Impact of antihypertensive combination and monotreatments on blood pressure variability: assessment by old and new indices. Data from a large ambulatory blood pressure monitoring database.

OBJECTIVES: High 24-h ambulatory blood pressure (ABP) variability is associated with poor cardiovascular outcomes. We analysed a large ABP monitoring database containing data from hypertensive patients treated with telmisartan/amlodipine combination or various monotherapies with the aim of quantifying the 24-h distribution of blood pressure (BP) reduction by treatment through the smoothness index and of developing and testing a new treatment-on-variability index (TOVI) to quantify the effects of treatment on both mean BP and BP variability. METHODS: ABP data were pooled from 10 studies (N = 4294) with a median follow-up of 60 days. Smoothness index was calculated by dividing the mean of treatment-induced hourly BP reductions by its SD. TOVI was calculated as the ratio of the mean of hourly BP reductions to weighted 24-h BP SD (weighted mean of daytime and night-time SDs) under treatment. RESULTS: The SBP/DBP smoothness index and TOVI values of telmisartan/amlodipine combination were significantly (P < 0.0001) higher (smoothness index: 1.81/1.51; TOVI: 2.71/2.13) compared with telmisartan 80  mg (smoothness index: 1.12/0.90; TOVI: 1.55/1.23), amlodipine 10  mg (smoothness index: 1.33/1.09; TOVI: 2.09/1.58), valsartan 160  mg (smoothness index: 1.01/0.81; TOVI: 1.35/1.07), ramipril 10  mg (smoothness index: 0.83/0.63; TOVI: 1.11/0.87) and placebo (smoothness index: 0.23/0.18; TOVI: 0.34/0.30), indicating a smoother 24-h BP reduction profile (higher smoothness index) as well as the achievement of significantly lower and smoother BP levels over 24  h (higher TOVI) with the combination. CONCLUSION: As compared with various monotherapies, the telmisartan/amlodipine combination was associated with a smoother BP reduction over 24  h and with a more favourable balance between mean 24-h BP reduction and the degree of BP variability on treatment, reflecting both its effectiveness in lowering BP levels and its longer duration of action. The agreement between smoothness index and TOVI demonstrates that they are similarly effective in the differentiation of antihypertensive treatments, although providing conceptually different information, the clinical relevance of which needs to be tested by ad-hoc outcome studies.

Impact of telmisartan on cardiovascular outcome in hypertensive patients at high risk: a Telmisartan Randomised AssessmeNt Study in ACE iNtolerant subjects with cardiovascular Disease subanalysis.

BACKGROUND: In the Telmisartan Randomised AssessmeNt Study in ACE iNtolerant subjects with cardiovascular Disease, all patients were at high cardiovascular risk, and a substantial proportion were hypertensive. We performed a post-hoc analysis to explore the hypothesis that telmisartan has a differential action in hypertensive vs. nonhypertensive patients. METHODS: The primary four-fold endpoint (composite of cardiovascular death, myocardial infarction (MI), stroke, or hospitalization for heart failure), the secondary three-fold endpoint (cardiovascular death, MI, and stroke), the individual components, new onset of left ventricular hypertrophy (LVH), and new onset of albuminuria were analyzed. RESULTS: There was no evidence for a significantly differential treatment effect of telmisartan in hypertensive and nonhypertensive patients for any endpoints, although the occurrence of the secondary three-fold endpoint was significantly lower in the telmisartan group (13.0%) compared with placebo (15.0%, P < 0.05) only in hypertensive patients. Moreover, data from this post-hoc analysis suggest that MI may be less frequent in hypertensive patients treated with telmisartan (3.8 vs. 5.1%; P < 0.05). Telmisartan may also reduce new onset of LVH (nonhypertensive patients P < 0.05; hypertensive patients P < 0.001) in both subgroups, and new onset of microalbuminuria and macroalbuminuria in hypertensive patients (P < 0.001 and P < 0.01, respectively).The effect of telmisartan in hypertensive and nonhypertensive patients at high cardiovascular risk was not different. This post-hoc analysis suggests that MI may be further reduced by telmisartan in hypertensive patients. Further investigations are needed to study the hypotheses raised by this explanatory analysis.

Blood pressure variability over 24 h: prognostic implications and treatment perspectives. An assessment using the smoothness index with telmisartan-amlodipine monotherapy and combination.

