Predictive factors of renal toxicities related to anti-VEGFR multikinase inhibitors in phase 1 trials.

Purpose Renal toxicities are common with angiogenesis multikinase inhibitors (AMKI), and can be limiting in phase I trials. Factors associated with such toxicities are poorly known. The aims of this exploratory study were to describe renovascular toxicities associated with AMKI, impact on drug development and to identify baseline parameters associated with the occurrence of renal toxicities in phase I trials. Methods Consecutive patients treated with AMKI in Gustave Roussy phase I unit between October 2005 and August 2013 were included. We retrospectively collected baseline characteristics and renovascular side effects. Associations were assessed in univariate and multivariate analyses. Results Overall, 168 patients were included: male 53.0 %, mean age 55.5 years old, history of hypertension 26.8 %, diabetes 6.0 %, atherosclerosis 13.6 %, stage 3 Chronic Kidney Disease (CKD, NKF-KDOQI) 17.2 %. Incidences of reno-vascular side effects were: hypertension 47.6 %, proteinuria 19.0 %, renal failure 11.9 % and thrombotic microangiopathy 10.1 %. Eighty percent of dose limiting toxicities (DLTs) were related to a renal toxicity. Multivariate analysis showed that onset of renal failure was associated with history of hypertension (p = 0.0003) and stage 3 CKD (p = 0.032). Conclusions A majority of the DLTs associated with AMKI in phase 1 trials are renal toxicities. Baseline hypertension and stage 3 CKD (NKF-KDOQI) might help to better identify patients at risk of AMKI-related renal toxicities.

First-line antiangiogenics for metastatic renal cell carcinoma: A systematic review and network meta-analysis.

BACKGROUND: Sunitinib, pazopanib, sorafenib, axitinib and bevacizumab are the five recommended antiangiogenic agents in first-line therapy for metastatic renal cell carcinoma (mRCC). Because these drugs underwent simultaneous clinical development, no direct efficacy and safety comparison was ever conducted, thus preventing optimal therapy choices. METHODS: We performed a traditional and network meta-analysis to evaluate the efficacy and safety of mRCC-recommended first-line antiangiogenic agents. After a systematic review of Medline and Embase up to July 2014, we identified randomized clinical trials (RCTs) evaluating the outcomes of mRCC patients treated with sunitinib, pazopanib, sorafenib, axitinib and bevacizumab as first-line treatment. Endpoints of interest were response rate, progression-free survival (PFS), overall survival (OS), and safety. RESULTS: We screened 769 abstracts and included nine RCTs with a total of 4282 patients. In the weighted pooled analysis, first-line antiangiogenic agents showed significant improvement in PFS (HR=0.6; 95% IC, 0.51-0.72) and OS (HR=0.85; 95% IC, 0.78-0.93) compared to control (placebo or interferon-alpha2a (INF)). Network meta-analysis showed no significant differences among antiangiogenic drugs in 6-month PFS, 1-year OS, disease control rate and drug-related safety for all-grade hypertension, diarrhea, weight-loss, nausea or anorexia. However, pazopanib showed a lower incidence of fatigue, anemia and hand foot skin reaction. CONCLUSIONS: This meta-analysis confirms the benefits of first-line antiangiogenic therapy in mRCC, with an improvement in OS. Sunitinib, pazopanib, axitinib and bevacizumab + INF offer similar efficacy but different safety profiles which can help clinicians to better personalize treatment decisions in patients with mRCC.

[Are cancer outpatients ready for e-medicine?] / Les patients ambulatoires atteints de cancer sont-ils prêts pour la télémédecine ?

