arrhythmias – atrial fibrillation clinical trial summary slides

Arrhythmias – Atrial Arrhythmias – Atrial FibrillationFibrillation

Clinical Trial Summary SlidesClinical Trial Summary Slides

www.cardiosource.com

Results• In ablation group, mean procedure duration 168 minutes, and average of 1.8 procedures performed• After month 3, 70% of medical therapy patients crossed over to ablation therapy• At 1 year, more patients in ablation group free of arrhythmic recurrence vs medical therapy group (Figure)• Oral anticoagulation therapy interrupted in 60% of ablation group and 25% of medical therapy group• 2 cases of tamponade in patients treated with ablationConclusions• Among patients with atrial fibrillation, catheter ablation was associated with ↑ rates of absence of AF compared with antiarrhythmic drug therapy• One limitation was short duration of AF needed to meet primary endpoint, only 3 minutes• Additionally, patients in trial had all previously failed antiarrhythmic drug therapy, and results may not be applicable to other AF patients who had not failed therapy or patients who are not symptomatic

75

7

0

20

40

60

80

100

A-4

Free of arrhythmic recurrence at 1 year

p < 0.05

%Trial Design: A-4 was a randomized trial of atrial fibrillation ablation (n=53) vs antiarrhythmic drugs (n=59)among patients with symptomatic atrial fibrillation (AF) who had failed antiarrhythmic drug therapy. Primaryendpoint was absence of AF for ≥3 minutes, either symptomatic or documented by one year.

Presented at Heart Rhythm Society 2006

Ablation Medical Therapy


16.3

7.0

0

5

10

15

20

13 13

0

5

10

15

20

A-COMET-I

Median time to AF recurrence

p=NS

Trial Design: A-COMET-I was a randomized trial of azimilide (125 mg twice daily for 1-3 days then oncedaily for 6 months; n=227) or placebo (n=219) in patients with AF converted to sinus rhythm by day 6.Primary endpoint was recurrence of AF, restricted to patients with structural heart disease (n=314).

Results• No difference in primary endpoint for azimilidevs placebo in patients with structural heartdisease (HR 1.104, p=0.46), and no difference inmedian time to AF recurrence (Figure)• 3 deaths due to cardiac arrhythmia in azimilidegroup• Serious adverse events occurred in 16.3% ofazimilide group and 7.3% of placebo group(Figure)• Torsades des pointes occurred in 2.6% (n=6) ofazimilide groupConclusions• Among patients with structural heart diseasewho had AF converted to sinus rhythm, treatmentwith azimilide was not associated with differencein arrhythmia recurrence through 6 monthscompared with placebo

Azimilide Placebo

Am Heart J 2006;151:1043-9

Serious adverse events

Day

s

%


1412

28

0

10

20

30

A-COMET-II

Median Time to AF Recurrence (HR 1.29 for placebo vs. azimilide, p = 0.032;HR 0.65 for sotalol vs. azimilide, p = 0.0002)

Trial Design: A-COMET-II was a randomized trial of azimilide (125 mg; n = 211), sotalol (160 mg twicedaily; n = 223), or placebo (n = 224) in patients with AF converted to sinus rhythm by day 4. Primaryendpoint was AF episode, flutter, or PSVT event for azimilide vs. placebo by 6 months.

Results• Primary endpoint ↓ in azimilide group vs. placebo but sotalol ↓ vs. azimilide (Figure)• Symptomatic events lasting >24 hours occurred in 23.2% of azimilide group, 16.1% of sotalol group, and 29% of placebo group• Withdrawal due to AEs ↑ in both azimilide group (12.3%) and sotalol group (13.9%) vs. placebo (5.4%, p < 0.01)• Torsade de pointes occurred in 2.4% (n = 5) of the azimilide group and none in the sotalol or placebo groupsConclusions• Among patients with persistent AF who had converted to sinus rhythm, treatment with azimilide was associated with reduction in primary endpoint compared with placebo, but sotalol was associated with reduction in endpoint compared with azimilide • As with the A-COMET-I study, there were more cases of torsade de pointes in the azimilide group• Azimilide does not appear to be a treatment alternative for patients with persistent AFAzimilide Placebo

Eur Heart J 2006;27:2224-31

Day

s

Sotalol


8.49.4

1.1 0.9 0.90.4

0

2

4

6

8

10

12

A to Z: Phase A

Death/MI/refractory ischemia

HR 0.88p=0.23

%

Trial Design: The A to Z, Phase A trial was a randomized, open label trial of treatment with enoxaparin(n=2026) or UFH (n=1961) as adjunctive therapy to baseline treatment with tirofiban and aspirin inpatients with non-ST elevation acute coronary syndromes. The primary endpoint was non-inferiority forthe composite of all-cause mortality, new MI, and documented refractory ischemia by 7 days.

DeathHR 1.26

p=NS

Results• Trial met pre-specified hypothesis of non-inferioritywith enoxaparin for death, MI or refractory ischemia• Upper 95% CI (HR 1.05) fell within the pre-specified non-inferiority boundary (HR 1.144)• No difference in any component of composite• Safety endpoints did not differ significantly: TIMImajor bleed (Figure), TIMI major or minor bleed(3.1% vs 2.2%, p=0.093) or transfusion (1% vs0.8%, p=0.405)Conclusions• Among patients with non-ST elevation acutecoronary syndromes treated with aspirin andtirofiban, treatment with enoxaparin was non-inferior for death, MI or refractory ischemia at 7days compared with UFH• First randomized trial to look at enoxaparin vsUFH in patients who all received GP IIb/IIIa inhibitor• SYNERGY trial will address efficacy of enoxaparinvs UFH in patients who are all treated with an earlyinvasive therapy (~60% of patients in A to Z treatedearly invasive)• Results of "Z Phase" (simvastatin vs standardcare) pending

TIMIMajor Bleed

p=0.076

Enoxaparin UFHn=2,026 n=1,961

Presented at ACC 2003


1.4

2.4

0

1

2

3

Results• Prior oral anticoagulation therapy used in 77% of patients• Trial discontinued early by data safety monitoring board due to evidence of superiority in primary endpoint with oral anticoagulant therapy (Figure)• Oral anticoagulant therapy group had ↓ rates of stroke (Figure) and non CNS embolism (0.10% per year vs 0.43% per year, p=0.005) Conclusions• Among patients with atrial fibrillation and at least one risk factor for stroke, treatment with oral angicoagulant therapy was associated with reduction in composite of stroke, non-CNS systemic embolism, MI, or vascular death compared with treatment with clopidogrel and aspirin• Trial discontinued early due to overwhelming efficacy for oral anticoagulant therapy• Oral anticoagulant therapy can be difficult to use and requires monitoring of INR on a regular basis• However, present trial confirms the efficacy of oral anticoagulant therapy

3.9

5.6

0

2

4

6

ACTIVE-W

Primary endpointRR 1.44

p = 0.0003

% p

er y

ear

Trial Design: ACTIVE-W was a randomized trial of clopidogrel (75 mg/day) and aspirin (75 to 100 mg/day)(n=3335) or oral angicoagulant therapy with warfarin (n=3371) among patients with atrial fibrillation. Primaryendpoint was composite of stroke, non-CNS systemic embolism, MI, or vascular death, evaluated for non-inferiority.

