Effectiveness and Safety of Ramipril Alone Compared With Telmisartan Alone and in Combination With Ramipril in Patients at High Risk for Cardiovascular Events. Patients Intolerant to Ramipril Were Entered in TRANSCEND, Telmisartan Compared to Placebo.

Study Overview
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Brief Summary
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The Ongoing Telmisartan Alone and in combination wiht Ramipril Global Endpoint trial (ONTARGET): The primary objectives are to determine if (a) telmisartan 80mg daily and ramipril 10mg daily combination therapy is more effective in reducing the composite endpoint of Cardiovascular Death (CV) death, Myocardial infarction (MI), stroke or hospitalization for Congestive Heart Failure (CHF) compared with ramipril 10mg alone; and (b) telmisartan 80mg daily is at least as effective as (i.e. not less effective than) ramipril 10mg daily, on this endpoint. Telmisartan Randomised Assessment Study in Angiotension converting Enzyme inhibitor intolerant subjects with Cardiovascular Disease. (TRANSCEND): The primary objective of the study is to determine if treatment with telmisartan 80mg daily is superior to placebo reducing the composite endpoint of Cardiovascular Death (CV), Myocardial Infarction ( MI)I, stroke or hospitalization for Congestive Heart Failure (CHF) in patients who are intolerant to Angiotension Converting Enzyme inhibitors.

Official Title
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ONTARGET ONgoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial A Large, Simple Randomized Trial of an Angiotensin II Receptor Antagonist (Telmisartan) and an ACE-Inhibitor (Ramipril) in Patients at High Risk for Cardiovascular Events and TRANSCEND Telmisartan Randomized AssessmeNt Study in aCE iNtolerant Subjects With Cardiovascular Disease. A Parallel Study Comparing the Effects of Telmisartan With Placebo and Outcomes in Patients at High Risk for Cardiovascular Events and Intolerant to ACE-I.

Conditions
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Cardiovascular Diseases

Intervention / Treatment
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* Drug: Telmisartan
* Drug: Combination of Telmisartan and Ramipril
* Drug: Ramipril


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Coronary Artery Disease: Previous Myocardial infarction(> 2 days prior to informed consent), or stable or previous unstable angina (> 30 days prior to informed consent) with documented multivessel coronary artery disease or a positive stress test, or multivessel Percutaneous Transluminal Coronary Angioplasty (> 30 days prior to informed consent), or previous multivessel Coronary Artery Bypass Grafting without angina (if surgery performed > 4 years prior to informed consent) or with recurrent angina after surgery. Other High Risk: Peripheral Arterial Disease: Previous limb bypass surgery or angioplasty or amputation, intermittent claudication on history with ankle/arm Blood Pressure ratio < 0.8 on at least one side, or significant stenosis by angiography or non-invasive testing Previous stroke Transient ischemic Attack > 7 days and < 1 year prior to informed consent Diabetes Mellitus (types I or II): with evidence of end-organ damage (retinopathy, Left ventricular hypertrophy, micro or macro albuminuria), or any evidence of previous cardiac or vascular disease. No definite and specific indication or contraindication for any of the study treatments. Written informed consent. Exclusion Criteria: A. Medication use: Inability to discontinue Angiotension Converting Enzyme (ACE) inhibitors or Angiotension 2 receptor antagonists (AIIAs). Patients with known hypersensitivity or intolerance to Angiotension 2 receptor antagonists (AIIAs) or Angiotension Converting Enzyme (ACE)inhibitors. NOTE: Patients with known intolerance to Angiotension Converting Enzyme inhibitor intolerance ( ACE-I) can be enrolled in the TRANSCEND study. B. Cardiovascular disease: Symptomatic congestive heart failure. Hemodynamically significant primary valvular or outflow tract obstruction (e.g. aortic or mitral valve stenosis, asymmetric septal hypertrophy, malfunctioning prosthetic valve). Constrictive pericarditis. Complex congenital heart disease. Syncopal episodes of unknown etiology < 3 months before informed consent. Planned cardiac surgery or angioplasty within three months. Uncontrolled hypertension on treatment (i.e.Blood pressure ( BP) > 160/100). Heart transplant recipient. Strokes due to subarachnoid hemorrhage C. Other conditions: Significant renal disease defined as: Renal artery stenosis; Creatinine clearance < 0.6 ml/min or serum creatinine > 265 umol/L (> 3.0 mg/dL); Hyperkalemia: potassium > 5.5 mmol/L. Proteinuria* (for TRANSCEND only). Hepatic dysfunction as defined by the following laboratory parameters: Serum Glutamate Pyruvate Transaminase( SGPT) Alaninaminotransferase (ALT) or Serum Glutamic Oxaloacetic Transaminase (SGOT) Aspartate aminotransferase (AST) > than 4 times upper limit of normal or additional criteria for hepatic impairment the upper limit of normal range, total Bilirubin > 20 umol/L, biliary obstructive disorders. Uncorrected volume depletion or sodium depletion. Primary aldosteronism. Hereditary fructose intolerance. Any other major non-cardiac illness expected to reduce life expectancy or interfere with study participation. Patient is simultaneously taking another experimental drug. Patient with significant disability that precludes regular attendance at clinic for follow-up. Patient has sufficient disability or other incapacity that precludes regular attendance at clinic for follow-up. Unable or unwilling to provide written informed consent.

