A randomized n-of-1 study comparing blood pressure measured on a clothed arm and on an arm with a rolled-up sleeve.

BACKGROUND: Blood pressure [BP] should be measured using a bare upper arm with an appropriately sized cuff. In practice, it is more convenient to measure BP on a bare arm below a rolled-up sleeve or on a sleeved arm. AIM: A n-of-1 randomized controlled trial was performed to assess the difference between BP measurements over a sleeve or below a rolled-up sleeve. METHODS: The study subject was male, white, 72 years old, BMI 26 kg/m2, arm circumference 29 cm, and under stable antihypertensive treatment. The mean of three BP measurements over a thin sleeve was compared with measurements below a rolled-up sleeve. Additional measurements on a completely bare arm, with thicker sleeves and up to three layers were performed. The order of measurements was determined by chance and two oscillometric devices were used. Descriptive statistics, Bland-Altman test and 2-side T test were used for comparisons. RESULTS: 504 measurements were performed: 50 % over the sleeve and 50 % below the rolled-up sleeve. The mean systolic blood pressure (SBP) was respectively 116.9 ± 9. 2 [95% CI 115.7-118.0, range 96-135] and 122.8 ± 9.2 [95% CI 121.7-124.0, range 103-139, p = 0.001] mm Hg. The mean diastolic blood pressure [DBP] was respectively 67.6 ± 6.8 [95% CI 66.8-68.4, range 52-84] and 71.8 ± 6.8 [95% CI 71.0-72.7, range 55-85, p = 0.001] mm Hg. There was no significant difference between the measurements over the sleeve and on the completely bare arm [n = 94, p = 0.97]. Sleeve thickness with 2 layers up to 3 mm thick did not affect the results. CONCLUSIONS: Blood pressure measurements over a thin sleeve were significantly lower than measurements below a rolled-up sleeve and match measurements on a completely bare arm.

Sputum induction for assessment of biomarkers in early respiratory drug development
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OBJECTIVE: To study the success rate and reproducibility of sputum induction (SI) in healthy subjects (HS) and asthma patients (AP). MATERIALS AND METHODS: 130 HSs/APs were recruited for early-phase studies to evaluate sputum biomarkers. SI and sample processing were performed according to standard protocols. RESULTS: Adequate samples were obtained from 46% of HSs and 80% of APs. There was no difference between the groups with adequate and nonadequate samples. Differences between HS and AP groups were minor. Reproducibility was 56.0% in HSs and 90.6% in APs. CONCLUSION: Sputum induction for biomarker assessment in early drug development is feasible in HSs and APs, but only modestly reproducible in HSs. The technique is complex and time consuming.
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Replacement of Amlodipine and Lercanidipine by Barnidipine: Tolerability and Effectiveness in a Real-Life Study.

INTRODUCTION: Hypertension is the leading cause of cardiovascular disease worldwide. Calcium channel blockers are an effective antihypertensive treatment, but frequently hypertension remains uncontrolled for many patients, partly due to tolerability issues. AIM: To assess the tolerability and effectiveness of barnidipine in mild to moderate hypertension patients switching treatment from other calcium channel blockers in daily practice. METHODS: BASIC-HT, a prospective real life study, enrolled 20,479 hypertensive patients initiating barnidipine treatment. The present paper focuses on a subgroup of patients in BASIC-HT for whom the previous treatment with amlodipine or lercanidipine was replaced by barnidipine. Tolerability and effectiveness of barnidipine in these patients were assessed at two visits during a 3-month follow up. RESULTS: In 1710 mild to moderate hypertension patients switching treatment from amlodipine or lercanidipine to barnidipine monotherapy or in combination with other antihypertensive drug classes, mean blood pressure decreased during 3-month follow-up. The mean systolic blood pressure decreased from 153.15 mmHg [95% CI 152.35-153.95] at baseline to 139.20 mmHg [95% CI 138.58-139.82] at visit 3, after 3 months. The mean diastolic blood pressure decreased from 88.85 mmHg at baseline [95% CI 88.36-89.34], to 81.56 mmHg [95% CI 81.20-81.91] at visit 3. Among these patients, 65.4% replaced their initial calcium channel blocker treatment to barnidipine for tolerability reasons. During the follow-up, the main adverse event reported was edema (4.8%). The nature and frequency of events reported in this subgroup of switcher patients were in line with those reported by the total population in BASIC-HT. CONCLUSION: This real-life study suggests that replacement of other calcium channel blockers with barnidipine is a valuable therapeutic option, especially when tolerability is an issue.

