ESC Congress 2008 ESC Congress 2008

Clinical Trial Summary SlidesClinical Trial Summary Slides

3T/2R

• Troponin I or T >3x ULN at 48 hours: 20% for tirofiban vs. 35% for placebo (p = 0.009)

• MACE at 30 days: 21% vs. 37% (0.006), respectively

• TIMI major bleeding at 30 days: 0 vs. 0

Trial design: Patients undergoing PCI were screened for poor response to aspirin and/or clopidogrel. Poor responders were then randomized to tirofiban (n = 132) or placebo (n = 131). Follow-up was 30 days.

Results

Conclusions

• Tirofiban is beneficial at reducing MI within 48 hours after PCI among poor responders to aspirin and/or clopidogrel

• Tirofiban also reduced MACE at 30 days

• There were no major bleeds in either group

Presented by Dr. Marco Valgimigli at ESC 2008

(p = 0.009) (p = 0.006)

Tirofiban Placebo

Troponin I or T >3x ULN at 48 hours

MACE at 30 days

%21

37

20

35

APPRAISE-1

• ISTH major or CRNM bleeding: 7.9% for 10 mg apixaban, 5.7% for 5 mg apixaban, 3% for placebo (p = 0.005 for high-dose vs. placebo and p = 0.09 for low-dose vs. placebo)

• Death, MI, recurrent ischemia, or stroke: 6.0%, 7.6%, 8.7% (p = 0.07 for high-dose vs. placebo and p = 0.21 for low-dose vs. placebo), respectively

Trial design: Patients recovering from an ACS were randomized to apixaban 10 mg daily (n = 318), apixaban 2.5 mg twice daily (n = 317), or placebo (n = 611). Study medications were administered for 6 months.

Results

Conclusions

• This dose-finding study reveals that bleeding is increased among patients with a recent ACS with higher doses of apixaban compared with placebo

• Although this study was not powered for efficacy, adverse events appeared to be lowest with 10 mg apixaban

Presented by Dr. John Alexander at ESC 2008

p = 0.005 for high-dose

vs. placebo

p = 0.09 for low-dose vs.

placebo

Apixaban

10 mg

Apixaban 5 mg

%

Placebo

7.9

5.7

3

ISTH major or clinically relevant nonmajor bleeding

ATHENA

• Dronedarone associated with a 24% ↓ in cardiac hospitalizations or death vs. placebo (p<0.001)

• Overall mortality similar (p = 0.18), cardiovascular mortality lower with dronedarone (p = 0.03)

• Higher GI side-effects and increased creatinine with dronedarone, other side-effects similar

Trial design: High-risk patients with paroxysmal or persistent atrial fibrillation or flutter were randomized to dronedarone 400 mg twice daily or placebo. Patients were followed for a mean of 21 months.

Results

Presented by Dr. Stefan Hohnloser at the Heart Rhythm Society 2008

Dronedarone(n = 2301)

Placebo(n = 2327)

•Dronedarone is safe and effective in the chronic management of atrial fibrillation in high-risk patients

•Head-to-head comparison with amiodarone awaited

6.0

0

5

10

Mortality

(p = 0.18)

Conclusions

%

10

%

5.05

0

1.21.8

(p = 0.027)

Stroke

BEAUTIFUL

• Difference in heart rate at 24 months: 5.6 bpm lower with ivabradine

• CV death, MI, or HF: 15.4% for ivabradine vs. 15.3% for placebo (p = 0.94)

• All-cause mortality: 10.4% vs. 10.1% (p = 0.55)

• HF admission: 7.8% vs. 7.9% (p = 0.85)

Trial design: Patients with stable CAD and moderate LV dysfunction were randomized to the sinoatrial node inhibitor, ivabradine (n = 5,479), or placebo (n = 5,438). Median follow-up was 19 months.

Results

Conclusions

• Ivabradine produces a sustained reduction in heart rate over long-term follow-up

• Among patients with stable coronary disease and moderate LV dysfunction, ivabradine does not improve mortality, MI, or HF admissions

Fox K, et al. Lancet 2008;Aug 31:[Epub before print]

(p = 0.94) (p = 0.55)

Ivabradine Placebo

CV death, MI, HF admission

All-cause mortality

% 10.4 10.1

15.4 15.3

%

0

5

15

2.0

9.9

20

CARDia

• Primary endpoint (death, MI, stroke) was similar between CABG and PCI (10.2% vs. 11.6%, p = 0.63)

• Significant ↓ in repeat revascularization in CABG arm (2% vs. 9.9%, p = 0.001). True in drug-eluting stent subset also

• Trend toward increased CVA in CABG arm (p = 0.09)

Trial design: Diabetic patients with multi-vessel disease or complex single-vessel disease, but not left main disease, were randomized to either CABG or PCI. Clinical outcomes were compared at 12 months.