Ages Eligible for Study
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Minimum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Intervention Model: Parallel Assignment


Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: Telmisartan|nan|
|Drug: Combination of Telmisartan and Ramipril|nan|
|Drug: Ramipril|nan|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| ONTARGET. Composite Endpoint of Cardiovascular Death, Non-fatal Myocardial Infarction, Non-fatal Stroke and Hospitalization for Congestive Heart Failure | The Ongoing Telmisartan Alone and combination with Ramipril global Endpoint trial (ONTARGET). Time to first event analysis of the following defined endpoints, Cardiovascular Death, Non-fatal myocardial infarction, non-fatal stroke and hospitalization for congestive heart failure. | 56 months | 
| ONTARGET. 3-fold Composite Endpoint of Doubling of Serum Creatinine, Progression to End Stage Renal Disease (ESRD) and All-cause Mortality in Diabetic Nephropathy Patients | ESRD is defined by initiation of dialysis, need for renal transplantation, or eGFR <15 mL/min/1.73 m². Diabetic nephropathy patients are diabetic patients with macro-albuminuria assessed as a Urinary Albumin Creatinine Ratio (UACR) ≥300 mg/g Crea at baseline. These renal outcomes were not adjudicated (apart from death). | 56 months | 
| TRANSCEND. Composite Endpoint of Cardiovascular Death, Non-fatal Myocardial Infarction, Non-fatal Stroke and Hospitalization for Congestive Heart Failure | Telmisartan Randomized Assessment Study in Angiotension Converting Enzyme inhibitor intolerant subjects with cardiovascular disease (TRANSCEND). Time to first event analysis of the following defined endpoints, Cardiovascular Death, Non-fatal myocardial infarction, non-fatal stroke and hospitalization for congestive heart failure. | 56 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| ONTARGET. Composite Endpoint of Cardiovascular Death, Non-fatal Myocardial Infarction and Non-fatal Stroke | The Ongoing Telmisartan Alone and combination with Ramipril global Endpoint trial (ONTARGET). Time to first event analysis of the following defined endpoints, non-fatal myocardial infarction or non-fatal stroke | 56 months | 
| ONTARGET. Cardiovascular Death | The Ongoing Telmisartan Alone and combination with Ramipril global Endpoint trial (ONTARGET). Time to the first event analysis of the endpoint cardiovascular death. | 56 months | 
| ONTARGET. Non-fatal Myocardial Infarction | The Ongoing Telmisartan Alone and combination with Ramipril global Endpoint trial (ONTARGET). Time to the first event analysis of the endpoint non-fatal myocardial infarction. | 56 months | 
| ONTARGET. Non-fatal Stroke | The Ongoing Telmisartan Alone and combination with Ramipril global Endpoint trial (ONTARGET). Time to first event analysis of the endpoint non-fatal stroke. | 56 months | 
| ONTARGET. Hospitalization for Congestive Heart Failure | The Ongoing Telmisartan Alone and combination with Ramipril global Endpoint trial (ONTARGET). Time to the first event analysis of the endpoint hospitalization for congestive heart failure. | 56 months | 
| ONTARGET. Doubling of Serum Creatinine in Diabetic Nephropathy Patients | Diabetic nephropathy patients are diabetic patients with macro-albuminuria assessed as a Urinary Albumin Creatinine Ratio (UACR) ≥300 mg/g Crea at baseline. | 56 months | 
| ONTARGET. Progression to End Stage Renal Disease (ESRD) in Diabetic Nephropathy Patients | ESRD is defined by initiation of dialysis, need for renal transplantation, or eGFR <15 mL/min/1.73 m². Diabetic nephropathy patients are diabetic patients with macro-albuminuria assessed as a Urinary Albumin Creatinine Ratio (UACR) ≥300 mg/g Crea at baseline. | 56 months | 
