Jürgen Scholze

Carotid intima-media thickness and plaque volume changes following 2-year angiotensin II-receptor blockade. The Multicentre Olmesartan atherosclerosis Regression Evaluation (MORE) study

Objective The Multicentre Olmesartan atherosclerosis Regression Evaluation (MORE) study was a double-blind trial in patients with hypertension at increased cardiovascular risk with carotid wall thickening and a defined atherosclerotic plaque that used non-invasive 2- and 3-dimensionaL (D) ultrasound (US), to compare the effects of a 2-year treatment based on either olmesartan medoxomil or atenolol on common carotid (CC) intima-media thickness (IMT) and plaque volume (PV). Methods A total of 165 patients (with systolic/diastolic blood pressure 140—180/ 90—105 mmHg) were randomized to receive either olmesartan (20—40 mg/day) or atenolol (50—100 mg/day). US was performed at baseline and 28, 52 and 104 weeks. The primary efficacy outcome was the change from baseline ( Δ) in CC-IMT assessed by 2D US. Secondary outcomes included Δ PV assessed by 3D US and blood pressure (BP). Results Olmesartan and atenolo produced comparable significant reductions in CC-IMT; mean Δ IMT (SEM) was -0.090 (0.015) mm for oLmesartan and -0.082 (0.014) mm for atenolol. Mean Δ PV was -4.4 (2.3) µl and 0.1 (1.5) µl in the olmesartan and atenolol treated subjects, respectively, without significant between-treatment differences. In the subgroup of patients with baseLine PV ≥ median (33.7 µl), significant between-treatment differences existed in Δ PV (p = 0.023), because PV regressed significantly with olmesartan (Δ PV: -11.5 (4.4) µl) but not with atenolol ( Δ PV: 0.6 (2.5) µl). In these patients BP reductions were comparabLe. Conclusions Carotid IMT and BP decreased similarly with olmesartan and atenolol, but only olmesartan reduced the volume of larger atherosclerotic plaques.

Epidemiological and economic burden of metabolic syndrome and its consequences in patients with hypertension in Germany, Spain and Italy; a prevalence-based model

BackgroundThe presence of metabolic syndrome in patients with hypertension significantly increases the risk of cardiovascular disease, type 2 diabetes and mortality. Our aim is to estimate the epidemiological and economic burden to the health service of metabolic syndrome in patients with hypertension in three European countries in 2008 and 2020.MethodsAn age, sex and risk group structured prevalence based cost of illness model was developed using the United States Adult Treatment Panel III of the National Cholesterol Education Program criteria to define metabolic syndrome. Data sources included published information and public use databases on disease prevalence, incidence of cardiovascular events, prevalence of type 2 diabetes, treatment patterns and cost of management in Germany, Spain and Italy.ResultsThe prevalence of hypertension with metabolic syndrome in the general population of Germany, Spain and Italy was 36%, 11% and 10% respectively. In subjects with hypertension 61%, 22% and 21% also had metabolic syndrome. Incident cardiovascular events and attributable mortality were around two fold higher in subjects with metabolic syndrome and prevalence of type 2 diabetes was around six-fold higher. The economic burden to the health service of metabolic syndrome in patients with hypertension was been estimated at €24,427, €1,900 and €4,877 million in Germany, Spain and Italy and forecast to rise by 59%, 179% and 157% respectively by 2020. The largest components of costs included the management of prevalent type 2 diabetes and incident cardiovascular events. Mean annual costs per hypertensive patient were around three-fold higher in subjects with metabolic syndrome compared to those without and rose incrementally with the additional number of metabolic syndrome components present.ConclusionThe presence of metabolic syndrome in patients with hypertension significantly inflates economic burden and costs are likely to increase in the future due to an aging population and an increase in the prevalence of components of metabolic syndrome.

Modelling the costs of care of hypertension in patients with metabolic syndrome and its consequences, in Germany, Spain and Italy

The presence of metabolic syndrome in patients with hypertension significantly increases the risk of cardiovascular disease, type 2 diabetes and mortality. Our aim is to estimate the economic burden to the health service of metabolic syndrome (MetS) in patients with hypertension and its consequences, in three European countries in 2008, and to forecast future economic burden in 2020 using projected demographic estimates and assumptions around the growth of MetS. An age-, sex- and risk group-structured prevalence-based cost of illness model was developed using the United States Adult Treatment Panel III of the National Cholesterol Education Program criteria to define MetS. Data sources included published information and public use databases on disease prevalence, incidence of cardiovascular events, prevalence of type 2 diabetes, treatment patterns and cost of management in Germany, Spain and Italy. The economic burden to the health service of MetS in patients with hypertension has been estimated at 24,427 €, 1,900 € and 4,877 € million in Germany, Spain and Italy, and is forecast to rise by 59, 179 and 157%, respectively, by 2020. The largest components of costs included the management of prevalent type 2 diabetes and incident cardiovascular events. Mean annual costs per hypertensive patient were around three-fold higher in subjects with MetS compared to those without and rose incrementally with the additional number of MetS components present. In conclusion, the presence of MetS in patients with hypertension significantly inflates economic burden, and costs are likely to increase in the future due to an aging population and an increase in the prevalence of components of MetS.

