A critical appraisal of vasomotor symptom assessment tools used in clinical trials evaluating hormone therapy compared to placebo.

OBJECTIVE: Vasomotor symptoms (VMS) have been consistently reported as the leading predictor of health-related quality of life (HRQOL) among menopausal women, and the strongest indication for treatment. The North American Menopause Society endorses the use of oral estrogen for the treatment of VMS based on a Cochrane meta-analysis. The Cochrane review concludes that oral hormone therapy reduces the frequency and severity of VMS. The objective of this review is to critically appraise the outcome measures used in these clinical trials to evaluate whether there is adequate evidence that oral hormone therapy improves HRQOL. METHODS: Each trial in the 2004 Cochrane review of oral hormone therapy for the management of VMS was evaluated with respect to study design, outcome measures, and method of analysis. RESULTS: Twenty-four randomized, double-blind, placebo-controlled clinical trials were appraised. Six trials were excluded from the Cochrane meta-analysis due to inadequate reporting of outcome measures. Of the remaining trials, 15 trials assessed only symptom frequency and/or severity. One trial used a subscale of the General Health Questionnaire. Two trials used the Greene Climacteric Scale, a validated outcome measure in menopausal women, to directly assess the impact of hormone therapy on HRQOL. Both studies showed an improvement in HRQOL in the hormone-treated group, although the sample size was small (n = 118) and the effect was modest. CONCLUSION: Although oral hormone therapy improves VMS scores, there is a paucity of evidence on whether it improves HRQOL in menopausal women. Future studies using validated, patient-reported outcome measures that directly assess HRQOL are needed.

[HTA and non-hormonal menopause treatment]. / HTA et traitements non-hormonaux de la ménopause.

Serotonin reuptake inhibitors, clonidine, gabapentin and pregabalin have shown moderate efficacy in menopausal disorders. The effect of phytoestrogens is reported to be modest, but the side effects are not well known.

Comparative efficacy and safety of estradiol transdermal preparations for the treatment of vasomotor symptoms in postmenopausal women: an indirect comparison meta-analysis.

OBJECTIVE: Divigel and Estrogel are estradiol gels for the treatment of postmenopausal women with moderate to severe vasomotor symptoms. They differ with respect to several factors including estradiol concentration and surface application, and cannot be compared solely on the basis of their estradiol dose. No randomized clinical trials have compared them head to head, but both have been compared with placebo. Therefore, the objective of this study was to conduct a systematic review and network meta-analysis of the two estradiol gels. METHODS: We performed a comprehensive systematic literature review. One publication reporting on one Divigel trial, three publications reporting on two Estrogel trials, and five publications reporting on other estradiol transdermal preparations were identified. Efficacy outcomes were change from baseline in daily hot flush frequency and change from baseline in daily hot flush severity. Safety outcomes were frequency of treatment-related adverse events (AEs) and frequency of treatment-emergent AEs leading to discontinuation. Bayesian indirect treatment comparison meta-analysis of trial-level data was performed in accordance with the International Society for Pharmacoeconomics and Outcomes Research, Academy of Managed Care Pharmacy, National Pharmaceutical Council (ISPOR-AMCP-NPC) Good Practice Questionnaire. All outcomes were compared with respect to doses of the considered preparations. RESULTS: For hot flush frequency, Divigel 0.25 mg was similar to Divigel 0.5 mg and to Estrogel 0.75 mg, and was statistically significantly superior to Estrogel 1.5 mg. The largest effect was observed with Divigel 1.0 mg (mean difference of 3.91 hot flushes/wk vs placebo), and was statistically significantly superior to all other interventions. The 1.5 mg Estrogel dose was associated with the smallest estimate of efficacy. For hot flush severity, Divigel 0.25 mg was similar to the efficacy of Divigel 0.5 mg, and for 0.25 mg and 0.5 mg of other estradiol gels, but was statistically inferior to Divigel 1.0 mg, Estrogel 0.75 mg, Estrogel 1.5 mg, and the 1.0 and 1.5 mg doses of all other estradiol gels. The estimated efficacy of Divigel 0.5 mg was similar to that of Estrogel 0.75 mg, Estrogel 1.5 mg, and the 0.25 and 0.5 mg doses of other transdermal estradiol preparations. Risks of treatment-related AEs for Divigel 0.25 mg, Divigel 0.5 mg, Estrogel 0.75 mg, and Estrogel 1.5 mg were similar and all were of a slightly higher risk than placebo. Among these, Divigel 1.0 mg, Estrogel 1.5 mg, and other gels 0.5 mg were statistically significantly less safe than placebo. However, for treatment-emergent AEs leading to discontinuation, none of the gels were associated with statistically significantly higher relative risks compared with placebo. In this study, statistically significant refers to the 95% credible intervals used in the Bayesian Network Analysis. CONCLUSIONS: Using network meta-analysis for indirect treatment comparison, we have shown that the efficacy of Divigel 0.25 mg, as measured by reduced hot flush frequency and severity, was similar to that of Divigel 0.5 mg and of Estrogel 0.75 and 1.5 mg. Overall, our analysis showed that Divigel 1.0 mg provided the best efficacy profile, but that this treatment was also associated with a higher risk of AEs. The network meta-analysis also showed that treatment with Estrogel 1.5 mg was associated with the smallest estimate of reduction in frequency of hot flushes.