INTRODUCTION: E-health offers new opportunities for improving cancer outpatients' monitoring. The aim of this study was to assess the level and the use of electronic communication tools owned by cancer outpatients currently undergoing antitumoral treatment. METHODS: This observational study consecutively recruited patients undergoing treatment at two day hospital oncology units from 1st to 31 October 2015. Each patient completed one standardised, anonymous questionnaire. RESULTS: Overall, 386 questionnaires were analysed, of which 244 and 142 patients were from each hospital. Of these patients, 73% had access to the Internet either directly or through a third party. More than 90% of the patients owned a mobile phone, and half of them had a smartphone with Internet access. An increasing age and the socioeconomic class level were significantly associated with the use of the Internet and of a smartphone. Half of the patients had accessed websites dedicated to health topics and a quarter had used mobile applications on health topics. One-third of those patients found these electronic tools helpful. After adjustment, an increasing age was significantly associated with a decreased use of such tools. The majority (87%) of the patients enjoyed receiving text message reminders from their hospital about their consultation schedule. CONCLUSION: Three in four cancer outpatients under treatment have access to the Internet and half use websites dedicated to health topics, with an impact of the age and the socioeconomic class level. Developing e-communication tools between caregivers and patients might be considered to improve their home monitoring.

Telomere Shortening in Middle-Aged Men with Sleep-disordered Breathing.

RATIONALE: Sleep disorders may lead to stress-induced premature aging and telomere shortening. OBJECTIVES: To determine whether obstructive sleep apnea syndrome causing intermittent hypoxemic episodes was associated with telomere shortening independently from the comorbidities associated with this syndrome. METHODS: We conducted a cross-sectional study in 161prospectivelly enrolled, untreated, middle-aged men free of known comorbidities related or unrelated to sleep apnea. Each participant underwent full standard overnight polysomnography. Patients with apnea sleep syndrome were naive to treatment. MEASUREMENTS AND MAIN RESULTS: In univariate analysis, we found that telomere shortening was associated with older age, apnea-hypopnea index, oxygen desaturation index, waist circumference, and fat mass. After adjustment for age, only apnea-hypopnea index and oxygen desaturation index were significantly related to telomere shortening. The mean telomere length ratio was 0.70 ± 0.37 in the participants without sleep apnea, compared with 0.61 ± 0.22 and 0.53 ± 0.16 in those with mild to moderate and severe sleep apnea, respectively (P = 0.01). In multivariate analysis, we found that oxygen desaturation index was the only factor independently associated with telomere length. Arterial stiffness assessed by carotid-femoral pulse wave velocity correlated negatively with telomere length. CONCLUSIONS: Intermittent hypoxemia due to obstructive sleep apnea syndrome is a major contributor to telomere shortening in middle-aged men. Oxidative stress may explain this finding.

Carotid-femoral pulse wave velocity is not increased in obesity.

BACKGROUND: There are conflicting results in the literature concerning the relationship between obesity and arterial stiffness, assessed by carotid-femoral pulse wave velocity (PWV). The discrepancies could be due to differences in carotid-femoral distance measurement and/or to the presence of pathologies frequently associated with obesity and which increase arterial stiffness. In this study, we examine the relationship between PWV and weight, without and with associated cardiovascular risk factors (diabetes and/or dyslipidemia). METHODS: PWV was assessed with a Complior SP device (Alam Medical, France) in 2,034 patients referred for ambulatory blood pressure monitoring. The carotid-femoral distance used to calculate PWV was measured with a flexible tape and from the estimated straight carotid-femoral distance obtained with a published equation. RESULTS: In the whole cohort, PWV did not differ significantly according to weight (9.6±2.1, 9.8±2.2 and 9.7±1.9 m/s in normal weight, overweight and obese subjects, respectively, with the distance measured with a tape). PWV was significantly higher in the four groups of patients with cardiovascular risk factors (e.g., 11.1±2.4, 11.0±2.7 and 10.4±2.0 m/s in normal weight, overweight, and obese subjects, respectively, in the group treated for diabetes and dyslipidemia) than in the group of patients without cardiovascular risk factors (8.5±1.6, 8.8±1.7 and 8.5±1.2 in normal weight, overweight, and obese subjects, respectively). There was no relationship between PWV value and weight status, whether or not there were cardiovascular risk factors, and whatever the distance used to calculate PWV. CONCLUSIONS: In our cohort, obesity per se was not associated with increased arterial stiffness.

Antihypertensive drug classes have different effects on short-term blood pressure variability in essential hypertension.

