Angiotensin II Receptor Blocker Telmisartan: Effect on Blood Pressure Profile and Left Ventricular Hypertrophy in Patients with Arterial Hypertension*

Transcription

1 The Journal of International Medical Research 2005; 33 (Suppl 1): 21A 29A Angiotensin II Receptor Blocker Telmisartan: Effect on Blood Pressure Profile and Left Ventricular Hypertrophy in Patients with Arterial Hypertension* OV IVANOVA, OA FOMICHEVA, LM SERGAKOVA, NA CHERNOVA, AN ROGOZA AND YA KARPOV Cardiology Research Complex, Moscow, Russian Federation In this open-label, non-comparative study, the anti-hypertensive efficacy and effect on left ventricular hypertrophy (LVH) of 24 weeks treatment with once-daily telmisartan mg was evaluated in 24 patients with mild-to-moderate hypertension and LVH. Patients were titrated to the higher dose of study drug at week 4 if they did not achieve blood pressure normalization (i.e. systolic blood pressure [SBP]/diastolic blood pressure [DBP] remained 140/90 mmhg). The antihypertensive action of telmisartan was assessed using clinic cuff measurements and 24-h ambulatory blood pressure monitoring, and left ventricular mass index (LVMI) was determined by two-dimensional echocardiography at baseline and after 24 weeks of therapy. Telmisartan significantly reduced mean 24-h, daytime and night-time SBP and DBP compared with baseline after 12 and 24 weeks of therapy. Target blood pressure levels, defined as SBP/DBP < 140/90 mm Hg, were achieved in 16 (69.6%) patients at the end of the treatment period. After 24 weeks of telmisartan treatment, LVMI decreased from ± 5.4 to ± 5.9 g/m 2. In conclusion, anti-hypertensive treatment with telmisartan for 24 weeks produced significant reductions in blood pressure and regression of LVH, as assessed by LVMI, in patients with hypertension and LVH. KEY WORDS: HYPERTENSION; LEFT VENTRICULAR HYPERTROPHY; AMBULATORY BLOOD PRESSURE MONITORING; ANGIOTENSIN II RECEPTOR BLOCKER; TELMISARTAN Introduction One of the crucial issues of contemporary cardiology is the effective management of target-organ damage in patients with essential hypertension. Left ventricular hypertrophy (LVH), as the major cardiac adaptation to pressure overload, is a strong and independent predictor of cardiovascular morbidity and mortality. 1 Several studies *Original published in Russian: Ivanova OV, Fomicheva OA, Sergakova LM, Chernova NA, Rogoza AN, Karpov YA, et al. Angiotensin II receptor blocker telmisartan: effect on 24-hour blood pressure profile and left ventricular hypertrophy in patients with hypertension. Kardiologiia 2002; 42: Translated and reproduced here by permission from Media Sfera, Moscow. 21A

2 suggest that LVH regression is associated with an improved prognosis in hypertensive patients. 2,3 As a result, prevention or regression of LVH in patients with concurrent hypertension, through blood pressure reduction, is a desirable treatment goal. There is, however, increasing evidence from studies such as Heart Outcomes Prevention Evaluation (HOPE) and Losartan Intervention For Endpoint reduction in hypertension (LIFE) that suggests that some antihypertensive agents confer target-organ protective effects above and beyond blood pressure control. 4,5 Angiotensin II is the principal effector molecule of the renin angiotensin aldosterone system, and plays a key role in the emergence and development of LVH and cardiac remodelling. 6 Research into the part played by angiotensin II in the pathogenesis of hypertension has led to the development of two classes of anti-hypertensive drugs: angiotensinconverting enzyme (ACE) inhibitors and, more recently, the angiotensin II receptor blockers (ARBs). The ARBs act by selectively blocking the binding of angiotensin II to angiotensin II type 1 (AT 1 ) receptors, and thus result in blockade of angiotensin II s harmful actions on the cardiovascular system. 