Efficacy and safety of a fixed-dose combination of lercanidipine and enalapril in daily practice. A comparison of office, self-measured and ambulatory blood pressure

Background: A fixed-dose combination (FDC) of enalapril and lercanidipine has been shown to be effective and safe in reducing blood pressure in randomized clinical trials. This study aims to determine effectiveness and safety in daily practice. Methods: This was a prospective, open-label, uncontrolled multicenter study, with a 3-month follow-up at general practitioners and internists. Patients were treated with an FDC of 20 mg enalapril maleate and 10 mg lercanidipine hydrochloride, and blood pressure was determined in the office (OBPM) and by discretionary self- (SBPM) and ambulatory- (ABPM) measurements. Results: Out of 622 patients (mean age 61.3 ± 13.3 years, 54.2% male): blood pressure was reduced by -29.2/-14.2 mmHg (OBPM) from baseline (164.4/95.2 mmHg). Pulse pressure was reduced by -15.0 ± 16.4 mmHg. Prevalence of microalbuminuria was reduced from 14.6% at baseline to 6.5% (p < 0.001). SBPM data were available for 71% of patients and ABPM for 12%. In the latter patients, blood pressure variability index was significantly reduced compared with baseline over 24 h (14.2 ± 4.2 vs 16.3 ± 4.0; p < 0.001) and with nighttime ABPM (13.7 ± 4.9 vs 15.2 ± 4.4; p = 0.022). Treatment was associated with a low incidence of adverse events (3.4%). Conclusions: The FDC of 20 mg enalapril-maleate and 10 mg lercanidipine-hydrochloride seems to be effective and well tolerated in clinical practice. It improved vascular surrogate end points, including pulse pressure, blood pressure variability and microalbuminuria.

Pharmacokinetics and safety of olmesartan medoxomil in combination with either amlodipine or atenolol compared to respective monotherapies in healthy subjects

The aim of this study was to investigate any influence on olmesartan plasma pharmacokinetics from amlodipine or atenolol. We analysed pharmacokinetics and safety of olmesartan medoxomil in combination with either amlodipine or atenolol compared to respective monotherapies in two separate studies. In one study, 18 subjects received once daily treatment for 7 days with olmesartan medoxomil 20 mg alone or with amlodipine 5 mg or amlodipine 5 mg alone. In the other study, atenolol 50 mg once daily replaced amlodipine. Concentration vs. time profiles for olmesartan monotherapy were similar to combination therapy. Mean olmesartan AUCss,τ for olmesartan alone and with amlodipine were 2439 and 2388 ng h/mL and for olmesartan alone and with atenolol were 2340 and 2247 ng h/mL. Corresponding olmesartan Css,max values were 465.7 and 439.5 ng/mL for amlodipine, and 447.4 and 423.8 ng/mL for atenolol. Median tmax values for olmesartan were 1.5 h for each group in each study. Bioequivalence was established for all pharmacokinetic parameters. Lack of significant pharmacokinetic interactions between olmesartan and amlodipine or atenolol provides a basis for combination therapy.

