AHA 2008 AHA 2008

Clinical Trial Summary SlidesClinical Trial Summary Slides

APPROACH

• Change in percent atheroma volume: -0.21% with rosiglitazone vs. 0.43% with glipizide (p = 0.12)

• Change in total atheroma volume: -3.9 mm3 vs. 1.2 mm3 (p = 0.04), respectively

• Death: 2.4% vs. 2.1%, respectively

• Myocardial infarction: 2.1% vs. 1.8%, respectively

Trial design: Diabetic patients were randomized to rosiglitazone titrated to 8 mg daily (n = 333) vs. glipizide titrated to 15 mg daily (n = 339). IVUS was performed at baseline and 18 months.

Results

Conclusions

• Among type 2 diabetic patients, the use of rosiglitazone does not reduce percent atheroma volume compared with glipizide

• There was a reduction in total atheroma volume with rosiglitazone

• CV outcomes were similar between groups

Presented by Dr. Richard Nesto at AHA 2008

(p = 0.12)

Rosiglitazone Glipizide

Change in percent atheroma volume

%

-0.21

0.43

%

0

5

15

3.95.5

20

ATLAS TIMI 46

• No difference between rivaroxaban and placebo in the primary outcome (death, MI, stroke, severe ischemia) (HR 0.79, 95% CI 0.60-1.05, p = 0.10)

• ↓ in death, MI, stroke with rivaroxaban (p = 0.028)

• Dose-response curve for bleeding with rivaroxaban, especially in the setting of dual antiplatelet therapy (p < 0.001)

Trial design: Patients with ACS were randomized to either rivaroxaban twice daily, once daily, or placebo. Clinical outcomes were compared at 6 months.

Results

Conclusions • Rivaroxaban has reasonable efficacy compared

with placebo in patients with ACS, with a higher bleeding risk

• ATLAS TIMI 46 was a phase II clinical trial conducted to identify safe and effective doses of rivaroxaban to be used in the phase III trial

Presented by Dr. C. Michael Gibson at AHA 2008

(p = 0.10)

Rivaroxaban(n = 1,166)

Placebo(n = 1,160)

(p = 0.028)

5

10

15

20

5.67.0

%

0

Primary outcome Death/MI/Stroke

10

BACH

• In the group admitted with CHF, MR-proADM was associated with a higher prognostic efficacy than both BNP and NT-proBNP (p < 0.001 for both)

• Log MR-proADM was associated with a significant improvement in prognostic ability for 90-day mortality in the multivariate model (p < 0.001)

Trial design: BACH was a biomarker trial, which compared the prognostic accuracy of mid regional pro-Adrenomedullin (MR-proADM), BNP, and NT-proBNP for 90-day mortality in patients presenting to the emergency room with shortness of breath.

Results

Conclusions• The diagnostic ability of MR-proADM for CHF

is unclear

• Clinical utility of these findings is limited

Presented by Dr. Stefan Anker at AHA 2008

(p < 0.001)

MR-proADM BNP

50

100

60.8

73.5

%

0

Prognostic accuracy in CHF patients

63.6

NT-proBNP

BICC

• Viral load reduction or elimination was better in IFNB-1b groups compared with placebo (p = 0.048)

• NYHA class was similar at 24 weeks (p = 0.073), quality of life was better in IFNB-1b group (p = 0.032)

• No change in echo or hemodynamic parameters

• Serious adverse events were similar (p > 0.05)

Trial design: Patients with CVC were randomized to either high-dose (8 million IU), low-dose (4 million IU) IFNB-1b, or placebo. Outcomes were compared at 24 weeks.

