Impact of elevated lipoprotein(a) on coronary artery disease phenotype and severity.

AIMS: A thorough characterization of the relationship between elevated lipoprotein(a) [Lp(a)] and coronary artery disease (CAD) is lacking. This study aimed to quantitatively assess the association of increasing Lp(a) levels and CAD severity in a real-world population. METHODS AND RESULTS: This non-interventional, cross-sectional, LipidCardio study included patients aged ≥21 years undergoing angiography (October 2016-March 2018) at a tertiary cardiology centre, who have at least one Lp(a) measurement. The association between Lp(a) and CAD severity was determined by synergy between PCI with taxus and cardiac surgery (SYNTAX)-I and Gensini scores and angiographic characteristics. Overall, 975 patients (mean age: 69.5 years) were included; 70.1% were male, 97.5% had Caucasian ancestry, and 33.2% had a family history of premature atherosclerotic cardiovascular disease. Median baseline Lp(a) level was 19.3 nmol/L. Patients were stratified by baseline Lp(a): 72.9% had < 65 nmol/L, 21.0% had ≥100 nmol/L, 17.2% had ≥125 nmol/L, and 12.9% had ≥150 nmol/L. Compared with the normal (Lp(a) < 65 nmol/L) group, elevated Lp(a) groups (e.g. ≥ 150 nmol/L) had a higher proportion of patients with prior CAD (48.4% vs. 62.7%; P < 0.01), prior coronary revascularization (39.1% vs. 51.6%; P = 0.01), prior coronary artery bypass graft (6.0% vs. 15.1%; P < 0.01), vessel(s) with lesions (68.5% vs. 81.3%; P = 0.03), diffusely narrowed vessels (10.9% vs. 16.5%; P = 0.01) or chronic total occlusion lesions (14.3% vs. 25.2%; P < 0.01), and higher median SYNTAX-I (3.0 vs. 5.5; P = 0.01) and Gensini (10.0 vs. 16.0; P < 0.01) scores. CONCLUSION: Elevated Lp(a) was associated with a more severe presentation of CAD. Awareness of Lp(a) levels in patients with CAD may have implications in their clinical management.

Patients with coronary artery disease (CAD) suffer with progressive plaque buildup in the walls of coronary blood vessels, which restricts blood flow and may result in serious cardiovascular outcomes such as chest pain (angina) and heart attacks (myocardial infarction). In this study, we assessed whether elevated levels of lipoprotein(a) [Lp(a)­a lipoprotein found in blood] are associated with more severe illness. We observed that elevated Lp(a) was associated with a higher proportion of patients with prior CAD, prior interventions on coronary blood vessels, and more diseased blood vessels. These collectively form what is considered a 'severe' clinical presentation of CAD, meaning a greater likelihood of adverse clinical outcomes.

Elevated lipoprotein(a) increases risk of subsequent major adverse cardiovascular events (MACE) and coronary revascularisation in incident ASCVD patients: A cohort study from the UK Biobank.

BACKGROUND AND AIMS: Elevated lipoprotein(a) [Lp(a)] is a genetic driver for atherosclerotic cardiovascular disease (ASCVD). We aimed to provide novel insights into the associated risk of elevated versus normal Lp(a) levels on major adverse cardiovascular events (MACE) in an incident ASCVD cohort. METHODS: This was an observational cohort study of incident ASCVD patients. MACE counts and incidence rates (IRs) per 100-person-years were reported for patients with normal (<65 nmol/L) and elevated (>150 nmol/L) Lp(a) within the first year after incident ASCVD diagnosis and overall follow-up. Cox proportional hazard models quantified the risk of MACE associated with a 100 nmol/L increase in Lp(a). RESULTS: The study cohort included 32,537 incident ASCVD patients; 5204 with elevated and 22,257 with normal Lp(a). Of those with elevated Lp(a), 41.2% had a subsequent MACE, versus 35.61% with normal Lp(a). Within the first year of follow-up, the IRs of composite MACE and coronary revascularisation were significantly higher (p < 0.001) in patients with elevated versus normal Lp(a) (IR difference 6.79 and 4.66). This trend was also observed in the overall follow-up (median 4.7 years). Using time to first subsequent MACE, a 100 nmol/L increase in Lp(a) was associated with an 8.0% increased risk of composite MACE, and 18.6% increased risk of coronary revascularisation during the overall follow-up period. CONCLUSIONS: The association of elevated Lp(a) with increased risk of subsequent MACE and coronary revascularisation highlights a population who may benefit from earlier and more targeted intervention for cardiovascular risk including Lp(a), particularly within the first year after ASCVD diagnosis. Proactive Lp(a) testing as part of routine clinical practice can help identify and better manage these higher-risk individuals.

