Fifteen years of LIFE (Losartan Intervention for Endpoint Reduction in Hypertension)—Lessons learned for losartan: An “old dog playing good tricks”

Abstract

There is an unmet need to prevent cardiovascular disease and chronic kidney disease development and progression worldwide. Losartan, the first angiotensin receptor blocker, was shown to exert significant cardioprotective and renoprotective effects in the LIFE (Losartan Intervention for Endpoint Reduction in Hypertension) and RENAAL (Reduction of Endpoints in NIDDM With the Angiotensin II Antagonist Losartan) trials. Losartan significantly prevented stroke and decreased serum uric acid levels and the rates of new‐onset diabetes mellitus and atrial fibrillation. The present review discusses the LIFE (and its subanalyses) and RENAAL trials and the translation of their results to clinical practice. The place of losartan in the current guidelines for hypertension management is also discussed. Losartan still represents an efficacious, safe, and cost‐effective therapeutic option in patients with hypertension who have left ventricular hypertrophy. Losartan is a useful antihypertensive agent for stroke prevention and in the management of patients with chronic kidney disease, atrial fibrillation, diabetes mellitus, albuminuria, and hyperuricemia.

1. INTRODUCTION

Cardiovascular disease (CVD) remains the major cause of death and an important cause of morbidity worldwide.1, 2 Regional differences may exist, eg, China bears the greatest stroke burden in the world3 and Central Asia has the highest rate of premature death from coronary heart disease.4 Chronic kidney disease (CKD) represents another global health burden, also being an independent CVD risk factor.5 Therefore, there is an unmet need to prevent CVD and CKD development as well as renal function deterioration based on both lifestyle interventions and drug therapy.6

Losartan, the first angiotensin receptor blocker (ARB), represents a safe and effective antihypertensive drug choice.7 Fifteen years ago, the results of the LIFE (Losartan Intervention For Endpoint Reduction in Hypertension) study highlighted the superiority of losartan compared with atenolol in terms of both cardioprotection and renoprotection in patients with hypertension who had left ventricular hypertrophy (LVH)8 in the presence of a comparable reduction in blood pressure. These historical findings highlighted the key role of the antagonism of the renin‐angiotensin system (RAS) in the prevention of clinical outcomes in hypertension.9 In this study, in fact, there was a striking significant superiority of losartan in the prevention of stroke, which was also reported to significantly decrease serum uric acid (SUA) levels and the rates of new‐onset diabetes mellitus (DM)10 and atrial fibrillation (AF).8, 11, 12 Furthermore, the RENAAL (Reduction of Endpoints in NIDDM With the Angiotensin II Antagonist Losartan) study showed that losartan, compared with placebo, prevented the progression of albuminuria and kidney function deterioration in patients with hypertensive DM with nephropathy.13

The present narrative review discusses the beneficial effects of losartan, apart from blood pressure (BP) lowering, based on the results of the RENAAL and LIFE trials (and their substudies). We also comment on the use of losartan in special patient populations including those with LVH, stroke, AF, DM, CKD, and hyperuricemia. Finally, the place of losartan in the current guidelines for hypertension management is discussed.

2. LIFE STUDY: “LOSARTAN BETTER THAN ATENOLOL”

The LIFE trial compared the effectiveness of losartan and atenolol on BP lowering, LVH, and CVD morbidity and mortality in 9193 patients with hypertension and LVH (aged 55–80 years) followed up for 4.8 years.8 BP was similarly decreased in both study groups (by 30.2/16.6 mm Hg and 29.1/10.1 mm Hg in the losartan and atenolol groups, respectively), whereas the rate of the primary composite end point (consisting of nonfatal myocardial infarction [MI], nonfatal stroke, and CVD death) was significantly lower in losartan‐treated patients than those taking atenolol (relative risk [RR], 0.87; 95% confidence interval [CI], 0.77–0.98 [P = .021].8 This losartan‐induced CVD benefit was even greater in patients older than 67 years compared with younger patients.14 Of note, the risk of fatal and nonfatal stroke was significantly lower in patients taking losartan compared with atenolol (RR, 0.75; 95% CI, 0.63–0.89 [P = .001]), whereas CVD mortality and the risk of fatal and nonfatal MI were similar in both groups. Furthermore, significantly fewer patients developed new‐onset DM in the losartan group than in the atenolol group.8 These findings highlighted the superiority of losartan in CVD prevention compared with atenolol, independently of their BP‐lowering effect.