Lancet 2006; 367: 1903-12

Oral Anticoagulant

Clopidogrel+ASA

Strokep = 0.001


0.80.5

2.9

5.5

0

1

2

3

4

5

6

7

ACUTE

Embolic Eventsp = 0.50

%

Trial Design: Multicenter, randomized trial comparing an early TEE-guided approach to aconventional approach of 3 weeks of warfarin prior to cardioversion for atrial fibrillation.Primary endpoint: Composite of cerebrovascular accident, transient ischemic attack, andperipheral embolism.

Hemorrhagic Eventsp = 0.03

Results• No difference in ischemic stroke or overall embolic events (Figure)• No difference in functional status or death at 8 wks • Overall bleeding ↑ in conventional group (Figure), with no difference in major bleeding• No difference in sinus rhythm at 8 weeks• TEE group cardioverted earlier (3 vs. 30.6 days) (p<0.001)

Conclusions• Among patients with atrial fibrillation of more than 2 day duration, early TEE-guided approach to cardioversion in atrial fibrillation was not associated with increased embolic events compared with 3 weeks of warfarin

Limitations• Underpowered (needed 3000, enrolled 1222)• Rates of embolism lower than in general population• Only 8 weeks of follow-up• Warfarin group ↑ antiarrhythmics at cardioversionTEE-guided ConventionalTEE-guided Conventional

NEJM 2001; 344:1411-20


Results• Median duration of AF at baseline was 5 days in enoxaparin group and 10 days in UFH group (p = 0.11)• TEE with CV: successful in 82% of each group• No major bleeds in the trial and no difference in minor bleeding rates (Figure)• Normal sinus rhythm at 5 weeks ↑ in enoxaparin group (Figure)• Median duration to discharge was shorter in enoxaparin group (4 vs. 5 days, p = 0.003)Conclusions• Among patients with AF undergoing TEE-guided CV, use of enoxaparin was associated with increase in normal sinus rhythm at 5 weeks compared with UFH without an increase in bleeding, although bleeding rate overall in trial was very low• Electrical CV was associated with increased risk of stroke, which led to a combination approach of TEE with short-term anticoagulation

57

76

0

20

40

60

80

100

4 4

0

2

4

6

ACUTE II

Minor Bleed(p = NS)

%

Trial Design: ACUTE II was a randomized trial of transesophageal echocardiography (TEE)-guidedcardioversion (CV) with enoxaparin (n = 76) vs. unfractionated heparin (UFH) (n = 79) in patients with AF.Patients were followed for 5 weeks.

Eur Heart J 2006;27:2858-65Enoxaparin UFH

Normal Sinus Rhythm at 5 Weeks

(p = 0.013)


67.9

92.9

0

20

40

60

80

100

2.5

1.9

0

1

2

3

ADOPT

AF burden

%Trial Design: ADOPT was a multi-center randomized trial of DDDR pacing set at 60 ppm with vs without theDynamic Atrial Overdrive (DAO) pacing algorithm programmed among patients with atrial fibrillation. Theprimary endpoint was symptomatic AF burden during 6 month follow-up.

J Am Coll Cardiol 2003;42:627-33

Results• Percentage of beats atrial paced in DAO ON group than DAO OFF group (Figure), showing algorithm performed as specified in stimulating atrium• Overall AF burden in DAO ON group vs DAO OFF group (Figure), and decrease consistent over time (p<0.005)• Symptomatic AF episodes in both DAO ON group (from 8.0 to 4.3 episodes) and DAO OFF group (from 8.3 to 3.2 episodes) from baseline levels (both p<0.001), but no difference between treatment groups in number of episodes at 6 months (p=NS)• Quality of life (QoL) scores improved in both armsConclusions• Among patients with atrial fibrillation, dynamicatrial overdrive pacing with the atrial fibrillationsuppression algorithm demonstrated overallreductions in atrial arrhythmia burden comparedwith conventional DDDR pacing aloneDAO OFF DAO ON

Percentage of beatsatrial paced

p<0.001

%


26.7 25.9

32.0 32.7

0

10

20

30

40

AFFIRM

RhythmControl

RateControl

MortalityHR = 1.15p = 0.08

%

Trial Design: AFFIRM was a multi-center randomized trial of rhythm control (n=2,033) vsrate control (n=2,027) in patients with atrial fibrillation and a high risk of stroke or death.Patients were followed for 5 years. The primary endpoint was all-cause mortality.

Composite 2°Endpoint*p = 0.33

N Engl J Med 2002;347:1825-33.

Results• All cause mortality did not differ between the rate and rhythm control arms• Hospitalization rate was higher in the rhythm control arm (80% vs 73%, p<0.001)Conclusions• There is no survival benefit to the strategy of rhythm control in elderly patients with atrial fibrillationLimitations• Trial enrolled high-risk elderly patients; extrapolation of results to other subgroups may not be appropriate

* Composite of death, disabling stroke, disabling anoxic encephalopathy, major bleeding, and cardiac arrest

RhythmControl

RateControl


Results• Abnormal TWA test was present in 65% of patients (200 patients were TWA negative and 92 were indeterminate TWA, all grouped as abnormal TWA)• Primary composite endpoint of cardiac death or life-threatening arrhythmias ↑ in those with abnormal TWA vs. normal TWA (HR 4.01, p = 0.002)• Negative predictive value of normal TWA test was 97.3% at 18 months for primary endpoint• Total mortality ↑ among patients with abnormal TWA (Figure), as was composite of arrhythmic death or life-threatening arrhythmias (HR 5.53, 95% CI 1.29-23.65, p = 0.004) Conclusions• Among patients with nonischemic cardiomyopathy, abnormal TWA was associated with fourfold increase in cardiac death or life-threatening arrhythmias through 2 years compared with patients with normal TWA• Identification of heart failure patients at high risk for life-threatening arrhythmias and death needed to target patients who would derive greatest benefit from ICD implantation

3

25

0

10

20

30

ALPHA

Total Mortality(HR 4.60,p = 0.002)

Trial Design: The ALPHA trial tested nonischemic cardiomyopathy patients with NYHA class II or III and LVEF<40% for T-wave alternans (TWA) abnormalities at baseline. Patients were then followed for 18-24 months forthe occurrence of life-threatening arrhythmias and death.

TWA Abnormal TWA Normal

n

Presented at ACC/i2 Summit 2007


Results• Compared with amiodarone alone, primary endpoint of AF by 24 months ↓ in amiodarone+losartan group and amiodarone+perindopril group, with no difference between losartan and perindopril groups (Figure)• Left atrial diameter at 24 months ↓ in amiodarone+losartan group and amiodarone+perindopril group vs amiodarone alone group (36 mm and 35 mm vs 38 mm, respectively; p<0.001 for each)• Frequency of adverse events similar between groups (8.5% for amiodarone alone and amiodarone + losartan groups, 14% for amiodarone + perindopril group)Conclusions• Among patients with lone paroxysmal AF, treatment with amiodarone + losartan or amiodarone + perindopril was associated with reduction in recurrent AF through 2 years compared with amiodarone alone• Prior studies complicated by inclusion of patients with LV dysfunction and hypertension so difficult to attribute reason for reduction in AF with addition of ACE-I or ARB

41

19

24

0

10

20

30

40

50

Amiodarone, Losartan, and Perindopril in Atrial Fibrillation

Atrial fibrillationp=0.006 alone vs amiodarone + losartan

p=0.04 alone vs amiodarone + perindopril

Trial Design: The study was a randomized trial of amiodarone alone (n=59), amiodarone plus losartan (n=59) oramiodarone plus perindopril (n=59) for 2 years in patients with lone paroxysmal AF. Primary endpoint wasincidence of AF from >14 days to 2 years.