Behandlung der Hypertonie bei Adipositas

Hintergrund: Hypertonie und Übergewicht/Adipositas sind in der Bevölkerung weit verbreitet und erhöhen unabhängig voneinander das kardiovaskuläre Risiko. In zahlreichen Studien konnte belegt werden, dass zwischen erhöhtem Bodymass-Index und Blutdrucksteigerung ein direkter Zusammenhang existiert. So ist es nicht verwunderlich, dass ca. jeder zweite Adipöse hyperton und jeder zweite Hypertoniker adipös ist. Gewichtsreduktion: Folglich ist die Gewichtsreduktion in allen Therapieempfehlungen der erste Schritt im Hypertoniemanagement übergewichtiger bzw. adipöser Patienten. Hierbei stehen eine hypokalorische, laktovegetabil orientierte Mischkost, adipositasgerechte Bewegungs- bzw. Ausdauersportarten mit gezieltem Muskelaufbau (z. B. Aquafitness u. a.) und Verhaltenstherapie im Vordergrund, wobei begleitende medikamentöse Verfahren in der langfristigen Gewichtsreduktion an Bedeutung gewinnen. Auf Orlistat und Sibutramin wird kurz hinsichtlich Wirkungsmechanismen, Erfolgsaussichten und Risiken eingegangen. Pharmakotherapie: Da allein mit nicht medikamentösen Methoden in über 90% der Patienten kein anhaltender gewichtsreduzierter und blutdrucksenkender Langzeiterfolg erzielt werden kann, wird in der Regel eine antihypertensive Pharmakotherapie erforderlich. Der differentialtherapeutische Einsatz der einzelnen Substanzklassen richtet sich dabei nach: 1. den pathophysiologischen Besonderheiten der adipositasassoziierten Hypertonie (gesteigertes RAAS, sympathisches Nervensystem und gleichzeitige Hypervolämie), 2. den häufig präexistenten metabolischen Störungen (Insulinresistenz, Dyslipidämie und diabetes mellitus Typ II) und 3. den häufig vorhandenen oder sich entwickelnden Organkomplikationen (linksventrikuläre Hypertrophie, koronare Herzerkrankung, Herzinsuffizienz, Nephropathie) bzw. Begleitkrankheiten (obstruktive Schlafapnoe, chronisch obstruktive Lungenerkrankung u. a.). Unter diesen Prämissen werden alle antihypertensiven Substanzklassen (Diuretika, Betarezeptorenblocker, Calciumantagonisten, ACE-Hemmer, AT1-Antagonisten und Antisympathotonika) mit den spezifischen Vorteilen, aber auch Risiken dargestellt, um anschließend Vorschläge zur Differential- und Kombinationstherapie zu unterbreiten und einen Ausblick auf essenziell “Nachzuholendes” bzw. neue medikamentöse Entwicklungen zu geben.Background: Hypertension and obesity are common medical conditions independently associated with increased cardiovascular risk. Many large epidemiological studies have demonstrated associations between body mass index and blood pressure, and there is evidence to suggest, that obesity is a causal factor in the development of hypertension in obese subjects. Weight Reduction and maintenance is an essential first step in the treatment of obesity-associated hypertension. Weight reduction may be achieved by behavior modification, diet, and exercise or by the use of anti-obesity medication. However, the long-term outcomes of weight management programs for obesity are generally poor, and most hypertensive patients will require antihypertensive drug therapy. Pathophysiology: Obese hypertensive patients often have metabolic abnormalities known to be exacerbated by commonly used antihypertensive agents but also obesity per se is often associated with endorgan damage including left ventricular hypertrophy, glomerular hyperfiltration and microalbuminuria, congestive heart failure or sudden cardiac death. Furthermore they have revealed volume expansion, increased cardiac output, and lower total peripheral resistance than lean patients. Hypertension in obese patients appears to be related to both increased sympathetic nervous system activity and activation of the renin-angiotensin systeme.Where antihypertensive therapy is necessary, the aim should be to use agents based on the hemodynamic and metabolic background and that have benefits beyond blood pressure lowering and improve the conditions most commonly linked with obesity-associated hypertension, such as hyperlipidaemia, Type II diabetes, left ventricular hypertrophy, coronary artery disease, or congestive heart failure. Pharmacotherapy: Based on their favorable metabolic profiles, it would appear that ACE inhibitors, angiotensin receptor blockers, calcium channel blockers, moxonidine and alphablockers can lower blood pressure without worsening the metabolic abnormalities, that is just one aspect of the problem. Yet, most guidelines fail to provide specific advice on the pharmacological management of hypertension in obese patients. This may be due to the fact that there are currently no studies that have addressed the efficacy of specific antihypertensive agents in reducing mortality in obese-hypertensive patients. This paper reviews the theoretical reasons for the differential use of the major classes of antihypertensive agents in the pharmacological management of obesity-related hypertension and also considers the potential role of anti-obesity agents.

Genetics of melatonin receptor type 2 is associated with left ventricular function in hypertensive patients treated according to guidelines

BACKGROUND Melatonin exerts multiple biological effects with potential impact on human diseases. This is underscored by genetic studies that demonstrated associations between melatonin receptor type 2 gene (MTNR1B) polymorphisms and characteristics of type 2 diabetes. We set out to test the hypothesis whether genetic variants at MTNR1B are also relevant for other disease phenotypes within the cardiovascular continuum. We thus investigated single nucleotide polymorphisms (SNPs) of MTNR1B in relation to blood pressure (BP) and cardiac parameters in hypertensive patients. METHODS Patients (n=605, mean age 56.2±9.4years, 82.3% male) with arterial hypertension and cardiac ejection fraction (EF) ≥40% were studied. Cardiac parameters were assessed by echocardiography. RESULTS The cohort comprised subjects with coronary heart disease (73.1%) and myocardial infarction (48.1%) with a mean EF of 63.7±8.9%. Analysis of SNPs rs10830962, rs4753426, rs12804291, rs10830963, and rs3781638 revealed two haplotypes 1 and 2 with frequencies of 0.402 and 0.277, respectively. Carriers with haplotype 1 (CTCCC) showed compared to non-carriers a higher mean 24-hour systolic BP (difference BP: 2.4mmHg, 95% confidence interval (CI): 0.3 to 4.5mmHg, p=0.023). Haplotype 2 (GCCGA) was significantly related to EF with an absolute increase of 1.8% (CI: 0.45 to 3.14%) in carriers versus non-carriers (p=0.009). CONCLUSION Genetics of MTNR1B point to impact of the melatonin signalling pathway for BP and left ventricular function. This may support the importance of the melatonin system as a potential therapeutic target.

