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.

• ONTARGET. Composite Endpoint of Cardiovascular Death, Non-fatal Myocardial Infarction, Non-fatal Stroke and Hospitalization for Congestive Heart Failure [ Time Frame: 56 months ]
  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.
• TRANSCEND. Composite Endpoint of Cardiovascular Death, Non-fatal Myocardial Infarction, Non-fatal Stroke and Hospitalization for Congestive Heart Failure [ Time Frame: 56 months ]
  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.

• ONTARGET. Composite Endpoint of Cardiovascular Death, Non-fatal Myocardial Infarction and Non-fatal Stroke [ Time Frame: 56 months ]
  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
• ONTARGET. Cardiovascular Death [ Time Frame: 56 months ]
  The Ongoing Telmisartan Alone and combination with Ramipril global Endpoint trial (ONTARGET). Time to the first event analysis of the endpoint cardiovascular death.
• ONTARGET. Non-fatal Myocardial Infarction [ Time Frame: 56 months ]
  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.
• ONTARGET. Non-fatal Stroke [ Time Frame: 56 months ]
  The Ongoing Telmisartan Alone and combination with Ramipril global Endpoint trial (ONTARGET). Time to first event analysis of the endpoint non-fatal stroke.
• ONTARGET. Hospitalization for Congestive Heart Failure [ Time Frame: 56 months ]
  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.
• ONTARGET. Newly Diagnosed Congestive Heart Failure [ Time Frame: 56 months ]
  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.
• ONTARGET. Cardiovascular Revascularization Procedure [ Time Frame: 56 months ]
  The Ongoing Telmisartan Alone and combination with Ramipril global Endpoint trial (ONTARGET).
• ONTARGET. Newly Diagnosed Diabetes [ Time Frame: 56 months ]
  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.
• ONTARGET. Cognitive Decline [ Time Frame: 56 months ]
  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.
• ONTARGET. New Onset of Atrial Fibrillation [ Time Frame: 56 months ]
  The Ongoing Telmisartan Alone and combination with Ramipril global Endpoint trial (ONTARGET). Time to first event analysis of endpoint new onset of atrial fibrillation.
• TRANSCEND. Composite Endpoint of Cardiovascular Death, Non-fatal Myocardial Infarction and Non-fatal Stroke [ Time Frame: 56 months ]
  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.
• TRANSCEND. Cardiovascular Death [ Time Frame: 56 months ]
  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.
• TRANSCEND. Non-fatal Myocardial Infarction [ Time Frame: 56 months ]
  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.
• TRANSCEND. Non-fatal Stroke [ Time Frame: 56 months ]
  Telmisartan Randomized Assessment Study in Angiotension Converting Enzyme inhibitor intolerant subjects with cardiovascular disease (TRANSCEND).
• TRANSCEND. Hospitalization for Congestive Heart Failure [ Time Frame: 56 months ]
  Telmisartan Randomized Assessment Study in Angiotension Converting Enzyme inhibitor intolerant subjects with cardiovascular disease (TRANSCEND).
• TRANSCEND. Newly Diagnosed Congestive Heart Failure [ Time Frame: 56 months ]
  Telmisartan Randomized Assessment Study in Angiotension Converting Enzyme inhibitor intolerant subjects with cardiovascular disease (TRANSCEND).
• TRANSCEND. Cardiovascular Revascularization Procedure [ Time Frame: 56 months ]
  Telmisartan Randomized Assessment Study in Angiotension Converting Enzyme inhibitor intolerant subjects with cardiovascular disease (TRANSCEND).
• TRANSCEND. Newly Diagnosed Diabetes [ Time Frame: 56 months ]
  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.
• TRANSCEND. Cognitive Decline [ Time Frame: 56 months ]
  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.
• TRANSCEND. New Onset of Atrial Fibrillation [ Time Frame: 56 months ]
  Telmisartan Randomized Assessment Study in Angiotension Converting Enzyme inhibitor intolerant subjects with cardiovascular disease (TRANSCEND).

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.

• Drug: Telmisartan
• Drug: Combination of Telmisartan and Ramipril
• Drug: Ramipril