Eur Heart J 2006; 27: 1841-1846

Amiodarone alone

Amiodarone + Losartan

%

Amiodarone + Perindopril


5.7

3.2

0

2

4

6

8

4.8

2.8

0

2

4

6

Anticoagulation in Cardioversion using Enoxaparin (ACE)

Primary composite endpoint – intent to

treatp=0.24

%

Trial Design: The ACE trial was a randomized trial of unfractionated heparin (n=248) compared with enoxaparin(n=248) followed by phenprocoumon in the cardioversion of nonvalvular atrial fibrillation. The primaryendpoint was a composite of cerebral-ischemic neurological events, systemic thromboembolism, death fromany cause, and major bleeding complications.

Circulation. 2004;109:997-1003

Results• Primary composite endpoint not significantly different between arms (Figure, RR 0.58, 95% CI 0.23-1.46)• Testing for noninferiority in the per protocol population, enoxaparin was not inferior to UFH (Figure, )• No significant differences in individual endpoints of major hemorrhage, embolic events or mortalityConclusions• Among patients with nonvalvular atrial fibrillation, treatment with enoxaparin was non-inferior compared to treatment with unfractionated heparin in the primary composite endpoint • Trial primarily confined to patients undergoing TEE guided cardioversion • Ease of use and lack of blood monitoring make enoxaparin an attractive option for anticoagulation prior to and after cardioversion for atrial fibrillation

UFH Enoxaparin

%

n=248n=248 n=212 n=216

Primary composite endpoint – per

protocolp=0.016 for non-

inferiority


Results• Only preliminary data available in 150 patients• At 9 months follow-up, freedom from recurrent AF and AT ↑ in CPVA patients vs medical therapy (Figure)• Of 8 patients who had recurrent AF in CPVA group, repeat ablation procedure performed in 3 patients, 1 of whom still had additional recurrent AF• Of 52 patients in medical therapy group who had recurrent AF, 38 had CPVA performed, 4 of whom still had additional recurrent AF• Significant decrease in left atrium diameter at 12 months in CPVA group (P<0.05) but no difference in medical therapy groupConclusions• Among patients with paroxysmal atrial fibrillation, treatment with circumferential pulmonary vein ablation was associated with reduction in recurrent AF and AT compared with conventional antiarrhythmic medical therapy• Present trial one of first randomized trials of CPVA in paroxysmal atrial fibrillation• CPVA recently shown to be beneficial in maintaining sinus rhythm in chronic atrial fibrillation

87

29

0

20

40

60

80

100

APAF

Freedom from recurrent AF and AT

at 9 monthsp < 0.001

%Trial Design: APAF was a randomized trial circumferential pulmonary vein ablation (CPVA) (n=99) comparedwith antiarrhythmic medical therapy (n=99) with flecainide (n=33), sotalol (n=33) or amiodarone (n=33) amongpatients with paroxysmal atrial fibrillation. Primary endpoint was freedom from recurrent atrial arrhythmias at1 year.

Presented at ACC 2006

CPVA Medical Therapy


47

35

0

20

40

60

ARCH

Indicenceof AF

%

Trial Design: ARCH was a single center, randomized double-blinded trial (n=300) designed totest whether treatment with low-dose intravenous amiodarone (1 gm/day for 2 days) would beassociated with a decreased incidence of atrial fibrillation (AF) in patients undergoing openheart surgery without a prior history of perioperative atrial fibrillation compared with placebo.Primary endpoints: Incidence of atrial fibrillation requiring treatment; length of hospital stay.


Results• Approx. 50% of patients took preoperative ß-blockers.• Study drug was terminated early in 4.4% amiodarone patients vs. 1.4% placebo patients (p=0.12).• AF developed in 47% of patients in placebo group vs 35% of patients in amiodarone group (relative risk reduction 26%, p=0.01), and effects were seen within the first few days of treatment.• First episode of post-operative AF occurred on mean post-operative day 2.9 in amiodarone-treated group and day 2.3 in the placebo group (p<0.01).• Length of hospital stay was not significantly different for amiodarone vs placebo (Figure).

Conclusions• Treatment with amiodarone was generally well-tolerated and was associated with a decreased incidence of atrial fibrillation, but no difference in length of hospital stay.• Atrial fibrillation occurred soon after discontinuing the infusion in the amiodarone-treated group.

Placebo Amiodarone

8.27.6

0

5

10

15Lengthof stay

158142

p=0.01 p=0.34D

ays

158142


2.3

5.6

0

2

4

6

ATRIA

JAMA 2001;285:2370-2375

Results• AF prevalence ↑ in men vs women (1.1% of men, 0.8% of women, p<0.001)• AF prevalence ↓ in those age <55 years vs >80 years (0.1% vs 9.0%)• Among those age >50 years, prevalence ↑ in blacks (2.2% vs. 1.5%, p<0.001)Conclusion• In a cross sectional study, AF was more common in men and in older people • Study estimates prevalence of AF will increase as US population ages

Trial Design: ATRIA was a cross-sectional study of adults in a large Californian HMOdesigned to determine age- and sex-specific prevalence of AF, with the goal of projectingprevalence of AF through the year 2050 by applying these calculations to U.S. census data.

Estimated Number of Millions of US Adults with AF

2001 2050


1.2

1.1

0.0

0.5

1.0

1.598

75

0

20

40

60

80

100

4.2

1.1

0

1

2

3

4

5

ATTEST

Median amountof atrial pacing

p<0.001

%

Trial Design: ATTEST was a randomized trial of preventive pacing and antitachycardia pacing (ATP) in patientswith symptomatic atrial fibrillation (AF) or atrial tachycardia (AT). All patients were implanted with a DDDRPpacemaker, and 1 month later patients were randomized to all prevention and ATP therapies ON (n=153) or OFF(n=171). The primary endpoints were AT/AF burden, total AT/AF frequency, and complication-free survival at 3month follow-up.