It should be mentioned that based on the results of the LIFE study, losartan therapy was found to be cost‐effective in treating patients with hypertension and LVH.15 Furthermore, when the benefits of losartan on stroke prevention were projected to an estimated European Union population of patients with hypertension and LVH, losartan was found to prevent almost 125,000 first strokes within 5.5 years, thus highlighting the importance of selecting the best therapeutic option in terms of public health strategy.16 Of note, losartan‐related benefits observed in the LIFE trial were greater in nonsmokers, followed by previous and current smokers.17 The latter also had the highest CVD risk followed by previous and never‐smokers.17 Moreover, moderate physical activity (>30 minutes twice per week) significantly decreased the primary composite end point (adjusted hazard ratio [HR], 0.70; P < .001) and its components, new‐onset DM (adjusted HR, 0.66; P < .001), and all‐cause mortality (adjusted HR, 0.65; P < .001).18 These findings highlight the importance of lifestyle intervention such as smoking cessation and exercise in combination with appropriate drug therapy to reduce individuals’ CVD risk.

Several mechanisms have been suggested to explain the losartan‐related benefits in stroke risk observed in the LIFE study including effects on LVH regression, left atrial diameter, brain natriuretic peptide, AF, central hemodynamics, thrombus formation/platelet aggregation, vascular structure, and metabolic parameters (such as new‐onset DM, serum uric acid, albuminuria, and lipid metabolism).19 In this context, although the effects of losartan and atenolol on arterial stiffness were comparable, contrasting hemodynamics were observed between the two groups, potentially affecting cardiac response.20 Values of 24‐hour ambulatory BP were comparably decreased in both groups, with a similar early morning BP surge and more frequent nondipping status in the losartan group.21 As expected, daytime heart rate was significantly reduced in the atenolol group.21

In a multicenter study performed in patients with isolated systolic hypertension, a condition typical of the elderly, the mean change from baseline in systolic BP was −27.4 mm Hg for 426 patients who received losartan and −28.1 mm Hg for 419 patients who received amlodipine, indicating that the BP‐lowering effect provided by losartan on systolic BP was noninferior to that of amlodipine.22

Furthermore, pulse pressure (PP) adversely affected CVD morbidity and mortality in atenolol‐treated patients; the higher the PP, the greater the risk.23 In contrast, the impact of PP on CVD risk was lower (and nonsignificant) in the losartan group.23 Losartan was also shown to reduce brain natriuretic peptide to a significantly greater extent than atenolol in patients with hypertension with LVH.24 Relating to lipids, losartan attenuated high‐density lipoprotein cholesterol reduction during antihypertensive therapy, thus leading to higher high‐density lipoprotein cholesterol levels in the losartan compared with the atenolol group.25 This difference in high‐density lipoprotein cholesterol was associated with fewer end points, thus partly explaining the losartan‐related CVD benefits.25 Furthermore, lower high‐density lipoprotein cholesterol levels during the LIFE trial were associated with an increased risk for new‐onset DM.26

Interestingly, risk scores have been developed based on the LIFE trial to predict CVD outcomes, potentially improving risk assessment of patients with hypertension and LVH.27 In this patient population, the Framingham risk score, as well as other scores, underestimated the risk in the higher‐risk patients and overestimated it in the lower‐risk categories.27 In Italy, the ForLife study,28 which enrolled about 800 general practitioners who recruited a total of 12 792 patients with hypertension, was based on the simple administration to patients of a “stroke calculator” based on the Framingham algorithm. Between the two visits, the estimated stroke risk score showed a reduction, with a significant shift of patients from high‐ to intermediate‐ and low‐risk categories. This reduction involved all subgroups, including patients with DM and LVH.28