6 ACE inhibitors, in contrast, act by overcoming angiotensin II production. ACE inhibitors may not totally prevent angiotensin II production due to the existence of alternative enzymatic pathways, leading to the so-called ACE escape. 7 However, the efficacy of ACE inhibitors in preventing target-organ damage has been demonstrated in numerous clinical trials. 8,9 As ARBs potentially provide a more complete blockade of angiotensin II, they may confer superior target-organ protection compared with ACE inhibitors. Telmisartan is a relatively recently developed ARB with a long elimination halflife (approximately 24 h) 10 that has been shown to provide well-tolerated 24-h blood pressure control with once-daily dosing. 11 The maximal blood pressure lowering action of telmisartan is achieved at a dose of 80 mg once daily. 10,12 The aim of this study was to examine the anti-hypertensive efficacy and effect of telmisartan mg monotherapy on remodelling of the left ventricular myocardium in patients with LVH and essential hypertension. Patients and methods PATIENTS Male and female patients with mild-tomoderate hypertension and LVH were eligible to participate in this trial. Mild-to-moderate hypertension was defined according to the World Health Organization International Society of Hypertension classification as systolic blood pressure (SBP) mmhg and/or diastolic blood pressure (DBP) mmhg. 13 LVH was defined as a left ventricular mass index (LVMI) of > 104 g/m 2 in women and > 116 g/m 2 in men, as assessed by two-dimensional echocardiography. 2 Major exclusion criteria included: symptomatic or malignant hypertension, ischaemic heart disease, congestive heart failure, retinal haemorrhage, uncontrolled diabetes mellitus, renal or hepatic impairment, obstructive biliary disease, stroke or transient ischaemic attack within the previous 6 months, pregnancy or lactation, or concomitant use of medications known to affect blood pressure. STUDY DESIGN This was an open-label, non-comparative study. Following a 1 2-week run-in period, during which any previous anti-hypertensive medication was discontinued, patients underwent a baseline assessment. Thereafter, eligible patients received telmisartan 40 mg once daily for 24 weeks. The dose of telmisartan was uptitrated to 80 mg once 22A

3 daily in patients who had SBP/DBP 140/90 mmhg at week 4. Patients were instructed to take their medication each morning. BLOOD PRESSURE EVALUATION Trough blood pressure 24 h after the receipt of telmisartan was assessed using a cuff sphygmomanometer with the patient in the seated position at baseline and at weeks 4, 12 and 24, according to Korotkov s method. Three measurements were taken 2 min apart, and mean cuff SBP and DBP were calculated. Pulse rate was also measured at baseline and at the end of the treatment period. At baseline and at weeks 12 and 24, 24-h ambulatory blood pressure monitoring (ABPM) was conducted using a portable TM monitor (A & D Company Ltd, Tokyo Japan). Blood pressure was recorded at 15-min intervals during the morning (07:00 09:59), at 30-min intervals during the daytime (10:00 22:59) and at 60-min intervals during the night-time (23:00 06:59). The following mean parameters were calculated from the 24-h ABPM recordings: SBP, DBP, mean arterial pressure (MAP) and pulse pressure (PP, i.e. SBP DBP) over three time periods (i.e. 24-h, daytime and night-time); daytime and night-time SBP and DBP variability (standard deviation of respective measurements) and pressure load (blood pressure in excess of 140/90 mmhg during daytime and in excess of 120/80 mmhg during night-time); SBP/DBP level of nighttime reduction (LNR); and SBP/DBP level of morning blood pressure volume (MV). The SBP/DBP MV (%) was calculated as maximum SBP/DBP during the period 06:00 12:00 divided by mean night-time SBP/DBP. LVH EVALUATION Two-dimensional echocardiography was conducted at baseline and at week 24, using a Hewlett Packard Sonos 2000 system. LVMI was calculated according to the formula of Devereux et al. 14 A 10 g/m 2 reduction in LVMI was considered a prognostically meaningful response. 