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ONTARGET - Ongoing telmisartan alone and in combination with ramipril global endpoint trial und TRANSCEND - Telmisartan randomized assessment study in ACE-I intolerant subjects with cardiovascular disease (30 Abbildungen)

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Abbildung
 
FÜR ÖSTERREICH: Weitere Informationen: Merck Gesellschaft mbH, Zimbagasse 5, 1147 Wien, Tel.: 01/576 00-0
Abbildung 0


 
 
ONTARGET - Ongoing telmisartan alone and in combination with ramipril global endpoint trial
Abbildung 1


Keywords: HypertonieMicardisONTARGETSartanStudieTelmisartan
 
 
MICARDIS ONTARGET - Ongoing telmisartan alone and in combination with ramipril global endpoint trial
Abbildung 2


Keywords: HypertonieMicardisONTARGETSartanStudieTelmisartan
 
 
ONTARGET trial programme
Abbildung 3: The ONTARGET Trial Programme will involve a total of 28,400 patients and will include two parallel studies. ONTARGET, the Micardis trial in cardiovascular protection. This is the principal trial in the ONTARGET Trial Programme and will involve 23,400 patients. TRANSCEND is the parallel study of ONTARGET which will assess the protective effects of telmisartan in 5000 patients intolerant to angiotensin converting enzyme (ACE) inhibitors.


Keywords: HypertonieMicardisONTARGETSartanStudieTelmisartan
 
 
ONTARGET - background
Abbildung 4: Telmisartan is an angiotensin II AT1 receptor blocker (ARB) with demonstrated antihypertensive activity. It is approved for hypertension, alone or in combination with other antihypertensive agents. Telmisartan has been shown to provide sustained 24-h blood pressure control, and remains effective even during the final 6 h of the once-daily dosing interval. [1, 2] Its antihypertensive effects are potentiated in combination with hydrochlorothiazide. [3] 1. Lacourcière Y, Lenis J, Orchard R, et al. A comparison of the efficacy and duration of action of the angiotensin II receptor blocker telmisartan to amlodipine. Blood Press Monit 1998;3:295-302. 2. Mallion JM, Siché JP, Lacourcière Y and the Telmisartan Blood Pressure Monitoring Group. ABPM comparison of the antihypertensive profiles of the selective angiotensin II receptor antagonists telmisartan and losartan in patients with mild-to-moderate hypertension. J Hum Hypertens 1999;13:657-664. 3. McGill J, Reilly P. Telmisartan plus hydrochlorothiazide versus telmisartan or hydrochlorothiazide monotherapy in patients with mild to moderate hypertension: a multicenter, randomized, double-blind, placebo-controlled, parallel-group trial. Clin Ther 2001;23:833-850.


Keywords: HypertonieMicardisONTARGETSartanStudieTelmisartan
 
 
ONTARGET - background
Abbildung 5: Ramipril is an ACE inhibitor. It is approved for the treatment of hypertension and congestive heart failure post myocardial infarction. It is also indicated for reducing the risk of cardiovascular morbidity and mortality in patients aged >= 55 years who have clinical evidence of cardiovascular disease, stroke or peripheral vascular disease, or diabetes plus one or more additional cardiovascular risk factors. It has proven antihypertensive properties throughout the 24-h dosing interval with a once-daily dose. [4, 5] It also prolongs survival in congestive heart failure patients after myocardial infarction. [6] Both telmisartan and ramipril exert an antihypertensive effect through modulation of the renin–angiotensin system, but they act on different effectors within the system. 4. Perticone F, Pugliese F, Ceravolo R, Mattioli PL. Amlodipine versus ramipril in the treatment of mild to moderate hypertension: evaluation by 24-hour ambulatory blood pressure monitoring. Cardiology 1994;85:36-46. 5. Schreiner M, Berendes B, Verho M, Langley A, Cairns V. Antihypertensive efficacy, tolerance, and safety of long-term treatment with ramipril in patients with mild-to-moderate essential hypertension. J Cardiovasc Pharmacol 1991;18(Suppl 2):S137-S140. 6. The Acute Infarction Ramipril Efficacy (AIRE) Study Investigators. Effect of ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure. Lancet 1993;342:821–828.


