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.

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.

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.

BACKGROUND: 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. METHODS: We studied 30 424 ONTARGET/TRANSCEND patients (mean age ±â€ŠSD, 66.4 ±â€Š7.0) 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. RESULTS: 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 ß-blockers (P < 0.01) than those in sinus rhythm. CONCLUSION: 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.

Erectile dysfunction predicts cardiovascular events in high-risk patients receiving telmisartan, ramipril, or both: 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: Although erectile dysfunction (ED) is associated with cardiovascular risk factors and atherosclerosis, it is not known whether the presence of ED is predictive of future events in individuals with cardiovascular disease. We evaluated whether ED is predictive of mortality and cardiovascular outcomes, and because inhibition of the renin-angiotensin system in high-risk patients reduces cardiovascular events, we also tested the effects on ED of randomized treatments with telmisartan, ramipril, and the combination of the 2 drugs (ONTARGET), as well as with telmisartan or placebo in patients who were intolerant of angiotensin-converting enzyme inhibitors (TRANSCEND). METHODS AND RESULTS: In a prespecified substudy, 1549 patients underwent double-blind randomization, with 400 participants assigned to receive ramipril, 395 telmisartan, and 381 the combination thereof (ONTARGET), as well as 171 participants assigned to receive telmisartan and 202 placebo (TRANSCEND). ED was evaluated at baseline, at 2-year follow-up, and at the penultimate visit before closeout. ED was predictive of all-cause death (hazard ratio [HR] 1.84, 95% confidence interval [CI] 1.21 to 2.81, P=0.005) and the composite primary outcome (HR 1.42, 95% CI 1.04 to 1.94, P=0.029), which consisted of cardiovascular death (HR 1.93, 95% CI 1.13 to 3.29, P=0.016), myocardial infarction (HR 2.02, 95% CI 1.13 to 3.58, P=0.017), hospitalization for heart failure (HR 1.2, 95% CI 0.64 to 2.26, P=0.563), and stroke (HR 1.1, 95% CI 0.64 to 1.9, P=0.742). The study medications did not influence the course or development of ED. CONCLUSIONS: ED is a potent predictor of all-cause death and the composite of cardiovascular death, myocardial infarction, stroke, and heart failure in men with cardiovascular disease. Trial treatment did not significantly improve or worsen ED. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT 00153101.

Effects of telmisartan, ramipril, and their combination on left ventricular hypertrophy in individuals at high vascular risk in the Ongoing Telmisartan Alone and in Combination With Ramipril Global End Point Trial and the Telmisartan Randomized Assessment Study in ACE Intolerant Subjects With Cardiovascular Disease.

BACKGROUND: Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers reduce left ventricular hypertrophy (LVH). The effect of these drugs on LVH in high-risk patients without heart failure is unknown. METHODS AND RESULTS: In the Ongoing Telmisartan Alone and in Combination With Ramipril Global End Point Trial (ONTARGET), patients at high vascular risk and tolerant of ACE inhibitors were randomly assigned to ramipril, telmisartan, or their combination (n=23 165). In the Telmisartan Randomized Assessment Study in ACE Intolerant Subjects With Cardiovascular Disease (TRANSCEND), patients intolerant of ACE inhibitors were randomized to telmisartan or placebo (n=5343). Prevalence of LVH at entry in TRANSCEND was 12.7%. It was reduced by telmisartan (10.5% and 9.9% after 2 and 5 years) compared with placebo (12.7% and 12.8% after 2 and 5 years) (overall odds ratio, 0.79; 95% confidence interval [CI], 0.68 to 0.91; P=0.0017). New-onset LVH occurred less frequently with telmisartan compared with placebo (overall odds ratio, 0.63; 95% CI, 0.51 to 0.79; P=0.0001). LVH regression was similar in the 2 groups. In ONTARGET, prevalence of LVH at entry was 12.4%. At follow-up, it occurred slightly less frequently with telmisartan (odds ratio, 0.92; 95% CI, 0.83 to 1.01; P=0.07) and the combination (odds ratio, 0.93; 95% CI, 0.84 to 1.02; P=0.12) than with ramipril, but differences between the groups were not significant. New-onset LVH was associated with a higher risk of primary outcome during follow-up (hazard ratio, 1.77; 95% CI, 1.50 to 2.07). CONCLUSIONS: In patients at high vascular risk, telmisartan is more effective than placebo in reducing LVH. New-onset LVH is reduced by 37%. The effect of combination of the 2 drugs on LVH is similar to that of ramipril alone.

