Journal of Postgraduate Medicine Medknow Publications and Staff Society of Seth GS Medical College and KEM Hospital, Mumbai, India ISSN: 0022-3859 EISSN: 0972-2823 Vol. 55, Num. 1, 2009, pp. 27-32

Journal of Postgraduate Medicine, Vol. 55, No. 1, January-March, 2009, pp. 27-32

Original Article

Telmisartan in daily clinical practice: Factors affecting efficacy in treatment of primary arterial hypertension

Bergovac M, Knezevic A, Plavec D, Trkulja V

Department of Pharmacology, Zagreb University School of Medicine, Zagreb
Correspondence Address:Department of Pharmacology, Zagreb University School of Medicine, Zagreb, vtrkulja@mef.hr

Date of Submission: 21-Feb-2008
Date of Decision: 24-Jun-2008
Date of Acceptance: 03-Aug-2008

Code Number: jp09007

Abstract

Keywords: Daily practice, essential hypertension, predictors, telmisartan

Inhibition of the renin-angiotensin-aldosterone system (RAAS) is an important strategy for treatment of hypertension. ^[1] Telmisartan is a highly selective antagonist of the Type 1 receptors for angiotensin II (AT ₁ receptors) with a long terminal elimination half-life. It allows for a consistent blood pressure (BP) control over 24 h with single daily administration. ^[2] Randomized controlled trials (RCTs) demonstrated its efficacy and safety in mild to moderate essential hypertension in a broad spectrum of patients - adults and elderly, patients receiving other antihypertensives , those with isolated systolic hypertension, patients with mild to moderate hepatic failure or with coexisting diabetes mellitus (DM), metabolic syndrome and/or chronic renal impairment. ^[2],[3] Post-marketing studies have generally been in line with RCTs. ^[2] Although they provide only a low level of evidence (typically observational or uncontrolled interventional designs), such studies are valuable in that they more closely represent daily clinical practice. This may be of relevance since significant differences (biological, socioeconomic, epidemiological) might exist between patients/care providers in RCTs and those in the routine daily practice. ^[4],[5] The present study aimed to investigate factors potentially affecting response to telmisartan in a setting reflecting daily clinical practice in treatment of mild to moderate essential hypertension.

Materials and Methods

This was a 12-week uncontrolled cohort study conducted at 25 sites specialized in the treatment of hypertension that are a part of the secondary healthcare network in Croatia (outpatient clinics). The sites were scattered across the country and formed 14 centers ( one to three sites/investigators per center) based on institutional/regional principle (a center per county {county hospital} and one in the state capital {university hospital}). Ethics Committee approval was obtained at each center.

Patients

Candidates were consecutive outpatients with incident or prevalent but not fully controlled essential hypertension (secondary hypertension positively excluded; primary aldosteronism treated as a specific exclusion criterion according to the approved telmisartan label ^[6] ). Inclusion criteria were: a) informed consent; b) age ≥18 years; c) seated diastolic blood pressure (SDBP) at both the screening visit and baseline visit ( four weeks later) ≥90 mm Hg and/or seated systolic blood pressure (SSBP) at both visits ≥140 mm Hg. Exclusion criteria were: a) using other RAAS inhibitors; b) known hypersensitivity to telmisartan or any constituent of the formulation; c) nursing mothers; d) any life-threatening condition; e) SDBP ≥114 or SSBP ≥200 mm Hg at either screening or at baseline visit; f) severe renal insufficiency (physician′s discretion); g) severe hepatic insufficiency (physician′s discretion); h) uncorrected circulating volume deficiency (physician′s discretion); i) uncorrected sodium deficiency; j) primary aldosteronism; k) hereditary fructose intolerance; l) obstructive biliary disease; m) drug or alcohol abuse; n) pregnant or women of childbearing potential not using appropriate contraception.

