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why ACE inhibitors and ARBs are used in HF.

why ACE inhibitors and ARBs are used in HF.

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  • JB
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  • 10/24/97 1 J:artemF151097Europa
  • 10/24/97 1 J:artemF151097Europa
  • This chart compares the design of three major studies of ACE inhibition: PEACE (trandolapril). 1 EUROPA (perindopril) 2 and HOPE (ramipril). 3 One difference to note is that the PEACE protocol has included a quantitative assessment of left ventricular ejection fraction, which neither of the other studies included. This means that the results of PEACE will provide the first evidence-based guidance for the treatment of patients with CAD and preserved left-ventricular function. This is important in that it is a patient type commonly seen both by primary-care physicians and specialists. Furthermore, the study follow-up period is also planned to be 5.2 years in PEACE, approximately one year longer than HOPE and EUROPA. The longer follow-up period is necessary in the PEACE study due to its lower-risk patients. The trial is powered to detect differences between the study groups based on the number of endpoints reached. With this lower-risk group, it will take longer to accumulate a sufficient number of endpoints reached. Another significant differences is the sponsorship of the studies. HOPE and EUROPA were funded by the pharmaceutical industry (the manufacturers of the study drug), while the PEACE study is sponsored by the United States' National Heart, Lung and Blood Institute (NHLBI). Trandolapril was chosen as the treatment agent for the PEACE study by an independent government body based on its pharmacologic characteristics and its proven mortality benefit. References: Pfeffer MA, Domanski M, Rosenberg Y, et al: Prevention of events with angiotensin-converting enzyme inhibition (the PEACE study design). Prevention of Events with Angiotensin-Converting Enzyme Inhibition. Am J Cardiol 1998; 82(3A):25H-30H. Fox KM; EURopean trial On reduction of cardiac events with Perindopril in stable coronary Artery disease Investigators: Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: randomised, double-blind, placebo-controlled, multicentre trial (the EUROPA study). Lancet 2003; 362(9386):782-8. Yusuf S, Sleight P, Pogue J, et al: Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med 2000; 342(3):145-53. Change title to read: PEACE design compared With EUROPA and HOPE
  • Transcript

    • 1. Vascular Protection in HF Studies & Learnings
    • 2. Heart Outcomes Prevention Evaluation Study A large, simple, randomized trial of Ramipril and vitamin E in patients at high risk for cardiovascular events
    • 3. HOPE conclusions:
      • There is overwhelming evidence that Ramipril prevents:
        • CV death, strokes and MI
        • Heart Failure, Revascularization
        • Development of diabetes
        • Diabetic microvascular complications and Nephropathy
      • These benefits are consistently observed in a very broad range of high risk patients and in addition to other effective therapies
      • The only adverse event is a 5% excess of cough
    • 4. Study rationale and design
    • 5. Study endpoints
      • CV mortality + non fatal MI + cardiac arrest
      Primary endpoint Secondary endpoints
      • Total mortality + non fatal MI + unstable angina + cardiac arrest
      • Heart failure
      • Revascularisation (PCI/CABG)
      • Stroke
    • 6. Design Placebo 0 12 24 -1/2 -1 Run-in period Randomisation Follow-up Months 36 48 Perindopril Perindopril 8 mg once daily 60 4 mg 8 mg
    • 7. Heart Failure Perindopril Placebo 5 0 1 2 3 4 Years p = 0.002 RRR: 39% 0.0 0.5 1.0 1.5 2.0 (%)
    • 8. Conclusion
    • 9. Summary of results
      • In EUROPA, the largest and longest trial of stable, low risk CAD patients, perindopril 8 mg/d significantly reduced:
        • CV mortality + non fatal MI + cardiac arrest: 20%
        • CV mortality and non fatal MI: 19%
        • Fatal + non fatal MI: 24%
        • Heart failure: 39%
    • 10. The Prevention of Events with Angiotensin Converting Enzyme Inhibition (PEACE) Trial
      • A double-blind, placebo-controlled, randomized trial
      • Sponsored by the National Heart, Lung, and Blood Institute
    • 11. Hypothesis
        • To test whether ACE inhibitor therapy, when added to modern conventional therapy, reduces CV mortality, MI, or coronary revascularization in low-risk, stable CAD patients with normal or mildly reduced LV function.
