Coronary Artery Disease

Clinical Trial Summary Slides

 ACADEMIC
Trial Design: Randomized controlled trial of Azithromycin (500 mg/d for 3 days, then 500 mg/wk
for 3 mo.) vs. placebo for secondary prevention of CAD in patients with positive C.
Pneumoniae titers. The two primary endpoints were: 1) global measurements of systemic
levels of CRP, IL-1, IL-6, TNF-alpha at 6 mo. and 2) combined endpoint of adverse
cardiovascular (CV) events at 2 yrs.
Results
40 700 • Azithromycin threapy associated with
Adverse CV reduction of a global score of 4
Global Inflammatory
Events inflammatory markers as well as in a
650 Score
HR 0.89 (0.51-1.61) p = 0.011 significant decline in global scores
Number of events

30 p = 0.74 Average Ranksum score from baseline at 6 months (p=0.011,

598 p=0.027, respectively).
25 600
• No significant differences in clinical
22 CV endpoints at up to 2 yrs.
20 550 532 Conclusions
• AZ threapy for secondary prevention
of CAD in patients with C. Pneumoniae
500 serologies may reduce inflammation,
10 but has no evident clinical CV effects in
this trial.
450
Limitations
n=150 n=152 n=150 n=152 • Study may have been underpowered
0 400 to detect a difference in clinical events
AZ Placebo AZ Placebo
between arms.
www.cardiosource.com Circulation 1999; 99: 1540-7; Circulation 2000; 102: 1755-60
 ACES
Trial Design: ACES was a multi-center, randomized, double-blind trial of the antibiotic azithromycin (600 mg
once weekly for 1 year; n=2004) or placebo (n=2008) among patients with stable coronary artery disease.
Primary endpoint was composite of coronary heart disease death, MI, coronary revascularization or
hospitalization for unstable angina at mean follow-up of 4 years.

Primary Composite CHD Death Results

30 p = NS 5 p = NS • Concomitant medications at baseline included statins
(76%), aspirin (87%) and beta-blockers (60%)
• No difference in primary composite endpoint of CHD
death, MI, revascularization or hospitalization for unstable
22.4 4
22.3 3.7 angina (Figure)
• Also no difference in any component of composite
20 3.2
endpoint, including CHD death (3.2% vs 3.7%), MI (6.8%
3 vs 6.5%), coronary revascularization (19.0% vs 18.4%) or
%

hospitalization for unstable angina (2.5% vs 2.7%) or

composite of CHD death or MI (9.5% vs 9.3%)
2 Conclusions
10 • Among patients with stable coronary artery disease,
secondary prevention treatment with the antibiotic
azithromycin was not associated with a reduction in
1
coronary events compared with placebo
• Lack of benefit with antibiotic therapy in present trial
similar to findings seen in PROVE-IT and WIZARD trials
0 0 • Given consistent lack of benefit with antibiotics for
widespread secondary prevention in ACS, therapy will
Azithromycin Placebo likely continue to be directed toward other methods of
prevention including high-dose statins and ACE inhibitors
www.cardiosource.com Presented at ESC 2004
 ACTIVATE
Trial Design: ACTIVATE was a randomized trial of pactimibe (100 mg per day for 18 months) (n=266), a novel
enzyme ACAT inhibitor, or placebo (n=268) among patients with symptomatic coronary artery disease. Primary
endpoints was change in percent atheroma volume on IVUS at 18 months.
Change in Percent Change in Absolute
Results
Atheroma Volume Atheroma Volume
at 18 months at 18 months • No difference in primary endpoint by treatment group,
1.0 with progression in both groups (Figure)
p = 0.77 p = 0.04
• For change in absolute total atheroma volume, placebo
0 group had more regression than pactimibe group (Figure)
0.8 • No difference in the composite of CV death, non-fatal MI,
0.69 stroke, hospitalization for unstable angina, or coronary or
carotid revascularization (26.5% vs 23.8%, p=0.53)
0.59 -1.3
0.6 Conclusions
-2
• Among patients with symptomatic coronary artery
%

disease, treatment with novel ACAT inhibitor pactimibe

mm 3

0.4 was not associated with reduction in atherosclerosis

progression compared with placebo at 18 month follow-up
-4 • Actually more disease regression with placebo than with
0.2
pactimibe in secondary endpoint of absolute atheroma
volume
• Given pro-atherogenic findings with pactimibe, future of
ACAT inhibition as target treatment for atherosclerosis is
0.0 -6 -5.6
unclear, although it is possible that changes in balance
between ACAT 1 and ACAT 2 inhibition could produce
Placebo Pactimibe
different results
www.cardiosource.com Presented at AHA 2005
 BRAVO
Trial Design: BRAVO was a randomized, double-blind trial comparing the oral GP IIb/IIIa antagonist lotrafiban
(30-50 mg/d; n=4,600) vs placebo (n=4,590) among patients with coronary and cerebrovascular disease.
Patients were to be treated for 2 years. The primary endpoint was the composite of death, MI, stroke, recurrent
ischemia requiring hospitalization, and urgent revascularization.
Mortality Primary Endpoint * Results
Serious bleeding
HR 1.33 HR 0.94 p<0.001 • Trial discontinued early due to  mortality in
p=0.026 p=0.19 lotrafiban arm (Figure); cause of excess death
20 10 primarily vascular related
17.5 • Cerebrovascular disease in 41% of patients at
3.0 enrollment
3 16.4 8.0
8 • Primary endpoint did not differ significantly
15 between lotrafiban and placebo arms
2.3 • Serious bleeding  in lotrafiban arm (8.0% vs
% 2.8%, p<0.001), and was more frequent in
%

6
patients who received higher doses of aspirin
%

2
10 (>162 mg/d), with or without lotrafiban
Conclusions
4 • Among patients with coronary and
2.8 cerebrovascular disease, treatment with the oral
1 GP IIb/IIIa lotrafiban was not associated with a
5
2 difference in primary endpoint, but lotrafiban
was associated with  in mortality, prompting
the trial to be discontinued early
• Similar increases in mortality observed in
0 0 0
earlier trials of oral GP IIb/IIIa inhibitors in
Lotrafiban Placebo patients with acute coronary syndromes
* Death/MI/stroke/recurrent ischemia
www.cardiosource.com requiring hospitalization/urgent revascularization Circulation 2003;108(4):399-406
 CAMELOT
Trial Design: CAMELOT was a randomized, double-blinded, placebo-controlled trial (n=1991) of
the effects of amlodipine or enalapril compared to placebo in normotensive patients with
coronary artery disease. Primary endpoint: Adverse cardiovascular events (composite of CV
death, nonfatal MI, resuscitated cardiac arrest, coronary revascularization, hospitalization for
angina or CHF, stroke/TIA, and any new diagnosis of peripheral vascular disease).
Results
Adverse CV Change in • Mean blood pressure ↓ 4.8/2.5 mmHg in amlodipine
40 10
Events %Atheroma group, ↓ 4.9/2.4 mmHg in enalapril group, and ↑
p<0.003 for Volume 0.7/0.6 mmHg in placebo group (p<0.001 for both
amlodipine p=NS for
treatments vs placebo)
8 • CV events ↓ in amlodipine group compared to
30 vs. placebo comparison
between groups enalapril (HR 0.81, p=0.1) and placebo (HR 0.69,
p=0.003; HR=0.85 for enalapril vs placebo, p=0.16)
23.1
6 (Figure)
%