Results

Conclusions

• Similar incidence of death, MI, or stroke in diabetics with CABG or PCI

• CABG was associated with fewer repeat revascularizations compared with PCI

• No difference in death, MI, but trend toward increased stroke with CABG, as suggested by other studies

Presented by Dr. Akhil Kapur at ESC 2008

(p = 0.63)

CABG(n = 254)

PCI(n = 256)

(p = 0.001)

5

10

15

20

10.211.6%

0

Primary endpoint Repeat revascularization

10

CARESS-in-AMI

• 86% of the immediate PCI group underwent PCI vs. 30% of the standard care group

• Death, MI, or refractory ischemia at 30 days (4.4% vs. 10.7%, p = 0.005)

• Refractory ischemia (0.3% vs. 4.0%, p = 0.003)

Trial design: STEMI patients admitted to non-PCI hospitals and initially treated with heparin, half-dose reteplase, and abciximab were randomized to immediate transfer for urgent PCI (n = 299) or standard therapy with rescue PCI if needed (n = 301).

Results

Conclusions

• STEMI patients treated with half-dose lytics and abciximab did better with immediate transfer for PCI

• This approach reduced death, MI, or refractory ischemia at 30 days

• Benefit driven by reduction in refractory ischemia

Di Mario C, et al. Lancet 2008;371:559-68

(p = 0.005) (p = 0.47)

% 4.4

10.7

3.42.3

Transfer for PCI(n = 299)

Standard therapy (n = 301)

MACE Major bleeding

%

0

5

15

4.8

10.1

20

DECREASE III

• Myocardial ischemia was significantly reduced with statin (OR 0.53; 95% CI 0.32-0.88, p = 0.016)

• LDL (p < 0.001) and hs-CRP (p 0.001) were lower in statin arm

• Incidence of adverse events was similar

Trial design: Patients undergoing noncardiac vascular surgery were randomized to fluvastatin XL or placebo, in addition to beta-blockers. Clinical outcomes were compared at 1 month.

Results

Conclusions

• Perioperative statin therapy was associated with improved outcomes in high-risk patients undergoing noncardiac vascular surgery

• Results add to current literature on the benefit of statins in the perioperative period

Presented by Dr. Don Poldermans at ESC 2008

(p = 0.016)

Fluvastatin XL(n = 250)

Placebo(n = 247)

(p = 0.039)

5

10

15

20

10.9

19.0

%

0

Myocardial ischemia CV death or MI

10

FIRE

• Total late enhancement zone at 5 days: 21.7 g for FX06 vs. 27.3 g for placebo (p = 0.21) and at 4 months: 15.4 g vs. 19.3 g (p = 0.36), respectively

• LVEF at 4 months: 49% vs. 49%, respectively

• Serious adverse events: 18% vs. 24%, respectively

Trial design: STEMI patients were randomized to the fibrin-derived peptide FX04 400 mg intravenously (n = 114) versus placebo (n = 120).

Results

Conclusions

• This study failed to meet its endpoint of a reduction in total late enhancement

• There was no difference in LVEF at follow-up

• There were no important safety signals with the use of this agent

Presented by Dr. Dan Atar at ESC 2008

(p = 0.36)

FX04 Placebo

Total late enhancement zone at 4 months

(g) 15.4

19.3

%

0

5

15

3.0 4.0

20

GISSI-HF: n-3 PUFA Study

• No difference between the two arms for primary endpoint (death), but significant difference noted on multivariate analysis (HR 0.91, 95.5% CI 0.83-1.0; p = 0.041)

• No difference in the incidence of first admission for heart failure, but fewer admissions for arrhythmia related issues (p = 0.013)

Trial design: Patients with symptomatic CHF were randomized to 1 g n-3 PUFA daily or placebo, in addition to optimal medical treatment. Clinical outcomes were compared at 12 months.

