Björn Dahlöf

Adverse events associated with unblinded, but not with blinded, statin therapy in the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid-Lowering Arm (ASCOT-LLA): a randomised double-blind placebo-controlled trial and its non-randomised non-blind extension phase.

BACKGROUNDnIn blinded randomised controlled trials, statin therapy has been associated with few adverse events (AEs). By contrast, in observational studies, larger increases in many different AEs have been reported than in blinded trials.nnnMETHODSnIn the Lipid-Lowering Arm of the Anglo-Scandinavian Cardiac Outcomes Trial, patients aged 40-79 years with hypertension, at least three other cardiovascular risk factors, and fasting total cholesterol concentrations of 6·5 mmol/L or lower, and who were not taking a statin or fibrate, had no history of myocardial infarction, and were not being treated for angina were randomly assigned to atorvastatin 10 mg daily or matching placebo in a randomised double-blind placebo-controlled phase. In a subsequent non-randomised non-blind extension phase (initiated because of early termination of the trial because efficacy of atorvastatin was shown), all patients were offered atorvastatin 10 mg daily open label. We classified AEs using the Medical Dictionary for Regulatory Activities. We blindly adjudicated all reports of four prespecified AEs of interest-muscle-related, erectile dysfunction, sleep disturbance, and cognitive impairment-and analysed all remaining AEs grouped by system organ class. Rates of AEs are given as percentages per annum.nnnRESULTSnThe blinded randomised phase was done between February, 1998, and December, 2002; we included 101u200880 patients in this analysis (5101 [50%] in the atorvastatin group and 5079 [50%] in the placebo group), with a median follow-up of 3·3 years (IQR 2·7-3·7). The non-blinded non-randomised phase was done between December, 2002, and June, 2005; we included 9899 patients in this analysis (6409 [65%] atorvastatin users and 3490 [35%] non-users), with a median follow-up of 2·3 years (2·2-2·4). During the blinded phase, muscle-related AEs (298 [2·03% per annum] vs 283 [2·00% per annum]; hazard ratio 1·03 [95% CI 0·88-1·21]; p=0·72) and erectile dysfunction (272 [1·86% per annum] vs 302 [2·14% per annum]; 0·88 [0·75-1·04]; p=0·13) were reported at a similar rate by participants randomly assigned to atorvastatin or placebo. The rate of reports of sleep disturbance was significantly lower among participants assigned atorvastatin than assigned placebo (149 [1·00% per annum] vs 210 [1·46% per annum]; 0·69 [0·56-0·85]; p=0·0005). Too few cases of cognitive impairment were reported for a statistically reliable analysis (31 [0·20% per annum] vs 32 [0·22% per annum]; 0·94 [0·57-1·54]; p=0·81). We observed no significant differences in the rates of all other reported AEs, with the exception of an excess of renal and urinary AEs among patients assigned atorvastatin (481 [1·87%] per annum vs 392 [1·51%] per annum; 1·23 [1·08-1·41]; p=0·002). By contrast, during the non-blinded non-randomised phase, muscle-related AEs were reported at a significantly higher rate by participants taking statins than by those who were not (161 [1·26% per annum] vs 124 [1·00% per annum]; 1·41 [1·10-1·79]; p=0·006). We noted no significant differences between statin users and non-users in the rates of other AEs, with the exception of musculoskeletal and connective tissue disorders (992 [8·69% per annum] vs 831 [7·45% per annum]; 1·17 [1·06-1·29]; p=0·001) and blood and lymphatic system disorders (114 [0·88% per annum] vs 80 [0·64% per annum]; 1·40 [1·04-1·88]; p=0·03), which were reported more commonly by statin users than by non-users.nnnINTERPRETATIONnThese analyses illustrate the so-called nocebo effect, with an excess rate of muscle-related AE reports only when patients and their doctors were aware that statin therapy was being used and not when its use was blinded. These results will help assure both physicians and patients that most AEs associated with statins are not causally related to use of the drug and should help counter the adverse effect on public health of exaggerated claims about statin-related side-effects.nnnFUNDINGnPfizer, Servier Research Group, and Leo Laboratories.

