Björn Dahlöf

Pulse pressure (PP) is an independent risk factor for cardiovascular (CV) disease and death but few studies have investigated the effect of antihypertensive treatments in relation to PP levels before treatment. The Avoiding Cardiovascular Events Through Combination Therapy in Patients Living With Systolic Hypertension (ACCOMPLISH) trial showed that the combination of benazepril+amlodipine (B+A) is superior to benazepril+hydrochlorothiazide (B+H) in reducing CV events. We aimed to investigate whether the treatment effects in the ACCOMPLISH trial were dependent on baseline PP. High‐risk hypertensive patients (n=11,499) were randomized to double‐blinded treatment with single‐pill combinations of either B+A or B+H and followed for 36 months. Patients were divided into tertiles according to their baseline PP and events (CV mortality/myocardial infarction or stroke) were compared. Hazard ratios (HRs) for the treatment effect (B+A over B+H) were calculated in a Cox regression model with age, coronary artery disease, and diabetes mellitus as covariates and were compared across the tertiles. The event rate was increased in the high tertile of PP compared with the low tertile (7.2% vs 4.4% P<.01). In the high and medium PP tertiles, HRs were 0.75 (95% confidence interval [CI], 0.60–0.95; P=.018) and 0.74 (CI, 0.56–0.98, P=.034), respectively, in favor of B+A. There was no significant difference between the treatments in the low tertile and no significant differences in treatment effect when comparing the HRs between tertiles of PP. B+A has superior CV protection over B+H in high‐risk hypertensive patients independent of baseline PP although the absolute treatment effect is enhanced in the higher tertiles of PP where event rates are higher.

We tested the impact of isolated systolic hypertension (ISH) on normalization of left ventricular (LV) structure during antihypertensive treatment. Baseline and annual echocardiograms were recorded in 873 hypertensive patients with electrocardiographic signs of LV hypertrophy during 4.8 years randomized losartan- or atenolol-based antihypertensive treatment in the Losartan Intervention For Endpoint (LIFE) reduction in hypertension study and classified as having ISH (n = 128) if systolic BP ≥ 160 mmHg and diastolic BP < 90 mmHg, or non-ISH divided into two groups by systolic BP ≥ 160 mmHg (non-ISH ≥ 160 mmHg) (n = 645) and systolic BP < 160 mm Hg (n = 100) (non-ISH < 160 mmHg), respectively. Patients with ISH were older, with higher prevalence of diabetes than non-ISH groups and higher pulse pressure/stroke volume index (all p < 0.05). Baseline systolic blood pressure (BP) differed between groups and was highest in the non-ISH ≥ 160 mmHg group (p < 0.05). Systolic BP reduction was less in the ISH group (p < 0.05). LV geometry did not differ between ISH and non-ISH ≥ 160 mmHg groups at baseline, but ISH had more residual LV hypertrophy of concentric type at the last study visit (p < 0.05). In multivariate analysis, less reduction of LV mass was predicted by ISH (β = - 0.07) independent of significant associations with baseline LVMi (β = 0.52) and atenolol-based treatment (β = - 0.08) and clinical confounders (all p < 0.05). ISH is associated with impaired normalization of LV mass during systematic antihypertensive treatment. The findings may help explain the higher cardiovascular event rate previously reported in ISH patients.

BACKGROUND: 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. METHODS AND RESULTS: 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 \u3e /=116 g/m in men and \u3e /=96 g/m in women) were divided into four groups; \u27eccentric nondilated\u27 (normal LVM/EDV and EDV), \u27eccentric dilated\u27 (increased EDV, normal LVM/EDV), \u27concentric nondilated\u27 (increased LVM/EDV with normal EDV), and \u27concentric dilated\u27 (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 \u3c 0.05). Similar differences existed between patients with eccentric dilated and those with eccentric nondilated LVH (all P \u3c 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 \u3c 0.05). CONCLUSION: The new four-group classification of LVH identifies dilated subgroups with reduced left ventricular function among patients currently classified with eccentric or concentric LVH