Barnidipine Real-Life Efficacy and Tolerability in Arterial Hypertension: Results from Younger and Older Patients in the BASIC-HT Study.

OBJECTIVE: The aim of this study was to compare the efficacy and tolerability of barnidipine, a strong lipophilic calcium channel blocker, in younger (≤55 for efficacy or <65 years for adverse events) versus older (>55 or ≥65 years) patients with uncomplicated hypertension. METHODS: 20,275 patients received barnidipine, 10 or 20 mg/day, as monotherapy or in combination with other antihypertensive drug(s) in the observational BArnidipine real-life Safety and tolerability In Chronic HyperTension (BASIC-HT) study. Efficacy and tolerability were assessed over a 3-month period. The present paper describes results from prespecified subgroup analyses by age not reported elsewhere. RESULTS: Both age groups showed a clinically meaningful decrease in blood pressure (BP) over time (p<0.0001). The mean systolic and diastolic BP after approximately 3 months of barnidipine therapy was well below the target value of <140/90 mmHg for individual patients, with no notable differences between age groups. The decrease in mean pulse pressure was greater in patients >55 years (-10.8 mmHg) than in patients ≤55 years (-8.7 mmHg) (p<0.0001) and the proportion of patients with pulse pressure >60 mmHg decreased from 61.1% at baseline to 24.8% at Visit 3 in patients >55 years and from 47.7% to 16.5% in patients ≤55 years (p<0.0001).The overall incidence of adverse events was low, leading to treatment discontinuation in only 3.0-3.6% of patients. Peripheral edema, a common adverse effect with calcium channel blockers in clinical practice, was reported by 2.7% of patients aged <65 years and by 4.6% of patients aged ≥65 years. CONCLUSION: The efficacy and tolerability profiles of barnidipine as monotherapy or in combination with other antihypertensive drugs were shown to be favorable in both younger and older patients in a real-life practice setting. Randomized double-blind controlled studies are needed to confirm these results.

Economic evaluation of different treatment modalities in acute kidney injury.

BACKGROUND: Major controversy exists regarding the preferred treatment option for acute kidney injury (AKI). The purpose of this study was to assess the incremental cost-effectiveness of continuous renal replacement therapy (CRRT) versus intermittent renal replacement therapy (IRRT) and conservative (CONS) AKI treatment in Belgium. METHODS: An area-under-the-curve model based on survival analysis was used to estimate costs and health outcomes using a 2-year time horizon. Input data were derived from the multi-centre Stuivenberg Hospital Acute Renal Failure 4 study. RESULTS: Analyses indicated that in-hospital mortality, hospitalization costs and hospital length of stay differed significantly between treatment modes. Follow-up mortality rates and follow-up cost per day showed no significant difference between the treatment modes. Utility values, which improved gradually after admission to the hospital, revealed no significant differences between the three treatment strategies. CONS treatment was associated with a 2-year cost of 33,802€ and 0.54 quality-adjusted life years (QALYs). The CRRT was the most expensive therapy with a cost of 51,365€ leading to 0.57 QALYs. The cost and QALYs associated with IRRT were 43,445€ and 0.50, respectively. One-way sensitivity analyses indicated the 'in-hospital mortality' as the variable with the greatest influence on the results. Probabilistic sensitivity analysis resulted in a significant difference in treatment costs but no significant difference in QALY gain. CONCLUSIONS: This study has indicated that the most expensive treatment (CRRT) associated with an incremental cost of approximately €7920 generates only a minor non-significant increase in QALYs of 0.07 compared with IRRT. Additionally, the results revealed that the RRTs did not result in a significant increase in QALYs despite their higher cost compared with the CONS treatment. From a health economic perspective, the latter seems to be the preferred treatment strategy.

Modelling of blood pressure and total cardiovascular risk outcomes after second-line valsartan therapy: the BSCORE study.

