Onset and duration of action of formoterol and tiotropium in patients with moderate to severe COPD.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) management guidelines recommend regular treatment with one or more long-acting bronchodilators for patients with moderate to severe COPD. OBJECTIVE: To compare the onset and duration of action of formoterol and tiotropium in patients with COPD. METHODS: This randomized, multicentre, open-label crossover study in 38 patients with COPD (mean age 64 years; mean FEV(1) 55% predicted) assessed the effect of 7 days of treatment with formoterol (12 microg b.i.d. via Foradil Aerolizer) vs. tiotropium (18 microg o.d. via Spiriva HandiHaler) on lung function measured over a period of 12 h after the first dose on day 1 and the last dose on day 8. RESULTS: The primary efficacy variable, FEV(1)-AUC during the first 2 h post-dose (FEV(1)-AUC(10-120 min)), was significantly higher for formoterol compared with tiotropium, with between-treatment differences of 124 ml (p = 0.016) after the first dose and 80 ml (p = 0.036) after 7 days' treatment in favour of formoterol. FEV(1) measured 12 h after inhalation did not differ statistically significantly between treatments. Adverse events occurred in 2 (5%) patients after treatment with formoterol and in 5 (12%) patients after treatment with tiotropium. CONCLUSION: This study demonstrates faster onset of action and greater bronchodilation of formoterol vs. tiotropium for bronchodilation within the first 2 h of inhalation (FEV(1)-AUC(10-120 min)) and comparable bronchodilation 12 h post-inhalation in patients with moderate to severe COPD.

Prophylaxis of thrombotic and embolic events in acute ischemic stroke with the low-molecular-weight heparin certoparin: results of the PROTECT Trial.

BACKGROUND AND PURPOSE: Patients with stroke are at substantial risk of thromboembolic complications and therefore require antithrombotic prophylaxis. To show the noninferiority of the low-molecular-weight heparin certoparin to unfractionated heparin (UFH) for the prevention of thromboembolic complications, we performed a randomized, double-blind, active-controlled multicenter trial in patients with acute ischemic stroke. METHODS: Overall, 545 patients were randomized within 24 hours of stroke onset to treatment with certoparin (3000 U anti-Xa OD; n=272) or UFH (5000 U TID; n=273) for 12 to 16 days. Patients with paresis of a leg and an National Institutes of Health Stroke Scale score of 4 to 30 points were included. The primary end point was a composite outcome of proximal deep vein thrombosis, pulmonary embolism, or death related to venous thromboembolism during treatment. Computed tomography was performed at trial entry, after 7 days, and when clinical deterioration occurred. RESULTS: The per-protocol analysis revealed 17 (7.0%) primary events in the certoparin group compared with 24 (9.7%) in the UFH group, thereby demonstrating noninferiority (P=0.0011), confirmed by intention-to-treat analysis (6.6% versus 8.8%; P=0.008). Major bleeding occurred during treatment in 3 patients allocated to certoparin (1.1%) and 5 patients allocated to UFH (1.8%). CONCLUSIONS: Certoparin (3000 U anti-Xa OD) is at least as effective and safe as UFH (TID) for the prevention of thromboembolic complications in patients with acute ischemic stroke.

Hemodynamic and metabolic responses to valsartan and atenolol in obese hypertensive patients.