Physical activity and exercise lower blood pressure in individuals with hypertension: narrative review of 27 RCTs

Regular physical activity (PA) reduces the blood pressure (BP) of individuals with hypertension. The present review analysed the scientific evidence for the BP lowering effect of aerobic PA in 27 randomised controlled studies on individuals with hypertension, and shows that regular medium-to-high-intensity aerobic activity reduces the BP by a mean of 11/5u2005mmu2005Hg (level of evidence, 3+). In addition, three randomised controlled trials (RCTs) on isometric (static) activity showed a BP reduction of similar magnitude in hypertensives; dynamic resistance training may show less effect, as shown in five available RCTs (level of evidence 2+). As both the prevalence of hypertension and physical inactivity are high and increasing in todays society, PA has a great role to play as a single (when indicated) or additive treatment for hypertension. Furthermore, as competitive athletes are getting older, it can be expected that more athletes at different competitive levels will have hypertension. Certain considerations must be applied regarding evaluation and treatment of hypertension in athletes. Eligibility for competitive sports may be affected if target organ damage (TOD) is present; however, an athlete with well-controlled BP, having no additional risk factors or TOD, is eligible for all sports.

Blood pressure variability predicts cardiovascular events independently of traditional cardiovascular risk factors and target organ damage: A LIFE substudy

Background: Assessment of antihypertensive treatment is normally based on the mean value of a number of blood pressure (BP) measurements. However, it is uncertain whether high in-treatment visit-to-visit BP variability may be harmful in hypertensive patients with left ventricular hypertrophy (LVH). Methods: In 8505 patients randomized to losartan vs. atenolol-based treatment in the LIFE study, we tested whether BP variability assessed as SD and range for BP6–24months measured at 6, 12, 18 and 24 months of treatment was associated with target organ damage (TOD) defined by LVH on ECG and urine albumin/creatinine ratio at 24 months, and predicted the composite endpoint (CEP) of cardiovascular death, nonfatal myocardial infarction (MI) or stroke occurring after 24 months (CEPu200a=u200a630 events). Results: In multiple regression models adjusted for mean BP6–24months and treatment allocation, neither high BP6–24months SD nor wide range were related to TOD at 24 months, except for a weak association between Sokolow–Lyon voltage and DBP6–24months SD and range (both &bgr;u200a=u200a0.04, Pu200a<u200a0.01). Independently of mean BP6–24months, treatment allocation, TOD and baseline characteristics in Cox regression models, CEP after 24 months was associated with DBP6–24months SD [hazard ratio per 1u200ammHg increase1.04, 95% confidence interval (95% CI) 1.01–1.06, Pu200a=u200a0.005], range (hazard ratio 1.02, 95% CI 1.01–1.03, Pu200a=u200a0.004), SBP6–24months SD (hazard ratio 1.01, 95% CI 0.99–1.02, Pu200a=u200a0.07) and range (hazard ratio 1.006, 95% CI 1.001–1.01, Pu200a=u200a0.04). Adjusted for the same factors, stroke was associated with DBP6–24months SD (hazard ratio 1.06, 95% CI 1.02–1.10, Pu200a=u200a0.001), range (hazard ratio 1.03, 95% CI 1.01–1.04, Pu200a=u200a0.001), SBP6–24months SD (hazard ratio 1.02, 95% CI 1.002–1.04, Pu200a=u200a0.04) and range (hazard ratio 1.008, 95% CI 1.001–1.02, Pu200a=u200a0.05), but MI was not. Conclusion: In LIFE patients, higher in-treatment BP6–24months variability was independently of mean BP6–24months associated with later CEP and stroke, but not with MI or TOD after 24 months.

Persistence of left ventricular hypertrophy is associated with increased cardiovascular morbidity and mortality in hypertensive patients with lower achieved systolic pressure during antihypertensive treatment.

