, Division of Cardiology, San Gennaro Hospital, Naples, Italy. An Agilent Sonos 5500^® echocardiograph (Philips Medical Systems) was employed, using harmonic fusion imaging mode with an S3 transducer. The electromagnetic spatial locator was attached to the transducer and interfaced with the compact three-dimensional cardiac imaging system (TomTec^®). The freehand image acquisition was performed from an apical window with the patient in the left recumbent position. Starting from a four-chamber view, the transducer was tilted slowly across the heart in a fan-like manner towards the anterior or posterior wall, encompassing the entire left ventricular volume by collecting 30 two-dimensional slices with one full cardiac cycle; data were digitally stored. Thereafter, acquisition was resumed with the transducer being slowly moved to the opposite side. The patient was instructed to avoid breathing during data acquisition.

The workstation acquired the two-dimensional video information with frame rates of 25 or 50 Hz (Echoscan 4.2 software, TomTec). An electromagnetic locator system (Flock of Birds, Ascension Technology Corp, Burlington, VT, USA) determined the transducer's three-dimensional spatial orientation, facilitating designation of spatial Cartesian coordinates to every frame (resolution/accuracy of the locator system : translation accuracy 0.18 cm root mean square (RMS); orientation accuracy 05° RMS). Electrocardiography and respiratory triggering enabled compensation for changes in the cardiac cycle; images acquired during inspiration and during beats with R–R intervals >150 ms were ignored. Respiratory gating was switched off during breath-held acquisitions; five or eight series of 10–12 heart beats during suspended respiration were acquired. Typically, both breath-held and free-breathing acquisitions were performed within 2.30 min (average 2.07 0.55 min: range 1.5–2.30 min).

The images were subsequently analysed using Echoview 4.2 TomTec software. The left ventricular mass was calculated by disc summation. The left ventricle was divided into multiple equidistant, parallel, transverse, short-axis cutting planes (7 mm) from the atrioventricular groove to the apex; the papillary muscles were not included. On each of these slices, the endocardium and the epicardium were traced and the area between them was measured by the computer. An inherent computer program calculated the volume of each slice. The total left ventricular volume was obtained by adding the values of the individual slices and the total myocardial mass was derived by multiplying the myocardial wall volume (ml) by the tissue density of the heart (g/ml). Each echocardiographic evaluation was reviewed by two independent observers to determine interobserver variability.

Patients with a left ventricular mass index (LVMI) related to body surface >130 g/m² in men and >110 g/m² in women, based on the upper 90th percentile from a local reference group of 150 apparently healthy, normotensive adults, were classified as having LVH.

Statistical analysis

ABPM data with 85% likely readings were analysed. All data are expressed as mean s.d. Statistical analysis was performed within treatment groups using Student's t-test for paired data. Differences between the treatment groups were compared by analysis of variance (ANOVA) with Bonferroni correction. A P-value of <0.05 was considered statistically significant.

Results

Patients

A total of 69 patients were enrolled (Table 1). No patients were being treated with cardiovascular drugs other than the assigned study drug, with the exception of three in the telmisartan group and two in the HCTZ group who were in receipt of statins. Of the enrolled patients, 65 completed the study; one in the telmisartan group withdrew because of dizziness and three in the HCTZ group were withdrawn due to insufficient response during the first month of active treatment.

Table 1 - Mean s.d. baseline characteristics of patients with mild-to-moderate hypertension (DBP 90–114 mmHg) randomised to once-daily treatment with telmisartan 80 mg or HCTZ 12.5 mg for 12 months.