BACKGROUND: European guidelines recommend that antihypertensive management should be graded as a function of total cardiovascular risk. AIMS: To examine the multilevel (patient- and physician-level) determinants of blood pressure and residual total cardiovascular risk outcomes associated with second-line valsartan therapy. METHODS: The BSCORE study was a prospective, multi-centre, pharmacoepidemiological study of the "real-world" effectiveness of second-line valsartan with or without hydrochlorothiazide. RESULTS: A total of 3497 patients were recruited by 354 physicians. Mean age was 63.8±12.0 years; 52.3% were male; 20.9% were smokers; 47.7% were dyslipidaemic; and 23.6% had diabetes. On average, reductions in blood pressure and increases in the proportions of patients with controlled blood pressure after 90 days were statistically significant (all P<0.001). Twenty-one percent of systolic blood pressure and 25.6% of diastolic blood pressure variability at follow-up was attributable to physician-level characteristics. Significant reductions in total cardiovascular risk were observed (P<0.001); with 12.5% of the variability in total cardiovascular risk change attributable to physician-level characteristics. Several independent determinants of blood pressure outcomes were identified, many of which are modifiable. CONCLUSIONS: Second-line valsartan therapy improves blood pressure outcomes under variable real-world conditions, and is associated with a decrease in total cardiovascular risk. Optimizing antihypertensive effectiveness, including the reduction of residual cardiovascular risk, involves managing concomitant conditions and risk factors, improving adherence, and identifying physician-level factors amenable to intervention.

Effectiveness of amlodipine-valsartan single-pill combinations: hierarchical modeling of blood pressure and total cardiovascular disease risk outcomes (the EXCELLENT study).

BACKGROUND: Both patient- and physician-related factors have been shown to explain variability in the outcomes of antihypertensive treatment. Total cardiovascular risk (TCVR) is increasingly used as a determinant of treatment effectiveness but has also been proposed as a treatment outcome. To our knowledge, no studies have reported how antihypertensive treatment impacts blood pressure and TCVR outcomes. OBJECTIVE: To examine in patients treated with a regimen including single-pill combinations (SPCs) of amlodipine/valsartan (1) blood pressure (BP) reduction and control, total cardiovascular risk (TCVR) change, and TCVR reduction of 1 class or more; (2) hierarchical patient- and physician-level determinants of these outcomes; and (3) predictors of uncontrolled BP and improved TCVR classification. METHODS: A prospective (90 days), multicenter, multilevel pharmacoepidemiologic study was conducted in 3546 patients with hypertension treated with SPC amlodipine/valsartan by 698 general practitioners. Statistical analysis included hierarchical linear and logistic modeling of BP and TCVR outcomes. RESULTS: Mean (SD) systolic BP (SBP) reductions were 20.1 (15.5) mm Hg and diastolic BP (DBP) reductions were 9.8 (10.3) mm Hg, with higher reductions among high-risk patients. SBP, DBP, and SBP/DBP control rates were 33.3%, 45.3%, and 25.5%, respectively, with lower rates among high-risk patients. Mean TCVR improvement was a reduction of 0.73 (0.96) classes (-4 [best] to +4 [worst]), with higher reductions for high-risk patients; 58.2% of patients achieved a TCVR reduction of 1 or more classes, with lower percentages for high-risk patients. Twenty-two percent of systolic variability and 26% of diastolic variability in 90-day BP values were attributable to a physician class effect, as was 16% of TCVR change. CONCLUSIONS: Regimens that include SPC amlodipine/valsartan formulations are effective in reducing BP and TCVR in a real-world observational setting. Hierarchical modeling identified patient- and physician-related determinants of BP values and TCVR change, as well as independent predictors of uncontrolled BP and reduced TCVR. TCVR is a scientifically feasible and clinically relevant effectiveness outcome of antihypertensive treatment.

Renal replacement therapy is an independent risk factor for mortality in critically ill patients with acute kidney injury.

INTRODUCTION: Outcome studies in patients with acute kidney injury (AKI) have focused on differences between modalities of renal replacement therapy (RRT). The outcome of conservative treatment, however, has never been compared with RRT. METHODS: Nine Belgian intensive care units (ICUs) included all adult patients consecutively admitted with serum creatinine >2 mg/dl. Included treatment options were conservative treatment and intermittent or continuous RRT. Disease severity was determined using the Stuivenberg Hospital Acute Renal Failure (SHARF) score. Outcome parameters studied were mortality, hospital length of stay and renal recovery at hospital discharge. RESULTS: Out of 1,303 included patients, 650 required RRT (58% intermittent, 42% continuous RRT). Overall results showed a higher mortality (43% versus 58%) as well as a longer ICU and hospital stay in RRT patients compared to conservative treatment. Using the SHARF score for adjustment of disease severity, an increased risk of death for RRT compared to conservative treatment of RR = 1.75 (95% CI: 1.4 to 2.3) was found. Additional correction for other severity parameters (Acute Physiology And Chronic Health Evaluation II (APACHE II), Sequential Organ Failure Assessment (SOFA)), age, type of AKI and clinical conditions confirmed the higher mortality in the RRT group. CONCLUSIONS: The SHARF study showed that the higher mortality expected in AKI patients receiving RRT versus conservative treatment can not only be explained by a higher disease severity in the RRT group, even after multiple corrections. A more critical approach to the need for RRT in AKI patients seems to be warranted.

