An international, open-label, randomised trial comparing a two-step approach versus the standard three-step approach of the WHO analgesic ladder in patients with cancer.

BACKGROUND: Worldwide, cancer pain management follows the World Health Organization (WHO) three-step analgesic ladder. Using weak opioids (e.g. codeine) at step 2 is debatable with low-dose strong opioids being potentially better, particularly in low- and middle-income countries where weak opioids are expensive. We wanted to assess the efficiency, safety and cost of omitting step 2 of the WHO ladder. PATIENTS AND METHODS: We carried out an international, open-label, randomised (1 : 1) parallel group trial. Eligible patients had cancer, pain ≥4/10 on a 0-10 numerical rating scale, required at least step 1 (paracetamol) of the WHO ladder and were randomised to the control arm (weak opioid, step 2 of the WHO ladder) or the experimental arm (strong opioid, step 3). Primary outcome was time to stable pain control (3 consecutive days with pain ≤3). Secondary outcomes included distress, opioid-related side-effects and costs. The primary outcome analysis was by intention to treat and the follow-up was for 20 days. RESULTS: One hundred and fifty-three patients were randomised (76 control, 77 experimental). There was no statistically significant difference in time to stable pain control between the arms, P = 0.667 (log-rank test). The adjusted hazard ratio for the control arm was 1.03 (95% confidence interval 0.72-1.49). In the control arm, 38 patients (53%) needed to change to a strong opioid due to ineffective analgesia. The median time to change was day 6 (interquartile range 4-11). Compared to the control arm, patients in the experimental arm had less nausea (P = 0.009) and costs were less. CONCLUSION: This trial provides some evidence that the two-step approach is an alternative option for cancer pain management.

Group therapy for people with bulimia nervosa: systematic review and meta-analysis.

BACKGROUND: Approximately 25% of people with bulimia nervosa (BN) who undertake therapy are treated in groups. National guidelines do not discriminate between group and individual therapy, yet each has potential advantages and disadvantages and it is unclear how their effects compare. We therefore evaluated how group therapy for BN compares with individual therapy, no treatment, or other therapies, in terms of remission from binges and binge frequency. METHOD: We performed a systematic review and meta-analysis of randomized controlled trials of group therapies for BN, following standard guidelines. RESULTS: A total of 10 studies were included. Studies were generally small with unclear risk of bias. There was low-quality evidence of a clinically relevant advantage for group cognitive behavioural therapy (CBT) over no treatment at therapy end. Remission was more likely with group CBT versus no treatment [relative risk (RR) 0.77, 95% confidence interval (CI) 0.62-0.96]. Mean weekly binges were lower with group CBT versus no treatment (2.9 v. 6.9, standardized mean difference = -0.56, 95% CI -0.96 to -0.15). One study provided low-quality evidence that group CBT was inferior compared with individual CBT to a clinically relevant degree for remission at therapy end (RR 1.24, 95% CI 1.03-1.50); there was insufficient evidence regarding frequency of binges. CONCLUSIONS: Conclusions could only be reached for CBT. Low-quality evidence suggests that group CBT is effective compared with no treatment, but there was insufficient or very limited evidence about how group and individual CBT compared. The risk of bias and imprecise estimates of effect invite further research to refine and increase confidence in these findings.

Application of Variable Life Adjusted Display (VLAD) to risk-adjusted mortality of esophagogastric cancer surgery.

PURPOSE: In the new era of revalidation, there is an increasing need to measure surgical outcome objectively. We apply a graphical method, the Variable Life Adjusted Display (VLAD), to esophagogastric resection for malignancy. This technique charts the cumulative difference between expected and actual risk-adjusted mortality over time, allowing observation of performance trends irrespective of case-mix. METHODS: P-POSSUM was applied retrospectively to 182 consecutive patients who underwent resection for esophageal or gastric malignancy in a district general hospital. The primary outcome measured was 30-day mortality. RESULTS: A total of 168 patients were eligible for inclusion, with a median age of 68 years. The overall 30-day mortality rate was 4.2% compared with 7.1% as predicted by P-POSSUM. The resulting VLAD plot demonstrates an upward trend of better than predicted surgical performance. CONCLUSIONS: VLAD has been hereby applied to esophagogastric surgery and has graphically demonstrated risk-adjusted trends in a single general surgeon's performance. For qualitative comparative purposes, including recertification, VLAD is judged to be a simple, directly interpretable, and useful technique for monitoring surgical performance.