Increased blood pressure variability (BPV) contributes to end-organ damage, cardiovascular events and mortality associated with hypertension. In a cohort of 2780 hypertensive patients treated by either calcium channel blockers (CCBs), diuretics, angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs) or ß-blockers alone or in combination, we compared indices of short-term BPV according to the different treatments. Short-term BPV was calculated as the standard deviation (s.d.) of 24 h, daytime or nighttime systolic blood pressure and diastolic blood pressure (SBP and DBP). Short-term BPV was compared between patients treated with a given antihypertensive class of interest (alone or in combination) and those not treated with this class, after controlling for ambulatory average blood pressure, heart rate, age, gender, propensity scores and carotid-femoral pulse wave velocity. Patients treated with CCBs (n=1247) or diuretics (n=1486) alone, or in addition to other drugs had significant lower s.d. of 24-h SBP compared with those not treated with these classes (mean differences in s.d. -0.50±0.50 mm Hg, P=0.001 and -0.17±0.15 mm Hg, P=0.05, respectively). There was no significant difference regarding treatment with or without ARBs, ACEIs and ß-blockers. The combinations of CCBs with diuretics or ARBs on top of other treatments resulted in a lower 24-h SBP variability (mean differences in s.d. -0.43±0.17 mm Hg, P=0.02 and -0.44±0.19 mm Hg, P=0.005 vs. other combination uses, respectively). Antihypertensive drug classes have differential effects on short-term BPV with a greater reduction in patients treated with CCBs and diuretics. The combinations of CCBs with diuretics may be the most efficient treatments in lowering BPV.

Effectiveness of anti-psychotics and related drugs in the Huntington French-speaking group cohort.

PURPOSE: Huntington's disease is a rare condition. Patients are commonly treated with antipsychotics and tetrabenazine. The evidence of their effect on disease progression is limited and no comparative study between these drugs has been conducted. We therefore compared the effectiveness of antipsychotics on disease progression. METHODS: 956 patients from the Huntington French Speaking Group were followed for up to 8 years between 2002 and 2010. The effectiveness of treatments was assessed using Unified Huntington's Disease Rating Scale (UHDRS) scores and then compared using a mixed model adjusted on a multiple propensity score. RESULTS: 63% of patients were treated with antipsychotics during the survey period. The most commonly prescribed medications were dibenzodiazepines (38%), risperidone (13%), tetrabenazine (12%) and benzamides (12%). There was no difference between treatments on the motor and behavioural declines observed, after taking the patient profiles at the start of the drug prescription into account. In contrast, the functional decline was lower in the dibenzodiazepine group than the other antipsychotic groups (Total Functional Capacity: 0.41 ± 0.17 units per year vs. risperidone and 0.54 ± 0.19 vs. tetrabenazine, both p<0.05). Benzamides were less effective than other antipsychotics on cognitive evolution (Stroop interference, Stroop color and Literal fluency: p<0.05). CONCLUSIONS: Antipsychotics are widely used to treat patients with Huntington's disease. Although differences in motor or behavioural profiles between patients according to the antipsychotics used were small, there were differences in drug effectiveness on the evolution of functional and cognitive scores.

Antihypertensive classes, cognitive decline and incidence of dementia: a network meta-analysis.

OBJECTIVES: Prevention of cognitive decline and dementia with blood pressure lowering treatments has shown inconsistent results. We compared the effects of different classes of antihypertensive drugs on the incidence of dementia, and on cognitive function. METHODS: We conducted a systematic review and included 19 randomized trials (18 515 individuals) and 11 studies (831 674 individuals) analysing the effects of antihypertensive treatment on cognition and on the incidence of dementia, respectively, in hypertensive patients without prior cerebrovascular disorders. Network meta-analysis was used for the comparison of antihypertensive classes. RESULTS: Antihypertensive treatment, regardless of the drug class, had benefits on overall cognition [effect size 0.05, 95% confidence interval (CI) 0.02-0.07] and all cognitive functions except language. Antihypertensive treatment reduced the risk of all-cause dementia by 9%, with reference to the control group (hazard ratio 0.91, 95% CI 0.89-0.94), when randomized trials and observationnal studies were combined (n = 15). Result was not significant with randomized trials alone (n = 4). Angiotensin II receptor blockers (ARBs) had larger benefits than placebo on overall cognition (adjusted effect size 0.60 ±â€Š0.18, P = 0.02). ARBs were more effective than ß-blockers (0.67 ±â€Š0.18, P = 0.01), diuretics (0.54 ±â€Š0.19, P = 0.04) and angiotensin-converting enzyme inhibitors (0.47 ±â€Š0.17, P = 0.04) in rank. The mean change in blood pressure did not differ significantly between the different antihypertensive drug classes. CONCLUSION: Our results support the notion that antihypertensive treatment has beneficial effects on cognitive decline and prevention of dementia, and indicate that these effects may differ between drug classes with ARBs possibly being the most effective.

