Chd-taskforce.com

International Task Force for Prevention
Of Coronary Heart Disease
Clinical management of risk factors
of coronary heart disease and stroke
Major recent drug trials
Losartan Intervention For Endpoint
reduction in hypertension study
International Task Force for Prevention of Coronary Heart DiseaseMajor recent drug trialsLosartan Intervention For Endpoint reduction in hypertension study T A B LE OF CON T E N T
Objective and design
Eligibility
Patients characteristics at randomisation (n=9194)
Medication at end of follow-up
Mean blood pressure reduction
Endpoints
Adverse Events
Reduction of left ventricular mass
Endpoints in the subgroup of patients with diabetes
Slide 10:
Reduction of left ventricular mass in the subgroup of diabetic patients
Clinical albuminuria and creatinine in the subgroup of patients with diabetes
Conclusions
International Task Force for Prevention of Coronary Heart Disease Losartan Intervention For Endpoint reduction in hypertension study Slide 1:
Objective and design
Losartan Intervention for Endpoint (LIFE)
Objective and Design
• Objective
Evaluation of the long-term effects (≥ 4 years) of losartan
(angiotensin II receptor blocker) compared to atenolol
(ß-blocker) in hypertensive patients with electrocardiographically
documented left ventricular hypertrophy (LVH) on the combined
incidence of cardiovascular mortality and morbidity
• Design
multicenter, double-blind, randomised, prospective,
active-controlled parallel group trial
Source: Dahlöf B et al., Am J Hypertension 1997;10:705-713
Objective and design
The treatment of hypertension mainly with diuretics and ß-blockers reduces cardio-vascular mortality and morbidity, largely due to a decreased incidence of stroke, butin a smaller degree of coronary events. Losartan is the first of a new class of hyperten-sive agents blocking angiotensin II at the type 1-receptor. Angiotensin II (A-II) is as-sociated with development of left ventricular hypertrophy (LVH), a strong independ-ent indicator of risk of cardiovascular morbidity and death. Thus, blocking A-II couldbe especially effective in reversing LVH.
The major hypothesis of the LIFE study is that in patients with essential hypertensionand LVH, losartan will reduce the incidence of cardiovascular morbidity and mortal-ity to a greater extent than the ß-blocker atenolol, possibly through a greater effect onthe regression of LVH.
International Task Force for Prevention of Coronary Heart DiseaseMajor recent drug trialsLosartan Intervention For Endpoint reduction in hypertension study Slide 2:
Eligibility
Eligibility
• Men and women between 55 and 80 years of age
with previously untreated or treated essential
hypertension and electrocardiographically documented
left ventricular hypertension (LVH).
• Mean through sitting
• diastolic blood pressure readings of 95 to 110 mm Hg
• systolic blood pressure readings of 160 to 200 mm Hg
Dahlöf B et al., Am J Hypertension 1998;32:989-997
Dahlöf B et al., Lancet 2002;359:995-1003
Eligibility
This slide shows eligibility criteria of the LIFE study, the largest study ever to be un-dertaken in patients with left ventricular hypertrophy (LVH) and one of the largestintervention studies in essential hypertension. This study involved 9194 hypertensiveswith LVH.
International Task Force for Prevention of Coronary Heart Disease Losartan Intervention For Endpoint reduction in hypertension study Slide 3:
Patients characteristics at randomisation (n=9194)
Patients Characteristics at Randomisation
(n=9194)
Losartan
Atenolol
(n=4605)
(n=4588)
Age (years)*
Women (%)
Body mass index (kg x m2)*
Systolic blood pressure (mm Hg)*
Diastolic blood pressure (mm Hg)*
Isolated systolic hypertension**(%)
Heart rate (bpm)*
Left ventricular mass
Cornell voltage-duration product (mmxms)*
Sokolow-Lyon (mm)*
5 year risk for a coronary event
estimated by Framingham Risk Score (%)*
Any vascular disease (%)
Diabetes (%)
Data are mean (SD)
** Definition ≥ 160/< 90 mm HG
Source: Dahlöf B et al., Lancet 2002;359:995-1003
Patients characteristics at randomisation (n=9194)
This slide shows the characteristics of the LIFE-participants (9194). 9193 were avail-able for final analyses, since one patient had wrongly been identified as randomiseddespite not receiving study drugs. The patients were enrolled from June, 1995, to May2, 1997, in 945 centres in Denmark (n=1391), Finland (n=1485), Iceland (n=133),Norway (n=1415), Sweden (n=2245), UK (n=817), and the USA (n=1707). Almost30 % of participants were untreated for their high blood pressure for at least 6 monthswhen screened for the study. This population was to be treated (goal, <140/90 mmHg) for at least 4 years after final enrolment and until at least 1040 patients suffermyocardial infarction, stroke, or cardiovascular death.