Outcome of acute kidney injury with different treatment options: long-term follow-up.

BACKGROUND AND OBJECTIVES: The multicenter Stuivenberg Hospital Acute Renal Failure 4 study investigated outcome in patients with acute kidney injury (AKI) stratified according to disease severity by the Stuivenberg Hospital Acute Renal Failure score. Patients in need of renal replacement therapy (RRT) received intermittent RRT or continuous RRT. This study investigated long-term mortality, renal function, comorbidity, and quality of life. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: All AKI hospital survivors were included. Mortality at 1 and 2 years of follow-up was traced for all patients. Between 1 and 2 years after hospital discharge, survivors were visited at home to determine morbidity (renal function), comorbidity (Charlson comorbidity index [CCI]), and quality of life (Medical Outcome Survey SF-36). RESULTS: The baseline population consisted of 595 AKI patients. Mortality rates were 23.0 and 7.6%, respectively, during the first and second year after discharge. Total mortality increased from 50.7% at discharge to 65.7% 2 years after AKI and was not related to disease severity or treatment modality offered during hospitalization. Two hundred four survivors could be visited at home. Mean serum creatinine did not differ between discharge and follow-up. CCI was only related with age. SF-36 scores were negatively correlated with CCI, age, and body mass index, but not with disease severity, renal function, or dialysis modality. CONCLUSIONS: Long-term outcome of AKI consists of a high additional mortality unrelated to treatment modality offered during hospitalization, varying evolution of renal recovery, and many comorbidities, but a mental health at the same level as the general population.

Rosuvastatin and cardiovascular events in patients undergoing hemodialysis.

BACKGROUND: Statins reduce the incidence of cardiovascular events in patients at high cardiovascular risk. However, a benefit of statins in such patients who are undergoing hemodialysis has not been proved. METHODS: We conducted an international, multicenter, randomized, double-blind, prospective trial involving 2776 patients, 50 to 80 years of age, who were undergoing maintenance hemodialysis. We randomly assigned patients to receive rosuvastatin, 10 mg daily, or placebo. The combined primary end point was death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. Secondary end points included death from all causes and individual cardiac and vascular events. RESULTS: After 3 months, the mean reduction in low-density lipoprotein (LDL) cholesterol levels was 43% in patients receiving rosuvastatin, from a mean baseline level of 100 mg per deciliter (2.6 mmol per liter). During a median follow-up period of 3.8 years, 396 patients in the rosuvastatin group and 408 patients in the placebo group reached the primary end point (9.2 and 9.5 events per 100 patient-years, respectively; hazard ratio for the combined end point in the rosuvastatin group vs. the placebo group, 0.96; 95% confidence interval [CI], 0.84 to 1.11; P=0.59). Rosuvastatin had no effect on individual components of the primary end point. There was also no significant effect on all-cause mortality (13.5 vs. 14.0 events per 100 patient-years; hazard ratio, 0.96; 95% CI, 0.86 to 1.07; P=0.51). CONCLUSIONS: In patients undergoing hemodialysis, the initiation of treatment with rosuvastatin lowered the LDL cholesterol level but had no significant effect on the composite primary end point of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. (ClinicalTrials.gov number, NCT00240331.)

Where are we with the management of hypertension? From science to clinical practice.