Burden of lipoprotein(a) for patients with atherosclerotic cardiovascular disease: A retrospective analysis from the United States.

BACKGROUND: Lipoprotein(a) (Lp(a)) is an inherited, independent, and causal risk factor for atherosclerotic cardiovascular disease (ASCVD). OBJECTIVE: To assess the burden of elevated Lp(a) for patients with ASCVD in a real-world setting in the United States. METHODS: This retrospective cohort study assessed US patients with available Lp(a) measurement and established ASCVD using Optum's Clinformatics Data Mart database (2007-2020). Index date was defined as the first diagnosis of an ASCVD event. Patient demographics, medications, health care resource utilization (HCRU), and occurrence of cardiovascular events were assessed for patients with elevated (≥150 nmol/L) vs normal (≥65 nmol/L) Lp(a) levels, within the first year of index date. HCRU was characterized by inpatient hospitalization, inpatient length of stay (LOS), outpatient visits, and emergency department (ED) visits. All comparative analyses of patients with elevated (≥150 nmol/L) vs normal (≥65 nmol/L) Lp(a) levels within the first year of index date were adjusted for age, sex, baseline statin use, and diabetes. RESULTS: 8,372 patients with ASCVD and Lp(a) measurement in nmol/L were included in this study. Patient demographics and baseline clinical characteristics were similar among those with normal and elevated Lp(a). However, the proportion of patients receiving statins and ß-blockers at baseline were significantly higher in the elevated vs normal Lp(a) group (54.76% vs 42.91%, P < 0.0001, and 30.92% vs 27.32%, P = 0.0183, respectively). At 1 year of follow-up, the rates per 100 person-years for ASCVD-related inpatient hospitalizations, outpatient hospitalizations, and ED visits were higher among patients with elevated Lp(a) compared with normal Lp(a) (13.33 vs 9.46, 89.08 vs 85.10, and 2.89 vs 2.29, respectively). The mean LOS per ASCVD-related hospitalization was 7.21 days in the elevated and 6.26 days in the normal Lp(a) group (P = 0.3462). During the 1-year post-index follow-up period, 15% of patients in the elevated Lp(a) group required revascularization compared with 10% of patients in the normal Lp(a) group (P = 0.0002). The odds of composite myocardial infarction, ischemic stroke, and revascularization occurrence of events within the first year of index was significantly higher in the elevated Lp(a) group compared with the normal Lp(a) group (1.46; 95% CI = 1.20-1.77; P < 0.05). CONCLUSIONS: HCRU within the first year of ASCVD diagnosis is substantial among patients with ASCVD and elevated Lp(a). Relatively higher rates of inpatient hospitalizations, increased LOS per hospitalization, and requirement of revascularization procedures within the first year of ASCVD index diagnosis were observed in patients with elevated Lp(a) compared with normal Lp(a) levels. Lp(a) testing in routine clinical practice could help in identification of high-risk patients with ASCVD and play an important role in the overall cardiovascular risk management, aiming to reduce the HCRU associated with ASCVD. DISCLOSURES: Ms Fonseca, Dr Laguna, Dr Itani, Dr Rachel Studer, and Dr Ferber are employees of Novartis Pharma AG, Basel, Switzerland. Ms Byrne is an employee of Novartis AG, Dublin, Ireland. Dr Costa-Scharplatz is an employee of Novartis Sweden AB, Stockholm, Sweden. Dr Heo and Ms Dillon are employees of Genesis Research. Genesis Research was commissioned to conduct the study (data extraction and analysis) on behalf of Novartis Pharma AG.

Association between sacubitril/valsartan initiation and changes in left ventricular ejection fraction: Insights from ARIADNE registry.