• Dehghan M, Mente A, Teo KK, Gao P, Sleight P, Dagenais G, Avezum A, Probstfield JL, Dans T, Yusuf S; Ongoing Telmisartan Alone and in Combination With Ramipril Global End Point Trial (ONTARGET)/Telmisartan Randomized Assessment Study in ACEI Intolerant Subjects With Cardiovascular Disease (TRANSCEND) Trial Investigators. Relationship between healthy diet and risk of cardiovascular disease among patients on drug therapies for secondary prevention: a prospective cohort study of 31 546 high-risk individuals from 40 countries. Circulation. 2012 Dec 4;126(23):2705-12. doi: 10.1161/CIRCULATIONAHA.112.103234.
• Barzilay JI, Gao P, Clase CM, Mente A, Mann JF, Sleight P, Yusuf S, Teo KK; OnTARGET/TRANSCEND Investigators. Albuminuria and rapid loss of GFR and risk of new hip and pelvic fractures. Clin J Am Soc Nephrol. 2013 Feb;8(2):233-40. doi: 10.2215/CJN.06640712. Epub 2012 Nov 26.
• Kappert K, Böhm M, Schmieder R, Schumacher H, Teo K, Yusuf S, Sleight P, Unger T; ONTARGET/TRANSCEND Investigators. 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). Circulation. 2012 Aug 21;126(8):934-41. doi: 10.1161/CIRCULATIONAHA.111.086660. Epub 2012 Jul 24.
• Neumann I, Grassi B. [Critically appraised article]. Rev Med Chil. 2012 Jan;140(1):117-20. Epub 2012 Apr 12. Spanish.
• Verdecchia P, Dagenais G, Healey J, Gao P, Dans AL, Chazova I, Binbrek AS, Iacobellis G, Ferreira R, Holwerda N, Karatzas N, Keltai M, Mancia G, Sleight P, Teo K, Yusuf S; Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint TrialTelmisartan Randomized AssessmeNt Study in ACE iNtolerant subjects with cardiovascular Disease Investigators. 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. J Hypertens. 2012 May;30(5):1004-14.
• Redon J, Mancia G, Sleight P, Schumacher H, Gao P, Pogue J, Fagard R, Verdecchia P, Weber M, Böhm M, Williams B, Yusoff K, Teo K, Yusuf S; ONTARGET Investigators. Safety and efficacy of low blood pressures among patients with diabetes: subgroup analyses from the ONTARGET (ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial). J Am Coll Cardiol. 2012 Jan 3;59(1):74-83.
• Mancia G, Schumacher H, Redon J, Verdecchia P, Schmieder R, Jennings G, Yusoff K, Ryden L, Liu GL, Teo K, Sleight P, Yusuf S. Blood pressure targets recommended by guidelines and incidence of cardiovascular and renal events in the Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial (ONTARGET). Circulation. 2011 Oct 18;124(16):1727-36. Epub 2011 Sep 26.
• Barzilay JI, Gao P, Rydén L, Schumacher H, Probstfield J, Commerford P, Dans A, Ferreira R, Keltai M, Paolasso E, Yusuf S, Teo K; TRANSCEND Investigators. Effects of telmisartan on glucose levels in people at high risk for cardiovascular disease but free from diabetes: the TRANSCEND study. Diabetes Care. 2011 Sep;34(9):1902-7. Epub 2011 Jul 25.
• Tobe SW, Clase CM, Gao P, McQueen M, Grosshennig A, Wang X, Teo KK, Yusuf S, Mann JF; ONTARGET and TRANSCEND Investigators. Cardiovascular and renal outcomes with telmisartan, ramipril, or both in people at high renal risk: results from the ONTARGET and TRANSCEND studies. Circulation. 2011 Mar 15;123(10):1098-107. Epub 2011 Feb 28.
• Barzilay JI, Gao P, O'Donnell M, Mann JF, Anderson C, Fagard R, Probstfield J, Dagenais GR, Teo K, Yusuf S; ONTARGET and TRANSCEND Investigators. Albuminuria and decline in cognitive function: The ONTARGET/TRANSCEND studies. Arch Intern Med. 2011 Jan 24;171(2):142-50.
• Dans AL, Teo K, Gao P, Chen JH, Jae-Hyung K, Yusoff K, Chaithiraphan S, Zhu J, Lisheng L, Yusuf S; Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial Investigators. In a subgroup of high-risk asians, telmisartan was non-inferior to ramipril and better tolerated in the prevention of cardiovascular events. PLoS One. 2010 Dec 21;5(12):e13694.
• Anderson C, Teo K, Gao P, Arima H, Dans A, Unger T, Commerford P, Dyal L, Schumacher H, Pogue J, Paolasso E, Holwerda N, Chazova I, Binbrek A, Young J, Yusuf S; ONTARGET and TRANSCEND Investigators. Renin-angiotensin system blockade and cognitive function in patients at high risk of cardiovascular disease: analysis of data from the ONTARGET and TRANSCEND studies. Lancet Neurol. 2011 Jan;10(1):43-53. Epub 2010 Oct 25.
• Böhm M, Baumhäkel M, Teo K, Sleight P, Probstfield J, Gao P, Mann JF, Diaz R, Dagenais GR, Jennings GL, Liu L, Jansky P, Yusuf S; ONTARGET/TRANSCEND Erectile Dysfunction Substudy Investigators. 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. Circulation. 2010 Mar 30;121(12):1439-46. Epub 2010 Mar 15.
• Verdecchia P, Sleight P, Mancia G, Fagard R, Trimarco B, Schmieder RE, Kim JH, Jennings G, Jansky P, Chen JH, Liu L, Gao P, Probstfield J, Teo K, Yusuf S; ONTARGET/TRANSCEND Investigators. 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. Circulation. 2009 Oct 6;120(14):1380-9. Epub 2009 Sep 21.
• Sleight P, Redon J, Verdecchia P, Mancia G, Gao P, Fagard R, Schumacher H, Weber M, Böhm M, Williams B, Pogue J, Koon T, Yusuf S; ONTARGET investigators. Prognostic value of blood pressure in patients with high vascular risk in the Ongoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial study. J Hypertens. 2009 Jul;27(7):1360-9.
• Mann JF, Schmieder RE, Dyal L, McQueen MJ, Schumacher H, Pogue J, Wang X, Probstfield JL, Avezum A, Cardona-Munoz E, Dagenais GR, Diaz R, Fodor G, Maillon JM, Rydén L, Yu CM, Teo KK, Yusuf S; TRANSCEND (Telmisartan Randomised Assessment Study in ACE Intolerant Subjects with Cardiovascular Disease) Investigators. Effect of telmisartan on renal outcomes: a randomized trial. Ann Intern Med. 2009 Jul 7;151(1):1-10, W1-2. Epub 2009 May 18.
• Telmisartan Randomised AssessmeNt Study in ACE iNtolerant subjects with cardiovascular Disease (TRANSCEND) Investigators; Yusuf S, Teo K, Anderson C, Pogue J, Dyal L, Copland I, Schumacher H, Dagenais G, Sleight P. Effects of the angiotensin-receptor blocker telmisartan on cardiovascular events in high-risk patients intolerant to angiotensin-converting enzyme inhibitors: a randomised controlled trial. Lancet. 2008 Sep 27;372(9644):1174-83. Epub 2008 Aug 29.
• Mann JF, Schmieder RE, McQueen M, Dyal L, Schumacher H, Pogue J, Wang X, Maggioni A, Budaj A, Chaithiraphan S, Dickstein K, Keltai M, Metsärinne K, Oto A, Parkhomenko A, Piegas LS, Svendsen TL, Teo KK, Yusuf S; ONTARGET investigators. Renal outcomes with telmisartan, ramipril, or both, in people at high vascular risk (the ONTARGET study): a multicentre, randomised, double-blind, controlled trial. Lancet. 2008 Aug 16;372(9638):547-53.
• ONTARGET Investigators; Yusuf S, Teo KK, Pogue J, Dyal L, Copland I, Schumacher H, Dagenais G, Sleight P, Anderson C. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med. 2008 Apr 10;358(15):1547-59. Epub 2008 Mar 31.
• Held C, Gerstein HC, Yusuf S, Zhao F, Hilbrich L, Anderson C, Sleight P, Teo K; ONTARGET/TRANSCEND Investigators. Glucose levels predict hospitalization for congestive heart failure in patients at high cardiovascular risk. Circulation. 2007 Mar 20;115(11):1371-5. Epub 2007 Mar 5.