Hydrocortisone for Treatment of Hypotension in the Newborn.

Newborns, and especially premature newborns, are at significant risk for developing hypotension in the first week or two after birth. The etiology of hypotension in the newborn may vary, but the very low birth weight and extremely low birth weight preterm infants are less likely to respond to conventional cardiovascular support when they develop hypotension. This article reviews the least conventional treatment using hydrocortisone for hypotension that is refractory to conventional volume replacement and/or vasopressor medications with the underlying assumption that sick and premature newborns have a relative or measured adrenal insufficiency. The addition of hydrocortisone in the treatment of hypotension in the newborn is becoming more common but is not universally advocated. However, the supportive evidence is growing, and, as reviewed, use of hydrocortisone requires judicious and cautious regard.

Transcranial Doppler assessment of cerebral vasomotor reactivity in evaluating the effects of vinpocetine in cerebral small vessel disease: a pilot study.

BACKGROUND: There are still dilemmas about the vasodilating effect of vinpocetine, a synthetic ethyl alkaloid vincamine. The method of measuring cerebral vasomotor reactivity (VMR) by transcranial Doppler (TCD) technique before and after administration of the medication was used to estimate the degree of arterioles vasodilatation. The aim of this study was to test of the vasodilating effect of vinpocetine in patients with cerebral small vessel disease (SVD) by measuring cerebral VMR. MATERIAL AND METHODS: Thirty patients with SVD were on 3-month-long oral treatment with 15 mg vinpocetine daily. Cerebral VMR was determined by breath holding test. The breath holding index (BHI) was calculated in standard manner and values > 0.69 were considered normal. At the baseline, before treatment (I), BHI, modified Rankin scale (mRS) score, Mini Mental State Examination (MMSE) score were determined. One month later (II) BHI was assessed again, while after 3 months of treatment (III) we analyzed BHI, mRS score and MMSE score. RESULTS: The average age of patients was 61.4 +/- 11.5 years (range 40 to 77 years), 18 (60%) female and 12 (40%) males. Values of BHIs were increased during treatment at the right MCA (I) 1.18 +/- 0.53, (II) 1.26 +/- 0.54, (III) 1.37 +/- 0.41, with statistical significance between I and III measurement (p < 0.05). An increase was noted on the left MCA (I) 1.25 +/- 0.53, (II) 1.31 +/- 0.55 and (III) 1.32 +/- 0.42, but it did not reach statistical significance (p > 0.05). Mean MMSE score significantly increased from baseline 27.4 +/- 2.3 to 28.5 +/- 2.0 after three months of treatment (p < 0.001). Functional status showed a statistically significant improvement with mRS score increasing from 2.1 +/- 1.0 to 1.1 +/- 0.6 (p < 0.001). CONCLUSION: This pilot study showed that 3-month-long oral treatment with vinpocetine 15 mg daily had tendency to increase BHI, indicating improvement of cerebral VMR. It is possible that higher doses of vinpocetine are needed to achieve substantial increase of VMR.