Crucial importance of using a sliding calliper to measure distance for carotid-femoral pulse wave velocity assessment.

BACKGROUND AND OBJECTIVES: In the past, different methods have been used to measure the carotid-femoral distance for the assessment of pulse wave velocity (PWV). However, the latest consensus published advises to use 80% of the direct straight carotid-femoral distance (D(0.8)) using either a flexible tape or a sliding calliper. We studied the influence of the use of a tape measure and a calliper on PWV values and provided equations to derive the straight D(0.8) distance from previous methodologies. METHODS: PWV was measured in patients referred for ambulatory blood pressure monitoring. Carotid-femoral, carotid-sternal notch, and sternal notch-femoral distances were measured with a tape and a sliding calliper. RESULTS: Two hundred and fifty-nine patients (141 men and 118 women) were recruited consecutively. Their BMI ranged from 18 to 45 kg/m(2) (28.4 ±â€Š5.0, mean ±â€ŠSD). As expected, distances measured with tape were longer (3.1 ±â€Š1.3 cm for D(0.8)) leading to higher values of PWV (0.6 ±â€Š0.3 m/s for PWV(0.8)). This difference was similar in men and women and depended for 20% on the BMI. Equations explaining more than 85% of variance can be used to convert tape carotid-femoral, carotid-sternal notch, and tape sternal notch-femoral distances to D(0.8). CONCLUSION: It is crucial to use a sliding calliper to assess distances for PWV measurement. The overestimation with flexible tape depends on the BMI but not on the sex. Conversion equations between previous methods and the D(0.8) method can be used.

Relationship between recommended chronic heart failure treatments and mortality over 8 years in real-world conditions: a pharmacoepidemiological study.

PURPOSE: We previously reported that chronic heart failure (CHF) treatments reduce the duration of hospitalisation, even in elderly patients. The present study aimed to determine whether CHF treatment also provides long-term benefits in terms of reduced mortality at 8 years. METHODS: A cohort of 281 patients who were admitted to a French teaching hospital with a main diagnosis of CHF were followed through the health insurance databases for 1 year and through the national mortality database for 8 years. RESULTS: Diuretics (236 patients, 84 %) and angiotensin-converting enzyme (ACE) inhibitors (193 patients, 69 %) were the most-frequently prescribed medications. The median duration of survival was 46 months. Mortality rates were significantly lower for patients administered beta-blockers (59 %) and statins (56 %) than for patients not exposed to these drugs (82 %, p < 0.001 and 78 %, p = 0.001 respectively). No significant differences in mortality were observed for spironolactone, diuretics or ACE inhibitors. After adjustment, beta-blocker treatment remained associated with a significantly lower risk of mortality (hazard ratio, HR = 0.54 [0.34-0.84]). After adjustment, the use of two or three CHF drugs was associated with longer survival (HR = 0.53 [0.36-0.77]) than the use of zero or one CHF drug. Statins were also associated with longer survival after adjustment (HR = 0.53 [0.31-0.89]). In patients 75 years of age or older (n = 73), only beta-blocker treatment was associated with a significantly lower risk of mortality (HR = 0.31 [0.16-0.63]) in multivariate analysis. CONCLUSIONS: The use of beta-blockers was associated with better survival rates. The use of statins was also associated with better survival at 8 years. Randomised controlled trials are required to confirm these observations.

Relationship between short-term blood pressure variability and large-artery stiffness in human hypertension: findings from 2 large databases.