Results

Conclusions

GISSI-HF Investigators. Lancet 2008;Aug 31:[Epub]

(p = 0.12)

n-3 PUFA(n = 3,494)

Placebo(n = 3,481)

(p = 0.013)

20

10

30 27.329.1

%

0

Mortality Arrhythmia related hospitalization

10• No significant difference in mortality in the n-3

PUFA arm, compared with placebo in patients with symptomatic heart failure, on optimal treatment

• However, multivariate analysis showed n-3 PUFA was associated with small reduction in mortality (absolute RR 1.8%) compared with placebo

• Exact mechanism is unclear, although reduction in readmission for arrhythmias was noted

GISSI-HF: Rosuvastatin Study

• All-cause mortality: 29% with rosuvastatin vs. 28% with placebo (p = 0.94)

• Death or hospital admission for cardiovascular reasons: 57% vs. 56% (p = 0.90), respectively

• Sudden cardiac death: 9.6% vs. 8.6% (p = 0.26), respectively

Trial design: Patients with chronic symptomatic HF were randomized to rosuvastatin 10 mg daily (n = 2,285) or placebo (n = 2,289). Median follow-up, 3.9 years.

Results

Conclusions

• Rosuvastatin 10 mg daily is not beneficial at reducing cardiac outcomes among patients with chronic symptomatic HF

• This study should not temper enthusiasm for statins in indicated situations like ACS

GISSI-HF Investigators. Lancet 2008;Aug 31:[Epub]

(p = 0.94) (p = 0.90)

Rosuvastati

nPlacebo

All-cause mortality

Death or hospital admission for CV

reasons

%

57 56

29 28

IBIS-2

• Lp-PLA2 reduced 59% by darapladib (p < 0.001)

• Plaque deformability: similar between the groups at follow-up (p = 0.22)

• Necrotic core volume: -0.5 mm3 with darapladib (p = 0.71); +4.5 mm3 with placebo (p = 0.009)

• MACE: 17% vs. 19% (p = ns), respectively

Trial design: Patients with CAD were randomized to darapladib 160 mg daily (n = 175) vs. placebo (n = 155). Patients underwent IVUS of a nonintervened segment at baseline and at 12 months.

Results

Conclusions

• Treatment with the Lp-PLA2 inhibitor

darapladib does not affect plaque deformability

• Darapladib appears to stabilize the necrotic lipid core

• Similar adverse events between the groups

Serruys PW, et al. Circulation 2008;Sep 1:[Epub]

p = 0.009, change with

placebo

p = 0.71, change with darapladib

mm

3

Darapladib Placebo

Change in necrotic core volume at follow-up

-0.5

4.5

LEADERS

• Successful stent implantation: 97.5% for biolimus vs. 95.7% for sirolimus (p = 0.05)

• Death, MI, or TVR: 9.2% vs. 10.5% (p = 0.003 for non-inferiority), respectively

• Stent thrombosis: 1.9% vs. 2.0% (p = 0.84), respectively

Trial design: Patients with stable coronary disease or ACS were randomized to the biolimus-eluting stent with a biodegradable polymer (n = 857) or the sirolimus-eluting stent with a durable polymer (n = 850). Follow-up was for 9 months.

Results

Conclusions

• Biolimus-eluting stent is non-inferior to sirolimus-eluting stent for death, MI, or TVR

• Higher rate of successful implantation with the biolimus-eluting stent

• Theoretically, a biodegradable polymer could decrease late stent thrombosis; however, longer-term follow-up is needed

Windecker S, et al. Lancet 2008;Sept 1:[Epub before print].

(p = 0.003 for non-inferiority) (p = 0.84)

Biolimus-eluting stent

Sirolimus-eluting stent

Death, MI, urgent revascularization

Stent thrombosis

%

1.9 2.0

9.210.5

PIHRATE

• ST-resolution at 60 minutes: 50% with thrombectomy vs. 41% with primary PCI (p = 0.28)

• Myocardial blush grade of 3: 76% vs. 59% (p = 0.023), respectively

• 6-month mortality: 4.0% vs. 3.1% (p = 0.74), respectively

Trial design: Patients with STEMI were randomized to aspiration thrombectomy plus PCI (n = 102) versus primary PCI alone (n = 94). Follow-up was 6 months.

