Telmisartan Randomized Assessment Study In ACE Intolerant Subjects With Cardiovascular Disease Research Articles

Relative and Combined Prognostic Importance of On-Treatment Mean and Visit-to-Visit Blood Pressure Variability in ONTARGET and TRANSCEND Patients.

URL: http//www.clinicaltrial.gov. Unique identifier: NCT00153101

Higher blood pressure as a risk factor for diseases other than stroke and ischemic heart disease.

Hypertension is an established risk factor for stroke, ischemic heart disease,1,2 and renal dysfunction.3 The management and prevention of hypertension are important to the prevention of these diseases. Recent evidence has suggested that hypertension also plays a central role in the underlying pathophysiological condition or at prodromal stages before the development of these diseases. Accumulating evidence also indicates that hypertension seems to be linked with common noncardiovascular diseases including dementia, cancer, oral health diseases (OHDs), and osteoporosis. In this brief review, we organize the reported results about the associations between hypertension and these diseases, discussing mainly epidemiological surveys, with the goal of clarifying the relationships between these diseases and hypertension. ### Atrial Fibrillation Atrial fibrillation (AF) is one of the most common types of chronic arrhythmia and is a risk factor for ischemic stroke.4 The Framingham Heart Study revealed that hypertension increases the risk of AF by factors of 1.5 for men and 1.4 for women.5 The Women’s Health Study and a cohort study of Norwegian men showed that high-normal blood pressure (BP) was associated with incident AF.6,7 All of these cohort studies were conducted in Westerners, and these associations were also confirmed in a recent Japanese cohort study.8 In that investigation, compared with normal BP and normal weight, systolic prehypertension with overweight was shown to be associated with an increased risk of incident AF ( P for interaction=0.04). Arterial stiffness, left ventricular hypertrophy, and increased left atrial size are important mediators of the relationship between BP and incident AF.9 Higher systolic BP (SBP) and overweight may mutually exacerbate left ventricular hypertrophy and hypertension, and consequently, they may synergistically increase the risk of AF. ### Chronic Kidney Disease and High BP Chronic kidney disease (CKD) is characterized by a progressive decline in an individual’s glomerular filtration rate over several decades, …

Clinical trial participation improves outcome: A matched historical cohort study

Well-conducted, investigator-led randomized controlled trials (RCTs) are the gold standard for evaluating the efficacy of new treatments and are a key component of evidence-based medicine. It is unclear whether participating in an RCT is beneficial to the individual before the results of RCTs are known. In a matched historical cohort study, we examined whether participation in RCTs was associated with improved health outcomes. Participants in the Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE), Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET), or Telmisartan Randomized Assessment Study in ACE-intolerant Subjects with Cardiovascular Disease (TRANSCEND) studies and non-participant controls were selected from patients attending outpatient clinics at Middlemore Hospital between 2001 and 2003. A total of 251 RCT participants and 502 randomly selected patients not enrolled in a trial but who met study entry criteria were matched for age, gender, and ethnicity. There was a significant difference in all-cause mortality for trial participants versus non-participants over the study period (unadjusted relative risk reduction (RRR) = 63%; 95% confidence interval (CI) = 28%-81%) and a significant reduction in cardiovascular mortality (unadjusted RRR = 81%; 95% CI = 17%-95%) favouring RCT participants. Allowing for co-morbidity, the adjusted RRR of all-cause mortality associated with trial participation was 55% (95% CI = 10%-77%). Active treatment in an RCT was found to be less explanatory than trial participation. The adjusted RRR for cardiovascular mortality associated with active treatment in a trial was 86% (95% CI = -2% to 98%), with trial participation found to be less explanatory than active treatment. The main limitations of this trial relate to its design as a retrospective study with a historical cohort comparison group. Limitations include lack of complete data for some patients, bias in selection of the comparison group, and the effects of confounding variables. However, the study design and analysis were planned so as to minimize these as much as possible. This study revealed significantly lower all-cause mortality among participants in industry-sponsored RCTs compared with non-participants who received routine hospital outpatient care. This effect was independent of study drug.