Short-term blood pressure (BP) variability predicts cardiovascular complications in hypertension, but its association with large-artery stiffness is poorly understood and confounded by methodologic issues related to the assessment of BP variations over 24 hours. Carotid-femoral pulse wave velocity (cfPWV) and 24-hour ambulatory BP were measured in 911 untreated, nondiabetic patients with uncomplicated hypertension (learning population) and in 2089 mostly treated hypertensive patients (83% treated, 25% diabetics; test population). Short-term systolic BP (SBP) variability was calculated as the following: (1) SD of 24-hour, daytime, or nighttime SBP; (2) weighted SD of 24-hour SBP; and (3) average real variability (ARV), that is, the average of the absolute differences between consecutive SBP measurements over 24 hours. In the learning population, all of the measures of SBP variability showed a direct correlation with cfPWV (SD of 24-hour, daytime, and nighttime SBP, r=0.17/0.19/0.13; weighted SD of 24-hour SBP, r=0.21; ARV, r=0.26; all P<0.001). The relationship between cfPWV and ARV was stronger than that with 24-hour, daytime, or nighttime SBP (all P<0.05) and similar to that with weighted SD of 24-hour SBP. In the test population, ARV and weighted SD of 24-hour SBP had stronger relationships with cfPWV than SD of 24-hour, daytime, or nighttime SBP. In both populations, SBP variability indices independently predicted cfPWV along with age, 24-hour SBP, and other factors. We conclude that short-term variability of 24-hour SBP shows an independent, although moderate, relation to aortic stiffness in hypertension. This relationship is stronger with measures of BP variability focusing on short-term changes, such as ARV and weighted 24-hour SD.

Do all antihypertensive drugs improve carotid intima-media thickness? A network meta-analysis of randomized controlled trials.

The many clinical trials investigating the effect of various antihypertensive drugs on carotid intima-media thickness (CIMT) produced conflicting results. We used meta-analysis to evaluate CIMT changes and network meta-analysis to rank drugs according to the magnitude of these changes. We identified 31 randomized controlled trials listed in three databases as of January 2008. Using a random-effects model, we found a significant CIMT decrease with antihypertensive drugs compared to placebo (-0.10 [-0.16; -0.04]). Overall effect sizes vs. placebo were significant for angiotensin-converting enzyme (ACE) inhibitors (-0.08 [-0.14; -0.02]), and a trend was found for beta-blockers (-0.09 [-0.19; 0.01]). The data did not allow other direct comparisons vs. placebo. Significant benefits were found for calcium-channel blockers (CCBs) compared to both ACE inhibitors (0.37 [0.20; 0.54]), as well as for angiotensin II receptor blockers (ARBs) compared to beta-blockers (0.42 [0.29; 0.55]). Diuretics were less efficient than CCBs (-0.09 [-0.16; -0.02]). Indirect comparisons with network meta-analysis showed significant effects of CCBs and ARBs vs. placebo (both P < 0.05) and vs. diuretics (both P < 0.001). The CIMT decrease with ACE inhibitors and beta-blockers was greater than with diuretics (both P < 0.05) but was not different from the placebo effect. In subgroup analyses, significant benefits occurred with lower baseline CIMT values and shorter treatment durations but were unrelated to the size of the blood pressure decrease. In conclusion, among antihypertensive drugs, CCBs and ARBs have the greatest effect on CIMT.

Heart rate increment analysis is not effective for sleep-disordered breathing screening in patients with chronic heart failure.

Frequency domain analysis of heart rate variation has been suggested as an effective screening tool for sleep-disordered breathing (SDB) in the general population. The aim of this study was to assess this method in patients with chronic congestive heart failure (CHF). We included prospectively 84 patients with stable CHF, left ventricular ejection fraction (LVEF) <45% and sinus rhythm. The patients underwent polygraphy to measure the apnoea/hypopnoea index (AHI) and simultaneous Holter electrocardiogram monitoring to measure the power spectral density of the very low frequency component of the heart rate increment, expressed as the percentage of total power spectral density [% very low frequency increment (%VLFI)]. %VLFI could be determined in 54 patients (mean age, 52.8 +/- 12.3 years; LVEF, 33.5 +/- 9.8%). SDB defined as AHI > or =15 h(-1) was diagnosed in 57.4% of patients. Percent VLFI was not correlated with AHI (r = 0.12). Receiver-operating characteristic curves constructed using various AHI cut-offs (5-30 h(-1)) failed to identify a %VLFI cut-off associated with SDB. The 2.4% VLFI cut-off recommended for the general population of patients with suspected SDB had low specificity (35%) and low positive and negative predictive values (35% and 54%, respectively). Heart rate increment analysis has several limitations in CHF patients and cannot be recommended as an SDB screening tool in the CHF population.