20.2
20
• In patients undergoing IVUS, no significant change
4.4
16.6 from baseline in amlodipine group (p=0.31), a trend
3.9
4 3.7 towards progression of atheroma in enalapril group
(p=0.08), and progression in placebo group (p=0.001)
10 Conclusions
2 • Among patients with CAD and relatively normal
blood pressures, treatment with amlodipine but not
enalapril was associated with a reduction in the
0 0 composite primary endpoint of CV events compared
to placebo, largely driven by a reduction in coronary
Placebo Enalapril Amlodipine revascularization and hospitalization from angina

www.cardiosource.com JAMA 2004;292:2217-25

 CARISA
Trial Design: The CARISA trial was a randomized, double-blind trial of ranolazine (750 mg 2x/d; n=279),
ranolazine (1000 mg 2x/d; n=275), or placebo (n=269) in patients with symptomatic chronic angina already
treated with other anti-anginal drugs. The primary endpoint was treadmill exercise duration at trough
ranolazine levels (i.e., 12 hours after last dosing).
Results
Trough exercise Time to onset of angina
duration 750 mg vs placebo, p=0.01 • Trough exercise duration  by 115.6 sec from baseline in
750 mg vs placebo, p=0.03 1000 mg vs placebo, p=0.03 both ranolazine groups (pooled) vs 91.7 sec in placebo
1000 mg vs placebo, p=0.03
160 group (p=0.01; Figure)
144.0
140.3
• Time to angina (Figure) and to electrocardiographic
115.4 115.8 ischemia also  in ranolazine groups at both peak and
120
trough
120 114.3 • Angina frequency significantly  from baseline by ~1
91.7 attack/week with each dose tested vs placebo
• Minimal differences in systolic blood pressure and heart
rate, with an average reduction in blood pressure of ~3 mm
seconds

seconds

80
80 (p0.05) and 2 beats/min heart rate with 1,000mg dose
• No difference in serious adverse events (6%-7% of
patients in each of the 3 groups
Conclusions
40
40 • Among patients with symptomatic chronic angina already
treated with anti-anginal drugs, treatment with ranolazine
was associated with an improvement in exercise duration,
time to onset of angina, and time to ischemia
0 0 • Results similar to MARISA trial which tested ranolazine
Placebo 750 mg ranolazine monotherapy

www.cardiosource.com 1000 mg ranolazine JAMA. 2004;291:309-316

 CARP
Trial Design: CARP (n=510) was a multicenter, VA-based randomized trial of revascularization
vs medical management prior to elective vascular surgery in stable patients with angiographic
evidence of coronary artery disease. Primary endpoint: Long-term mortality through study
period (median follow-up 2.7 years).

Results
Mortality at Postoperative • One third of patients were scheduled for abdominal
follow-up MI aortic aneurysm surgery
30 20
p=NS p=NS • No difference in primary endpoint of long-term
mortality by study arm (Figure)
22.0
23.0 • No significant differences between study groups in
14.3
15 30-day mortality (3.1% vs. 3.4%, p=0.82) or post-
20 operative MI (Figure)
11.6
• Delay in time to performance of vascular surgery
%

longer in revascularization arm (54 days vs 18 days in

10
medical therapy arm, p<0.001)
Conclusions
10 • Routine revascularization prior to elective vascular
5 surgery not associated with improved outcomes
compared to aggressive medical management
• Results support current ACC/AHA guidelines which
recommend revascularization in high risk/unstable
0 0 patients or patients who require revascularization
Revasc Medical Therapy independent of surgery being performed

www.cardiosource.com Presented at AHA Scientific Sessions 2004

 CHARISMA
Trial Design: CHARISMA was a randomized, double-blind trial of clopidogrel (n=7802; 75 mg daily) or placebo
(n=7801), on top of background therapy with aspirin (75-162 mg once daily) among high-risk patients with
stable cardiovascular disease. Primary endpoint was composite of cardiovascular death, MI, or stroke. Median
follow-up was 2.3 years.
Death, MI, stroke or Results
CV death, MI, or stroke hospitalization for ischemic event • No difference in primary endpoint of CV death,
RR 0.93 RR 0.92
10 20 MI, or stroke between clopidogrel plus aspirin
p = 0.22 p = 0.04
17.9 group and placebo plus aspirin group (Figure)
16.7 • Secondary endpoint ↓ in clopidogrel plus aspirin
8 group (Figure)
7.3 • Benefit of clopidogrel evident in symptomatic
15
6.8
cohort for primary endpoint (6.9% vs 7.9%, RR
0.88, p=0.046) but not in asymptomatic cohort
6
(6.6% vs 5.5%, RR 1.20, p=0.20)
%
%

10 • In asymptomatic cohort, mortality ↑ in clopidogrel

group (5.4% vs 3.8%, p=0.04)
4
• Moderate bleeding ↑ in clopidogrel group (2.1%
vs 1.3%, p<0.001)
5 Conclusions
2
• Among high-risk patients with stable CV disease,
dual antiplatelet therapy with aspirin plus
clopidogrel was not associated with a difference in
0 0 CV death, MI, or stroke compared to aspirin
monotherapy
Clopidogrel Placebo

www.cardiosource.com N Engl J Med 2006;354:epub before print

 CIAO
Trial Design: CIAO was a randomized trial of PCI with heparin (70 IU/kg) or placebo (saline) in patients
undergoing elective PCI. Heparin could be used in both groups to flush the catheters. Patients were followed
for 6 months.
Results
Manual Compression Coronary Complications
• Mean procedure time was 11 minutes
Time p < 0.05
15 p < 0.05 • GP IIb/IIIa inhibitors were not used in either arm
6
• Manual compression was longer in the heparin
13.1 5.2 group (Figure)
• Coronary complications ↑ in the heparin group
(Figure), all of which were dissections in the
heparin arm
10 4 • No cases of guiding catheter thrombosis in
either group
%

• No difference in CK-MB elevation

%

5.4
5 2
0 0
Heparin
www.cardiosource.com
Conclusions
• Among patients undergoing elective PCI for
2.2 stable angina, PCI without IV heparin was not
associated with increased complications or
adverse events compared to PCI with heparin
• However, it should be noted that this was a
small, single-center trial conducted in very low-
risk patients
• Larger, multicenter, randomized trials are
needed before this technique should be
No Heparin considered an alternative
Presented at TCT 2006
 COURAGE
Trial Design: COURAGE was a randomized trial of optimal medical therapy alone (n = 1,138) or PCI in addition
to optimal medical therapy (n = 1,149) in patients with stable but severe coronary artery disease. Primary
endpoint was composite of death or nonfatal MI through median 4.6-year follow-up.

Death or MI Freedom From Angina Results

(HR 1.05, at 5 Years • Multivessel disease present in 69% of patients at entry
p = 0.62) (p = 0.35) • No difference in primary endpoint of death or MI for
25 100
PCI group vs. medical therapy group (Figure),
components of composite, or hospitalization for ACS
(12.4% for PCI vs. 11.8% for medical therapy, HR 1.07,
20 19.0 18.5 80 74 p = 0.56)
72
• Angina significantly ↓ in both groups during follow-up,
%

with no difference between PCI and medical therapy at 5

15 60 years (Figure), but slightly ↑ rates of freedom from
angina in early time frame with PCI
%

• PCI costs averaged $5,295 ↑ than medical therapy

10 40 through 3 years (p < 0.0001)
• In cost-effectiveness analysis, PCI was estimated at
$217,000 per quality-adjusted life-year gained; $50,000
often used as benchmark for acceptable C/E therapies
5 20
Conclusions
• Among patients with stable but severe coronary artery
disease, treatment with PCI was not associated with a
0 0
difference in death or MI compared with medical therapy
Optimal Medical Optimal Medical through 5 years of follow-up, but was associated with
Therapy + PCI Therapy Alone much higher costs
www.cardiosource.com N Engl J Med 2007;356:1503-1516
 CREATE
Trial Design: CREATE was a randomized, 2 x 2 factorial trial in patients with coronary artery disease (CAD) and
major depression evaluating interpersonal psychotherapy (IPT) for 12 weeks in addition to clinical
management (n = 142) or clinical management only (n = 142). In the other factor, patients were randomized to
the SSRI citalopram (20 to 40 mg/day; n = 142) or placebo (n = 142). Primary endpoint was change from
baseline to 12 weeks on the Hamilton Depression Rating Scale (HAM-D).

