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L osartan I ntervention F or E ndpoint Reduction in Hypertension Study

L osartan I ntervention F or E ndpoint Reduction in Hypertension Study. LIFE Study Overview Double-blind, randomized trial to compare the effects of losartan and atenolol on cardiovascular morbidity and mortality in high-risk patients with hypertension and left ventricular hypertrophy (LVH)

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L osartan I ntervention F or E ndpoint Reduction in Hypertension Study

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  1. Losartan Intervention For Endpoint Reduction in Hypertension Study LIFE Study Overview Double-blind, randomized trial to compare the effects of losartan and atenolol on cardiovascular morbidity and mortality in high-risk patients with hypertension and left ventricular hypertrophy (LVH) Population • 9,193 patients (55 to 80 years old) from 945 sites in 7 countries • previously treated or untreated essential hypertension (systolic BP 160–200 mmHg or diastolic BP 95–115 mmHg) • ECG LVH • 1,195 patients (13%) had diabetes at baseline www.hypertensiononline.org Dahlof B, et al. Lancet. 2002;359:995-1003.

  2. LIFE Study Design Assessed for eligibility n=10,780 • Ineligible (n=1,558) • failed protocol • criteria (n=1,343) • unwilling to • participate (n=215) Randomized n=9,222 Excluded for irregularities (n=29) Losartan n=4,605 Atenolol n=4,588 4,605 available for intention-to-treat analyses 44 withdrew consent 57 vital status only 4 lost to follow-up 4,588 available for intention-to-treat analyses 34 withdrew consent 50 vital status only 8 lost to follow-up www.hypertensiononline.org Dahlof B, et al. Lancet. 2002;359:995-1003.

  3. Primary Endpoint Composite of cardiovascular mortality, fatal and non-fatal myocardial infarction, and fatal and non-fatal stroke Other predefined endpoints total mortality angina pectoris† heart failure† coronary or peripheral revascularization procedures resuscitated cardiac arrest new-onset diabetes mellitus LIFE Study Endpoints* *Each endpoint includes only first event; patients could appear in more than one category.†Requiring hospital admission www.hypertensiononline.org Dahlof B, et al. Lancet. 2002;359:995-1003.

  4. LIFE Study Distribution of 9,193 Participants Among 7 Countries Finland16% Iceland1% Denmark15% Norway15% United States19% Sweden24% United Kingdom9% www.hypertensiononline.org Dahlof B, et al. Lancet. 2002;359:995-1003.

  5. LIFE Study Dosing Losartan 100 mg + HCTZ 12.5-25 mg + others* Titration to target blood pressure <140/90 mmHg Losartan 100 mg + HCTZ 12.5 mg Losartan 50 mg + HCTZ 12.5 mg Losartan 50 mg Placebo Atenolol 50 mg Atenolol 50 mg + HCTZ 12.5 mg Atenolol 100 mg + HCTZ 12.5 mg Atenolol 100 mg + HCTZ 12.5-25 mg + others* 14 7 1 2 4 6 1 1.5 2 2.5 3 3.5 4 5 1 DAY MONTH YEAR *Other antihypertensives excluding ACEIs, AII antagonists, beta-blockers www.hypertensiononline.org Dahlof B, et al. Lancet. 2002;359:995-1003.

  6. LIFE Study Baseline Characteristics* (1) *P=NS for all comparisons www.hypertensiononline.org Dahlof B, et al. Lancet. 2002;359:995-1003.

  7. LIFE Study Baseline Characteristics* (2) *P=NS for all comparisons www.hypertensiononline.org Dahlof B, et al. Lancet. 2002;359:995-1003.

  8. LIFE Study Distribution of Therapy* Losartan (mean dosage 82 mg) 50 mg only 50 mg + additional drugs* Off study drugs 100 mg with or without additional drugs* Alone Atenolol (mean dosage 79 mg) With HCTZ only With other drugs only With HCTZ and other drugs *At endpoint or end of follow-up www.hypertensiononline.org Dahlof B, et al. Lancet. 2002;359:995-1003.

  9. LIFE Study Blood Pressure and Heart Rate Results *P=0.017 †P<0.0001 www.hypertensiononline.org Dahlof B, et al. Lancet. 2002;359:995-1003.

  10. LIFE Study Blood Pressure During Follow-up Systolic Mean Arterial mmHg Diastolic Losartan Atenolol 54 48 0 6 12 18 24 30 36 42 Study Month Dahlof B, et al. Lancet. 2002;359:995-1003. Reprinted with permission from Elsevier Science. www.hypertensiononline.org

  11. Losartan (n) 4605 4524 4460 4392 4312 4247 4189 4112 4047 3897 1889 901 Atenolol (n) 4588 4494 4414 4349 4289 4205 4135 4066 3992 3821 1854 876 LIFE Study Primary Composite Endpoint 16 Intention-to-treat 14 Adjusted risk reduction 13·0%, P=0·021 Unadjusted risk reduction 14·6%, P=0·009 12 10 Atenolol Proportion of patients with first event (%) 8 Losartan 6 4 2 Study Month 0 6 12 18 24 30 36 42 48 54 60 66 Dahlof B, et al. Lancet. 2002;359:995-1003. Reprinted with permission from Elsevier Science. www.hypertensiononline.org