Results

Conclusions• Among STEMI patients, a strategy of

aspiration thrombectomy compared with primary PCI failed to improve ST-resolution after PCI, although it did enhance myocardial blush grade of 3

• Mortality was similar between the groups

Presented by Dr. Dariusz Dudek at ESC 2008

(p = 0.28) (p = 0.74)

Aspiration thrombectomy

Primary PCI

ST-segment resolution at 60

minutes

6-month mortality

% 4.03.1

5041 %

REGENT

• EF change: +3% selected cells (p = 0.04), +3% unselected cells (p = 0.01), 0% control (p = 0.73) (p = ns between groups)

• Death: 1.3%, vs. 1.3%, vs. 2.5% (p = 0.92), respectively

• Myocardial infarction: 5.0%, vs. 1.3%, vs. 5.0% (p = 0.61), respectively

Trial design: Patients with acute MI and LV dysfunction (EF ≤40%) were randomized to selected CD34+ CXCR4+ bone marrow cells (n = 80), unselected bone marrow cells (n = 80), or control (n = 40). Follow-up was 6 months.

Results

Conclusions

• In patients with acute MI and LV dysfunction, both selected and unselected bone marrow derived stem cells minimally increased LVEF at 6 months

• This did not translate into a difference in LVEF at follow-up between the groups

• Similar adverse events between the groups

Presented by Dr. Michal Tendera at ESC 2008

p = ns for stem cell LVEF change compared

with control

Selected

stem cells

Unselected stem cells

%

21 3720 35

Control

Change in LVEF at 6 months

3 3

0

REVERSE

• Patients worsened: 16% with CRT vs. 21% with optimal medical therapy (p = 0.1)

• LV end-systolic volume index: decreased 18.4 ml/m2 vs. 1.3 ml/m2 (p < 0.0001), respectively

• Risk of heart failure hospitalization reduced with CRT (p = 0.03)

Trial design: Patients with LV dysfunction (NYHA class I-II) and wide QRS were randomized to cardiac resynchronization therapy (CRT) (n = 419) or optimal medical therapy (n = 191).

Results

Conclusions

• CRT for mild heart failure does not reduce the percentage of patients that clinically worsen

• CRT improves LV end-systolic volume index and reduces the risk of hospitalization compared with optimal medical therapy

(p = 0.1)

Presented Dr. Cecilia Linde at SCAI-ACC i2 Summit/ACC 2008

16 21%

Percentage worsened

CRT Medical therapy

%

0

1

2

44.1

2.53

5

SEAS

• 61% ↓ in LDL in ezetimibe/simvastatin arm

• No difference in the composite endpoint between the two groups (HR 0.96, 95% CI 0.83-1.12)

• Increased incidence of cancer (9.9% vs. 7.0%, p = 0.03) and cancer deaths (4.1% vs. 2.5%, p = 0.05) with ezetimibe/simvastatin

Trial design: Patients with asymptomatic mild to moderate calcific AS were randomized to treatment with ezetimibe/simvastatin 10/40 mg or placebo. Cardiovascular outcomes over 4 years were compared.

Results

Conclusions

• No benefit with ezetimibe/simvastatin in asymptomatic AS patients other than a reduction in atherosclerotic events

• Final full publication is awaited

Pedersen TR. Press release July 21, 2008

(p = NS)

Ezetimibe/ Simvastatin

(n = 943)

Placebo(n = 930)

(p = 0.05)

10

20

30

40 35.338.2

%

0

Composite endpoint Deaths from cancer

%

0

5

15

5.9

13.7

20

SYNTAX

• MACCE was significantly lower in CABG arm compared with PCI (12.1% vs. 17.8%, p = 0.0015), especially for diabetics (p = 0.0025)

• Significant ↓ in the need for repeat revascularization in CABG arm (p = 0.0001)

• Death and MI were similar; CVA ↑ with CABG (p = 0.003)

Trial design: Patients with severe three-vessel disease or left main (LM) disease were randomized to either CABG or DES-PCI with paclitaxel-eluting stents. Clinical outcomes were compared at 12 months.

