RAAS Modulation: Novel Strategies for Reducing Cardiovascular Risk

PowerPoint PresentationEpidemiology/Guideline
Update:
VBWG
0.0
1.4
3.0
11.6
11.5
16.8
0.3
0.2
1.6
3.6
6.3
10.3
0
5
10
15
20
Men
Women
NHANES 1999–2002
≥75
Age
As shown by NHANES data covering 1999–2002, the prevalence of coronary heart disease (CHD) rises sharply after age 55 years in both men and women.1 This finding implies that most high-risk patients seen in clinical practice will fall in this age group.
1. American Heart Association. Heart Disease and Stroke Statistics—
2005 Update. Dallas, Tex: American Heart Association; 2005.
VBWG
in Americans
C Accidents
Data compiled for 2002
Total cardiovascular (CV) disease, including diseases of the heart, cerebrovascular disease, and arterial disorders, remains the leading cause of death in the United States.1
Data compiled from death certificates by the National Center for Health Statistics for 2002 indicate that CV disease claimed 927,448 American lives in 2002, including 433,825 men and 493,623 women.1
Overall, CV disease claims about as many Americans each year as
the next 5 leading causes of death combined.
1. CDC/NCHS and NHLBI. In: Heart Disease and Stroke Statistics–2005 Update. Dallas, Tex: American Heart Association; 2005.
VBWG
Growing prevalence
21.8
23.0
23.9
23.7
24.3
5.9
6.4
6.5
6.6
6.6
+11.9%
+11.5%
The slide summarizes unadjusted estimated prevalence data from the January–September 2004 National Health Interview Survey.1 As shown, the prevalences of obesity and diabetes appear to have grown at comparable rates over the past 5 years.
1. National Center for Health Statistics. Early release of selected estimates based on data from the January-September 2004 National Health Interview Survey: 3/23/2005. Available at: www.cdc.gov/nchs/nhis.htm.
VBWG
Management of Patients with Chronic Stable
Angina: Asymptomatic patients
Class I recommendations for pharmacotherapy to prevent MI and death
1. Aspirin in the absence of contraindication in patients with prior MI
(Level of evidence: A)
2. -Blockers as initial therapy in absence of contraindications in
patients with prior MI (Level of evidence: B)
3. Lipid-lowering therapy in patients with documented CAD
and LDL-C >130 mg/dL, with target LDL <100 mg/dL
4. ACEI in patients with CAD who have diabetes and/or
systolic dysfunction (Level of evidence: A)
Gibbons RJ et al. J Am Coll Cardiol. 2003;41:159-68.
Based on HOPE
The ACC/AHA 2002 guideline update for the management of patients with chronic stable angina included a new recommendation for ACE inhibitors.1 Based on the results of the HOPE trial, these agents were recommended for patients with CAD who also have diabetes and/or left ventricular systolic dysfunction.
The guideline states, “The results of HOPE were extremely impressive when one considers the magnitude of the difference between ramipril and placebo in the primary outcomes of cardiovascular death, MI, and stroke.”1
1. Gibbons RJ, Abrams J, Chatterjee K, Daley J, Deedwania PC, Douglas JS,
et al. ACC/AHA 2002 guideline update for the management of patients with chronic stable angina—summary article: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients with Chronic Stable Angina).
J Am Coll Cardiol. 2003;41:159-168. Full report available at: www.acc.org/clinical/guidelines/stable/IV_treatment.htm.
VBWG
stable angina or asymptomatic CAD
Based on HOPE and EUROPA
To prevent MI or death and reduce symptoms in patients
with chronic stable angina (Level of evidence: A)
To prevent MI and death in asymptomatic patients with:
– Evidence of CAD and with systolic dysfunction
of CAD (Level of evidence: B)
Snow V et al. Ann Intern Med. 2004;141:562-7.
More recently, the American College of Physicians revisited the ACC/AHA 2002 guideline update in the light of the publication of the EUROPA results.1 The ACP recommendations for ACE inhibitors (ACEI) based on this updated evidence is summarized on the slide.
1. Snow V, Barry P, Fihn SD, Gibbons RJ, Owens DK, Williams SV, et al, for the American College of Physicians/American College of Cardiology Chronic Stable Angina Panel. Primary care management of chronic stable angina and asymptomatic suspected or known coronary artery disease:
A clinical practice guideline from the American College of Physicians.
Ann Intern Med. 2004;141:562-567.
ACEIs, ARBs
Atherosclerosis, hypertension
The slide shows a diagrammatic representation of the RAAS, along with ACE inhibitor and AT1 receptor blocker sites of action.1
Adverse (proatherogenic) effects of angiotensin II (Ang II) are mediated through the AT1 receptor. Thus, both ACE inhibition and AT1 receptor blockers are potentially antiatherogenic.
The clinical relevance of effects mediated by the AT2 receptor are controversial, although data suggest they may be vasculoprotective.
1. Nickenig G. Should angiotensin II receptor blockers and statins be combined? Circulation. 2004;110:1013-1020.
VBWG
Struthers AD, MacDonald TM. Cardiovasc Res. 2004;61:663-70.
Jacoby DS, Rader DJ. Arch Intern Med. 2003;163:1155-64.
Zisman LS. Eur Heart J. 2005;26:322-4.
Effects
Chymostatin-
ACE2 Ang I Ang (1–9), Ang (1–7)
1. Struthers AD, MacDonald TM. Review of aldosterone- and angiotensin II-induced target organ damage and prevention. Cardiovasc Res. 2004;61:663-670.
2. Jacoby DS, Rader DJ. Renin-angiotensin system and atherothrombotic disease: From genes to treatment. Arch Intern Med. 2003;163:1155-1164.
3. Zisman LS. ACE and ACE2: A tale of two enzymes. Eur Heart J. 2005;
26:322-324.
and cause myocardial and vascular fibrosis.
Enzymes other than angiotensin-converting enzyme (ACE) also
generate Ang II.2 These include cathepsin G, a chymostatin-sensitive
Ang II-generating system, and chymase.
ACE2 is a novel ACE homologue that converts Ang I to Ang (1–9)
and Ang (1–7).2,3
IL-6
MCP-1
PDGF
LOX-1
PAI-1
TF
TGF-
VCAM
ICAM
Adhesion
Endothelial
dysfunction
Endothelial
dysfunction
Major proatherogenic effects of Ang II are listed on the slide.1
Subsequent slides in this section will address each topic as it
is highlighted.
First, recent data on the effect of Ang II on endothelial function
will be presented.
VBWG
0
1
2
3
4
2.5
3.5
2.4
2.9
3.3
Controls
and Neurohormonal activation Trial (substudy of EUROPA)
HUVEC = human umbilical vein endothelial cell
The PERindopril–Thrombosis, InflammatioN, Endothelial dysfunction and Neurohormonal activation Trial (PERTINENT)1 was a substudy of the EURopean trial On reduction of cardiac events with Perindopril in stable coronary Artery disease (EUROPA) study.2 EUROPA randomized 12,218 patients with stable CAD to placebo or the ACE inhibitor perindopril 8 mg. PERTINENT was designed to test the hypothesis that the ACE inhibitor would have possible vascular and antiatherosclerotic effects (the effects of perindopril on clinical outcomes in EUROPA is discussed later in this
slide kit).
Human umbilical vein endothelial cells (HUVEC) were isolated and incubated for 72 hours with serum from 45 healthy volunteers and 87 EUROPA participants (44 in placebo and 43 in perindopril groups). The slide shows activity of endothelial nitric oxide (NO) synthase (eNOS), the main source of NO in endothelial cells. As shown, eNOS activity was depressed at baseline in EUROPA patients compared with controls, illustrating the endothelial dysfunction characteristic of CAD. At 1 year, eNOS activity in the placebo group remained depressed, while eNOS activity in the ACE inhibitor group was similar to the controls.
Thus, 1 year of perindopril treatment in CAD patients had a beneficial effect on endothelial function by increasing eNOS activity.
1. Ferrari R, Remme WJ, Simoons M, Bertrand M, Fox K, for EUROPA investigators. PERTINENT: A substudy of EUROPA. Available at: www.europa-trial.org.
2. Fox KM, EUROPA 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;362:782-788.
VBWG
Koh KK et al. Am J Cardiol. 2004;93:1432-5.
0.15
1.14
1.66
1.32
0.0
0.5
1.0
1.5
2.0
Placebo
*
*
*
Koh et al administered placebo, losartan 100 mg, irbesartan 300 mg, and candesartan 16 mg for 2 months to 122 patients with mild to moderate hypertension.1 The slide shows flow-mediated vasodilation (expressed as percent change from baseline) in each group. Each AT1 receptor blocker significantly improved flow-mediated vasodilation (P = 0.005 vs placebo).
1. Koh KK, Han SH, Chung W-J, Ahn JY, Jin DK, Kim HS, et al.
Comparison of effects of losartan, irbesartan, and candesartan on
flow-mediated brachial artery dilation and on inflammatory and
thrombolytic markers in patients with systemic hypertension.
Am J Cardiol. 2004;93:1432-1435.
Impaired
Inflammation
The next slide will present recent data on the anti-inflammatory effects of ACE inhibition.1
VBWG
and inflammation
20 Patients with type 2 diabetes
Marketou ME et al. J Am Coll Cardiol. 2005;45 (suppl A):396A.
Baseline
* P < 0.05 vs baseline
370
264
0
100
200
300
400
Marketou et al randomized 40 patients with type 2 diabetes to placebo (n = 20) or perindopril 4 mg (n = 20).1 All patients had relatively well-controlled baseline BP (124 mm Hg systolic) and glucose (HbA1c <7.5%).
As shown, after 6 months significant reductions in lipid peroxides,
tumor necrosis factor- (TNF-), and interleukin-6 (IL-6), compared
with baseline, were observed in the ACE inhibitor group.