    • 12. Inclusion Criteria
      • Age  50 years
      • Coronary artery disease
        • MI, or
        • CABG or PCI, or
        • Coronary angiogram with obstruction of  50% luminal diameter in at least one native vessel
      • LVEF > 40%
      • Tolerated 2 week run-in of 2 mg/day trandolapril
    • 13. Comparison of Patients in the HOPE, EUROPA, and PEACE Trials 58 NA NA Mean LV EF 133/78 137/82 139/79 Mean SBP/DBP 91 92 76 Aspirin/antiplatelet 70 58 29 Lipid lowering 60 62 40 Beta blocker 55 12 65 60 EUROPA n=12218 72 17 55 64 PEACE n=8290 66 Mean age 40 Prior CABG or PCI 38 Diabetes mellitus 53 Prior MI HOPE n=9297 Characteristic % (unless otherwise specified)
    • 14. CHF as a primary cause of hospitalization or death 1 The PEACE trial investigators. Angiotensin-Converting-Enzyme Inhibition in Stable Coronary Artery Disease (the PEACE trial). N Engl J Med 2004;351:2-58-68 Risk Reduction 25% p=0.02 Placebo (absolute incidence 1529/4132) Trandolapril (absolute incidence 115/4158) 3.7% 2.8% Patients (%) 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0
    • 15. PEACE Compared with EUROPA, HOPE studies ACE Inhibitor Quantitative LVEF assessment Inclusion criteria Exclusion criteria Primary endpoint No. of patients Mean follow-up Industry sponsored
      • HOPE
      • Ramipril
      • No
      • Age > 55 with one of the following:
        • Documented CAD (> 1 month post-MI, CABG or PTCA, > 50% stenosis on > 2 arteries or positive stress)
        • Peripheral vascular disease
        • Stroke
        • Diabetes associated with one other cardioascular risk factor
      • LVEF known to be < 40%
      • Combined: MI, stroke, cardiovascular death
      • 9,297
      • 4.5 years
      • EUROPA
      • Perindopril
      • No
      • Age > 18 and:
        • Documented CAD (> 3 months post-MI, > 6 months post-PTCA or CABG, > 70% stenosis)
      • Clinical heart failure
      • Combined: CV death, non-fatal MI or, cardiac arrest
      • 12,218
      • 4.2 years
      • Yes
      • PEACE
      • Trandolapril
      • Yes
      • Age > 50 and:
        • Documented CAD (> 3 months post-MI, PTCA or CABG, > 50% stenosis)
        • LVEF > 40 % (< 18 months before randomisation)
      • LVEF < 40 %
      • Combined: MI, cardiovascular death, need for PTCA or CABG
      • 8,290
      Yes No 5.2 years
    • 16. Congestive Heart Failure, LV Dysfunction and ACE-Is
      • ACE Inhibitors have been shown to cause
        • regression in LV Hypertrophy
        • improve LV dysfunction
        • decrease mortality in patients with CHF
      • Clinical trials
        • CONSENSUS
        • SOLVD-TREATMENT
        • SAVE
        • CHARM
      • V-HEFT II
      • SOLVD-Prevention
    • 17. ACE Inhibitor Studies in LV Dysfunction post MI
      • SAVE NEJM 1992:327:669-667.