International Task Force for Prevention of Coronary Heart DiseaseMajor recent drug trialsLosartan Intervention For Endpoint reduction in hypertension study Slide 4:
Medication at end of follow-up
Medication at End of Follow-Up
Drug doses
Losartan
50 mg only
Atenolol
50 mg plus
additional drugs*
Mean follow-up
100 mg only
4.8 years
100 mg w ith HCTZ
Compliance
84 % Losartan
100 mg with other drugs
80 % Atenolol
100 mg w ith HCTZ and
other drugs
Off study drugs
% of participants on
* Including hydrochlorothiazide (HCTZ)
study drug at endpoint
or end of follow-up
Source: Dahlöf B et al., Lancet 2002;359:995-1003
Medication at end of follow-up
This slide shows the distribution of study drugs at the end of follow-up or at occur-rence of the first primary endpoint, if earlier. The distribution of additional drugs ontop of masked study drug and hydrochlorothiazide did not differ between groups.
Mean doses of losartan and atenolol in patients who stayed on study drugs until theend of study were 82 and 79 mg, respectively.
International Task Force for Prevention of Coronary Heart Disease Losartan Intervention For Endpoint reduction in hypertension study Slide 5:
Mean blood pressure reduction
Mean Blood Pressure (BP) Reduction
Systolic BP
Diastolic BP
Baseline
end of study
Blood pressure target of ≤ 140 mm Hg was achieved in 49% of the
losartan-based and in 46% of the atenolol-based patients for
systolic BP and 89% in both treatment groups for diastolic BP ≤ 90 mm Hg
Source: Dahlöf B et al., Lancet 2002;359:995-1003
Mean blood pressure reduction
This slide shows, that similar reductions in systolic and diastolic blood pressure wereachieved with both drugs.
International Task Force for Prevention of Coronary Heart DiseaseMajor recent drug trialsLosartan Intervention For Endpoint reduction in hypertension study Slide 6:
Endpoints
Endpoints
Endpoint
Losartan
Atenolol
Adjusted hazard ratio*
(n=4605)
(n=4588)
Primary composite endpoint **
Cardiovascular mortality
Myocardial infarction
Other prespecified endpoints
Total mortality
New-onset diabetes***
0.4 0.6 0.8 1.0 1.2 1.4
For degree of left ventricular hyperthrophy and Framingham risk
Losartan
Atenolol
score at randomisation.
** No. of patients with 1st primary event
*** In patients without diabetes at randomisation (losartan, n=4019; atenolol, n=3979)
Source: Dahlöf B et al., Lancet 2002;359:995-1003
Endpoints
This slide shows that losartan reduced cardiovascular morbidity and mortality morethan atenolol. Losartan treatment resulted in a remarkable significant 25% relativerisk reduction for stroke compared with atenolol.
Despite the central importance of blood pressure in the complications of hypertension,additional adjustment of the main outcome for small differences in systolic and dia-stolic pressure (see slide 5) had little effect on the estimate of the benefit associatedwith losartan. The greater effect of losartan compared with atenolol on primary com-posite endpoints may have been due to the greater reduction of left ventricular mass(LVH) with losartan (see slide 8) as well as due to benefits beyond blood-pressurereduction and LVH regression. This benefit could result from increased protectionagainst the detrimental effects of angiotensin II or from specific effects of losartan.
Among other prespecified endpoints, there was a significant 25% lower incidence ofnew-onset diabetes in the losartan than the atenolol group. This lower rate of new-onset diabetes with losartan may be due to a differential effect on insulin resistance.
There was also a trend for lower total mortality with losartan.
International Task Force for Prevention of Coronary Heart Disease Losartan Intervention For Endpoint reduction in hypertension study Slide 7:
Adverse Events
Adverse Events
(p=0.0001)
drug-related
Losartan
(p=0.0001)
Atenolol
(p=0.087)
serious,
drug-related
(%) Proportion
(p=0.006)
of patients who
dropped out
20 because of
adverse events
* p is for between-group differences
Source: Dahlöf B et al., Lancet 2002;359:995-1003
Adverse Events
This slide shows that discontinuation as a result of adverse events was significantlyless common in losartan than atenolol patients.
International Task Force for Prevention of Coronary Heart DiseaseMajor recent drug trialsLosartan Intervention For Endpoint reduction in hypertension study Slide 8:
Reduction of left ventricular mass
Reduction of Left Ventricular Mass *
Baseline
End of study
Cornell voltage-
Sokolow-Lyon
duration product
Losartan
Atenolol
Losartan
Atenolol
Change from
baseline
* by electrocardiographical diagnosis
** p<0.0001 for difference from change in Atenolol group
Source: Dahlöf B et al., Lancet 2002;359:995-1003
Reduction of left ventricular mass
This slide illustrates left ventricular mass at baseline and at the end of study measuredwith two different criterions , the Cornell voltage-duration product and the Sokolow-Lyon voltage. Because combined electrocardiography (ECG) assessment of QRSdu-ration and Cornell voltage and duration enhances sensitivity for detection of left ven-tricular hypertrophy (LVH) at acceptable levels of specificity, the product of QRSduration and Cornell voltage was used to recognise LVH. Sokolow-Lyon voltage waschosen as an alternative LVH criterion.