Keywords: ACE-HemmerHypertonieMicardisONTARGETRamiprilSartanStudieTelmisartan
 
 
ONTARGET - from HOPE to ONTARGET
Abbildung 6: Committed to involve over 23,000 patients worldwide, ONTARGET is the largest ARB clinical trial ever conducted. It reflects Boehringer Ingelheim's ongoing dedication to cardiovascular research. ONTARGET will build on the results of the landmark Heart Outcomes Prevention Evaluation (HOPE) trial, with the aim of identifying treatment strategies that will translate into improved patient outcomes. [7] 7. The Heart Outcomes Prevention Evaluation Study Investigators. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med 2000;342:145-153.


Keywords: HOPEHypertonieMicardisONTARGETSartanStudieTelmisartan
 
 
ONTARGET - the HOPE study
Abbildung 7: The HOPE study was a double-blind, randomized, placebo-controlled trial, conducted by 267 study centres in 19 countries. [7] Inclusion criteria for the study were a history of coronary artery disease, stroke, peripheral vascular disease, or diabetes plus at least one other cardiovascular risk factor (hypertension, elevated total cholesterol levels, low high-density lipoprotein cholesterol levels, cigarette smoking, or documented microalbuminuria). Exclusion criteria were known heart failure with an ejection fraction below 0.40, existing ACE inhibitor or vitamin E medication, uncontrolled hypertension or overt nephropathy, or a history of myocardial infarction or stroke within 4 weeks of study initiation. 9297 patients underwent randomization, 4645 to treatment with ramipril and 4652 to placebo. Among the total patients randomized, 2480 were women, 5128 were at least 65 years of age, 8162 had cardiovascular disease, 4355 had hypertension, and 3577 had diabetes. The mean follow-up period for the study was 4.5 years. 7. The Heart Outcomes Prevention Evaluation Study Investigators. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med 2000;342:145-153.


Keywords: ACE-HemmerHOPEHypertonieRamipril
 
 
HOPE study results: primary end point
Abbildung 8: In the HOPE population, treatment with ramipril significantly reduced the risk of the combined cardiovascular endpoint (cardiovascular mortality, myocardial infarction and stroke) by 22% (651 patients in the ramipril group vs 826 patients in the placebo group [p<0.001]). [7] Cardiovascular mortality alone was reduced by 26% in the ramipril group compared with the placebo-treated patients (282 patient deaths in the ramipril group and 377 patient deaths in the placebo group [p<0.001]). Similarly, the percentage of patients experiencing myocardial infarction was reduced by 20% by ramipril treatment (459 patients in the ramipril group compared with 570 patients in the placebo group [p<0.001]). Ramipril also reduced the incidence of stroke by 32% (156 patients in the ramipril group compared with 226 patients in the placebo group [p<0.001]). 7. The Heart Outcomes Prevention Evaluation Study Investigators. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med 2000;342:145-153.


Keywords: ACE-HemmerDiagrammHOPEHypertonieprimärer EndpunktRamipril
 
 
HOPE study results: secondary end point
Abbildung 9: All-cause mortality was reduced by 16% in ramipril-treated patients compared with placebo-treated patients (p=0.005). [7] Significantly fewer patients in the ramipril group than in the placebo group underwent revascularization (742 vs 852 patients, respectively, 15% reduction; p=0.002). There was a trend towards fewer hospitalizations for heart failure in the ramipril group (141 vs 160 patients, 12% reduction; p=0.25). The incidence of complications relating to diabetes was decreased with ramipril treatment by 16% (299 vs 354 patients; p=0.03). 7. The Heart Outcomes Prevention Evaluation Study Investigators. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med 2000;342:145-153.


Keywords: ACE-HemmerDiagrammHOPERamiprilsekundärer EndpunktStudie
 
 
ONTARGET - Rationale
Abbildung 10: ARBs exert their antihypertensive effects by selectively blocking the angiotensin II type 1 (AT1) receptors. This receptor subtype mediates most of the negative cardiovascular effects of its substrate, angiotensin II, including vasoconstriction, sodium and water retention, sympathetic nervous system activation and growth-promoting effects. Importantly, ARBs do not block type 2 (AT2) receptors, which are responsible for many of the beneficial effects of angiotensin II, such as tissue regeneration and the inhibition of inappropriate cell proliferation. ACE inhibitors mediate an antihypertensive effect earlier in the renin–angiotensin cascade, preventing the conversion of angiotensin I to angiotensin II. ACE is also a kininase and is involved in the catabolism of various kinin peptides such as bradykinin. As a consequence of ACE inhibition, plasma levels of bradykinin increase. Bradykinin is associated with beneficial vasodilatory and tissue protective effects.