1. Marketou ME, Zacharis EA, Nikitovic D, Kochiadakis GE, Karalis IK, Simantirakis ES, et al. Beneficial modification of oxidative stress and systemic inflammation in normotensive patients with diabetes type 2 after angiotensin-converting enzyme inhibition treatment.
J Am Coll Cardiol. 2005;45(suppl A):396A. Abstract 808-6.
VBWG
LOX-1
VCAM
ICAM
Ang II and mechanisms of atherosclerosis
IL-6
MCP-1
PDGF
Impaired
Adhesion
The next slides will discuss pathways linking Ang II to lipid oxidation and monocyte adhesion.1
VBWG
Mehta JL, Li D. J Am Coll Cardiol. 2002;39:1429-35.
OxLDL
expression
Formation of oxidized LDL (oxLDL) is a key step in the pathogenesis of atherosclerosis. The oxLDL receptor (LOX-1) is present mostly on the surface of endothelial cells, although small amounts have also been detected in vascular smooth muscle cells, macrophages, and platelets.1 LOX-1–mediated ingestion of oxLDL activates mitogen-activated protein kinases (MAPKs) in the cell, which in turn activate nuclear factor-B (NF-B), a transcriptional factor involved in expression of monocyte chemoattractant protein-1 (MCP-1). In turn, MCP-1 leads to adhesion molecule expression.
As shown, LOX-1 expression is upregulated by a number of factors. In particular, Ang II, via the AT1 receptor, increases LOX-1 expression. Conversely, oxLDL, via LOX-1, upregulates the AT1 receptor.
1. Mehta JL, Li D. Identification, regulation and function of a novel
lectin-like oxidized low-density lipoprotein receptor. J Am Coll Cardiol. 2002;39:1429-1435.
VBWG
via lipoxygenase pathway
Bai = baicalein (12-lipoxygenase inhibitor)
Limor R et al. Am J Hypertens. 2005;18:299-307.
Ang II
10-7 mol/L+
400
Limor et al studied Ang II-mediated upregulation of LOX-1 expression in human vascular smooth muscle cells.1 At a concentration of
10-7 mol/L, Ang II increases expression of LOX-1 approximately
2.5-fold. In the presence of losartan or baicalein (a specific blocker
of 12-lipoxygenase), this effect was almost completely abolished.
The investigators concluded that, at least in vascular smooth muscle cells, the 12-lipoxygenase pathway may be important for
Ang II-dependent signal transduction.
1. Limor R, Kaplan M, Sawamura T, Sharon O, Keidar S, Weisinger G, et al. Angiotensin II increases the expression of lectin-like oxidized low-density lipoprotein receptor-1 in human vascular smooth muscle cells via a lipoxygenase-dependent pathway. Am J Hypertens. 2005;18:299-307.
VBWG
TGF-
IL-6
MCP-1
PDGF
Impaired
Proliferation fibrosis
The next slide discusses recent data on the effects of ACE inhibition on cell proliferation.1
VBWG
5.31
2.9
–1.9
–3
0
2
4
6
8.21
7.86
–3.53
–4
0
5
10
Mean baseline LVEF 58%, all groups

Placebo
Ramipril
10 mg
A Heart Outcomes Prevention Evaluation (HOPE) substudy compared the effects of two doses of ramipril (10 mg and 2.5 mg/day) on LV mass
and function in 446 evaluable patients. The results demonstrated a significant dose-dependent effect.1
After 4 years, LV mass increased in both the placebo and ramipril
2.5-mg groups. In contrast, LV mass decreased by 3.53 g in the
ramipril 10-mg group (P = 0.03 for trend).
LV end-systolic volume increased with placebo and ramipril 2.5 mg,
in contrast with a reduction of 1.90 mL with ramipril 10 mg
(P = 0.001 for trend).
1. Lonn E, Shaikholeslami R, Yi Q, Bosch J, Sullivan B, Tanser P, et al. Effects of ramipril on left ventricular mass and function in cardiovascular patients with controlled blood pressure and with preserved left ventricular ejection fraction: A substudy of the Heart Outcomes Prevention Evaluation (HOPE) Trial. J Am Coll Cardiol. 2004;43:2200-2206.
VBWG
with angiotensin receptor blockade
Patients with hypertension and LVH
Change in
LV mass
The Losartan Intervention for Endpoint Reduction in Hypertension
(LIFE) trial randomized 9193 patients with hypertension and left ventricular hypertrophy (LVH) to losartan-based or atenolol-based antihypertensive therapy. The slide summarizes results of an echocardiographic substudy in 457 losartan-treated and
459 atenolol-treated patients with 1 follow-up measurement.1
After 1 year, a greater decrease in mean LV mass was noted in the losartan group compared with the atenolol group and this difference persisted to the final echocardiogram (P = 0.009).
1. Devereux RB, Dahlöf B, Gerdts E, Boman K, Nieminen MS, Papademetriou V, et al. Regression of hypertensive left ventricular hypertrophy by losartan compared with atenolol: The Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) trial. Circulation. 2004;110:1456-1462.
VBWG
PAI-1
TF
IL-6
MCP-1
PDGF
Impaired
Endothelial
dysfunction
Adhesion
Thrombosis
Thrombosis
The next slides discuss data on the effects of RAAS modulation on fibrinolytic balance.1
VBWG
inhibition vs AT1 receptor blockade
Ramipril 10 mg
Losartan 100 mg
20 insulin-resistant, hypertensive patients treated for 6 weeks
To ensure elevated baseline levels of PAI-1, Brown et al treated 20 insulin-resistant hypertensive patients with hydrochlorothiazide 12.5 mg. Subjects were then randomized to ramipril (n = 9) or losartan (n = 11) for 6 weeks.1 Dosing was adjusted to achieve a diastolic BP <90 mm Hg.
At 1 week, both treatments significantly decreased PAI-1 antigen levels
(P = 0.046). At 3 weeks, however, PAI-1 levels had returned to baseline in the losartan group. PAI-1 antigen levels in the ramipril group remained significantly decreased from baseline at 3 and 6 weeks.
1. Brown NJ, Kumar S, Painter CA, Vaughan DE. ACE inhibition versus angiotensin type 1 receptor antagonism: Differential effects on PAI-1 over time. Hypertension. 2002;40:859-865.
VBWG
Differing effects of ARBs
%
126 Patients with hypertension
Koh et al randomized 126 patients with hypertension to placebo, losartan 100 mg, irbesartan 300 mg, or candesartan 16 mg for 2 months.1
Compared with placebo or losartan, irbesartan and candesartan significantly lowered plasma levels of PAI-1 antigen.
The clinical significance of these differing effects on fibrinolytic balance is not known.
1. Koh KK, Chung W-J, Ahn JY, Han SH, Kang WC, Seo Y-H, et al. Angiotensin II type 1 receptor blockers reduce tissue factor activity and plasminogen activator inhibitor type-1 antigen in hypertensive patients:
A randomized, double-blind, placebo-controlled study. Atherosclerosis. 2004;177:155-160.
VBWG
inhibition vs AT1 receptor blockade
Matsumoto T et al. J Am Coll Cardiol. 2003;41:1373-9.
*P < 0.05 vs baseline
25
Ang II induces PAI-1 release. In contrast, bradykinin induces tissue plasminogen activator (tPA) release.
Matsumoto et al randomized 45 hypertensive patients with atypical
chest pain to a 4-week treatment with perindopril 4 mg, losartan
50 mg, or no treatment (control).1
Immediately after the final dose, graded doses of bradykinin were administered into the left coronary artery. In a dose-dependent manner, bradykinin increased coronary blood flow, coronary vasomotor responses, and tPA in all 3 groups.
Perindopril and losartan augmented bradykinin-mediated vasodilation to similar extents (data not shown). However, as shown, tPA levels in the perindopril group were significantly higher than in the losartan and
control groups (P < 0.05 for both comparisons).
1. Matsumoto T, Minai K, Horie H, Ohira N, Takashima H, Tarutani Y, et al.
Angiotensin-converting enzyme inhibition but not angiotensin II type-1 receptor antagonism augments coronary release of tissue plasminogen activator in hypertensive patients. J Am Coll Cardiol. 2003;41:1373-1379.
VBWG
Studies in several animal models of atherosclerosis demonstrated reduced lesion progression with ACE inhibitor or AT1 receptor blocker1
Regression of human carotid plaque demonstrated with ramipril (SECURE2), losartan (LAARS3), and fosinopril (PHYLLIS4)
1Jacoby DS, Rader DJ. Arch Intern Med. 2003;163:1155-64.
2Lonn E et al. Circulation. 2001:103;919-25.
3Ludwig M et al. Clin Ther. 2002;24:1175-93.
4Zanchetti A et al. Stroke. 2004;35:2807-12.
Studies in several animal models1 show reduced progression of atherosclerotic lesions with either ACE inhibition or AT1 receptor blockade. Regression of human carotid plaque with RAAS modulation has been demonstrated in 3 large studies.
SECURE2: The Study to Evaluate Carotid Ultrasound changes in patients treated with Ramipril and vitamin E, a HOPE substudy, was conducted in 732 high-risk patients with CV disease, cerebrovascular disease, peripheral arterial disease, or diabetes plus ≥1 risk factors. There was a dose-dependent effect with ramipril over 4.5 years. The 10-mg dose was associated with a 37% reduction in intima-media thickness (IMT) rate of change compared with placebo. The 2.5-mg dose had a lesser, nonsignificant effect.
LAARS3: The Losartan Vascular Regression Study randomized 280 hypertensive patients to losartan 50 mg or atenolol 50 mg for 2 years. The IMT rate of change was reduced by similar amounts in both groups (decreases of 0.038 mm/yr and 0.037 mm/yr, respectively; P ≤ 0.001 vs baseline for both comparisons).
