LIFE

Published

Dahlof B, et al. "Cardiovascular Morbidity and Mortality in the Losartan Intervention for Endpoint reduction in hypertension study (LIFE)". The Lancet. 2002. 359:995-1003.
PubMed • Full text • PDF

Clinical Question

Among hypertensive patients with left ventricular hypertrophy (LVH), does losartan lower stroke, MI, or CVD mortality compared to atenolol?

Bottom Line

Among hypertensive patients with LVH, losartan lowers risk of stroke, MI, or CVD mortality when compared to atenolol.

Major Points

Multiple landmark trials (VA Cooperative Trial in 1967, HDFP in 1979, SHEP in 1989) previously demonstrated a reduction in cardiovascular morbidity and mortality with the treatment of hypertension. In addition to lowering blood pressure, left ventricular hypertrophy (LVH) had also been shown to be an independent risk factor for cardiovascular events in hypertensive patients. As angiotensin II has been shown to contribute to development of LVH, blocking angiotensin II theoretically could reduce LVH and therefore reduce cardiovascular events.

Published in 2002, the Cardiovascular Morbidity and Mortality in the Losartan Intervention For Endpoint Reduction in Hypertension (LIFE) trial was conducted to determine if administration of losartan compared to atenolol in hypertensive patients would confer further reduction in cardiovascular morbidity and mortality independent from effects on blood pressure.

The primary composite outcome of cardiovascular morbidity (MI or stroke) and mortality showed a relative risk reduction of 13% between the two groups, favoring losartan. This reduction in the primary outcome was primary driven by a 25% relative risk reduction in stroke. This suggested that losartan reduced rates of stroke independent of blood pressure reduction. Rates of MI and CVD mortality were similar between groups. There was a significant reduction in LVH in the losartan group compared to the atenolol group. Patients on atenolol had significantly higher drop-out rates secondary to adverse events.

The number needed to treat (NNT) for 5 years in the general study population to prevent stroke was 54. Of note, reduction in stroke was significantly greater in patients with cerebrovascular disease (NNT = 25), isolated systolic hypertension (NNT = 24), and atrial fibrillation (NNT = 9). A 2012 Cochrane meta-analysis investigating the use of beta-blockers in hypertension concluded that RAS inhibitors prevented more strokes compared to beta-blockers, but were not significantly different in preventing cardiovascular mortality, cardiovascular disease, and coronary heart disease. Rates of discontinuation were similarly found to be higher when using beta-blockers compared to RAS inhibitors. An accompanying LIFE paper on the diabetic subgroup (n=1195) demonstrated a reduction of the primary endpoint by 34% (p=0.03), total mortality by 39% (P=0.0002) and cardiovascular mortality by 37% (P=0.03). Heart failure admissions were reduced by 41% (p=0.02). Rates of new onset diabetes was less in the group treated with losartan, along with reduced rates of new onset atrial fibrillation.