Study flow, patient evaluations and treatment

Three post-baseline visits were scheduled in four -week intervals (at Week 4, Week 8 and Week 12, study end ), all during a.m . Blood pressure was measured using mercury manometers. Different cuff sizes were available, and all measurements were done by trained personnel. At each visit, SSBP and SDBP were measured thrice ( two min apart) to obtain mean values. Patients were instructed to take telmisartan during a.m. hence all BP measurements were at trough. In case they forgot to take telmisartan during a.m., patients were to take it as soon as they remembered it, but not after 02:00 p.m. - in such a case, they were to take the next scheduled dose the next morning. At the screening visit, demographics; medical history and physical examination; concomitant treatments; co-morbidity; laboratory tests (hematology, serum and urine chemistry) were recorded. At baseline visit, final decision about enrolment was made and telmisartan 1 x 40 mg/day was introduced. At later visits, telmisartan could be up-titrated to 1 x 80 mg/day if BP was not < 140/90 mm Hg. In patients already receiving antihypertensives at baseline, these drugs could be withdrawn once BP was < 140/90 mm Hg. With BP higher than that despite telmisartan up-titration, other antihypertensives (excluding other RAAS inhibitors) could be (re)-introduced.

As a standard of care, all patients received instructions regarding dietary regime (considering also diabetes and/or obesity where needed) and lifestyle measures. At each visit, they received the exact number of telmisartan doses for the next four weeks, i.e., till the next visit. They were also provided with a list of days till the next visit and had to check drug consumption and dose (compliance diary). At each visit, compliance was assessed for the preceding four-week period as a ratio: doses used (dispensed-returned) / dispensed (%), and the diary. For other antihypertensive drugs, patients received standard instructions for use. Compliance was assessed based on diaries. Other (concomitant) treatments were followed by appropriate instructions and were recorded, but compliance was not specifically checked. At study end, safety laboratory tests were repeated.

Outcomes

The primary efficacy measure was difference in SSBP/SDBP at post-baseline visits vs. baseline. Secondary outcomes were telmisartan dose (80 mg or 40 mg) and use of additional antihypertensives (yes or no) during the post-baseline period. Safety evaluation was of secondary interest and was based on incidence of adverse events.

Sample size

Sample size for the study was not precisely calculated. As we were not aware of the number of potentially relevant effects on the primary outcome, we made an approximation that we believed would provide a reasonable power to detect practically important effects. We assumed a linear mixed model for longitudinal data with one within-subject factor (post-baseline visits) with first-order autocorrelation (correlation=0.6) and with two two-level between-subject factors that we expected to impact the response: telmisartan mono- or add-on treatment (we expected 55-60% prevalent patients already receiving antihypertensive drugs) and obesity (we expected around 25% obese patients). We defined the lowest detectable difference for both between-subject factors as 2.5 mm Hg difference in SSBP and as 1.5 mm Hg difference in SDBP reduction. With these parameters and a set of different residual variances a simulation based on 100 Monte Carlo samples indicated that 270 patients would ascertain> 80% power. Considering the assumed dropout rate, 290 patients were to be enrolled. To keep a reasonable balance among the centers, not more than 25 and not less then 15 patients were to be recruited by each centre.

Data analysis

All enrolled patients formed safety population. Efficacy outcomes were analyzed in the intent-to-treat (ITT) and per-protocol (PP) population: ITT= patients who received at least one telmisartan dose and had at least one post-baseline BP evaluation; PP= patients completing 12 weeks with regular evaluations. SAS 9.1 software (SAS Inc., Cary, NC, USA) was used for statistical analysis. Differences in SSBP and SDBP at post-baseline visits vs. baseline were analyzed by fitting mixed-effects models that accounted for within-center (patients "clustered" in centers) and within-subject (three visits in four-week intervals) correlations (proc mixed with random and repeated statements). First-order autoregressive covariance structure provided the best model fit (Akaike′s information criterion) for repeated data. Telmisartan dose (80 mg or 40 mg) and use of other antihypertensives during the post-baseline period (yes or no) were analyzed by fitting general estimating equation (GEE) models (proc genmod with binomial distribution, logit link and a repeated statement).