15 TOLERABILITY The incidence and severity of all adverse events that occurred during the study period were recorded. STATISTICAL ANALYSIS Data are expressed as mean ± SE, unless otherwise stated. Statistical analyses were performed using Microsoft Windows Excel. Differences between baseline and posttreatment values were assessed with the paired Student s t-test. A P-value of < 0.05 was regarded as statistically significant. Pearson s correlation coefficients were calculated. Results PATIENTS A total of 24 patients were included in the study. One patient was excluded from the analysis due to premature discontinuation because of an adverse event. The mean ± SD age of patients was 55.7 ± 1.8 years, and 41.7% of the trial population was female. At the end of the run-in period, seven (29.2%) patients had mild hypertension (SBP/DBP /90 99 mmhg) and 17 (70.8%) moderate hypertension (SBP/DBP / mmhg). Mean baseline clinic SBP/DBP was ± 2.4/98.2 ± 1.1 mmhg, and mean duration of hypertension was 11.4 ± 1.9 years. CLINIC BLOOD PRESSURE At week 4, six (26.1%) patients achieved blood pressure normalization (SBP/DBP 140/90 mmhg). The dose of telmisartan was uptitrated to 80 mg once daily in the remaining 17 patients who had not achieved 23A

4 blood pressure normalization at this time point. Twelve (52.2%) patients achieved blood pressure normalization by week 12. In all seven patients with mild hypertension, blood pressure was normalized, and an additional nine (39.1%) patients had a good blood pressure response ( 10% reduction in SBP and DBP) after 24 weeks of treatment. Telmisartan significantly (P < for all) reduced mean SBP and DBP compared with baseline observations after 12 and 24 weeks (Table 1). At week 12, SBP and DBP were reduced from baseline by 14.3 ± 1.4% and 14.2 ± 1.6%, respectively. At week 24, SBP and DBP were reduced from baseline by 15.9 ± 1.2% and 15.0 ± 1.2%, respectively. There was no significant change in mean pulse rate after treatment with telmisartan compared with baseline: the mean pulse rate was 72.2 ± 1.8 beats/min at baseline and 73.9 ± 1.8 beats/min at week H ABPM Telmisartan reduced several mean ABPM parameters compared with baseline (Table 2). At week 12, telmisartan brought about a significant reduction in mean values of SBP, MAP, DBP, SBP pressure load and DBP pressure load over each of the pre-defined ABPM intervals (P < 0.01 for all). There was no significant change from baseline in mean PP or blood pressure variability (data not shown) over each of the pre-defined ABPM intervals after treatment with telmisartan. Telmisartan reduced mean SBP and DBP by comparable amounts during each of the pre-defined ABPM intervals at week 24 in comparison with baseline. Telmisartan reduced 24-h SBP and DBP by 10.9 ± 1.3% and 10.6 ± 1.7%, daytime SBP and DBP by 10.6 ± 1.4% and 10.4 ± 1.7%, and night-time SBP and DBP by 11.7 ± 2.3% and 11.4 ± 3.1%, respectively. Blood pressure control was maintained over 24 h with once-daily telmisartan (Fig. 1). Target mean ambulatory blood pressures (daytime mean: 140/90 mmhg; night-time mean: 125/75 mmhg) were attained by 16 (69.6%) patients at week 24. Two (8.7%) patients were unresponsive (< 7 mmhg drop in 24-h mean SBP and < 5 mmhg drop in 24-h mean DBP) to telmisartan 80 mg. Although telmisartan increased baseline SBP LNR from 10.5 ± 2.0% to 14.2 ± 1.5% and