Losartan Intervention For Endpoint Reduction In Hypertension Research Articles

TIME-VARYING SERUM URIC ACID PREDICTS NEW-ONSET ATRIAL FIBRILLATION IN TREATED HYPERTENSIVE PATIENTS

Objective: The Losartan Intervention For Endpoint reduction in hypertension (LIFE) study was the first clinical outcome trial to suggest that lowering of serum uric acid by a uricosuric drug such as losartan has a beneficial effect on cardiovascular outcome independently of changes in renal function or blood pressure. LIFE also showed less new-onset atrial fibrillation in hypertensive patients receiving losartan vs. atenolol based treatment. Because losartan reduces serum uric acid levels, we investigated relations of serum uric acid with new-onset atrial fibrillation in the study. Design and method: Hypertensive patients with electrocardiographic left ventricular hypertrophy and no prior atrial fibrillation (n = 8243) were treated for 5.0 ± 0.4 years with losartan or atenolol based therapy. Associations of serum uric acid with new-onset atrial fibrillation documented by Minnesota coding were assessed by Cox models using serum uric acid and systolic blood pressure as time-varying covariates to take into account changes of serum uric acid related to losartan or diuretic treatment, changes in renal function, and aging. Results: Time-varying serum uric acid was associated with new atrial fibrillation defined by Minnesota code (HR = 1.19 per 16.8 umol/L [1 mg/dL] [95% CIs, 1.12–1.26], P < 0.0001), independent of losartan treatment (HR = 0.75 [95% CIs, 0.61–0.93], P = 0.007), older age (HR = 1.95 per 7.0 years [95% CIs, 1.73–2.20], P < 0.0001), male sex (HR = 1.46 [95% CIs, 1.09–1.94], P = 0.010) and higher Cornell voltage duration product (HR = 1.10 per 1023 msec x mm [95% CIs, 1.01–1.21], P = 0.034). Similar results were obtained in Cox models with serum uric acid levels partitioned according to baseline quartiles and in which atrial fibrillation was defined by physician reports or by both Minnesota coding and physician reports. Conclusions: Thus, we found a strong relationship between time-varying serum uric acid levels during antihypertensive treatment and new-onset atrial fibrillation in elderly patients with left ventricular hypertrophy. Our data suggest that in-treatment serum uric acid is a strong predictor for new onset atrial fibrillation in hypertensive patients, independent of effects of antihypertensive treatment, age, sex, and electrocardiographic left ventricular hypertrophy. Further research is needed to clarify how serum uric acid may provoke atrial fibrillation.

Development of systolic dysfunction unrelated to myocardial infarction in treated hypertensive patients with left ventricular hypertrophy. The LIFE Study

Aim: While it is commonly thought that left ventricular (LV) systolic function may insidiously deteriorate in hypertensive patients, few prospective data are available to support this notion. Methods: We evaluated 680 hypertensive patients (66 ± 7 years; 45% women) with electrocardiographic (ECG)-LV hypertrophy (ECG-LVH) enrolled in the Losartan Intervention For Endpoint reduction in hypertension (LIFE) echo-sub-study free of prevalent cardiovascular disease and with baseline ejection fraction (EF) ≥ 55%. Echocardiographic examinations were performed annually for 5 years during anti-hypertensive treatment. Development of reduced systolic function was defined as incident EF &lt; 50%. Results: During a mean follow-up of 4.8 ± 1 years, 37 patients developed reduced EF without an inter-current myocardial infarction (5.4%). In analysis of covariance, patients who developed reduced EF were more often men, had greater baseline LV diameter and LV mass, lower mean EF (all P &lt; 0.05), and similar diastolic function indices. At the last available examination before EF reduction, independently of covariates, patients with reduced EF showed a significant increase in left atrium (LA) size, LV diameter, end-systolic stress and mitral E/A ratio, as compared to those who did not develop reduced EF (all P &lt; 0.05). In time-varying Cox regression analysis, also controlling for baseline EF, predictors of developing reduced EF were higher in-treatment LV diameter [hazard ratio (HR) = 5.19 per cm; 95% confidence interval (CI): 2.58–10.41] and higher in-treatment mitral E/A ratio (HR = 2.37 per unit; 95% CI: 1.58–3.56; both P &lt; 0.0001). Conclusions: In treated hypertensive patients with ECG-LVH at baseline, incident reduced EF is associated with the development of dilated LV chamber and signs of increased LV filling pressure (ClinicalTrials.gov identifier: NCT00338260).

Incident left bundle branch block predicts cardiovascular events and death in hypertensive patients with left ventricular hypertrophy. The LIFE Study

Aim: Whether incident left bundle branch block (LBBB) is associated with increased cardiovascular (CV) morbidity and mortality in treated hypertensive patients with left ventricular hypertrophy (LVH) is unknown. Thus, the present study aimed to examine CV outcomes of incident LBBB in treated hypertensive patients with LVH. Methods: In the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study, 9,193 hypertensive patients with LVH on screening electrocardiogram (ECG) were randomized to losartan or atenolol based treatment. Participants (n = 8,567) did not have LBBB (Minnesota code 7.1) on baseline ECG. Cox regression models controlling for significant covariates assessed independent associations of incident LBBB with CV events and all-cause mortality during 4.8 years mean follow-up. Results: Annual follow-up ECGs identified 295 patients (3.4%) with incident LBBB associated with male gender (P &lt; 0.05), older age, higher Cornell voltage (both P &lt; 0.005) and history of diabetes, isolated systolic hypertension and prevalent CV disease. When adjusted for the history of previous CV disease, diabetes, isolated systolic hypertension, the Framingham risk score, ECG-LVH and randomized study treatment, Cox regression models showed that incident LBBB predicted higher risk of the composite endpoint CV death, myocardial infarction and stroke [hazard ratio (HR) 1.9, 95% confidence intervals (CIs) 1.3–2.9, P &lt; 0.001], CV death (HR 3.0, 95% CIs 1.84–5.0, P &lt; 0.001), heart failure (HR 3.6, 95% CIs 1.9–6.6, P &lt; 0.001) and all-cause mortality (HR 3.0, 95% CIs 2.0–4.3, P &lt; 0.001). Conclusions: These data suggest that among hypertensive patients with ECG-LVH receiving aggressive antihypertensive therapy, incident LBBB independently predicts increased risk of subsequent CV events including congestive heart failure and CV and all-cause mortality (ClinicalTrials.gov identifier: NCT00338260).