Full table

Antihypertensive efficacy

ABPM gave a 95% mean of successful readings, with no differences between baseline and after 12 months of active treatment. Telmisartan 80 mg reduced 24-h mean SBP from 157 11 to 133 7 mmHg (P<0.001) and 24-h mean DBP from 96 6 to 83 5 mmHg (P<0.001; Figure 1). In the patients treated with HCTZ 25 mg, 24-h mean SBP was reduced from 154 10 to 144 11 mmHg (P<0.003) and 24-h mean DBP from 95 7 to 87 8 mmHg (P<0.003; Figure 1). ANOVA showed that telmisartan brought about a significantly (P<0.001) greater reduction in 24-h mean SBP and DBP compared with HCTZ. In addition, telmisartan resulted in a greater reduction compared with HCTZ in mean blood pressure between 21 and 24 h after the last dose (data not shown). The percentage of patients with cuff supine DBP <90 mmHg or a reduction in both SBP and DBP of 10 mmHg was 74% in the telmisartan group and 56% in the HCTZ group.

Figure 1.

Change in 24-h mean SBP and DBP after 12 months' double-blind treatment with once-daily telmisartan 80 mg and HCTZ 25 mg.

Full figure and legend (47K)

Left ventricular mass

Telmisartan produced a significant reduction in LVMI from 141 16 to 125 19 g/m² (P<0.001). after 12 months' treatment (Figure 2a). By contrast, the reduction in the patients treated with HCTZ from 139 20 to 135 22 g/m² did not achieve statistical significance (P = 0.38). ANOVA showed that telmisartan was significantly superior (P<0.001) to HCTZ in reducing LVMI. At baseline, LVH, defined as an LVMI of >130 g/m² in males and >110 g/m² in females, was present in 26 (65%) of the 40 evaluable patients in the telmisartan group and 14 (56%) of the 25 evaluable patients in the HCTZ group. Normalisation of LVMI was achieved in nine (34%) telmisartan-treated compared with two (14%) HCTZ-treated patients. In the remaining LVH patients, a reduction in LVMI was observed in 12 (46%) in the telmisartan group and in three (21%) in the HCTZ group. Interobserver variability calculated LVMI was in the range 3.2–4.5%. No difference in left ventricular diastolic diameter at baseline and end of treatment was found (telmisartan 5.28 0.19 vs 5.25 0.18 cm; HCTZ 5.20 0.22 vs 5.16 0.20 cm; Figure 2b). As myocardial volume was calculated directly, any variations in left ventricular diastolic diameter had no impact on LVMI determination.

Figure 2.

Change in (a) LVMI and left ventricular diastolic diameter after 12 months' double-blind treatment with once-daily telmisartan 80 mg and HCTZ 25 mg.

Full figure and legend (85K)

Relationship between LVM and blood pressure

The ratio of LVMI percentage change : 24-h mean blood pressure percentage change (%LVMI/% BP) was higher in patients treated with telmisartan for both SBP and DBP (0.75 and 0.86, respectively) compared with values for the HCTZ-treated patients (0.45 and 0.34, respectively). Multiple comparisons showed a significant greater benefit (P<0.05) for telmisartan-treated patients compared with HCTZ-treated patients.

Safety

No first-dose hypotension was observed with telmisartan. In the telmisartan group, adverse events were mostly mild in severity and only one patient withdrew because of mild dizziness. No patient experienced a cough in either group. No adverse laboratory parameters were noted, other than serum potassium levels of <3.7 mmol/l in two patients after 11 months of HCTZ treatment. Following treatment, no significant changes in fasting glucose levels or lipid profile were observed.

Discussion

LVH regression can be regarded as an important end point when considering the efficacy of antihypertensive agents. LVH can adversely impact on the quality of life and heralds increased risk of cardiovascular morbidity and mortality.² However, a recently published meta-analysis showed that not all classes of antihypertensive drugs are equally effective in reversing LVH.¹⁹

In the present study, ABPM showed that telmisartan significantly lowered 24-h mean SBP and DBP. Reductions in SBP and DBP achieved with HCTZ were significantly smaller, and a lower percentage of HCTZ-treated patients had a post-treatment cuff supine DBP of <90 mmHg or a reduction in both cuff supine SBP and DBP of 10 mmHg. ABPM showed that telmisartan's antihypertensive effect occurred not only in the daytime but also at the end of the dosing interval, thus demonstrating that its antihypertensive efficacy using a once-daily regimen persists throughout the 24 h between doses. This observation is consistent with a meta-analysis of clinical studies in which telmisartan was evaluated using ABPM.²⁵