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Impact of Sex on Cardiovascular Outcome in Patients at High Cardiovascular Risk

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.

Sex and Cardiovascular Risk

There are more women than men living with cardiovascular disease, and the absolute annual number of cardiovascular deaths among women exceeds that in men.1 Although sex differences in cardiovascular risk are recognized in the risk stratification tools (eg, Framingham Risk Score, CHA2DS2-VASc score) and sex-specific risk management guidelines developed for clinical practice, it has to be recognized that women remain underrepresented in clinical trials. Approximately half of the individuals with hypertension, diabetes mellitus, or coronary artery disease are women, yet women make up only 25% to 44% of patients enrolled in trials studying these disorders.2 Furthermore, fewer than a third of primary trial publications include sex-specific results.2 Article see p 934 The sex-specific analysis of the large Ongoing Telmisartan Alone and in Combination With Ramipril Global End Point Trial (ONTARGET) and Telmisartan Randomized Assessment Study in ACE-Intolerant Subjects With Cardiovascular Disease (TRANSCEND) trials by Kappert et al3 adds new data from 9378 women and 22 168 men with or at high risk of cardiovascular disease. Despite the large number of women, they made up <30% of the study population. The analysis was performed to assess sex differences in outcomes regardless of treatment arm. Such an analysis, derived from large randomized, controlled trials, provides the advantage of systematic follow-up and adjudication of outcomes in a controlled setting but the potential disadvantage of selection bias. The baseline characteristics of the study population demonstrate important differences: Women were more likely to qualify for entry into the trials with diabetes mellitus and stroke, whereas men were more likely to have coronary artery disease. Women were also older and more likely to be hypertensive and obese than men. Lifestyle factors differed, with women being less active and less likely to consume tobacco or alcohol and having received less education than men. …

Blood pressure and other determinants of new-onset atrial fibrillation in patients at high cardiovascular risk in the Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial/Telmisartan Randomized AssessmeNt Study in ACE iNtolerant subjects with cardiovascular Disease studies

Evidence on new-onset atrial fibrillation in high-risk vascular patients without heart failure is limited. New-onset atrial fibrillation was a prespecified secondary objective of the Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial (ONTARGET)/Telmisartan Randomized AssessmeNt Study in ACE iNtolerant subjects with cardiovascular Disease (TRANSCEND) studies. We studied 30 424 ONTARGET/TRANSCEND patients (mean age ± SD, 66.4 ± 7.0) with vascular disease or complicated diabetes who were in sinus rhythm at entry. A copy of ECG was sent to central office every time new atrial fibrillation was detected by investigators. During a median follow-up period of 4.7 years, new atrial fibrillation occurred in 2092 patients (15.1 per 1000 patient-years). Risk of atrial fibrillation increased with age, SBP and pulse pressure, left ventricular hypertrophy, BMI, serum creatinine and history of hypertension, coronary artery disease and cerebrovascular disease (all P < 0.01). After adjustment for BMI and other variables, atrial fibrillation risk increased with hip circumference. History of hypertension was associated with a 34% higher risk of new atrial fibrillation. New atrial fibrillation portended an increased risk of congestive heart failure [hazard ratio 2.89, 95% confidence interval (CI) 2.45-3.40, P < 0.01] and cardiovascular death (hazard ratio 1.22, 95% CI 1.05-1.41, P < 0.01). Risk of stroke was unaffected (hazard ratio 1.14, 95% CI 0.93-1.40), whereas that of myocardial infarction was reduced (hazard ratio 0.64, 95% CI 0.50-0.82). Patients with new atrial fibrillation were more likely to receive vitamin K antagonists (P < 0.01), statins (P < 0.05) and β-blockers (P < 0.01) than those in sinus rhythm. New atrial fibrillation is common in high-risk vascular patients and is associated with several risk factors including history of hypertension. Hip circumference was the strongest anthropometric predictor. Despite extensive use of modern therapies, new atrial fibrillation carries a high risk of congestive heart failure and death over a relatively short term.