Time-varying serum uric acid predicts new-onset atrial fibrillation in treated hypertensive patients. The LIFE Study

Aim: The Losartan Intervention For Endpoint reduction in hypertension (LIFE) Study showed less new-onset atrial fibrillation (AF) in hypertensive patients receiving losartan- vs. atenolol-based treatment. Because losartan reduces serum uric acid (SUA) levels, the aim of the present study was to investigate relations of SUA with new-onset AF in the study. Methods: Hypertensive patients with electrocardiographic (ECG) left ventricular hypertrophy (LVH) and no prior AF (n = 8,243) were treated for 5.0 ± 0.4 years with losartan- or atenolol-based therapy. Associations of SUA with new-onset AF documented by Minnesota coding were assessed by Cox models using SUA and systolic blood pressure as time-varying covariates to take into account changes of SUA related to losartan or diuretic treatment, changes in renal function, and aging. Results: Time-varying SUA was associated with new AF defined by Minnesota code [hazard ratio (HR) = 1.19 per 16.8 μmol/L (1 mg/dL), (95% confidence intervals (CIs), 1.12–1.26), P &lt; 0.0001], independent of losartan treatment [HR = 0.75 (95% CIs, 0.61–0.93), P = 0.007], older age [HR = 1.95 per 7.0 years (95% CIs, 1.73–2.20), P &lt; 0.0001], male sex [HR = 1.46 (95% CIs, 1.09–1.94), P = 0.010] and higher Cornell voltage-duration product [HR = 1.10 per 1,023 ms·mm (95% CIs, 1.01–1.21), P = 0.034]. Similar results were obtained in Cox models with SUA levels partitioned according to baseline quartiles and in which AF was defined by physician reports or by both Minnesota coding and physician reports. Conclusions: In-treatment SUA is a strong predictor for new-onset AF in hypertensive patients, independent of effects of antihypertensive treatment, age, sex, and ECG-LVH. Further research is needed to clarify how uric acid may provoke AF (ClinicalTrials.gov identifier: NCT00338260).

A Point System Table to Estimate the Risk of Cardiovascular Events in Patients with Hypertension and Left Ventricular Hypertrophy: The LIFE Study

We aimed to assess some readily available patient characteristics such as urinary albumin excretion as predictors of a primary composite event of myocardial infarction, cerebral stroke, and cardiovascular death among patients with hypertension and left ventricular hypertrophy, and develop risk algorithms for the outcomes. A “Cox proportional hazards” model identified the baseline variables that significantly affected the occurrence of the composite endpoint in 9193 elderly hypertensive patients with left ventricular hypertrophy in the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study. We developed a risk point table, which assigned points to various risk factors, including the important age-gender interaction term, by adapting the point system algorithm developed from Framingham data. The Cox model identified 12 predictors of risk for the endpoint. Points for age were calculated separately for females and males due to the age-gender interaction. The risk estimates that were defined by total points were compared to those that were determined by the Cox model, and the weighted κ value for the agreement was 0.89. Thus, several patient characteristics predicted cardiovascular events in patients with hypertension and left ventricular hypertrophy, with age, gender, and urinary albumin excretion being the most important. The risk point table is an intuitive method to compare the relative contribution of the cardiovascular risk predictors and explain complicated statistical models such as the interaction term to patients and their physicians.

A novel method for interpreting survival analysis data: description and test on three major clinical trials on cardiovascular prevention

BackgroundMajor results of randomized clinical trials on cardiovascular prevention are currently provided in terms of relative or absolute risk reductions, including also the number needed to treat (NNT), incorrectly implying that a treatment might prevent the occurrence of the outcome/s under investigation. Provided that these results are based on survival analysis, the primary measure of which is time-to-the outcome and not the outcome itself, we sought an alternative method to describe, analyse and interpret clinical trial results consistent with this assumption, so as to better define qualitative and quantitative heterogeneity of various therapeutic strategies in terms of their effects and costs.MethodsThe original Kaplan-Meier graphs of three major positive cardiovascular prevention trials (PROVE-IT, LIFE and HOPE) were captured from the PDF images of the article and then digitalized. We calculated the difference between the placebo and active treatment curves and plotted it as a function of time to describe the event-free time gain (Time-Gain) produced by the active treatment. By calculating the exposure to the active treatment in terms of months (MoT) as a function of time and dividing it for the corresponding time-dependent number of event-free years gained (i.e. months/12), we described the kinetics of the pharmaco-economic index MoT/y+. The same procedure was repeated replacing MoT with the actual number of patients being treated at each time point as a function of time to obtain the NNT to gain 1 event-free year (NNT/y+) curve.ResultsThe Time-Gain curves depict the kinetics of the treatment-related effect over time and possess the peculiar feature of being smooth and accurately fitted by second-order polynomial functions (a*time2 + b*time); similarly, also the MoT/y+ and NNT/y+ curves can be accurately fitted by power functions (a*timeb).These curves and indices allow to fully appreciate the quantitative and qualitative heterogeneity, both in terms of effects and costs, of the different therapeutic strategies adopted in the three trials.ConclusionsWith our novel method, by exploiting original Kaplan-Meier curves from three major clinical trials on cardiovascular prevention, we generate new information on the actual consequences of choosing a therapeutic strategy vs another, thus ultimately providing the clinical gain in terms of time-dependent functions. Accurately assessing clinically and economic meaningful results from any intervention trial reporting positive results through this approach, facilitates objective comparisons and increases reliability in predicting survival among the various therapeutic options provided.Trial registrationPROVE-IT (Pravastatin or Atorvastatin Evaluation and Infection Therapy (TIMI22), Clinical trial registration number: NCT00382460, date of registration: September 29, 2006, study start date: November 2000).LIFE (Losartan Intervention For Endpoint Reduction in Hypertension (LIFE) Study, Clinical trial registration number: NCT00338260, date of registration: June 20, 2006, study start date: June 1995).HOPE (Heart Outcomes Prevention Evaluation; we could not find Clinical trial registration number and date of registration).