PHYLLIS4: The Plaque Hypertension Lipid-Lowering Italian Study randomized 508 hypertensive, hypercholesterolemic patients to fosinopril 20 mg, hydrochlorothiazide 25 mg, fosinopril plus pravastatin 40 mg, or
hydrochlorothiazide plus pravastatin. Treatment was for 2.6 years. IMT significantly progressed by 0.010 mm/yr in the group receiving diuretic alone
(P = 0.01) but was essentially unchanged in the other groups.
2. Lonn E, Yusuf S, Dzavik V, Doris I, Yi Q, Smith S; SECURE Investigators. Effects of ramipril and vitamin E on atherosclerosis: The Study to Evaluate Carotid Ultrasound changes in patients treated with Ramipril and vitamin E (SECURE). Circulation. 2001;103:919-925.
3. Ludwig M, Stapff M, Ribeiro A, Fritschka E, Tholl U, Smith RD, Stumpe KO. Comparison of the effects of Losartan and Atenolol on common carotid artery intima-media thickness in patients with hypertension: Results of a 2-year, double-blind, randomized controlled study. Clin Ther. 2002;24:1175-1193.
4. Zanchetti A, Crepaldi G, Bond MG, Gallus G, Veglia F, Mancia G, et al, on behalf of PHYLLIS Investigators. Different effects of antihypertensive regimens based on fosinopril or hydrochlorothiazide with or without lipid lowering by pravastatin on progression of asymptomatic carotid atherosclerosis: Principal results of PHYLLIS—A randomized double-blind trial. Stroke. 2004;35:2807-2812.
VBWG
carotid plaques: Potential role in
plaque stabilization
Carotid endarterectomy specimens
Cipollone et al randomized 70 patients with symptomatic carotid artery stenosis to irbesartan 300 mg or chlorthalidone 50 mg for 4 months prior to scheduled endarterectomy.1 Following the procedure, carotid plaque samples were analyzed for matrix metalloproteinases (MMP-2 and MMP-9), inducible cyclooxygenase-2 (COX-2), and prostaglandin E2-dependent synthase (PGES-1).
As shown, the AT1 receptor blocker, but not the diuretic, significantly blunted expression of all four proteins. A previous study from the same group had shown that activation of MMP-2 and MMP-9 is controlled by a COX-2/PGES-1 pathway. The new data extend this finding by showing that this pathway is modulated by the AT1 receptor.
1. Cipollone F, Fazia M, Iezzi A, Pini B, Cuccurullo C, Zuchelli M, et al. Blockade of the angiotensin II type-1 receptor stabilizes atherosclerotic plaques in humans by inhibiting prostaglandin E2-dependent matrix metalloproteinase activity. Circulation. 2004;109:1482-1488.
VBWG
Modulation in
CAD Patients
The next section presents results of recent clinical trials of RAAS modulation in patients with CAD and preserved left ventricular function. To provide an historical context for these data, the original trials of ACE inhibition in post-MI patients with heart failure or left ventricular dysfunction will be summarized.
VBWG
trials in acute MI
Odds ratio (95% CI)
Deaths (n)/Randomized (n)
ACE Inhibitor MI Collaborative Group. Circulation. 1998;97:2202-12.
*IV infusion followed by oral therapy
This meta-analysis included data from all randomized trials with more than 1000 patients in which an ACE inhibitor was initiated during the acute phase of an MI (0–36 hours) and continued for 4 to 6 weeks thereafter.1
At 30 days, there were 3501 deaths (7.1%) and 3740 deaths (7.6%) in the ACE inhibitor and control groups, respectively. The odds reduction was
7% (95% CI, 2%–11%).
1. ACE Inhibitor Myocardial Infarction Collaborative Group. Indications for ACE inhibitors in the early treatment of acute myocardial infarction: Systematic overview of individual data from 100,000 patients in randomized trials. Circulation. 1998;97:2202-2212.
VBWG
trials in post-MI LV dysfunction and HF
AIRE Study Investigators. Lancet. 1993;342:821-8.
Køber L et al. N Engl J Med. 1995;333:1670-6.
SOLVD Investigators. N Engl J Med. 1991;325:293-302.
SOLVD Investigators. N Engl J Med. 1992;327:685-91.
Pfeffer MA et al. N Engl J Med. 1992;327:669-77.
AIRE
TRACE
SOLVD
(Treatment)
SAVE
0.002
0.001
0.0036
0.019
0
5
10
15
20
25
P
30
SOLVD
(Prevention)
0.30
27%
22%
8%
16%
19%
Duration of follow-up in these trials ranged from 15 to 42 months. Observed risk reductions for MI ranged from 11% to 25%. These
findings provide a basis for the design of large-scale trials in high-risk
CAD patients with normal LV function.1-5
1. 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.
2. Køber L, Torp-Pedersen C, Carlsen JE, Bagger H, Eliasen P, Lyngborg K, et al. A clinical trial of the angiotensin-converting-enzyme inhibitor trandolapril in patients with left ventricular dysfunction after myocardial infarction. Trandolapril Cardiac Evaluation (TRACE) Study Group.
N Engl J Med. 1995;333:1670-1676.
3. The SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure.
N Engl J Med. 1991;325:293-302.
4. The SOLVD Investigators. Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions. N Engl J Med. 1992;327:685-691.
5. Pfeffer MA, Braunwald E, Moye LA, Basta L, Brown EJ Jr, Cuddy TE,
et al. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. Results of the survival and ventricular enlargement trial. N Engl J Med. 1992;327:669-677.
VBWG
Aldosterone blockade and AT1 receptor blockade: Trials in post-MI/LV dysfunction or HF
Pitt B et al. N Eng J Med. 1999;341:709-17.
VALIANT
Months
Captopril
Valsartan
0.4
0.1
0.2
6
12
24
30
36
0.3
0.0
Probability
HR 1.00 (0.90–1.11)
HR 0.98 (0.89–1.09)
P = 0.73)
1. Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, et al, for the Randomized Aldactone Evaluation Study (RALES) Investigators. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med. 1999;341:709-717.
2. Pitt B, Remme WJ, Zannad F, Neaton J, Martinez F, Roniker B, et al, for the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study Investigators. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction.
N Engl J Med. 2003;348:1309-1321.
3. Pfeffer MA, McMurray JJV, Velazquez EJ, Rouleau J-L, Køber L, Maggioni AP, et al, for the Valsartan in Acute Myocardial Infarction Trial Investigators. Valsartan, Captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. N Engl J Med. 2003;349:
1893-1906.
The Randomized Aldactone Evaluation Study (RALES) randomized
1633 patients with NYHA class III or IV heart failure to placebo or spironolactone 25 mg.1 All patients were treated with an ACE inhibitor and loop diuretic; most patients also received digoxin. The trial was terminated early. There was a 30% relative risk reduction in mortality with spironolactone compared with placebo (relative risk [RR], 0.70; 95% CI, 0.60 to 0.82; P < 0.001).
The Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) randomized 6632 patients with post-MI LV dysfunction and heart failure to placebo or the selective aldosterone blocker eplerenone 50 mg.2 Subjects were eligible for randomization 3 to 14 days after the index event. At baseline, 87% of subjects were receiving ACE inhibitors or AT1 receptor blockers, 75% beta-blockers, 60% diuretics, and 88% aspirin. At study end, there was a 15% relative risk reduction in all-cause death associated with eplerenone compared with placebo (RR, 0.85; 95% CI, 0.75 to 0.96; P = 0.008).
The Valsartan in Acute Myocardial Infarction (VALIANT) trial randomized 14,703 patients with post-MI LV dysfunction and heart failure to valsartan
160 mg 2 daily, valsartan 80 mg 2 daily plus captopril 50 mg 3 daily,
or captopril 50 mg daily.3 Subjects were eligible for randomization the day of or up to 10 days after the index events. At study end, there was no difference among the group with regard to all-cause mortality.
VBWG
HOPE Study Investigators. N Engl J Med. 2000;342:145-53.
EUROPA Investigators. Lancet. 2003;362:782-8.
PEACE
HOPE
15
5
10
0
20
0
Placebo
Ramipril
2. EUROPA 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;362:782-788.
3. PEACE Trial Investigators. Angiotensin-converting-enzyme inhibition in stable coronary artery disease. N Engl J Med. 2004;351:2058-68.
4. Pitt B, O’Neill B, Feldman R, Ferrari R, Schwartz L, Mudra H, et al, for the
QUIET Study Group. The Quinapril Ischemic Event Trial (QUIET): Evaluation of chronic ACE inhibitor therapy in patients with ischemic heart disease and preserved left ventricular function. Am J Cardiol. 2001;87:1058-1063.
5. Pitt B. ACE inhibitors for patients with vascular disease without left ventricular dysfunction–May they rest in PEACE? N Engl J Med. 2004;351:2115-2117.
Four major trials have been conducted in high-risk CAD patients with normal
LV function.
HOPE demonstrated the benefit of ramipril 10 mg in high-risk stable CAD patients without LV dysfunction or heart failure. The primary outcome (CV death, MI, and stroke) was reduced 15% after 1 year and 22% at the end of the study.1
EUROPA, conducted in lower-risk patients with stable CAD and no heart failure, demonstrated a 20% reduction with perindopril 8 mg in the primary outcome
(CV death, MI, and cardiac arrest).2 Thus, HOPE and EUROPA demonstrated comparable benefits with long-term treatment.
In contrast, PEACE demonstrated a neutral effect of trandolapril 4 mg on the primary outcome (CV death, MI, and revascularization) in lower-risk patients
with stable CAD and no LV dysfunction.3
QUIET was conducted in 1750 patients who had undergone coronary angioplasty or atherectomy at baseline.4 Subjects were randomized to quinapril 20 mg or placebo. This study also demonstrated a neutral effect for the ACE inhibitor studied.