Results

Conclusions

• IFNB-1b was associated with a nearly twofold increase in viral load reduction or elimination compared with placebo in patients with CVC

• Results of phase III trial are awaited

Presented by Dr. Heinz Peter Schultheiss at AHA 2008

(p = 0.048)

IFNB-1b(n = 95)

Placebo(n = 48)

20

40

17

32

%

0

Viral load reduction or elimination

FIT Heart

• Percent change in LDL: -1.0% for special intervention vs. -2.0% for control (p = NS)

• HDL at follow-up: 58.7 mg/dl vs. 57.6 mg/dl (p = 0.01), respectively

• BMI at follow-up: 27.7 kg/m2 vs. 28.4 kg/m2 (p = 0.88), respectively

Trial design: Family members of a hospitalized cardiac patient were randomized to a special intervention program for risk factor modification (n = 250) vs control (n = 251). Follow-up was 1 year.

Results

Conclusions

• Among family members of a hospitalized cardiac patient, a special intervention program is not more effective than a control program in lowering LDL cholesterol

• Special intervention was associated with a slightly higher HDL, although similar BMI at follow-up

Mosca L, et al. Circ Cardiovasc Qual Outcomes 2008;1:98-106

(p = NS)

Special intervention program

Control

Percent change in LDL cholesterol

%

-1.0

-2.0

ml/

min

/kg

0

0.7

0.1

1.0

HF-ACTION

• No difference in mortality/hospitalizations between the two arms (HR 0.93, 95% CI 0.84-1.02, p = 0.13). On adjustment for other prognostic factors, was ↓ in exercise training arm (p = 0.03)

• CV mortality & CV hospitalizations (p = 0.14), 6-minute walk distance (p = 0.26) similar, but peak VO2 higher in the exercise training arm

• Serious side effects similar between the two arms

Trial design: Patients with symptomatic systolic CHF on optimal medical therapy were randomized to either exercise training or usual medical care. Clinical outcomes were compared at 3 years.

Results

Conclusions

• Prescribed exercise training program in patients with systolic CHF safe and effective, when added on to optimal medical therapy

• Strengthens current recommendations for exercise in CHF patients

Presented by Dr. David Whellan at AHA 2008

(p = 0.26)

Exercise training(n = 1,159)

Usual care(n = 1,172)

(p < 0.0001)

5

10

15

20

1213

m

0

Change in 6-minute walk distance

Change in Peak VO2

0.5

HF-ACTION Substudy

• Kansas City Cardiomyopathy Questionnaire score at follow-up: +5 points in the exercise group vs. +2 points in the usual care group (p = 0.001)

• Clinical improvement: 53% of the exercise group vs. 33% of the usual care group (p < 0.001)

Trial design: Patients with CHF (NYHA II-IV) were randomized to an aerobic exercise training program (n = 1,159) vs. usual care (n = 1,172). Median follow-up was 2.5 years.

Results

Conclusions

• Among patients with CHF due to LV systolic dysfunction, participation in an exercise program modestly improves health status compared with usual care

• This benefit is seen early, within the first 3 months

Presented by Dr. Kathryn Flynn at AHA 2008

(p = 0.001)

Exercise group Usual care

Change in Kansas City Cardiomyopathy Questionnaire at follow-up

Po

ints

5

2

%

0

5

15

10.7 10.7

20

I-PRESERVE

• No difference between irbesartan and placebo arms in the primary outcome (death/CV hospitalization) (HR 0.95, 95% CI 0.86-1.05, p = 0.35)

• Incidence of mortality (p = 0.98), worsening CHF (p > 0.05), change in NT-proBNP (p = 0.14) similar

• Most side effects similar, except ↑ risk of serious hyperkalemia with irbesartan (3% vs. 2%, p = 0.01)

Trial design: Patients with heart failure and preserved ejection fraction (EF) were randomized to either irbesartan or placebo. Clinical outcomes were compared at 5 years.