EFFECT OF LOSARTAN ON PLATELET RESPONSES TO CLASSIC AGONISTS

Losartan is a competitive antagonist of the angiotensin II receptor and it is used to treat hypertension. In the seminal Losartan Intervention For Endpoint Reduction in Hypertension (LIFE) study, losartan prevented more cardiovascular events and death than atenolol for a similar reduction in blood pressure. It was suggested that losartan may possess pleiotropic effects that could contribute to its clinical benefits. Among the beneficial pharmacological effects of losartan, it has been suggested that losartan could be an effective antithrombotic drug, through competition with the thromboxane receptor due to similarities between the drug and the endogenous thromboxane A2, an established platelet response amplifier.

Antihypertensive therapy prevents new-onset atrial fibrillation in patients with isolated systolic hypertension: the LIFE study

Aims: Atrial fibrillation (AF) is associated with increased cardiovascular risk and the incidence increases with age, hypertension and left ventricular hypertrophy (LVH). Reducing in-treatment systolic blood pressure (SBP) prevents new-onset AF but has previously not been studied in patients with isolated systolic hypertension (ISH). We aimed to investigate the effect on preventing new-onset AF by decreased in-treatment SBP in patients with ISH compared to patients with non-ISH.Methods and results: Double-blind, randomized, parallel-group study of 1320 patients with ISH and electrocardiographic (ECG) LVH, included among the 9193 patients in the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study. Annual ECGs were Minnesota coded centrally, and new-onset AF was evaluated in 1248 ISH patients and compared with 7583 non-ISH patients during mean 4.8 ± 0.9 years follow-up. Cox regression analyses were used to assess the effect of reduced in-treatment SBP. New-onset AF occurred in 61 (4.9%) ISH patients and 292 (3.9%) non-ISH patients. In multivariate analysis lower in-treatment SBP was associated with 17% risk reduction (p = 0.008) for new-onset AF in ISH patients and 9% risk reduction (p = 0.006) in non-ISH patients per 10 mmHg decrease in in-treatment SBP, independent of treatment modality, baseline risk factors, baseline SBP and in-treatment heart rate and ECG-LVH. There was a significant interaction (p = 0.041) in favor of SBP reduction and AF prevention in ISH vs. non-ISH patients.Conclusion: Our data suggest that the effect of in-treatment SBP reduction in preventing new-onset AF is stronger in ISH compared to non-ISH patients with hypertension and ECG-LVH. However, the principal findings were the same in ISH and non-ISH patients.

How does blood pressure change in hypertensive patients with atrial fibrillation after successful electrical cardioversion?