Reduction in mean HAM-D at 12 weeks Results

20 20 • Mean HAM-D score at baseline was 30
p = 0.005 p = 0.06
• Primary endpoint of reduction in mean HAM-D
score improved in citalopram group vs. placebo but
14.9 did not differ for IPT vs. clinical management
15 15 14.4 (Figure)
12.1 • Results similar for secondary endpoint of
11.6 reduction in mean BBI-II score
• Neither blood pressure nor ECG variables such
10 10 as mean QTc interval differed between citalopram
and placebo groups
Conclusions
5
• Among patients with CAD and major depression,
5
treatment with the SSRI citalopram was associated
with larger improvement in depression compared
with placebo at 12 weeks
0 0 • No difference in improvement in depression for
Citalopram Placebo Clinical comparison of IPT and clinical management
IPT
Management JAMA. 2007;297:367-379
www.cardiosource.com
 DAIS
Trial Design: DAIS was a randomized placebo-controlled trial (n=418) designed to assess
whether correcting lipoprotein abnormalities with fenofibrate (200 mg/day) in patients with type
2 diabetes would decrease the rate of angiographic progression of coronary artery disease.
Primary endpoint: Change in mean coronary artery segment diameter (mm).
Results
-0.20 -0.20
• Half of study patients had history of prior CAD.
 Minimum  Mean
• Total cholesterol, LDL, and triglycerides significantly 
Lumen Segment
and HDL significantly  in fenofibrate arm compared to
Diameter Diameter
placebo (p<0.001 for each).
-0.15 -0.15 • Fenofibrate was associated with smaller decrease in
minimum lumen diameter (-0.06 vs. -0.10 mm, p=0.029),
P=0.029 P=0.171
smaller increase in % diameter stenosis (2.11 vs. 3.65%,
-0.10 p=0.02), and a nonsignificantly smaller decrease in
-0.10 -0.10 primary endpoint of mean segment diameter (-0.06 vs. -
-0.08 0.08 mm, p=0.171).
mm
mm

• There was a mild correlation between angiographic

-0.06 -0.06 changes and changes in lipid profiles; effect of fenofibrate
-0.05 was similar in all subgroups.
-0.05
Conclusions
• Although the primary endpoint was not significantly
different between groups, the reduced rates of disease
0.00 0.00 progression measured by parameters of focal disease
including % diameter stenosis and min lumen diameter
Placebo Fenofibrate
suggests that lipid-lowering therapy in diabetics can result
in the slowing of focal coronary atherosclerotic disease.
www.cardiosource.com Lancet 2001; 357: 905-10
 Duke Database: Treatment for Symptomatic CAD
Trial Design: This report describes outcomes of patients within a large single-center
prospective observational registry of patients with symptomatic CAD (n=9,263) referred
for cardiac catheterization and treated with a strategy of medical therapy, PTCA, or
CABG. The primary endpoint was 5-year adjusted survival.
Results
1 Vessel 2 Vessel 3 Vessel
• Medically treated patients had highest
100 Disease Disease Disease
prevalence of CHF and other comorbidities
94 95 93 • There was  disease extent in PTCA group, and
 severe disease in CABG group
5-year Adjusted Survival

91 91
90 89 Conclusions
86 • Data support survival advantage of CABG over
medical therapy for severe forms of multivessel
81 disease, and suggest modest survival trend for
80 PTCA over medical therapy in patients with milder
forms of disease
• Despite carefully adjust for baseline imbalances
72
between treatment groups and for potential bias in
70 treatment strategies based upon these
imbalances, an important limitation of this analysis
is the non-randomized comparison between
treatments
60 • This study was completed prior to widespread
Medical PTCA CABG use of stenting
n = 3557 n = 2626 n = 3080
www.cardiosource.com Circulation 1994; 89(5): 2015-2025
 ENCORE-I
Trial Design: ENCORE-I was a multicenter randomized trial of nifedipine 30-60 mg/d (n=84), cerivastatin
0.4 mg/d (n=85), and their combination (n=89) vs placebo (n=85) in patients with coronary artery disease
(CAD) undergoing PCI. The primary endpoint was change in acetylcholine-induced coronary vascular
response at the highest dose of acetylcholine on the most constricted segment at 6 month follow-up.
Results
30 Change in acetylcholine-induced
• Change in mean luminal diameter in most
vasoconstriction
constricted segment from baseline in response to
acetylcholine larger in nifedipine arm vs placebo but
not cerivastatin or combo arm
p=0.04
• Change in all segments improved in nifedipine arm
20 18.8 and in combo arm vs placebo but not cerivastatin arm
p=NS p=NS • Smaller improvement in patients not taking ACE-I in
placebo group vs those taking ACE-I (6.0+/-3.6% vs
%

12.9 21.2+/-8.0%, p=0.11)

10.0 11.1 Conclusions
• Among patients with CAD undergoing PCI, treatment
10 with nifedipine but not cerivastatin improved coronary
endothelial function in the most constricted segment
at 6 month follow-up
• ENCORE-II underway to detect effects of nifedipine
on coronary morphology
0 Limitations
Placebo Nifedipine Cerivastatin Cerivastatin • Cerivastatin withdrawn from market due to possible
+Nifedipine cases of fatal rhabdomyolysis
www.cardiosource.com Circulation. 2003;107:422-428
 ENCORE II
Trial Design: ENCORE II was a randomized trial of the calcium antagonist nifedipine (30-60 mg) plus statin
therapy on coronary endothelial function compared with statin therapy alone among patients with coronary
heart disease. Primary endpoint was change in minimum lumen diameter (MLD) in response to acetylcholine
at 18-24 month follow-up.
Change in MLD Atheroma volume
Results
in response to on IVUS
25 6 • Primary endpoint of percent change in MLD in response
acetylcholine p = 0.594
5.4 to acetylcholine  in nifedipine arm vs control (Figure)
p = 0.0007
• In the subset of patients enrolled after cerivastatin use
20 was discontinued, difference in primary endpoint was
18.3
larger (17.5% for nifedipine vs 0.95% for control,
4 p<0.0001)
15
• No difference in atheroma volume on IVUS by treatment
3.2 group (Figure) or in absolute change in atheroma volume
%

(-2.1 vs 3.0 mm3, p=NS)

Conclusions
10
• Among patients with coronary heart disease, treatment
6.9 2
with nifedipine plus statin therapy was associated with
improvement in primary endpoint of coronary endothelium
5
function at 18-24 months compared with statin therapy
alone but was not associated with plaque size on IVUS
• These data confirm results in ENCORE I, which also
0 0 showed improvement in endothelial function associated
with nifedipine plus statin therapy
Nifedipine Control

www.cardiosource.com Presented at ESC 2004

 EPAT
Trial Design: The EPAT trial was a randomized, double-blind trial of unopposed estrogen replacement therapy
(ERT) with estradiol (1 mg/d) (n=97) versus placebo (n=102) in healthy postmenopausal women without pre-
existing cardiovascular disease. Patients were followed for 2 years. The primary endpoint was annualized
progression rate of carotid IMT at follow-up.
Annualized Progression Rate of Carotid IMT Results
All Patients No Lipid-lowering Lipid-lowering • Primary endpoint of carotid IMT progression  in
p=0.046 Therapy Therapy estradiol arm vs placebo (Figure)
p=0.002 p=NS • In subgroup analysis, carotid IMT progression  in
0.014 0.0134 estradiol arm vs placebo among patients who did not
receive lipid-lowering therapy (n=77) but did not differ
0.012
in patients who received lipid-lowering medication
(Figure)
• No difference between treatment groups in
0.010
cardiovascular events (9 events in 7 subjects)
mm/y