The management of elevated blood pressure in patients at high cardiovascular risk is still a subject of debate. The authors review current international guidelines and results of large clinical trials and recent meta-analyses to discuss the different approaches in patients at high risk for cardiovascular events. The different treatment options are considered in view of the modern approach and of the different classes of drugs (diuretics, angiotensin-converting enzyme inhibitors, calcium channel blockers, beta-blockers, and angiotensin II receptor blockers) currently in use. A case report is presented as an illustration of the difficulties related to the management of high blood pressure in patients at increased risk. The benefits of the use of 2 medications that include an inhibitor of the renin-angiotensin-aldosterone system and a calcium channel blocker or a diuretic are discussed. Choosing the proper drugs and correct doses are important considerations for the long-term management of hypertension.

Intermittent versus continuous renal replacement therapy for acute kidney injury patients admitted to the intensive care unit: results of a randomized clinical trial.

BACKGROUND: There is uncertainty on the effect of different dialysis modalities for the treatment of patients with acute kidney injury (AKI), admitted to the intensive care unit (ICU). This controlled clinical trial performed in the framework of the multicentre SHARF 4 study (Stuivenberg Hospital Acute Renal Failure) aimed to investigate the outcome in patients with AKI, stratified according to severity of disease and randomized to different treatment options. METHODS: This was a multicentre prospective randomized controlled trial with stratification according to severity of disease expressed by the SHARF score. ICU patients were eligible for inclusion when serum creatinine was >2 mg/dL, and RRT was initiated. The selected patients were randomized to intermittent (IRRT) or continuous renal replacement therapy (CRRT). RESULTS: A total of 316 AKI patients were randomly assigned to IRRT (n = 144) or CRRT (n = 172). The mean age was 66 (range 18-96); 59% were male. Intention-to-treat analysis revealed a mortality of 62.5% in IRRT compared to 58.1% in CRRT (P = 0.430). No difference between IRRT and CRRT could be observed in the duration of ICU stay or hospital stay. In survivors, renal recovery at hospital discharge was comparable between both groups. Multivariate analysis, including the SHARF score, APACHE II and SOFA scores for correction of disease severity, showed no difference in mortality between both treatment modalities. This result was confirmed in pre-specified subgroup analysis (elderly, patients with sepsis, heart failure, ventilation) and after exclusion of possible confounders (early mortality, delayed ICU admission). CONCLUSIONS: Modality of RRT, either CRRT or IRRT, had no impact on the outcome in ICU patients with AKI. Both modalities need to be considered as complementary in the treatment of AKI (Clinical Trial: SHARF 4, NCT00322933, http://ClinicalTrials.gov).

Efficacy and tolerability of olmesartan medoxomil in patients with mild to moderate essential hypertension: the OLMEBEST Study.

BACKGROUND AND OBJECTIVE: Achieving target BP is important to control the increased cardiovascular risk associated with uncontrolled hypertension. However, failure to respond to therapy is common with all classes of antihypertensive agents. Angiotensin II type 1 receptor antagonists (angiotensin receptor blockers [ARBs]) possess many of the positive features of angiotensin-converting enzyme inhibitors, with fewer adverse effects. However, many patients fail to respond adequately to low-dose monotherapy. This study examined whether olmesartan medoxomil dose titration and olmesartan medoxomil/hydrochlorothiazide combination therapy were therapeutically equivalent in patients with mild to moderate essential hypertension who had shown an inadequate response to low-dose olmesartan medoxomil monotherapy. METHODS: This was a prospective, parallel group, partially randomised, double-blind study set in 463 centres in nine European countries. 2306 male and female adult patients aged 18-75 years with mild to moderate essential hypertension (sitting diastolic BP [DBP] > or =90mm Hg and <110mm Hg) were enrolled. All enrolled patients received open-label olmesartan medoxomil 20mg once daily for 8 weeks. At the end of this period, patients whose BP had not normalised (sitting DBP > or =90mm Hg) were randomised to receive olmesartan medoxomil monotherapy (40mg once daily, n = 302) or olmesartan medoxomil (20mg once daily)/hydrochlorothiazide (12.5mg once daily) combination therapy (n = 325) for 4 weeks. The main outcome measure was change in mean sitting DBP during randomised treatment. RESULTS: After 8 weeks of open-label treatment with olmesartan medoxomil 20 mg/day, 76% of patients showed a DBP response (sitting DBP <90mm Hg or reduction of > or =10mm Hg). During the randomised phase of the study, both treatments were associated with further improvements in sitting SBP/DBP: a reduction of 5.3/5.1mm Hg with olmesartan medoxomil 40 mg/day, and a reduction of 10.8/7.9mm Hg with olmesartan medoxomil/hydrochlorothiazide combination therapy. Final mean BPs of 145.3/90.9mm Hg (olmesartan medoxomil 40 mg/day) and 140.7/88.7mm Hg (olmesartan medoxomil 20mg + hydrochlorothiazide) were achieved, compared with a mean BP of 160.8/100.5mm Hg at baseline. The two treatments were not therapeutically equivalent. Sitting DBP showed a response and was normalised (<90mm Hg) in 62% and 47% of olmesartan medoxomil monotherapy patients, respectively. In the combination therapy group, these endpoints were achieved by 71% (response) and 59% (normalisation) of patients. Treatment with olmesartan medoxomil 40 mg/day was associated with a lower frequency of adverse events than olmesartan medoxomil/hydrochlorothiazide combination therapy (21.5% vs 28.3%, respectively). CONCLUSION: For patients who did not achieve adequate BP control after initial treatment with olmesartan medoxomil 20 mg/day, olmesartan medoxomil dose titration (to 40 mg/day) or addition of hydrochlorothiazide (12.5 mg/day) elicited a sitting DBP response in the majority of patients who had failed to respond to low-dose monotherapy, and normalisation of sitting DBP in approximately 50% of patients. Both these strategies represent effective and well tolerated treatment options in patients who show an inadequate response to low-dose monotherapy with olmesartan medoxomil.