      • CONSENSUS II NEJM 1992;327:678-684
      • AIRE Lancet 1993;342:821-828
      • ISIS-4 Circulation 1993 Supplement I
      • GISSI 3 Lancet 1994;343:1115-1122
      • TRACE NEJM 1995;333:1670-1676
      • SMILE NEJM 1995;332:80-85
    • 18. ACEI and Angiotensin II Antagonism in CHF 69 1.10 >3.0 CHARM 70 1.2 >2.5 SAVE 70 1.2 >2.0 SOLVD 45 1.4 >3.4 CONSENSUS GFR (ml/min) Mean/Median (mg/dL) Mean Creatinine Exclusion
    • 19. Compensatory changes in heart failure
      • Activation of SNS
      • Activation of RAS
      • Increased heart rate
      • Release of ADH
      • Release of atrial natriuretic peptide
      • Chamber enlargement
      • Myocardial hypertrophy
    • 20. The role of angiotensin II in the progression of heart failure Coronary artery disease Cardiac overload Cardiomyopathy Left ventricular dysfunction  Arterial blood pressure  Angiotensin II  Peripheral organ blood flow  Skeletal muscle blood flow Exercise intolerance  Renal blood flow Oedema Cardiac remodelling Renin release Aldosterone release Vasoconstriction Na+ and water retention Inotropy and hypertrophy of vascular and cardiac cells Left ventricular dilation & hypertrophy Pump failure
    • 21. ACEs & ARBs in patient with heart failure: implications from recent trials
    • 22. ACE Inhibitors: physiologic benefits
      • Arteriovenous Vasodilatation
      •  pulmonary arterial diastolic pressure
      •  pulmonary capillary wedge pressure
      •  left ventricular end-diastolic pressure
      •  systemic vascular resistance
      •  systemic blood pressure
      •  maximal oxygen uptake (MVO2)
    • 23. ACE Inhibitors: physiologic benefits
      •  LV function and cardiac output
      •  renal, coronary, cerebral blood flow
      • No change in heart rate or myocardial contractility
      • no neurohormonal activation
      • resultant diuresis and natriuresis
    • 24. ACE Inhibitors: clinical benefits
      • Increases exercise capacity
      • Improves functional class
      • Attenuation of LV remodeling post MI
      • Decrease in the progression of chronic HF
      • Decreased hospitalization
      • Enhanced quality of life
      • Improved survival
    • 25. ACE Inhibitors and Remodeling
      • Remodeling of the LV post MI can be seen within 3 hours, with increased end-diastolic and end-systolic volumes.
      • Early Ramapril in Anterior Infarct was associated with substantial recovery of wall motion within 14 days post MI.*
      *Circulation 1997; 95:2643-2651. Healing and Early Afterload Reducing Therapy (HEART) Trial Investigators.
    • 26. Ace Inhibitors
      • ACE inhibitors are the most widely used vasodilators for CHF as they block the production of angiotensin II, which is abnormally high in congestive heart failure.
        • Angiotensin II causes vasoconstriction with increased workload on the left ventricle, and it is directly toxic to the left ventricle at excessive levels.
      • ACE inhibitors are important because they not only improve symptoms, but they also have been proven to significantly prolong the lives of people with heart failure. They do this by slowing progression of the heart damage and in some cases improving heart muscle function.
    • 27. ACE-Inhibitors (ACE-I)
    • 28. AIRE
      • AIRE Study demonstrated efficacy of ramipril on mortality and morbidity in CHF post-MI NYHA class I-III patients
        • 2006 patients enrolled in a double-blind,randomized, placebo-controlled study
        • 27% reduction in the risk of death
        • 23% decrease in progression to severe / resistant heart failure
      Lancet. 1993; 342:821-828
    • 29. Guidelines to ACE Inhibitor Therapy
      • All patients with symptomatic heart failure and those in functional class I with significantly reduced left ventricular function should be treated with an ACE inhibitor, unless contraindicated or not tolerated
      • ACE inhibitors should be continued indefinitely
      • It is important to titrate to the dosage regimen used in the clinical trials … in the absence of symptoms or adverse effects on end-organ perfusion
      • In very severe heart failure, hydralazine and nitrates added to ACE inhibitor therapy can further improve cardiac output
    • 30. Guidelines to ACE inhibitor therapy -HF ACE Inhibitor therapy in heart failure patients (Ejection Fraction < 0.40)
    • 31. ARBS Can Angiotensin II receptor blockers (ARBs) be used as alternative to ACE inhibitors in ARBs?