OBJECTIVE: None of the current hypertension guidelines provides specific guidance regarding pharmacological management of obese hypertensive patients. Treatment recommendations for lean hypertensives may not be simply extrapolated to obese hypertensive persons. DESIGN: Randomized, double-blind, parallel-group study with a 13-week treatment period. SETTING: Multicenter study in Germany. PATIENTS: Obese patients with mild to moderate uncomplicated essential hypertension. INTERVENTION: Patients were treated with valsartan at a maximal dose of 160 mg/day or with atenolol at a maximal dose of 100 mg/day. Hydrochlorothiazide at doses of 12.5-25 mg was added in patients with blood pressure > 140/90 mmHg on monotherapy. MAIN OUTCOME MEASURES: Blood pressure, lipid and glucose metabolism, and highly sensitive C-reactive protein (hsCRP) were monitored. RESULTS: Sixty-seven patients were randomized to valsartan and 65 patients to atenolol. With valsartan, systolic blood pressure (SBP) decreased from 160.8 +/- 8.9 to 140.5 +/- 13.3 mmHg and diastolic blood pressure (DBP) from 96.1 +/- 7.0 to 85.1 +/- 8.1 mmHg by the end of the study. With atenolol, SBP decreased from 159.3 +/- 6.8 to 139.8 +/- 14.5 mmHg and DBP from 95.0 +/- 6.8 to 83.5 +/- 7.5 mmHg (P = 0.91 for SBP and P = 0.34 for DBP between interventions). Body weight did not change with either treatment. We did not see a significant difference in the response of lipid levels or hsCRP between interventions. To assess the cumulative effect of each intervention on glucose metabolism over the trial duration, we calculated individual areas under the curve for homeostasis model assessment for insulin resistance (HOMA-IR) over time. The resulting area under the curve was significantly smaller with valsartan compared with atenolol (P = 0.02). CONCLUSIONS: Beta-adrenoreceptor blockers and AT1-receptor blockers, particularly in combination with low-dose diuretics, effectively lower blood pressure in obese hypertensives. However, metabolic responses differ between both treatment strategies, with beneficial effects of AT1-receptor blockers. AT1-receptor blockers are a good choice in obese hypertensives, given the profoundly increased diabetes risk in this population.

Prognostic value of the QRS duration in patients with heart failure: a subgroup analysis from 24 centers of Val-HeFT.

BACKGROUND: This study investigated whether QRS duration (QRS D) is a prognostic indicator in patients with heart failure (New York Heart Association [NYHA] classes II-IV). METHODS AND RESULTS: This subgroup analysis included 248 patients with heart failure recruited in the German centers of the Valsartan Heart Failure Trial (Val-HeFT). Mean age was 60 years, mean NYHA class was 2.3, and mean left ventricular ejection fraction (EF) was 27.9%. Electrocardiograms were recorded and analyzed at the beginning of the study, at 2 weeks, 4 months, 1 year, and 2 years. The mean observation period for mortality was 25 months. Patients > or = 65 years and patients with an EF <20% had a significantly longer QRS D (P = .02; P = .0005). NYHA class, etiology of heart failure, therapy with angiotensin-converting enzyme inhibitors, amiodarone or beta-blockers, implanted defibrillator, and atrial fibrillation had no significant influence on QRS D. Total mortality was 9%: 14 patients died suddenly, 7 from heart failure, 2 from noncardiac causes. Kaplan-Meier plots show significantly different survival rates for patients with QRS D <120 ms, QRS D 120-159 ms, or QRS D > or = 160 ms (P = .0085). Multivariate analysis showed that QRS D was the only independent risk factor for all-cause mortality (P = .008). NYHA class, EF, atrial fibrillation, age, and gender failed to qualify as independent prognostic factors. CONCLUSION: QRS duration in the surface electrocardiogram is an easily obtainable parameter with a significant prognostic impact in patients with congestive heart failure and a reduced EF. In this German subgroup of Val-HeFT patients, it was an independent predictor of all-cause mortality.

Long-term efficacy and safety of pimecrolimus cream 1% in adults with moderate atopic dermatitis.

BACKGROUND: Pimecrolimus cream 1% is a non-steroid, selective inflammatory cytokine inhibitor indicated for atopic dermatitis (AD). OBJECTIVE: To compare the safety and efficacy of pimecrolimus cream 1%-based treatment versus conventional therapy in adults with moderate AD. METHODS: Patients were randomized to receive pimecrolimus cream 1% (n = 62) or vehicle (n = 68) at the first signs/symptoms of AD, for 24 weeks as required. A moderately potent topical corticosteroid (prednicarbate 0.25% cream) was allowed in both groups to treat flares. RESULTS: Corticosteroids were required on fewer days in the pimecrolimus group, compared with the vehicle group (9.7 vs. 37.8%, p < 0.001). Furthermore, 59.7% of pimecrolimus-treated patients experienced no flares during the study period, compared with 22.1% of vehicle-treated patients (p < 0.001). Pimecrolimus cream 1% was well tolerated throughout the study. CONCLUSION: For adults with moderate AD, pimecrolimus cream 1% is well tolerated, reduces the incidence of flares, reduces/eliminates corticosteroid use, improves long-term disease control and enhances the patients' quality of life.