Results

Conclusions

• Irbesartan was not associated with a reduction in CV mortality and morbidity in patients with heart failure and preserved EF

• Results were similar to those for candesartan and perindopril

Massie BM, et al. N Engl J Med 2008;Nov 11:[Epub]

Presented by Dr. Peter Carson at AHA 2008

(p = 0.35)

Irbesartan(n = 2,067)

Placebo(n = 2,061)

(p = 0.98)

50

100

36.0 37.0

%

0

Primary outcome Mortality

10

%

0

5

15

2.7 3.0

20

JPAD

• No difference between aspirin and nonaspirin group in the total atherosclerotic events (HR 0.80, 95% CI 0.58-1.10, p = 0.16)

• Significant ↓ in fatal coronary and cerebrovascular events (p = 0.0037)

• No difference in nonfatal MI (p = 0.5), hemorrhagic strokes (p = 0.48), mortality (p = 0.67)

• ↑ bleeding with aspirin, not statistically significant

Trial design: Patients with type 2 diabetes and no prior coronary artery disease were randomized in an open-label fashion to either aspirin 81 or 100 mg daily or no aspirin. Clinical outcomes were compared at 5 years.

Results

Conclusions

• Findings suggest no reduction in total atherosclerotic events, but reduction in total coronary and cerebrovascular events with aspirin in diabetic patients

• Findings need to be validated by other studies

Ogawa H, et al. JAMA 2008;300:2134-41

Presented by Dr. Hisao Ogawa at AHA 2008

(p = 0.16)

Aspirin(n = 1,262)

No aspirin(n = 1,277)

(p = 0.67)

5

10

15

20

5.46.7

%

0

Atherosclerotic events Mortality

10

0

1.0

1.25

2

JUPITER

• Rosuvastatin associated with a significant ↓ in the primary outcome of MI, stroke, unstable angina, revascularization, or cardiovascular death (HR 0.56, 95% CI 0.46-0.69, p < 0.00001)

• All-cause mortality ↓ with rosuvastatin (p = 0.02)

• Serious adverse effects were similar (p = 0.60)

Trial design: Apparently healthy patients with LDL cholesterol <130 mg/dl and hs-CRP ≥2 mg/L were randomized to rosuvastatin 20 mg daily or placebo. Clinical outcomes were compared at a median of 1.9 years.

Results

Conclusions• Rosuvastatin was associated with a significant

reduction in major cardiovascular events, including death, in patients with LDL <130 mg/dl, but high hs-CRP (≥2.0 mg/L)

• May require revision of current guidelines

Presented by Dr. Paul Ridker at AHA 2008

(p < 0.00001)

Rosuvastatin(n = 8,901)

Placebo(n = 8,901)

(p = 0.02)

2

0.77

1.36

Eve

nts

/100

per

son

-yea

rs

0

Primary outcome All-cause mortality

1

Ridker PM, et al. NEJM 2008;359:2195-207

1

Eve

nts

/100

per

son

-yea

rs

PHS II

• Neither vitamin C nor vitamin E associated with a reduction in major cardiovascular events compared with placebo (p = 0.86, 0.91, respectively)

• No difference in individual outcomes studied

• No increase in adverse events, except increased hemorrhagic stroke with vitamin E (p = 0.04)

Trial design: PHS II randomized healthy males in a factorial design to active vitamins E & C, active vitamin E & placebo vitamin C, placebo vitamin E & active vitamin C, & placebo vitamins E and C. Clinical outcomes were compared at 10 years.

Results

Conclusions

• Vitamins C or E not helpful in the primary prevention of cardiovascular events in healthy patients

• Confirms earlier studies with vitamin E; one of the first studies with vitamin C

Sesso HD, et al. JAMA 2008;300:2123-33

Presented by Dr. J. Michael Gaziano at AHA 2008

Vit E n = 7,315

Placebon = 7,312

Placebon = 7,326

0

10

20

10

20

%

0

8.48.5 8.5 8.6%

Vit Cn = 7,329

Major cardiovascular events

(p = 0.86) (p = 0.91)

SEARCH

• No difference in the incidence of major vascular events between high- vs. low-dose simvastatin, or folate + vitamin B12 vs. placebo (p > 0.05 for both)

• No difference in individual outcomes studied

• ↑ risk of myopathy in high-dose vs. low-dose simvastatin arms (0.88% vs. 0.05%, p < 0.05)

Trial design: A 2 x 2 factorial study in which patients with a recent MI were randomized to either simvastatin 80 mg or 20 mg daily, and folic acid + vitamin B12 or placebo. Patients were followed for a mean of 6.7 years.