AIMS: We tested the hypothesis that initiation versus non-initiation of sacubitril/valsartan is associated with a more favorable subsequent change in left ventricular ejection fraction (LVEF) in a real-world setting. METHODS: A prospective, non-randomized, double-arm, open-label, cohort study had been conducted across 687 centers in 17 European countries enrolling HFrEF patients aged ≥18 years with symptoms of HF (New York Heart Association [NYHA] II-IV) and "reduced LVEF". For the current analysis, 2602 patients with LVEF measured at baseline and follow-up were chosen, of which 860 (33%, mean age 67 years, 26% women) were started on sacubitril/valsartan at baseline and 1742 (67%, 68 years, 23% women) were not. Patients started on sacubitril/valsartan had higher NYHA class and lower LVEF. RESULTS: LVEF increased from mean 32.7% to 38.1% in the sacubitril/valsartan group versus from 35.9% to 38.7% in the non-sacubitril/valsartan group (mean difference in increase 2.6%, p < 0.001). LVEF increased from baseline in 64% versus 53% of patients and increased by ≥5% (absolute %) in 50% versus 35% of patients in the sacubitril/valsartan versus non-sacubitril/valsartan groups, respectively. In the overall cohort, initiation of sacubitril/valsartan was independently associated with any increase in LVEF (adjusted odds ratio [OR] 1.49 [1.26-1.75]) and with increase by ≥5% (OR 1.65 [1.39-1.95]). CONCLUSION: Initiating versus not initiating sacubitril/valsartan was independently associated with a greater subsequent increase in LVEF in this real-world setting. Reverse cardiac remodeling may be one mechanism of benefit of sacubitril/valsartan.

Outcomes with sacubitril/valsartan in outpatients with heart failure and reduced ejection fraction: The ARIADNE registry.

AIMS: ARIADNE aimed to assess the association between effects of sacubitril/valsartan and no sacubitril/valsartan treatment and clinical characteristics, functional capacity, and clinical outcomes (cause-specific mortality and hospitalizations) in outpatients with heart failure (HF) with reduced ejection fraction (HFrEF). METHODS: ARIADNE was a prospective European registry of 9069 patients with HFrEF treated by office-based cardiologists or selected primary care physicians. Of the 8787 eligible for analysis, 4173 patients were on conventional HF treatment (non-S/V group), whereas 4614 patients were either on sacubitril/valsartan treatment at enrolment or started sacubitril/valsartan within 1 month of enrolment (S/V group). We also generated a restricted analysis set (rS/V) including only those 2108 patients who started sacubitril/valsartan treatment within the month prior to or after enrolment. RESULTS: At the baseline, average age of patients enrolled in the study was 68 years, and 23.9% (2099/8787) were female. At the baseline, the proportions of patients with New York Heart Association (NYHA) Class III symptoms were 30.9 (1288/4173), 42.8 (1974/4614), and 48.2% (1015/2108), in non-S/V, S/V, and rS/V groups, respectively. After 12 months of treatment, the proportion of patients with NYHA Class III at baseline who improved to Class II was 32.0% (290/907) in the non-S/V group vs. 46.3% (648/1399) in S/V group and 48.7% (349/717) in rS/V group. The overall mortality rate was 5.0 per 100 patient-years. Rates of HF hospitalizations were high (20.9, 20.3, and 21.2 per 100 patient-years in the non-S/V, S/V, and rS/V groups, respectively). Emergency room visits without hospitalization occurred in 3.9, 3.2, and 3.9% of patients in the non-S/V, S/V, and rS/V groups, respectively. CONCLUSIONS: This large HFrEF European registry provides a contemporary outcome profile of outpatients with HFrEF treated with or without sacubitril/valsartan. In a real-world setting, sacubitril/valsartan was associated with an improvement of symptoms in patients with HFrEF compared with the conventional HFrEF treatment.

Utilization of sacubitril/valsartan in patients with heart failure with reduced ejection fraction: real-world data from the ARIADNE registry.

