1 Atrial Fibrillation Findings in the LIFE Trial.

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Atrial Fibrillation Findings in the LIFE Trial

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1. Background — Atrial Fibrillation (AF) and Cardiovascular Risk

2. New-Onset AF in the LIFE Trial

3. Reduced Cardiovascular Risk in Patients with AF at Baseline

4. Overall Conclusions

Outline

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Background

• AF increases cardiovascular morbidity and mortality

• AF increases risk of stroke

• Patients with hypertension have an increased risk of developing AF

• The combination of hypertension and AF further increases cardiovascular risk

Benjamin EJ et al Circulation 1998;98:946–952; Krahn AD et al Am J Med 1995;98:476–484; Hart RG et al Ann Intern Med 2003;138:831–838; Straus SE et al JAMA 2002;288:1388–1395.

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Angiotensin II Receptor Blockade Reduces New-Onset Atrial Fibrillation and Subsequent Stroke

Compared to Atenolol: The LIFE Study

J Am Coll Cardiol 2005;45:712–719.

Kristian Wachtell, Mika Lehto, Eva Gerdts, Michael H. Olsen, Björn Hornestam, Björn Dahlöf, Hans Ibsen, Stevo Julius, Sverre E. Kjeldsen,

Lars H. Lindholm, Markku S. Nieminen, Richard B. Devereux

Recently published in the Journal of the American College of Cardiology

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LIFE AF Substudy Design

• 8851 hypertensive patients with left ventricular hypertrophy (LVH) but without AF

• Random assignment to once-daily losartan or once-daily atenolol for a mean of 4.8 years

• ECGs at baseline and at yearly follow-up

ECG=electrocardiograms

Wachtell K et al J Am Coll Cardiol 2005;45:712–719.

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* Titration encouraged if SiDBP >90 mmHg or SiSBP >140 mmHg but was mandatory if SiBP >160 / 95 mmHg**Other antihypertensives excluding ACEIs, AII antagonists, beta-blockersHCTZ=hydrochlorothiazide, SiDBP= sitting diastolic blood pressure, SiSBP=sitting systolic blood pressure Adapted from Dahlöf B et al Lancet 2002; 359:995–1003.

Design/Dosing Titration

Day 14

Day7

Day1

Mth1

Mth2

Mth 4

Mth6

Yr1

Yr1.5

Yr2

Yr2.5

Yr3

Yr3.5

Yr4

Yr5

Titration to target blood pressure: <140/90 mmHg*

Placebo Losartan 50 mg

Atenolol 50 mg

Losartan 50 mg + HCTZ 12.5 mg*

Losartan 100 mg + HCTZ 12.5 mg*

Losartan 100 mg + HCTZ 12.5- 25 mg + others**

Atenolol 50 mg + HCTZ 12.5 mg*

Atenolol 100 mg + HCTZ 12.5 mg*

Atenolol 100 mg + HCTZ 12.5- 25 mg + others**

Trial Profile of Subpopulation

1556 ineligible1341 did not meet protocol criteria215 were unwilling to participate

10,778 assessed for eligibility

9222 randomized

Losartan group4298 available for analysis

150 patients with new-onset AF

Atenolol group4182 available for analysis

221 patients with new-onset AF

8851 study patients

29 excluded for irregularities at one center

342 with a history of AF at baseline

Adapted from Wachtell K et al J Am Coll Cardiol 2005;45:712–719.7

Baseline Characteristics of Patients with New-Onset AF*

* AF was identified from yearly ECGs that underwent Minnesota coding for AF at one ECG core center.

Losartan-based Atenolol-based Characteristics regimen (n =150) regimen (n = 221)

Age (years) 70.3 + 6.9 70.7 + 6

Women (%) 75 (50 ) 106 (48)

Systolic BP (mmHg) 177.3 + 14.2 177.8 + 13.5

Diastolic BP (mmHg) 97.9 + 8.8 96.5 + 8.4

ECG evidence of LVH

Cornell voltage-duration (mVms) 2990 + 993 2975 + 929

Sokolow-Lyon (mV) 30 + 11.5 30.8 + 10.9

Heart rate (beats/min) 74.3 + 11.4 72.4 + 11.6

Framingham risk (%) 23.7 + 9.5 24.2 + 9.4

8 Adapted from Wachtell K et al J Am Coll Cardiol 2005;45:712–719.

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Losartan Significantly Reduced the Risk of New-Onset AF by 33%

HR = hazard ratio; CI = confidence intervalAdapted from Wachtell et al J Am Coll Cardiol 2005;45:712–719.