Results

Conclusions

• CABG was associated with fewer repeat revascularizations compared with DES-PCI in patients with LM or three-vessel disease, but a higher rate of stroke

• No difference in death, MI, or thrombosis

• Diabetics are especially more likely to benefit with CABG compared with DES-PCI

Presented by Dr. Patrick Serruys at ESC 2008

(p = 0.0015)

CABG(n = 897)

DES-PCI(n = 903)

(p = 0.0001)

5

10

15

20

12.1

17.8

%

0

MACCE Repeat revascularization

10

%

0

5

15

8.8

3.0

20

SYNTAX Registry

• Main reason for PCI only: inoperable (comorbidities); main reason for CABG only: complex anatomy

• PCI outcomes: MACCE (20.4%), mortality (7.3%), MI (4.2%), repeat revascularization (12%), CVA (0)

• CABG outcomes: MACCE (8.8%), mortality (2.5%), MI (2.5%), repeat revascularization (3%), CVA (2.2%)

Trial design: Patients with severe three-vessel or left main (LM) disease who did not meet criteria for entry into the SYNTAX trial were followed for 12 months in the SYNTAX CABG and PCI registry.

Results

Conclusions

• The SYNTAX registry describes outcomes in PCI and CABG in patients not eligible for the SYNTAX trial

• Of all-comers with three-vessel and/or LM disease, 6.4% were considered inoperable; 35% not feasible for PCI

Presented by Dr. Friedrich Mohr at ESC 2008

MACCE

Repeat revascularization

5

15

20

25

12.0

20.4

%

0DES-PCI (n = 198)

1010

20

25

10

CABG (n = 1,077)

%

0

5

15

6.0

2.0

20

TIME-CHF

• No difference in final NT-BNP between the 2 arms

• No difference in the survival (p = 0.06) or hospitalization-free survival (p = 0.46), but ↓ in CHF hospitalization-free survival (p = 0.008)

• Greater reductions in patients younger than 75 years

• Quality of life better in older patients with standard therapy

Trial design: Patients with chronic systolic HF were randomized to intensified BNP-guided therapy or standard therapy, with the specific inclusion of patients ≥75 years. Clinical outcomes were compared at 18 months.

Results

Conclusions

• Intensified BNP-guided therapy was not associated with better survival

• Elderly patients do better with standard therapy, including in quality-of-life assessment

Presented by Dr. H.P. Brunner-La Rocca at ESC 2008

Standard therapy(n = 248)

Intensified therapy(n = 251)

(p < 0.05)

Change in quality of life, Age ≥75 years

10

TIMIC

• Majority in immunosuppressive therapy arm showed an ↑ in LVEF (26.4-48.0%) and ↓ in LV end-diastolic diameter (LVEDD) (68.6-52.8 mm)

• None of the patients in the placebo arm improved; some showed further ↓ in LVEF and ↑ in LVEDD

Trial design: Patients with virus-negative inflammatory cardiomyopathy were randomized to either immunosuppressive therapy with prednisone and azathioprine or placebo for 6 months. Echocardiographic parameters were compared at 6 months.

Results

Conclusions

• Immunosuppressive therapy in virus-negative inflammatory cardiomyopathy may be associated with an improvement in LVEF and LVEDD, compared with placebo

• Clinical outcomes are awaited

• May represent novel approach to heart failure management in these patients

Presented by Dr. Andrea Frustaci at ESC 2008

(p < 0.05)

Immunosuppressive therapy(n = 43)

Placebo(n = 42)

-15

15

30 21.6

-8.1

% 0

Change in LVEF from baseline

TRANSCEND

• No difference between telmisartan (15.7%) and placebo (17.0%) in the incidence of the primary outcome (CV death, MI, stroke, CHF) (p = 0.22)

• Stroke, death, or MI was reduced with telmisartan (p = 0.05)

• No difference in mortality (p = 0.49); marginal reduction in MI (3.9% vs. 5.0%, p = 0.06)

Trial design: Patients at high risk for cardiovascular events, and with intolerance to ACE inhibitors, were randomized to telmisartan or placebo. Patients were followed for a median of 56 months.

Results

Conclusions

TRANSCEND Investigators. Lancet 2008;Aug 31:[Epub]

Telmisartan(n = 2,954)

Placebo(n = 2,972)

•Telmisartan is not more effective than placebo in reducing the incidence of the composite primary endpoint, but does reduce the incidence of stroke, death, or MI

•May be an alternative in high-risk patients, who are intolerant to ACE inhibitors

15.7

%

0

10

Primary endpoint

2017.0

0

10

15

5

Mortality

12.3 11.7

%

(p = 0.22) (p = 0.49)