AT/AF burdenp=0.20


Results• Detection confirmed in 99.9% of AT/AF episodes with stored electrograms• Median amount of atrial pacing was larger in the ON group vs OFF group• ATP terminated 54% of treated episodes in ON group• No significant differences occurred in AT/AF burden, total frequency, or symptomatic frequency between the ON and OFF groups (Figure)• System-related, complication-free survival was 90.2% by Kaplan-Meier estimateConclusions• Among patients with symptomatic AF or AT, there was no difference in AT/AF burden or frequency with atrial prevention and termination therapies combined in a DDDRP pacemaker, despite an increase in the relative amount of atrial pacing and an ATP efficacy of 54%• High proportion of ventricular pacing (median 99%) may have limited any potential benefit from atrial therapies• Bradycardia-induced AT/AF may have been suppressed by DDDR pacing

ATP ON ATP OFF

AT/AF TotalFrequency

p=0.65h/

mon

th

epis

odes

/mon

th


44

91

0

20

40

60

80

100

Ablation group

Results• Procedure duration 193 minutes in ablation group, with fluoroscopy time of 25 minutes• Major ablation-related complications occurred in 4.4% of ablation group• Primary endpoint of atrial arrhythmia free survival improved in ablation group (Figure) Conclusions• Among patients with paroxysmal or persistent atrialfibrillation who have already failed antiarrhythmicdrugs, use of catheter ablation was associated with areduction in atrial fibrillation recurrence at 1 yearcompared with antiarrhythmic drug therapy alone• Prior studies of ablation in AF have been primarilynon-randomized or single center, and success hasbeen defined only in terms of symptom relief• Present study is first multicenter, randomized trial toshow a benefit of preventing AF recurrence withsingle session of catheter ablation

CACAF%

Trial Design: CACAF was a randomized, open-label trial of a single session of catheter ablation in addition toantiarrhythmic drugs (n=68) or antiarrhythmic drugs alone (n=69) in patients with paroxysmal or persistent AFwho have already failed antiarrhythmic drugs. Primary endpoint was absence of atrial tachyarrhythmiarecurrence during 12 month follow-up.

European Heart Journal 2006;27:216-221

Control group

Atrial fibrillationrecurrence

p<0.001


4.3

5.8

0

2

4

6

Canadian Atrial Fibrillation Anticoagulation Study (CAFA)

Placebo Warfarin

Primary end pointp =0.25

n=191 n=187

Trial Design: CAFA was a randomized trial of warfarin vs. placebo for the primary prevention ofstroke and systemic embolism in patients with non-valvular atrial fibrillation. The primary end pointwas combined stroke, systemic embolism, intracranial hemorrhage, and other fatal hemorrhage.The trial was terminated early after accruing roughly 60% of its target enrollment due to thepublication of the AFASAK and SPAF trials which convincingly documented the efficacy of warfarinfor this indication.

0.5

2.6

0

1

2

3

Placebo Warfarin

Major bleedingp=NS

n=191 n=187


Results• Warfarin associated with non-significant 26% in primary end point in intention to treat analysis at avg. 15 months follow-up (Figure) • Stroke and systemic embolism by 55% in warfarin arm (2.7% vs. 5.8%, p=0.07) in on-treatment analysis• Major bleeding non-significantly with warfarin (Figure), as was minor bleeding (16% vs. 9.4%)Conclusions• Warfarin was associated with a non-significant reduction in the risk of stroke and systemic embolism compared with placebo in patients with non-valvular AF, with a slight increase in the risk of serious hemorrhage• Study was underpowered due to early termination, but results consistent with other studies of warfarin in AF


63.0

35.0

0

20

40

60

80

CTAF (Canadian Trial of Atrial Fibrillation)

Sotalol /Propafenone

Amiodarone

AF Recurrencep <0.001

Trial Design: CTAF was a prospective multi-center trial that randomized AF patients toopen-label amiodarone (maintenance 200 mg/d, n=201) vs. sotalol (80-160 mg bid, n=101)or propafenone (450-600 mg/d, n=101). The primary endpoint was time to first AFrecurrence. Patients were followed an average of 16 months.

17.0 18.0

0

10

20

30 Major non-fatal eventsp = NS

New Engl J Med 2000; 342(13):913-20

Results• Amiodarone significantly likelihood of recurrent AF (Figure)• Median time to AF recurrence 98 days for sotalol/propafenone; incalculable for amiodarone (<50% recurrence)• Study drug discontinuation for non-cardiac side effects slightly more likely with amio than sotalol/propafenone (18% vs. 11%, p=0.06)• No difference in death (4.5% vs. 4.0%) or major non-fatal events (Figure)Conclusions• Oral amiodarone associated with nearly 50% reduction in recurrent AF compared with sotalol or propafenoneSotalol /

Propafenone Amiodarone


3.3

30.3

0

15

30

45

Danish dofetilide in atrial fibrillation and flutter study

Placebo Dofetilide

Conversion to sinus rhythmp < 0.006

Am Heart J 1999;137:1062-69

n=30 n=66

%

Results• Conversion to sinus rhythm with dofetilide vs placebo (Figure)• 3% incidence of torsades de pointes with dofetilideConclusions• Among patients with sustained AF or AFl, IV dofetilide associated with conversion to sinus rhythm • Low incidence of complicationsLimitations• Low absolute conversion rate

Trial Design: This was a multi-center randomized trial of intravenous dofetilide (n=66)compared with placebo (n=30) in patients with atrial fibrillation and atrial flutter. Theprimary endpoint was conversion to sinus rhythm within 3 hours of infusion.


1.2

2.3

0

1

2

3

4

15

40

47

57

0

10

20

30

40

50

60

Efficacy and Safety of Ibutilide Fumarate for the Conversion of Atrial Arrhythmias After Cardiac Surgery

Conversion to Sinus

%

Trial Design: Randomized trial of the safety and efficacy of 0.25, 0.5 and 1.0 mg ibutilide infusioncompared with placebo in conversion of atrial arrhythmias among patients following cardiac surgery(n=302).

Polymorphic VT

Circulation 1999; 100:369-375

Results• Conversion to sinus rhythm ↑ in ibulitide vs placebo (p=0.0001) (Figure)• Conversion with ibutilide atrial flutter ↑ vs atrial fibrillation (78% vs 44% in the 1 mg group)• ↑ doses of ibutilide associated with ↓ time to conversion (23, 33 and 36 minutes for 1, 0.5 and 0.25)• Polymorphic VT ↑ in ibutilide group vs placebo (Figure)

Conclusions• Among patients who develop atrial fibrillation or atrial flutter following cardiac surgery, ibutilitide treatment was associated with a higher rate of conversion to sinus rhythm and with increased rates of polymorphic ventricular tachycardia within 72 hours

Limitations• Small sample size, limited statistical analysis• Only 72 hours of follow-upPlacebo 0.25 0.5 1.0

n=

Placebo Ibutilide


158

59

0

50

100

150

200

Results• Time from randomization to recurrence of AF/AFL longer in dronedarone arm vs placebo in both EURIDIS and ADONIS trials• Majority of recurrent events were symptomatic• Time to first symptomatic AF/AFL recurrence was longer in dronedarone group vs placebo in both EURIDIS trial (p=0.0055) and ADONIS trial (p=0.021)• Ventricular rate at first recurrence ↓ in dronedarone group vs placebo in both EURIDIS trial (102.3 vs 117.5 bpm, p<0.001) and ADONIS trial (104.6 vs 116.6, p<0.001)• Findings consistent in prespecified subgroups, including patients with recent cardioversion and amiodarone prior to randomization• No difference in combined trials for safety endpointsConclusions• Among patients with atrial fibrillation or atrial flutter, treatment with the novel antiarrhythmic agent dronedarone was associated with a reduction in time to recurrent AF/AFL compared with placebo at 1 year follow-up, with no evidency of toxicity• Additional studies needed to evaluate efficacy of dronedarone therapy with amiodarone

41

96

0

25

50

75

100

125

EURIDIS and ADONIS

EURIDISRR 0.78

p = 0.0138

Day

s Trial Design: EURIDIS and ADONIS were randomized (2:1), double-blind trials to evaluate the safety andefficacy of dronedarone (400 mg twice per day, n=828), a novel antiarrhythmic agent that is a derivative ofamiodarone, compared with placebo (n=409) among patients with atrial fibrillation or atrial flutter. Primaryendpoint was time from randomization to first documented AF/AFL recurrence.