AIMS: To compare baseline characteristics of patients with heart failure with reduced ejection fraction (HFrEF) initiated on sacubitril/valsartan compared with patients continued on conventional heart failure (HF)-treatment in a European out-patient setting. METHODS AND RESULTS: Between July 2016 and July 2019, ARIADNE enrolled 8787 outpatients aged ≥18 years with HFrEF from 17 European countries. Choice of therapy was solely at the investigators' discretion. In total, 4173 patients were on conventional HF-treatment (non-S/V group), while 4614 patients were on sacubitril/valsartan either at enrolment or started sacubitril/valsartan within 1 month of enrolment (S/V group). Of these, 2108 patients started sacubitril/valsartan treatment ±1 month around enrolment [restricted S/V (rS/V) group]. The average age of the patients was 68 years. Patients on S/V were more likely to have New York Heart Association (NYHA) class III or IV symptoms (50.3%, 44.6%, 32.1% in rS/V, S/V, and non-S/V, respectively) and had lower left ventricular ejection fraction (LVEF; 32.3%, 32.7%, and 35.4% in rS/V, S/V, and non-S/V, respectively; P < 0.0001). The most frequently received HF treatments were angiotensin-converting enzyme inhibitor/angiotensin receptor blocker (ACEI/ARB; ∼84% in non-S/V), followed by ß-blockers (∼80%) and mineralocorticoid receptor antagonists (MRAs; 53%). The use of triple HF therapy (ACEI/ARB/angiotensin receptor neprilysin inhibitor with ß-blockers and MRA) was higher in the S/V groups than non-S/V group (48.2%, 48.2%, and 40.2% in rS/V, S/V, and non-S/V, respectively). CONCLUSION: In this large multinational HFrEF registry, patients receiving sacubitril/valsartan tended to be younger with lower LVEF and higher NYHA class. Fewer than half of the patients received triple HF therapy.

PRospective Evaluation of natriuretic peptide-based reFERral of patients with chronic heart failure in primary care (PREFER): a real-world study.

OBJECTIVE: To assess current management practice of heart failure with reduced ejection fraction (HFrEF) in multinational primary care (PC) and determine whether N-terminal-pro-B-type natriuretic peptide (NT-pro-BNP)-guided referral of HFrEF patients from PC to a cardiologist could improve care, defined as adherence to European Society of Cardiology (ESC) guideline-recommended pharmacotherapy. METHODS: PRospective Evaluation of natriuretic peptide-based reFERral of patients with chronic HF in PC (PREFER) study enrolled HFrEF patients from PC considered clinically stable and those with NT-pro-BNP ≥600 pg/mL were referred to a cardiologist for optimisation of HF treatment. The primary outcome of adherence to ESC HF guidelines after referral to specialist was assessed at the second visit within 4 weeks of cardiologist's referral and no later than 6 months after the baseline visit. Based on futility interim analysis, the study was terminated early. RESULTS: In total, 1415 HFrEF patients from 223 PCs from 18 countries in Europe were enrolled. Of these, 1324 (96.9%) were considered clinically stable and 920 (65.0%) had NT-pro-BNP ≥600 pg/mL (mean: 2631 pg/mL). In total, 861 (60.8%) patients fulfilled both criteria and were referred to a cardiologist. Before cardiologist consultation, 10.1% of patients were on ESC guideline-recommended HFrEF medications and 2.7% were on recommended dosages of HFrEF medication (defined as ≥50% of ESC guideline-recommended dose). Postreferral, prescribed HFrEF drugs remained largely unchanged except for an increase in diuretics (+4.6%) and mineralocorticoid receptor antagonists (+7.9%). No significant increase in patients' adherence to guideline-defined drug combinations (11.2% post-referral vs 10.1% baseline) or drug combinations and dosages (3.3% postreferral vs 2.7% baseline) was observed after cardiologist consultation. CONCLUSIONS: PREFER demonstrates substantial suboptimal treatment of HFrEF patients in the real world. Referral of patients with elevated NT-pro-BNP levels from PC to cardiologist did not result in meaningful treatment optimisation for treatments with known mortality and morbidity benefit.

OUTSTEP-HF: randomised controlled trial comparing short-term effects of sacubitril/valsartan versus enalapril on daily physical activity in patients with chronic heart failure with reduced ejection fraction.

