We found predominantly moderate quality evidence that all-cause mortality is similar when first-line RAS inhibitors are compared to other first-line antihypertensive agents .
First-line thiazides caused less HF and stroke than first-line RAS inhibitors .
Compared with first-line CCBs , first-line RAS inhibitors reduced HF but increased stroke .
The magnitude of the reduction in HF exceeded the increase in stroke .
The small differences in effect on blood pressure between the different classes of drugs did not correlate with the differences in the primary outcomes
BACKGROUND Renin-angiotensin system ( RAS ) inhibitors are widely prescribed for treatment of hypertension , especially for diabetic patients on the basis of postulated advantages for the reduction of diabetic nephropathy and cardiovascular morbidity and mortality .
Despite widespread use of angiotensin converting enzyme ( ACE ) inhibitors and angiotensin receptor blockers ( ARBs ) for hypertension in both diabetic and non-diabetic patients , the efficacy and safety of RAS inhibitors compared to other antihypertensive drug classes remains unclear .
OBJECTIVES To evaluate the benefits and harms of first-line RAS inhibitors compared to other first-line antihypertensive drugs in patients with hypertension .
Effects of Losartan or Atenolol in Hypertensive Patients without Clinically Evident Vascular Disease: A Substudy of the LIFE Randomized Trial
Context The Losartan Intervention for Endpoint reduction in hypertension ( LIFE ) trial showed that losartan-based treatment improved cardiovascular outcomes more than atenolol-based treatment in patients with hypertension and left ventricular hypertrophy . Because the study sample was heterogeneous , clinicians wondered about effects in the lower-risk participants . Contribution This analysis of lower-risk participants without known vascular disease showed that both losartan and atenolol reduced blood pressure similarly . Cardiovascular events , particularly strokes , and new-onset diabetes occurred less frequently with losartan than with atenolol . Implication s Patients with hypertension and left ventricular hypertrophy but no known vascular disease benefit more from losartan than atenolol . The Editors Benefits of lowering blood pressure by using antihypertensive treatment are well established , especially in high-risk individuals ( 1 ) . However , treated hypertensive patients still have more cardiovascular events than matched normotensive adults . Possible reasons are failure to normalize blood pressure ; adverse effects of reninangiotensin system overactivity ; and residual target organ damage , such as left ventricular hypertrophy ( LVH ) . Recent evidence has supported the hypothesis that reversal of LVH has prognostic benefit independent of blood pressure lowering ( 2 , 3 ) . Reducing cardiovascular event rates by reninangiotensin system inhibition was initially shown by a comparison of the angiotensin-converting enzyme inhibitor ramipril with placebo in patients with clinical ly evident vascular disease in the Heart Outcomes Prevention Evaluation ( HOPE ) trial ( 4 ) . Subsequently , the Losartan Intervention for Endpoint reduction in hypertension ( LIFE ) study ( 5 ) showed that the angiotensin II AT1-receptor antagonist losartan reduced cardiovascular morbidity and mortality compared with active antihypertensive therapy with the -blocker atenolol ( 6 - 8 ) . This study also linked this benefit to hypertrophy regression ( 9 ) . The LIFE trial enrolled hypertensive patients with electrocardiogram-defined LVH and included patients at especially high risk because of clinical ly evident vascular disease ( 5 , 10 ) . Thus , antagonism of potentially toxic angiotensin II effects has been shown to reduce cardiovascular events in trials conducted wholly or partly in patients with preexisting atherosclerotic disease , but whether this is also true in most hypertensive patients without clinical ly evident vascular disease has not been extensively analyzed . Accordingly , we performed a subgroup analysis in the LIFE study to determine whether angiotensin II AT1-receptor antagonism with losartan reduces cardiovascular morbidity and mortality , compared with active therapy with established -blockerbased therapy , in hypertensive participants with electrocardiogram-defined LVH who did not have clinical ly evident coronary , cerebral , or peripheral arterial disease at the time of enrollment . Methods Study Design The LIFE study is an investigator-initiated , multinational , multicenter , double-blind , double-dummy , r and omized , active-controlled , parallel-group study . The primary objective was to evaluate the long-term effects of once-daily losartan-based antihypertensive therapy compared with atenolol-based antihypertensive therapy in patients with hypertension and electrocardiogram-defined LVH on cardiovascular morbidity and mortality . The complete LIFE study protocol , with study design , organization , clinical measures , end point definitions , choice of comparative agent , statistical considerations , recruitment details , patient characteristics , and main outcomes , has been published ( 5 - 9 , 11 ) . Patients gave informed consent under protocol s approved by the concerned ethics committees ; an independent data and safety monitoring board oversaw the trial . Target Population , Treatment , and Measurement of LVH A total of 9193 patients 55 to 80 years of age with previously treated or untreated hypertension and electrocardiogram-defined LVH ( 5 ) were r and omly assigned after 1 to 2 weeks of placebo use to losartan or atenolol if trough sitting blood pressures were 160 to 200/95 to 115 mm Hg . The present analysis included all LIFE participants , with particular focus on the subgroup without previous diagnoses of coronary , cerebral , or peripheral vascular disease by either self-report or report of treating physicians . Patients in the present subgroup analysis were enrolled from 26 June 1995 through 2 May 1997 . A total of 6886 r and omly assigned patients from centers in Denmark ( 1030 ) , Finl and ( 1237 ) , Icel and ( 96 ) , Norway ( 1112 ) , Sweden ( 1634 ) , the United Kingdom660 , and the United States ( 1067 ) did not have clinical ly evident vascular disease . Patients were followed for 4 years or longer with regular visits and upward titration of the medication dose to reach the goal blood pressure of less than 140/90 mm Hg ( 