Safety and efficacy of olmesartan: an observational pooled-analysis of 156,682 hypertensive patients

Background: Angiotensin type 1 receptor blockers are recommended for first-line antihypertensive treatment. Methods: We performed a pooled-analysis of 20 post-authorization surveys of olmesartan involving 156,682 hypertensive patients. Olmesartan was used as monotherapy or in combination with other antihypertensive drugs, for example, hydrochlorothiazide. Objectives: We assessed the safety of olmesartan by monitoring adverse drug reactions (ADRs). The number of patients achieving systolic and diastolic blood pressure (BP) targets (< 140/90 mmHg in the overall population, < 130/80 mmHg in high-risk patients) or responding to treatment (BP decrease of ≥ 20/10 mmHg) was also determined. Results: In all, 43.8% of patients received olmesartan monotherapy, 29% olmesartan with hydrochlorothiazide and 27.2% olmesartan in combination with other antihypertensives. The frequency of ADRs was 0.4% and not altered by dose, age ≥ 65 years or presence of co-morbidities. About 90% of patients were responders. Blood pressure targets were achieved in 52.8 and 35.7% of patients without risk factors and in the overall cohort, but only in 8.1 and 27.5% of patients with renal dysfunction or taking NSAIDs. Conclusion: Olmesartan was very well tolerated. Responder rates to olmesartan were high, although BP targets were only achieved in a minority of patients at high risk, with renal dysfunction or taking NSAIDs.

Effect of high-dose valsartan on inflammatory and lipid parameters in patients with Type 2 diabetes and hypertension.

AIMS The present study aimed to explore the impact of the angiotensin type 1 receptor blocker valsartan (VAL) on inflammatory-/lipid-/glucose parameters in hypertensive diabetic patients with and without coronary artery disease (CAD). METHODS This was a 16-week, randomized, double-blind, placebo-controlled two-center study with VAL 320 mg/d in 109 hypertensive diabetic patients (n=56 non-CAD; n=53 CAD). RESULTS VAL treatment did not significantly affect serum interleukin-6 (IL-6) or tumor necrosis factor alpha (TNFalpha) levels in the overall study population but significantly reduced serum IL-6 in the subgroup with high inflammatory load at baseline (IL-6>median (2.0 ng/L), n=54: [median, ng/L]): VAL: from 3.5 to 2.4; placebo: from 3.2 to 3.5; p=0.035). VAL significantly lowered total- and LDL-cholesterol in the whole study population: [median, mg/dL]: total cholesterol: VAL: from 178 to 168; placebo: from 174 to 173, p=0.039; LDL-cholesterol: VAL: from 96 to 90, placebo: from 102 to 103, p=0.006, whereas glycemic parameters were not affected. CONCLUSIONS The present study demonstrates significant anti-inflammatory efficacy of VAL in hypertensive diabetic patients with enhanced inflammatory burden. High-dose VAL therapy significantly lowered total- and LDL-cholesterol levels. The combined actions of cholesterol and blood pressure lowering by VAL may provide additional clinical benefits for these high-risk patients.

Verordnung von Antihypertensiva bei geriatrischen Pflegeheimbewohnern in Deutschland

OBJECTIVE To analyse and evaluate the use of antihypertensive medication in elderly patients of nursing homes in Germany. METHODS Data from a large German health insurance company were collected in a cross sectional study. Included were all insured persons aged 65 years or older, who were residents of a nursing home between 1 April and 30 June 2007 throughout Germany. Antihypertensive drugs were those classified according to the current guidelines published by the German Hypertension Society. RESULTS The study comprised 8,685 residents of nursing homes, 84 % women. The mean age was 84 years (range 65 - 106 years). Antihypertensive drug prescriptions accounted for 17 % of all drug prescriptions and about 70 % of all residents received at least one prescription for antihypertensive drugs. The most frequently prescribed antihypertensive drugs were diuretics, of which 70 % were loop diuretics. Potentially inappropriate combinations of antihypertensive drugs were noted in 5.2 % of patients receiving these drugs. CONCLUSION Antihypertensive drugs account for a notable part (17 %) of all drug prescriptions in elderly residents of nursing homes throughout Germany. These results indicate that only a minority of all residents were treated with potentially inappropriate or potentially harmful drug combinations. However, the relatively high rate of prescriptions for loop diuretics is a matter of potential concern in this vulnerable group of patients.