[Consensus conference of the Mexican Association for the Study of Climateric on veralipride prescription for patients with vasomotor symptoms]. / Consenso de la Asociación Mexicana para el Estudio del Climaterio para la indicación de veraliprida a pacientes con síntomas vasomotores.

Vasomotor symptoms are one of the main reasons for climateric women to consult a physician. Hormone therapy is the first treatment choice, but it is not indicated to all patients. Veralipride is an option for those who cannot or will not try hormone treatment. The Mexican Association for the Study of Climateric (AMEC) assembled an interdisciplinary group of medical experts so that they revised the medical literature on the subject and reached a consensus on veralipride indication, doses, counterindications and safety. The recommendations of the consensus conference on veralipride are: (1) Physicians must be familiar with its indication, side effects, pharmacokinetics and dosage. (2) Patients must be informed on other therapeutical options. (3) Patients' mental and neurological state must be evaluated, in particular to identify movement disorders, extrapyramidal symptoms (tremor or dystonia), anxiety and depression that can be mistaken for climateric symptoms. (4) Any adverse effect associated with the drug must be reported. (5) A random multicenter trial must be carried out in order to identify the frequency and severity of side effects, and (6) Written information on possible health risks when using the drug must be provided.

Clinical impact of vasomotor function assessment and the role of ACE-inhibitors and statins.

Impaired endothelial function is recognised as one of the earliest events of atherogenesis. Endothelium-dependent vasomotion has been the principal method to assess endothelial function. In this article, we will discuss the clinical value of the different techniques to evaluate endothelium-dependent vasomotion. To date, there seems not to be a simple and reliably endothelial function test to identify asymptomatic subjects at increased risk for cardiovascular disease in clinical practice. Recent studies indicate that pharmacological interventions, in particular with ACE-inhibitors and statins, might improve endothelial function. However, there is no solid evidence that improvement of endothelial function is a necessity for the observed reduction in cardiovascular events by these compounds. Overall, at this moment, there is no place in clinical practice for the use of endothelial function as a method for risk assessment or target of pharmacological interventions.

[Clinical assessment of major artery vasomotor endothelial function: methodology and importance for evaluating aging as a cardiovascular risk factor]. / Klinicka procena vazomotorne funkcije endotela magistralnih arterija: metodologija i znacaj za evaluaciju starenja kao faktora kardiovaskularnog rizika.

UNLABELLED: AGING AS A CARDIOVASCULAR RISK FACTOR: Atherosclerosis is the major cause of mortality in the Western world (>50%) as well as in Serbia and Montenegro (>60%). Atherosclerosis/arteriosclerosis functional and structural vascular changes as a consequence of angina pectoris, myocardial infarction, transient ischemic cerebrovascular attacks, stroke, ischaemic attacks in peripheral circulation and/or thromboembolic complications. Aging, lipids (oxidized LDL), infective agents, inflammation, increased glucose level, hypertension, smoking, increased homocysteine level, oxidative stress etc. are recognized as factors which lead to endothelial dysfunction and cause atherosclerosis. Thus, in response to such attacks endothelium releases different substances like: nitric oxide, prostacyclin, endothelium-derived hyperpolarizing factor (EDHF), endothelin, bradykinin, angiotensin II, free oxygen radicals etc. which could be involved in the pathogenesis of atherosclerosis. Atherosclerosis/arteriosclerosis begins with endothelial vasomotor and anti-thrombotic dysfunction and it is of strategic importance to discover this condition earlier. In regard aging, both higher thickness and stiffness of arterial blood vessels appear following an incidence of cardiovascular diseases. DIAGNOSTIC METHODS: Over the last decade non-invasive, echosonographic method for visualization of carotid intima-media thickness (indicator of arteriosclerosis/atherosclerosis) was introduced in clinical practice. However, it is also used to compare brachial artery diameter changes, linear velocity and bloodflow which are estimated during basal conditions, during ischemia, during reactive hyperemia (endothelium/independent phase) as well as with left ventricular mass index. DISCUSSION AND CONCLUSION: Due to aging there is a decreased response to reactive hyperemia, increased carotid intima-media thickness and increased left ventricular mass, but there is a lack of time-dependent correlation. First endothelial dysfunction occur twenty years before any manifestations appear--as typical vascular and ventricular remodeling. During this period certain markers, for example homocysteine, and diagnostic procedures are important parts of primary prevention.