Efficacy and Safety of Valsartan 160mg/Hydrochlorothiazide 25mg Combination in Patients with Hypertension not Adequately Controlled by Valsartan 160mg/Hydrochlorothiazide 12.5mg.

BACKGROUND AND OBJECTIVE: Hypertension guidelines emphasise the need to treat high blood pressure (BP) early and aggressively, giving fixed-dose combinations special consideration. Hitherto, it has not been assessed in a sequential way whether hypertensive patients with inadequately controlled hypertension with an angiotensin II receptor antagonist/hydrochlorothiazide combination benefit from a dose increase of the diuretic. We investigated the efficacy and safety of valsartan 160mg/hydrochlorothiazide 25mg combination in patients with hypertension that was not adequately controlled by valsartan 160mg/hydrochlorothiazide 12.5mg. PATIENTS AND METHODS: This was a multicentre, single-group, prospective study of 646 patients with moderate hypertension (diastolic BP [DBP] 100-109mm Hg). Patients were treated for 4 weeks with valsartan 160mg/hydrochlorothiazide 12.5mg (phase 1: weeks 1-4). In case of non-response (DBP >/=90mm Hg; n = 224) patients were treated for a further 4 weeks with valsartan 160mg/hydrochlorothiazide 25mg (phase 2: weeks 5-8). The primary efficacy measure was a change in mean sitting trough DBP at study end compared with the beginning of phase 2 in the intention-to-treat (ITT) population (n = 221). RESULTS: Mean age of patients at entry was 58.6 years; 53.7% of patients were female. In phase 1, systolic BP (SBP)/DBP decreased from a baseline value of 161.9/103.3mm Hg by -16.1/-12.4mm Hg (normalisation rate 38.3%, response rate 64.5%). In phase 2, in the ITT non-responder population the additional SBP/DBP decrease was -8.4/-8.3mm Hg. Overall, the normalisation rate in all patients was 55.4% and the responder rate was 76.3%.Tolerability of both the valsartan 160mg/hydrochlorothiazide 12.5mg and the valsartan 160mg/hydrochlorothiazide 25mg combinations was very good, and the switch to the higher dose did not result in an increase in adverse events (AEs) or laboratory abnormalities. Only 16.6% of patients in phase 1 and 10.3% of patients in phase 2 experienced one or more AEs. CONCLUSION: In patients with moderate hypertension, first-line therapy with the fixed-dose valsartan/hydrochlorothiazide combination leads to high normalisation and response rates. Patients with hypertension not controlled by valsartan 160mg/ hydrochlorothiazide 12.5mg clearly benefit from dose titration to valsartan 160mg/hydrochlorothiazide 25mg with a clinically relevant additional BP response and have excellent tolerability.

Reduction of venous thromboembolism following prolonged prophylaxis with the low molecular weight heparin Certoparin after endoprothetic joint replacement or osteosynthesis of the lower limb in elderly patients.