Presented at ESC 2004

Dronedarone Placebo

ADONISRR 0.72

p = 0.0017

Time from randomization to recurrence of AF/AFL


8.5%

7.5%

0%

5%

10%

Heparin in Acute Embolic Stroke Trial (HAEST)

Dalteparin ASA

Recurrent strokep = 0.73

n=224 n=225

Trial Design: HAEST was a randomized, double-dummy/double-blind trial comparing aspirin(160 mg/d) with dalteparin (100 IU/kg sc bid), a low molecular weight heparin for patientswith atrial fibrillation and acute ischemic stroke. The primary end point was recurrentischemic stroke at 14 days. Secondary end points included stroke progression, death, andcerebral hemorrhage.

14.2%

11.6%

0%

5%

10%

15%

Dalteparin ASA

Cerebral bleedsp = 0.41

n=224 n=225

Lancet 2000;355:1205-10

Results• Recurrent ischemic stroke at 14 days similar between groups (Figure)• No significant difference in cerebral bleeds at 14 days (Figure)• No significant differences between groups in progression of symptoms (10.7% vs. 7.6%, p=0.26) or all-cause mortality (9.4% vs. 7.1%, p=0.40)

Conclusions• In AF patients with acute ischemic stroke, dalteparin and aspirin produced similar short-term results• Despite intuitive appeal, early anticoagulation of these patients does not yield substantial clinical benefit


3.6

5.1

0

2

4

6

8

Results• Primary endpoint of death or heart failure hospitalization met criteria for non-inferiority (Figure) • All-cause mortality also met criteria for non-inferiority but not superiority (Figure)• During follow-up, RV pacing in DDDR AVSH group averaged 10%Conclusions• Among patients implanted with ICD for standard indications, use of dual chamber DDDR AVSH pacing was non-inferior to single chamber VVI-40 pacing for death or HF hospitalization at 1 year• Results differ from DAVID trial, which showed treatment with dual-chamber pacing was associated with ↑ mortality or CHF hospitalizations by 1 year vs ventricular backup pacing in patients with LV dysfunction and standard indication for ICD therapy but not pacing• Several differences between trials, including pacing at lower threshold in present trial (60 bpm vs 70 bpm in DAVID) and patient population, which in INTRINSIC RV excluded patients with >20% RV pacing in first week

6.4

9.5

0

5

10

15

INTRINSIC RV

Death or HF hospitalization

by 1 yearp < 0.001 for non-inferiority

p = 0.072 for superiority

%

Trial Design: INTRINSIC RV was a randomized trial of ICD programming of DDDR AV search hysteresis (AVSH)60-130 (n=502) or programming of VVI-40 (n=486) among patients implanted with a VITALITY AVT ICD who had<20% RV pacing after 1 week of DDDR programming. Primary endpoint was death or heart failurehospitalization through one year, evaluated for non-inferiority.


DDDR AVSH VVI-40

Mortality by 1 yearp < 0.001 for non-inferiority

p = 0.23 for superiority


18

25

0

10

20

30

Results• No procedural complications in RFA group• Conversion to sinus rhythm occurred in all patients in amiodarone group• Primary endpoint of AFL recurrence ↑ in amiodarone group versus RFA group (Figure)• No difference in atrial fibrillation between groups (Figure) or mortality (16% in amiodarone group vs. 11% in RFA group, p = 0.7)Conclusions• Among patients with first episode of symptomatic AFL, treatment with RFA was associated with reduction in recurrence of AFL at mean 13-month follow-up compared with cardioversion and amiodarone therapy• While AFL was reduced with RFA, there was no difference in frequency of atrial fibrillation with RFA compared to amiodarone therapy • Economic implications of first-line therapy with RFA for initial AFL are unknown

29.5

3.8

0

10

20

30

40

LADIP

AFL recurrence(p < 0.001)

%

Trial Design: LADIP was a randomized trial of amiodarone therapy (n = 52) versus radiofrequency catheterablation (RFA) (n = 52) in patients with a first episode of symptomatic atrial flutter (AFL). Primary endpoint wastime to recurrence of AFL confirmed by ECG at mean 13-month follow-up.

Circulation 2006;114:1676-81

Amiodarone RFA

Atrial Fibrillation(p = 0.3)

%


59.9

48.7

0

25

50

75

METAFER

Placebo Metoprolol

RecurrentAtrial Fibrillation/

Atrial Flutterp = 0.005

J Am Coll Cardiol 2000; 36 (1):139-46

n=197 n=197

%

Results• Recurrent atrial fibrillation or atrial flutter in metoprolol CR/XL group vs placebo (Figure)• In subset of patients who underwent electrical cardioversion, 106 of 163 patients (65.0%) in placebo group had recurrent atrial fibrillation vs 82 of 162 patients (50.6%) in metoprolol CR/XL group (p=0.002)• In patients who had recurrent atrial fibrillation, median time to relapse was 7.5 days in placebo group vs 13.0 days in metoprolol CR/XL group (p = 0.001)• Patients who had recurrent atrial fibrillation or flutter had mean heart rate of 107 27 beats/min in placebo group vs 98

23 beats/min in metoprolol CR/XL group (p=0.015) • No significant difference was found in rate of adverse events Conclusions• Among patients with persistent atrial fibrillation, metoprolol CR/XL was associated with a reduction in the primary endpoint of recurrent atrial fibrillation after cardioversion to normal sinus rhythm when compared to placebo with a similar safety profile, suggesting metoprolol CR/XL may be safe and effective treatment for prevention of recurrent atrial fibrillation after conversion to normal sinus rhythm

Trial Design: METAFER was a multi-center randomized trial of long-acting metoprolol (CR/XL)compared with placebo in patients with a history of persistent atrial fibrillation who were successfullycardioverted to sinus rhythm. Patients were followed for 6 months. The primary endpoint wasrecurrent atrial fibrillation or flutter at 6 months following cardioversion.


Results• Mean duration study drug prior to cardioversion, 27 days• Sinus rhythm not obtained at time of cardioversion in 4 metoprolol patients (5%) and 6 placebo patients (7%)• Early re-initiation of AF within 2 hours occurred in 7 placebo patients and no metoprolol patients (p < 0.01)• No difference in need for repeat cardioversion (Figure)• Primary endpoint of sinus rhythm at 6 months ↑ in metoprolol vs. placebo group (Figure) Conclusions• Among patients with persistent AF who undergo direct current cardioversion, pretreatment with metoprolol was associated with higher rate of maintenance of sinus rhythm at 6 months compared with placebo• Other agents used to maintain sinus rhythm following cardioversion include class I and III antiarrhythmic drugs; however, these agents can also be proarrhythmic• Metoprolol did not appear to be proarrhythmic, although larger studies would be needed to more fully evaluate its safety in this population

26

46

0

10

20

30

40

5049

47

0

10

20

30

40

50

Metoprolol and Cardioversion for Atrial Fibrillation

Sinus Rhythm at 6 Months (p < 0.01)

%

Trial Design: The study was a randomized, double-blind trial of pretreatment with metoprolol (n = 83) orplacebo (n = 85) for ≥1 week prior to direct current cardioversion in patients with persistent atrial fibrillation(AF). Primary endpoint was number of patients in sinus rhythm 6 months after the first cardioversion.