| ONTARGET. All-cause Mortality in Diabetic Nephropathy Patients | Diabetic nephropathy patients are diabetic patients with macro-albuminuria assessed as a Urinary Albumin Creatinine Ratio (UACR) ≥300 mg/g Crea at baseline. | 56 months | 
| ONTARGET. Doubling of Serum Creatinine | ONTARGET. Nephropathy subcategory: doubling of serum creatinine | 56 months | 
| ONTARGET. Progression to ESRD | ONTARGET. Nephropathy subcategory: Progression to ESRD. Progression to ESRD is defined as initiation of dialysis, need for renal transplantation, or eGFR <15 mL/min/1.73 m². | 56 months | 
| ONTARGET. New Microalbuminuria | ONTARGET. Nephropathy subcategory: New microalbuminuria. New microalbuminuria is defined as Urinary Albumin Creatinine Ratio ≥30 mg/g Crea in patients with a Urinary Albumin Creatinine Ratio <30 mg/g Crea at baseline. | 56 months | 
| ONTARGET. New Macroalbuminuria | ONTARGET. Nephropathy subcategory: New macroalbuminuria. New macroalbuminuria is defined as Urinary Albumin Creatinine Ratio ≥300 mg/g Crea in patients with a Urinary Albumin Creatinine Ratio <300 mg/g Crea at baseline. | 56 months | 
| ONTARGET. Combined Endpoint of Doubling of Serum Creatinine, Progression to ESRD, New Microalbuminuria, or New Macroalbuminuria | ONTARGET. Nephropathy subcategory: Combined endpoint of doubling of serum creatinine, progression to ESRD, new microalbuminuria, or new macroalbuminuria | 56 months | 
| ONTARGET. Normalisation From Micro- or Macroalbuminuria to Normoalbuminuria | ONTARGET. Nephropathy subcategory: Normalisation from micro- or macroalbuminuria to normoalbuminuria. Normalisation from micro- or macroalbuminuria to normoalbuminuria is defined as UACR <30 mg/g Crea in patients with a UACR ≥30 mg/g Crea at baseline. | 56 months | 
| ONTARGET. Newly Diagnosed Congestive Heart Failure | The Ongoing Telmisartan Alone and combination with Ramipril global Endpoint trial (ONTARGET). Time to the first event analysis of the endpoint Newly diagnosed Congestive Heart failure. | 56 months | 
| ONTARGET. Cardiovascular Revascularization Procedure | The Ongoing Telmisartan Alone and combination with Ramipril global Endpoint trial (ONTARGET). | 56 months | 
| ONTARGET. Newly Diagnosed Diabetes | The Ongoing Telmisartan Alone and combination with Ramipril global Endpoint trial (ONTARGET). Time to the first event analysis of the endpoint Newly diagnosed Diabetes. Only calculated for those patients without diabetes at baseline. | 56 months | 
| ONTARGET. Cognitive Decline | The Ongoing Telmisartan Alone and combination with Ramipril global Endpoint trial (ONTARGET). Time to first event analysis of the endpoint cognitive decline i.e. Comparison of the Mini mental state Evaluation (MMSE) of patients at baseline with that at the 2years and end of trial. A decrease in MMSE from baseline represents a cognitive decline. This outcome measure is only available for those patients who had MMSE at baseline. | 56 months | 
| ONTARGET. New Onset of Atrial Fibrillation | The Ongoing Telmisartan Alone and combination with Ramipril global Endpoint trial (ONTARGET). Time to first event analysis of endpoint new onset of atrial fibrillation. | 56 months | 
| TRANSCEND. Composite Endpoint of Cardiovascular Death, Non-fatal Myocardial Infarction and Non-fatal Stroke | Telmisartan Randomized Assessment Study in Angiotension Converting Enzyme inhibitor intolerant subjects with cardiovascular disease (TRANSCEND). Time to first event analysis of the following defined endpoints, Cardiovascular Death, Non-fatal myocardial infarction, non-fatal stroke and hospitalization for congestive heart failure. | 56 months | 
| TRANSCEND. Cardiovascular Death | Telmisartan Randomized Assessment Study in Angiotension Converting Enzyme inhibitor intolerant subjects with cardiovascular disease (TRANSCEND). Time to the first event analysis of the endpoint cardiovascular death. | 56 months | 