Arterial stiffness predicts severe progression in systemic sclerosis: the ERAMS study.

OBJECTIVE: The ERAMS study addressed the value of arterial stiffness in predicting the severity of systemic sclerosis. METHODS: ERAMS was a prospective multicentre cohort study including patients with definite systemic sclerosis. Arterial stiffness was measured by the standardized non-invasive QKd 100-60 method. Clinical evaluation, biological measurements, functional respiratory tests and cardiac Doppler echography were performed at inclusion then each year until 3 years' follow-up was completed. Progression was defined as mild (articulations, muscle, oesophagus or skin involvement) or severe (lung, heart or kidney involvement) by a critical event committee. The prediction of severe progression was studied for QKd 100-60 as well as clinical and biological data at baseline by univariate and multivariate analysis. RESULTS: Ninety-nine patients were included (81 women, 18 men, mean age 57 years, standard deviation 12.5). Although their blood pressure profile was normal, half the patients had increased arterial stiffness (QKd 100-60<200 ms). There was a significant relationship between age-adjusted arterial stiffness and decrease in carbon dioxide diffusion (P<0.03) or haemoglobin rate (P<0.01). By univariate analysis, severe progression after 3 years was predicted by age (P=0.04), lung involvement (P=0.04), diffusion of lung carbon oxide (DLCO) (P<0.01), skin score (P=0.02), haemoglobin (P<0.01) and baseline Qkd 100-60 divided into two classes according to the median (P<0.01). By multivariate analysis, only haemoglobin rate [odds ratio (OR) 0.4, 95% confidence interval (CI) 0.2-0.9] and QKd 100-60 (OR 19.6, 95% CI 1.2-308.2) predicted severe progression of systemic sclerosis. CONCLUSION: The measurement of arterial stiffness by the QKd method is a useful objective method for assessing the prognosis of systemic sclerosis independently from other data.

Impact of somatostatin analogs on the heart in acromegaly: a metaanalysis.

CONTEXT: Acromegaly can be complicated by cardiomyopathy. Treatment with somatostatin analogs has been shown to improve some cardiac parameters, but most published clinical trials involved few patients and were not randomized or controlled. In addition, their results are rather variable. OBJECTIVE: The objective of the study was to conduct a metaanalysis aimed at obtaining a more accurate picture of the effect of somatostatin analogs on the heart in patients with acromegaly. DESIGN: We systematically reviewed all studies of somatostatin analogs in acromegaly. Eighteen studies were identified in three databases. We conducted a combined analysis of the effects of somatostatin analogs by using the overall effect size to evaluate significance and by computing the weighted mean differences with and without treatment to assess the effect size. RESULTS: Somatostatin analog treatment was associated with significant reductions in the heart rate [-5.8 (2.1) beats/min], the left ventricular mass index [-22.3 (6.7) g/m(2)], interventricular septum thickness [-0.3 (0.2) mm], left ventricular posterior wall thickness [-0.8 (0.4) mm], and the ratio of the E-wave and A-wave peak velocities of the mitral flow profile [0.2 (0.1)]. It was also associated with improved exercise tolerance [1.6 (0.4) min]. Trends toward beneficial effects were noted for the left ventricular end-diastolic dimension [-1.5 (2.2) mm] and the left ventricular ejection fraction [3.3% (1.7%)]. Overall effect sizes were not significant for blood pressure, left ventricular end-systolic dimension, or fractional shortening. Bigger improvements were observed in studies with larger falls in IGF-I and/or GH levels and studies of younger patients. CONCLUSION: This metaanalysis confirms that somatostatin analog therapy aimed at achieving stringent control of serum GH/IGF-I concentrations in patients with acromegaly is associated with significant positive effects on morphological and functional hemodynamic parameters.