Keywords: AngiotensinHypertonieMicardisONTARGETSartanSchemaStudieTelmisartan
 
 
ONTARGET - rationale
Abbildung 11: During chronic treatment with ACE inhibitors, some patients may experience a reactive, persistent and detrimental increase in angiotensin II levels due to compensatory stimulation of alternative pathways of angiotensin II formation, a phenomenon known as angiotensin II escape. Angiotensin II escape is a marker of poor cardiovascular outcome.


Keywords: AngiotensinHypertonieMicardisONTARGETSartanStudieTelmisartan
 
 
ONTARGET - rationale
Abbildung 12: Treatment of patients at high risk of cardiovascular complications with a combination of telmisartan and ramipril has a three-fold rationale: AT1 receptor blockade by telmisartan should avert the negative consequences of angiotensin II escape associated with ramipril monotherapy treatment. Due to the selectivity of telmisartan for the AT1 receptors, any excess angiotensin II will only act at the AT2 receptors. Stimulation of AT2 receptors appears to be associated with beneficial effects. The potential tissue-protective properties associated with increased plasma bradykinin levels will be preserved.


Keywords: ACE-HemmerAngiotensinHypertonieMicardisONTARGETRamiprilSartanStudieTelmisartan
 
 
ONTARGET - objectives
Abbildung 13: Despite the sound rationale for combining an ARB with an ACE inhibitor, there are currently only two other large-scale trials that will include analyses to examine the efficacy of an ARB vs an ACE inhibitor and their combination. These are the Candesartan in Heart Failure – Assessment of Reduction in Mortality and Morbidity (CHARM), [8] and the Valsartan In Acute Myocardial Infarction Trial (VALIANT). [9] ONTARGET will investigate the efficacy of telmisartan monotherapy compared with ramipril monotherapy in preventing cardiovascular morbidity and mortality in a high-risk population. ONTARGET will determine any additional benefit of combining telmisartan with ramipril, compared with the ACE inhibitor alone. 8. Swedberg K, Pfeffer M, Granger C, et al. Candesartan in Heart Failure - Assessment of Reduction in Mortality and Morbidity (CHARM): rationale and design. J Card Fail 1999;5:276-282. 9. Pfeffer MA, McMurray J, Leizorovicz A, et al. Valsartan in acute myocardial infarction trial (VALIANT): rationale and design Am Heart J 2000;140:727-734.


Keywords: ACE-HemmerHypertonieMicardisONTARGETRamiprilSartanStudieTelmisartan
 
 
ONTARGET - a global trial
Abbildung 14: ONTARGET will aim to recruit 23,400 patients. ONTARGET is a global trial recruiting patients throughout Europe, North America, South America, Africa, Australasia, and Asia.


Keywords: ACE-HemmerHypertonieMicardisONTARGETRamiprilSartanStudieTelmisartan
 
 
ONTARGET - participating countries
Abbildung 15: ONTARGET will recruit patients from 40 countries. There will be approximately 1000 participating patient centres worldwide.