AIMS: OUTSTEP-HF compared the effect of sacubitril/valsartan vs. enalapril on 6-min walk test (6MWT) distance, non-sedentary daytime physical activity and heart failure (HF) symptoms in patients with HF with reduced ejection fraction (HFrEF). METHODS AND RESULTS: Ambulatory patients (n = 621) with stable symptomatic HFrEF were randomised 1:1 to sacubitril/valsartan (n = 310) or enalapril (n = 311). Changes in physical activity and mean daily non-sedentary daytime activity from baseline to Week 12 were measured using 6MWT and a wrist-worn accelerometer device, respectively. After 12 weeks, 6MWT improved by 35.09 m with sacubitril/valsartan [97.5% confidence interval (CI) 27.85, 42.32] and by 26.11 m with enalapril (97.5% CI 18.78, 33.43); however, there was no significant difference between groups [least squares means treatment difference: 8.98 m (97.5% CI -1.31, 19.27); P = 0.0503]. Mean daily non-sedentary daytime activity decreased by 27 min with sacubitril/valsartan and by 21 min with enalapril [least squares means treatment difference: -6 min (97.5% CI -25.7, 13.4), P = 0.4769] after 12 weeks. 6MWT improved by ≥30 m in 51% of patients in the sacubitril/valsartan group vs. 44% of patients treated with enalapril (odds ratio 1.251, 95% CI 0.895, 1.748). At Week 4, non-sedentary daytime activity increased by ≥10% in 58% of patients treated with sacubitril/valsartan vs. 64% with enalapril; 58% of patients treated with sacubitril/valsartan reported improved HF symptoms as assessed by patient global assessment vs. 43% with enalapril. However, these differences did not persist at Week 12. CONCLUSION: After 12 weeks of treatment, there was no significant benefit of sacubitril/valsartan on either 6MWT or daytime physical activity measured by actigraphy compared with enalapril.

Preclinical and Early Clinical Profile of a Highly Selective and Potent Oral Inhibitor of Aldosterone Synthase (CYP11B2).

Primary hyperaldosteronism is a common cause of resistant hypertension. Aldosterone is produced in the adrenal by aldosterone synthase (AS, encoded by the gene CYP11B2). AS shares 93% homology to 11ß-hydroxylase (encoded by the gene CYP11B1), responsible for cortisol production. This homology has hitherto impeded the development of a drug, which selectively suppresses aldosterone but not cortisol production, as a new treatment for primary hyperaldosteronism. We now report the development of RO6836191 as a potent (Ki 13 nmol/L) competitive inhibitor of AS, with in vitro selectivity >100-fold over 11ß-hydroxylase. In cynomolgus monkeys challenged with synthetic adrenocorticotropic hormone, single doses of RO6836191 inhibited aldosterone synthesis without affecting the adrenocorticotropic hormone-induced rise in cortisol. In repeat-dose toxicity studies in monkeys, RO6836191 reproduced the adrenal changes of the AS-/- mouse: expansion of the zona glomerulosa; increased expression of AS (or disrupted green fluorescent protein gene in the AS-/- mouse); hypertrophy, proliferation, and apoptosis of zona glomerulosa cells. These changes in the monkey were partially reversible and partially preventable by electrolyte supplementation and treatment with an angiotensin-converting enzyme inhibitor. In healthy subjects, single doses of RO6836191, across a 360-fold dose range, reduced plasma and urine aldosterone levels with maximum suppression at a dose of 10 mg, but unchanged cortisol, on adrenocorticotropic hormone challenge, up to 360 mg, and increase in the precursors 11-deoxycorticosterone and 11-deoxycortisol only at or >90 mg. In conclusion, RO6836191 demonstrates that it is possible to suppress aldosterone production completely in humans without affecting cortisol production. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01995383.

Biomarkers for cardiovascular risk assessment in autoimmune diseases.

Autoimmune diseases, such as antiphospholipid syndrome, systemic lupus erythematosus, and rheumatoid arthritis, are characterized by a high prevalence of cardiovascular (CV) disease (CVD), which constitutes the leading causes of morbidity and mortality among such patients. Although such effects are partly explained by a higher prevalence of traditional CV risk factors, many studies indicate that such factors do not fully explain the enhanced CV risk in these patients. In addition, risk stratification algorithms based upon traditional CV risk factors are not as predictive in autoimmune diseases as in the general population. For these reasons, the timely and accurate assessment of CV risk in these high-risk populations still remains an unmet clinical need. An enhanced contribution of different inflammatory components of the immune response, as well as autoimmune elements (e.g. autoantibodies, autoantigens, and cellular response), has been proposed to underlie the incremental CV risk observed in these populations. Recent advances in proteomic tools have contributed to the discovery of proteins involved in CVDs, including some that may be suitable to be used as biological markers. In this review we summarize the main markers in the field of CVDs associated with autoimmunity, as well as the recent advances in proteomic technology and their application for biomarker discovery in autoimmune disease.

Definition of human apolipoprotein A-I epitopes recognized by autoantibodies present in patients with cardiovascular diseases.