3. LOSARTAN AND LVH

Overall, LVH has been associated with an increased CVD risk, and LVH regression during antihypertensive treatment has been reported to significantly decrease cardiovascular events.29 In this context, an echocardiographic substudy of the LIFE trial showed that losartan‐treated patients had a greater reduction in LV mass index compared with the atenolol group.30 This difference was observed independently of sex, age, and severity of LVH at baseline. This benefit was attributed mainly to decreased concentricity of LV geometry (observed in both groups) and to a smaller increase in LV diameter (observed only in patients taking losartan).30 Of note, concomitant hydrochlorothiazide use was related to a greater regression of LVH. This effect was even greater in patients treated with losartan compared with those treated with atenolol.31 In this regard, it is important to mention that in the LIFE trial, combination therapy mostly based on the use of thiazide diuretics and CCBs was undertaken in more than 80% of patients within 6 months in both arms.

In cohort substudies of the LIFE trial, regression of LVH was associated with reduced risk for new‐onset heart failure (HF), HF hospitalization, and mortality in the losartan group.32, 33 It was also reported that LV mass regression, achieved by losartan in the LIFE trial, was associated with improved diastolic filling in echocardiography,34 thus possibly explaining the decreased rates of AF and HF in losartan‐treated patients. Furthermore, in another prospective cohort substudy of this trial, lower LV mass was associated with significantly reduced risks for stroke, CVD, and all‐cause mortality, independently of BP values and antihypertensive treatment.30 These findings strongly support the need to reduce LV mass in order to decrease CVD risk in patients with hypertension and LVH, subsequently highlighting the importance of losartan treatment (associated with greater LV mass lowering) in these patients. Furthermore, in a subpopulation of the LIFE study, it was shown that during 2 years of effective antihypertensive treatment, LVH continued to regress, despite the small BP reductions after the first year of therapy, highlighting the need to continue losartan therapy in order to maximize LVH regression.35 Furthermore, in the LIFE study, BP, cardiac output, and PP were similarly improved in both sexes.36 However, LV mass regression observed in the LIFE study was greater in women.36 Of note, primary end point events, stroke, total mortality, and new‐onset DM, were significantly reduced in losartan‐treated women compared with atenolol‐treated women in the LIFE study, whereas CVD mortality and hospitalization for HF did not differ between the two groups.37

A previous pilot study reported attenuation of the progression of myocardial hypertrophy and fibrosis following losartan therapy in patients with hypertrophic cardiomyopathy,38 although conflicting results have been reported in this condition.39, 40

4. LOSARTAN IN PATIENTS WITH HYPERTENSION AND COMORBIDITIES

4.1. Stroke

Losartan therapy significantly lowered the risk of fatal and nonfatal stroke compared with atenolol‐based therapy in the LIFE trial.8 This significant benefit was mostly accounted for by atherothrombotic strokes. The risk of embolic and hemorrhagic strokes was also decreased in losartan‐treated patients compared with the atenolol‐treated group, but the difference did not achieve significance.41 Of note, the number needed to treat to prevent a stroke within 5 years was 54, falling to 25, 24, and nine for those with a history of stroke, isolated hypertension, and AF, respectively.41 These findings strongly support the use of losartan in these patient populations to reduce the risk of incident stroke.

In the LIFE study, new‐onset AF was significantly reduced in the losartan compared with the atenolol group (RR, 0.67; 95% CI, 0.55–0.83 [P < .001]), independently of BP lowering.12 The risks for CVD events, stroke, and hospitalization for HF were two, three, and five times higher in patients who developed AF during the study.12 However, in these patients with new‐onset AF, significantly fewer strokes (0.49, 95% CI, 0.29–0.86 [P = .01]) and composite end points (0.60, 95% CI, 0.38–0.94 [P = .03]) were observed in losartan‐ vs atenolol‐treated patients.12 These findings strongly support the use of losartan in patients with hypertension and LVH in order not only to reduce the risk of new‐onset AF but also the risk of CVD, and especially stroke, in patients developing AF. The primary composite of CVD morbidity and mortality was also significantly reduced in losartan‐treated patients with hypertension with LVH and AF (at baseline) compared with the atenolol‐treated patients in the LIFE study (HR, 0.58; 95% CI, 0.39–0.88 [P = .009]).42 In detail, CVD death (HR, 0.58; 95% CI, 0.33–0.99 [P = .048]) and stroke (HR, 0.55; 95% CI, 0.31–0.97 [P = .039]) occurred in significantly fewer patients in the losartan group than the atenolol group, whereas MI rates did not differ between the two groups.42 Furthermore, the losartan‐related benefits for the primary end point and CVD mortality were significantly greater in patients with AF at baseline compared with those with sinus rhythm.42

