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 < 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 < 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 < 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 < 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 < 0.05), older age, higher Cornell voltage (both P < 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 < 0.001], CV death (HR 3.0, 95% CIs 1.84–5.0, P < 0.001), heart failure (HR 3.6, 95% CIs 1.9–6.6, P < 0.001) and all-cause mortality (HR 3.0, 95% CIs 2.0–4.3, P < 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 < 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 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?

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

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.

Left Ventricular Wall Stress-Mass-Heart Rate Product and Cardiovascular Events in Treated Hypertensive Patients: LIFE Study.

In the Losartan Intervention for End Point Reduction in Hypertension (LIFE) study, 4.8 years' losartan- versus atenolol-based antihypertensive treatment reduced left ventricular hypertrophy and cardiovascular end points, including cardiovascular death and stroke. However, there was no difference in myocardial infarction (MI), possibly related to greater reduction in myocardial oxygen demand by atenolol-based treatment. Myocardial oxygen demand was assessed indirectly by the left ventricular mass×wall stress×heart rate (triple product) in 905 LIFE participants. The triple product was included as time-varying covariate in Cox models assessing predictors of the LIFE primary composite end point (cardiovascular death, MI, or stroke), its individual components, and all-cause mortality. At baseline, the triple product in both treatment groups was, compared with normal adults, elevated in 70% of patients. During randomized treatment, the triple product was reduced more by atenolol, with prevalences of elevated triple product of 39% versus 51% on losartan (both P≤0.001). In Cox regression analyses adjusting for age, smoking, diabetes mellitus, and prior stroke, MI, and heart failure, 1 SD lower triple product was associated with 23% (95% confidence interval 13%-32%) fewer composite end points, 31% (18%-41%) less cardiovascular mortality, 30% (15%-41%) lower MI, and 22% (11%-33%) lower all-cause mortality (all P≤0.001), without association with stroke (P=0.34). Although losartan-based therapy reduced ventricular mass more, greater heart rate reduction with atenolol resulted in larger reduction of the triple product. Lower triple product during antihypertensive treatment was strongly, independently associated with lower rates of the LIFE primary composite end point, cardiovascular death, and MI, but not stroke.

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

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.