Keywords: ACE-HemmerHypertonieMicardisONTARGETRamiprilSartanStudieTelmisartan
 
 
ONTARGET will be the largest ARB trial to date
Abbildung 16: There are many ongoing clinical trials involving ARBs. However, with an anticipated patient recruitment target of 23,400 and an expected duration of up to 5.5 years, ONTARGET is the largest ARB trial ever undertaken. The ongoing Diabetics Exposed to Telmisartan and Enalapril (DETAIL) study compares telmisartan with the ACE inhibitor, enalapril, in patients with hypertension and concurrent type II diabetes and diabetic nephropathy. Patients (n=272) will be followed up for 5 years. [10] The Irbesartan type II Diabetic Nephropathy Trial (IDNT) was a 3-year trial studying the effect of irbesartan on the progression of renal disease and mortality in 1715 type II diabetic patients with overt nephropathy and hypertension. [11] Candesartan in Heart Failure – Assessment of Reduction in Mortality and Morbidity (CHARM) is an ongoing programme investigating the clinical usefulness of candesartan cilexetil. Approximately 7600 patients have been enrolled and will be followed up for a minimum of 2 years.8 The Valsartan Antihypertensive Long-term Use Evaluation (VALUE) trial compares the ARB, valsartan, with the calcium channel blocker, amlodipine. The incidence of cardiac morbidity and mortality will be studied in 15,320 patients for approximately 4 years. [12] The Losartan Intervention For Endpoint reduction in hypertension (LIFE) study is an ongoing trial comparing the effects of losartan with those of the beta-blocker, atenolol, on the reduction of cardiovascular morbidity and mortality in 9194 patients. It is expected to continue for at least 4 years (until 1450 patients reach a primary endpoint). [13, 14] 8. Swedberg K, Pfeffer M, Granger C, et al. Candesartan in Heart Failure - Assessment of Reduction in Mortality and Morbidity (CHARM): rationale and design. J Card Fail 1999;5:276-282. 10. Rippin J, Bain SC, Barnett AH. Rationale and design of diabetics exposed to telmisartan and enalapril (DETAIL) study. J Diabetes Complications 2001;In press. 11. Rodby RA, Rohde RD, Clarke WR, et al. The Irbesartan Type II Diabetic Nephropathy Trial: study design and baseline patient characteristics. Nephrol Dial Transplant 2000;15:487-497. 12. Mann J, Julius S. The Valsartan Antihypertensive Long-term Use Evaluation (VALUE) trial of cardiovascular events in hypertension. Rationale and design. Blood Press 1998;7:176-183. 13. Dahlöf B, Devereux R, de Faire U, et al. The Losartan Intervention For Endpoint reduction (LIFE) in Hypertension study: rationale, design, and methods. Am J Hypertens 1997;10;705-713. 14. Dahlöf B, Devereux RB, Julius S, et al. Characteristics of 9194 patients with left ventricular hypertrophy. The LIFE study. Hypertension 1998;32:989-997.


Keywords: ACE-HemmerDiagrammHypertonieMicardisONTARGETRamiprilSartanStudieTelmisartan
 
 
ONTARGET - patient profile
Abbildung 17: The ONTARGET patient population will be 55 years of age or more. Patients will be at high risk of cardiovascular disease due to a history of coronary artery disease, stroke, peripheral vascular disease or diabetes mellitus type 1 or 2 with end-organ damage (microalbuminuria, abnormal ankle/brachial index [<0.8] or left ventricular hypertrophy). Patients with congestive heart failure will be excluded from the study.


Keywords: ACE-HemmerHypertonieMicardisONTARGETPatientencharakteristikRamiprilSartanStudieTelmisartan
 
 
ONTARGET - study design
Abbildung 18: ONTARGET is a double-blind, double-dummy, parallel-group study. ONTARGET will compare three treatment groups: + telmisartan 80 mg once daily + ramipril 10 mg once daily + a combination of telmisartan 80 mg and ramipril 10 mg once daily. The full dose of ramipril will only be given after forced titration from 2.5->5->10 mg per day due to concerns over first-dose hypotension.


Keywords: ACE-HemmerDesignHypertonieMicardisONTARGETRamiprilSartanStudieTelmisartan
 
 
ONTARGET - study design
Abbildung 19: Patients will be randomized to one of three treatment groups: + telmisartan 80 mg once daily + ramipril 10 mg once daily + a combination of telmisartan 80 mg and ramipril 10 mg once daily. The aim is to enrol 7800 patients in each treatment group.


Keywords: ACE-HemmerDesignHypertonieMicardisONTARGETRamiprilSartanSchemaStudieTelmisartan
 
 
ONTARGET - time line
Abbildung 20: Patient recruitment into ONTARGET will begin in 2001. ONTARGET is anticipated to complete within 5.5 years.


Keywords: ACE-HemmerDesignHypertonieMicardisONTARGETRamiprilSartanSchemaStudieTelmisartan
 
 
ONTARGET - primary end point
Abbildung 21: The primary endpoint for ONTARGET is similar to that for HOPE. There will be a combined cardiovascular endpoint comprising: + cardiovascular mortality + stroke + acute myocardial infarction + hospitalization for congestive heart failure.