Eur Heart J 2007;28:1351-7

Metoprolol Placebo

Repeat Cardioversion(p = NS)

%


Results• Freedom from atrial fibrillation without anti-arrhythmic medication and ≥1 procedure at 6 months was present in 72% of PVI group and 0% of AVN ablation group (p < 0.05)• No difference in use of anti-arrhythmic therapy • EF ↑ in PVI group vs. AVN ablation group (Figure)• Improvement in 6-minute walk test ↑ in PVI group more than AVN ablation group (Figure)• Quality-of-life score was better in PVI group (60 vs. 80, p < 0.001)Conclusions• Among patients with atrial fibrillation and CHF, PVI was associated with improvements in EF, 6-minute walk test, and quality-of-life scores at 6 months compared to AVN ablation with biventricular pacing • Results of the present study, which favor rhythm control over rate control, differ from the AFFIRM trial, which favored rate control over rhythm control• However, many differences exist between studies, including population with CHF in the present study and mode of rate and rhythm control

58

95

0

20

40

60

80

10035

28

0

10

20

30

40

PABA CHF

Improvement in 6-Minute Walk Test

(p < 0.001)

%Trial Design: PABA CHF was a randomized trial of pulmonary vein isolation (PVI; n = 39) or AV node (AVN)ablation with biventricular pacing (n = 38) in patients with atrial fibrillation and CHF. Primary endpoints were 6-minute walk test, Minnesota Living With Heart Failure Questionnaire, and ejection fraction onechocardiography at 6 months.

Presented at AHA 2006

PVI AVN Ablation

Ejection Fraction(p < 0.001)

%


2 2

3

0

1

2

3

4

PATAF

Primary EndpointAnnual event rate

HR for low AC vs ASA: 0.91, p=NSHR for standard AC vs ASA: 0.78, p=NS

Trial Design: Randomized trial designed to assess the effectiveness of aspirin versus low-doseor standard dose anticoagulation (AC) in preventing thromboembolism in patients with non-rheumatic atrial fibrillation in general practice. Primary endpoint: Systemic embolism, stroke,major hemorrhage and vascular death. Mean follow-up 2.7 years.

BMJ 1999; 319:958-964

Results• Patients well matched for baseline characteristics• Compared with aspirin, no difference with low-dose AC (HR 0.91, 95% CI 0.61 to 1.4) or with standard dose AC (HR 0.78, 95% CI 034 to 1.8)• In per protocol analysis, HR for primary events was 0.77 (95% CI 0.49 to 1.2) in low-dose AC group and 0.87 (95% CI 0.34 to 2.2) in standard AC group compared with aspirin• No significant differences in risk of bleeding between treatment groupsConclusions• Among patients with non-rheumatic atrial fibrillation, standard or low anticoagulation was not shown to be more effective than aspirin• Authors recommendations based on these results were that the prophylactic choice in primary care is aspirin if there is no clear indication for full dose anticoagulation

Low-dose anticoagulation

Standard doseanticoagulation131122

% p

er y

ear

Aspirin141


Results• Pacing implantation successful in 102 of 146 patients in BV group and 82 of 106 patients in RV group• Mean distance walked during 6-minute walk test at 6 months was 345.6 m in BV group vs 323.6 m in RV group, a greater improvement in BV group (Figure)• Peak VO2 at 6 months by 1.02 ml/kg/min in BV group (p<0.01) but did not change significantly in RV group (0.09 ml/kg/min, p=0.43)• Exercise duration significantly improved in BV group (41.6, p<0.01) but no difference in RV group (19.8, p=0.19)• No difference in survival (p=0.21)Conclusions• Among patients with chronic atrial fibrillation refractory to pharmaceutical therapy undergoing ablate and pace therapy, use of biventricular pacing was associated with an improvement in the primary endpoint of exercise capacity at 6 months compared with permanent right ventricular pacing• Improvements were noted with BV therapy in the 3 measures of functional capacity of 6 minute walk test distance, peak VO2, and exercise duration

82.4

56.8

0

20

40

60

80

100

PAVE

Change in distance walked

at 6 month6 min walk test

p = 0.03

m

Trial Design: PAVE was a randomized trial of biventricular (BV) pacing (n=146) or permanent right ventricular(RV) pacing (n=106) in patients with chronic atrial fibrillation (AF) refractory to pharmaceutical therapyundergoing ablate and pace therapy. Primary endpoint was exercise capacity as assessed by 6 minute walktest.

Presented at ACC Scientific Sessions 2004

BV Pacing RV Pacing

www.cardiosource.comObserved Rate

Results• CHADS risk score for predicting stroke, averaged 2.5, which corresponds to expected annual stroke risk of stroke of 6.3%• Mortality 5.4% • Total cardiac tamponade in 2 patients and pericardial effusion in 2 patients• 3 TIAs occurred in 2 patients• Observed annual stroke rate ↓ than expected based on CHADS risk score (Figure)Conclusions• Among patients with atrial fibrillation at high-riskfor embolization and stroke, use of PLAATO devicefor percutaneous left atrial appendage occlusionwas feasible and was associated with a lower thanexpected stroke rate based on baseline stroke riskestimate• Randomized trial need to assess efficacy ofPLAATO device

2.2

6.3

0

2

4

6

8

PLAATOTrial Design: PLAATO was a registry of patients with atrial fibrillation at high-risk for embolization and stroketreated with the PLAATO device for percutaneous left atrial appendage occlusion (n=111). Patients werefollowed for mean of 9.8 months. Primary endpoint was major adverse events at 30 days.


Risk-scorePredicted Rate

%

Annual Stroke Rate


22.6

17.2

0

10

20

30

RACE

Composite 1°Endpoint

N Engl J Med 2002;347:1834-40.

%

Results• Sinus rhythm occurred in 10% of the rate control group vs 39% of the rhythm control group at follow-up• The –5.4% difference in the primary composite endpoint met the criterion for non-inferiority between rate and rhythm controlConclusions• Rate control is not inferior to rhythm control in patients with recurrent, persistent AF

Trial Design: RACE was a multi-center randomized non-inferiority trial of rate control vsrhythm control in patients with with recurrent persistent atrial fibrillation. Patients werefollowed for a minimum of 2 years. The primary endpoint was a composite ofcardiovascular death, hospital admissions for heart failure, thromboembolic complications,severe bleeding, pacemaker implantation, and severe adverse effects of therapy .

Rhythm Control Rate Control

n=266 n=256


59.0

54.2

0

20

40

6044.4

4.5

0

10

20

30

40

50

Radiofrequency Ablation During Mitral Valve

Sinus rhythm at 12 months

p<0.001

(%)

Trial Design: The study was a randomized, patient-blind trial of left atrial radiofrequency ablation (RFA)during mitral valve surgery (n=49) vs mitral valve surgery alone (n=48) in patients with continuous atrialfibrillation. Primary endpoint was presence of sinus rhythm at 12 months.