    • 32. ARBS
      • Angiotensin II receptor blockers (ARBs) work by preventing the effect of angiotensin II at the tissue level.
        • usually prescribed for people who cannot take ACE inhibitors because of side effects.
      • Both are effective, but ACE inhibitors have been accepted longer due to a greater number of clinical trial data and patient information.
    • 33. Candesartan in Heart Failure CHARM Trial
    • 34. CHARM Trial
      • CHARM Added
      • Patients with LVEF < 40% and treated with an ACE-inhibitor
      • CHARM Alternative
      • Patients with LVEF < 40% and ACE-inhibitor intolerant
      • Endpoints (follow-up minimum 2 years):
        • Primary – Component trials: cardiovascular mortality or CHF hospitalization
        • Primary – Overall trial results: All-cause mortality
      European Society of Cardiology 2003 7,601 patients with heart failure 3 Individual component randomized trials with the ARB candesartan (4 or 8 mg/day, titrated to target dose of 32 mg) or placebo
      • CHARM Preserved
      • Patients with LVEF >40% with or without ACE-inhibitor
    • 35. CHARM Overall Program All-cause mortality HR 0.91 95% CI 0.83-1.00 p=0.055 European Society of Cardiology 2003 CV Mortality or CHF Hospitalization HR 0.84 p<0.0001
    • 36. CHARM Added Trial CV Mortality or CHF hospitalization HR 0.85 p=0.011 European Society of Cardiology 2003 CV Mortality HR 0.84 p=0.02
    • 37. CHARM Alternative Trial CV Mortality or CHF hospitalization HR 0.77 p=0.0004 European Society of Cardiology 2003 CV Mortality HR 0.85 p=0.072
    • 38. CHARM Preserved Trial CV Mortality or CHF hospitalization HR 0.89 p=0.118 European Society of Cardiology 2003 CV Mortality HR 0.99 p=0.918
    • 39. CHARM Trial
      • CHARM Overall: Among symptomatic heart failure patients, treatment with ARB candesartan was associated with lower CV mortality and a trend toward lower all-cause mortality compared with placebo
      • CHARM Added: Among patients with symptomatic heart failure and an ejection fraction < 40% treated with an ACE-inhibitor, additional treatment with the ARB candesartan was associated with reduction in the primary endpoint of cardiovascular death or heart failure hospitalizations
    • 40. CHARM Trial
      • CHARM Alternative: Among patients with symptomatic heart failure and an ejection fraction < 40% who were ACE-inhibitor intolerant, treatment with the ARB candesartan was associated with reduction in the primary endpoint of cardiovascular death or heart failure hospitalizations
      • CHARM Preserved: Among patients with symptomatic heart failure and an ejection fraction >40%, treatment with the ARB candesartan was associated with a non-significant reduction in the primary endpoint of cardiovascular death or heart failure hospitalizations
    • 41. ON going T elmisartan A lone and in combination with R amipril G lobal E ndpoint T rial The Telmisartan trial in cardiovascular protection Presented on 31 st March, 2008 at ACC Annual Meeting, Chicago By Chief Investigator – Prof. Salim Yusuf
    • 42. Background
      • Telmisartan is:
        • An Angiotensin II AT1 Receptor Blocker (ARB)
        • approved for hypertension, alone or in combination with another antihypertensive agent
      Blood Press Monit 1998;3:295–302. 2. J Hum Hypertens 1999;13:657–664. 3. Clin Ther 2001;23:833–850.
    • 43. Background
      • Ramipril is:
        • An Angiotensin Converting Enzyme (ACE) inhibitor
      • approved for
        • hypertension
        • congestive heart failure post myocardial infarction
        • reduction of cardiovascular risk in high-risk patients aged  55 years
      Cardiology 1994;85:36–46. J Cardiovasc Pharmacol 1991;18(Suppl 2):S137–S140. Lancet 1993;342:821–828.
    • 44. Background
      • ACE-inhibitors (e.g. ramipril in the HOPE trial) reduces CV death, MI, stroke and CHF hospitalization in those with CVD or Diabetes in the absence of ventricular dysfunction or heart failure
      • ACE-inhibitors are not tolerated by 15% to 25% of patients
    • 45.