The Salt Controversy and Hypertension

Excess sodium intake is linked to higher blood pressure (BP), which, in turn, increases risk of stroke, coronary artery disease, heart failure and renal disease. However, defining “excess” sodium intake is controversial. Dietary Guidelines for Americans 2005 recommended that specific groups (persons with hypertension, all middle-aged and older adults, and all blacks [ie, 70% of the US adult population]) should limit sodium intake to 1500 mg/d.1 For other adults, the recommendation is <2300 mg/d.1 The Institute of Medicine supports these guidelines,2 the basis being that decreasing daily sodium consumption to 2300 mg/d (or less) would result in fewer cases of hypertension and cardiovascular (CV) death, thereby decreasing the costs associated with hypertension ($73.4 billion in 2009). Using the National Health and Nutrition Examination Survey (NHANES) data for 2005 to 2006, the Centers of Disease Control and Prevention estimated average daily sodium intake and sources of sodium and calories by food category in US adults. They reported that only 5.5% of adults consumed <1500 mg of sodium per day and only 18.8% of adults consumed <2300 mg/d of sodium. Only 9.6% of adults adhered to the recommended sodium intake outlined above.3 About 10% of the sodium intake comes from discretionary sources (table salt and salt added while cooking), making sodium restriction difficult to accomplish.4 Recent studies now suggest that both low and high sodium intake are harmful and that dietary salt intake should be limited to around 4 g/d to 5 g/d (1 g of salt = 400 mg of sodium). A recent publication by O’Donnell and colleagues5 demonstrated the association between urinary sodium excretion and CV events may be J-shaped, based on data from the Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial (ONTARGET) and Telmisartan Randomized Assessment Study in ACE Intolerant Subjects With Cardiovascular Disease (TRANSCEND) studies.6,7 They estimated 24-hour urinary sodium and potassium excretion from a morning fasting urine sample noting sodium and potassium excretions of 4.77 g and 2.19 g/d, respectively. Compared with the baseline sodium excretion of 4.0 g to 5.99 g of sodium per day, CV death was increased by 9.7% in the group with 7 g to 8 g of sodium excretion per day and by 11.2% in the group with >8 g of sodium per day. There was also an 8.6% increase in CV death and hospitalizations for congestive heart failure in the group with <3 g of sodium excretion per day, indicating a J-shaped curve between sodium excretion and CV events. Stolarz-Skrzypek and colleagues8 also reported an association of lower sodium excretion and higher CV mortality. In this prospective population study of 3681 participants (who were family members of participants enrolled in the Flemish study on genes, environment, and health outcomes and the European project on genes in hypertension),9,10 2096 participants were normotensive at baseline. CV deaths across tertiles of 24-hour urine sodium excretion were highest (50 of 1220) in the low sodium excretion tertile (mean Na 106 mmol/d) compared with 24 of 1250 in the middle sodium excretion tertile (mean Na 165 mmol/d) and 10 of 1211 in the highest sodium excretion tertile (mean 250 mmol/d; P=.001). Although systolic blood pressure and diastolic blood pressure changes over time aligned with changes in sodium excretion, this association did not translate into higher risk of hypertension and CVD complications from blood pressure. Reasons proposed for why low sodium could increase CVD include an increase in sympathetic nervous system activation, decreased insulin sensitivity, and activation of the renin-angiotensin-aldosterone-system with progressive sodium restriction.11 What conclusions can we draw from the available data without large-scale prospective studies specifically addressing this question? Our take on the current situation is that the 2300 mg of sodium daily, as recommended by the original American Heart Associations guidelines, represents the best balance of what a hypertensive patient can likely achieve and which is usually within the nadir in these J-curve associations. To convert sodium to salt, multiply the sodium figure in milligrams (mg) by 2.5 and then divide by 1000.