5 , 10 ) . Electrocardiogram Coding and LVH Criteria All screening , baseline , annual , and end point electrocardiograms were evaluated at one core reading center . Patients were accepted into the study if a screening electrocardiogram fulfilled the LVH criteria ( 5 , 10 ) . On the basis of evidence that combined electrocardiogram assessment of QRS voltage and duration enhances sensitivity for LVH detection at acceptable levels of specificity ( 12 , 13 ) , the product of QRS duration multiplied by Cornell voltage ( with sex adjustment of 8 mm in women [ 14 ] and a partition value of > 2440 mm ms ) was chosen to recognize hypertrophy . Because of evidence that the sex adjustment was excessive and that patients with LVH by traditional electrocardiogram criteria were being missed , two changes were made for patients recruited after 30 April 1996 :  Sex adjustment of Cornell voltage was reduced to 6 mm , and SokolowLyon voltage greater than 38 mm was accepted as an alternative criterion ( 10 ) . As previously described , it was estimated ( and later confirmed with electrocardiography in a sub study of 960 patients [ 15 ] ) that more than 70 % of patients who met LIFE electrocardiogram criteria from one screening electrocardiogram had anatomic LVH . Outcome Measures The primary end point of cardiovascular morbidity and death was a composite of the first occurrence of cardiovascular death , stroke , or clinical ly evident myocardial infa rct ion . Other prespecified outcomes were total mortality , angina pectoris or heart failure requiring hospitalization , coronary or peripheral revascularization procedures , resuscitated cardiac arrest , and new-onset diabetes . An end point committee , blinded to therapy , separately review ed clinical records for all events reported by clinical centers to determine whether they met protocol end point criteria . The Electrocardiogram Core Center evaluated regression of hypertrophy on the electrocardiogram . New-onset diabetes , defined according to 1985 World Health Organization criteria ( 16 ) , was reported by investigators on the basis of fasting hyperglycemia on two occasions or a positive result on a glucose tolerance test . Sitting blood pressure was measured at trough ( that is , 24 hours after dose ; range , 22 to 26 hours ) . Adverse experiences , classified as drug-related or nondrug-related , as well as serious or nonserious , according to International Conference on Harmonization guidelines for good clinical practice , were recorded by investigators using open-ended worksheets at every visit . The LIFE study ran its full course , and end point follow-up was stopped at midnight local time , 16 September 2001 , which was the time-point for the last end point to count . After the stopping date , patients had a follow-up clinic visit or at least a check of vital status within 6 weeks . Statistical Analysis Allocation numbers were associated with treatment groups by using a computer-generated allocation schedule ; patients were considered r and omly assigned when they received an allocation number . Blinding was maintained in a double-dummy fashion : All patients received both blinded losartan and blinded atenolol : One tablet consisted of active treatment and one tablet consisted of placebo . All cardiovascular end points were analyzed by using the intention-to-treat approach ; all r and omly assigned patients were included in their assigned treatment group , and all available follow-up information was included from r and omization through the end of the study . Only events confirmed by the end point committee were analyzed . Patients with several end points were counted as having had an event in all relevant end point analyses ; however , only the first event in a specific category counted in individual analyses . Safety analyses included all r and omly assigned patients from r and omization through 16 September 2001 or permanent discontinuation of therapy with blinded study medication , whichever came first . Differences between treatment groups in rates of clinical events were assessed by Cox regression models with degree of LVH ( using Cornell voltage duration product and SokolowLyon voltage as continuous variables ) and the Framingham risk score ( 17 ) defined by baseline characteristics as covariates . This adjusted analysis was chosen a priori as primary to account for differences in key risk predictors at baseline . Secondary unadjusted analyses were performed to vali date the adjusted results . Interaction between treatment and vascular disease status was tested by including indicators for these factors and the product of these indicators in a Cox regression model . Treatment effects were measured by hazard ratios ( relative risks ) , and their 95 % CIs were calculated from Cox regression models . The risk reduction for losartan versus atenolol was calculated as : 100 ( 1 relative risk ) . Event rates over time are presented as KaplanMeier curves . Adjustment for blood pressure was based on Cox regression models with blood pressure values throughout the trial as time-varying covariates . Differences between groups in changes in electrocardiogram
We found predominantly moderate quality evidence that all-cause mortality is similar when first-line RAS inhibitors are compared to other first-line antihypertensive agents .
First-line thiazides caused less HF and stroke than first-line RAS inhibitors .
Compared with first-line CCBs , first-line RAS inhibitors reduced HF but increased stroke .
The magnitude of the reduction in HF exceeded the increase in stroke .
The small differences in effect on blood pressure between the different classes of drugs did not correlate with the differences in the primary outcomes
BACKGROUND Renin-angiotensin system ( RAS ) inhibitors are widely prescribed for treatment of hypertension , especially for diabetic patients on the basis of postulated advantages for the reduction of diabetic nephropathy and cardiovascular morbidity and mortality .
Despite widespread use of angiotensin converting enzyme ( ACE ) inhibitors and angiotensin receptor blockers ( ARBs ) for hypertension in both diabetic and non-diabetic patients , the efficacy and safety of RAS inhibitors compared to other antihypertensive drug classes remains unclear .
OBJECTIVES To evaluate the benefits and harms of first-line RAS inhibitors compared to other first-line antihypertensive drugs in patients with hypertension .