      • ONTARGET is the largest ARB clinical trial ever conducted
      • It has built on the positive results from the landmark Heart Outcomes Prevention Evaluation (HOPE) trial, which investigated the effect of Ramipril on cardiovascular risk
      From HOPE to
    • 46. The HOPE study
      • Double-blind, randomized, placebo-controlled trial
      • Over 9500 patients at high risk of cardiovascular disease
      • 4.5-year treatment period
      • Compared the risk of cardiovascular events with the ACE inhibitor, ramipril (10 mg/day), vs placebo, both given as add-on to existing antihypertensive therapy
      N Engl J Med 2000;342:145–153.
    • 47. HOPE study results – primary endpoints Combined cardiovascular endpoint Cardiovascular mortality, myocardial infarction, stroke Cardiovascular mortality Myocardial infarction Stroke -22% p<0.001 -26% p<0.001 -20% p<0.001 -32% p<0.001 Ramipril n = 4645 , Placebo n=4652 The HOPE Study Investigators, 2000
    • 48. HOPE study results – secondary endpoints All-cause mortality Need for revascularization Hospitalization for heart failure Complications relating to diabetes -16% p=0.005 -15% p=0.002 -12% p=0.25 -16% p=0.03 Ramipril n = 4645 , Placebo n=4652 The HOPE Study Investigators, 2000
    • 49. Questions:
      • Will an ARB (telmisartan) be as effective and better tolerated or “non-inferior” to Ramipril ?
      • Is the combination of Telmisartan and Ramipril superior to Ramipril alone ?
    • 50. AT 1 RECEPTOR Vasoconstriction Sodium retention Water retention SNS activation Growth-promoting effects AT 2 RECEPTOR Tissue regeneration Inhibitor of inappropriate cell proliferation SNS = Sympathetic Nervous System ANGIOTENSIN I ANGIOTENSIN II Bradykinin Inactive fragments ACE inhibitor ARB Rationale
    • 51. ANGIOTENSIN I ANGIOTENSIN II ARB AT 1 RECEPTOR Vasoconstriction Sodium retention Water retention SNS activation Growth-promoting effects AT 2 RECEPTOR Tissue regeneration Inhibitor of inappropriate cell proliferation Angiotensin II escape Bradykinin Inactive fragments ACE inhibitor SNS = Sympathetic Nervous System Rationale
    • 52.
      • Telmisartan and Ramipril combination therapy should:
      • avert the negative consequences of angiotensin II escape associated with ramipril treatment
      • prevent any excess angiotensin II acting at AT 1 receptors
      • retain potential tissue-protective benefits associated with increased bradykinin levels
      Rationale
    • 53.
      • To compare the efficacy of telmisartan with the ACE inhibitor, ramipril, in preventing cardiovascular morbidity and mortality
      • To determine any additional benefit of combining telmisartan with an ACE inhibitor, compared with the ACE inhibitor alone
      Objectives
    • 54. Europe 23 countries Australia 2 countries Asia 9 countries North America 2 countries South America 3 countries Africa 1 country A global trial
    • 55. Argentina France Netherlands Spain Australia Germany New Zealand Sweden Austria Greece Norway Switzerland Belgium Hong Kong Philippines Taiwan Brazil Hungary Poland Thailand Canada Ireland Portugal Turkey China Italy Russia UK Czech Republic Korea Singapore Ukraine Denmark Malaysia Slovakia United Arab Emirates Finland Mexico South Africa USA Participating countries
    • 56. Patient treatment years  ARB trial to date is the largest
    • 57.