Guidelines

2017 ACC AHA AAPA ABC ACPM AGS APhA ASH ASPC NMA PCNA Hypertension (2017, adapted)

• New definitions for BP ranges: Normal BP is <120/<80, elevated BP is 120-129/<80, stage 1 HTN is 130-139/80-89, and stage 2 HTN is ≥140/≥90 mm Hg
• Use antihypertensive medications if prior clinical CVD or 10-year ASCVD risk score is ≥10% and BP is ≥130/≥80 mm Hg (COR I, LOE A for SBP and C-EO for DBP)
• Use antihypertensive medications if no prior clinical CVD and 10-year ASCVD risk score is <10% and BP is ≥140/≥90 mm Hg (COR I, LOE C-LD)
• First line agents include thiazide diuretics (chlorthalidone preferred), CCBs, and ACE-inhibitors or ARBs (COR I, LOE A)
  • Initial use of two first-line agents from different classes is recommended if stage 2 HTN and average BP is >20/10 mm Hg above target (COR I, LOE C-EO)
  • Initial use of one first-line agent is reasonable if stage 1 HTN and BP goal <130/80 mm Hg (COR IIa, LOE C-EO)
• Specific population recommendations:
  • Among black adults without CKD or HF, initial treatment should be with a thiazide or CCB (COR I, LOE B-R)
    • Black adults are likely to need ≥2 agents to achieve BP <130/90 mm Hg (COR I, LOE C-LD)
  • Age ≥65
    • Community-dwelling - Treat SBP to <130 mm Hg (COR I, LOE A)
    • High burden of comorbidities and limited life expectancy - Consider patient preference and use a team-based approach to decide intensity of BP lowering and choice of antihypertensives (COR IIa, LOE C-EO)
  • Stable CAD - Treat to BP goal <130/80 mm Hg (COR I, LOE B-R for SBP and C-EO for DBP)
    • Preferred medications are proven beta-blockers, ACE-inhibitors, or ARBs for compelling reasons (prior MI, stable angina), with addition of other medications including dihydropyridine-CCBs (especially for angina; COR I, LOE B-NR), thiazide diuretics, and/or mineralocorticoid receptor antagonists as needed (COR I, LE B-R for SBP and C-ED for DBP)
  • Prior stroke or TIA- Restart or initiate antihypertensives within a few days of the index event (COR I, LOE A for restarting; COR I, LOE B-R for initiation if BP >140/90); a BP goal <130/80 may be reasonable (COR IIb, LOE B-R)
    • If no history of HTN and BP <140/90, the usefulness of antihypertensives is not well-established (COR IIb, LOE C-LD)
    • If lacunar infarct, a target SBP <130 mm Hg may be reasonable (COR IIb, LOE B-R)
    • Preferred agents are thiazide diuretic, ACE-inhibitor or ARB, or combination of thiazide+ACE-inhibitor (COR I, LOE A)
  • CKD - Treat to BP goal <130/80 mm Hg (COR I, LOE B-R for SBP and C-EO for DBP)
    • If CKD stage ≥III or stage I or II with albuminuria ≥300 mg/day or ≥300 mg/g alb:creat, treating with ACE-inhibitor (COR IIa, LOE B-R) or ARB (COR IIb, LOE C-EO) is reasonable to slow kidney disease progression
    • If kidney transplantation, it's reasonable to target BP <130/80 mm Hg (COR IIa, LOE B-NR for SBP and C-EO for DBP), with calcium antagonist as choice to improve GFR and kidney survival (COR IIa, LOE B-R)
  • DM - Treat to BP goal <130/80 mm Hg (COR I, LOE B-R for SBP and C-EO for DBP)
    • Any first-line medication is effective (COR I, LOE A), but consider ACE-inhibitors and ARBs if albuminuria (COR IIb, LOE B-NR)
  • PAD - Treat similarly to patients with HTN and no PAD (COR I, LOE B-NR)
  • Increased risk for development of HF - Treat to <130/80 (COR I, LOE B-R for SBP and C-EO for DBP)
  • HFrEF - Treat with goal-directed medical therapy (e.g., proven beta-blockers, ACE-inhibitors or ARBs, etc.) targeting BP <130/80 mm Hg (COR I, LOE C-EO)
    • Do not use non-dihydropyridine CCBs (COR III, LOE B)
  • HFpEF and volume overload - Use diuretics to control HTN (COR I, LOE C-EO)
    • If persistent HTN and managed volume overload, use ACE-inhibitors or ARBs and beta-blockers to attain an SBP <130 mm Hg (COR I, LOE C-LD)

Design

• Multicenter, double blinded, randomized control trial
• N=9222
  • Losartan (n=4605)
  • Atenolol (n=4588)
• Mean follow-up: 4.8 years
• Analysis: Intention-to-treat
• Primary outcome:
  • Stroke, MI, or CVD mortality

Population

Inclusion Criteria

• 55-80 years
• Treated or untreated hypertension, with BP 160-200/95-115 after 1-2 weeks of placebo run-in
• ECG signs of LVH

Exclusion Criteria

• Secondary Hypertension
• MI or stroke within past six months
• Angina requiring B-blocker or CCB treatment
• Heart failure or LV ejection fraction 40% or less
• Disorder requiring treatment with ARB, B-blocker, hydrochlorothiazide, or ACE inhibitor (by physician opinion)

Baseline Characteristics

From both groups combined.