Assessment of vasoreactivity in brain edema by acetazolamide activation SPECT and PET.

Our study was performed to find out cerebrovascular reactivity post acetazolamide administration in patients with peritumoral edema. Adult patients (n = 9) underwent CBF measurement by 99mTc-HMPAO SPECT pre and post 1 gram i.v. acetazolamide. In all patients, this procedure was repeated once again within 10 days of performing tumor removal. Five of these patients also underwent CBF measurement pre and post 1 gram i.v. acetazolamide post surgery only using oxygen-15 labeled H2O PET. Asymmetry index (AI) was calculated as ratio of ROI counts in the peritumoral edematous area and symmetrical ROI on the contralateral normal hemisphere. The AI increased after acetazolamide in edematous gray matter post operatively though the resting AI remained almost same post operatively. AI in edematous white matter showed non-significant increase post operatively both at rest and after acetazolamide. Good linear correlation of AI between PET and SPECT was observed both in gray and white matter. The improvement of vascular reactivity in edematous gray matter after tumor removal suggests that mass effect not only reduces CBF but also suppresses vascular reactivity. White matter vascular reactivity in early post operative period is little improved, possibly due to factors other than mass effect i.e. excess water accumulation in white matter perivascular space.

Persistent pulmonary hypertension of the newborn and smoking and aspirin and nonsteroidal antiinflammatory drug consumption during pregnancy.

OBJECTIVE: Prenatal causation of persistent pulmonary hypertension of the newborn (PPHB) is suggested by a specific pattern of pulmonary vascular remodeling observed immediately after birth in some infants with fatal PPHN. The goal of this study was to determine whether PPHN is associated with fetal exposure to: (1) tobacco and marijuana smoking (ie, contributors to fetal hypoxemia), (2) consumption of aspirin and other nonsteroidal antiinflammatory drugs (ie, inhibitors of prostaglandin synthesis), and (3) cocaine use (ie, a contributor to vasospasm). DESIGN: Case-control interview study. SETTING: Two Harvard-affiliated newborn intensive care units. PARTICIPANTS: Mothers of case infants who had PPHN or who met criteria for the referent group. INTERVENTIONS: During July 1985 through April 1989, we interviewed mothers of 103 infants with PPHN and 298 control infants. Because of potential selection bias that might result from recruiting only inborn control infants even though two-thirds of cases were outborn, separate analyses compared the 103 total and 35 inborn infants with PPHN with the 298 inborn control infants. Multivariate analyses were used to adjust for potential confounding factors, including maternal education and Medicaid health insurance (ie, two markers of socioeconomic status), other antenatal factors found to be associated with PPHN (ie, maternal urinary tract infection and diabetes mellitus), and the infant's sex. MAIN OUTCOME MEASURES: Self-reported use or consumption of tobacco, marijuana, cocaine, aspirin, and other nonsteroidal antiinflammatory drugs during pregnancy. RESULTS: The adjusted odds ratios (and 95% confidence intervals) for maternal pregnancy exposures to the factors of principal interest among the total study population were: aspirin, 4.9 (1.6-15.3); and nonsteroidal antiinflammatory drugs, 6.2 (1.8-21.8); for the inborn group they were aspirin, 9.6 (2.4-39.0); and nonsteroidal antiinflammatory drugs, 17.5 (4.3-71.6). Although the association between tobacco smoking during pregnancy and PPHN was elevated in univariate analyses, with odds ratios (and 95% confidence intervals) of 2.0 (1.2-3.4) and 1.3 (0.6-3.3) for total and inborn populations, respectively, the relationship was not significant after adjustment for all other factors in the final logistic regression model. Acknowledged illicit drug use was too infrequent (3.2%) to evaluate. CONCLUSION: Maternal consumption of nonsteroidal antiinflammatory drugs and aspirin during pregnancy or the reasons these drugs were ingested seem to contribute to an increased risk of PPHN.