      • Single blind run-in (n=29,019)
      • Randomized, double blind, double dummy study conducted in 733 centers in 40 countries (n=25,620) with three treatment arms as follows:
        • Telmisartan 80 mg/day
        • Ramipril 10 mg/day
        • Combination of Telmisartan 80 mg + Ramipril 10 mg/day
      • Total 56 months (5.5 years) follow-up with 99.8% outcome ascertainment
      Study design
    • 58. Study Medications Run-in (Single Blind) Day 1-3 Ram 2.5 mg + Tel Placebo Day 4-10 Ram 2.5 mg + Tel 40 mg Day 11-18 Ram 5.0 mg + Tel 40 mg Randomization (Double Blind) 2 weeks Ram Placebo + Tel 80 mg Ram 5 mg + Tel Placebo Ram 5 mg + Tel 80 mg Then Full doses (Tel 80 mg daily, Ram 10 mg daily) for the 3 arms
    • 59. Telmisartan 80 mg/day + ramipril 10 mg/day 8502 patients Ramipril 10 mg/day 8576 patients Telmisartan 80 mg/day 8542 patients 5.5 years Screening/enrolment Double-blind treatment Study Medications
    • 60. 2001 2002 2003 2004 2005 2006 2007 2008 Randomization begins Year Timeline
    • 61. Statistical Considerations
      • In HOPE the hazard ratio for ramipril v plac : 0.77
      • 40 th percentile : 0.794
      • Excess risk of placebo/ramipril : 1.26
      • Half of above : 1.13
      • For non-inferiority (Telmisartan v ramipril) the one-sided 97.5% CI should be below 1.13.
      • Assuming an annual event rate of 3.97%, 7800 patients per group followed for 4.5 yrs provides :
      • -89% power for NI (T v R)
      • -93% power superiority (T + R v R)
      • Total randomized: 25,620 in 18 months
    • 62. Reasons for Not Randomizing Patients % Run-in Completed (n=29,018) 100 Not Randomized 11.71 Creatinine elevated 0.22 Potassium elevated 0.77 Persistent symptomatic hypotension 1.70 Death 0.09 Total Medical Reasons 2.78 Compliance <75% 3.87 Other reasons 3.01 Patient Decision 2.06 Total Patient Reasons 5.93
    • 63.
      • Composite primary endpoint of:
      • cardiovascular mortality
      • stroke
      • acute myocardial infarction
      • hospitalization for congestive heart failure
      Primary endpoint
    • 64.
      • cardiovascular mortality
      • stroke
      • acute myocardial infarction
      Key Secondary endpoints HOPE trial Outcome
    • 65.
      •  55 years of age
      • At high risk of cardiovascular disease
      • No patients with congestive heart failure
      Patient profile
    • 66. Key Baseline Characteristics Ramipril Telmisartan Combination N 8576 8542 8502 Age 66.4 66.4 66.5 % females 27.2 26.3 26.5 % CAD 74.4 74.5 74.7 % Stroke/TIA 21.0 20.6 20.9 % Diabetes 36.7 38.0 37.9 BP 141.8/82.1 141.7/82.1 141.9/82.1 Statins 61.0 62.0 61.8 Antiplatelet 80.5 81.1 81.1  -blocker 56.5 56.9 57.4
    • 67. Change in BP (mmHg) Ramipril Telmisartan Combination Systolic -6.0 -6.9 -8.4 Diastolic -4.6 -5.2 -6.0
    • 68. Time to Permanent Discontinuation of Study Medication Years of Follow-up Cumulative Hazard Rates 0.0 0.1 0.2 0.3 0.4 0 1 2 3 4 Telmisartan Ramipril # at Risk Yr 1 Yr 2 Yr 3 Yr 4 T 8542 7954 7384 6909 6478 R 8576 7796 7165 6681 6254
    • 69. Reasons for Permanently Stopping Study Medications Ram N=8576 Tel N=8542 Tel vs. Ram RR P Hypotension 149 229 1.54 0.0001 Syncope 15 19 1.27 0.4850 Cough 360 93 0.26 <0.0001 Diarrhea 12 19 1.59 0.20 Angioedema 25 10 0.40 0.0115 Renal Impairment 60 68 1.14 0.46 Any Discontinuation 2099 1962 0.94 0.02