Demographics

• Demographics: Age 66.9y, female 54%, White race 92%, Black race 6%
• BP: 174.4 / 97.8
• Heart rate: 73.8
• BMI: 28.0
• Cornell voltage-duration product (mm x ms): 2828.8
• Sokolow-Lyon (mm): 30.0
• Framingham Risk Score: 0.224
• Current smokers: 16%

Medical History

• Any vascular disease: 25%
  • Coronary heart disease: 16%
  • Cerebrovascular disease: 8%
  • Peripheral vascular disease: 6%
• Atrial Fibrillation: 14%
• Isolated systolic hypertension: 14%
• Diabetes: 13%

Interventions

• All groups were started on placebo therapy for minimum 1-2 weeks, and those with BP 160-200/95-115 were randomized to an arm that began with losartan or atenolol
• Patients in both groups received similar escalation of drug therapy, as per below protocol:
  • Losartan 50mg or Atenolol 50mg
  • Losartan 50mg or Atenolol 50mg; + hydrochlorothiazide 12.5mg
  • Losartan 100mg or Atenolol 100mg; + hydrochlorothiazide 12.5mg
  • Losartan 100mg or Atenolol 100mg; + hydrochlorothiazide 12.5mg-25mg; + other antihypertensive treatment

Outcomes

Presented as losartan vs atenolol. Hazard ratios adjusted for Framingham risk score and LVH.

Primary Outcome

Stroke, MI, or CVD mortality

11% vs. 13% (HR 0.87; 95% CI 0.77 to 0.98; P=0.02)

Secondary Outcomes

Stroke

5% vs. 7% (HR 0.75; 95% CI 0.63 to 0.89; P=0.001)

MI

4% vs. 4% (HR 1.07; 95% CI 0.88 to 1.31; P=0.491)

CVD mortality

4% vs. 5% (HR 0.89; 95% CI 0.73 to 0.107; P=0.21)

New Onset Diabetes

6% vs. 8% (HR 0.75; 95% CI 0.63 to 0.88; P=0.001)

Rates of revascularization, admissions for angina, admissions for heart failure, total mortality, and resuscitated cardiac arrest did not differ between the two groups.

Additional Outcomes

Reduction in Cornell voltage-duration product (mmxms)

290 vs. 124 (P<0.0001)

Reduction in Sokolow-Lyon voltage (mm)

4.6 vs. 2.7 (P<0.0001)

Mean final BP

144.1/81.3 (MAP 102.2) vs. 145.4/80.9 (MAP 102.4)

BP target achieved (<140/90)

48% vs. 45%

Heart Rate Reduction

-1.8 BPM vs. -7.7 BPM

Average drug dose

82mg vs. 79mg

Adherence

84% vs. 80%

Subgroup Analysis

Primary Endpoint in Low Risk Patients (No Vascular Disease or Diabetes)

8% vs. 9% (RR = 0.82, p=0.03)

Adverse Events

All, leading to drop out

See Figure 6 on page 1000 for bar graph depiction of these events.

All: ~13% vs. ~17% (p<0.0001)

Drug Related: ~6% vs. ~10% (p<0.0001)

Serious: ~5% for both (P=0.087)

Serious, drug related: <1% vs ~1.5% (p=0.006)

Statistically significant prespecified adverse events

Bradycardia: 1% vs. 9%

Cold extremities: 4% vs. 6%

Hypotension: 3% vs. 2%

Sexual dysfunction: 4% vs. 5%

Criticisms

• Population included few non-white individuals
• non-statistical increase in myocardial infarction in losartan group despite reduction in LVH
• Increased drop-out and fewer patients proceeding to combination therapy in atenolol group
• Subgroup analysis reveals diabetic population had higher systolic pressure and lower diastolic pressure in atenolol group

Funding

Merck, as an unrestricted grant.