Various reasons have been suggested for the difference in outcome—including
the low-risk population, the drug or dose used, and notably, the study was underpowered to provide evidence of a reduction in hard outcomes such as
MI and CV death.4,5
These issues as they relate to the optimal use of ACE inhibition in high-risk
CAD patients without LV dysfunction are discussed in following slides.
VBWG
0.5
1.0
1.5
HOPE showed that ramipril 10 mg daily exerted a significant cardioprotective effect among high-risk patients with CAD or vascular disease with no history of heart failure or LV systolic dysfunction.1
EUROPA confirmed these findings in patients with stable CAD but without heart failure who were treated with perindopril 8 mg/day.2
Treatment significantly reduced the primary composite outcomes of
CV mortality, nonfatal MI, and stroke in HOPE and of CV death, MI, and resuscitated cardiac arrest in EUROPA, as well as the individual outcomes of MI and CV mortality.
Reductions in stroke and cardiac arrest were significant in HOPE and showed favorable trends in EUROPA, which studied a lower-risk population and had a low incidence of these events.
1. HOPE Study Investigators. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med. 2000;342(3):145-153.
2. EUROPA 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;362:782-788.
2.0
1.0
EUROPA: perindopril 8 mg
HOPE: ramipril 10 mg
No -blockers
Hazard ratio
These data show subgroup analyses of treatment effects in HOPE and EUROPA. (Hazard ratios in HOPE are for MIs and for the primary
outcome in EUROPA.)1,2
In both studies, there was a positive effect of treatment with lipid-lowering agents and beta-blockers, indicating that ACE inhibition had
a benefit beyond the effect of standard therapies.1,2
1. Dagenais GR, Yusuf S, Bourassa MG, Yi Q, Bosch J, Lonn EM, et al. Effects of ramipril on coronary events in high-risk persons: Results of the Heart Outcomes Prevention Evaluation Study. Circulation. 2001;104:522-526.
2. EUROPA Investigators. Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: Randomised, double-blind, placebo-controlled multicentre trial
VBWG
Angiotensin Converting Enzyme inhibition
Objective: Assess effect of ACEI in patients
with stable CAD and normal/slightly
reduced LV function
Design: 8290 patients randomized to trandolapril 4 mg or placebo
Follow-up: 4.8 years
outcome: CV death, nonfatal MI, CABG, PCI
The Prevention of Events With Angiotensin Converting Enzyme Inhibition trial (PEACE) had a similar design as EUROPA and was conducted in a similar patient population.1
VBWG
Trandolapril
4% Risk reduction
P = 0.43
PEACE results showed that in patients with stable CAD and without
LV dysfunction, treatment with trandolapril 4 mg/day was not
associated with a reduction in the primary outcome (CV death, MI,
or coronary revascularization).1
The incidence of the primary outcome was 21.9% versus 22.5% in the trandolapril and placebo groups, respectively. There was a 4% relative risk reduction in the trandolapril group (hazard ratio [HR] 0.96; 95% CI, 0.88–1.06) but it was insignificant (P = 0.43).
The PEACE results contrast with HOPE and EUROPA, which show comparable benefits of treatment.
1. PEACE Trial Investigators. Angiotensin-converting-enzyme inhibition in
stable coronary artery disease. N Engl J Med. 2004;351:2058-2068.
VBWG
ACE inhibitor
Perindopril 8 mg
CV death, MI, cardiac arrest
PEACE N = 8290 (4.8 years)
Trandolapril 4 mg
CV death, MI, coronary revascularization
QUIET N = 1750 (2.25 years)
Quinapril 20 mg
CV death, MI, coronary revasc, cardiac arrest, hosp for angina
HOPE N = 9297 (4.5 years)
Ramipril 10 mg
Vascular disease (80% had CAD) LVEF ≥40%, or No heart failure Age ≥55 years
CV death, MI, stroke
Four major randomized placebo-controlled clinical trials examined the efficacy of different ACE inhibitors in high-risk patients with stable CAD and normal LV function: HOPE, EUROPA, PEACE, and Quinapril Ischemic Event Trial (QUIET).
HOPE studied the effects of ramipril 10 mg in 9297 high-risk patients
(age ≥55 years) with vascular diseases (80% with CAD) or with diabetes
plus ≥1 other CV risk factor but without LV dysfunction or heart failure.1
EUROPA studied the effects of perindopril 8 mg in 12,218 patients
(ages ≥18 years) with CAD and without heart failure.2
PEACE was a somewhat smaller trial that studied the effect of trandolapril 4 mg
in 8290 patients (ages ≥50 years) with CAD and preserved LV function.3
Originally, the primary outcome of PEACE was CV death or nonfatal MI, but the trial was not powered to determine this outcome. After randomizing 1584 patients, the Steering Committee decided that recruiting the necessary 14,000 patients was not feasible. At this point, the sample size was reduced to 8100 and the primary outcome expanded to include coronary revascularization.
QUIET randomized 1750 patients with CAD and LVEF ≥40% to quinapril or placebo. At baseline, all patients had undergone successful coronary angioplasty
or atherectomy.4
1. HOPE 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.
double-blind, placebo-controlled, multicentre trial (the EUROPA study).
Lancet. 2003;362:782-788.
stable coronary artery disease. N Engl J Med. 2004;351:2058-2068.
4. Pitt B, O’Neill B, Feldman R, Ferrari R, Schwartz L, Mudra H, et al, for the QUIET Study Group. The Quinapril Ischemic Event Trial (QUIET): Evaluation of chronic ACE inhibitor therapy in patients with ischemic heart disease and preserved left ventricular function. Am J Cardiol. 2001;87:1058-1063.
VBWG
without HF: Key baseline characteristics
N 9,297 12,218 8,290 1,750
Follow-up (yrs) 4.5 4.2 4.8 2.3
ACEI/dose (mg) R-10 P-8 T-4 Q-20
Age (yrs) 66 60 64 58
Men (%) 73 85 82 82
CAD/Cor rev (%) 80/44 100/55 100/72 100/100
Diabetes (%) 39 12 17 16
HTN (%) 47 27 46 47
Prior MI (%) 53 65 55 49
EF NA NA 58 59
PVD (%) 43 7 NA NA
HOPE EUROPA PEACE QUIET
All four trials were conducted in at-risk patients, but there were key differences in baseline risk factors.1-4
On average, HOPE patients were older than those in the other trials.
Many more patients in HOPE (39%) had diabetes versus EUROPA
(12%), PEACE (17%), and QUIET (12%).
More patients in PEACE (72%), QUIET (100%), and EUROPA (55%) had undergone coronary revascularization than in HOPE.
These differences in baseline characteristics suggest that HOPE participants had the highest risk, while the risk levels for participants in EUROPA, PEACE, and QUIET were similar.
double-blind, placebo-controlled, multicentre trial (the EUROPA study). Lancet. 2003;362:782-788.
2. HOPE 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.
VBWG
*at study end
†at 3 yrs
without HF: CV therapies at entry/during study
HOPE
EUROPA
PEACE
QUIET
47
32
36
0/7*
Diuretics (%)
15
10
13
NA
Patients in all four trials were treated with ACE inhibition in addition to other CV protective therapies, including antiplatelet agents (mostly aspirin), beta-blockers, lipid-lowering agents, and antihypertensive agents.1-4
Subjects in EUROPA and PEACE tended to be more aggressively treated at baseline than subjects in the other two trials, reflecting changes in clinical practice.
1. EUROPA 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;362:782-788.
N Engl J Med. 2000;342:145-153.
4. Pitt B, O’Neill B, Feldman R, Ferrari R, Schwartz L, Mudra H, et al, for the QUIET Study Group. The Quinapril Ischemic Event Trial (QUIET): Evaluation of chronic ACE inhibitor therapy in patients with ischemic heart disease and preserved left ventricular function. Am J Cardiol. 2001;87:
1058-1063.
VBWG
Sleight P et al. Lancet 2001;358:2130-1.
ACEI outcome trials in CAD patients
without HF: BP at entry/during study
BP (mm Hg)
3.3/1.2
5/2
3/1.2
NA
HOPE and EUROPA had run-in phases, during which all patients received open-label ACE inhibitor.1,2
BP reduction was relatively modest in HOPE, EUROPA, and PEACE.1-4
These data were not available for QUIET.5
Baseline BP was lowest in QUIET (124/74 mm Hg).5
1. EUROPA Investigators. Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: Randomised, double-blind, placebo-controlled, multicentre trial
2. HOPE 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.
4. Sleight P, Yusuf S, Pogue J, Tsuyuki R, Diaz R, Probstfield J.
Blood-pressure reduction and cardiovascular risk in HOPE study. Lancet. 2001;358:2130-2131.
5. Pitt B, O’Neill B, Feldman R, Ferrari R, Schwartz L, Mudra H, et al, for
the QUIET Study Group. The Quinapril Ischemic Event Trial (QUIET): Evaluation of chronic ACE inhibitor therapy in patients with ischemic heart disease and preserved left ventricular function. Am J Cardiol. 2001;87:
1058-1063.
VBWG
ACEI outcome trials in CAD patients without HF: Differences in baseline CV risk
HOPE Study Investigators. N Engl J Med. 2000;342:145-53.
HOPE
EUROPA
PEACE
Annualized
QUIET
1.8
1.0
0.8
0.7
2.7
1.5
1.1
2.0
0.0
1.0
2.0
3.0
Baseline risk, indicated by annualized fatal and nonfatal CV event rates in
the placebo groups, was highest among the HOPE participants.1-4
The placebo groups in PEACE, EUROPA, and QUIET had lower and roughly similar annualized rates of CV death and nonfatal MI.1,3,4
However, the absolute risk of CV events was high in all four trials.