The peri- and postsurgical thromboembolic prophylaxis with low molecular weight heparins is a well established therapy regimen, but the optimum duration of prophylaxis after surgery still remains uncertain. A few studies have pointed to the fact that the thromboembolic risk of high-risk patients persists longer than the in-hospital period correlating with respective hypercoagulatory conditions. The aim of the present study was to test if a prolongation of thromboprophylaxis with the low molecular weight heparin Certoparin further reduces the rate of thromboembolism in high-risk patients after orthopedic surgery. The "Long-term Thromboprophylaxis"-Study was a multicenter, randomized, double-blind, placebo-controlled trial. 360 patients who underwent endoprothetic joint replacement or osteosynthesis of the lower limb were initially enrolled, all of them received prophylactically 3000 U anti-Xa of Certoparin once daily for 14 days followed by randomization to prolonged Certoparin application or to placebo up to day 42. Patients were screened for deep vein thrombosis by sonography every week. Coagulation markers (fibrin monomers and D-dimers) were determined during the course of the study. Venous thromboembolism during the prolongation period was observed in 18 patients receiving placebo versus 8 patients of the prolonged Certoparin group (12.1% versus 5.0%, intention-to-treat sample). The analysis revealed a statistically significant difference in favor of Certoparin (p=0.020), which was confirmed by per-protocol analysis (14.2% versus 5.5%, p=0.012). The differences remained significant, if analyses considered only clinically symptomatic thromboembolic events (p=0.040). Patients who developed a thrombosis showed a strong increase of coagulation markers as compared to patients without subsequent thrombosis. The respective differentiation started around 18 days before diagnosis of thrombosis. Only one minor bleeding complication was observed during prolonged Certoparin prophylaxis. The present study shows that patients after joint replacement or osteosynthesis of the lower extremities have a persisting risk to develop thromboembolic complications beyond the routine duration of thromboprophylaxis. Extended prophylaxis with Certoparin resulted in a significantly lower rate of thromboembolism and should be strongly recommended.

Direct comparison of the effects of valsartan and amlodipine on renal hemodynamics in human essential hypertension.

BACKGROUND: To elucidate the renoprotective mechanism of AT(1)-receptor blockers, we compared the effects of the AT(1)-receptor blocker valsartan with those of the calcium channel blocker amlodipine on renal hemodynamics and microcirculation. METHODS: A total of 58 patients (50.2 +/- 9.0 years) with mild to moderate essential hypertension were included in a randomized, double-blind study to receive either valsartan (80 to 160 mg) or amlodipine (5 to 10 mg). Renal plasma flow (RPF) and glomerular filtration rate (GFR) were measured before and after 8 weeks of treatment. Glomerular hydrostatic pressure (P(Glo)) and resistances of the afferent (R(A)) and efferent (R(E)) arterioles were calculated according to the Gomez formulas. RESULTS: Blood pressure control was similar in both groups. RPF did not change with either treatment. In contrast, GFR increased with amlodipine (+8 +/- 14 mL/min; P <.01) but was preserved with valsartan. Amlodipine caused a more marked increase in the R(E)/R(A) ratio than valsartan (+0.26 +/- 0.26 v +0.13 +/- 0.24, P <.05), which was paralleled by an increase in P(Glo) in patients treated with amlodipine (+1.9 +/- 4.3 mm Hg; P <.05) but not in those treated with valsartan. CONCLUSIONS: At similar blood pressure control, valsartan maintained GFR and P(Glo), whereas amlodipine led to glomerular hyperfiltration and an increase in P(Glo). The results might explain the favorable renal outcome with AT(1)-receptor blocker therapy.

Comparison of six-month outcome of patients initially treated for acute deep vein thrombosis with a low molecular weight heparin Certoparin at a fixed, body-weight-independent dosage or unfractionated heparin.

BACKGROUND AND OBJECTIVES: Body weight-adjusted subcutaneous low molecular weight heparin (LMWH) has been proven to be more effective and safer than aPTT-adjusted intravenous unfractionated heparin (UFH) for the initial treatment of patients with acute symptomatic deep venous thrombosis (DVT) based on analyses pooling the results of studies with different LMWHs. We investigated whether these findings hold for a particular LMWH by pooling the results of two independent studies. DESIGN AND METHODS: Patients with acute symptomatic proximal DVT (n=1758), proven by ascending phlebography or compression ultrasound, received either a fixed, body weight independent dose of 8,000 IU Certoparin b.i.d. (n=893) for 8.6 days or intravenous UFH (n=865) adjusted to an 1.5 to 3.0-fold prolongation of the aPTT for 12.0 days both followed by vitamin K-antagonists for 6 months. RESULTS: Venous thromboembolism (VTE) re-occurred in 5.1% and 3.1% (RRR 0.62, CI 0.39-0.98, 2p=0.04), major bleeding in 3.5% and 1.9% (RRR 0.55, CI 0.31-0.99, 2p=0.05), mortality in 3.6% and 2.1% (RRR 0.59, CI 0.34-1.04, 2p=0.08), and the composite outcome of all three events in 10.3% and 6.3% (RRR 0.61, CI 0.44 to 0.84, 2p=0.002) of patients at 6 months initially randomised to UFH and LMWH, respectively. INTERPRETATION AND CONCLUSIONS: The initial treatment of acute DVT with a fixed dose of the LMWH, certoparin, is more effective in reducing, over 6 months, the re-occurrence of VTE and the composite outcome of recurrent VTE, major bleeding, and mortality without any relation of the bodyweight of the patients to recurrent venous thromboembolism or major bleeding complications.