If the restoration of sinus rhythm (SR) by electrical cardioversion (ECV) in patients with atrial fibrillation (AF) may have a role in inducing blood pressure (BP) changes over time, it remains a largely unaddressed topic. This appears surprising in relation to the fact that AF and systemic hypertension constitute two closely related clinical entities. Indeed, AF is the most common sustained cardiac arrhythmia and, in turn, hypertension is the most common comorbid condition associated with AF.1 Moreover, the risk of stroke, heart failure, and cardiovascular mortality in patients with both AF and hypertension is markedly greater when compared with either condition alone. AF is a rapidly growing public health and socio-economic burden worldwide. It has been calculated that the total number of individuals with clinically diagnosed AF could increase from around 30-35 million (estimated data in 2010) to over 60-70 million over the next 30 years, as a result of demographic changes related to the progressive increase in life expectancy and the rising prevalence of risk factors for AF such as hypertension, diabetes mellitus, obesity, and chronic kidney disease.2 The clinical relevance of hypertension as a primary risk factor for AF in the general population has been clearly demonstrated by the Framingham Study researchers 25 years ago.3 In an analysis of 4731 individuals free of AF at entry, hypertension, defined as taking BP lowering drugs or a systolic BP of 160 mm Hg or greater, was associated with a 50% higher risk of incident AF in men and a 40% higher risk in women. Recent findings from the Clinical Practice Research Datalink (CPRD), a primary care database representative of the UK population in terms of age, sex, and ethnicity, examining 4.3 million individuals and 128 468 incident AF events, showed that systolic and diastolic BP were positively related to risk of AF.4 A 20-mm Hg higher usual systolic BP was associated with a higher risk of AF [hazard ratio (HR) 1.21]. In the Women's Health Study, including 34 221 participants free of prevalent cardiovascular disease at baseline, clinic BP was strongly associated with incident AF, and systolic BP was a better predictor than diastolic BP. Of note, systolic BP levels within the non-hypertensive range were independently associated with incident AF even after taking into account BP changes over time.5 It is worth noting that information on the contribution of ambulatory BP monitoring (ABPM) components to the risk of developing AF is scanty. Data collected from 2776 subjects randomly recruited from the general population in five European countries showed that each standard deviation (SD) increase in baseline 24-hour, daytime and nighttime systolic BP was associated with a 27%, 22%, and 20% significant increase in the risk for incident AF, respectively.6 In the Oulu Project Elucidating Risk of Atherosclerosis (OPERA), the value of ABPM components in predicting the long-term risk of AF was assessed in 903 subjects with or without hypertension aged 40 to 59 years.7 Among the baseline ABPM components, the nighttime mean systolic BP turned out to be an independent predictor of the occurrence of AF (HR = 1.07 per every 5 mm Hg increase). A mounting body of evidence suggests that reductions in BP can lower the risk of developing new AF. There is debate about the hypothesis that more intensive treatment aimed at greater reduction of BP can have an additional positive effect in preventing new-onset AF. The Losartan Intervention For Endpoint reduction in hypertension (LIFE) study examined whether lower achieved systolic BP (≤130 mm Hg) was associated with a lower incidence of AF compared with standard systolic BP control (131-141 mm Hg) and less-adequate control (systolic BP ≥142 mm Hg) in 8831 hypertensive patients with left ventricular hypertrophy.8 Compared to patients with in-treatment SBP ≥142 mm Hg, those with in-treatment SBP ≤130 mm Hg had a 40% lower risk of incident AF and those with in-treatment SBP of 131 to 141 mm Hg with a 24% lower risk, respectively. Finally, a number of studies indicated that a sub-optimal treatment of elevated BP in patients with AF is associated with a markedly higher risk of stroke and cardiac events. The Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) Trial reported that elevated BP measurements at any point during the trial were associated with a subsequent 50% increase in risk of stroke or systemic embolism (HR, 1.53).9 In this complex scenario, the study of Olbers et al offers a new piece of evidence on BP changes following the SR restoration obtained with ECV.10 In their retrospective analysis, including 487 patients with AF, who underwent elective ECV, a recovery of an SR was observed in 59.3% (n = 289) of the cases after one week. In the group of patients converted to SR, there was a significant increase in systolic BP (from 129 ± 17 mm Hg to 137 ± 18 mm Hg, P < 0.001), with a decrease in diastolic BP (from 82 ± 9 mm Hg to 79 ± 10 mm Hg, P < 0.01). In contrast, no significant changes in both systolic and diastolic were found in the group of 198 patients with persistent or relapsing AF. Before commenting the strengths and limitations of the paper by Olbers et al,10 it may be useful to briefly summarize the findings provided by previous studies on this topic. In a paper aimed to assess changes in exercise capacity, echocardiographic parameters, and plasma atrial natriuretic peptide concentrations in 42 patients with persistent AF, before and 30 days after ECV there were no statistical differences in office BP between the two groups with and without successful procedure.11 No statistically significant change in daily BP, as assessed by ABPM performed before and after ECV, was found by Olsen et al12 in a group of 42 AF patients. In particular, they failed to demonstrate differences between the patients who achieved SR and those who maintained AF. In a further small ABP-based study including 18 hypertensive patients with successful ECV, the restoration of SR resulted in a sustained decrease in diastolic and mean BP one day after ECV and this trend persisted after 1-month of follow-up.13 A further investigation focused on the impact of ECV on sublingual microcirculation by side-stream darkfield imaging in 14 patients converted from AF to SR and showed a significant decrease in systolic and diastolic BP after the procedure.14 A retrospective study by Ramirez et al,15 encompassing a total of 159 hypertensive patients with AF, suggested that successful catheter ablation was associated with a reduction in BP, whereas an opposite trend was observed after 1 year of follow-up in patients with failed ablation. More recently, Maselli et al demonstrated that office systolic BP increased significantly (+5 mm Hg) in 63 patients after thirty days from the recovery of SR by ECV, while, on the contrary diastolic BP showed an opposite tendency (−5 mm Hg).16 A subsequent study by the same group, in which 54 hypertensive patients underwent ABPM the day before and one month after cardioversion, documented that patients maintaining a SR at follow-up (n = 34) had significantly higher 24-hour, nighttime and daytime systolic BP, and significantly lower 24-hour, daytime, and nighttime diastolic BP.17 Whereas no significant BP changes were observed in patients with persistent or recurrent AF at follow-up (n = 20). Overall, these findings do not allow conclusions to be drawn about the effects of successful ECV on BP. This is clearly related to the significant differences between the various studies in terms of numerosity, clinical features of patients, follow-up duration, and methods of BP measurement. Many pathophysiological mechanisms can be invoked to explain the reduction of BP associated with restoration of SR. AF is associated with an increase in sympathetic nerve activity resulting in vascular and renal changes that promote hypertension. Furthermore, numerous studies have shown that AF is associated with activation of the renin-angiotensin-aldosterone system (RAAS), endothelial dysfunction and depressed nitric oxide bioavailability. Indeed, it has been reported that a successful ECV in patients with persistent AF is accompanied by a marked reduction in aldosterone levels.18 On the other hand, studies that have shown an increase in systolic pressure have called for several hemodynamic changes following ECV (ie, an increase of the ejection fraction, the duration of the diastolic phase, and the cardiac output) in support of their results. The above-mentioned changes may be particularly relevant in AF patients with ventricular dysfunction and marked irregularity of the ventricular response. The study by Olbers et al, showing a clear-cut increase of the systolic BP values and consequently of the prevalence uncontrolled hypertensive (+40%) after restoration of SR, has the merit of being based on the largest series published so far. A very critical point in this type of study represented by variations in therapy during follow-up was appropriately addressed by the authors analyzing the data of the subgroup in which therapy after ECV was not changed (ie, 371 out 487 patients). Even eliminating the confounding effect of therapeutic modifications, the increase in systolic BP remained clinically relevant and similar to that observed in the total sample. An additional interesting observation is that not only hypertensive patients but also those without a pre-existing diagnosis of hypertension exhibited significant BP increments after ECV. Although the information provided by this study is based on a retrospective design, a short duration of follow-up (reduction of sympathetic and RAAS activation may take longer than a week) and supine BP measurement has the great value to stress the issue of BP control in AF hypertensive patients submitted to ECV. In conclusion, the findings from the Olbers study suggest that restoration of SR in individuals with FA may require a re-evaluation of antihypertensive therapy in order to reduce the high cardiovascular risk associated with insufficient BP control in this setting;19 but, at the same time, they indicate that further investigations are needed to clarify the controversial aspects of this important topic. The authors report no conflicts of interest.

Fifteen years of LIFE (Losartan Intervention for Endpoint Reduction in Hypertension)-Lessons learned for losartan: An "old dog playing good tricks".

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.

Which Target Blood Pressure in Year 2018? Evidence from Recent Clinical Trials.

The Systolic Blood Pressure Intervention Trial (SPRINT) suggested a favourable effect of lowering blood pressure to < 120/80 mmHg in high-risk hypertensive patients; however, new American guidelines in 2017 have not followed SPRINT but lowered its recommended treatment target to < 130/80 mmHg. We aimed to review the latest research from large randomised controlled trials and observational analyses in order to investigate the evidence for new treatment targets. We assessed recent data from the Action to Control Cardiovascular Risk in Diabetes Blood Pressure (ACCORD) study, the International Verapamil-Trandolapril Study (INVEST), the Telmisartan, Ramipril or Both in Patients at High Risk for Vascular Events trial (ONTARGET)/the Telmisartan Randomised AssessmenNt Study in aCE iNtolerant participants with cardiovascular Disease (TRANSCEND) study and The Losartan Intervention For Endpoint Reduction in Hypertension (LIFE) study. These studies confirm a positive effect on cardiovascular protection with blood pressure lowering treatment to between 120-140 mmHg in patients with and without diabetes, but no additional effect of lowering blood pressure to < 120 mmHg; possibly too aggressive treatment may increase both cardiovascular morbidity and mortality. Thus, a target blood pressure< 130/80 mmHg appears appropriate in most high-risk hypertensive patients. Additionally, early and sustained BP control below this target is required for optimal cardiovascular protection.