The Losartan Intervention For Endpoint reduction in hypertension (LIFE) study has previously demonstrated a beneficial effect of losartan compared to atenolol-based antihypertensive treatment in patients with essential hypertension and left-ventricular hypertrophy (LVH). However, patient age often influences the choice of antihypertensive drugs. Therefore, we investigated the influence of age on the effects of losartan versus atenolol-based antihypertensive treatment. A total of 9193 hypertensive patients with LVH aged 45-83 years were followed for a mean of 4.8 years. Blood pressure, high-density lipoprotein cholesterol (HDL-C), Sokolow-Lyon voltage, Cornell voltage-duration product and urine albumin-creatinine ratio (UACR) were measured yearly throughout the study. Patients were divided into two age groups according to the median age of 67 years and the effects of losartan versus atenolol-based antihypertensive treatment on the primary composite endpoint (CEP) consisting of cardiovascular death, nonfatal stroke or nonfatal myocardial infarction were investigated. The beneficial effect of losartan versus atenolol-based treatment was greater in the group of patients older than 67 years [hazard ratio 0.79 (0.69-0.91), P = 0.001] compared to the group of patients younger than 67 years [hazard ratio 1.03 (0.82-1.28), P = 0809], P = 0.045 for interaction. The beneficial effects of losartan versus atenolol-based antihypertensive treatment on pulse pressure, HDL-C, UACR, and Cornell and Sokolow-Lyon voltage were not more pronounced in patients older than 67 years compared to patients younger than 67 years. All five risk factors considered as time-varying covariates predicted CEP independently (P < 0.01) with the exception of pulse pressure (P = 0.37) and the interaction between age and treatment on outcome remained significant (P = 0.042). We showed a greater beneficial effect of losartan versus atenolol-based antihypertensive treatment in the group of patients older than 67 years compared to the group of patients younger than 67 years. This difference was not explained by a more pronounced effect of losartan-based treatment on any of the cardiovascular risk factors demonstrated to have independent prognostic importance.

Pulse pressure (PP) has been related to risk of cardiovascular events in hypertension. However, less is known about modification of this risk marker during antihypertensive treatment in patients with left ventricular (LV) hypertrophy.Associations of in-treatment PP with LV systolic function and cardiovascular events was assessed in 883 patients with electrocardiographic LV hypertrophy during 4.8 years of randomized losartan- or atenolol-based treatment within the echocardiographic substudy of the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study.PP was similarly reduced by both treatments. In different multiple regression models, lower in-treatment PP was independently associated with lower in-treatment LV ejection fraction (beta=0.16), stress-corrected midwall shortening (beta=0.20), stroke volume (beta=0.11) and cardiac index (beta=0.07, all p<0.05). In time-varying Cox regression models, 10 mmHg lower in-treatment PP was associated with a 28% higher rate of cardiovascular events [hazard ratio, HR = 1.28 (1.09 - 1.52), p<0.01] independent of in-treatment LV mass and ejection fraction, history of ischemic heart disease, Framingham risk score and study treatment allocation.During systematic antihypertensive treatment in hypertensive patients with electrocardiographic LV hypertrophy, lower in-treatment PP was associated with lower in-treatment LV function and cardiac output as well as higher rate of cardiovascular events.

Introduction: The Losartan Intervention For Endpoint reduction in hypertension (LIFE) study is the first, and, so far, the only endpoint trial in patients with hypertension and left ventricular hypertrophy (LVH) to show a divergent therapeutic outcome of one treatment modality over another with equivalent blood pressure control. The purpose of this article is to review post hoc sub-analyses of LIFE study data and other clinical studies that offer some insight into possible treatment-related differences contributing to the superior stroke outcome of losartan versus atenolol beyond blood pressure reduction. Methods: Relevant randomized clinical trials and review articles were identified through a MEDLINE search of English-language articles published between 1990 and 2006 using the search terms losartan, atenolol, LIFE, hypertension, and LVH. Articles describing major clinical studies, new data, or mechanisms pertinent to the LIFE study were selected for review. Results: Differences in blood pressure or in the distribution of add-on medications were not evident between study groups in the LIFE study. Thus, the observed outcomes benefits favoring losartan may involve other possible mechanisms, including differential effects of losartan and atenolol on LVH regression, left atrial diameter, atrial fibrillation, brain natriuretic peptide, vascular structure, thrombus formation/platelet aggregation, serum uric acid, albuminuria, new-onset diabetes, and lipid metabolism. Alternative explanations for the LIFE study findings have also been put forward, including the choice of atenolol as an appropriate active comparator and differential effects between treatment groups on central pulse pressure. Additional clinical trials are needed to determine if the beneficial effects of losartan seen in LIFE are shared by other inhibitors of the renin–angiotensin system. Conclusion: Sub-analyses of the LIFE study data suggest that losartan's stroke benefit may arise from a mosaic of mechanisms rather than a single action. Further studies are expected to continue to delineate the mechanisms of differential responses to treatments in LIFE.