Results• Presence of sinus rhythm ↑ in RFA group vssurgery alone group (Figure)• Reduction in BNP level from baseline to 12months ↑ in RFA group (-76 fmol/ml vs -30 fmol/ml,p=0.02)• Ejection fraction at 12 months ↑ in RFA group(Figure)• No difference in operative or post-operativecomplicationsConclusions• Among patients with continuous atrial fibrillation,treatment with left atrial RFA during mitral valvesurgery was associated with higher rates of sinusrhythm at 12 months compared with mitral valvesurgery alone• Given lack of operative complications or mortalityobserved in RFA group vs mitral valve surgeryalone, these promising findings warrant largermulticenter trials to further validate findings

Surgery + RFA Surgery alone

JAMA. 2005;294:2323-2329

Ejection fractionat 12 months

p=0.004

(%)


4.95.4

0

2

4

6

8

Results• Trial stopped early after interim analysis met superiority criteria of dual-chamber minimal ventricular pacing • Median % of ventricular beats paced ↓ in dual-chamber minimal ventricular pacing group vs. conventional dual-chamber pacing group (9.1% vs. 99.0%, p < 0.001)• No difference in % of atrial beats paced between groups (71.4% vs. 70.4%, p = 0.96)• Primary endpoint of persistent AF ↓ in minimal ventricular pacing group (Figure, HR 0.60)• No difference in mortality (Figure)Conclusions• Among patients with sinus-node disease, use of dual-chamber minimal ventricular pacing was associated with reduction in AF compared with conventional pacing • RV stimulation during dual-chamber pacing has been thought to be culprit factor in adverse effects on LV pump function, leading to no mortality benefit with dual-chamber pacing, and in some cases, increased heart failure• Dual-chamber minimal ventricular pacing was associated with reduced ventricular desynchronization and with reduced AF

7.9

12.7

0

5

10

15

SAVE PACe%

Trial Design: In the SAVE PACe trial, patients with sinus-node disease received dual-chamber pacemakers andwere then randomized to dual-chamber minimal ventricular pacing (n = 530) or conventional dual-chamberpacing (n = 535). Primary endpoint was time to persistent atrial fibrillation at a mean 1.7 years of follow-up.

Dual-Chamber Minimal Ventricular

Pacing

Conventional Dual-Chamber Pacing Group

Persistent AF (p = 0.009)

Mortality(p = 0.54)

N Engl J Med 2007;357:1000-8


95 9498

0

20

40

60

80

100

44

5051

0

20

40

60

Sotalol or Amiodarone vs Digoxin for Atrial Fibrillation

Conversion to Sinus Rhythm

p=NS

%

Trial Design: The trial was a randomized trial of rapid high-dose IV infusions of amiodarone (10mg/kg in 30minutes; n=52), sotalol (1.5mg/kg infused in 10 minutes; n=45) or digoxin (500 g in 20 minutes; n=43) inpatients presenting to the emergency department with recent symptomatic atrial fibrillation. The primaryendpoint was rate of reversion to sinus rhythm.

Results• Rate control occurred more quickly with rapid infusion of sotalol or amiodarone vs digoxin• Rate control significantly better than digoxin with sotalol at 30 minutes (p<0.005), 3 hours (p<0.005), and 6 hours (p<0.032), and better with amiodarone at 30 minutes and 3 hours (p=0.02 for both)• No significant difference in pharmacological conversion to sinus rhythm by treatment group (Figure)• Cardioversion after study drug infusion and defibrillation, was high in all 3 groups and did not differ between treatment groups (Figure)• Serious adverse reactions trended in amiodarone group (n=7), including symptomatic hypotension (n=5, p=0.035)Conclusions• Among patients with recent symptomatic atrial fibrillation, treatment with rapid infusion of sotalol or amiodarone was associated with improved rate control compared with digoxin but there was no significant difference in the time to cardioversion between treatment groups

Sotalol Amiodarone

Cardioversion afterStudy Drug Infusion

and Defibrillationp=NS

%

Digoxin

Am Heart J 2004;147(1):E3


Results• Mean number of months since AF diagnosis 8 months in sotalol group, 9 months in propafenone group, and 8 months in placebo group• AF relapse or side effects ↓ for propafenone group vs sotalol or vs placebo; sotalol group ↓ vs placebo• Mean time to event longer for propafenone group (26 months) vs sotalol (18 months) or vs placebo (11 months) • Study drug discontinued due to significant side effects in 5 of 69 patients who received sotalol and 5 of 45 patients who received propafenoneConclusions• Among patients with recurrent symptomatic AF, long-term treatment with propafenone was associated with areduction in atrial fibrillation relapse and side effectscompared with both sotalol and placebo, while sotalol wasassociated with a reduction compared with placebo• Event rate began to diverge in propafenone group after6 months and continued through follow-up, suggestingbenefit throughout long-term treatment

52

8188

0

20

40

60

80

100

Sotalol vs Propafenone for Long-term Maintenanceof Normal Sinus Rhythm

AF Relapse or Side Effectsp<0.001 for Propafenone vs Sotalol

p<0.001 for Propafenone vs Placebop<0.001 Sotalol vs Placebo

%

Trial Design: Patients with recurrent symptomatic atrial fibrillation were randomized in a single-blind mannerto sotalol (titrated upward to 480 mg daily; n=85), propafenone (150 mg 3 times per day maintenance dose;n=86) or placebo (3 tablets per day; n=83). Patients were followed for up to 48 months.

Am J Cardiol 2004;94:1563-1566Propafenone Sotalol

Placebo


9.0

6.1

8.1

11.9

0

2

4

6

8

10

12

14

SPORTIF II

Minor Bleeding

(%)

Trial Design: SPORTIF II was a randomized tolerability and safety trial of treatment with the novel, oraldirect thrombin inhibitor ximelagatran (20, 40 or 60 mg bid; n=187) vs warfarin (n=67) in patients withnonvalvular atrial fibrillation and at least one additional risk factor for stroke. Patients were followed for14 weeks. The primary endpoints were thromboembolic events and bleedings.

Results• No systemic embolic events in either arm; 1 nonfatal ischemicstroke in 60 mg ximelagatran arm and 0 in warfarin arm• 1 TIA in the 60 mg ximelagatran arm and 2 in the warfarin arm• No major bleeding in ximelagatran arms and 1 major bleed inwarfarin arm• No difference in minor bleeding (Figure)• Liver enzyme elevation elevated in 4.3% of patients inximelagatran arms vs 0 in warfarin armConclusions• Among patients with nonvascular atrial fibrillation and >1additional risk factor for stroke, treatment with oral directthrombin inhibitor ximelagatran was tolerable and safe with nodifference in the primary endpoints of thromboembolic eventsand bleedings• Unlike warfarin, ximelagatran does not require coagulationmonitoring and is delivered in a fixed oral dose• Elevations in liver enzymes may require monitoring• Open-label SPORTIF III trial showed non-inferiority betweenximelagatran and warfarin for stroke or systemic embolic events• Double-blind SPORTIF V trial underway


20 mgWarfarin 60 mg40 mgXimelagatran


5.86.3

0

2

4

6

8

1.6

1.2

0

1

2

SPORTIF V

Stroke or SystemicEmbolic Events

Absolute 0.45% annual in ximelagatran arm(95% CI -0.13-1.03)

p=0.13

Even

t rat

e pe

r ye

ar (%

)

Trial Design: SPORTIF V was a randomized, double-blind trial of treatment with the novel, oral directthrombin inhibitor ximelagatran (n=1,960) vs warfarin (n=1,962) in patients with atrial fibrillation and atleast one additional risk factor for stroke. Patients were followed for a mean of 20 months. The primaryendpoint was non-inferiority for the composite of stroke and systemic embolic events.