HR: 0.67 [95% CI: 0.55–0.83], p<0.001Adj HR: 0.67 [95% CI: 0.55–0.83], p<0.001

0 6 12 18 24 30 36 42 48 54 60 660

1

2

3

4

5

6

7

8

Time (months)

Pro

po

rtio

n o

f p

atie

nts

wit

h f

irst

eve

nt

(%)

Losartan group

Atenolol group

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Patients with New-Onset AF Had an Increased Risk of Cardiovascular Events

Ref 5, page 717, Table 3, lines 2-4, 6, 8-10

0

5

10

15

20

25

Patients withnew-onset AF(n = 371)

Patients withsinus rhythm(n = 8480)

7.5%

15.4%

6.7%

4.2% 5% 4%

Per

cen

tag

e

Cardiovascularmortality

Fatal or Nonfatalstroke

MICompositeendpoint

22.1%

10.7%

(n=28) (n=352) (n=57) (n=428) (n=25) (n=342)(n=82) (n=911)

Adapted from Wachtell K et al J Am Coll Cardiol 2005;45:712–719.

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Losartan group Atenolol group(n=150) (n=221)

Baseline

Systolic 177.3 + 14.2 177.8 + 13.5

Diastolic 97.9 + 8.8 96.5 + 8.4

Reduction*,**

Systolic 28.5 + 18.9 27.3 + 19.3

Diastolic 15.8 + 10.1 15.9 + 10.0

* Mean + SD

** At end of follow-up or last visit before endpoint

SD = standard deviation

Losartan- and Atenolol-Based Regimens Resulted in Similar BP Reductions in Patients with New-Onset AF

mmHg


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Study Summary

• Patients with new-onset AF had an increased risk of cardiovascular events, irrespective of treatment regimen

– Twofold increase in the risk of CV mortality

– Threefold increase in the risk of fatal or nonfatal stroke

• Losartan and atenolol provided similar BP reductions in patients with new-onset AF

• A losartan-based regimen provided a 33% risk reduction in new-onset AF versus an atenolol-based regimen


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Authors’ Conclusion

“…new-onset AF and subsequent stroke were significantly reduced by losartan- compared with atenolol-based antihypertensive treatment, with similar blood pressure reduction.”

Kristian Wachtell, et al.


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Cardiovascular Morbidity and Mortality in Hypertensive Patients with a History of Atrial Fibrillation:

The LIFE Study

J Am Coll Cardiol 2005;45:705–711.

Kristian Wachtell, Björn Hornestam, Mika Lehto, David J. Slotwiner, Eva Gerdts, Michael H. Olsen, Peter Aurup, Björn Dahlöf, Hans Ibsen,

Stevo Julius, Sverre E. Kjeldsen, Lars H. Lindholm, Markku S. Nieminen, Jens Rokkedal, Richard B. Devereux

Recently published in the Journal of the American College of Cardiology

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LIFE AF Substudy Design

• 342 hypertensive patients with LVH and ECG-documented AF or atrial flutter or history of AF

• Random assignment to once-daily losartan or once-daily atenolol for a mean of 4.8 years

• ECGs at baseline and at yearly follow-up


Baseline Demographics of Patients with History of AF

Patients on Losartan Patients on Atenolol Characteristics (n = 157) (n = 185)

Age (years) 69.9 + 6.7 70.7 + 6.2

Women — n (%) 64 (41 ) 84 (45.2)

Systolic BP (mmHg) 177 + 14 175 + 14

Diastolic BP (mmHg) 97 + 10 96 + 10

ECG evidence of LVH

Cornell voltage-duration (mVms) 2968 + 1392 3120 + 1393

Sokolow-Lyon (mV) 32.3 + 11.1 31.8 + 10.2

Heart rate (beats/min) 75 + 14 76 + 14

Framingham risk score 0.270 + 0.104 0.262 + 0.103

Current atrial fibrillation — n (%) 51(32.5) 64 (34.6)

Adapted from Wachtell K et al J Am Coll Cardiol 2005;45:705–711.16

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Losartan-Based Regimen Resulted in 42% Risk Reduction in the Primary Composite Endpoint* in Patients with a History of AF at Baseline

HR: 0.58 (0.39–0.87), p=0.009Adj HR: 0.58 (0.39–0.88), p=0.009

* Composite endpoint was first occurrence of cardiovascular death, stroke, and MI.