Effects of Telmisartan on Glucose Levels in People at High Risk for Cardiovascular Disease but Free From Diabetes

OBJECTIVESeveral large clinical trials suggest that ACE inhibitors may reduce the incidence of diabetes. Less is known about the effects of angiotensin receptor blockers (ARBs) on reducing incident diabetes or leading to regression of impaired fasting glucose (IFG) or impaired glucose tolerance (IGT) to normoglycemia.RESEARCH DESIGN AND METHODSParticipants were 3,488 adults at high risk for cardiovascular disease but free from diabetes (mean age 67 years; 61% male) in the Telmisartan Randomized Assessment Study in ACE Intolerant Subjects With Cardiovascular Disease (TRANSCEND) study. The participants were randomized to the ARB telmisartan 80 mg (n = 1,726) or placebo (n = 1,762) in addition to usual care.RESULTSDuring a median 56 months, 21.8% of participants treated with telmisartan and 22.4% of those on placebo developed diabetes (relative ratio 0.95 [95% CI 0.83–1.10]; P = 0.51). Participants originally diagnosed with IFG and/or IGT were equally likely to regress to normoglycemia (26.9 vs. 24.5%) or to progress to incident diabetes (20.1 vs. 21.1%; P = 0.59) on telmisartan or placebo.CONCLUSIONSThere was no evidence that addition of the ARB telmisartan to usual care prevents incident diabetes or leads to regression of IFG or IGT in people at high risk for cardiovascular disease but free from diabetes.

Cardiovascular and Renal Outcomes With Telmisartan, Ramipril, or Both in People at High Renal Risk

Background— In the Ongoing Telmisartan Alone and in Combination With Ramipril Global End Point Trial (ONTARGET), dual therapy did not reduce cardiovascular or renal outcomes compared with either angiotensin-converting enzyme inhibitors or angiotensin receptor blockers alone. Previous controlled trials with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers have demonstrated greater cardiovascular and renal benefit in people with renal risk. We hypothesized that dual therapy would be more effective than monotherapy in patients with low glomerular filtration rate and elevated albuminuria. Methods and Results— Post hoc analysis was performed of renal subgroups of dual therapy versus monotherapy for the ONTARGET study and angiotensin receptor blocker versus placebo for the Telmisartan Randomized Assessment Study in ACE Intolerant Subjects With Cardiovascular Disease (TRANSCEND). The studies featured hazard ratios by subgroups and Cox regression models with factors for treatment, subgroup, and interactions. The main cardiovascular outcome was the composite of cardiovascular death, myocardial infarction, stroke, or hospitalization for heart failure, and the main renal outcome was the composite of chronic dialysis or doubling of creatinine. In ONTARGET, there was no cardiovascular or renal benefit from dual over monotherapy in any subgroup, even with low glomerular filtration rate and/or elevated albuminuria. In TRANSCEND, in the comparison of angiotensin receptor blocker with placebo, there was a significant interaction for the main renal outcome ( P =0.01) in the direction of harm for patients with normoalbuminuria (0.37 versus 0.16 events per 100 patient-years; hazard ratio, 2.35; confidence interval, 1.33 to 4.15) but a trend to benefit with microalbuminuria (0.52 versus 0.89 events per 100 patient-years; hazard ratio, 0.60; confidence interval, 0.25 to 1.46) and macroalbuminuria (1.57 versus 2.60 events per 100 patient-years; hazard ratio, 0.71; confidence interval, 0.21 to 2.44). Conclusions— This post hoc analysis does not support dual therapy over monotherapy in high–vascular risk patients with low glomerular filtration rate or albuminuria. This observation is a post hoc comparison and should be interpreted appropriately. Clinical Trial Registration— URL: http://clinicaltrials.gov Identifier: NCT00153101.

Telmisartan and cardioprotection

Cardiovascular risk reduction has been the target of several large clinical trials in the last decade. As the activation of the renin-angiotensin-aldosterone system (RAAS) plays a central role in the pathogenesis of atherosclerosis and cardiovascular disease, RAAS blockade has been suggested to be among the most efficient cardioprotective interventions, as revealed with the angiotensin converting enzyme (ACE) inhibitors trials. The angiotensin receptor blockers’ (ARBs) efficacy in lowering blood pressure has been very well established. Telmisartan is however the first ARB to show a promising role in reducing cardiovascular risk in high-risk patients. This article will highlight the role of telmisartan in cardioprotection, underlying specifically the results of two major randomized controlled trials: ONTARGET (ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial) and TRANSCEND (Telmisartan Randomized AssessmeNt Study in aCE-iNtolerant subjects with cardiovascular Disease).