Results

Patient eligibility and characteristics

Of the 290 enrolled patients (all Caucasians), eight never returned for a post-baseline evaluation and it could not be determined whether they had ever taken telmisartan. They were contacted by phone to establish reasons for dropping out of the study. The remaining 282 patients represented the ITT population. Of those, seven withdrew during the study resulting in 275 study completers (PP). Compliance to telmisartan was high and practically identical for ITT and PP patients. The lowest individual compliance for any between-visit period was 93% (26 out of 28 scheduled doses used), but considering all patients, compliance was> 97% for each between-visit period (number of used/dispensed doses for the group). Compliance to other antihypertensive drugs (where used) was also high (constantly> 90 considering individual patients,> 95% for the group).

Patient characteristics are summarized in [Table - 1]. Concomitant treatments were practically identical for ITT and PP patients: the most frequently used other antihypertensives (preexisting) in prevalent patients were dihydropyridine-type calcium antagonists (mostly amlodipine) (30% / 31% for PP), beta-blockers (mostly atenolol) (26% / 25.8%) and thiazide diuretics (mostly chlorthalidone) (15.6% / 16%). The most prevalent "non-antihypertensive" treatments included acetylsalicylic acid (24.6%), statins (19.5%), glyceryl trinitrate (9.6%), insulin (9.6%) and glybenclamid (4.4%).

Reasons for withdrawal and safety

Overall, 15/290 patients (5.2%) withdrew from the study: ten due to adverse events (insomnia and tremor in one subject each {0.3%}; hypotension, hypertension, headache and hypersensitivity reaction in two subjects each {0.7%}) although they were mild to moderate; three due to reasons unrelated to drug safety/efficacy and two were lost to follow-up. At least one adverse event was reported by 28/290 patients (9.7%). The most incident adverse events were headache and stomachache (1.4% each) and diarrhea, vertigo and potency problems (1.0% each). No serious or severe adverse events were reported.

Efficacy - descriptive

Blood pressure continuously decreased during the study [Table - 2]. Telmisartan was up-titrated to 80 mg/day in 30.5% of patients after four weeks and in additional 10% after eight weeks of treatment [Table - 2]. Proportion of patients receiving telmisartan together with other antihypertensives fell from the start of the study (61.0%) towards Week 8 (42.7%) and was 51.3% at study end [Table - 2] almost exclusively reflecting withdrawal and re-introduction of these drugs in prevalent patients.

Efficacy - analysis

There were significant differences among centers regarding post-baseline SSBP (intraclass correlation coefficient {ICC} 7.8% ITT, 7.7% PP, both P=0.019) and SDBP changes vs. baseline (ICC 11.0% ITT, 10.7% PP, both P=0.013) justifying treatment of centers as "clusters". The initial regression models accounted for a number of demographic and disease-related variables (depicted in [Table - 1]) and their interactions, and were reduced by successively removing effects with P-values> 0.25. The final models are summarized in [Table - 3]. The results were practically identical for ITT and PP patients. Blood pressure reductions vs. baseline were more prominent (P< 0.05) with elapse of time. Post-baseline reduction in SSBP was significantly (P< 0.05) greater (by around 4.0 mm Hg) in incident patients (telmisartan monotherapy) than in prevalent patients (telmisartan add-on therapy) [Table - 3]. For SDBP, post-baseline reduction was also greater (P< 0.05) in incident than in prevalent patients (by around 3.0 mm Hg), in diabetics than in non-diabetics (by around 3.6-3.7 mm Hg), in men than in women (0.05 [Table - 3]. DiabetesFNx01obesity interaction was insignificant, however simple main effects from the interaction term indicated that SDBP reduction was greatest in diabetic, non-obese patients (n=22, 12 men {55%}, mean±standard error -16.96±1.38 mm Hg), and lowest in non-diabetic, obese patients (n=75, 38 men {51%}, mean±standard error -11.12±0.93 mm Hg), difference: -5.84 mm Hg, simultaneous 95% confidence intervals -10.3 to -1.34, adjusted P=0.015. Practically the same was observed for PP patients (not shown).