Effect of renal impairment on the pharmacokinetics of exenatide.

AIMS: To evaluate the pharmacokinetics (PK), safety and tolerability of a single exenatide dose in patients with renal impairment (RI). METHODS: Exenatide (5 or 10 microg) was injected subcutaneously in 31 subjects (one with Type 2 diabetes) stratified by renal function [Cockcroft-Gault creatinine clearance (CrCL), number of subjects]: normal (>80 ml min(-1), n = 8), mild RI (51-80 ml min(-1), n = 8), moderate RI (31-50 ml min(-1), n = 7) or end-stage renal disease (ESRD) requiring haemodialysis (n = 8). PK data were combined with four previous single-dose studies in patients with Type 2 diabetes to explore the relationship of exenatide clearance (CLp/F) and CrCL. RESULTS: Mean half-life for healthy, mild RI, moderate RI and ESRD groups were 1.5, 2.1, 3.2 and 6.0 h, respectively. After combining data from multiple studies, least squares geometric means for CLp/F in subjects with normal renal function, mild RI, moderate RI and ESRD were 8.14, 5.19, 7.11 and 1.3 l h(-1), respectively. Exenatide was generally well tolerated in the mild and moderate RI groups, but not in subjects with ESRD due to nausea and vomiting. Simulations of exenatide plasma concentrations also suggest patients with ESRD should have a propensity for poor tolerability at the lowest available therapeutic dosage (5 microg q.d.). CONCLUSIONS: Since tolerability and PK changes were considered clinically acceptable in patients with mild to moderate RI, it would be appropriate to administer exenatide to these patients without dosage adjustment. However, poor tolerability and significant changes in PK make the currently available therapeutic doses (5 and 10 microg) unsuitable in severe RI or ESRD.

Use of the microvascular free fibula transfer as a salvage reconstruction for failed anterior spine surgery due to chronic osteomyelitis.

BACKGROUND: Several factors influence the osseous union of spinal fusions, including the substrate used for arthrodesis, the biology of the fusion bed, as well as local host factors. While cancellous bone grafting is useful in simple cases with no major bony defects, corticocancellous strut grafts are indicated in reconstructions requiring mechanical support. The size and location of the spinal defect to be reconstructed determine what type of vascularized bone graft is indicated. According to the literature, locations suitable for reconstruction using a microvascular free fibula graft include the cervical spine and, less frequently, the cervicothoracic, thoracic, thoracolumbar, and lumbar spine. Using the microvascular free vascularized fibula graft as a salvage procedure for failed anterior spine surgery due to bacterial spinal osteomyelitis has not been reported. METHODS AND RESULTS: Four cases of spinal osteomyelitis after attempted spinal fusion are presented. In all cases, a microvascular free fibula graft was successfully used for secondary spinal fusion and clearance of documented bacterial osteomyelitis. The operative approach is described. CONCLUSIONS: Use of the vascularized free fibula graft for correction of primary and secondary spinal deformities, as well as for reconstruction after excision of malignant spine tumors, has been well documented. On the basis of their experience, the authors also recommend microvascular fibula transplantation as a salvage procedure for failed anterior spine surgery due to chronic osteomyelitis.