DBP LNR from 11.6 ± 2.2% to 15.6 ± 1.7% by week 24, these increases did not achieve statistical significance (P = 0.07 and 0.08, respectively) (Table 2). At baseline, eight (34.8%) patients had a normal SBP LNR and 10 (43.5%) had a normal DBP LNR. In addition, there was a significant correlation between SBP LNR and DBP LNR (r = 0.86; P < 0.001). At baseline, three (13.0%) patients had elevated night-time SBP (in relation to daytime SBP) and four (17.4%) patients had TABLE 1: Mean ± SE reductions from baseline in mean seated cuff systolic blood pressure (SBP) and diastolic blood pressure (DBP) after 12 and 24 weeks of treatment with telmisartan mg once daily in 23 patients SBP SBP reduction DBP DBP reduction Stage of study (mmhg) (mmhg) (mmhg) (mmhg) Baseline ± ± 1.1 Week ± 2.6 a 23.4 ± ± 1.7 a 14.0 ± 1.6 Week ± 2.4 a 26.1 ± ± 1.1 a 14.7 ± 1.3 a P < compared with baseline. 24A

5 TABLE 2: Mean ± SE blood pressure after 12 and 24 weeks of treatment with telmisartan mg once daily over various ambulatory blood pressure monitoring periods in 23 patients Parameter Baseline Week 12 Week h SBP (mmhg) ± ± 2.4 a ± 1.9 a MAP (mmhg) ± ± 1.6 a 95.6 ± 1.3 a DBP (mmhg) 87.0 ± ± 1.5 a 77.4 ± 1.3 a PP (mmhg) 69.0 ± ± ± 2.6 Daytime (10:00 22:59) SBP (mmhg) ± ± 2.5 a ± 2.2 a MAP (mmhg) ± ± 1.7 a 97.9 ± 1.5 a DBP (mmhg) 89.0 ± ± 1.6 a 79.0 ± 1.4 a PP (mmhg) 70.5 ± ± ± 2.7 SBP PL (%) 70.6 ± ± 4.6 a 39.6 ± 4.8 a DBP PL (%) 49.6 ± ± 3.8 a 19.8 ± 3.4 a Night-time (23:00 06:59) SBP (mmhg) ± ± 5.2 b ± 1.8 b MAP (mmhg) 97.1 ± ± 1.8 a 84.5 ± 1.4 a DBP (mmhg) 78.1 ± ± 1.8 a 67.9 ± 1.4 a SBP PL (%) 74.7 ± ± 7.3 a 30.2 ± 5.9 a DBP PL (%) 41.0 ± ± 5.7 a 11.8 ± 3.7 a PP (mmhg) 61.2 ± ± ± 2.3 SBP LNR (%) 10.5 ± ± ± 1.5 DBP LNR (%) 11.6 ± ± ± 1.7 a P < 0.001, b P < 0.01 compared with baseline. SBP, systolic blood pressure; MAP, mean arterial pressure; DBP, diastolic blood pressure; PP, pulse pressure; PL, pressure load; LNR, level of night-time reduction. elevated night-time DBP (in relation to daytime DBP). At week 24, 12 (52.2%) patients had a normal 24-h SBP circadian rhythm. The number of patients with a normal 24-h DBP circadian rhythm at the end of the treatment period did not change. Telmisartan significantly (P < 0.001) reduced morning (06:00 11:59) SBP from ± 3.8 mmhg to ± 3.5 mmhg, and morning DBP from ± 1.9 mmhg to 95.3 ± 1.9 mmhg. However, at week 24 there was no significant change from baseline in SBP MV ( %) or DBP MV ( %). 25A

6 A 100 B 180 Baseline Telmisartan DBP (mmhg) SBP (mmhg) :00 06:00 12:00 18:00 00:00 00:00 06:00 12:00 18:00 00:00 Time of day Time of day FIGURE 1: Mean 24-h diastolic blood pressure (DBP) (A) and systolic blood pressure (SBP) (B) at baseline and after 24 weeks treatment with telmisartan mg once daily in 23 patients LVH At week 24, telmisartan significantly reduced myocardial mass by 11.3% (P = 0.03), LVMI by 10.9% (P = 0.02), left ventricular posterior wall thickness by 7.1% (P = 0.002) and interventricular septum thickness by 5.0% (P = 0.03) from baseline (Table 3). There was no significant change in end-diastolic or endsystolic left ventricular dimensions at the end of the treatment period (data not shown). However, 17 patients (73.9%) had prognostically meaningful (> 10 g/m 2 ) reductions in LVMI, five of whom (21.7%) had normal LVMI ( 104 g/m 2 in women, 116 g/m 2 in men) measurements after 24 weeks of therapy. Baseline LVMI was significantly correlated with duration of hypertension (r = 0.67; P < 0.001). The correlations between baseline LVMI and night-time PP (r = 0.38; P = 0.07), night-time SBP pressure load (r = 0.32; P = 0.13) and DBP LNR (r = 0.27; P = 0.2) were not significant. The reduction of LVMI following telmisartan treatment correlated significantly with clinical DBP reduction (r = 0.44; P = 