1. EUROPA 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;362:782-788.
N Engl J Med. 2000;342:145-153.
VBWG
without HF: Annualized all-cause mortality—
placebo vs general population
Anderson RN, Smith BL. Natl Vital Stat Rep. 2005;53:1-90.
*Mean age in years
General
population
General
population
As shown, subjects in HOPE, PEACE, EUROPA, and QUIET were at higher risk than the general population, as demonstrated by higher rates of all-cause death in the placebo groups.1-5
double-blind, placebo-controlled multicentre trial (the EUROPA study). Lancet. 2003;362:782-788.
5. Anderson RN, Smith BL. Death: Leading causes for 2002. Natl Vital Stat Rep. 2005;53:1-90.
VBWG
without HF: Annualized CV mortality—
placebo vs general population
*Mean age in years
Anderson RN, Smith BL. Natl Vital Stat Rep. 2005;53:1-90.
CV mortality
0.7
1.8
0.3
0.8
1.0
0.7
General
population
General
population
As shown, subjects in HOPE, PEACE, EUROPA, and QUIET were at higher risk than the general population, as demonstrated by higher rates of CV death in the placebo groups.1-5
1. EUROPA 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;362:782-788.
4. Pitt B, O’Neill B, Feldman R, Ferrari R, Schwartz L, Mudra H, et al, for the QUIET Study Group. The Quinapril Ischemic Event Trial (QUIET): Evaluation of chronic ACE inhibitor therapy in patients with ischemic heart disease and preserved left ventricular function.
Am J Cardiol. 2001;87:1058-1063.
5. Anderson RN, Smith BL. Death: Leading causes for 2002.
Natl Vital Stat Rep. 2005;53:1-90.
VBWG
without HF: Cumulative evidence
Pooled all-cause mortality results
Meta-analysis of the HOPE, EUROPA, and PEACE data showed a
significant 14% relative risk reduction in all-cause mortality
(odds ratio, 0.86; 95% CI, 0.79-0.94; P < 0.001).1
1. Yusuf S, Pogue J. ACE inhibition in stable coronary artery disease.
N Engl J Med. 2005;352:937-939.
VBWG
MI
Stroke
CME Monograph; UF College of Medicine. 2004;6(3).
HOPE, EUROPA, PEACE, QUIET
When the QUIET data were added to the meta-analysis shown on the
last slide, the risk reduction for all-cause death was unaffected.1-5
MI and stroke were also significantly reduced.
1. EUROPA Investigators. Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: Randomised, double-blind, placebo-controlled, multicentre trial
N Engl J Med. 2000;342:145-153.
4. Pitt B, O’Neill B, Feldman R, Ferrari R, Schwartz L, Mudra H, et al, for
the QUIET Study Group. The Quinapril Ischemic Event Trial (QUIET): Evaluation of chronic ACE inhibitor therapy in patients with ischemic heart disease and preserved left ventricular function. Am J Cardiol. 2001;87:
1058-1063.
5. Pepine CJ, Probstfield JL. A HOPE for PEACE? Update on the role of ACE inhibition in CAD patients. In: Vascular Biology in Clinical Practice:
A CME monograph. University of Florida College of Medicine; Gainesville, Fla. 2004;6(3).
VBWG
CAMELOT: Trial of BP reduction with ACEI or CCB in CAD patients without HF
Study design: Randomized, double-blind, multicenter,
24-month trial in patients with angiographically documented CAD, LVEF ≥40%, and no HF
(N = 1991)
or placebo added to background therapy
with -blockers and/or diuretics
vs placebo
using IVUS (n = 274)
Outcome: Change in percent atheroma volume
Nissen SE et al. JAMA. 2004;292:2217-26.
The Comparison of Amlodipine vs Enalapril to Limit Occurrences of Thrombosis (CAMELOT) study was a randomized, double-blind, multicenter, 24-month comparison of treatment with a calcium channel antagonist (amlodipine 10 mg), an ACE inhibitor (enalapril 20 mg), and placebo in normotensive patients with CAD.1
Entry criteria for CAMELOT included angiographically documented CAD
(1 lesions in a native coronary artery with >20% stenosis) plus diastolic
BP <100 mm Hg (with or without treatment). Patients with LVEF <40% or moderate to severe HF were excluded.
The primary outcome was the incidence of CV events for amlodipine versus placebo. Events included CV death, nonfatal MI, resuscitated cardiac arrest, coronary revascularization, hospitalization for angina or congestive heart failure, fatal/nonfatal stroke or transient ischemic attack, and new diagnosis of peripheral vascular disease.
CAMELOT also included a substudy of 274 patients in whom the progression of atherosclerosis was measured by intravascular ultrasound (IVUS).
1. Nissen SE, Tuzcu EM, Libby P, Thompson PD, Ghali M, Garza D, et al, for the CAMELOT Investigators. Effect of antihypertensive agents on cardiovascular events in patients with coronary disease and normal blood pressure: The CAMELOT Study: A randomized controlled trial. JAMA. 2004;292:2217-2226.
VBWG
with amlodipine and enalapril
Primary outcome = incidence of CV events
Cumulative
P = 0.16
P = 0.1
P = 0.003
Placebo
655
588
558
525
488
Enalapril
673
608
572
553
529
Amlodipine
663
623
599
574
535
The primary outcome occurred in 23.1% of placebo-treated patients, 16.6% of amlodipine-treated patients HR, 0.69; 95% CI, 0.54–0.88;
P = 0.003 vs placebo), and 20.2% of enalapril-treated patients
(HR, 0.85; 95% CI, 0.67–1.07; P = 0.16 vs placebo).1 The difference in primary outcome for amlodipine versus enalapril was not significant (HR, 0.81; 95% CI, 0.63–1.04; P = 0.10).
1. Nissen SE, Tuzcu EM, Libby P, Thompson PD, Ghali M, Garza D, et al, for the CAMELOT Investigators. Effect of antihypertensive agents on cardiovascular events in patients with coronary disease and normal blood pressure: The CAMELOT Study: A randomized controlled trial. JAMA. 2004;292:2217-2226.
VBWG
~120 mm Hg systolic
BP reduction >10 mm Hg
Hemodynamic effects may also modulate
clinical outcome
– Combinations of drugs with differing modes of action
– Lower BP targets in special populations
Pepine CJ. JAMA. 2004;292:2271-3.
The CAMELOT results suggest that the optimal systolic BP level in
CAD patients without HF may be <140 mm Hg and perhaps in the
120-mm Hg range.1
The effect of BP reduction on atherosclerosis appeared to be related to the degree of reduction. There appeared to be no progression at a systolic BP reduction of ~10 mm Hg. Regression of CAD was suggested with systolic BP reduction >10 mm Hg.
However, the relation of BP reduction to clinical outcome in
CAD patients is complex. Hemodynamic effects may also modulate
clinical outcome.
Thus, further studies are needed to evaluate different BP levels and
BP-lowering strategies in this patient population.
1. Pepine CJ. What is the optimal blood pressure and drug therapy for patients with coronary artery disease? JAMA. 2004;292:2271-2273.
VBWG
ACEI outcome trials in CAD patients without HF: Clinical implications
Cumulative evidence supports ACE inhibitors for stable
CAD patients with/without clinical signs of HF
Not all ACE inhibitors can be assumed to have
comparable effects for all indications
– Dose and individual properties of ACEIs
are important
– Benefit may be less in patients with well
controlled risk factors
Randomized clinical trial evidence and guidelines should guide selection of effective ACE inhibitor and dose for
CAD patients without HF
Pitt B. N Engl J Med. 2004;351:2115-7.
The pooled data from these trials supports the use of ACE inhibition in stable patients with CAD and without clinical signs of heart failure.1
Not all ACE inhibitors can be assumed to have comparable effects on vascular protection. Dose, as well as lipophilicity, tissue specificity, or other features of these agents, may be important.1
Benefits of ACE inhibition may also depend on baseline risk. Patients with well-controlled risk factors may benefit less from ACE inhibition than those whose risk factors are less well-controlled.
While the ultimate decision on which agent to use is based on the physician’s judgment, evidence-based medicine and current guidelines should guide treatment decisions.
VBWG
results in ACEI trials
– Dose for CAD patients can’t be predicted from studies
in HF or hypertension
Differences in baseline risk (age, diabetes, HTN, PAD)
Inclusion of revascularization in primary outcome
Lack of power
Pitt B et al. Am J Cardiol. 2004;87:1058-63.
Yusuf S, Pogue J. N Engl J Med. 2005;352:937-8.
Pitt B. N Engl J Med. 2004;351:2115-7.
Pepine CJ, Probstfield JL. Vasc Bio Clin Pract.
CME Monograph; UF College of Medicine. 2004;6(3).
Several explanations have been suggested for the disparate outcome observed in PEACE and QUIET—including the drug or dose used, inclusion of revascularization in the primary outcome (an outcome more dependent on practice patterns than on medical therapy), lack of power to provide a statistically significant reduction in hard outcomes such as MI and CV death, and poor adherence to assigned medication.1-4
1. Pitt B, O’Neill B, Feldman R, Ferrari R, Schwartz L, Mudra H, et al, for the QUIET Study Group. The QUinapril Ischemic Event Trial (QUIET): Evaluation of chronic ACE inhibitor therapy in patients with ischemic heart disease and preserved left ventricular function. Am J Cardiol. 2001;87:
1058-1063.
2. Yusuf S, Pogue J. ACE inhibition in stable coronary artery disease.
N Engl J Med. 2005;352:937-939.