0

10

20

Losartan

Atenolol

Time (months)

Pro

po

rtio

n o

f p

atie

nts

w

ith

fir

st e

ven

t

40

30

Losartan: 157 151 142 136 131 69Atenolol: 185 166 155 143 132 57

50

Number of Patients:


0 6 12 18 24 30 36 42 48 54 60 66 72

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Losartan-Based Regimen Resulted in a 45% Risk Reduction in Stroke in Patients with a History of AF

Time (months)


Number of Patients:

0 6 12 18 24 30 36 42 48 540

5

10

Losartan

Atenolol

Pro

po

rtio

n o

f p

atie

nts

w

ith

fir

st e

ven

t (%

)

15

60 66 72

20 HR: 0.55 [0.31–0.97], p=0.038Adj. HR: 0.58 [0.31–0.97], p=0.045


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Losartan-Based Regimen Resulted in a 42% Risk Reduction in Cardiovascular Death in Patients with a History of AF

Time (months)


Number of Patients:

0 6 12 18 24 30 36 42 48 540

10

20

Losartan

Atenolol

Pro

po

rtio

n o

f p

atie

nts

w

ith

fir

st e

ven

t (%

)

30

60 66 72

HR: 0.58 [0.33–0.99], p=0.048Adj. HR: 0.58 [0.33–0.99], p=0.045


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0 6 12 18 24 30 36 42 48 540

Losartan

Atenolol

Time (months)

Pro

po

rtio

n o

f p

atie

nts

w

ith

fir

st e

ven

t (%

)

HR = 1.63, 95% CI = 0.65–4.04, p = 0.296Adj. HR: 1.49 [0.60–3.72], p=0.392

60 66 72


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7

6

5

4

3

2

1

Losartan-Based Regimen Had No Significant Effect on the Risk of Myocardial Infarction

Number of Patients:


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0 6 12 18 24 30 36 42 48 540

10

Losartan

Atenolol

Time (months)

Pro

po

rtio

n o

f p

atie

nts

w

ith

fir

st e

ven

t (%

)

30HR: 0.67 [0.42–1.05], p=0.079Adj. HR: 0.67 [0.42–1.06], p=0.09

60 66 72


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Losartan-Based Regimen Displayed a Nonsignificant Trend to Reduce the Risk of All-Cause Mortality

Number of Patients:


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Losartan- and Atenolol-Based Regimen Resulted in Similar BP Reductions in Patients with a History of AF

0 6 12 18 24 30 36 42 48 5460

80

90

100

120

130

140

Losartan

Atenolol

Study Month

BP

(m

mH

g)

110

160

170

180

150

70

Systolic

MeanArterial

Diastolic


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Study Summary

In hypertensive patients with LVH and a history of AF

• Losartan- and atenolol-based regimens provided similar BP reductions

• A losartan-based regimen was associated with a 42% risk reduction in the composite endpoint

• Patients on a losartan-based regimen had a 42% risk reduction in cardiovascular death

• A 45% risk reduction in stroke was observed in patients on a losartan-based regimen


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Authors’ Conclusion

“Losartan-based antihypertensive therapy was more effective than an atenolol-based regimen in reducing the risk of the primary composite endpoint of CV morbidity and CV mortality as well as the secondary endpoints of stroke and CV death in hypertensive patients with ECG LVH and a history of AF.”

Kristian Wachtell, et al.


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Cardiac Pathology and Ischemic Stroke

Vaziri SM et al Circulation 1994;89:724–730; Hart RG et al Ann Intern Med 2003;138:831–838; Fyrenius A et al Heart 2001;86:448–455; Shinokawa N et al Chest 2001;120:840–846.

LVH or atrial enlargement

AF

Left atrial blood stasis and emboli formation

Thrombotic or embolic

event

Ischemic stroke

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Overall AF Risk Findings

• AF increases cardiovascular morbidity and mortality and the risk of stroke in hypertensive patients with ECG-confirmed LVH.

• Patients with new-onset AF have an approximate:

– Twofold increased risk of cardiovascular events

– Threefold increased risk of fatal or nonfatal stroke

Benjamin EJ et al Circulation 1998;98:946–952; Krahn AD et al Am J Med 1995;98:476–484; Hart RG et al Ann Intern Med 2003;138:831–838; Straus SE et al JAMA 2002;288:1388–1395; Wachtell K et al J Am Coll Cardiol 2005;45:712–719.

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Overall Treatment Comparison: Losartan vs. Atenolol

• In patients without AF at baseline, a losartan-based regimen provided a 33% risk reduction in new-onset AF versus an atenolol-based regimen

• In patients with a history of AF at baseline, a losartan- versus an atenolol-based regimen was associated with:

– 42% risk reduction in the composite endpoint (cardiovascular death, stroke, or MI)

– 45% risk reduction in stroke

– 42% risk reduction in cardiovascular death

– No significant differences in MI

• These two studies provide the first documented evidence that one antihypertensive medication (a regimen based on losartan) was more effective than another (a regimen based on atenolol) in reducing the development of new-onset AF and in reducing CV morbidity and mortality in hypertensive patients with LVH and a history of AF, with comparable reductions in BP

Wachtell K et al J Am Coll Cardiol 2005;45:712–719; Wachtell K et al J Am Coll Cardiol 2005;45:705–711.

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References

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Atrial Fibrillation Findings

in the LIFE Trial

1 Atrial Fibrillation Findings in the LIFE Trial.

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