Results• Trial met pre-specified hypothesis of non-inferiority with ximelagatran for prevention of strokeand systemic embolic events• No difference in ICH (0.6% in each arm) or majorbleed (2.4% with ximelagatran vs 3.1% for warfarin,p=NS)• No difference in secondary endpoint primaryevents+major bleed+death (Figure)• Liver enzyme elevation >3xULN in ximelagatranarm (6.0% vs 0.8%, p<0.001)Conclusions• Among patients with nonvascular atrial fibrillationand >1 additional risk factor for stroke, treatmentwith oral direct thrombin inhibitor ximelagatran wasnon-inferior for primary endpoint of stroke orsystemic embolic events• Unlike warfarin, ximelagatran does not requirecoagulation monitoring and is delivered in a fixedoral dose• Elevations in liver enzymes may requiremonitoring• Results similar to open-label SPORTIF III trial

Primary Events +Major Bleeding + Death

p=0.527

Ximelagatran Warfarin n=1,960 n=1,962

AHA 2003 Late Breaking Trials


5.5

6.1

0

2

4

6

8

2.5

4.9

0

2

4

6

8

STAF

Primary Endpointp=0.99

% p

er y

ear

Trial Design: STAF was a randomized trial of rhythm control (restoration and maintenance of sinus rhythm;n=100) vs rate control (pharmacologic or invasive rate-control and anticoagulation; n=100) in patients withatrial fibrillation. Patients were followed for a mean of 19.6 months. The primary endpoint was death,cardiopulmonary resuscitation, cerebrovascular event, and systemic embolism at follow-up.

Mortality


Results• No difference in primary endpoint or any components of the composite endpoint• 18 of the 19 primary endpoints occurred in AF vs only 1 in sinus rhythm (p=0.049)• No difference in the secondary endpoints of syncope, (0 vs 1, p=0.99), bleeding (6.8%/year in rhythm-control arm vs 4.9%/year in rate-control arm; p=0.99), or quality of life• Patients in the rhythm-control group hospitalized significantly more often (54 vs 26 hospitalizations, p<0.001) and longer (449 days vs 314 days, p<0.001)• Sinus rhythm maintained in only 23% of patients after 3 yearsConclusions• Among patients with atrial fibrillation, there was no difference in the primary endpoint between rhythm control and rate control• Lack of difference may be since so few patients managed with rhythm control (23%) were able to be maintained in sinus rhythm over the long termRhythm Control Rate Control

3.1

0.6

0

1

2

3

4

CerebrovascularEvent


Results• Mean cryoablation procedure time 21 minutes• Primary endpoint of sinus rhythm at 6 months ↑ in mitral valve surgery with cryoablation group vs mitral valve surgery alone group (Figure), a finding maintained at 12 months (73% vs 49%, p=0.042)• Adverse events relatively infrequent• Bleeding requiring re-operation occurred in 1 patient in surgery alone group and 3 patients in cryoablation groupConclusions• Among patients with permanent AF and mitral valve disease, mitral valve surgery with pulmonary vein isolation using cryoablation was associated with higher rates of sinus rhythm at 6 months compared with mitral valve surgery without cryoablation• While present study demonstrated benefit of cryoablation with mitral valve surgery, data from present trial do not provide information of effect of cryoablation with coronary bypass surgery

73

46

0

20

40

60

80

100

SWEDMAF

Sinus rhythmat 6 months

p = 0.024

%Trial Design: SWEDMAF was a randomized trial of mitral valve surgery alone (n=35) or mitral valve surgerywith pulmonary vein isolation using cryoablation (n=30) among patients with permanent atrial fibrillation (AF)and mitral valve disease. Primary endpoint was sinus rhythm at 6 months.


Mitral Valve Surgery + Cryoablation

Mitral Valve Surgery Alone


1

11

0

5

10

15

20

TWA in CHF%

Trial Design: The TWA in CHF study evaluated the association of T wave alternans (TWA) withdevelopment of an arrhythmic event in patients with left ventricular dysfunction who have not yet hadan arrhythmic event. Patients (n=590) underwent exercise testing with TWA and a 24-hour Holterrecording. Patients were followed for 12.2 months. The primary endpoint was arrhythmic death andnon-fatal cardiac arrest. Results

• TWA test positive in 30%, negative in 34% andindeterminate in the remaining 36% of patients• All-cause mortality at 2 years was higher in TWA positivepatients vs TWA neg patients (HR 9.7, log rank p<0.01)• Among patients who were TWA negative and had an EF<30% (n=78), only 1 death occurred during follow-up• Positive TWA remained associated with mortality (HR 8.4,p<0.01) after adjusting for ejection fractionConclusions• Among patients with left ventricular dysfunction who havenot yet had an arrhythmic event, T wave alternans wasassociated with risk of death• TWA may provide additional risk stratification for patientswho, despite a low EF, may have low mortality and littlebenefit from an ICD• Given high cost of ICDs, risk stratification methods will bevaluable in identifying an optimal patient population for useof the therapy• Further follow-up is needed to determine if the TWAremains associated with long-term follow-up• Results of primary endpoint of arrhythmic death and non-fatal cardiac arrest are pending

All-causeMortalityHR 9.7p < 0.01

TWA Negative TWA Positive

ACC 2003 Late Breaking Trials


Results• No difference in primary endpoint of permanent AF for comparison of acute vs. routine serial cardioversion or for digoxin vs. verapamil (Figures)• Beta-blocker therapy to maintain adequate rate control ↑ in digoxin group vs. verapamil group (60% vs. 38%, p = 0.01) • Patients in acute group had more ECVs than serial group (median 3 vs. 2, p < 0.05; ≥3 ECVs 54% vs. 33%, p < 0.01)• Patients in the digoxin group had more ECVs than verapamil group (median 3 vs. 2, p < 0.001; ≥3 ECVs 60% vs. 28%, p < 0.001)Conclusions• Among patients with persistent AF, acute ECV was not associated with a difference in permanent AF by 18 months compared with routine serial ECVs• Additionally, verapamil was not associated with a difference in permanent AF by 18 months compared with digoxin for rate control before ECV

28

36

0

10

20

30

40

32 31

0

10

20

30

40

VERDICT

Permanent AF by 18 Months

%

Trial Design: VERDICT was a randomized, factorial trial of: 1) acute (within 24 hours) (n = 74) or routine serialelectrical cardioversions (ECVs) (n = 70); and 2) verapamil (120-360 mg/day, n = 74) vs. digoxin (0.125-0.25mg/day, n = 70) for rate control before ECV. Patients were randomized in the month prior to ECV. Primaryendpoint was permanent AF by 18 months.


Acute Cardioversion

Serial Cardioversion

(p = 0.33)

%

(p = 0.85)

Digoxin Verapamil

arrhythmias – atrial fibrillation clinical trial summary slides

Documents