Blood pressure control at the end of the dosing interval is particularly important. The majority of patients find it most convenient to take their antihypertensive medication in the morning after rising. This means that minimal drug levels, and hence the pharmacodynamic trough effect, coincide with the early morning surge in blood pressure.²⁶ Blood pressure control throughout the 24-h period is important to gain complete benefit from antihypertensive therapy. The Study on Ambulatory Monitoring of blood Pressure and Lisinopril Evaluation (SAMPLE) showed that LVH regression was predicted much more closely by treatment-induced changes in ambulatory blood pressure, which provide a measure of antihypertensive activity throughout the dosing interval, than clinic blood pressure, which indicates the extent of blood pressure control at an isolated time point.²⁷ The morning is also the time of the day when the risk of cardiovascular events is at its highest,²⁶ hence, the importance of the control of blood pressure at this time to prevent target-organ damage and reduce cardiovascular morbidity. The present study established the superiority of telmisartan in the control of blood pressure at the end of the dosing interval.

In our investigation, telmisartan 80 mg, but not HCTZ 25 mg, brought about significant LVMI regression. The duration of treatment in the present study was only 12 months; it is likely that a more marked benefit would be gained from treatment for a longer period. In the Losartan Intervention For Endpoint reduction (LIFE) study, LVH regression continued in the second year despite only small reductions in blood pressure after the first year of therapy.²⁸

The effect of telmisartan on left ventricular mass observed in this study may not be due exclusively to a reduction in blood pressure but also as the result of a blood pressure-independent mechanism possibly due to its action on the RAA system. The study, however, was not designed to establish the link between blood pressure control and LVH regression. Nevertheless, in our present study, telmisartan achieved a greater %LVMI/%BP ratio than HCTZ. These data support the hypothesis that the telmisartan-induced reduction of LVH could depend on the drug-related effect on the RAA system and not only on BP. Furthermore, the present results suggest a superiority of telmisartan compared with losartan. A previous study established similar %LVMI/%BP values for HCTZ to those observed in the present study, whereas the ratios for losartan were lower than those for telmisartan found in the current study.²⁹ The relationship between blood pressure control and LVH will be addressed in the Telmisartan Effectiveness on Left ventricular MAss Reduction (TELMAR) study,³⁰ the aim of which is to achieve good blood pressure control using either telmisartan- or metoprolol-based therapy, thus any selective effect on LVM, determined using magnetic resonance imaging, beyond blood pressure reduction will be elucidated.

The use of three-dimensional echocardiography in patients with an optimal acoustic window in the present study avoided any inaccuracy due to the poor quality of the two-dimensional images.³¹ The relatively small number of patients evaluated in the present study may be regarded as a potential limitation. However, three-dimensional assessment of LVM has been demonstrated to require fewer patients than two-dimensional echocardiography.²⁰

Both treatments were well tolerated in the present study, in which there were about 15 000 patient-days exposure to telmisartan and 10 000 to HCTZ. Treatment with HCTZ can result in metabolic disturbances.³² In the present study, no changes in fasting blood glucose or lipid profile were observed. Hypokalaemia was detected in two patients after 11 months of HCTZ treatment. By contrast, after 12 months of telmisartan treatment, no clinically significant variations in laboratory parameters were noted: the lipid profile and fasting blood glucose remained unchanged, and no patient displayed hyperkalaemia or hypouricaemia. Thus, there is a high degree of safety and tolerability that permits the use of telmisartan in patients with various pathologies.

In conclusion, these data demonstrate that telmisartan is more effective than HCTZ in reducing blood pressure in patients with mild-to-moderate hypertension and also results in a greater reduction of LVMI.

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Acknowledgements

We express our thanks to Michele A Tedesco for the review of the manuscript.