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:

1. 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
2. Previous stroke
3. Transient ischemic Attack > 7 days and < 1 year prior to informed consent
4. 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:

1. Inability to discontinue Angiotension Converting Enzyme (ACE) inhibitors or Angiotension 2 receptor antagonists (AIIAs).
2. 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:

1. Symptomatic congestive heart failure.
2. Hemodynamically significant primary valvular or outflow tract obstruction (e.g. aortic or mitral valve stenosis, asymmetric septal hypertrophy, malfunctioning prosthetic valve).
3. Constrictive pericarditis.
4. Complex congenital heart disease.
5. Syncopal episodes of unknown etiology < 3 months before informed consent.
6. Planned cardiac surgery or angioplasty within three months.
7. Uncontrolled hypertension on treatment (i.e.Blood pressure ( BP) > 160/100).
8. Heart transplant recipient.
9. Strokes due to subarachnoid hemorrhage

C. Other conditions:

1. Significant renal disease defined as:

   1. Renal artery stenosis;
   2. Creatinine clearance < 0.6 ml/min or serum creatinine > 265 umol/L (> 3.0 mg/dL);
   3. Hyperkalemia: potassium > 5.5 mmol/L.
   4. Proteinuria* (for TRANSCEND only).
2. 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.
3. Uncorrected volume depletion or sodium depletion.
4. Primary aldosteronism.
5. Hereditary fructose intolerance.
6. Any other major non-cardiac illness expected to reduce life expectancy or interfere with study participation.
7. Patient is simultaneously taking another experimental drug.
8. Patient with significant disability that precludes regular attendance at clinic for follow-up.
9. Patient has sufficient disability or other incapacity that precludes regular attendance at clinic for follow-up.
10. Unable or unwilling to provide written informed consent.