0.04). The correlations between LVMI reduction and night-time DBP pressure load reduction (r = 0.39; P = 0.07) and night-time SBP pressure reduction (r = 0.33; P = 0.12) did not achieve statistical significance. TABLE 3: Mean ± SE reductions in indicators of left ventricular hypertrophy after 24 weeks of treatment with telmisartan mg once daily in 23 patients Parameter Baseline Week 24 P-value Myocardial mass (g) ± ± LVMI (g/m 2 ) ± ± LV posterior wall thickness (cm) 1.13 ± ± Interventricular septum thickness (cm) 1.20 ± ± LVMI, left ventricular mass index; LV, left ventricular. 26A

7 ADVERSE EVENTS One patient (4.3%) discontinued the trial because of an adverse event (fine skin rash). No other adverse events were observed. Discussion In this open-label, non-comparative study, 24 weeks of telmisartan treatment significantly reduced mean SBP and DBP as assessed by clinic seated blood pressure and by 24-h ABPM. In addition, telmisartan restored the 24-h blood pressure circadian rhythm and significantly reduced LVMI, a quantitative measure of LVH, after 24 weeks of treatment. A higher percentage of patients achieved blood pressure normalization as assessed by ABPM (69.6% of patients) compared with clinic blood pressure (52.2% of patients). This discrepancy between results may be explained by white-coat hypertension, i.e. persistently elevated clinic blood pressure in combination with a normal ambulatory blood pressure. 16 Telmisartan reduced mean daytime and night-time SBP and DBP by > 10%. These results are similar to those obtained from a previous study, which compared the anti-hypertensive efficacy of telmisartan and amlodipine using ABPM. 17 Telmisartan was found to reduce 24-h mean DBP by 11%, mean daytime DBP by 11% and mean night-time DBP by 10.5% at the end of 12 weeks treatment. Trough:peak ratios are useful predictors for the duration of action for antihypertensive agents. 18 In this study, the trough:peak ratio was 71% for SBP and 74% for DBP, which exceeds the 50% threshold for anti-hypertensive drug efficacy. 19 Similarly, a previous study has shown that 4 weeks treatment with once-daily temisartan 40 or 80 mg produced ratios of 66% for both SBP and DBP. 10 The results from both studies demonstrate that once-daily telmisartan provides effective blood pressure control over the entire 24-h dosing interval, including the potentially risky early morning hours. As blood pressure variability is an important determinant of target-organ damage, it follows that those agents which reduce variability may improve the risk of morbidity associated with hypertension. 20 The similarity in blood pressure reductions after 12 and 24 weeks of treatment suggests that the efficacy of telmisartan did not decline over the treatment period. Moreover, chronic treatment with telmisartan resulted in an increase in the number of patients with a normal 24-h blood pressure circadian rhythm, as assessed by LNR, and no patient had an increase in night-time blood pressure. Hypertensive patients in whom the normal nocturnal decrease in blood pressure is absent (i.e. non-dippers ) are at heightened risk of target-organ damage and have a poorer prognosis. 21 Therefore, the restoration of a normal blood pressure circadian rhythm with telmisartan treatment, as seen in this study, may regress LVH and improve prognosis. The early morning surge in blood pressure is postulated to be a precipitating factor in acute cardiovascular episodes, such as a stroke, transient ischaemic attack, myocardial infarction or sudden death. 22 In this study, the presence of a blood pressure surge in the early morning was evaluated using absolute values of morning blood pressure elevation, as well as by calculating morning blood pressure volumes. The results show that once-daily telmisartan significantly reduced peak morning SBP and DBP. However, no distinct change in morning blood pressure volume was identified at the end of the treatment period. As once-daily telmisartan provides sustained 24-h blood pressure control and attenuates the early 27A