Cardiac effects of growth hormone treatment in chronic heart failure: A meta-analysis.

CONTEXT: Experimental studies suggest that GH treatment may improve cardiovascular parameters in chronic heart failure (CHF). However, clinical trials involved small numbers of patients and did not allow a conclusion to be drawn on the effect of this treatment in humans. OBJECTIVE: We systematically reviewed and analyzed all randomized controlled trials and open studies of sustained GH treatment in CHF. STUDY SELECTION: Twelve trials were identified in three databases. We conducted a combined analysis of GH effects on cardiovascular parameters using the overall effect size to evaluate significance and computing the weighted mean differences with and without treatment to assess effect size. DATA SYNTHESIS: GH treatment significantly modified morphological cardiovascular parameters [interventricular septum thickness, +0.55 (sd, 0.43) mm (P < 0.001); posterior wall thickness, +1.01 (0.44) mm (P < 0.01); left ventricle (LV) end-diastolic diameter, -2.02 (1.22) mm (P < 0.01); and LV end-systolic diameter, -5.30 (2.33) mm (P < 0.05)]; LV and systemic hemodynamics [LV end-systolic wall stress, -38.9 (13.3) dynes/cm(2) (P < 0.001); LV ejection fraction, +5.10 (1.74)% (P < 0.05); and systemic vascular resistance, +195.0 (204.5) dyn x sec(-1) x cm(-5) (P < 0.01)]; and functional parameters [New York Heart Association class, -0.97 (0.23) (P < 0.01); exercise duration, +103.7 (37.6) sec (P < 0.001); and maximal oxygen uptake, +2.48 (1.76) ml/kg x min (P < 0.01)]. Subgroup analysis and meta-regression showed significant relationships between the IGF-I response and GH treatment effects. CONCLUSION: Our meta-analysis suggests that GH treatment improves several relevant cardiovascular parameters in patients with CHF. However, these results must be confirmed by a large randomized placebo-controlled trial on hemodynamic, morphological, and functional parameters during long-term high-dose GH treatment of patients with CHF.

Pharmacokinetics of hydroxyurea 1,000 mg coated breakable tablets and 500 mg capsules in pediatric and adult patients with sickle cell disease.

Little is known about the pharmacokinetics of hydroxyurea in patients with sickle cell disease (SCD). Our aims were to evaluate bioequivalence between standard hydroxyurea capsules and a new formulation of 1,000 mg coated breakable tablets in adults and to compare pharmacokinetic parameters in adults and children with SCD. Fifteen adults received hydroxyurea capsules and tablets in a randomized cross-over study. Eleven children received hydroxyurea tablets. The results showed bioequivalence between capsules and tablets in adults. Pharmacokinetic parameters were not significantly different between adults and children. Considerable inter-individual variability was noted.

Different effects of ambulatory blood pressure monitoring on subjective and objective sleep quality.

OBJECTIVE: To determine whether ambulatory blood pressure monitoring affects objective and subjective sleep quality in patients tested at home. METHODS: Seventy consecutive patients (40 women and 30 men, aged 53+/-15 years), having ambulatory blood pressure monitoring to monitor the efficacy of antihypertensive treatment or to distinguish between hypertension or white-coat hypertension had an evaluation of their sleep quality on a first night with ambulatory blood pressure monitoring and the three following nights without ambulatory blood pressure monitoring. Ambulatory blood pressure monitoring was performed with an auscultatory device with a measure every 15 min during 24 h. Sleep evaluation criteria were both subjective (sleep quality score and sleep questionnaire) and objective (wrist actigraphy monitoring). Sleep parameters during night 1 with ambulatory blood pressure monitoring were compared with those during night 4 without ambulatory blood pressure monitoring. Usual quality of sleep of the patients was assessed by the mean sleep quality score over 7 consecutive days. RESULTS: The sleep quality score was significantly higher for night 4 than for night 1 (7.3+/-2.1 vs. 5.3+/-2.3; P<0.0001). In contrast, actigraphy parameters (actual sleep time, mean activity score, and fragmentation index) were similar on night 1 and night 4 (6.7+/-1.2 vs. 6.9+/-1.2, 13.2+/-9.8 vs. 12.1+/-8.4, and 31.0+/-14.5 vs. 29.9+/-14.3, respectively). Subjective sleep quality was significantly altered by ambulatory blood pressure monitoring in good sleepers (mean sleep quality score > or =7, 73% of patients) but not in poor sleepers. The effect of ambulatory blood pressure monitoring on subjective sleep quality did not differ between dippers and nondippers. CONCLUSIONS: Objective sleep quality as assessed by wrist actigraphy is not significantly altered by ambulatory blood pressure monitoring, whereas subjective sleep quality is adversely affected in good sleepers.