Reappraisal of role of angiotensin receptor blockers in cardiovascular protection

Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) have shown cardioprotective and renoprotective properties. These agents are recommended as first-line therapy for the treatment of hypertension and the reduction of cardiovascular risk. Early studies pointed to the cardioprotective and renoprotective effects of ARBs in high-risk patients. The ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) established the clinical equivalence of the cardioprotective and renoprotective effects of telmisartan and ramipril, but did not find an added benefit of the combination over ramipril alone. Similar findings were observed in the Telmisartan Randomized AssessmeNt Study in aCE INtolerant subjects with cardiovascular Disease (TRANSCEND) trial conducted in ACEI-intolerant patients. In ONTARGET, telmisartan had a better tolerability profile with similar renoprotective properties compared with ramipril, suggesting a potential clinical benefit over ramipril. The recently completed Olmesartan Reducing Incidence of Endstage Renal Disease in Diabetic Nephropathy Trial (ORIENT) and Olmesartan and Calcium Antagonists Randomized (OSCAR) studies will further define the role of ARBs in cardioprotection and renoprotection for high-risk patients.

In a Subgroup of High-Risk Asians, Telmisartan Was Non-Inferior to Ramipril and Better Tolerated in the Prevention of Cardiovascular Events

Background and ObjectivesResults of the recently published ONTARGET study (The Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial) showed that telmisartan (80 mg/day) was non-inferior to ramipril (10 mg/day) in reducing cardiovascular events. Clinicians in Asia doubt tolerability of these doses for their patients. We therefore analyzed data from this study and a parallel study TRANSCEND (Telmisartan Randomized Assessment Study in ACE Intolerant Subjects with Cardiovascular Disease). Our objectives were to compare Asians and non-Asians with respect to the following:1) Effectiveness of telmisartan vs. ramipril in reducing cardiovascular events;2) Proportions who reached the full dose of telmisartan, ramipril or placebo; and3) Proportions of overall discontinuations, and discontinuations due to adverse effects.MethodThe ONTARGET study randomized 25,620 patients at risk of cardiovascular events to ramipril, telmisartan, or their combination. The primary composite endpoint was death caused by cardiovascular disease, acute MI, stroke, and hospitalization because of congestive heart failure. TRANSCEND randomized 5926 high-risk patients with a history of intolerance to ACE-inhibitors to telmisartan or placebo. The primary outcome was the same. In this substudy, we compared Asians and non-Asians as to how well they tolerated telmisartan (given in both studies) and ramipril (given in ONTARGET).Results1) Telmisartan was non-inferior to ramipril in lowering the primary endpoint among Asians (RR = 0.92; 95% CI: 0.74, 1.13); 2) more Asians achieved the full dose of either drug; 3) less withdrew (overall); and 4) less withdrew for adverse effects. Furthermore, telmisartan was better tolerated than ramipril. This advantage was greater among Asians.Conclusion and SignificanceAlthough Asians had lower BMI than non-Asians, Asians tolerated both drugs better. Regulatory agencies require reporting of safety and effectiveness data by ethnicity, but few comply with this requirement. This study shows that safety data in ethnic subgroups can help assess applicability of results to specific populations.Trial RegistrationClinicalTrials.gov NCT00153101