Assessment of cerebral vasomotor reactivity by transcranial Doppler ultrasound and breath-holding. A comparison with acetazolamide as vasodilatory stimulus.

BACKGROUND AND PURPOSE: Evaluating cerebrovascular vasomotor reactivity seems to be of prognostic relevance for patients with occlusive internal carotid artery disease. To evaluate its clinical usefulness, the recently introduced breath-holding maneuver as a carbon dioxide-dependent vasodilatory stimulus was compared with the acetazolamide challenge by means of transcranial Doppler ultrasound and stable xenon-enhanced computed tomography. METHODS: In a total of 134 middle cerebral arteries of 74 patients (mean +/- SD age, 62 +/- 9 years) with unilateral or bilateral occlusive carotid artery disease, vasomotor reactivity was estimated by the increase of middle cerebral artery mean blood velocity by transcranial Doppler ultrasound, comparing the breath-holding maneuver and 1 g IV acetazolamide as vasodilatory stimuli. The carotid artery findings were classified as normal, stenosis of 50% to < 70%, 70% to < 90%, 90% to 99%, and occlusion. Eighteen of the 74 patients additionally underwent stable xenon-enhanced computed tomography to calculate the increase of mean cortical regional cerebral blood flow in the middle cerebral artery territory after acetazolamide stimulation. RESULTS: The percentage of mean regional cerebral blood flow changes (n = 36 hemispheres) correlated best with the absolute mean blood velocity changes while breath-holding (P = .007, r = .4332). The absolute mean regional cerebral blood flow changes correlated best with the percentage of mean blood velocity changes after acetazolamide stimulation (P = .004, r = .4580). On all 134 middle cerebral arteries, both vasodilatory stimuli correlated highly significantly (P < .0001) when comparing increases in absolute (r = .5448) or relative (r = .3516) mean blood velocity. Both stimulation techniques similarly indicated significantly reduced vasomotor reactivity with increasing degree of internal carotid artery lesions (P < or = .01). However, the acetazolamide challenge differentiated more accurately between the various groups of internal carotid artery findings. CONCLUSIONS: The assessment of vasomotor reactivity by transcranial Doppler ultrasound correlates with cerebral blood flow changes even when different vasodilatory stimuli are used. In cooperative patients the breath-holding maneuver as vasodilatory stimulus seems clinically useful for a first estimation of cerebral vasomotor reactivity.

Simultaneous assessment of vasoreactivity using transcranial Doppler ultrasound and cerebral blood flow in healthy subjects.

Blood flow velocities in both middle cerebral arteries and regional cerebral blood flow in their perfusion territories were measured simultaneously in 36 healthy subjects. In 20 subjects, the measurements were first performed under basal conditions and then repeated 15-20 min after an intravenous injection of 1 g of acetazolamide. Reproducibility of simultaneous blood flow and velocity measurements was tested by examining 16 subjects on two occasions under basal conditions with an interval of 20 min. Relatively good reproducibility was found for repeated measurements of velocity and blood flow, being best when side-to-side asymmetry was assessed. The increase in blood flow velocities after acetazolamide was symmetrical (right side, 34.2%; and left side, 35.5%), and the velocity increase was significantly correlated with basal values. The increase in cerebral blood flow was also symmetrical (right side, 29.8%; left side, 30.1%) but not correlated with basal flow values. No significant relationship was found between velocity increase and increase in regional cerebral blood flow. This finding is probably not only due to methodological inaccuracies but may suggest that acetazolamide has an effect on the diameter of the middle cerebral artery or on the magnitude of this artery's perfusion territory. This study supports the use of acetazolamide for assessing cerebral vasoreactivity following the definition of lower limits for velocity and flow increase and for asymmetry of the response.