Utilisation of medications recommended for chronic heart failure and the relationship with annual hospitalisation duration in patients over 75 years of age. A pharmacoepidemiological study.

OBJECTIVES: Trials in chronic heart failure (CHF) include few patients older than 75 years, who represent a large proportion of CHF patients. We evaluated the influence of age on CHF-medication use and of CHF medications on hospitalisation in patients older than 75 years. METHODS: Included in our nested case-control study were 281 patients admitted in 2000 to a French teaching hospital with a main diagnosis of CHF and monitored over a 12-month period. Patient characteristics, medications at discharge, outpatient medications and hospitalisation frequency and duration were compared by means of univariate and multivariate analyses. RESULTS: Patients older than 75 years (n=150) and 75 years or younger (n=131) were similar with regard to NYHA class and ejection fraction. At discharge, diuretic use was similar in the two groups, but fewer older patients were prescribed angiotensin-converting enzyme (ACE) inhibitors (48% versus 63%, P<0.01) or beta-blockers (19% versus 37%, P<0.001). During follow-up, total re-admission rate and mean number of re-admissions were similar; however, total hospitalisation duration was greater in patients older than 75 years (38+/-77 days) than in those 75 years or younger (26+/-59 days) (P<0.01). In patients over 75 years, shorter 12-month hospitalisation duration was associated with prescription of diuretics (P<0.001), ACE inhibitors (P<0.001), beta-blockers (P<0.01) and digitalis (P<0.05). CONCLUSIONS: Recent advances in CHF therapy are generally applied less to patients over 75 years of age-associated with longer annual hospitalisation duration in this population. Appropriate CHF medications at hospital discharge appear to reduce annual hospitalisation duration in patients older than 75 years.

Cardiac autonomic control during balloon carotid angioplasty and stenting.

Hemodynamic alterations during balloon carotid angioplasty (BCA) and stenting have been ascribed to the consequences of direct carotid baroreceptor stimulation during balloon inflation. BCA with stenting in patients with carotid atheromatous stenoses offers a unique opportunity for elucidating the cardiovascular autonomic response to direct transient intravascular stimulation of the baroreceptors. We analysed the consequences of BCA on the autonomic control of heart rate and on breathing components in nine patients with atheromatous stenoses involving the bifurcation and the internal carotid. A time-frequency domain method, the smoothed pseudo-Wigner-Ville transform (SPWVT), was used to evaluate the spectral parameters (i.e., the instantaneous amplitude and centre frequency (ICF) of the cardiovascular and respiratory oscillations). Those parameters and their dynamics (8 and 24 h later) were evaluated during and after the procedure. BCA stimulates baroreceptors in all patients, which markedly reduces heart rate and blood pressure. Vagal baroreflex activation altered the respiratory sinus arrhythmia in terms of amplitude and frequency (ICF HF RR shifted from 0.27 +/- 0.03 to 0.23 +/- 0.04 Hz pre-BCA vs. BCA, respectively; p < 0.01). Both the high- and low-frequency amplitudes of heart rate oscillations were altered during carotid baroreceptor stimulation, strongly supporting a contribution of the baroreflex to the generation of both oscillations of heart rate. Carotid baroreceptors stimulation increased the inspiratory time (Ti) (1.5 +/- 0.5 to 2.3 +/- 0.6 s pre-BCA vs. BCA, respectively; p < 0.01). In awake patients, BCA with stenting of atheromatous stenosis involving the bifurcation and internal carotid causes marked changes in the cardiac autonomic and respiratory control systems.