Autoantibodies to apolipoprotein A-I (anti-apoA-I IgG) have been shown to be both markers and mediators of cardiovascular disease, promoting atherogenesis and unstable atherosclerotic plaque. Previous studies have shown that high levels of anti-apoA-I IgGs are independently associated with major adverse cardiovascular events in patients with myocardial infarction. Autoantibody responses to apoA-I can be polyclonal and it is likely that more than one epitope may exist. To identify the specific immunoreactive peptides in apoA-I, we have developed a set of methodologies and procedures to isolate, purify, and identify novel apoA-I endogenous epitopes. First, we generated high purity apoA-I from human plasma, using thiophilic interaction chromatography followed by enzymatic digestion specifically at lysine or arginine residues. Immunoreactivity to the different peptides generated was tested by ELISA using serum obtained from patients with acute myocardial infarction and high titers of autoantibodies to native apoA-I. The immunoreactive peptides were further sequenced by mass spectrometry. Our approach successfully identified two novel immunoreactive peptides, recognized by autoantibodies from patients suffering from myocardial infarction, who contain a high titer of anti-apoA-I IgG. The discovery of these epitopes may open innovative prognostic and therapeutic opportunities potentially suitable to improve current cardiovascular risk stratification.

Randomized study to compare valsartan +/- HCTZ versus amlodipine +/- HCTZ strategies to maximize blood pressure control.

OBJECTIVE: Delays in achieving blood pressure (BP) control may increase morbidity and mortality in patients with hypertension. Thus, deciding which antihypertensive agent to use and at what dosage, in addition to determining when to initiate combination therapy and which agents to combine, is important for achieving BP control. METHODS: This randomized, double-blind, 14-week study was conducted to compare the efficacy and tolerability of various doses of valsartan +/- hydrochlorothiazide (HCTZ) versus amlodipine +/- HCTZ for maximizing BP control in 1,285 patients with uncontrolled hypertension. Patients with stage 1 hypertension and naïve to antihypertensive therapy (33.9%) started valsartan 160 mg or amlodipine 5 mg. Treatment-naïve patients with stage 2 hypertension (13.5%) or those uncontrolled on current antihypertensive monotherapy (52.6%) started valsartan 160 mg/HCTZ 12.5 mg or amlodipine 10 mg. At weeks 4, 8, and 11, patients not achieving BP control were up-titrated (maximum: valsartan 320 mg/HCTZ 25 mg, amlodipine 10 mg/HCTZ 25 mg). RESULTS: At study end, 78.8% of patients on valsartan +/- HCTZ were controlled (BP <140/90 mmHg) and still on study medication versus 67.8% on amlodipine +/- HCTZ (P < 0.0001). Amlodipine-treated patients had a higher incidence of peripheral edema (22.4% vs 2.2%) and associated discontinuations (7.3% vs <1%). Initiating therapy earlier with valsartan/HCTZ, rather than titrating monotherapy to its maximum dose before adding a second agent, was superior to amlodipine monotherapy or amlodipine +/- HCTZ for achieving BP control, and avoided excessive treatment adjustments and maintained tolerability.

Coadministration of valsartan 160 and 320 mg and simvastatin 20 and 40 mg in patients with hypertension and hypercholesterolemia: a multicenter, 12-week, double-blind, double-dummy, parallel-group superiority study.