Endothelial dysfunction early after heart transplantation. Assessment with intravascular ultrasound and Doppler.

BACKGROUND: Allograft vasculopathy after heart transplantation is thought to represent a response to endothelial injury in the graft vessels. To assess endothelial function before the onset of anatomic disease, coronary vasomotor responses to adenosine, acetylcholine, and nitroglycerin were evaluated in transplant recipients by intravascular ultrasound imaging and Doppler flow studies. METHODS AND RESULTS: Nine patients were studied 1 year after heart transplantation. Acetylcholine provoked significant vasoconstriction to 82% of maximal coronary diameter but was associated with an increase in mean coronary blood flow from 63.1 to 204 ml/min. Coronary blood flow increased fivefold in response to adenosine, a normal response. CONCLUSIONS: The vasomotor response to acetylcholine at 1 year after heart transplantation is consistent with endothelial dysfunction in the epicardial conduit vessels. Microvascular function as judged by coronary flow reserve appears to be normal.

Does intracoronary papaverine dilate epicardial coronary arteries? Implications for the assessment of coronary flow reserve.

Intracoronary papaverine is used as a means to induce a strong and short-lasting hyperemia in several recently developed methods to measure coronary flow reserve. Changes in stenosis geometry from papaverine would influence the measured coronary flow reserve. Therefore, we investigated the influence of intracoronary papaverine on stenosis geometry with quantitative analysis of the coronary angiogram and assessed the influence of papaverine on pressure-flow characteristics of the stenosis and coronary flow reserve. The cross-sectional areas (mean +/- SD) of the stenosis increased 18% +/- 7% after papaverine. The normal proximal and distal parts of the coronary artery dilated 5% +/- 2% after papaverine. This results in a decrease of the calculated pressure drop over the stenosis varying from 20% to 30%. Coronary flow reserve of a flow-limiting epicardial stenosis is overestimated by 16% when papaverine is used to induce hyperemia. These papaverine-induced changes can nevertheless be circumvented by maximal vasodilation of the major epicardial coronary artery with 3 mg intracoronary isosorbidedinitrate prior to the investigation of the coronary flow reserve with papaverine.

[Assessment of the influence of pharmacologic substances on pressor vasomotor reflexes in anesthetized animals]. / K otsenke vliianiia farmakologicheskikh veshchestv na pressornye vazomotornye refleksy u narkotizirovannykh zhivotnykh.

Causes accounting for differing results of experiments during studies on the effects of morphine and chlordiazepoxide upon the intensity of pressor vasomotor reflexes provoked by an electric stimulation of afferent fibers in the tibial nerve were investigated in tests set up on urethan and chloralose anesthetized animals. With this purpose in view the relationship between the amplitude of the vasomotor reflexes and the intensity of electric stimulation, as well as the nature of the drugs action upon the vasomotor reflexes, depending on the stimulation parameters adopted during their registration, were studied. The intensity and the nature of changes of the pressor vasomotor reflexes are shown to depend not only on the properties of the test drugs, but also upon the intensity of electric stimulation employed in the experiment during registration of the reflexes. The most adequate procedure for investigating the effect of pharmaceutics on the intensity of vasomotor reflexes, e. g. a study into the influence exerted by drugs on the threshold of the reflexes origination, is proposed.

Quantitative thermographic assessment of inositol nicotinate therapy in Raynaud's phenomena.

The basal temperature of the hands has been measured by quantitative thermography in a group of normal controls and rheumatoid patients exhibiting Raynaud's phenomenon. The thermographic index for both the dorsum of the hand and the fingers was significantly lower in the patients with Raynaud's. Oral treatment with inositol nicotinate (Hexopal) was followed by an initial rise in the thermographic index in both areas. After the initial increase the temperature fell again but then rose after two months treatment. At nine months two subjects on continuous therapy had higher indices than the four who had discontinued therapy. It is suggested that long-term treatment with nicotinate acid derivatives may produce improvement in the peripheral circulation by a different mechanism than the transient effect detected by short-term studies.