4. Pepine CJ, Probstfield JL. A HOPE for PEACE? Update on the role of ACE inhibition in CAD patients. In: Vascular Biology in Clinical Practice:
A CME monograph. University of Florida College of Medicine; Gainesville, Fla. 2004;6(3).
VBWG
Are all ACEIs the same: Survival post-MI by ACEI at discharge
P < 0.001 log-rank
n = 421
n = 905
n = 276
n = 889
n = 2201
n = 2577
n = 243
Pilote et al conducted a claims-based nonrandomized study comparing the effectiveness of different ACE inhibitors in reducing mortality in elderly survivors of MI.1
The study included 7512 patients age ≥65 years who filled a prescription for an ACE inhibitor within 30 days of discharge from the hospital after acute MI and who continued to receive the same drug for at least 1 year.
Results showed that ramipril and perindopril were associated with larger relative reductions in mortality compared with several other
ACE inhibitors.
The results suggest that not all drugs within the class of ACE inhibitors should be considered to have the same effect.
Given that this was a retrospective, observational study of an administrative database, a large randomized clinical trial or prospective study would be necessary to confirm these results.
1. Pilote L, Abrahamowicz M, Rodrigues E, Eisenberg MJ, Rahme E. Mortality rates in elderly patients who take different
angiotensin-converting enzyme inhibitors after acute myocardial infarction: A class effect? Ann Intern Med. 2004;141:102-112.
VBWG
with Ramipril Global Endpoint Trial
†Telmisartan Randomized Assessment Study in
ACE Intolerant Subjects with Cardiovascular Disease
Patients
Treatment
ONTARGET*
55 years with CAD, stroke, PAD, or diabetes + end-organ damage (N = 25,620)
Ramipril 10 mg Telmisartan 80 mg Ramipril 10 mg + telmisartan 80 mg
5.5
TRANSCEND†
55 years, ACEI intolerant, with CAD, stroke, PAD, or diabetes + end-organ damage (N = 5776)
Telmisartan 80 mg Placebo
CV death, MI, stroke, hosp for heart failure
The Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET) randomized 25,620 high-risk patients to telmisartan 80 mg, ramipril 10 mg, or their combination.1 Eligible subjects were 55 years of age with coronary, cerebrovascular, or peripheral vascular disease, or have diabetes with evidence of end-organ damage. Patients will be followed for up to 5.5 years. The primary outcome is a composite of CV death, nonfatal MI, nonfatal stroke, or hospitalization for congestive heart failure.
The Telmisartan Randomized Assessment Study in ACE Intolerant Subjects with Cardiovascular Disease (TRANSCEND) randomized
high-risk patients to telmisartan 80 mg or placebo.1 The same entry criteria as ONTARGET were used, with the addition that patients enrolled in this trial had to be intolerant of ACE inhibitors. The
projected enrollment is 6000 patients. Length of follow-up and
the primary outcome are the same as in ONTARGET.
1. The ONTARGET/TRANSCEND Investigators. Rationale, design, and baseline characteristics of 2 large, simple, randomized trials evaluating telmisartan, ramipril, and their combination in high-risk patients: 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. Am Heart J. 2004;148:52-61.
VBWG
HOPE Study Investigators. Lancet. 2000;355:253-9.
Daly CA et al. Eur Heart J. 2005. epub;April 28.
MICRO-HOPE PERSUADE
or ≥1 CV risk factor No heart failure
Normal LV function
Follow-up (years): 4.5 4.2
outcome: stroke cardiac arrest
and DiabEtes (substudy of EUROPA)
MICRO-HOPE and PERSUADE studied the effect of long-term
treatment with ACE inhibition on CV risk in patients with diabetes.
MICRO-HOPE (a substudy of HOPE) investigated the effect of ramipril 10 mg/day in 3577 patients with diabetes and CV disease or diabetes plus ≥1 CV risk factor and preserved LV function. The primary outcome was a composite of CV death, MI, and stroke.1
PERSUADE (a substudy of EUROPA) investigated the effects of perindopril 8 mg/day in 1502 patients with diabetes plus documented CAD and no clinical signs of heart failure. The primary outcome was a composite of CV death, MI, and cardiac arrest.2
1. HOPE Study Investigators. Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: Results of the HOPE study and MICRO-HOPE substudy. Lancet. 2000;355:253-259.
2. Daly CA, Fox KM, Remme WJ, Bertrand ME, Ferrari R, Simoons ML, on behalf of the EUROPA investigators. The effect of perindopril on cardiovascular morbidity and mortality in patients with diabetes in the EUROPA study: Results from the PERSUADE substudy. Eur Heart J. 2005 April 28; epublished ahead of print.
VBWG
Daly CA et al. Eur Heart J. 2005. In press.
PERSUADE
P = 0.0004
In MICRO-HOPE, Kaplan Meier curves show an early and consistent benefit of ramipril 10 mg in patients with diabetes. There was a 25% relative risk reduction in the primary outcome of MI, stroke, or
CV death (P = 0.0004).1
In PERSUADE, treatment with perindopril 8 mg once daily for 5 years reduced the primary outcome of CV death, MI, and cardiac arrest by
19% (P = 0.131).2
The results of PERSUADE support and extend the observations in MICRO-HOPE to a somewhat lower-risk population of diabetic patients.
2. Daly CA, Fox KM, Remme WJ, Bertrand ME, Ferrari R, Simoons ML, on behalf of the EUROPA investigators. The effects of perindopril on cardiovascular morbidity and mortality in patients with diabetes in the EUROPA study: Results from the PERSUADE substudy. Eur Heart J. 2005 April 28; epublished ahead of print.
VBWG
Daly CA et al. Eur Heart J. 2005. In press.
Primary outcome
Total mortality
CV mortality
All MI
(N = 1502)
The PERSUADE results indicated a consistent trend towards benefit in the perindopril 8 mg group across primary and secondary outcomes.1 The confidence intervals (CI) overlapped with unity, indicating that the results did not reach statistical significance. However, as shown, the results are consistent with those of MICRO-HOPE.2
1. Daly CA, Fox KM, Remme WJ, Bertrand ME, Ferrari R, Simoons ML, on behalf of the EUROPA investigators. The effect of perindopril on cardiovascular morbidity and mortality in patients with diabetes in the EUROPA study: Results from the PERSUADE substudy. Eur Heart J. 2005 April 28; epublished ahead of print.
VBWG
HOPE Study Investigators. Lancet. 2000;355:253-9.
3.0
2.5
2.0
1.5
1.0
0.5
0
1
2
3
4.5
Placebo
The results of MICRO-HOPE demonstrate that ACE inhibition
(ramipril 10 mg) has vasculoprotective as well as renoprotective effects in individuals with type 2 diabetes.1
The risk for overt nephropathy was reduced by 24% after 4.5 years. At baseline, 32% of patients in MICRO-HOPE had microalbuminuria. Treatment lowered the risk of nephropathy in those who did and did not have baseline microalbuminuria.
The CV benefits included significant reductions in MI, stroke, and
CV death.
Ramipril 10 mg also was associated with a significant reduction in the
albumin-creatinine ratio at both 1 year (P = 0.001) and end of study
(P = 0.02).
1. HOPE Study Investigators. Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: Results of the
HOPE study and MICRO-HOPE substudy. Lancet. 2000;355:253-259.
VBWG
LIFE: Comparison of treatment effects in overall population vs with diabetes
Patients with hypertension and LVH
Dahlöf B et al. Lancet. 2002;359:995-1003.
Lindholm LH et al. Lancet. 2002;359:1004-10.
0.5
1.0
1.5
Hazard ratio
In the overall population enrolled in the LIFE trial, the effects of losartan on the primary outcome were driven by a significant 35% relative risk reduction in stroke.1 Stroke reduction in the losartan group may have been related in part to the large BP reduction achieved (30.2/16.6 mm Hg).
Relative to atenolol, there were trends toward an increase in risk of MI
and a decrease in risk of CV death.
Results in the diabetic cohort showed a different pattern.2 There was a 37% relative risk reduction in CV death (P = 0.028) and trends toward reduced risk of stroke (21% risk reduction, P = 0.204) and MI (17% risk reduction,
P = 0.073).
1. Dahlöf B, Devereux RB, Kjeldsen SE, Julius S, Beevers G, de Faire U, et al, for the LIFE Study Group. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): A randomised trial against atenolol. Lancet. 2002;359:995-1003.
2. Lindholm LH, Ibsen H, Dahlöf B, Devereux RB, Beevers G, de Faire U, et al, for the LIFE Study Group. Cardiovascular morbidity and mortality in patients with diabetes in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): A randomized trial against atenolol. Lancet. 2002;359:1004-1010.
VBWG
Renal and CV outcomes
*Doubling of baseline serum creatinine, end-stage
renal disease (IDNT, RENAAL): progression to
diabetic nephropathy (IRMA-2)
Secondary outcomes (CV)
Average duration (years)
IDNT (N = 1715)
Irbesartan 300 mg/d vs amlodipine 10 mg
20% vs placebo, (P = 0.02) and 23% vs amlodipine (P = 0.006)
Combined CV outcomes: NS
16% (P = 0.02)
3.4
Irbesartan 150–300 mg vs placebo
39% with 150 mg (P = 0.08) 70% with 300 mg (P < 0.001)
Nonfatal CV events: NS
2
The Irbesartan Diabetic Nephropathy Trial (IDNT) randomized 1715 patients with type 2 diabetes, hypertension, and nephropathy to irbesartan 300 mg, amlodipine 10 mg, or placebo.1 After a mean of 2.6 years, irbesartan reduced the primary outcome (composite of doubling of baseline serum creatinine, end-stage renal disease, or all-cause mortality) by 20% vs placebo (P = 0.02) and by 23% vs amlodipine (P = 0.006). There were no significant differences between treatments in CV outcomes.
The Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan Study (RENAAL) randomized 1514 patients with type 2 diabetes and nephropathy to losartan 100 mg or placebo.2 After a mean of 3.4 years, losartan reduced the primary outcome (composite of doubling of baseline serum creatinine, end-stage renal disease, or all-cause mortality) by
16% (P = 0.02). There were no differences between groups with regard to CV outcomes.
The Irbesartan Microalbuminuria Type 2 Diabetes in Hypertensive Patients Study (IRMA-2) assessed the effect of irbesartan 150 mg or 300 mg daily vs placebo in 590 patients with type 2 diabetes, hypertension, and microalbuminuria.3 Compared with placebo, irbesartan was associated with risk reductions in the primary outcome (time to onset of nephropathy) of 39% (150-mg group, P = 0.08) and 70% (300-mg group, P < 0.001). This study did not assess the impact of treatment on CV outcomes.
1. Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA, Lewis JB, et al; Collaborative Study Group. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes.
N Engl J Med. 2001;345:851-860.
2. Brenner BM, Cooper ME, de Zeeuw D, Keane WF, Mitch WE, Parving HH, et al; RENAAL Study Investigators. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med. 2001;345:861-869.
3. Parving H-H, Lehnert H, Bröchner-Mortensen J, Gomis R, Andersen S, Arner P, for the Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria Study Group.N Engl J Med. 2001;345:870-878.
VBWG
Yusuf S et al. Lancet. 2004;364:937-52.
Risk factor
Current smoking
Women
Men
INTERHEART is a large international study of MI risk factors with 15,152 cases (patients) and 14,820 controls. It was conducted in 52 countries and includes every inhabited continent.1
The study objective was to determine the relation of smoking, history
of hypertension or diabetes, waist/hip ratio, dietary patterns, physical activity, consumption of alcohol, blood apolipoproteins (Apo), and psychosocial factors (stress, depression) to MI. Participants were followed for 4 years. Collectively, these nine risk factors accounted for 90% of the risk for a first MI in both sexes and at all ages throughout the world.
As shown, INTERHEART recorded similar odds ratios in men and women for the association of acute MI with smoking, elevated lipid levels, abdominal obesity, composite of psychosocial variables, and vegetable and fruit consumption. However, the increased risk associated with hypertension and diabetes was greater in women than in men.
Women seemed to benefit more than men from the protective effects of exercise and alcohol.
These findings support the importance of lifestyle modification in
CV risk reduction.
1. Yusuf S, Hawken S, Ounpuu S, Dans T, Avezum A, Lanas F, et al. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): Case-control study. Lancet. 2004;364:
937-952.
VBWG
Fatal/nonfatal CV events
1989
48% MI
The Lyon Diet Heart Study randomized 605 post-MI subjects to prudent Western-style diet or to diet rich in fruits, vegetables, and fish, and incorporating an alpha-linoleic acid (ALA)-based margarine.1 After 46 months, there was 68% risk reduction in cardiac death and nonfatal MI (P = 0.0001).
The GISSI-Prevenzione study randomized 11,324 post-MI patients to placebo or 1 g/d omega-3 fatty acid fish-oil supplements.1 After 3.5 years, there was a 20% risk reduction in all-cause mortality (95% CI, 6%–33%) and 30% risk reduction in CV death (95% CI, 13%–44%).
The Indian Experiment of Infarct Survival Trial randomized 360 post-MI patients to placebo, eicosapentaenoic acid (EPA) supplement, or ALA supplement.1 After 1 year, the EPA supplement was associated with 50% risk reduction in cardiac death (P < 0.05) and 48% risk reduction in nonfatal MI (P < 0.05). The ALA supplement was associated with 40% risk reduction in cardiac events (P < 0.05)
(data not shown).
The Indo-Mediterranean Diet Heart Study randomized 1000 patients with angina, MI, or multiple risk factors to a National Cholesterol Education Program Step 1 diet or to a diet rich in whole grains, fruits, vegetables, walnuts, mustard seed, and soybean oil.1 After 2 years, the Mediterranean-style diet was associated with a 33% risk reduction in MI (P < 0.001).
The Diet and Reinfarction Trial randomized 2000 post-MI men to their usual diet or to a diet with fish consumption twice weekly (300 g total).1 After 2 years, there was 29% risk reduction in all-cause mortality and 27% risk reduction in fatal MI.
1. Parikh P, McDaniel MC, Ashen D, Miller JI, Sorrentino M, Chan V, et al. Diets and cardiovascular disease: An evidence-based assessment.
J Am Coll Cardiol. 2005;45:1379-1387.
VBWG
Parikh P et al. J Am Coll Cardiol. 2005;45:1379-87.
Trichopoulou A et al. BMJ. 2005;330:991-7.
Knoops KTB et al. JAMA. 2004;292:1433-9.
2002
(N = 2339)
related to death
†Greater adherence associated with lower mortality
The Cardiovascular Health Study followed 5201 subjects ≥65 years of age for 7 years.1 The Physicians’ Health Study followed 20,551 men for 17 years.1 Both studies found an inverse association between blood levels of n-3 fatty acids and risk of death.
The Nurses’ Health Study followed 84,688 women for 16 years.1 High consumption of fish (5 weekly) was associated with 45% risk reduction in CHD death (RR 0.55, 95% CI 0.33–0.90).
The Healthy Aging: A Longitudinal Study in Europe followed 2339 men and women, 70 to 90 years of age, from 11 European countries.2 Adherence to a Mediterranean-style diet was associated with a 23% risk reduction in 10-year all-cause mortality (HR 0.77, 95% CI 0.68–0.88).
Two reports have been published from the European Prospective Investigation into Cancer and Nutrition.3,4 Both trials quantified adherence to a Mediterranean-style diet on a scale of 0 to 9, with a higher number indicating greater adherence. Both demonstrated that greater adherence was associated with lower mortality (see next slide).
1. Parikh P, McDaniel MC, Ashen D, Miller JI, Sorrentino M, Chan V, et al. Diets and cardiovascular disease: An evidence-based assessment.
J Am Coll Cardiol. 2005;45:1379-1387.
2. Knoops KTB, de Groot LCPGM, Kromhout D, Perrin A-E, Moreiras-Varela O, Menotti A, van Staveren WA. Mediterranean diet, lifestyle
factors, and 10-year mortality in elderly European men and women:
The HALE Project. JAMA. 2004;292:1433-1439.
3. Trichopoulou A, Costacou T, Bamia C, Trichopoulos D. Adherence to a Mediterranean diet and survival in a Greek population. N Engl J Med. 2003;348:2599-2608.
4. Trichopoulou A, Orfanos P, Norat T, Bueno-de-Mesquita B, Ocké M, Peeters PH, et al. Modified Mediterranean diet and survival: EPIC-elderly prospective cohort study. BMJ. 2005;330:991-997.
VBWG
Decrease in mortality with Mediterranean diet: EPIC–elderly prospective cohort study
Trichopoulou A et al. BMJ. 2005;330:991-7.
Objective: Assess effect on mortality of modified Mediterranean diet in subjects free from CHD, stroke, or cancer
Design: N = 74,607, age ≥60 years, from
9 European countries
Dietary adherence estimated on scale of 0 (low) to 9 (high)
Follow-up: Median 89 months
8% all-cause mortality
The European Prospective Investigation into Cancer and Nutrition
(EPIC)–elderly prospective cohort study followed 74,607 men and women, ≥60 years of age, from 9 European countries.1 After a median of 89 months, each 2-point increase in adherence was associated with an 8% risk reduction in all-cause mortality.
1. Trichopoulou A, Orfanos P, Norat T, Bueno-de-Mesquita B, Ocké M, Peeters PH, et al. Modified Mediterranean diet and survival: EPIC-elderly prospective cohort study. BMJ. 2005;330:991-997.
VBWG
82
20
9
84
18
9
34
11
1
66
13
8
0
15
30
45
60
75
90
Mediterranean vs control diet
Esposito et al randomized 180 patients with the metabolic syndrome to a Mediterranean diet or to a prudent diet (carbohydrates 50% to 60%, proteins 15% to 20%, total fat <30%) for 2 years.1
The proportion of patients with 3 components of the metabolic syndrome dropped from 82% at baseline to 34% at 2 years in the Mediterranean diet group, and from 84% to 66% in the control diet group (P < 0.001 for the difference between control and Mediterranean diet). Similar trends were also demonstrated in patients with 4 and 5 components of the metabolic syndrome.
The investigators concluded that a Mediterranean-style diet is effective in reducing the prevalence of the metabolic syndrome.1
1. Esposito K, Marfella R, Ciotola M, Di Palo C, Giugliano F, Giugliano G, D’Armiento M, D’Andrea F, Giugliano D. Effect of a Mediterranean-style diet on endothelial dysfunction and markers of vascular inflammation in the metabolic syndrome: A randomized trial. JAMA. 2004;292:1440-1446.
VBWG
Diabetes Prevention Program Research Group. N Engl J Med. 2002;346:393-403.
0
0
10
20
30
40
0.5
1.0
1.5
2.0
2.5
3.2
3.5
4.0
Year
31%
58%
P
< 0.001
< 0.001
The Diabetes Prevention Program Research Group randomized 3234 persons with elevated fasting and post-load glucose concentrations to placebo, troglitazone 400 mg, metformin 850 mg twice daily, or intensive lifestyle modification, which included weight reduction ≥7% and exercise for ≥150 minutes/week.
Mean age of study subjects was 51 years; mean BMI 34.0; 68% of subjects were women; 45% of participants belonged to minority groups.
The troglitazone arm was terminated early because of concerns over
liver toxicity.