Abstract Aim. To determine if persistence of electrocardiographic (ECG) left ventricular hypertrophy (LVH) during aggressive systolic blood pressure (SBP) lowering would identify patients at increased risk. Methods and results. Adjudicated outcomes were examined in relation to the presence of LVH by mean in-treatment Cornell product (CP) in 463 hypertensive patients with mean in-treatment SBP ≤ 130 mmHg randomly assigned to losartan- or atenolol-based treatment. During mean follow-up of 4.4 ± 1.3 years, persistence of mean CP > 2440 mm ms in 211 patients (45.6%) was associated with significantly higher 4-year rates of cardiovascular death (8.9% vs 3.4%, p = 0.003), myocardial infarction (7.0% vs 3.3%, p = 0.010), stroke (8.5% vs 2.1%, p = 0.002), the composite endpoint of these events (20.0% vs 7.0%, p < 0.001) and all-cause mortality (14.9% vs 10.0%, p = 0.015). In multivariate Cox analyses, adjusting for a propensity score for CP LVH, randomized treatment and Framingham risk score entered as standard covariates and in-treatment diastolic BP and Sokolow–Lyon voltage LVH entered as time-varying covariates, persistence of CP LVH remained associated with statistically significant increased risks of cardiovascular death (hazard ratio, HR = 2.51, 95% CI 1.10–5.70), stroke (HR = 2.63, 95% CI 1.03–6.97) and the composite endpoint (HR = 2.46, 95% CI 1.36–4.45). Conclusions. These findings suggest that persistence of LVH in a subset of these patients may in part explain the lack of benefit found in hypertensive patients despite treatment to lower SBP.

Racial Differences in Incident Atrial Fibrillation Among Hypertensive Patients During Antihypertensive Therapy

BACKGROUNDnBlacks have a higher prevalence of risk factors for atrial fibrillation (AF), such as hypertension, obesity, and heart failure, than nonblacks. Although population-based studies have demonstrated a lower prevalence and incidence of AF in blacks, the relationship of incident AF to race among hypertensive patients undergoing blood pressure lowering has been less extensively examined.nnnMETHODSnIncident AF was examined in 518 black and 8,313 nonblack hypertensive patients with electrocardiographic left ventricular hypertrophy (LVH) with no history of AF in sinus rhythm on their baseline electrocardiogram, who were randomly assigned to losartan- or atenolol-based treatment.nnnRESULTSnDuring a mean of 4.7±1.1 years of follow-up, new-onset AF occurred in 701 patients (7.9%); 5-year AF incidence was significantly lower in black than nonblack patients (6.1 vs. 8.3%; P = 0.03). In univariable Cox analyses, black race was associated with a 37% lower risk of new AF (hazard ratio (HR) = 0.63; 95% confidence interval (CI) = 0.45-1.00; P = 0.05). In multivariable Cox analyses adjusting for randomized treatment, age, sex, diabetes, history of heart failure, myocardial infarction, ischemic heart disease, stroke, peripheral vascular disease, smoking status, baseline body mass index, serum total and high-density lipoprotein cholesterol, creatinine, glucose, and urine albumin/creatinine ratio as standard risk factors, and for incident myocardial infarction, in-treatment heart rate, systolic and diastolic pressure, Cornell product, and Sokolow-Lyon voltage LVH treated as time-varying covariables, black race remained associated with a 45% decreased risk of developing new AF (HR = 0.55; 95% CI = 0.35-0.87; P = 0.01).nnnCONCLUSIONSnIncident AF is substantially less common among black than nonblack hypertensive patients.

Amlodipine+Benazepril is Superior to Hydrochlorothiazide+Benazepril Irrespective of Baseline Pulse Pressure: Subanalysis of the ACCOMPLISH Trial

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.

Potential Clinical Application of Angiotensin 2 Receptor Agonists

In this chapter, we explore the factors influencing the selection of a clinical target for the early clinical development of an AT 2 (AT 2 R) agonist for use in man. We discuss the requirements for an Investigational New Drug application. The only available oral AT 2 R agonist with an extensive preclinical documentation, outlined in previous chapters, is used as the model for this discussion. The growing body of preclinical data in a wide range of areas relevant to clinical applications justifies human proof of concept clinical studies with compound 21 or other AT 2 R agonists in several indication areas.