Initial models fitted to data on post-baseline telmisartan dose (80 mg or 40 mg) or to use of other antihypertensives (yes or no) were reduced in the same way as the models analyzing the primary outcome. The final models regarding telmisartan dose are summarized in [Table - 4]. The results were practically identical for ITT and PP patients. Odds of being prescribed 80 mg dose at any time during the post-baseline period were significantly (P< 0.05) higher in obese patients (odds ratio {OR} around 1.90) and lower (P< 0.05) in men (OR around 0.51) [Table - 4]. The only factor affecting the use of other antihypertensives (in addition to telmisartan) during the study was the fact that telmisartan was introduced to a preexisting treatment at the beginning of the study (not shown).

Discussion

The present practice-based study aimed to assess factors potentially affecting response to telmisartan in patients with mild to moderate hypertension in a setting reflecting daily clinical routine. Hence, no patient selection criteria or treatment modalities other than those outlined in the approved telmisartan label ^[6] were employed (indications, contraindications, precautions). To avoid interference of purely technical factors ^[7] we standardized the BP measuring procedure and accounted for within-center correlations. Blood pressure change vs. baseline is a common efficacy outcome in antihypertensive drug trials. Administered telmisartan doses and use of other antihypertensives (over time) were considered as complementary outcomes, since dose titration and/or combination with other drugs are inherent to telmisartan use. ^[2],[6] In two similar large observational ^[8] or uncontrolled ^[9] studies with unselected outpatients receiving telmisartan monotherapy or a combination with hydrochlorothiazide (N=6319) ^[8] or with other antihypertensives (N=1941) ^[9] mean SSBP/SDBP reductions at Week 12 were -28.5 mm Hg and -14.1 mm Hg, respectively ^[8] and -20.2 mm Hg and -11.8 mm Hg, respectively. ^[9] The n-weighted mean reductions calculated from these two studies are -26.5 mmHg and -13.6 mmHg for SSBP and SDBP, respectively, which compares well with the present data and supports their external validity.

Regression analysis indicated that patients started on telmisartan monotherpy (incident) apparently responded better than those in whom telmisartan was added to a preexisting treatment (prevalent): the two groups were comparably likely to be administered the higher dose (80 mg) during the post-baseline period, but BP reductions were greater in the "mono" group. An analysis of the antihypertensive and lipid-lowering treatment to prevent heart attack trial (ALLHAT) data identified patients already receiving antihypertensive treatment at baseline as less likely to achieve BP control during the study. ^[10] This could be ascribed to a more complex pathophysiological background of hypertension, but also to a poorer compliance in patients receiving multiple drugs. Considering the rather high compliance in the present study, our observations are likely to be due to the former. It should be noted, however, that there was a trend of withdrawals of preexisting treatments in the present study. This was done in around one-third of prevalent patients by Week eight, likely guided by a promising initial response and an intention to replace an unsuccessful monotreatment (preexisting) with telmisartan. However, this strategy was apparently "too optimistic" as preexisting treatments were re-introduced to around half of these patients. The most prevalent preexisting treatments were calcium channel antagonists, beta blockers and thiazide diuretics. Of the potential combinations of telmisartan with other antihypertensives, the one with hydrochlorothiazide has been most extensively studied, ^[2],[3] but in studies in which telmisartan was added to preexisting treatments the response to telmisartan was not affected by the nature of the preexisting treatment. ^[3] The present study was too small and inappropriate to evaluate whether the type of preexisting treatment influenced the response to telmisartan. The results are in agreement with the known ability of telmisartan to improve BP values in previously unsuccessfully treated patients. ^[3],[11] They suggest, however, that these patients might require higher telmisartan doses and/or more time to achieve desired goals.