  12. LIFE Study Cardiovascular Mortality 8 Intention-to-treat 7 Adjusted risk reduction 11·4%, P=0·21 Unadjusted risk reduction 13·3%, P=0·14 6 5 Atenolol Proportion of patients with first event (%) 4 Losartan 3 2 1 0 6 12 18 24 36 42 48 54 60 66 30 Study Month Dahlof B, et al. Lancet. 2002;359:995-1003. Reprinted with permission from Elsevier Science. www.hypertensiononline.org

  13. LIFE Study Fatal and Non-Fatal Myocardial Infarction 7 Intention-to-treat Adjusted Risk Reduction -7·3%, P=0·49 Unadjusted Risk Reduction -5·0%, P=0·63 6 5 Losartan 4 Proportion of patients with first event (%) Atenolol 3 2 1 0 6 12 18 24 36 42 48 54 60 66 30 Study Month Dahlof B, et al. Lancet. 2002;359:995-1003. Reprinted with permission from Elsevier Science. www.hypertensiononline.org

  14. LIFE Study Fatal and Non-Fatal Stroke 8 Intention-to-treat Adjusted risk reduction 24·9%, P=0·001 Unadjusted risk reduction 25·8%, P=0·0006 7 6 Atenolol 5 Proportion of patients with first event (%) Losartan 4 3 2 1 0 6 12 18 24 36 42 48 54 60 66 30 Study Month Dahlof B, et al. Lancet. 2002;359:995-1003. Reprinted with permission from Elsevier Science. www.hypertensiononline.org

  15. 9 8 7 6 5 4 3 2 1 0 6 12 18 24 36 42 48 54 60 66 30 LIFE Study New-Onset Diabetes 10 Intention-to-treat Adjusted risk reduction 25%, P=0·001 Unadjusted risk reduction 25%, P=0·001 Atenolol Proportion of patients with first event (%) Losartan Study Month Dahlof B, et al. Lancet. 2002;359:995-1003. Presented by B Dahlof at the American College of Cardiology Scientific Sessions Late-Breaking Clinical Trials III, 2002. www.hypertensiononline.org

  16. LIFE Study Discontinuation Rates Due to Adverse Events (AE) 20 P<0.0001 16 Atenolol Losartan P<0.0001 12 Proportion of patients who dropped-out because of AE (%) 8 4 P=0.006 0 Serious, drug-related All Drug-related Dahlof B, et al. Lancet. 2002;359:995-1003. Reprinted with permission from Elsevier Science. www.hypertensiononline.org

  17. LIFE Study Change in Cornell Voltage Duration Product and Sokolow-Lyon Cornell Product Sokolow-Lyon 0 -2 -4 -6 -8 Change from baseline (%) -10 P<0.0001 -12 -14 Losartan -16 Atenolol P<0.0001 -18 Dahlof B, et al. Lancet. 2002;359:995-1003. Reprinted with permission from Elsevier Science. www.hypertensiononline.org

  18. Losartan (n) 586 569 558 548 532 520 513 501 484 459 237 127 0 6 12 18 24 36 42 48 54 60 66 30 Atenolol (n) 609 588 562 552 540 527 507 486 472 434 204 99 LIFE Study DiabetesSubgroupPrimary Composite Endpoint 24 Adjusted risk reduction 24·5%, P=0·031 Unadjusted risk reduction 26.7%, P=0·017 20 16 Atenolol Losartan Proportion of patients with first event (%) 12 8 4 Study Month Lindholm LH, et al. Lancet. 2002;359:1004-1010. Reprinted with permission from Elsevier Science. www.hypertensiononline.org

  19. LIFE Study Diabetes Subgroup Primary Composite Endpoint and Components No. of events P value Adjusted hazard ratio (95% CI) Endpoints Composite 242 0.031 0.028 CV Death 99 NS 116 Stroke Myocardial infarction NS 91 Total Mortality 0.002 167 0.5 1 1.5 Favors losartan Favors atenolol Lindholm LH, et al. Lancet. 2002;359:1004-1010. Presented by B Dahlof at the American College of Cardiology Scientific Sessions Late-Breaking Clinical Trials III, 2002. www.hypertensiononline.org

  20. 0 6 12 18 24 36 42 48 54 60 66 30 LIFE Study Diabetes SubgroupTotal Mortality 24 Adjusted risk reduction 38·7%, P=0·002 Unadjusted risk reduction 40·1%, P=0·001 20 16 Atenolol Proportion of patients with first event(%) 12 8 Losartan 4 Study Month Lindholm LH, et al. Lancet. 2002;359:1004-1010. Reprinted with permission from Elsevier Science. www.hypertensiononline.org

  21. LIFE Study Summary • Losartan-based compared with atenolol-based antihypertensive therapy was associated with: • reduced cardiovascular morbidity and mortality (-13%) • fewer strokes (-25%) • similar blood pressure reduction • Losartan reduced the rate of new-onset diabetes (-25%) • In the diabetic subgroup, losartan reduced the rate of: • combined endpoint of cardiovascular morbidity and mortality (-25%) • all-cause mortality (-39%) Dahlof B, et al. Lancet. 2002;359:995-1003. Lindholm LH, et al. Lancet. 2002;359:1004-1010. www.hypertensiononline.org

  22. LIFE Study Conclusions • Losartan reduced the combined risk of cardiovascular morbidity and mortality compared to atenolol with benefits not explained by blood pressure reduction • Losartan reduced the rate of new-onset diabetes • Losartan was significantly better tolerated than atenolol • Among diabetics, losartan reduced cardiovascular morbidity and mortality Dahlof B, et al. Lancet. 2002;359:995-1003. Lindholm LH, et al. Lancet. 2002;359:1004-1010. www.hypertensiononline.org

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