LIFE

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Dahlof et al. "Cardiovascular Morbidity and Mortality in the Losartan Intervention for Endpoint reduction in hypertension study (LIFE)". The Lancet. 2002. 359:995-1003.
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Clinical Question

Among hypertensive patients with left ventricular hypertrophy, does losartan prevent more cardiovascular morbidity and death compared to atenolol?

Bottom Line

Losartan prevents more cardiovascular morbidity and death compared to atenolol, although this composite endpoint was driven mostly by a reduction in stroke.

Major Points

Multiple landmark trials (VA Cooperative Trial, HDFP, SHEP) 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[1]. 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 myocardial infarction and cardiovascular death did not differ between the two 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 results of this trial led to B-blockers being dropped from the list of recommended first line agents (thiazide, CCB, ACEI, ARB) for the treatment of hypertension in the JNC clinical guidelines[2].

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).[3]

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.[4]

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).[5]

Rates of new onset diabetes was less in the group treated with losartan, along with reduced rates of new onset atrial fibrillation.

Guidelines

Eighth Joint National Committee Guidelines (JNC 8) (2014, adapted)[2]

In the general nonblack population, including those with diabetes, initial antihypertensive treatment should include a thiazide-type diuretic, calcium channel blocker (CCB), angiotensin-converting enzyme inhibitor (ACEI), or angiotensin receptor blocker (ARB). (Moderate Recommendation – Grade B)

Design

  • Multicenter, multinational double-blinded, double-dummy randomized control trial
  • N=9222
    • Losartan (n=4605)
    • Atenolol (n=4588)
  • Follow-up: 4.8 years (minimum 4 years for all patients)
  • Analysis: Intention-to-treat
  • Primary outcome:
    • Composite Endpoint of Stroke, Myocardial Infarction, and Cardiovascular Death
  • Secondary outcomes:
    • Individual components of primary composite end point
    • Mortality
    • Angina pectoris or heart failure requiring hospitalization
    • Coronary or peripheral revascularization procedures
    • Resuscitated cardiac arrest
    • New onset diabetes mellitus

Population

Inclusion Criteria

  • 55-80 years
  • Treated or untreated hypertension
  • 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 angiontensin receptor blocker, B-blocker, hydrochlorothiazide, or ACE inhibitor (by physician opinion)

Baseline Characteristics

From both groups combined.

Demographics

  • Age: 66.9y
  • Female: 54%
  • White: 92%, Black 6%
  • Blood Pressure, Systolic: 174.4
  • Blood Pressure, Diastolic: 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

  • Target blood pressure: <140/90
  • All groups were started on placebo therapy for minimum 1-2 weeks
  • Patients were randomised to either group if blood pressure was 160-200 mmHg systolic, 95-115 mmHg diastolic, or both
  • Antihypertensive regimen titration was encouraged with sBP > 140 mmHg or dBP > 90 mmHg, and mandatory if sBP > 160 mmHg or dBP > 95 mmHg
  • 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 unless otherwise specified.

Primary Outcome

Cardiovascular Morbidity (MI or stroke) and Cardiovascular Death
11% vs. 13% (HR = 0.87; p=0.02)

Secondary Outcomes

Unadjusted primary composite endpoint
11% vs. 13% (HR = 0.85; p=0.009)
Stroke
5% vs. 7% (HR = 0.75; p=0.001)
New Onset Diabetes
6% vs. 8% (HR = 0.75; p=0.001)
Myocardial Infarction
4% vs. 4% (HR = 1.07; p=0.491)
Cardiovascular Mortality
4% vs. 5% (HR = 0.89,; P=0.206)

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

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 AE: Losartan < Atenolol (p<0.0001)
  • Drug Related: Losartan < Atenolol (p<0.0001)
  • Serious: p=NS
  • Serious, drug related: Losartan < Atenolol (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%

Left Ventricular Hypertrophy

  • 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)

Other

  • sBP reduction: 30.2 vs. 29.1 (p=0.017)
  • dBP reduction: 16.6 vs. 16.8 (p=NS)
  • 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%

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[6]
  • Subgroup analysis reveals diabetic population had higher systolic pressure and lower diastolic pressure in atenolol group[6]

Funding

  • Funding provided by Merck
    • Study steering committee had free access to all data
    • Steering committee free to interpret data and write paper with statistics independently validated

Further Reading

  1. Mathew J, et al. "Reduction of cardiovascular risk by regression of electrocardiographic markers of left ventricular hypertrophy by the angiotensin-converting enzyme inhibitor ramipril." Circulation. 2001;104(14):1615-21.
  2. 2.0 2.1 James PA, et al. "2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8)." JAMA. 2014:311(5).
  3. Kizer JR, et al. Stroke reduction in hypertensive adults with cardiac hypertrophy randomized to losartan versus atenolol: the Losartan Intervention For Endpoint reduction in hypertension study." Hypertension. 2005;45(1)46-52.
  4. Wiysonge CS, et al. "Beta-blockers for hypertension." Cochrane Database Syst Rev. 2012;11:CD002003.
  5. Lindholm LH, et al. "Cardiovascular morbidity and mortality in patients with diabetes in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol." Lancet. 2002;359(9311);1004-10.
  6. 6.0 6.1 Messerli FH. "The LIFE study: the straw that should break the camel's back." Eur Heart J. 2003;24(6):487-9.