In ICARUS, a substudy of the LIFE trial, the density and number of atherosclerotic lesions in the common carotid arteries did not differ between the losartan and atenolol groups during 3 years of treatment.43 However, the sample size of this substudy was too small (n = 81), thus limiting the statistical power to detect any differences in carotid plaque development. Further research is needed to elucidate the impact of losartan on carotid atherosclerosis.

4.2. Diabetes Mellitus

In the LIFE study, patients with hypertensive DM had less regression of LVH following antihypertensive therapy as well as higher CVD morbidity and mortality compared with those without DM.44, 45 Patients with DM also had higher BMI and PP as well as lower LV ejection fraction and estimated glomerular filtration rate, being more prone to albuminuria.45 However, in a prespecified subgroup of patients with DM in the LIFE study, the primary end point occurred in significantly fewer patients taking losartan compared with those taking atenolol (RR, 0.76; 95% CI, 0.58–0.98 [P = .031]).46 Furthermore, significantly greater reductions were observed in all‐cause and CVD mortality in the losartan compared with the atenolol group (RR, 0.61; 95% CI, 0.45–0.84 [P = .002] for all‐cause death and RR, 0.63; 95% CI, 0.42–0.95 [P = .028] for CVD death, respectively).46 Similarly, significantly fewer hospitalizations for HF were observed in losartan‐treated patients with DM compared with atenolol‐treated patients (HR, 0.57; P = .019).47

In another post hoc analysis of the LIFE study, significantly fewer sudden cardiac deaths occurred in the losartan‐treated patients with DM compared with the atenolol group (RR, 0.49; 95% CI, 0.26–0.92 [P = .027]).48 Losartan‐related benefits on sudden cardiac death may be attributed to antiarrhythmic effects, regression of LVH, reduction of atrial fibrosis, and inhibition of the sympathetic nervous system (by blunting the facilitating effect of angiotensin II on sympathetic tone).48

The RENAAL study involved 1513 patients with DM and nephropathy followed up for a mean of 3.4 years.13 Compared with placebo, losartan was found to significantly decrease the incidence of serum creatinine doubling (by 25%; P = .006) and end‐stage renal disease (by 28%; P = .002); proteinuria also declined by 35% with losartan (P < .001 vs placebo).13 Although mortality rates did not differ between the two groups, the composite end point of doubling serum creatinine levels, end‐stage renal disease, or death was significantly reduced in the losartan‐treated patients compared with those taking placebo (by 16%; P = .02).13 These benefits exceeded those attributed to the small differences in BP seen between the two groups. CVD morbidity and mortality were similar in the losartan and placebo groups. In contrast, the rate of hospitalization for HF was significantly reduced with losartan compared with placebo (by 32%; P = .005).13

These findings strongly support the use of losartan in patients with DM to minimize CVD morbidity and mortality as well as the risk for HF hospitalization and progression of diabetic nephropathy.

4.3. Chronic kidney disease

CKD, microalbuminuria, and macroalbuminuria have been associated with CVD morbidity and mortality.49, 50, 51, 52 In this context, baseline albuminuria was related to a higher risk for the primary composite end point in the LIFE trial.53 Furthermore, both losartan and atenolol decreased albuminuria but the reduction was significantly greater with losartan (33% vs 25%, respectively).53 It was estimated that one fifth of the benefits on the primary composite end point observed with losartan therapy could be attributed to the greater decrease in albuminuria.53

Losartan‐induced renoprotective effects were also observed in patients with diabetic nephropathy in the RENAAL study.13 These benefits highlight the importance of losartan therapy in patients with hypertension and CKD (with or without DM) to prevent the progression of renal disease. Of note, CKD may frequently coexist with AF in patients with hypertension, further increasing CVD risk.54 As mentioned above, losartan was shown to improve both CVD and renal outcomes in patients with hypertension (with or without AF), thus representing a useful approach in such cases.