Fixed-dose, body weight-independent subcutaneous low molecular weight heparin Certoparin compared with adjusted-dose intravenous unfractionated heparin in patients with proximal deep venous thrombosis.

Subcutaneous body weight-adjusted low molecular weight heparin (LMWH) has been proven as effective and safe as intravenous aPTT-adjusted unfractionated heparin (UFH) for the treatment of patients with acute deep venous thrombosis (DVT). In this study we evaluate the efficacy of the initial treatment of proximal DVT with a fixed-dose, body weight-independent application of the LMWH Certoparin with a six month follow-up. In a prospective, multicentre, randomized, active-controlled study 1220 patients with objectively diagnosed proximal DVT were randomly assigned to subcutaneous 8000 U anti-factor Xa of Certoparin twice daily for 10 to 14 days or intravenous aPTT-adjusted UFH for 5 to 8 days. Both regimen were followed by oral anticoagulation for 6 months. The primary end point was the rate of symptomatic and objectively confirmed thromboembolic events within 6 months. The aim of the study was to demonstrate the non-inferiority of the Certoparin regimen as compared to UFH. The per-protocol analysis revealed 22 (3.8%) thromboembolic events in the Certoparin group and 24 (4.3%) in patients assigned to UFH within 6 months, thereby proving the non-inferiority (p<0.01), confirmed by intent-to-treat analysis (p<0.001). Major bleeding occurred in 6 and 7 patients started on Certoparin or UFH during the treatment period. Thromboembolic events were equally distributed in body weight categories with < 50, 50-80 and >80 kg as followed: 0, 3.6% and 4.1% of patients for the Certoparin group and 0, 4.6% and 4.2% of patients for the UFH group. The same was true for major bleeding complications with 0, 2.9% and 1.5% for Certoparin and 0, 3.5% and 4.2% for UFH. Overall mortality was 1.9% in the Certoparin group and 2.7% in the UFH group. Fixed-dose body weight-independent subcutaneous LMWH Certoparin is at least as efficacious and safe as intravenous aPTT-adjusted UFH for the initial treatment of acute proximal DVT. This effect is maintained during a 6-months follow-up of treatment with oral anticoagulation.

AT1-receptor blockade improves augmentation index: a double-blind, randomized, controlled study.

OBJECTIVE: Arterial hypertension leads to vascular structural and functional adaptive processes that are influenced by angiotensin II. To analyze the effects of AT receptor blockade on vascular function we determined augmentation index. METHODS AND DESIGN: A total of 60 patients (53 +/- 10 years) with essential hypertension mean [blood pressure (BP) 173 +/- 9/102 +/- 3 mmHg] were randomized to 6 weeks double-blind therapy with either valsartan 80 mg, hydrochlorothiazide (HCTZ) 25 mg or placebo once daily. Radial artery pressure wave was determined by applanation tonometry before and after therapy. The central aortic pressure wave and augmentation index were derived by a generalized transfer function. RESULTS: Active therapy similarly reduced systolic and diastolic blood pressure (SBP, DBP) (valsartan: -22 +/- 18/-11 +/- 11 mmHg, HCTZ: -22 +/- 23/-14 +/- 14 mmHg, all P < 0.001). However, only valsartan, but no HCTZ reduced the augmentation index (valsartan: from 148 +/- 18 to 126 +/- 24, < 0.001; HCTZ: from 145 +/- 19 to 142 +/- 18, NS). Augmentation index reduction was greater with valsartan (-22 +/- 11) than with HCTZ (-3 +/- 11) and placebo (0 +/- 13) (P < 0.01 for pairwise comparison of valsartan versus HCTZ and placebo after Bonferroni correction). Differences remained significant after taking changes in supine BP into account (covariance, P < 0.01). CONCLUSIONS: Blood pressure reduction with the AT receptor antagonist valsartan but not with hydrochlorothiazide reduced the augmentation index in essential hypertension.