Aliskiren, a novel orally effective renin inhibitor, provides dose-dependent antihypertensive efficacy and placebo-like tolerability in hypertensive patients.

BACKGROUND: Stopping the detrimental effects of the renin-angiotensin system at the most upstream point of the cascade offers theoretical advantages for cardiovascular protection. This study compares the antihypertensive efficacy and safety of the novel oral renin inhibitor aliskiren with placebo and an active comparator. METHODS AND RESULTS: The study was a randomized, multicenter, double-blind, placebo-controlled, active-comparator 8-week trial in patients with mild-to-moderate hypertension (mean sitting diastolic blood pressure [DBP] > or =95 and <110 mm Hg). After a 2-week, single-blind placebo run-in, 652 patients were randomized to receive double-blind treatment with once-daily oral doses of aliskiren (150, 300, or 600 mg), irbesartan 150 mg, or placebo. Aliskiren 150, 300, and 600 mg effectively lowered both trough mean sitting DBP and systolic blood pressure (SBP) (P<0.001 versus placebo for both variables). The least-squares mean reductions in trough DBP were 9.3+/-0.8, 11.8+/-0.8, and 11.5+/-0.8 mm Hg, respectively, versus 6.3+/-0.8 mm Hg for placebo, and the least-squares mean reductions in trough SBP were 11.4+/-1.3, 15.8+/-1.2, and 15.7+/-1.2 mm Hg, respectively, versus 5.3+/-1.2 mm Hg for placebo. The antihypertensive effect of aliskiren 150 mg was comparable to that of irbesartan 150 mg (8.9+/-0.7 and 12.5+/-1.2 mm Hg, least-squares reduction in mean sitting DBP and SBP, respectively, for irbesartan). Aliskiren 300 and 600 mg lowered mean sitting DBP significantly more than irbesartan 150 mg (P<0.05). Aliskiren showed safety and tolerability comparable to those of placebo and irbesartan; the incidence of adverse events and number of patients discontinuing therapy were similar in all groups. CONCLUSIONS: Once-daily oral treatment with aliskiren lowers blood pressure effectively, with a safety and tolerability profile comparable to that of irbesartan and placebo, in patients with mild-to-moderate hypertension. Aliskiren 150 mg is as effective as irbesartan 150 mg in lowering blood pressure.

Pharmacokinetics of atorvastatin and its metabolites after single and multiple dosing in hypercholesterolaemic haemodialysis patients.

BACKGROUND: Patients with chronic renal failure commonly suffer from a secondary form of complex dyslipidaemia, and may benefit from lipid-lowering treatment. Atorvastatin has been shown to reduce efficiently the levels of atherogenic lipoproteins also in patients with renal failure, but pharmacokinetic data in haemodialysis patients are lacking. METHODS: In this study, hypercholesterolaemic haemodialysis patients received 40 mg (n=12) or 80 mg (n=11) atorvastatin once daily, first as a single dose and then continuously for 2 weeks. Plasma levels of atorvastatin and its active and inactive metabolites were measured by LC/MS/MS, and pharmacokinetic parameters (C(max), t(max), AUC, t(1/2)) compared between single and multiple dosing, and between the different doses. RESULTS: The pharmacokinetic parameters of the parent drug atorvastatin acid were not significantly different after single and 2-week multiple dosing; they showed dose-proportionality between the 40 and 80 mg dose, and were comparable to findings in healthy volunteers. Dose-proportionality and absence of accumulation was also observed for the major active metabolite ortho-hydroxy-atorvastatin and the inactive metabolites atorvastatin lactone and ortho-hydroxy-atorvastatin lactone, but the levels of the active metabolite were relatively lower, and the inactive metabolites higher, compared with healthy volunteers. The para-hydroxy-metabolites constituted only a minor pathway in atorvastatin's metabolic elimination. Haemodialysis did not cause enhanced clearance of atorvastatin or its metabolites, the drug was well tolerated and there were no serious adverse events. CONCLUSION: While subtle differences may exist in the metabolic processing of atorvastatin in haemodialysis patients, active drug did not accumulate nor did it show enhanced elimination, and levels were comparable to those measured in healthy volunteers. Therefore there is no need to adapt atorvastatin dosage in this particular patient population.