Higher pulse pressure/stroke volume index is associated with impaired outcome in hypertensive patients with left ventricular hypertrophy the LIFE study

We tested the prognostic impact of a marker of arterial stiffness, pulse pressure/stroke volume index (PP/SVi), in patients with hypertension and left ventricular (LV) hypertrophy. We used data from 866 patients randomized to losartan or atenolol-based antihypertensive treatment, over a median of 4.8 years, in the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study. The association of PP/SVi with outcomes was tested in Cox regression analyses and reported as hazard ratio (HR) and 95% confidence intervals (CI). In multivariate regression, reduction of PP/SVi was independently associated with male gender, reduction in systolic blood pressure (BP) and relative wall thickness and with an increase in left ventricular ejection fraction (all p < .05). After adjusting for confounders, higher baseline PP/SVi predicted a 38% higher hazard of combined major fatal and non-fatal cardiovascular events (95% CI 1.04–1.84), and higher hazard of cardiovascular mortality (HR 2.35 (95% CI 1.59–3.48) and stroke (HR 1.45 (95% CI 1.06–1.99) (all p < .05). Higher PP/SVi also predicts higher rate of hospitalization for HF (HR 2.15 (95% CI 1.48–3.12) and a 52% higher hazard of all-cause mortality (95% CI 1.10–2.09) (both p < .05). In hypertensive patients with electrocardiographic LV hypertrophy, higher PP/SVi was associated with increased cardiovascular morbidity and mortality.

Digoxin use and risk of mortality in hypertensive patients with atrial fibrillation.

Digoxin is widely used for rate control of atrial fibrillation. However, recent studies have reported conflicting results on the association of digoxin with mortality when used in patients with atrial fibrillation. Moreover, the relationship of digoxin use to mortality in hypertensive patients with atrial fibrillation has not been examined. All-cause mortality was examined in relation to in-treatment digoxin use in 937 hypertensive patients with ECG left ventricular hypertrophy in atrial fibrillation at baseline (n = 134) or who developed atrial fibrillation during follow-up (n = 803), randomly assigned to losartan or atenolol-based treatment, in post-hoc analysis of a substudy of the Losartan Intervention For Endpoint Reduction in hypertension (LIFE) trial. During 4.7 ± 1.1 years of mean follow-up, 167 patients died (17.8%) and 372 (39.7%) were treated with digoxin. In univariate Cox analyses, in-treatment digoxin use, entered as a time-varying covariate, was associated with a 61% higher risk of dying (hazard ratio 1.61, 95% confidence interval 1.18-2.19, P = 0.003). After adjusting for other univariate predictors of death in this population, including age, diabetes, history of ischemic heart disease, stroke, or heart failure, baseline Cornell product, QRS duration, heart rate, serum glucose, creatinine and high-density lipoprotein cholesterol, and a propensity score for digoxin use entered as standard covariates, and for in-treatment heart rate, pulse pressure, and Sokolow-Lyon voltage treated as time-varying covariates, digoxin use was no longer a significant predictor of mortality (hazard ratio 1.04, 95% confidence interval 0.73-1.48, P = 0.839). In hypertensive patients with ECG left ventricular hypertrophy with existing or new atrial fibrillation, digoxin use is not associated with a significantly increased risk of all-cause mortality after adjusting for other independent predictors of death and for the factors associated with the propensity to use digoxin in this population. These findings suggest that factors other than digoxin use may account for the increased mortality found with digoxin use in some studies. .

Relationship of left ventricular systolic function to persistence or development of electrocardiographic left ventricular hypertrophy in hypertensive patients: implications for the development of new heart failure.

Persistence or development of ECG left ventricular hypertrophy (LVH) by Cornell product criteria is associated with an increased risk of developing heart failure compared with regression or continued absence of LVH. We postulated that this association might be in part mediated via worse left ventricular systolic function in patients with new or persistent ECG LVH. Baseline and year-3 ECG LVH and left ventricular midwall shortening (MWS) were examined in 725 hypertensive patients in the Losartan Intervention For Endpoint reduction in hypertension (LIFE) echocardiographic substudy. Sex-specific criteria were used for abnormal MWS (<14% in men and <16% in women) and abnormal stress-corrected MWS (scMWS; <87% in men and <90% in women). Cornell product LVH greater than 2440 mm ms defined ECG LVH. Between baseline and year-3 follow-up, there was continued absence or regression of ECG LVH in 427 patients and persistence or development of new LVH in 298 patients. At baseline, although there were no significant differences in the mean values of MWS and scMWS, patients with persistence or development of ECG LVH at year 3 had significantly higher baseline prevalences of abnormal MWS (41.9 vs. 30.2%, P = 0.001) and abnormal scMWS (27.4 vs. 20.5%, P = 0.034). At year-3 follow-up, persistence or development of new LVH was associated with significantly lower mean MWS (16.5 ± 2.3 vs. 17.2 ± 1.9%, P < 0.001) and scMWS (104.2 ± 13.1 vs. 106.5 ± 10.9%, P = 0.005), and with higher prevalence and odds of abnormal MWS [23.8 vs. 10.8%, P < 0.001, odds ratio (OR) 2.50, 95% confidence interval (CI) 1.66-3.75, P < 0.001] and abnormal scMWS (11.0 vs. 5.8%, P = 0.011, OR 2.02, 95% CI 1.16-3.51, P = 0.013). After controlling for differences in age, sex, race, treatment group, baseline and change from baseline to year 3 of heart rate, Sokolow-Lyon voltage, systolic and diastolic pressure and baseline severity of LVH by Cornell product, persistent or new ECG LVH remained associated with two-fold increased odds of abnormal MWS (OR 2.20, 95% CI 1.39-3.47, P = 0.001) or scMWS (OR 1.90, 95% CI 1.03-3.50, P = 0.040) at year 3. Persistence or development of new ECG LVH during antihypertensive therapy is associated with an increased risk of left ventricular systolic dysfunction after 3 years' follow-up. These findings provide insight into a possible mechanism by which changes in ECG LVH are associated with the changing risk of developing heart failure. http://clinicaltrials.gov/ct/show/NCT00338260?order=1.