• Pill compliance high in both arms (92% placebo vs

0.008
95% estradiol, p=0.08)
Conclusions
0.006
• Among healthy postmenopausal women without pre-
0.0036 existing cardiovascular disease, treatment with
0.004
unopposed ERT estradiol was associated with
reduction in carotid IMT progression through 2 years
0.002
of follow-up
• However, given negative findings of clinical
0.000 outcomes associated with hormone replacement
therapy in HERS, ERA and WHI trials, results of the
-0.002
-0.0017
-0.0013
-0.0019 -0.0016
present trial should be interpreted cautiously

www.cardiosource.com Estradiol Placebo Ann Intern Med. 2001;135:939-953

 EUROACTION
Trial Design: EUROACTION was a randomized trial of usual care (n = 2,613 patients and 1,634 partners) or
EuroAction intervention program (n = 2,778 patients and 1,632 partners) in patients with or at high risk for
coronary heart disease and their partners. Patients were followed for 1 year to assess adherence to lifestyle,
risk factor, and therapeutic goals for CV disease prevention of the Joint European Societies’ Guidelines.
Met Recommended Fruit and
Results
Vegetable Intake Guidelines
• More patients in the intervention group met
Coronary Disease High-Risk Cohort recommended fruit and vegetable intake
Cohort guidelines (Figure) as did their partners
100 100
• Other improvements with intervention group
included reduced consumption of saturated fat
80
78 to <10% of caloric intake, increased
80
72 consumption of oily fish, increased physical
%

activity targets, and increased blood pressure

60
targets
60
Conclusions
• Among patients with or at high risk for coronary
39 heart disease and their partners, use of nurse-
40 35 40
led prevention intervention program was
associated with improvements in lifestyle
20 20 modifications compared with usual care
• Present trial is one of first large-scale behavior
modification/risk reduction studies to target not
0 0 only coronary heart disease patients, but also
partners of these patients
Intervention Usual Care
www.cardiosource.com Presented at ESC 2006
 EUROPA
Trial Design: EUROPA was a randomized, double-blind trial of the ACE-inhibitor perindopril (8 mg/day, n=6,110)
vs placebo (n=6,108) among low-risk patients with stable coronary artery disease. Patients were followed for a
mean of 3.4 years. The primary endpoint was cardiovascular mortality, non-fatal MI, and cardiac arrest.
Results
CV death/non-fatal MI/ CV Mortality • 80% of patients remained on treatment at 3 years
cardiac arrest p=0.107 • Systolic blood pressure  5 mm Hg and diastolic
12 p=0.0003 5 blood pressure  2 mm Hg in the perindopril arm
• Primary composite endpoint of cardiovascular
9.9 4.1 mortality, non-fatal MI, and cardiac arrest  in
perindopril arm vs control (Figure)
4
3.5 • Among the components of composite, CV death
8.0 (Figure) and cardiac arrest (0.1% vs 0.2%) were not
8 significantly reduced but nonfatal MI  with
%

3 perindopril (4.8% vs 6.2%, p=0.001)

%

Conclusions
• Among patients with stable coronary artery disease,
treatment with the ACE-I perindopril was associated
2
with a reduction in the primary endpoint of
4 cardiovascular mortality, non-fatal MI, and cardiac
arrest compared with placebo
1 • ACE inhibitors previously shown to be effective in
other patient populations, including heart failure, left
ventricular dysfunction, and high-risk coronary artery
disease (CAD) patients
0 0 • Present trial largest to show benefit in stable, low-
Perindopril Placebo risk CAD patients
www.cardiosource.com Presented at ESC 2003; Lancet 2003 362: 782-88
 FRISC II
Trial Design: FRISC II was a multicenter randomized trial comparing the LMW heparin
dalteparin to placebo in patients with unstable CAD (n=2267), and comparing an invasive vs
conservative treatment strategy (n=2457). Mean follow-up was 6 months. Primary endpoint
was death or MI at 3 months.

Death or MI Death or MI Results

at 3 months at 6 months • Death MI  in dalteparin arm at 1 month but not 3
15 p=0.17 p=0.03 months
12.1 • Major bleed (3.0% vs 1.8%) and ICH (0.8 vs. 0%)
↑ with dalteparin
10 9.4
8.0 • Death/MI ↓ in invasive strategy (Figure), as was
%

6.7 MI alone (7.8% vs. 10.1%), but mortality (1.9 vs.

2.9%) not statistically significant
5
Conclusions
• Among patients with unstable coronary artery
disease, treatment with dalteparin was not
0
associated with a reduction in death or MI
n= • Early invasive strategy, however, was associated
Dalteparin Invasive with reduction in death or MI
Placebo Non-invasive
www.cardiosource.com Lancet 1999; 354: 701-7
 FRISC-II: Late Follow-Up
Trial Design: FRISC-II was a randomized trial of an early invasive (angiography +/- revascularization) vs a
conservative management strategy in patients with unstable coronary artery disease. Primary endpoint was
death or MI at 6 months. Patients were followed for 5 years.

Death Death or MI Results

15 at 5 years at 5 years • By 5 years, revascularization performed in
30
p=0.69 p=0.009 80% of invasive group and 52% of conservative
group
24.5 • Death ↓ in invasive strategy at 2 years (3.7%
vs 5.4%, p=0.038), but no difference in death at
10.1 5 years (Figure)
9.7 19.9
10 20 • Composite of death or MI ↓ in invasive strategy
(Figure), driven by reduction in MI (12.9% vs.
%

5 10
0 0
Invasive Strategy
www.cardiosource.com
17.7%, p = 0.002)
• Reduction in death or MI restricted to higher
risk patients, with no benefit in patients with
FRISC risk score of 0-1 (10.3% for invasive
strategy vs 8.2% for conservative strategy)
Conclusions
• Among patients with unstable angina, early
invasive approach was associated with
reduction in mortality at 2 years compared with
conservative management strategy, but these
findings not maintained through 5 years, when
there was no difference in death between
Conservative Strategy
treatment strategies
Presented at ESC 2006
 HERS
Trial Design: HERS was a multicenter randomized trial of estrogen + progestin (n=1,380) compared to
placebo (n=1,383) in prevention of coronary heart disease (CHD) events in postmenopausal women
with established CHD. Average follow up was 4.1 years. Primary endpoint was CHD death or nonfatal
MI.
CHD events
Results
HR 0.99 (0.8-1.22)
200 • No difference in CHD events between groups
(Figure)
172 176
• Patients in HRT arm had 11%  LDL and 10% 
Gallbladder HDL (p<0.001 each)
150 Disease • Venous thromboembolic events  in HRT
# of events

HR 1.38 (1.0-1.92) group, as was gallbladder disease (Figure)

Conclusions
100 84 • Among post-menopausal women with
VTE established CHF, use of HRT was not associated
HR 2.89 (1.5-5.58) 62 with  CHD events was associated with  risk of
VTE and gallbladder disease
50 34 • Based on findings of no overall cardiovascular
benefit and possible increased adverse events,
12
HRT for secondary prevention of CHD not
0 recommended

HRT Placebo
www.cardiosource.com JAMA 1998;280(7):605-13
 HIT
Trial Design: Double-blind placebo controlled prospective randomized trial (n=2531) designed to
assess whether treatment with Gemfibrozil would reduce the incidence of death from coronary
artery disease and nonfatal myocardial infarction in patients with CAD with low levels of both HDL
and LDL an moderately elevated triglycerides. Median follow-up was 5.1 years.