Keywords: ACE-HemmerHypertonieMicardisONTARGETprimärer EndpunktRamiprilSartanStudieTelmisartan
 
 
ONTARGET - secondary end points
Abbildung 22: ONTARGET will also evaluate the incidence of: + newly diagnosed congestive heart failure + revascularization procedures + newly diagnosed diabetes + dementia + new-onset atrial fibrillation + microvascular complications of diabetes.


Keywords: ACE-HemmerHypertonieMicardisONTARGETRamiprilSartansekundärer EndpunktStudieTelmisartan
 
 
TRANSCEND - Telmisartan Randomized AssessmeNt Study in ACE-I INtolerant Subjects with Cardiovascular Disease
Abbildung 23


Keywords: HypertonieMicardisSartanStudieTelmisartanTRANSCEND
 
 
TRANSCEND - background
Abbildung 24: The HOPE study has shown that ACE inhibition with ramipril reduces the risk of a cardiovascular event in high-risk patients by 22%. However, a considerable proportion of patients who receive an ACE inhibitor develop intolerable side-effects, such as cough, resulting in discontinuation of therapy. [15] TRANSCEND is the parallel study of ONTARGET that will assess the protective effects of telmisartan in patients who are intolerant to ACE inhibitors. 15. Ravid D, Lishner M, Lang R, Ravid M. Angiotensin-converting enzyme inhibitors and cough: a prospective evaluation in hypertension and in congestive heart failure. J Clin Pharmacol 1994;34:1116-1120.


Keywords: HOPEHypertonieMicardisSartanStudieTelmisartanTRANSCEND
 
 
TRANSCEND - objectives
Abbildung 25: TRANSCEND will assess the efficacy of telmisartan 80 mg in reducing cardiovascular morbidity and mortality in patients who are at high cardiovascular risk but are unable to tolerate ACE inhibitor treatment. It should provide evidence that ARB therapy is beneficial in this patient population; this is already assumed by many physicians.


Keywords: HypertonieMicardisSartanStudieTelmisartanTRANSCEND
 
 
TRANSCEND - patient profile
Abbildung 26: Patients in TRANSCEND will be 55 years of age or more. As in ONTARGET, they will be at high risk of cardiovascular disease due to a history of coronary artery disease, stroke, peripheral vascular disease or diabetes mellitus type 1 or 2 with end-organ damage (microalbuminuria, abnormal ankle/brachial index [<0.8] or left ventricular hypertrophy). Patients with congestive heart failure will not be included. Patients will also be intolerant to treatment with ACE inhibitors. TRANSCEND will aim to recruit a total of 5000 patients.


Keywords: HypertonieMicardisPatientencharakteristikSartanStudieTelmisartanTRANSCEND
 
 
TRANSCEND - study design
Abbildung 27: TRANSCEND is a double-blind, placebo-controlled study. Patients will be randomized to one of two treatment groups: + telmisartan 80 mg once daily + placebo.


Keywords: DesignHypertonieMicardisSartanStudieTelmisartanTRANSCEND
 
 
TRANSCEND - study design
Abbildung 28: Patients will be randomized to: + telmisartan 80 mg once daily + placebo. It is intended to enrol 2500 patients in each treatment arm. Patient recruitment into TRANSCEND will begin in 2001. The study is expected to complete within 5.5 years.


Keywords: DesignHypertonieMicardisSartanStudieTelmisartanTRANSCEND
 
 
TRANSCEND - primary end point
Abbildung 29: The primary endpoint for TRANSCEND is the same as that for ONTARGET. It will be a composite endpoint of: + cardiovascular mortality + stroke + acute myocardial infarction + hospitalization for congestive heart failure.


Keywords: HypertonieMicardisprimärer EndpunktSartanStudieTelmisartanTRANSCEND
 
 
TRANSCEND - secondary end points
Abbildung 30: TRANSCEND will also evaluate the incidence of: + newly diagnosed congestive heart failure + revascularization procedures + newly diagnosed diabetes + dementia + new-onset atrial fibrillation + microvascular complications of diabetes.


Keywords: HypertonieMicardisSartansekundärer EndpunktStudieTelmisartanTRANSCEND
 
 
 
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