Systolic left ventricular function according to left ventricular concentricity and dilatation in hypertensive patients

Left ventricular hypertrophy [LVH, high left ventricular mass (LVM)] is traditionally classified as concentric or eccentric based on left ventricular relative wall thickness. We evaluated left ventricular systolic function in a new four-group LVH classification based on left ventricular dilatation [high left ventricular end-diastolic volume (EDV) index and concentricity (LVM/EDV)] in hypertensive patients. Nine hundred thirty-nine participants in the Losartan Intervention For Endpoint reduction in hypertension (LIFE) echocardiography substudy had measurable LVM at enrolment. Patients with LVH (LVM/body surface area ≥116 g/m in men and ≥96 g/m in women) were divided into four groups; 'eccentric nondilated' (normal LVM/EDV and EDV), 'eccentric dilated' (increased EDV, normal LVM/EDV), 'concentric nondilated' (increased LVM/EDV with normal EDV), and 'concentric dilated' (increased LVM/EDV and EDV) and compared to patients with normal LVM. At baseline, 12% had eccentric nondilated, 20% eccentric dilated, 29% concentric nondilated, and 14% concentric dilated LVH, with normal LVM in 25%. Compared with the concentric nondilated LVH group, those with concentric dilated LVH had significantly lower pulse pressure/stroke index and ejection fraction; higher LVM index, stroke volume, cardiac output, left ventricular midwall shortening, left atrial volume and isovolumic relaxation time; and more had segmental wall motion abnormalities (all P < 0.05). Similar differences existed between patients with eccentric dilated and those with eccentric nondilated LVH (all P < 0.05). Compared with patients with normal LVM, the eccentric nondilated had higher LV stroke volume, pulse pressure/stroke index, Cornell voltage product and SBP, and lower heart rate and fewer were African-American (all P < 0.05). The new four-group classification of LVH identifies dilated subgroups with reduced left ventricular function among patients currently classified with eccentric or concentric LVH.

A Review of the Use of Angiotensin Receptor Blockers for the Prevention of Cardiovascular Events in Patients with Essential Hypertension Without Compelling Indications

To review the role of angiotensin receptor blockers (ARBs) for the prevention of cardiovascular events in patients with essential hypertension without other compelling indications. Peer-reviewed clinical trials, review articles, and relevant treatment guidelines were identified from MEDLINE and Current Content database (both 1966-November 15, 2012) using the search terms angiotensin receptor blockers (ARBs), azilsartan, candesartan, eprosartan, irbesartan, losartan, olmesartan, telmisartan, valsartan, hypertension, myocardial infarction, stroke, heart failure, and cardiovascular outcomes. Results were limited to human trials published in English. Citations from articles were also reviewed for additional references. The focus was on clinical trials evaluating cardiovascular end points of ARBs used in patients with essential hypertension without compelling indications. Data supporting the use of ARBs for reducing cardiovascular events in patients with essential hypertension without compelling indications are inconsistent. To date, only candesartan and losartan have shown a significant reduction in cardiovascular morbidity within this sizable subgroup of patients. In the Study on Cognition and Prognosis in the Elderly (SCOPE) trial, candesartan showed a 27.8% reduction in nonfatal stroke versus placebo (95% CI 1.3-47.2; p = 0.04). Moreover, losartan demonstrated a decrease in all cardiovascular events compared to atenolol in the Cardiovascular Morbidity and Mortality in the Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) study (RR 0.87; 95% CI 0.77-0.98; p = 0.021). Data supporting the use of ARBs for reducing cardiovascular events in patients with essential hypertension without compelling indications are limited and inconclusive. More studies are needed before ARBs can be routinely recommended as first-line therapy for hypertension management in patients without other compelling indications.