In-office blood pressure (BP) measurements have recognized limitations, including the inability to collect BP information over a long period of time, and during an individual's usual daily activities. Home or ambulatory BP monitoring (ABPM) may therefore be used to complement conventional office measurements, thereby improving prognostic value. Of particular relevance is the ability of 24 h ABPM to quantify the degree of BP variability over 24 h, which has been shown to be a significant and independent risk factor for cardiovascular (CV) morbidity and mortality. Twenty-four hour BP variability is indeed strongly associated with clinical outcomes, and the ability of ABPM to provide a quantification of BP throughout the 24-h period during an individual's normal daily routine is one of the reasons for its high prognostic value. The smoothness index (SI) provides a useful measure of antihypertensive treatment efficacy over the 24 h dosing period, its values being highest with antihypertensive agents that have large and consistent effects across 24 h. Telmisartan and amlodipine are long-acting antihypertensive drugs that, in combination, not only reduce 24 h mean BP more than the respective monotherapies but also provide a significantly greater SI. The provision of homogeneous 24 h BP control has important clinical implications. Maintaining smooth BP over the entire 24 h dosing period may contribute to the improvement of CV outcomes, and reductions in BP variability may decrease end organ damage, and reduce CV risk.

Impact of sex on cardiovascular outcome in patients at high cardiovascular risk: analysis of the Telmisartan Randomized Assessment Study in ACE-Intolerant Subjects With Cardiovascular Disease (TRANSCEND) and the Ongoing Telmisartan Alone and in Combination With Ramipril Global End Point Trial (ONTARGET).

BACKGROUND: Epidemiological data suggest that sex independently contributes to cardiovascular risk. Clinical trials are often hampered by the enrollment of few female patients. METHODS AND RESULTS: The Ongoing Telmisartan Alone and in Combination With Ramipril Global End Point Trial (ONTARGET) and the parallel Telmisartan Randomized Assessment Study in ACE Intolerant Subjects With Cardiovascular Disease (TRANSCEND) included a large proportion of female patients (9378 female versus 22 168 male patients). Differences in male and female patients enrolled in ONTARGET/TRANSCEND were analyzed for the primary 4-fold end point (composite of cardiovascular death, myocardial infarction, stroke, or admission to hospital for heart failure), a secondary 3-fold end point (cardiovascular death, myocardial infarction, stroke), and individual components of the primary composite. Baseline characteristics included age, ethnicity, body mass index, physical activity, tobacco use, alcohol consumption, formal education, clinical diagnosis for study entry, patient history, and concomitant medication. Patients were followed up until death or the end of the study (median, 56 months). Compared with male patients, female patients had a 19% significantly lower risk for the 4-fold end point and 21% for the 3-fold end point (after adjustment for study, treatment, and the above baseline values). Similarly, the adjusted risk for cardiovascular death (17%) and myocardial infarction (22%), but not for stroke and hospitalization for heart failure, was also significantly lower in women. Diabetic female patients were characterized by a higher risk for acute myocardial infarction compared with diabetic male patients, whereas alcohol consumption resulted in significantly lower risk in women. CONCLUSIONS: In our analysis made up of 70.3% male and 29.7% female patients, an ≈20% lower risk for the combined cardiovascular end points in female patients was observed despite treatment with cardioprotective agents. This difference was driven primarily by a significantly lower incidence of myocardial infarction. Thus, we demonstrate in a large interventional trial that sex greatly affects the occurrence of cardiovascular events in patients with vascular disease or high-risk diabetes mellitus. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00153101.

Rationale, design, and baseline characteristics of 2 large, simple, randomized trials evaluating telmisartan, ramipril, and their combination in high-risk patients: the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial/Telmisartan Randomized Assessment Study in ACE Intolerant Subjects with Cardiovascular Disease (ONTARGET/TRANSCEND) trials.

BACKGROUND: Angiotensin-converting enzyme (ACE) inhibitors reduce mortality, myocardial infarction, stroke, heart failure, need for revascularization, nephropathy, and diabetes and its complications. Although angiotensin-II receptor blockers (ARBs) have been less extensively evaluated, theoretically they may have "protective" effects similar to those of ACE inhibitors, but with better tolerability. Currently, there is uncertainty about the role of ARBs when used alone or in combination with an ACE inhibitor in high-risk populations with controlled hypertension. OBJECTIVES: Primary objectives of the ONgoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET) are to determine if the combination of the ARB telmisartan and the ACE inhibitor ramipril is more effective than ramipril alone, and if telmisartan is at least as effective as ramipril. The Telmisartan Randomized AssessmeNt Study in aCE iNtolerant subjects with cardiovascular Disease (TRANSCEND) will determine if telmisartan is superior to placebo in patients who are intolerant of ACE inhibitors. The primary outcome for both trials is the composite of cardiovascular death, myocardial infarction, stroke, or hospitalization for heart failure. METHOD: High-risk patients with coronary, peripheral, or cerebrovascular disease or diabetes with end-organ damage are being recruited and followed for 3.5 to 5.5 years in 2 parallel, randomized, double-blind clinical trials. PROGRESS: Recruitment from 730 centers in 40 countries for ONTARGET (n = 25,620) was completed in July 2003. For TRANSCEND, 5776 patients (out of a projected total of 6000) have been recruited (by May 10, 2004). Baseline patient characteristics are comparable to the Heart Outcomes Prevention Evaluation (HOPE) trial, the basis of the design of the current study, confirming that patients are at high-risk.