Specific barriers to the conduct of randomized trials.

Large randomized trials are required to provide reliable evidence of the typically moderate benefit of most interventions. To be affordable, such trials need to be simple; to be widely applicable, they need to be close to normal clinical practice. However, current regulations and guidelines have hugely increased trial complexity, effectively becoming barriers to their design and conduct. Key barriers include inadequate funding, overly complex regulations producing needlessly complex trial procedures, excessive monitoring, over restrictive interpretation of privacy laws without evidence of subject benefit, and inadequate understanding of methodology. Complex regulations result in multiple ethics approvals for a multi-center study, unnecessary complexity in the study protocol, delays in securing regulatory approval, and cumbersome regulatory procedures, even for drugs widely used in clinical practice. The type of detailed safety monitoring currently needed in trials of new drugs is being applied indiscriminately to all studies including a simpler and basic level of monitoring that constitutes good practice in most trials could be agreed on, with that level being exceeded only in specific instances. More evidence about the pros and cons of alternative approaches to data quality monitoring would help inform this process. Complex procedures in the form of multiple-page consent forms, overzealous monitoring of side effects and adverse events, source data verification, and over-restrictive approaches to protocol amendments, can impede, rather than facilitate, trial objectives. Finally, further education on the nuances and functions of randomisation would facilitate trial conduct, and reduce the need for burdensome complexity. A radical re-evaluation of existing trial guidelines is needed, based on a clear understanding of the important principles of randomized trials, with the objective of eliminating unnecessary documentation and reporting without sacrificing validity or safety. Researchers should encourage public debate about how best to strike the balance between regulation and cost.

Progress and problems for randomized clinical trials: from streptomycin to the era of megatrials.

Randomized clinical trials (RCTs) are the definitive contributors to evidence-based medicine. RCTs assessing serious outcomes in cardiovascular disease have grown, with 'megatrials' becoming more common with the realization that wrong conclusions resulted from random error in inadequately sized trials. Simple design and a heterogeneous patient population were early features, but multinational trials have increased in scientific, logistical, bureaucratic, regulatory, and legal complexity. These studies now exceed the financial means of academia or medical charities. Governments have left the bill with the pharmaceutical industry, encouraging a symbiosis with academics, who contribute medical and scientific expertise, and access to patients. Industry provides pharmacological, pharmaceutical, technical and regulatory know-how, good clinical practice expertise, and legal assistance during the trial. Study supervision is then in the hands of an independent steering committee and associated subcommittees, until appropriate dissemination of results. Prospectively defined interaction with the sponsor facilitates unbiased design and conduct, but arrangements need careful implementation to avoid conflicts of interest. The patient is protected by a strong data safety monitoring board that is wholly independent. Megatrials are under threat from over-regulation, increasing costs, and difficulties in execution. These issues merit urgent public and political education and debate.

Benefits, challenges, and registerability of the polypill.

Guidelines for the management of cardiovascular disease (CVD) stress the importance of treating global risk, rather than individual risk, factors. Patients at high cardiovascular (CV) risk, for example, benefit from a combination of aspirin, antihypertensive agents, lipid-lowering drugs, and possibly folic acid. As the number of medications that a patient requires increases, adherence and compliance to therapy are likely to decrease. The use of affordable, multiple-target, fixed-combination 'polypills', which concomitantly reduce multiple risk factors without increasing the pill burden or the risk of adverse effects, has the potential to improve CV risk factor management, thereby reducing the incidence of CVD. This review discusses the benefits of the polypill and the challenges and requirements for its success and registerability. Discussions with regulatory bodies are required in order to obtain some 'balance' between an overcautious registration approach and the potentially large public health benefits that are likely to arise from the use of polypills.

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.