Cardiovascular protection: a breakthrough for high-risk patients

Blockade of the renin–angiotensin system (RAS) with angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers (ARBs) has been shown to reduce cardiovascular mortality and morbidity in various patient populations. The recent ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) and Telmisartan Randomized AssessmeNt Study in aCE iNtolerant subjects with cardiovascular Disease (TRANSCEND) studies with the ARB telmisartan, the largest outcome trial programme with an ARB, have extended this evidence base in the broadest cross section of cardiovascular high-risk patients, and provided important new insights into the benefits of RAS blockade. ONTARGET and TRANSCEND recruited patients who were at high risk of vascular events. These patients, who did not have established heart failure and had well controlled blood pressure, had not previously been studied in clinical trials with ARBs. Telmisartan provided cardiovascular protection similar to ramipril but was better tolerated. These studies add to the growing evidence that the effects of RAS inhibitors are not solely dependent on blood pressure reduction. Angiotensin II exerts diverse pro-atherosclerotic effects, and hence blockade of the RAS may directly inhibit the development and progression of atherosclerosis. Finally, together with other smaller outcomes studies, ONTARGET and TRANSCEND provide useful insights into the relative importance of hypertension and other risk factors at different stages of the ‘cardiovascular continuum’. The evidence suggests that high blood pressure has a major impact on cardiovascular risk in the early stages of the continuum, whereas other risk factors like RAS activation become progressively important in later stages.

Lessons learned from the ONTARGET and TRANSCEND trials

Cardiovascular disease (CVD) accounts for one of every three deaths in the United States. In recent years, a greater understanding of the renin-angiotensin-aldosterone system's (RAAS) contribution to CVD, particularly in the area of blood pressure regulation, has emerged. Thus, interrupting or blocking the RAAS has become a key component in the treatment of hypertension and other cardiovascular conditions. The role of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in reducing CVD in high-risk populations has been demonstrated by two recently completed major trials: the Ongoing Telmisartan Alone and in Combination with Ramipril Global endpoint Trial (ONTARGET) and the Telmisartan Randomized Assessment Study in ACE-Intolerant Subjects with Cardiovascular Disease (TRANSCEND). This article describes these key studies and their outcomes and identifies critical issues that they raise for clinical practice in terms of choosing the most effective therapy for patients with existing CVD.

Preventing stroke: the PRoFESS, ONTARGET, and TRANSCEND trial programs

Renin-angiotensin system blockers have been shown to reduce stroke risk, partly independent of their blood pressure-lowering effect. The PReventiOn regimen For Effectively avoiding Second Strokes (PRoFESS) trial, ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) and Telmisartan Randomized AssessmeNt Study in aCE-iNtolerant subjects with cardiovascular Disease (TRANSCEND) recently showed potential benefits of the angiotensin II receptor blocker, telmisartan, in reducing secondary strokes. In PRoFESS, 20 332 ischemic stroke patients were randomized to telmisartan 80 mg versus placebo and to two antiplatelets in a 2 x 2 factorial design. After a mean exposure of 2 years, telmisartan showed a nonsignificant lower rate of recurrent stroke versus placebo [880 versus 934; hazard ratio 0.95; 95% confidence interval (CI) 0.86-1.04]. In a post-hoc analysis, from 6 months, telmisartan significantly reduced the number of strokes versus placebo (533 versus 608; hazard ratio 0.88; 95% CI 0.78-0.99; P = 0.042). In the stroke subgroup of ONTARGET, telmisartan 80 mg showed a trend toward reducing recurrent stroke versus ramipril 10 mg (hazard ratio 0.91; 95% CI 0.79-1.05). In the TRANSCEND study, 5926 patients who were intolerant to angiotensin-converting enzyme inhibitors were treated with 80 mg telmisartan or placebo. In a combined analysis of PRoFESS and TRANSCEND, the incidence of the composite of stroke, myocardial infarction, or vascular death was 12.8% for telmisartan versus 13.8% for placebo (hazard ratio 0.91; 95% CI 0.85-0.98; P = 0.013).