4.4. Hyperuricemia

Elevated SUA levels have been linked to increased CVD risk.55, 56 Hyperuricemia is also an independent predictor of DM.57 In the LIFE trial, SUA levels were directly associated with CVD events, with this association being greater in women.11 Losartan therapy attenuated the increase in SUA levels compared with atenolol treatment, explaining 29% of losartan‐induced benefit on the primary end point.11 Furthermore, SUA was an independent predictor for new‐onset DM in patients with hypertension with LVH.58 Apart from the cardiometabolic benefits, SUA reduction was also associated with the renoprotective effects of losartan as shown in the RENAAL study.59 In detail, the risk for renal events was lowered by 6% for every 0.5‐mg/dL reduction in SUA levels, an effect that was independent of estimate glomerular filtration rate, albuminuria, and other risk factors.59 It was calculated that almost one fifth of losartan‐induced renal benefits could be attributed to SUA lowering in this group of patients with DM and nephropathy. Of note, this SUA‐reducing effect refers to losartan alone and does not involve the E‐3174 metabolite of this compound. It occurs early after losartan administration and it is both dose‐dependent and transient.60 Losartan enhances SUA excretion by inhibition of URAT1‐mediated renal tubule urate reabsorption, with a peak uricosuric effect observed 2 to 4 hours after drug administration.59 This process could increase urinary uric acid levels, thus predisposing to supersaturation of uric acid and the development of uric acid nephropathy.59 However, losartan exerts urinary alkalinizing effects, thus minimizing the risk of developing uric acid crystals.59

Based on the above, losartan represents an attractive therapeutic option to treat hypertension in patients with or without DM also in terms of SUA lowering. This feature could be useful in patients also receiving long‐term thiazide‐based therapy.

5. LOSARTAN IN HYPERTENSION GUIDELINES

The new (2017) guidelines for prevention, diagnosis, evaluation, and management of hypertension by the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines recommend as initial antihypertensive drug therapy any one of the following drug categories: ARBs (including losartan), angiotensin‐converting enzyme inhibitors (ACEIs), thiazide diuretics, and calcium channel blockers (CCBs).61 ACEIs should be replaced by ARBs when cough or bronchial responsiveness develops. Furthermore, patients with chronic cough should be initially treated with an ARB.

With regard to comorbidities, in patients with stable ischemic heart disease, ARBs (including losartan), ACEIs, or certain β‐blockers should be the first therapeutic option to lower BP, whereas ARBs, ACEIs, mineralocorticoid receptor antagonists, diuretics, third‐generation β‐blockers, and angiotensin receptor‐neprilysin inhibitors could be the initial drug choice in cases of HF.61 Patients with HF with preserved EF and symptoms of volume overload should be treated with diuretics, combined with ARBs (including losartan) or ACEIs and β‐blockers to attain BP goals. Of note, the BP target for all of the above patients is <130/80 mm Hg.61 In patients with stroke or transient ischemic attack, ARBs, ACEIs, or thiazide diuretics could be used to achieve a BP <140/90 mm Hg (or even <130/80 mm Hg). Patients with AF should be treated with an ARB (including losartan) to prevent AF recurrence.61 All first‐line antihypertensive drug classes are effective in patients with DM (ie, ARBs, ACEIs, diuretics, and CCBs), but in the presence of albuminuria, ARBs or ACEIs should be preferred.61 Furthermore, in patients with CKD, the use of an ACEI (or an ARB if ACEIs are not tolerated) may be useful to delay disease progression. Similar to the other ARBs, losartan should not be used in combination with either an ACEI or direct renin inhibitor as well as during pregnancy or in patients with a history of angioedema with ACEIs.61 Potassium levels and renal function should be monitored in patients treated with any ARB.