BACKGROUND: Together, high blood pressure (BP) and high cholesterol levels constitute a cumulative risk for coronary heart disease (CHD). Elevations in cholesterol increase BP through upregulation of angiotensin type 1 receptors, with a corresponding increase in cholesterol oxidation due to elevations in BP. Hence, control of low-density lipoprotein cholesterol (LDL-C) and BP through coadministration of an antihypertensive and a statin have potential benefit in the management of CHD. OBJECTIVES: This study examined the dose response to simvastatin 20 and 40 mg in reducing LDL-C and the efficacy and tolerability of a high dose of valsartan (320 mg) when administered with simvastatin. METHODS: In this multicenter, 12-week, double-blind, double-dummy, parallel-group superiority study, patients with hypertension and hypercholesterolemia were randomized to receive valsartan 160 mg along with simvastatin 20 or 40 mg. At week 6, valsartan was titrated upward to 320 mg in both groups. The primary efficacy variable was the change in LDL-C, calculated using the Friedewald formula or measured directly (depending on triglyceride levels) and analyzed for superiority. Secondary efficacy variables were the change in LDL-C and the proportion of patients achieving LDL-C and BP control. Safety assessments included the occurrence of adverse events (AEs) and serious AEs, and changes in hematology and biochemistry variables, vital signs, and findings on physical examinations. RESULTS: Eight hundred seventy-two patients were randomized to receive double-blind treatment, and the intent-to-treat population included 838 patients. The combination of valsartan 160 mg + simvastatin 40 mg was statistically superior to that of valsartan 160 mg + simvastatin 20 mg in reducing LDL-C at week 6 (least squares mean percent change from baseline: -38.5% vs -33.6%, respectively; P < 0.001); at week 12, the corresponding values were -36.8% in the valsartan 320 mg + simvastatin 40 mg group and -32.7% in the valsartan 320 mg + simvastatin 20 mg group (P = 0.002). Rates of combined LDL-C and BP control at week 6 were 35.1% (146/416) in the valsartan 160 mg + simvastatin 20 mg group and 37.4% (154/412) in the valsartan 160 mg + simvastatin 40 mg group; at week 12, rates of combined control were 50.7% (212/418) in the valsartan 320 mg + simvastatin 20 mg group and 50.0% (206/412) in the valsartan 320 mg + simvastatin 40 mg group. AEs occurred in 24.3% (102/420) of the valsartan 160/320 mg + simvastatin 20 mg group and 22.2% (93/419) of the valsartan 160/320 mg + simvastatin 40 mg group. CONCLUSIONS: In these patients with hypertension and hypercholesterolemia, coadministration of valsartan and simvastatin was well tolerated and was associated with significant reductions from baseline in BP and LDL-C. Coadministered with valsartan 160/320 mg in the evening, simvastatin 40 mg had superior LDL-C-lowering efficacy to simvastatin 20 mg.

Public health value of fixed-dose combinations in hypertension.

It is well documented that reducing blood pressure (BP) in hypertensive individuals reduces the risk of cardiovascular (CV) events. Despite this, many patients with hypertension remain untreated or inadequately treated, and fail to reach the recommended BP goals. Suboptimal BP control, whilst arising from multiple causes, is often due to poor patient compliance and/or persistence, and results in a significant health and economic burden on society. The use of fixed-dose combinations (FDCs) for the treatment of hypertension has the potential to increase patient compliance and persistence. When compared with antihypertensive monotherapies, FDCs may also offer equivalent or better efficacy, and the same or improved tolerability. As a result, FDCs have the potential to reduce both the CV event rates and the non-drug healthcare costs associated with hypertension. When FDCs are adopted for the treatment of hypertension, issues relating to copayment, formulary restrictions and therapeutic reference pricing must be addressed.

Combination therapy with valsartan/hydrochlorothiazide at doses up to 320/25 mg improves blood pressure levels in patients with hypertension inadequately controlled by valsartan 320 mg monotherapy.

OBJECTIVES: To investigate the efficacy and tolerability of valsartan (Val) 320 mg once daily (o.d.), Val/hydrochlorothiazide (HCTZ) 320/12.5 mg o.d. and Val/HCTZ 320/25 mg o.d. in patients with hypertension not adequately controlled by Val monotherapy. METHODS: This double-blind, active-controlled, parallel-group, randomized trial recruited patients > or =18 years with mild-to-moderate essential hypertension, defined as mean sitting diastolic blood pressure (MSDBP) of > or =95 mmHg and <110 mmHg without treatment. After washout, 3805 eligible patients received Val 320 mg o.d. single-blind for 4 weeks. Subsequently, patients with MSDBP > or =90 and <110 mmHg (n=2702) were randomized to double-blind treatment with Val 320 mg, Val/HCTZ 320/12.5 mg or Val/HCTZ 320/25 mg for 8 weeks. Mean changes in MSDBP and mean sitting systolic BP (MSSBP) from the start of the single-blind period were analysed, as well as the proportion of responders (MSDBP <90 mmHg or > or =10 mmHg decrease from the start of the double-blind period). Tolerability and safety were also assessed. RESULTS: Reductions in MSDBP and MSSBP were observed in all groups. Both combinations were associated with significantly greater reductions than monotherapy for MSDBP and MSSBP at Weeks 8 and 12 (all p<0.0001). Both combinations also resulted in significantly greater proportion of responders at study end (74.9% and 68.8% for Val/HCTZ 320/25 mg and Val/HCTZ 320/12.5 mg, respectively) than monotherapy (52.7%; both p < 0.0001). In addition, a dose-response was observed with increasing dose of HCTZ with respect to MSSBP. All treatments were well tolerated. CONCLUSIONS: The combination ofVal and HCTZ at doses of 320/12.5 mg and 320/25 mg increases antihypertensive efficacy in patients with mild-to-moderate hypertension inadequately controlled with Val 320 mg monotherapy, without compromising tolerability.