| TRANSCEND. Non-fatal Myocardial Infarction | Telmisartan Randomized Assessment Study in Angiotension Converting Enzyme inhibitor intolerant subjects with cardiovascular disease (TRANSCEND). Time to the first event analysis of the endpoint non-fatal myocardial infarction. | 56 months | 
| TRANSCEND. Non-fatal Stroke | Telmisartan Randomized Assessment Study in Angiotension Converting Enzyme inhibitor intolerant subjects with cardiovascular disease (TRANSCEND). | 56 months | 
| TRANSCEND. Hospitalization for Congestive Heart Failure | Telmisartan Randomized Assessment Study in Angiotension Converting Enzyme inhibitor intolerant subjects with cardiovascular disease (TRANSCEND). | 56 months | 
| TRANSCEND. Doubling of Serum Creatinine | TRANSCEND. Nephropathy subcategory: doubling of serum creatinine | 56 months | 
| TRANSCEND. Progression to ESRD | TRANSCEND. Nephropathy subcategory: Progression to ESRD. Progression to ESRD is defined as initiation of dialysis, need for renal transplantation, or eGFR <15 mL/min/1.73m² | 56 months | 
| TRANSCEND. New Microalbuminuria | TRANSCEND. Nephropathy subcategory: New microalbuminuria. New microalbuminuria is defined as UACR ≥30 mg/g creatinine [Crea] in patients with a UACR <30 mg/g Crea at baseline | 56 months | 
| TRANSCEND. New Macroalbuminuria | TRANSCEND. Nephropathy subcategory: New macroalbuminuria. New macroalbuminuria is defined as UACR ≥300 mg/g creatinine [Crea] in patients with a UACR <300 mg/g Crea at baseline | 56 months | 
| TRANSCEND. Combined Endpoint of Doubling Serum Creatinine, Progression to ESRD, New Microalbuminuria or New Macroalbuminuria | TRANSCEND. Nephropathy subcategory: Combined endpoint of doubling serum creatinine, progression to ESRD, new microalbuminuria or new macroalbuminuria | 56 months | 
| TRANSCEND. Normalisation From Micro- or Macroalbuminuria to Normoalbuminuria | TRANSCEND. Nephropathy subcategory: Normalisation from micro- or macroalbuminuria to normoalbuminuria. Normalisation from micro- or macroalbuminuria to normoalbuminuria is defined as UACR <30 mg/g Crea in patients with a UACR ≥30 mg/g Crea at baseline. | 56 months | 
| TRANSCEND. New Onset of Atrial Fibrillation | Telmisartan Randomized Assessment Study in Angiotension Converting Enzyme inhibitor intolerant subjects with cardiovascular disease (TRANSCEND). | 56 months | 
| TRANSCEND. Cognitive Decline | Telmisartan Randomized Assessment Study in Angiotension Converting Enzyme inhibitor intolerant subjects with cardiovascular disease (TRANSCEND). Time to first event analysis of the endpoint cognitive decline i.e. Comparison of the Mini mental state Evaluation (MMSE) of patients at baseline with that at the 2years and end of trial. A decrease in MMSE from baseline represents a cognitive decline. This outcome measure is only available for those patients who had MMSE at baseline. | 56 months | 
| TRANSCEND. Newly Diagnosed Diabetes | Telmisartan Randomized Assessment Study in Angiotension Converting Enzyme inhibitor intolerant subjects with cardiovascular disease (TRANSCEND). Time to the first event analysis of the endpoint Newly diagnosed Diabetes. Only calculated for those patients without diabetes at baseline. | 56 months | 
| TRANSCEND. Cardiovascular Revascularization Procedure | Telmisartan Randomized Assessment Study in Angiotension Converting Enzyme inhibitor intolerant subjects with cardiovascular disease (TRANSCEND). | 56 months | 
| TRANSCEND. Newly Diagnosed Congestive Heart Failure | Telmisartan Randomized Assessment Study in Angiotension Converting Enzyme inhibitor intolerant subjects with cardiovascular disease (TRANSCEND). | 56 months |