A greater reduction of left ventricular mass was attained with losartan than with at-enolol, which was independent of blood pressure reduction. This effect may resultfrom a more complete protection against angiotensin II with losartan, whether gener-ated by the circulating renin-angiotensin system or other mechanisms, especially sinceangiotensin II is a myocardial growth factor and an independent risk factor for cardio-vascular disease.
International Task Force for Prevention of Coronary Heart Disease Losartan Intervention For Endpoint reduction in hypertension study Slide 9:
Endpoints in the subgroup of patients with diabetes
Endpoints in the Subgroup of Patients
with Diabetes
Endpoint
Losartan
Atenolol
Adjusted hazard ratio*
Primary composite endpoint **
Cardiovascular mortality
Myocardial infarction
Other prespecified endpoints
Total mortality
0.4 0.6 0.8
Losartan
Atenolol
For degree of left ventricular hypertrophy and Framingham
risk score at randomisation.
** No. of patients with 1st primary event)
Source: Lindholm LH et al., Lancet 2002;359:1004-1010
Endpoints in the subgroup of patients with diabetes
This slide shows the results of the prespecified subgroup of patients who had diabetesmellitus at the start of the LIFE study (n=1195). Losartan was more effective thanatenolol in reducing cardiovascular morbidity and mortality as well as mortality fromall causes in patients with hypertension, diabetes, and left ventricular hypertrophy.
In the non-diabetic patients, the almost 15% reduction of the primary outcome wasmostly driven by the 24% reduction of stroke (see slide 6), but in the subgroup of pa-tients with diabetes, the 24% reduction in primary endpoint was linked with the re-duction in cardiovascular and total mortality.
International Task Force for Prevention of Coronary Heart DiseaseMajor recent drug trialsLosartan Intervention For Endpoint reduction in hypertension study Slide 10:
Reduction of left ventricular mass in the subgroup of diabetic patients
Reduction of Left Ventricular Mass *
in the Subgroup of Diabetic Patients
Baseline
End of study
Cornell voltage-
Sokolow-Lyon
duration product
Losartan
Atenolol
Losartan
Atenolol
Change from
baseline
-13.6 %**
* by electrocardiographical diagnosis
** p<0.0001 for difference from change in Atenolol group
Source: Lindholm LH et al., Lancet 2002;359:1004-1010
Reduction of left ventricular mass in the subgroup of diabetic patients
Losartan was more effective than atenolol in reversing left ventricular hypertrophy,which is likely to result from more complete protection against angiotensin II withlosartan, whether generated by the circulating renin-angiotensin system or othermechanisms, especially since angiotensin II is a myocardial growth factor and an in-dependent risk factor for cardiovascular disease.
International Task Force for Prevention of Coronary Heart Disease Losartan Intervention For Endpoint reduction in hypertension study Slide 11:
Clinical albuminuria and creatinine in the subgroup of patients with diabetes
Clinical Albuminuria and Creatinine Concentrations
in the Subgroup of Patients with Diabetes
mmol/L**
Clinical Albuminuria*
Serum creatinine concentration
Baseline
Baseline 1
Time (years)
Time (years)
Losartan (n=586)
Atenolol (n=609)
* Urine albumin to creatinine ratio ≥ 33.93 mg/mmol (≥ 300mg/g)
** Data are mean (SD)
Source: Lindholm LH et al., Lancet 2002;359:1004-1010
Clinical albuminuria and creatinine in the subgroup of patients with diabetes
This slide shows the number (%) of diabetic patients with clinical albuminuria andmean serum creatinine concentrations (mmol/L), two markers of renal function. Inthis subgroup study of patients with diabetes, albuminuria was reported significantlyless often in the losartan than in the atenolol group. Angiotensin II antagonists such aslosartan have beneficial renal effects in patients with diabetes and nephropathy.
International Task Force for Prevention of Coronary Heart DiseaseMajor recent drug trialsLosartan Intervention For Endpoint reduction in hypertension study Slide 12:
Conclusions
Conclusions
• Losartan prevents more cardiovascular morbidity and
death than atenolol for a similar reduction in blood pressure
and is better tolerated
• Losartan is more effective than atenolol in reversing left
ventricular hypertension
• Losartan prevents more new-onset diabetes than atenolol
• Losartan has beneficial renal effects in patients with
diabetes and nephropathy
Dahlöf B et al., Lancet 2002;359:995-1003
Lindholm LH et al., Lancet 2002;359:1004-1010
Conclusions
The conclusions of the LIFE study are shown in this slide.

Source: http://www.chd-taskforce.com/pdf/sk_life.pdf