8 morning rise in blood pressure, it could potentially reduce the incidence of adverse cardiovascular episodes. Anti-hypertensive drugs should be assessed not only on the basis of their influence on blood pressure, but also on their capacity to regress or prevent target-organ damage. 1,2 LVH is the first stage of the cardiovascular continuum, thus if left untreated, it may lead to further target-organ damage and eventually to end-organ damage. 2,3 In this study, telmisartan resulted in a significant reduction in LVH after just 24 weeks treatment, as indicated by a significant regression of LVMI. Moreover, 21.9% of patients had a normal LVMI at the end of the treatment period. Therefore, telmisartan is predicted to reduce the risk of cardiovascular disease and death in patients with essential hypertension and LVH. There was a significant correlation between clinical DBP reduction and decrease in LVMI. In addition, the correlations between the reduction in night-time SBP pressure load and DBP pressure load, measured by ABPM, and the decrease in LVMI, approached significance the lack of significance probably being attributed to the small sample size. Telmisartan was well tolerated in this study, with only one patient experiencing an adverse event. This result is consistent with previously reported results from large-scale trials of telmisartan. In conclusion, the present study demonstrates that the ARB telmisartan mg given once daily is an effective and well-tolerated drug for the treatment of hypertension. It reduces SBP and DBP equally, both during the daytime and night-time, restores the initially disrupted 24-h blood pressure circadian rhythm, and reduces peak blood pressure during the critical morning hours. Furthermore, treatment with this anti-hypertensive agent over a period of 24 weeks leads to a clear regression of LVH. Acknowledgements The authors thank GlaxoSmithKline and Boehringer Ingelheim for supplying the study drug, and Alden Translations, UK, for the English translation of this article. Conflicts of interest No conflicts of interest were declared in relation to this article. Copyright 2005 Cambridge Medical Publications References 1 Verdecchia P, Carini G, Circo A, Dovellini E, Giovannini E, Lombardo M, et al: Left ventricular mass and cardiovascular morbidity in essential hypertension: the MAVI study. J Am Coll Cardiol 2001; 38: Levy D, Salomon M, D Agostino RB, Belanger AJ, Kannel WB: Prognostic implications of baseline electrocardiographic features and their serial changes in subjects with left ventricular hypertrophy. Circulation 1994; 90: Muiesan ML, Salvetti M, Rizzoni D, Castellano M, Donato F, Agabiti-Rosei E: Association of change in left ventricular mass with prognosis during long-term antihypertensive treatment. J Hypertens 1995; 13: Dahlof B, Devereux RB, Kjeldsen SE, Julius S, Beevers G, de Faire U, et al: Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet 2002; 359: Mancini GB, Stewart DJ: Why were the results of the Heart Outcomes Prevention Evaluation (HOPE) trial so astounding? Can J Cardiol 2001; 17 (Suppl A): 15A 17A. 6 Kim S, Iwao H: Molecular and cellular mechanisms of angiotensin II-mediated cardiovascular and renal diseases. Pharmacol Rev 2000; 52: Hollenberg NK, Fisher ND, Price DA: Pathways for angiotensin II generation in intact human tissue: evidence from comparative pharmacological interruption of the renin system. Hypertension 1998; 32: A

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