Nonfatal MI or Nonfatal M, Stroke, Results

Death from CAD or Death from CAD • Overall compliance with treatment 75%
30 P=0.006 30 P<0.001 • At one year mean HDL 6%  in Gemfibrozil group
compared to placebo (34 mg/dl vs. 32 mg/dl, p<0.001),
26.0
mean cholesterol level 4%  (170 mg/dl vs. 177 mg/dl,
25 25
p<0.001), mean triglyceride level 31%  (115 mg/dl vs.
21.7
20.4 166 mg/dl, p<001), while mean LDL was 113 mg/dl in
20 20 both groups
17.3
• Death from coronary artery disease or nonfatal MI  in
%

15
Gemfibrozil group (Figure), as was combined outcome of
15
death due to CAD, nonfatal MI or stroke (Figure)
• Only side effect more commonly in Gemfibrozil group
10 10 was dyspepsia
Conclusions
5 5
• Among patients with coronary artery disease and low
1267 1264 1267 1264 HDL levels but without high LDL levels, treatment with
0 0 the lipid-lowering agent Gemfibrozil was associated with
a reduction in the risk of death from coronary artery
Placebo Gemfibrozil disease or nonfatal myocardial infarction by 22%
compared with placebo
www.cardiosource.com N Engl J Med 1999;341;410-8
 HOPE-2
Trial Design: HOPE-2 was a randomized, double-blind trial of treatment with folic acid 2.5 mg, vitamins B6 50
mg and B12 1 mg (n = 2,758), or placebo (n = 2,764) among patients with pre-existing cardiovascular (CV)
disease or diabetes. Primary endpoint was composite of CV death, MI, or stroke. Mean follow-up was 5 years.

CV Death, MI, or Stroke Stroke Results

(RR 0.95 (RR 0.75 • Baseline homocysteine levels 12.2 µmol/L; ↓ to
25 p = 0.41) 6
p = 0.03) 9.9 µmol/L at 2 years in folic group
• No difference in primary endpoint of CV death,
5.3
MI, or stroke between folic group and placebo
19.8 plus aspirin group (Figure)
20 18.8
• Stroke ↓ in folic group (Figure)
4.0 • No difference in cancer (13.0% vs. 12.3%, RR
4
1.06, p = 0.47) or cancer death (3.4% each)
15
between treatment groups
%
%

Conclusions
• Among patients with pre-existing CV disease or
10
diabetes, treatment with homocysteine lowering
2 vitamins folic acid and vitamin B were not
associated with reduction in composite of death,
5 MI, or stroke at 5-year follow-up compared with
placebo
• Despite reducing homocysteine concentrations
0 0 by ~25%, there was no apparent clinical benefit
with folic acid and vitamin B treatment on CV
Folic Vitamin Placebo events, with the exception of reduction in stroke
www.cardiosource.com N Engl J Med 2006;354:1567-77
 ILLUSTRATE
Trial Design: ILLUSTRATE was a randomized, double-blind trial of torcetrapib (60 mg; n = 591), a cholesteryl
ester transfer protein (CETP) inhibitor, in addition to atorvastatin vs. atorvastatin alone (n = 597) in patients
with coronary disease. Patients underwent IVUS at baseline and 24 months. Primary endpoint was change in
percent atheroma volume. Results
CHD Death, MI, Stroke,
• HDL at follow-up ↑ in torcetrapib group vs. atorvastatin
Change in Percent Hospitalization for UA, alone group (72.1 mg/dl vs. 43.9 mg/dl, p < 0.001)
Atheroma Volume 30 or Coronary
0.3
(p = 0.72) Revascularization • BP ↑ in torcetrapib group by 6.5/2.8 mm Hg
(p = NS) • No difference in primary endpoint of change in percent
atheroma volume (Figure)
• Mortality was 1.4% in torcetrapib group and 1.0% in
21.0 atorvastatin alone group
0.19 19.6
0.2 20 • Clinical composite endpoint did not differ between
groups (Figure)
• Blood pressure-related adverse events ↑ in torcetrapib
%

group (23.7% vs. 10.6%)

0.12
Conclusions
0.1 10 • Among patients with coronary disease, treatment with
CETP inhibitor torcetrapib in addition to atorvastatin was
not associated with a difference in change in percent
atheroma volume compared with atorvastatin alone at
24-month follow-up
• No effect on atherosclerosis progression, despite
0.0 0 having expected impact on ↑ HDL and ↓ LDL
Torcetrapib Control • Commercial development of torcetrapib recently halted
after large trial showed ↑ in mortality with torcetrapib
www.cardiosource.com N Engl J Med 2007;356:1304-16
 IMAGINE
Trial Design: IMAGINE was a randomized trial of the ACE-inhibitor quinapril (up to 40 mg daily) (n=1,280) or
placebo (n=1,273) in patients early (within 7 days) following coronary bypass surgery. Primary endpoint was
Composite of CV death or resuscitated cardiac arrest, nonfatal MI, coronary revascularization, hospitalization
for unstable angina, documented angina not requiring hospitalization, stroke, or heart failure requiring
hospitalization at median 3 year follow-up.
CV death or
2 Results
resuscitated cardiac arrest
• Time from surgery to randomization 4 days
p=NS
• No significant difference in primary composite endpoint by
1.6
treatment group, but was directionally ↑ in quinapril group
(HR 1.15, p=0.21)
1.3 • No difference in any component of composite endpoint,
including CV death or resuscitated cardiac arrest (Figure)
• Primary endpoint showed ↑ risk in quinapril group vs
%

1 placebo during first 3 months following CABG (HR 1.52,

p=0.04), but no difference after 3 months (HR 1.08, p=0.52)
Conclusions
• Among patients undergoing CABG, initiation of ACE
inhibitor quinapril early post-surgery was not associated
with difference in primary composite endpoint compared
with placebo at median 3 year follow-up, with data
suggesting possible increased risk during first 3 months
0 following surgery

Quinapril Placebo

www.cardiosource.com Presented at ESC 2005

 INVEST
Trial Design: INVEST was a randomized, open label trial of treatment with the calcium antagonist
verapamil SR (n=11,267) or the non-calcium antagonist atenolol (n=11,309) in patients with hypertension
and coronary artery disease. Patients were followed for a mean of 2.7 years. The primary endpoint was
non-inferiority for the composite of all-cause mortality, non-fatal MI or non-fatal stroke.
Death/MI/Stroke Results
RR 0.98 Death Stroke • Trial met pre-specified hypothesis of non-inferiority
12 p=0.57 p=0.72 p=0.33 with verapamil for death, MI or stroke (Figure0
• No difference in any component of composite
9.9 10.2 • New onset diabetes  in verapamil arm (7.03% vs
10 8.23%, p<0.05)
• Primary endpoint+new onset diabetes  in
7.8 7.9 verapamil arm (14.63% vs 16.25%, p<0.05)
8 • More than half of patients using >3 drugs at follow-
up (51% and 52%, respectively)
6 Conclusions
• Among hypertensive CAD patients, treatment
%

strategy with calcium antagonist verapamil was non-

4 inferior for all-cause mortality, MI and stroke
compared with treatment with a non-calcium
antagonist strategy with atenolol
2 1.2 1.3 •drugs
Majority of patients in each arm treated with >3
at follow-up, indicating complexity of therapy
required in patients with both hypertension and CAD
0 • New onset diabetes reduction noteworthy;
however, it was not a pre-specified endpoint and
n=11,267 Verapamil n=11,309 Atenolol should be considered hypothesis generating, not a
conclusive treatment effect
www.cardiosource.com JAMA 2003;290 2805-2816
 JIKEI Heart Study
Trial Design: JIKEI was a randomized trial of usual care plus valsartan (80 mg/d, titrated to 40-160 mg/d) (n =
1,541) or usual care alone (n = 1,540) in Japanese patients with heart failure, ischemic heart disease, or
hypertension. Primary endpoint was any cardiovascular (CV) event at 3-year follow-up.