Losartan

Losartan, an angiotensin II receptor blocker (ARB), is licensed for use for a number of clinical indications including chronic heart failure, diabetic nephropathy and hypertension (including reduction in stroke risk in hypertension with left ventricular hypertrophy [LVH]). In addition to potentially reducing the risk of cardiovascular events, it is often better tolerated than other classes of antihypertensive agents. Figure 1 outlines the pharmacological actions of losartan. The renin-angio-tensin-aldosterone (RAAS) enzymatic cascade begins with the cleavage of angiotensinogen by renin to form the inactive decapeptide angiotensin-I. This is subsequently metabolised to angiotensin II by angiotensin converting enzyme (ACE). The pharmacological actions of losartan The discovery of specific angiotensin II receptor antagonists has confirmed the existence of various subtypes of angiotensin II receptors. All known clinical effects of angiotensin II are mediated via the angiotensin II type 1 (AT1) receptors which are located in the heart, kidney, vascular smooth muscle cells, brain, adrenal gland, platelets, adipocytes and placenta. Activation of the AT1 receptor stimulates vasoconstriction, sodium retention, endothelin and vasopressin release as well as activating sympathetic activity, promoting myocyte hypertrophy and cardiac fibrosis, and suppressing plasma renin secretion. Losartan was the first orally active AT1 receptor antagonist licensed for use and has been shown in vitro to compete with binding of angiotensin II to AT1 receptors. EXP 3174 is the major active metabolite of losartan and mediates most of its effects. The Optimal Trial in Myocardial Infarction with the Angiotensin II Antagonist Losartan (OPTIMAAL) was a multinational, double-blind, randomised, parallel group study comparing losartan with the ACE inhibitor captopril on mortality in patients with acute myocardial infarction and evidence of left ventricular dysfunction.1 In all, 5477 patients were randomly assigned treatment with losartan or captopril and titrated to target dose (50mg losartan daily, 50mg captopril three times daily) as tolerated with mean follow up of 2.7 years. The primary endpoint was all-cause mortality. There was a non-significant difference in total mortality in favour of captopril but losartan was significantly better tolerated with fewer patients discontinuing study medication. The Evaluation of Losartan in the Elderly (ELITE) study enrolled 722 patients aged 65 or more with NYHA class II–IV heart failure and ejection fractions of 40% or less.2 Subjects were randomised to receive either losartan 50mg once daily or captopril 50mg three times daily for 48 weeks. The frequency of the primary endpoint of increases in serum creatinine was the same in both groups, although fewer losartan patients discontinued therapy for adverse events. Admissions with heart failure were the same in both groups and NYHA functional class improved significantly and to a comparable extent from baseline after long-term treatment with both losartan and captopril. Unexpectedly, death and/or hospital admission for heart failure were recorded in 9.4% of the losartan group and 13.2% of the captopril patients. This risk reduction was primarily due to a decrease in all-cause mortality observed with the losartan group because of an apparent reduction in sudden cardiac deaths. The ELITE-II study, a double blind, randomised controlled trial enrolling 3152 patients aged 60 or over with NHYA class II–IV heart failure and ejection fraction of 40% or less, failed to replicate these findings with no significant difference in all-cause mortality or sudden cardiac death identified between the two treatment groups.3 However, ELITE-II did confirm the tolerability of losartan in comparison with captopril with significantly fewer patients discontinuing therapy because of adverse events. The Heart Failure Endpoint evaluation of Angiotensin II Antagonist Losartan (HEAAL) study investigated whether higher doses of ARB could achieve improved clinical outcomes. A total of 3846 patients with NYHA II–IV heart failure, ejection fraction of 40% or less and intolerance to ACE inhibitors were randomly assigned to losartan 50mg or 150mg per day.4 The primary endpoint was death or admission for heart failure. Higher-dose losartan reduced rates of death or admission for heart failure although adverse events such as renal dysfunction, hypotension and hyperkalaemia were more common in the 150mg treatment group. A small study has investigated the effects of addition of ARB to ACE inhibitor therapy in patients with severe congestive heart failure.5 This study showed that functional status improved by at least one NYHA class in 9 of 16 patients receiving losartan compared with 1 of 17 patients receiving placebo. There was also an improvement in peak VO2 after six months' treatment in the group receiving losartan in addition to ACE inhibitor. Losartan has been shown to reduce albumin excretion in hypertensive patients with non-diabetic renal disease, an effect that occurred in the absence of a change in glomerular filtering properties.6 A multicentre, open-label study evaluated the blood pressure lowering activity, tolerability and safety of losartan in 112 hypertensive patients with mild, moderate and severe chronic kidney disease.7 Losartan was administered daily for 12 weeks either as monotherapy or in combination with another non-ACE inhibitor antihypertensive agent following a three-week placebo period. Losartan was shown to reduce systolic and diastolic blood pressure in groups with mild, moderate and severe renal dysfunction. Creatinine clearance and glomerular filtration rate remained stable after 12 weeks. Hyperkalaemia required discontinuation of therapy in only one patient. The Losartan Intervention for Endpoint reduction in hypertension (LIFE) study was a double-blind, randomised, parallel group trial with 9193 participants between 55 and 80 years of age with essential hypertension and LVH, an independent risk factor for cardiovascular morbidity and death.8 Patients were randomised to once-daily losartan or atenolol based antihypertensive therapy for at least four years. Blood pressures were substantially reduced in both groups. There was a reduction in the primary composite endpoint in the losartan group (relative risk 0.87, 95% CI 0.77–0.98; p=0.021) and less fatal or non-fatal stroke (relative risk 0.75, 95% CI 0.63–0.89; p=0.001). Losartan also showed greater reduction of LVH compared with atenolol after four years of treatment.9 There was also a lower rate of adverse events in the losartan group. A multicentre, double-blind study randomised 407 patients to receive either losartan or enalapril for a 12-week period to evaluate the blood pressure lowering effects and tolerability of the drugs in patients with essential hypertension. Both drugs reduced systolic and diastolic blood pressure from baseline at six and 12 weeks of follow up. The only difference between the groups was that there was increased reporting of dry cough as a side effect in the group receiving ACE inhibitor therapy.10 The benefits of combination treatment with losartan and hydr-o-chlorothiazide have also been investigated in essential hypertension. Losartan was found to produce an additive reduction in systolic and diastolic blood pressures and was well tolerated among study subjects.11 Hospitalisation for heart failure was a secondary endpoint in the LIFE study; 1147 of 1195 patients with diabetes did not have a history of heart failure. Each case was reviewed and confirmed by the Endpoint Classification Committee using clinical or diagnostic findings. Losartan significantly reduced the first hospitalisations for heart failure compared with atenolol in patients with diabetes (hazard ratio 0.57, p=0.019).12 These findings were replicated in the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) study where 1413 of 1513 patients with diabetes did not have a diagnosis of heart failure.13 Losartan significantly reduced the first hospitalisations for heart failure compared with losartan in this study. In a randomised, placebo controlled trial of 147 normo-tensive patients with type 2 diabetes and microalbuminuria, five weeks of treatment with losartan reduced albumin excretion compared with placebo. Side effects did not differ between the treatment groups.14 The first major randomised controlled clinical trial evaluating the effects of losartan on progression of renal disease and death among patients with type 2 diabetes who were at high risk of developing endstage renal disease was the RENAAL study. At total of 1513 patients with diagnoses of type 2 diabetes and nephropathy were enrolled in this randomised, double-blind study and were allocated to receive either losartan or placebo in addition to conventional antihyper-tensive therapy for a mean of 3.4 years. The primary composite outcome included a doubling of serum creatinine from baseline, development of endstage renal disease and death. Secondary composite endpoints included a composite of cardiovascular morbidity and mortality, proteinuria and rate of progression of renal disease. There was a 16% reduction in the losartan group compared with the placebo group of patients reaching the primary endpoint. There was a 25% reduction in risk of doubling serum creatinine and a 28% risk reduction for development of endstage renal disease in the losartan group, but no significant difference in death rates between the two groups. The composite of cardiovascular morbidity and mortality was similar in both groups, but losartan significantly reduced rates of hospitalisation for heart failure.12 The LIFE study included 1195 patients with diabetes, hypertension and left ventricular hypertrophy.12 Subjects were randomised to receive either losartan or atenolol based therapy and followed up for at least four years. Mean blood pressure fell to a similar degree in both subgroups. The primary composite endpoint of cardiovascular death, stroke or myocardial infarction was reduced in the group receiving losartan-based therapy. In addition to this, all-cause mortality was significantly reduced in the losartan subgroup. Losartan was more effective than atenolol in reducing LVH. Losartan was found to reduce the risk of development of diabetes by 25% in the 7998 patients without diabetes in the LIFE study compared with atenolol.15 The results of a systematic review are not conclusive, but suggest that diabetes incidence is unchanged or decreased by treatment with ACE inhibitors and ARBs.16 Taken together, the results of the OPTIMAAL and ELITE II studies suggest that losartan offers an alternative if ACE inhibitor therapy is not tolerated in chronic heart failure. The LIFE diabetes substudy confirmed that these benefits are also applicable to patients with diabetes. For the 2578 patients with diabetes included in the LIFE and HEAAL studies without a history of heart failure, losartan treatment was associated with significant risk reduction in hospitalisation for new-onset heart failure confirming its benefit in patients at high renal and cardiovascular risk. Focusing on renal disease, losartan has been shown to reduce albumin excretion in hypertensive patients with non-diabetic renal disease. Furthermore, in patients with varying degrees of renal insufficiency ranging from mild to severe, losartan was effective at lowering blood pressure and proteinuria. These benefits have been confirmed in patients with type 2 diabetes and microalbuminuria. It is well tolerated among patients with diabetic nephro-pathy. ARBs are an established therapeutic option in the management of hypertension and have been proven to reduce the frequency of cardiovascular death, including stroke, as well as reducing LVH in hypertensive populations. It is often better tolerated than other classes of antihypertensive agent, particularly ACE inhibitors and beta blockers. GC, GMcK, HS: none. MF has received payments for lectures and advisory boards from Merck Sharp & Dohme. Losartan, an angiotensin II receptor blocker, is safe and effective in the management of patients with chronic heart failure, renal impairment and hypertension where it may reduce the risk of cardiovascular events The benefits of losartan extend to patients with diabetes, and losartan may have a role in preventing the development and progression of diabetic nephropathy Losartan is often better tolerated than other classes of agents used for similar indications