When the Clinical Trials Raise More Questions Than Answers: Blood Pressure Controversy Beyond the TRANSCEND Results

Many trials have reported that in high-risk hypertensive patients, blood pressure (BP) control must be effectively achieved as soon as possible, following the motto ‘‘the lower and the sooner, the better.’’ Surprisingly, in the Telmisartan Randomized Assessment Study in ACEIntolerant Subjects With Cardiovascular Disease (TRANSCEND) where all of the patients were high-risk and more than 75% were hypertensive, a marked reduction in BP did not attain the expected results. This study included patients who were treated with an angiotensin receptor blocker and who were intolerant to angiotensinconverting enzyme (ACE) inhibitor therapy. Could this be due to BP-lowering benefits that will depend only on baseline values? Should we accept that BP reduction is just one goal, and not the most relevant, in high-risk hypertensive patients? Could there be a BP threshold beyond which further reduction will not be effective in improving outcomes? After TRANSCEND, the answers are more than ever ‘‘blowing in the wind.’’ It must be kept in mind that most of the population included in trials in which a significant improvement after intensive BP reduction has been demonstrated exhibited higher baseline BPs. These patients markedly benefit from an antihypertensive regimen. On the other hand, it had been assumed that the results of the Heart Outcomes Prevention Evaluation (HOPE) could be directly translated to the TRANSCEND population. However, patients included in these studies were significantly different. In the HOPE study, patients were less rigorously treated, with fewer antiplatelets, statins, and b-blockers used. What results would have been obtained with ramipril as part of a regimen as it was in the HOPE trial if tested on the TRANSCEND study population? It is likely that the benefits would have been less dramatic. Since the management of hypertensive patients has markedly improved in the past decades, the benefits provided by the addition of new drugs to regimens that include other antihypertension agents, statins, or aspirin, will be less promising in terms of morbidity and mortality reduction.

Glucose intolerance and diabetes as risk factors for cognitive impairment in people at high cardiovascular risk: Results from the ONTARGET/TRANSCEND Research Programme

Aims To assess the cross-sectional associations of the measures of glycemia and cognitive function in subjects at high cardiovascular risk. Methods Setting and patients: The ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) and concurrent Telmisartan Randomized Assessment Study in ACE intolerant Subjects with Cardiovascular Disease (TRANSCEND) are multi-center, randomized, controlled investigations of different approaches to angiotensin receptor blockade in over 30,000 high CV risk subjects. Baseline data in both trials was used to analyze relationships between measures of glycemic control and cognition. Outcomes: The univariate and multivariate relationships between diabetes status, fasting plasma glucose (FPG), and scores on the Mini-Mental State Examination (MMSE) were assessed. Results In subjects with diabetes, the mean MMSE score was 0.4 units lower than in those without diabetes ( P < 0.0001). In all subjects, a 1 mmol/L higher FPG value was associated with a MMSE score that was 0.06 units lower ( P < 0.0001). The association persisted after adjustment for several cardiovascular risk factors. Conclusions Dysglycemia is a risk factor for impaired cognitive function in this broadly representative, high-risk study population. Prospective studies can more reliably discern temporal associations, including the effects of glucose lowering in this clinical group.

Telmisartan/Hydrochlorothiazide in the Treatment of Hypertension

Telmisartan blocks the detrimental actions of angiotensin II mediated via the angiotensin type 1 receptor. Unique features of telmisartan are high lipophilicity and a long terminal elimination half-life (~ 24 h). Telmisartan/hydrochlorothiazide is indicated for hypertensive patients unable to achieve target blood pressure with either monotherapy. Fixed-dose combination tablets containing telmisartan 40 or 80 mg and hydrochlorothiazide 12.5 mg are widely available; in addition, telmisartan/hydrochlorothiazide 80/25 mg is available in the USA. Telmisartan/hydrochlorothiazide is superior to losartan/hydrochlorothiazide and valsartan/hydrochlorothiazide in maintaining blood pressure control in the risky early morning hours at the end of the dosing interval. Furthermore, telmisartan/ hydrochlorothiazide provides superior 24-h mean blood pressure reduction and is better tolerated than amlodipine/hydrochlorothiazide in elderly patients with predominantly systolic hypertension. Telmisartan has the potential to confer additional reno- and cardioprotection to that due to blood pressure control. The cardioprotective activity of renin–angiotensin system blockade with telmisartan alone and in combination with ramipril is currently being evaluated in the ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) and the Telmisartan Randomized AssessmeNt Study in aCE iNtolerant subjects with cardiovascular Disease (TRANSCEND). In total, 31,546 patients have been enrolled worldwide and are being followed for up to 5.5 years.