Results
• Trial discontinued early due to evidence of
benefit
HR Through 3 Years • Blood pressure ↓ at follow-up by 8.2 mm Hg/4.7
mm Hg in valsartan group and 7.2 mm Hg/3.7
mm Hg in control group
• Primary endpoint of any CV event ↓ in valsartan
Any CV Event 0.61 group vs. control group (Figure, p = 0.00021)
• Stroke ↓ in valsartan group (p = 0.028), as was
Stroke 0.60 heart failure hospitalizations (p = 0.029) and
HF Hosp. 0.54 angina hospitalizations (p < 0.0001)
• No difference in death or MI
Angina Hosp. 0.35 Conclusions
• Among Japanese patients with heart failure,
0.5 1.0 1.5 ischemic heart disease, or hypertension, addition
Valsartan Better Control Better of valsartan to usual care was associated with
reduction in primary endpoint of any CV event
compared with usual care alone at median 3-year
follow-up
• Benefit in CV events in valsartan group not fully
explained by blood pressure reduction
www.cardiosource.com Presented at ESC 2006
 METEOR
Trial Design: METEOR was a randomized (5:2), double-blind trial of rosuvastatin (40 mg; n = 702) or placebo (n
= 282) in patients at low risk for cardiovascular disease. Patients underwent carotid ultrasound prior to
randomization and at 6, 12, 18, and 24 months. Primary endpoint was annualized rate of change in maximum
carotid intima-media thickness (CIMT).
Results
Annual change in • At baseline, mean CIMT 1.15 mm in rosuvastatin group and
CIMT for 12 carotid 1.17 mm in placebo group
0.02 artery sites • LDL levels ↓ to greater extent in rosuvastatin group vs placebo
p < 0.001 group (-48.8% vs. -0.3%, p < 0.001) and HDL levels ↑ to greater
extent in rosuvastatin group
0.0131
• Change in CIMT showed nonsignificant regression in
rosuvastatin group and progression in placebo group (Figure)
0.01 • Myalgia occurred in 12.7% of rosuvastatin group and 12.1% of
placebo group
mm/year

Conclusions
• Among asymptomatic patients at low risk for cardiovascular
disease, treatment with rosuvastatin was associated with
0.00 reduction in CIMT compared with placebo at 2 years
• ASTEROID trial previously showed regression in
-0.0014 atherosclerosis disease, as assessed by intravascular
ultrasound with rosuvastatin, but did not have comparator arm
• Impact of aggressive lipid lowering on clinical events not
evaluated in this trial, particularly given low risk population
-0.01 • Larger JUPITER trial will evaluate impact of rosuvastatin
Rosuvastatin Placebo therapy on clinical events in patients with low to normal LDL,
but elevated CRP JAMA 2007;297:1344-53
www.cardiosource.com
 NICE
Trial Design: NICE was a multicenter randomized trial designed to evaluate whether
isosorbide-5-mononitrate (ISMN) 50 mg once daily for 12 weeks is associated with
improvement in exercise duration among 126 patients with NYHA Class 2-3 CHF secondary
to CAD.
Increase in exercise duration
Results
All patients Patients with • Trend towards longer exercise time
at 12 weeks LVEF 31-40%
p = 0.087 at 24 weeks with ISMN in whole cohort (Figure)
p = 0.035 • Significant improvement in exercise
120 115 120
time among patients with LVEF 31-40%
treated with ISMN vs placebo at 24
100 100 weeks (Figure)
90
Seconds

• No difference in quality of life or LVEF

80 80 between ISMN and placebo
• No change in atrial natriuretic peptide
60
60 60 or plasma norepinephrine between
ISMN and placebo
Conclusions
40 40
• Among patients with Class 2-3 CHF
20 secondary to CAD, isosorbide
20 20 mononitrate was not associated with
longer exercise time, improved quality
n=58 n=68 n=22 n=22 of life, or decrease in neurohormonal
0 0
markers of heart failure
ISMN Placebo Cardiology 1999;91:1-7
 PATCH
Trial Design: PATCH was a multi-center randomized trial of chelation therapy with EDTA compared with
placebo in patients with stable ischemic heart disease. Patients were followed for 27 weeks. The
primary endpoint was the change in time required in order to achieve a minimum of 1 mm ST segment
depression on a treadmill test 27 weeks after randomization.

Results
• Mean time to ischemia  by average of 54 seconds
100 (95% CI 23 to 84, p<0.001) in placebo group vs 63
Time to ischemia
seconds (95% CI 29 to 95, p<0.001) in EDTA group
p = 0.69
• Mean difference between two groups not statistically
75 significant at 9 seconds (95% CI -36 to 53, p=0.69;
63.0 Figure)
Seconds

54.0 • No significant difference between two groups in VO2

time to anaerobic threshold, Duke Activity Status Index,
50 Seattle Angina Questionnaire, or Health Status Survey
Short Form
Conclusions
• Among patients with coronary artery disease and stable
25 angina, chelation therapy with EDTA was not associated
with a significant improvement in quality of life or
exercise capacity compared to placebo
n=43 n=41
0 • These findings suggest that chelation therapy with
Placebo EDTA EDTA is not effective in patients with chronic, stable,
ischemic heart disease
www.cardiosource.com JAMA 2002; 287 (4):481-6
 PEACE
Trial Design: PEACE was a randomized, double-blind study of the ACE inhibitor trandolapril (n=4,158)
compared with placebo (n=4,132) among patients with stable coronary artery disease without heart failure.
Median follow-up 4.8 years. Primary endpoint was composite of death from cardiovascular causes, nonfatal
MI, or coronary revascularization.
Results
Death/MI/Coronary New-onset Diabetes • No difference in primary endpoint of death/MI/coronary
Revascularization HR 0.83 revascularization (Figure) or any individual component of
HR 0.96 p = 0.01 composite
25 p = 0.43 15
22.5 • New onset diabetes ↓ in trandolapril arm (Figure), as was
21.9
CHF as primary cause of hospitalization or death (2.8% vs
20 11.5 3.7%, HR 0.75, p=0.02)
• Side effects leading to study drug discontinuation ↑ in
9.8
trandolapril group (14.4% vs 6.5%, p<0.001), as were
%

10
15 cough (39.1% vs 27.5%, p<0.01) and syncope (4.8% vs
3.9%, p=0.04)
Conclusions
10 • Among patients with stable coronary artery disease and
5
without heart failure, treatment with the ACE inhibitor
trandolapril was not associated with a reduction in the
5 primary endpoint of cardiovascular death, nonfatal MI or
coronary revascularization compared with placebo at a
median follow-up of 4.8 years
0 0
• Results differ from HOPE and EUROPA, but PEACE may
Trandolapril Placebo have had more intensive management of baseline risk
factors (statin use, revascularization)
www.cardiosource.com N Engl J Med 2004;351:2058-68