The Task Force for the Management of Arterial Hypertension of the European Society of Hypertension and the European Society of Cardiology (ESC) published its guidelines in 2013, setting BP goals at <140/90 mm Hg62 and a new set of guidelines is expected for the summer of 2018. ARBs, ACEIs, diuretics, β‐blockers, and/or mineralocorticoid receptor antagonists are so far recommended in patients with HF or severe LV dysfunction to decrease hospitalization and mortality rates. These guidelines also mention that losartan and valsartan (ARBs) are more effective in preventing first occurrence of AF than atenolol (β‐blocker) or amlodipine (CCB) in patients with hypertension with LVH.62 In these patients, ARBs, ACEIs, and CCBs may regress LVH and thus should be preferred. Apart from HF and LVH, ARBs should be used in patients with microalbuminuria, proteinuria, renal dysfunction (even in end‐stage renal disease), previous stroke or MI, metabolic syndrome, and DM.62

Of note, similarly to atenolol, losartan has been shown to prevent aortic aneurysm enlargement in patients with Marfan syndrome.63 The 2017 guidelines of the ESC/European Association for Cardio‐Thoracic Surgery for the management of valvular heart disease report that β‐blockers and/or losartan may reduce the risk of aortic complications and may slow aortic root dilatation in patients with Marfan syndrome, thus being attractive therapeutic options before and after surgery in these patients.64 Furthermore, they mention, as a common clinical practice, the use of a β‐blocker or losartan in cases with bicuspid aortic valve if the ascending aorta and/or aortic root is dilated.64

In the LIFE study, losartan was shown to significantly reduce the composite primary end point of CVD morbidity and death in patients with hypertension who have LVH. This CVD benefit was independent of BP lowering and it was mainly driven by losartan‐induced significant decreases in stroke prevalence and mortality. Furthermore, fewer cases of new‐onset DM and AF occurred in the losartan group compared with atenolol. Losartan therapy was also associated with a greater regression of LVH than atenolol. When patients with DM were examined separately, there were significantly fewer sudden cardiac deaths and hospitalizations for HF in losartan‐treated patients.

In both the LIFE and RENAAL trials, losartan exerted renoprotective effects by decreasing albuminuria and preventing the deterioration of kidney function as well as by lowering SUA levels. These effects contributed to the losartan‐induced CVD benefits observed in these trials.

6. CONCLUSIONS

Based on the above data and the current guidelines for hypertension management, losartan appears to be an efficacious, safe, and cost‐effective therapeutic option with demonstrated cardioprotective and renoprotective properties in patients with hypertension who have LVH. Losartan represents a suitable antihypertensive approach in patients with stroke, AF, DM, albuminuria, and hyperuricemia.

CONFLICT OF INTEREST

N.K. has given talks, attended conferences, and participated in trials sponsored by Amgen, Angelini, Astra Zeneca, Boehringer Ingelheim, Galenica, MSD, Novartis, Novo Nordisk, Sanofi‐Aventis, and WinMedica. C.T. has received consultancy, research grant and honoraria fees from Servier, Menarini, Medtronic, Bayer, Novartis, Astra‐Zeneca, Boehringer Ingelheim, Pfizer, Chiesi, Recordati, Sanofi, MSD, and Vianex. D.U. has given talks, attended conferences, and participated in trials sponsored by Amgen, Astra‐Zeneca, Boehringer‐Ingelheim, Menatini, MSD, Novartis, Novo Nordisk, and Sanofi‐Aventis. M.V. has participated in advisory boards of MSD, Menarini International, Novartis, and Daiichi Sankyo, and has received lecture honoraria from MSD, Menarini International, Novartis, Bayer, Boehringer Ingelheim, and Daiichi Sankyo.

Katsiki N, Tsioufis K, Ural D, Volpe M. Fifteen years of LIFE (Losartan Intervention for Endpoint Reduction in Hypertension)—Lessons learned for losartan: An “old dog playing good tricks”. J Clin Hypertens. 2018;20:1153–1159. 10.1111/jch.13325