Obesity contributes to hypertension trough several mechanisms ^[12] including the fact that adipocytes are the main source of circulating angiotensinogen. ^[13] In the ALLHAT study, obesity was an independent negative predictor of successful BP management. ^[13] Inhibitors of RAAS, and in particular AT ₁ antagonists, have specific actions on the adipose tissue resulting in beneficial metabolic effects besides the antihypertensive one. ^[13] Telmisartan is effective in obese hypertensive patients ^[2] and apparently superior to valsartan in obese patients with Type 2 diabetes. ^[14] However, to our knowledge, potential differences in telmisartan efficacy in obese and non-obese patients have not been investigated. In the present study, obesity appeared to be an independent negative predictor of SDBP response to telmisartan: during the post-baseline weeks obese patients were almost twice more likely to be prescribed the higher dose (80 mg), but SDBP reduction was significantly smaller than in non-obese patients. Considering that BP recordings were done by trained personnel using appropriate cuff sizes, these observations are unlikely to be artifactual. Similarly, telmisartan is effective in hypertensive diabetic patients (apparently superior to valsartan) ^[14] and provides benefits beyond BP reduction (metabolic, renal function) ^[2] , but potential differences between diabetic and non-diabetic patients in response to telmisartan have not been investigated. In the present study, SDBP reduction appeared greater in diabetic than in non-diabetic patients with comparable delivered doses. Since the absolute number of diabetics in the study was relatively low, random error could not be unequivocally excluded. On the other hand, the results were consistent for ITT and PP patients (ruling-out attrition bias), and by including consecutive patients and considering the inclusion/exclusion criteria, we believe that we avoided selection bias. The results were consistent in that SDBP reduction was greatest in diabetic, non-obese patients and lowest in non-diabetic, obese ones. We do not see a straightforward explanation for this observation. In a large post-marketing observational safety surveillance study data on change in BP after six months of treatment with telmisartan were collected for 19743 patients. ^[15] Telmisartan (40 mg or 80mg) was introduced as a mono- or add-on treatment and was further combined with a variety of other antihypertensives. Doses were up-titrated and down-titrated over time. In a univariate analysis, systolic and diastolic BP reductions at six months vs. "baseline" appeared comparable in men and women, diabetic and non-diabetic patients, those with or without cardiovascular comorbidity and patients < 65 or> 65 years of age. This apparent discrepancy vs. the present study might be due to the fact that obesity was not considered (and diabetes and obesity seem to "work in opposite directions") and that effects were evaluated after a longer period of treatment. Furthermore, this surveillance study ^[15] found no differences in BP reduction between men and women, whereas in the present study men apparently responded better than women - SDBP reduction was slightly greater (with borderline significance), but they were twice less likely to be prescribed the higher telmisartan dose, which is in line with the results of a similar study in the US. ^[16] After six weeks of telmisartan monotherapy (40 mg/day for two weeks with optional up-titration to 80 mg after the second week), systolic BP reduction vs. baseline was significantly (P< 0.001) greater in men than in women. Potential between-gender differences in up-titration of telmisartan to 80 mg were not reported. ^[16] Generally, gender does not have a major impact on the efficacy of telmisartan that would require gender-specific dosing or dose adjustments. ^[2],[3],[6] Still, the present results and the results of others ^[16] indicate that, at least in the early phases of treatment, BP response in women is somewhat less pronounced and that women might require higher doses or longer period of time to attain the same level of BP reduction as men.

In conclusion, the present study indicated several demographic and co-morbid patient characteristics apparently affecting antihypertensive effect of telmisartan. The observed effects are moderate in size and do not question the well-established efficacy of telmisartan. We believe, however, that they should be taken into account in attempts to optimize the use of telmisartan in treatment of mild to moderate essential hypertension in routine daily practice, especially during the early phases of treatment.

References

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