Trial Design: PERTINENT was a substudy of the randomized EUROPA trial which compared the ACE inhibitor
perindopril with placebo among patients with stable coronary artery disease. Serum samples at baseline and 1
year in 87 patients were analyzed for markers of endothelial function. Von Willebrand factor (vWF) was
measured in 1,157 patients.
Apoptosis
p < 0.05
8 4
7.0
6 3
4.7
4 2
2 1
0 0
Perindopril
www.cardiosource.com
PERTINENT
Results
• ecNOS activity ↑ in perindopril group vs placebo at 1
ecNOS activity
year follow-up (Figure) but no difference in ecNOS
p < 0.05
expression at 1 year (8.7 vs 7.6, p=NS)
• Apoptosis at 1 year follow-up ↓ in perindopril group vs
3.3 placebo (Figure)
• Healthy control group had ↑ ecNOS activity (3.5) and
2.9
ecNOS expression (3.9) and ↓ apoptosis (1.3%) compared
with baseline levels in trial patients (p<0.01 for each)
• vWF at 1 year ↓ in perindopril group (128 vs 135, p<0.05)
Conclusions
• Among subgroup of patients enrolled in the EUROPA trial
with stable coronary artery disease, treatment with the
ACE inhibitor perindopril was associated with improved
endothelium function at 1 year as assessed by lower
apoptosis and vWF compared with placebo
• EUROPA trial showed reduction in cardiovascular events
in perindopril arm that went beyond expected effect from
blood pressure reduction
• Data from present study provide potential vascular or
Placebo anti-atherosclerotic mechanistic explanation for excess
benefit observed in EUROPA trial
Presented at ESC 2004
 PIOSTAT
Trial Design: PIOSTAT was a randomized, double-blind trial of 12 weeks of treatment with simvastatin plus
placebo (40 mg; n = 43), pioglitazone plus placebo (45 mg; n = 39), or simvastatin plus pioglitazone
combination (n = 43) in nondiabetic patients with CV disease and elevated hs-CRP. Primary endpoint was
change in hs-CRP from baseline to 12-week follow-up.
Results
25 Peripheral Edema • Hs-CRP at 12 weeks was reduced from baseline in all three
treatment groups, but to a greater degree with combination
22.2
therapy (from 3.49 mg/L to 2.06 mg/L, p < 0.001) than pioglitazone
and simvastatin monotherapy groups (3.64 mg/L to 2.48 mg/L and
20 3.26 mg/L to 2.81 mg/L)
• No change in LDL cholesterol from baseline to 12 weeks in
pioglitazone group (from 3.50 to 3.56 mmol/L) but LDL was
15 reduced from baseline in simvastatin group (from 3.60 to 2.32
mmol/L) and combination group (from 3.68 to 2.40 mmol/L)
11.4 • Peripheral edema was highest in combination group (Figure)
%

Conclusions
10
• Among nondiabetic patients with CV disease and elevated hs-
7.0 CRP, treatment with combination of pioglitazone and simvastatin
was associated with greater reduction in hs-CRP at 12 weeks
5 compared with monotherapy
• Pioglitazone was shown to reduce composite of death, MI, or
stroke by 3 years in PROactive trial in type 2 diabetics, but as with
0 the present study, was associated with excess of edema
• Data from present study extend observations of pioglitazone in
Simvastatin Pioglitazone nondiabetic patients to show reduction in inflammatory parameters
www.cardiosource.com Combination J Am Coll Cardiol 2007;49:290-7
 PROSPER Trial
Trial Design: The PROSPECT trial was a multi-center randomized trial of pravastatin
compared with placebo in 5,804 elderly patients with or at high-risk for cardiovascular
disease. Follow-up averaged 3.2 years. The primary endpoint was CV death / MI / stroke.
20 Dth / MI / stroke Dth / MI Death Results
p = 0.014 p = 0.006 p = 0.043
16.2 • Primary endpoint significantly reduced
in the pravastatin arm
15 14.1 • All components of the endpoint except
12.2 stroke showed a benefit with pravastatin

10.1 Conclusions
%

10 • PROSPER was the first major trial to

show a benefit with a lipid-lowering agent
specifically in high-risk elderly patients

5 4.2 Limitations
3.3 •The major safety concern was the  rate
of any cancer in the pravastatin arm
(8.5% vs 6.8%), which was not confirmed
0 in a meta-analysis
Prava- Placebo Prava- Placebo Prava- Placebo
statin statin statin
www.cardiosource.com Lancet 2002; 360: 1623–30
 PROTECT-CAD
Trial Design: PROTECT-CAD was a randomized trial of bone marrow mononuclear cells (BM MNC) (1x106 or
2x106 cells/0.1 ml, n=19) or control (n=9) via catheter-based direct endomyocardial injection using guided
electromechanical mapping among patients with severe coronary artery disease who have failed conventional
therapies. Primary endpoint was exercise treadmill time at 6 months.
Exercise Treadmill Time Results
at Baseline and Follow-up • Mean number of injections 14.6/patient, with mean
600 p < 0.05 for BMC procedural time of 152 minutes
p = NS for control • At 6 month follow-up, primary endpoint of exercise
time improved in BMC group but did not differ in control
464 group (Figure)
439
404 • No sustained ventricular tachycardias on Holter and
392
400 no symptomatic arrhythmias
sec

• One patient in control group and no patients in BMC

group died during follow-up
Conclusions
• Among patients with severe CAD who have failed
200 conventional therapies, endomyocardial implantation of
autologous bone marrow mononuclear cells associated
with longer exercise duration at 6 month follow-up
compared with baseline but no difference in control
group, although direct head-to-head comparison
0 between BMC and control group was not made
BMC; Baseline Control; Baseline • Larger trials would be needed to validate findings
• No dose response observed between low and high
BMC; Follow-up Control; Follow-up dose groups
www.cardiosource.com Presented at ACC 2006
 QUIET
Trial Design: QUIET was a randomized, multicenter, placebo-controlled trial (n=1750) designed
to study whether the ACE-Inhibitor quinapril (20 mg/day) would reduce adverse cardiac events
and the angiographic progression of coronary artery disease in patients with ischemic heart
disease and preserved left ventricular function. Primary endpoint: Time to first cardiac event.

Results
80
Frequency
80
Frequency • Mean duration of follow-up was 27 months.
of Cardiac of Disease • Time to first ischemic event was similar; frequency
Events Progression of cardiac events was 38% in both groups (p=0.6).
• There was no difference between groups in early or
60 60 late major cardiac events or all-cause mortality.
P=0.71
P=0.6 49
• There was no difference in the incidence of PTCA in
47 the groups.
%

• In the angiographic substudy of 477 patients, there

40 38 38 40
was no difference in disease progression (47% for
quinapril vs. 49% for placebo, p=0.71).

Conclusions
20 20 • Among patients with CAD and preserved LV
function, treatment with quinapril 20 mg/day was not
associated with a decrease in ischemic events or
progression of disease at 2 years.
0 0 • This result stands in contrast to the larger HOPE
n=872
study, which demonstrated a reduction in events with
n=878 Quinapril Placebo
the ACE-Inhibitor ramipril during a mean 5 year
follow-up period.
www.cardiosource.com Am J Cardiol 2001; 87: 1058-63
 REACH Registry
Trial Design: The REACH Registry followed patients with stable atherothrombosis to
evaluate risk factors and cardiovascular event rates. Patients were followed for 1 year.