Mitral Annular Calcification and Incident Ischemic Stroke in Treated Hypertensive Patients: The LIFE study.

Background Fibro-calcification of the mitral annulus (MAC) has been associated with increased risk of ischemic stroke in general populations. This study was performed to assess whether MAC predicts incidence of ischemic stroke in treated hypertensive patients with left ventricular hypertrophy (LVH). Methods Baseline and follow-up clinical and echocardiographic parameters were assessed in 939 hypertensive patients with electrocardiogram (ECG) LVH participating in the Losartan Intervention for Endpoint reduction in hypertension (LIFE) echocardiography substudy (66±7 years; 42% women; 11% with diabetes) who did not have aortic or mitral valve stenosis or prosthesis. Results MAC was found in 458 patients (49%). Patients with MAC were older (68±7 vs. 65±7 years); were more often women (47% vs. 37%); had higher baseline systolic blood pressure (BP) (175±14 vs. 172±15mm Hg), left atrial diameter (4.0±0.5 vs. 3.8±0.6cm), and left ventricular mass index (58±13 vs. 55±12g/m(2.7)) and included more patients with proteinuria (30% vs. 21%; all P < 0.01). During a mean follow-up of 4.8 years, 58 participants had an ischemic stroke. Risk of incident ischemic stroke was significantly related to presence of MAC (log rank = 9; P < 0.01). In multivariable Cox regression analysis models, MAC was associated with increased risk of ischemic stroke (hazard ratio = 1.78-2.35), independent of age, baseline or time-varying systolic BP, prevalence or incidence of atrial fibrillation, history of previous cerebrovascular disease, and other well-recognized confounders, such as sex, time-varying left ventricular mass, left atrial diameter, and urinary albumin/creatinine ratio (all P < 0.05). Conclusions MAC is common in treated hypertensive patients with ECG LVH and is an independent predictor of incident ischemic stroke.

Treatment of diastolic dysfunction in hypertension

Diastolic dysfunction is present in half of patients with hypertension and has been shown to be associated with increased cardiovascular morbidity and mortality, as well as the development of heart failure. With the high prevalence of hypertension and its associated complications, treatment of diastolic dysfunction in hypertension is an important and desirable goal. Angiotensin converting enzyme inhibitors and angiotensin receptor blockers have been shown to be effective in improvement of measures of diastolic function and are recommended as first-line agents in the control of hypertension in patients with diastolic heart failure. Beta-blockers, calcium channel blockers, and diuretics have also shown some efficacy in improved indices of diastolic filling. However, the independent impact of these pharmacologic interventions on prognosis and outcome in diastolic dysfunction has yet to be clarified. The Irbesartan in Heart Failure with Preserved Ejection Fraction (I-PRESERVE) study, Candesartan in Heart Failure: Assessment in Reduction of Mortality and Morbidity (CHARM-Preserved) trial and the Losartan Intervention For End-point Reduction in Hypertension (LIFE) Study all failed to show improved morbidity and mortality with these drugs although, the LIFE study showed reduced heart failure hospitalization in hypertensive patients with normal in-treatment diastolic function. The Trial Of Preserved Cardiac function heart failure with an Aldosterone anTagonist (TOPCAT) is an on-going large, international study evaluating the effect of spironolactone on cardiovascular mortality, aborted cardiac arrest, or hospitalization for diastolic heart failure. This and other studies will provide further insight into the pathophysiology and management of patients with diastolic dysfunction.

Contrasting Hemodynamic Mechanisms of Losartan- vs. Atenolol-Based Antihypertensive Treatment: A LIFE Study

Pharmaceutical differences in central hemodynamics might influence cardiac response to antihypertensive treatment despite similar lowering of brachial blood pressure (BP). Data from all patients with at least two echocardiographic examinations in the Losartan Intervention For Endpoint Reduction in Hypertension (LIFE) echocardiographic substudy (n = 801); high-risk patients on losartan- vs. atenolol-based antihypertensive therapy. Echocardiography was performed annually for 4 years to measure stroke index (SI), heart rate, cardiac index (CI), conduit artery stiffness assessed as pulse pressure/stroke index (PP/SI) and total peripheral resistance index (TPRI). Atenolol- and losartan-based therapy reduced BP similarly (cumulative difference in mean brachial blood pressure 0.3 mm Hg, P = 0.65). After 4 years the cumulative means of SI and heart rate were 1.8 ml/m(2) higher and 5.7 beats/min lower on atenolol-based treatment, respectively (both P < 0.001). This kept CI below baseline in atenolol-treated patients, whereas in the losartan group CI was unchanged from baseline throughout the study. TPRI was decreased more and remained lower in the losartan group (cumulative difference in mean TPRI 287 dynes/sec(-5)/cm/m(2), P < 0.001). These findings partly explained univariate differences in systolic- and diastolic function indices between the two treatments; fully adjusted losartan was only associated with a smaller left atrial diameter (cumulative mean difference 0.07 cm; 95% confidence intervals, -0.13 to -0.01, P = 0.03). Contrasting hemodynamics impacted cardiac response to similar reductions in brachial BP on losartan- vs. atenolol-based therapy. The similar reduction of PP/SI suggests that the antihypertensive regimens used in the LIFE study had comparable effects on arterial stiffness (LIFE study; NCT00338260)