Pimecrolimus cream in the long-term management of atopic dermatitis in adults: a six-month study.

BACKGROUND: Pimecrolimus cream (Elidel, SDZ ASM 981), a non-steroid inhibitor of inflammatory cytokines, is effective in the treatment of atopic dermatitis (AD). We assessed whether early treatment of AD signs/symptoms reduces the need for topical corticosteroids. OBJECTIVE: To investigate the efficacy and safety of pimecrolimus cream 1% in the long-term management of adult AD. METHODS: 192 adults with moderate to severe AD were randomised (1:1) for twice daily (b.i.d.) treatment of early signs or symptoms of AD with either pimecrolimus cream 1% or vehicle cream (control group) to prevent progression to flares. Treatment was given as needed for 24 weeks. In the event of flares, a moderately potent corticosteroid (prednicarbate 0.25% cream) was permitted as rescue medication in both groups. The percentage of days on which a topical corticosteroid was used to treat disease flares was the main outcome measure. RESULTS: Corticosteroid medication was used on 14.2% (95% confidence interval, CI: 8.3-21.1) of the days of the 24-week treatment period in the pimecrolimus group and on 37.2% (95% CI: 30.4-44.0) of the days in the control group (p < 0.001). In total, 44.8% (43/96) of patients in the pimecrolimus group did not experience a flare compared with 18.8% (18/96) of patients in the control group. The median time to first flare was 144 days in the pimecrolimus group and 26 days in the control group (p < 0.001). Pimecrolimus treatment was also associated with improvement in signs and symptoms of AD, pruritus, patients' self-assessment and quality of life. CONCLUSIONS: Pimecrolimus cream 1% b.i.d. is an effective, well-tolerated, long-term treatment for AD in adults, substantially reducing the number of flares compared to a conventional therapy and consequently reducing or eliminating the need for corticosteroid treatment.

Effects of selective angiotensin II receptor blockade on sympathetic nerve activity in primary hypertensive subjects.

OBJECTIVE: The role of the renin-angiotensin system in the regulation of sympathetic nervous activity in human hypertension was evaluated in patients with moderate primary hypertension. For that purpose, the effects of selective angiotensin II (ANG II) receptor blockade by valsartan on sympathetic outflow to the muscle vascular bed and hemodynamic parameters were examined. Results were compared with the effects of the peripherally acting calcium antagonist amlodipine. DESIGN: Eighteen hypertensive but otherwise healthy subjects were examined in a double-blind, placebo-controlled, cross-over protocol receiving either valsartan or amlodipine or placebo for 7 days in a randomized sequence. Treatment periods were separated by washout periods of 2 weeks. METHODS: At the seventh day of treatment, blood pressure, heart rate, muscle sympathetic nerve activity (MSNA), norepinephrine, renin and angiotensin were measured during resting conditions. Additionally, parameters were measured after administration of negative pressure of -15 mmHg to the lower part of the body and after a cold pressor test. RESULTS: Both antihypertensive drugs significantly decreased oscillometrically measured systolic blood pressure and diastolic blood pressure without any difference in effect. While valsartan did not affect the heart rate at rest, amlodipine increased it significantly. Likewise, MSNA was significantly enhanced by amlodipine but not by valsartan. Only ANG II receptor blockade increased renin and angiotensin levels. CONCLUSIONS: Selective ANG II receptor blockade not only decreases blood pressure, but also shifts the baroreflex set-point for the initiation of counter-regulatory reflex responses of heart rate and blood pressure towards normal blood pressure levels. Thus, data suggest that ANG II plays a pathogenetic role in the elevation of the baroreflex set point in primary hypertensive subjects.