Results
10 • At baseline, diabetes present in 44.1% of subjects,
CV Death/ MI / Stroke hypercholesterolemia in 72.1%, and multiple risk factors
at 1 Year in 18.3%
• At 1 year, composite of CV death, MI or stroke ↑ in
symptomatic patients than asymptomatic patients
All Symptomatic Asymptomatic (Figure)
patients patients patients
• Among cohort with single arterial disease (CAD, CVD,
%

or PAD), CV death, MI or stroke occurred in 3.4% of

population vs 6.0% in patients with polyvascular disease
5 • Highest event rates were in patients with CAD, CVD
3.9
3.5 and PVD (7.4%)
Conclusions
• Among patients with stable or at high-risk for
1.7 atherothrombosis, CV event rates were relatively high
and increased with number of symptomatic arterial
diseases compared with patients with risk factors only
• Geographic variation existed in event rates, as did
0 variation in age group and less so by gender

www.cardiosource.com Presented at ACC 2006

 REGRESS
Trial Design: REGRESS was a multicenter randomized study of pravastatin 40 mg once daily
compared to placebo in symptomatic men with coronary artery disease. Patients were followed for 2
years. The primary endpoints were average mean segment diameter (MSD) and average minimum
obstruction diameter (MOD). Secondary endpoint was clinical events at 2 years.

Mean segment Minimum obstruction Clinical events

diameter diameter p = 0.02 Results
p = 0.019 p = 0.001 • Decrease in MSD and MOD ↓
0.00 0.00 100 in pravastatin group (Figure)
89 • Freedom from clinical events ↑
-0.02 -0.02
81 in pravastatin group (Figure)
80

% event -free after 2 years

Change in MOD
Change in MSD

-
-0.04 -0.04 0.03
Conclusion
60 • Treatment with pravastatin
-0.06 -0.06 40 mg/day for 2 years was
-
0.06 40
associated with less
-0.08 -0.08 progression of coronary
atherosclerosis and fewer new
-0.10 -0.10
- 20 cardiovascular events
0.09
- compared to placebo
0.10
-0.12 -0.12 0
Limitation
Placebo Pravastatin • Only men included in study
n = 434 n = 450
www.cardiosource.com Circulation 1995;91:2528-40
 REVASC
Trial Design: REVASC was a multi-center randomized trial of AdVEGF121, an angiogenic growth factor
(n=27) delivered via a minithoracotomy with direct intramyocardial injections throughout the free wall
of the left ventricle vs control (n=29) in patients with severely symptomatic CAD who were not
candidates for conventional revascularization. Patients were followed for 26 weeks. The primary
endpoint was exercise treadmill time to additional 1-mm ST depression at 12 weeks.
Results
1.5 • 1 endpoint of change in time to 1 mm ST depression from baseline on
12 Weeks 26 Weeks ETT was not improved at 12 weeks (p=0.36), but was improved at 26
p = 0.36* p = 0.024* weeks (p=0.024)
1.1 • Total exercise duration improved at both 12 weeks (p=0.011) and 26
weeks (p=0.014), as did time to level 2 angina (p=0.006 at 12 weeks,
Minutes to 1mm

1.0 p=0.002 at 26 weeks)

ST depression

• Angina frequency, stability and disease perception score from Seattle

Angina Questionnaire all improved from baseline to 6, 12, and 26 weeks
in the AdVEGF arm (p<0.001 for each) but not in the medical care arm
• No difference in SAEs between the 2 arms
0.5 0.4 Conclusions
• First randomized trial to deliver angiogenic genes by direct
intramyocardial injections
• 1 endpoint negative; many 2 endpoints favored AdVEGF arm
Limitations
0.0 • No blinding to therapy received; placebo effect cannot be discounted
AdVEGF * P-values for change • Lack of benefit with 1 endpoint and small sample size do not support
n = 27 from baseline time
clinical application of therapy; additional blinded study may be warranted
www.cardiosource.com AHA 2002, Late Breaking Trials
 SPACE
Trial design: SPACE was a multi-center, randomized, double-blind, placebo-controlled trial
of high-dose vitamin E supplementation (800 IU/day) in hemodialysis patients with pre-
existing cardiovascular disease. 198 patients were followed for a median time of 519 days.
Primary end-point was composite of cardiovascular events (MI, PVD, Stroke, UA, or
sudden death).
Primary Endpoint Myocardial Infarction Results
RR 0.54 RR 0.45 • Primary endpoint ↓ in vitamin E group
40 20 (Figure)
p = 0.016 p=0.04 18.2
34.3 • MI ↓ in vitamin E group (Figure)
• Total mortality did not differ between
30 15 groups (31.2% vitamin E vs 29.3% placbeo)
Conclusions
%

• Among hemodialysis patients with pre-

20 18.6 10 existing CV disease, high-dose vitamin E
8.2
supplementation was associated with a
significant reduction in composite
10 5 cardiovascular disease endpoint and
myocardial infarction
Limitations
n=97 n=99 n=97 n=99
0 0 • Insufficient power to detect differences in
Vit E Placebo Vit E Placebo primary endpoint components

www.cardiosource.com Lancet 2000;356:1213-18

 St. Francis Heart Study
Trial Design: The St. Francis Heart Study was a prospective study of the use of coronary calcification
assessed by electron-beam computed tomography (EBCT) for risk stratification in patients with no
prior history, symptoms, or signs of atherosclerotic CVD. Patients (n=5585) were followed for 4.3 years
to assess the development of atherosclerotic cardiovascular disease (ASCVD) events.
800
Results
20 • Mean calcification score  in patients
p<0.0001 Calcium Score
who subsequently developed ASCVD
Thresholds event
• Presence of baseline score >100
Mean Baseline Calcification Score

584
600
15 14.1 associated with  incidence of any
Positive Predictive Value

ASCVD (RR 9.5, 95% CI 6.5-13.8), all

coronary events (8.6% event rate, RR
10.5
10.7, 95% CI 7.1-16.3), and MI or
400 10 8.6 coronary death (RR 9.9, 95% CI 5.2-
18.9)
Conclusions
• Among patients with no prior history,
200
142 5 3.2 symptoms, or signs of ASCVD,
development of an ASCVD event was
associated with  baseline calcium score
n=122 • Association independent of standard
0 0 risk factors in MV model and provided
CV event No >0 >100 >200 >600
CV event additional risk stratification within
Score Threshold Framingham risk score
www.cardiosource.com Presented at ACC 2003
 WAFACS
Trial Design: WAFACS was a randomized trial of folic acid (2.5 mg/day), vitamin B6 (50 mg/day), and vitamin
B12 (1 mg/day) (n = 2,721) or placebo (n = 2,721) in women with or at increased risk for CV disease. The trial
was a factorial part of the larger WACS trial. Primary endpoint was composite of CV death, MI, stroke, or
revascularization through mean 7.3-year follow-up.
CV Death, MI, Stroke, Results
or Revascularization • No difference in primary endpoint between groups (Figure) or
500 (p = 0.65) individual components of composite
• Due to introduction of folic acid fortification into food supply during
406 the study period, folic acid levels in the subgroup of patients with
390
400 blood samples ↑ from baseline to study end in both active treatment
group (9.0-39.6 ng/ml, p < 0.001), and to a lesser degree in the
placebo group (9.2-16.4 ng/ml, p < 0.001)
300 • However, homocysteine levels not reduced in placebo group (12.3
µmol/L at both time points), but ↓ in active treatment group (from
n

12.2 µmol/L at baseline to 10.0 µmol/L at study end, p < 0.001)

200 Conclusions
• Among women with or at risk for CV disease, treatment with folic
acid and vitamin B were not associated with differences in primary
100 endpoint of CV death, MI, stroke, or revascularization through
mean 7-year follow-up compared with placebo
• Results were similar to the HOPE-2 trial, which showed no benefit
0 with folic acid or vitamin B among patients with pre-existing CV
disease or diabetes, and the NORVIT trial, which showed no benefit
Active Treatment Placebo with folic acid or vitamin B for post-MI care
www.cardiosource.com Presented at AHA 2006