    • 70. Time to Primary Outcome
    • 71. Primary Outcome & HOPE Primary Outcome Ram Tel Tel vs Ram N (%) N (%) RR (95% CI) P (non-inf) N 8576 8542 Primary Outcome CV Death, MI, Stroke, CHF Hosp 1412 (16.46%) 1423 (16.66%) 1.01 (0.94-1.09) 0.0038 (Adjusted for SBP) 1.02 (0.95-1.10) 0.0055 HOPE Primary Outcome CV Death, MI, Stroke 1210 (14.11%) 1190 (13.93%) 0.99 (0.91-1.07) 0.0009 (Adjusted for SBP) 0.99 (0.91-1.07) 0.0012
    • 72. ONTARGET Non-Inferiority Comparison
    • 73. Combination vs Ramipril
    • 74. Time to Primary Outcome
    • 75. Telmisartan vs Ramipril:Pre-specified Subgroup Analysis No. of Patients Incidence of Primary Outcome in Ramipril Group 0.7 1.0 1.3 Relative Risk in Telmisartan Group (95% Confidence Interval) Telmisartan better Ramipril better Primary Composite Hx of CVD No Hx of CVD SBP < 134 134 - 150 > 150 Diabetes No Diabetes HOPE Risk Score Low Medium High Age < 65 65 - 75 > 75 Male Female 17118 15627 1486 5704 6042 5352 6390 10723 5709 5664 5745 7319 7310 2489 12537 4581 16.4 16.7 13.1 16.2 14.9 18.3 20.6 14.0 10.4 15.0 23.8 13.0 17.2 24.1 16.7 15.7
    • 76. Telmisartan + Ramipril vs Ramipril : Pre-specified Subgroups Incidence of Primary Outcome 0.7 1.0 1.3 Relative Risk in Ramipril & Telmisartan Group (95% Confidence Interval) Ramipril & Telmisartan better Ramipril better Primary Composite Hx of CVD No Hx of CVD SBP <= 134 134 < SBP <= 150 SBP > 150 Diabetes No Diabetes HOPE Low Risk Score HOPE Medium Risk Score HOPE High Risk Score Age < 65 65 <= Age < 75 Age >= 75 Male Female No. of Patients 17078 15589 1484 5714 6019 5329 6364 10709 5637 5596 5845 7362 7177 2539 12497 4581 in Ramipril Group 16.4 16.7 13.1 16.2 14.9 18.3 20.6 14.0 10.4 15.0 23.8 13.0 17.2 24.1 16.7 15.7
    • 77. Reasons for Permanently Stopping Study Medications Ram N=8576 Ram + Tel N=8502 Ram + Tel vs. Ram RR P Hypotension 149 406 2.75 <0.0001 Syncope 15 29 1.95 0.032 Cough 360 392 1.10 0.1885 Diarrhea 12 39 3.28 0.0001 Angioedema 25 18 0.73 0.30 Renal Impairment 60 94 1.58 0.0050 Any Discontinuation 2099 2495 1.20 <0.0001
    • 78. Conclusions: Telmisartan vs. Ramipril (1)
      • Telmisartan is clearly “non-inferior” to Ramipril, with most ( 95-100%) of the benefits preserved as shown in HOPE study
      • Consistent results on a range of:
            • Secondary outcomes
            • Subgroups
    • 79. Conclusions: Telmisartan vs. Ramipril (2)
      • 3. Telmisartan exhibits superior overall tolerability:
            • Less cough and angioneurotic edema
            • More mild hypotensive symptoms, but no difference in severe hypotensive symptoms, such as syncope
    • 80. Conclusions: Telmisartan plus Ramipril vs. Ramipril
      • Combination therapy does not reduce the primary outcome to a greater extent compared to ramipril alone with slightly higher adverse events.
    • 81. Clinical Implications of
      • Telmisartan is as effective as ramipril, with a better tolerability at reducing cardiovascular risk in patients with vascular disease or high-risk diabetes, even when heart failure is not present.
      • Combination therapy is not superior to Ramipril.
      • From ONTARGET, it may be concluded that Telmisartan can prevent every 5th Cardiovascular event.
      • Temisartan may be used instead of ramipril in HF cases.
    • 82. Thank you!

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