Results

Conclusions

(p > 0.05) (p > 0.05)

Major vascular events • Neither high-dose (vs. low-dose) simvastatin nor folate + vitamin B12 (vs. placebo) effective in reducing major vascular events in patients with a recent MI

• Statin data contrary to other trials on this topic, folate + vitamin B12 data similar

Presented by Dr. Rory Collins at AHA 2008

Simvastatin 80 mgn = 6,031

Placebon = 6,031

Simvastatin 20 mgn = 6,033

Folate/ Vit B12

n = 6,033

0

5050

%

0

25.524.5 25.724.8

%

%

0

5

15

4.96.0

20

TIMACS

• No difference in primary outcome (death, MI, stroke) between the two arms (HR 0.85, 95% CI 0.68-1.06, p = 0.15), except in high-risk patients (HR 0.65, 95% CI 0.48-0.88, p = 0.005)

• Death, MI, refractory ischemia ↓ in early invasive arm (p = 0.0002), due to ↓ in refractory ischemia (p < 0.0001); death (p = 0.81), stroke (p = 0.74) similar

• Major bleeding was similar (p = 0.53)

Trial design: Patients with NSTEMI were randomized to an early (within 24 hours) or delayed (after 36 hours) invasive strategy. Clinical outcomes were compared at 6 months.

Results

Conclusions

• An early invasive strategy (within 24 hours) is not associated with harm compared with a delayed invasive strategy (after 36 hours) in patients with NSTEMI, and may be beneficial in high-risk patients

• Significant reduction in refractory ischemia with an early invasive strategy

Presented by Dr. Shamir Mehta at AHA 2008

(p = 0.15)

Early invasive(n = 1,593)

Delayed invasive(n = 1,438)

(p = 0.81)

5

10

15

20

9.711.4%

0

Primary endpoint Mortality

10

THINRS

• Death, stroke, or major bleeding: 7.9% per patient-year for self-testing vs. 8.9% per patient-year for conventional testing (p = 0.1)

• Death: 3.4% vs. 3.7%, respectively

• Major bleeding: 3.9% vs. 4.5%, respectively

Trial design: Patients who required chronic anticoagulation were randomized to patient self INR testing (n = 1,465) vs conventional monthly INR testing (n = 1,457). Follow-up was 4.5 years.

Results

Conclusions

• Patient self-testing for INR monitoring does not reduce the composite outcome of death, stroke, or major bleeding

• No signal for increased adverse events, such as major bleeding, with self-testing

Presented by Dr. Alan Jacobson at AHA 2008

(p = 0.1)

Patient self INR testing

Conventional INR testing

Death, stroke, or major bleeding

% p

er p

atie

nt-

year

7.9

8.9

%

0

5

15

01.8

20

VASP-Guided PCI

• Stent thrombosis more frequent in the routine PCI arm compared with VASP-guided PCI (p = 0.03)

• MACE ↓ in the VASP-guided PCI arm (p < 0.001), mainly due to ↓ in MI (p = 0.01). Rates of cardiovascular death, urgent revascularization were similar (p = 0.06 for both)

• Bleeding rates were similar (p = 0.8)

Trial design: Patients undergoing nonemergent PCI, and a VASP index of ≥50% were randomized to either routine management, or VASP-guided further loading doses of clopidogrel until VASP index <50%. Clinical outcomes were compared at 30 days.

Results

Conclusions • VASP-guided PCI, with an aim to reduce the VASP

index below 50%, was associated with better outcomes in patients undergoing nonemergent PCI and VASP index ≥50%

• Needs to be corroborated by other studies

Presented by Dr. Frank Paganelli at AHA 2008

(p = 0.03)

VASP-guided PCI(n = 214)

Routine PCI(n = 215)

(p = 0.06)

5

10

15

20

0.5

4.7

%

0

Stent thrombosis CV death

10