Valsartan improves arterial stiffness in type 2 diabetes independently of blood pressure lowering.

Increased arterial stiffness, as estimated from aortic pulse wave velocity (Ao-PWV), and albuminuria are independent predictors for cardiovascular disease in type 2 diabetes mellitus (T2DM). Whether angiotensin receptor blockers (ARBs), drugs with cardio-renal protective effects, improve Ao-PWV to a greater extent than other equipotent antihypertensive medications remains unclear. After a 4-week washout phase, we compared the effects of valsartan (n=66), an ARB, with that of amlodipine (n=65), a calcium channel blocker on Ao-PWV in 131 T2DM patients with pulse pressure (PP) >or=60 mm Hg and raised albumin excretion rate (AER) in a 24-week randomized, double-blind, parallel group study. Hydrochlorothiazide (HCTZ) 25 mg/d was added to valsartan 160 mg and amlodipine 5 mg/od uptitrated to 10 mg/od after 4 weeks to ensure equivalent BP control. After 24 weeks brachial and central aortic PP had fallen to a similar extent with attained mean (SD) brachial and central PP of 61.6 (13.6) and 47.3 (14.1) mm Hg in the valsartan/HCTZ group and 61.5 (12.2) and 47.3 (9.9) mm Hg in the amlodipine group, respectively. Ao-PWV showed a significantly greater reduction, mean (95% CI), -0.9 m/s (-1.4 to -0.3) for valsartan/HCTZ compared to amlodipine (P=0.002). AER fell significantly only with Val/HCTZ from 30.8(20.4, 46.5) to 18.2(12.5, 26.3) mcg/min, (P=0.01) with between treatment difference in favor of Val/HCTZ of -15.3mcg/min (P<0.001). Changes in AER and Ao-PWV were not correlated. Valsartan/HCTZ improves arterial stiffness and AER to a significantly greater extent than amlodipine despite similar central and brachial BP control. These 2 effects, which appear independent of each other, may explain the specific cardio-renal protective properties of ARBs.

Efficacy of the combination of amlodipine and valsartan in patients with hypertension uncontrolled with previous monotherapy: the Exforge in Failure after Single Therapy (EX-FAST) study.

In this randomized, double-blind, multicenter study, patients whose blood pressure (BP) was uncontrolled by monotherapy were switched directly to amlodipine/valsartan 5/160 mg (n=443) or 10/160 mg (n=451). After 16 weeks, BP control (levels <140/90 mm Hg or <130/80 mm Hg for diabetics) was achieved in 72.7% (95% confidence interval [CI], 68.6-76.9) of patients receiving amlodipine/valsartan 5/160 mg and in 74.8% (95% CI, 70.8-78.9) receiving amlodipine/valsartan 10/160 mg. Incremental reductions from baseline in mean sitting systolic and diastolic BP were significantly greater with the higher dose (20.0+/-0.7 vs 17.5+/-0.7 mm Hg; P=.0003 and 11.6+/-0.4 vs 10.4+/-0.4 mm Hg; P=.0046). Incremental BP reductions were also achieved with both regimens irrespective of previous monotherapy, hypertension severity, diabetic status, body mass index, and age. Peripheral edema was the most frequent adverse event. These results provide support for the BP-lowering benefits of complementary antihypertensive therapy with amlodipine and valsartan in patients with hypertension uncontrolled by previous monotherapy.

[Monoclonal antibodies: Comparative methods for in vitro production]

The growth of antibody producing hybridoma in the abdominal cavity of the mouse with subsequent harvesting of the ascites fluid is a simple method for the production of monoclonal antibodies. However, due to the massive painful stress of the animal, this method is no longer tolerated by the legislator. In search of alternative methods the scientist has the choice between different techniques: Static tissue culture, spin- or roller-cultures as well as the production in bioreactors (automated cell culture devices). The presented work investigates the different methods and describes their applicability in a research lab. The results clearly show that for any desired amount of antibodies a production technique is available which allows the omission of the use of the "ascites-mouse".