Over an average follow-up of 2.8 years, the incidence of type 2 diabetes was 11 cases per 100 person years in the placebo group versus 7.8 in the metformin and 4.8 in the lifestyle-intervention groups (data not shown). This represents a reduction of 58% in diabetes incidence with lifestyle interventions and 36% with metformin.
The effects were similar in both men and women and in all racial and ethnic groups. Intensive lifestyle intervention was at least as effective in older as in younger participants.
The results support the hypothesis that type 2 diabetes can be prevented or delayed in persons who are at high risk for the disease by treatment with metformin and lifestyle modification. Lifestyle intervention was particularly effective—1 case of diabetes was prevented per 7 persons treated for 3 years.
1. Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA, Nathan DM, for Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346:393-403.
VBWG
Diabetes. 2005;54:1150-6.
Placebo
Metformin
Lifestyle
Troglitazone*
The slide summarizes the results of the troglitazone arm up to its early termination at 1.5 years.1 As shown, there was a 75% lower incidence of new-onset diabetes in the troglitazone group than in the placebo group.
1. The Diabetes Prevention Program Research Group. Prevention of
type 2 diabetes with troglitazone in the diabetes prevention program.
Diabetes. 2005;54:1150-1156.
lifestyle intervention or metformin on development of metabolic syndrome
Orchard TJ et al. Ann Intern Med. 2005;142:611-9.
N = 3234 with impaired glucose tolerance (FG ≥95 mg/dL);
47% without metabolic syndrome at baseline
0.75
0.45
0.15
0.30
0.00
1
2
3
4
0.60
17%
51%
P*
0.03
<0.001
More recent data from the Diabetes Prevention Program show that incidence of the metabolic syndrome (as defined by ATP III criteria) was reduced by 51% in the lifestyle intervention group (P < 0.001) and by 17% in the metformin group (P = 0.03) compared with placebo.1
The investigators noted that the treatment effect associated with lifestyle intervention appeared to be most strongly related to reduction in waist circumference and BP.
1. Orchard TJ, Temprosa M, Goldberg R, Haffner S, Ratner R, Marcovina S, Fowler S, for the Diabetes Prevention Program Research Group. The effect of metformin and intensive lifestyle intervention on the metabolic syndrome: The Diabetes Prevention Program randomized trial.
Ann Intern Med. 2005;142:611-619.
0.12
0.06
0.02
0.04
0.00
1
2
3
4
0.08
0.10
Hazard
ratio
5
6
7
Placebo
Ramipril
Years
Of the original 267 centers that participated in HOPE, 174 agreed to participate in extended follow-up (HOPE-TOO), representing 4528 patients.1 All patients were given open-label ACE inhibitor (the overwhelming majority received ramipril 10 mg).
After a mean follow-up of 7.1 years in HOPE/HOPE-TOO, there was a
30% relative risk reduction in new-onset diabetes (relative risk 0.70; 95% CI, 0.57–0.86).
Over the 2.6-year period of HOPE-TOO, there was a 34% relative risk reduction in new-onset diabetes (relative risk, 0.66; 95% CI, 0.46–0.96), suggesting an incremental reduction during this period.
1. Bosch J. Extended follow-up of the ramipril component of the
Heart Outcomes Prevention Evaluation (HOPE-TOO). Presented at: European Society of Cardiology Congress 2003; September 3, 2003; Vienna, Austria. Available in: Circulation. 2005; in press.
VBWG
diagnosed diabetes
Sever PS et al. Lancet. 2003;361:1149-58.
Randomized active treatment vs control
(e.g. placebo, diuretic, or β-blocker diuretic)
ACEI or ARB
CA
A number of trials in addition to HOPE have demonstrated reduction in new-onset diabetes with newer therapies based on RAAS modulation or calcium channel blockade compared with placebo or therapies with diuretics or beta-blockers.1,2
1. Pepine CJ, Cooper-DeHoff RM. Cardiovascular therapies and risk for development of diabetes. J Am Coll Cardiol. 2004;44:509-512.
2. Sever PS, Dahlöf B, Poulter NR, Wedel H, Bevers G, Caulfield M, et al, for ASCOT investigators. Prevention of stroke and coronary events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm (ASCOT-LLA): A multicentre randomised controlled trial. Lancet. 2003;361:1149-1458.
VBWG
with RAAS modulation
Califf RM. Eur Heart J Suppl. 2003;5 (suppl C):C13-18.
Leiter LA, Lewanczuk RZ. Am J Hypertens. 2005;18:121-8.
* Diabetes Reduction Approaches with
Ramipril and Rosiglitazone Medications
Glucose Tolerance Outcomes Research
Ramipril 15 mg Rosiglitazone 8 mg Placebo
3 yrs
Impaired glucose tolerance (N = 9518)
Valsartan 160 mg Nateglinide 60 mg Valsartan 160 mg + nateglinide 60 mg Placebo
Until accrual of 1000 CV events
2007
The Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medications (DREAM) trial is underway in 5269 subjects >30 years of age with impaired fasting glucose or impaired glucose tolerance.1,2 Subjects were randomized to ramipril 15 mg, rosiglitazone 8 mg, or placebo using a
22 factorial design and followed for ≥3 years. Two consecutive fasting glucose measurements ≥7.0 mmol/L or 2-hour glucose measurements
≥11.1 mmol/L in a 3-month period will be considered diagnostic for
new-onset diabetes. An ultrasound study will also assess the effects of the treatments on progression of carotid plaque. Anticipated completion is 2006.
The Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) trial is in progress in 9518 subjects >50 years of age with impaired glucose tolerance.2,3 Subjects were randomized to nateglinide 60 mg, valsartan 160 mg, their combination, or placebo using a
22 factorial design. Primary outcome is a composite of MI, stroke,
CV death, revascularization, and hospitalization for angina or heart failure. Progression to diabetes is a secondary outcome. NAVIGATOR is CV outcome–driven and will continue until 1000 patient-events have accrued. Anticipated completion is 2007.
1. Gerstein HC, Yusuf S, Holman R, Bosch J, Pogue J; the DREAM Trial Investigators. Rationale, design and recruitment characteristics of a large, simple international trial of diabetes prevention: The DREAM trial. Diabetologia. 2004;47:1519-1527.
2. Califf RM. Insulin resistance: A global epidemic in need of
effective therapies. Eur Heart J Suppl. 2003;5(suppl C):C13-C18.
3. Leiter LA, Lewanczuk RZ. Of the rennin-angiotensin system and reactive oxygen species type 2 diabetes and angiotensin II inhibition.
Am J Hypertens. 2005;18:121-128.
Antman EM et al. J Am Coll Cardiol. 2004;44:671-719.
Class 1
RAAS modulation
ACEI for all patients (Level of evidence: A) ARB for ACEI-intolerant patients with HF or LVEF <0.40 (Level of evidence: B) Aldosterone blocker for patients on ACEI with LVEF <0.40 and HF or diabetes (Level of evidence: A)
Lipid lowering
Statins in patients with LDL-C >100 mg/dL (Level of evidence: A) or with LDL-C <100 mg/dL (Level of evidence: B)
Beta-blockade
Antiplatelet therapy
Aspirin 75-162 mg for all patients (Level of evidence: A)
ACC/AHA guidelines for the management of patients with STEMI advise the use of ACE inhibitors, beta-blockers, and aspirin in all patients at discharge (level of evidence: A).1
Statins are recommended in patients with LDL-C >100 mg/dL (level of evidence: A). Use of statins in patients with LDL-C <100 mg/dL is
given a level of evidence of B.1
1. Antman EM, Anbe DT, Armstrong PW, Bates ER, Green LA, Hand M, et al. ACC/AHA guidelines for the management of patients with
ST-elevation myocardial infarction—Executive Summary: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 1999 Guidelines for the Management of Patients With Acute Myocardial Infarction). J Am Coll Cardiol. 2004;44:671-719.
VBWG
Available at www.acc.org
Class 1
RAAS modulation
ACEI for patients with CHF, LV dysfunction (EF <0.40), hypertension, or diabetes (Level of evidence: A)
Lipid lowering
Lipid-lowering agents + diet in patients with LDL >130 mg/dL, including after revascularization (Level of evidence: A) Lipid-lowering agents if LDL-C after diet is >100 mg/dL (Level of evidence: C)
Beta-blockade
Antiplatelet therapy
Aspirin 75-325 mg/d (Level of evidence: A) Clopidogrel 75 mg/d if aspirin is contraindicated (Level of evidence: B)
ACC/AHA guidelines for management of patients with unstable angina (UA) or NSTEMI recommend ACE inhibition in patients with chronic heart failure, LV dysfunction (LVEF <40%), hypertension, or diabetes (level of evidence: A).1 The guidelines cite HOPE outcomes as supporting the consideration of ACE inhibition in these patients.
Lipid-lowering agents are recommend in patients with LDL-C >125 mg/dL (level of evidence: A) or in patients with LDL-C >100 mg/dL (level of evidence: C).
Beta-blockers (level of evidence: B) and aspirin (level of evidence:
A) are also recommended in all patients. Clopidogrel is reserved for those in whom aspirin is contraindicated (level of evidence: B).
1. Braunwald E, Antman EM, Beasley JW, Califf RM, Cheitlin MD, Hochman JS, et al; American College of Cardiology; American Heart Association; Committee on the Management of Patients With Unstable Angina. ACC/AHA 2002 guideline update for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction–summary article: A report of the American College of Cardiology/American Heart Association task force on practice guidelines (Committee on the Management of Patients With Unstable Angina).
J Am Coll Cardiol. 2002;40:1366-1374. Full text available at: www.acc.org/clinical/guidelines/unstable/unstable.pdf.
VBWG
AHA. Heart Disease and Stroke Statistics–2005 Update.
0

Documents

RAAS Modulation: Novel Strategies for Reducing Cardiovascular Risk