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
Vascular Protection in HF Studies & Learnings
Heart Outcomes Prevention Evaluation Study A large, simple, randomized trial of Ramipril and vitamin E in patients at high risk for cardiovascular events
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.
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
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)
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
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
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
Diabetes associated with one other cardioascular risk factor
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
ACEs & ARBs in patient with heart failure: implications from recent trials
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.
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
Guidelines to ACE inhibitor therapy -HF ACE Inhibitor therapy in heart failure patients (Ejection Fraction < 0.40)
ARBS Can Angiotensin II receptor blockers (ARBs) be used as alternative to ACE inhibitors in ARBs?
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
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
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
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.
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
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
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
Europe 23 countries Australia 2 countries Asia 9 countries North America 2 countries South America 3 countries Africa 1 country A global trial
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
Patient treatment years ARB trial to date is the largest
Change in BP (mmHg) Ramipril Telmisartan Combination Systolic -6.0 -6.9 -8.4 Diastolic -4.6 -5.2 -6.0
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
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