Reprinted article "The fate of the claudicant--a prospective study of 1969 claudicants".

A prospective study of 1969 patients with intermittent claudication receiving placebo medication for a minimum of 1 year is reported. Patients were carefully monitored and only four patients were lost to follow-up. Annual mortality was 4.3%. Thirty-six patients developed a definite myocardial infarction, 27 a major stroke, 32 required a major amputation and 111 required surgical or radiological intervention for deteriorating ischaemia of the leg. The entry characteristics of the patients were analysed as a predictor of serious cardiovascular events. The most sensitive predictors of total mortality were age, history of coronary heart disease and an ankle/arm pressure ratio below 0.5. Of the laboratory measurements performed only the initial white cell count was a significant predictor of myocardial infarction, stroke and vascular deaths.

Randomised comparison of uterine artery embolisation (UAE) with surgical treatment in patients with symptomatic uterine fibroids (REST trial): 5-year results.

OBJECTIVE: To compare the long-term results of uterine artery embolisation (UAE) with surgery for women with symptomatic uterine fibroids. DESIGN: Pragmatic, open, multicentre, randomised trial. SETTING: Twenty-seven participating UK secondary care centres. SAMPLE: Women aged ≥18 years with symptomatic fibroids who were considered to justify surgical treatment. METHODS: In total, 157 women were randomised (in a 2:1 ratio): 106 to UAE and 51 to surgery (hysterectomy 42; myomectomy nine). MAIN OUTCOME MEASURES: Quality of life at 5 years, as assessed by the Short Form General Health Survey (SF-36). Secondary measures included complications, adverse events and the need for further intervention. RESULTS: There were no significant differences between groups in any of the eight components of the SF-36 scores at 5 years (minimum P = 0.45). Symptom score reduction and patient satisfaction with either treatment was very high, with no group difference. Rates of adverse events were similar in both groups (19% embolization and 25% surgery; P = 0.40). The 5-year intervention rate for treatment failure or complications was 32% (UAE arm) and 4% (surgery arm), respectively. The initial cost benefit of UAE over surgery at 12 months was substantially reduced because of subsequent interventions, with treatments being cost neutral at 5 years. CONCLUSIONS: We have found that UAE is a satisfactory alternative to surgery for fibroids. The less invasive nature of UAE needs to be balanced against the need for re-intervention in almost a third of patients. The choice should lie with the informed patient.

The effects of uterine artery embolisation and surgical treatment on ovarian function in women with uterine fibroids.

OBJECTIVE: The aim of this study was to evaluate and compare both ovarian function and menstrual characteristics following uterine artery embolisation (UAE) and surgery. DESIGN: Subgroup of women from a randomised controlled trial. SETTING: Gynaecology and radiology units in Scotland, UK. POPULATION: Ninety-six women from the randomised controlled trial comparing embolisation with surgery as a treatment for fibroids (REST), which recruited 157 patients (106 UAE; 51 surgery). METHODS: Seventy-three women undergoing UAE and 23 women undergoing surgery (with ovarian conservation) had serum follicle-stimulating hormone (FSH) measurements taken on day 3 of the menstrual cycle prior to treatment, and at 6 and 12 months post-treatment. Data on menstrual cycle characteristics was also collected. MAIN OUTCOME MEASURES: Ovarian failure, as defined by an FSH level of >40 iu/l, and change in duration of menses and length of menstrual cycle. RESULTS: There was no significant difference in the rate of ovarian failure at 12 months between UAE (11%) and surgical patients (18%) (P = 0.44). This finding was not influenced by age. The mean duration of menstrual flow decreased significantly, from baseline to 12 months, by 1.7 days (SD 3.8), (95% CI 0.8-2.6). There was no statistically significant change in mean cycle length at 12 months (0.7 days [SD 4.9]; 95% CI [-0.5, 1.9]). CONCLUSIONS: There is no evidence for UAE accelerating a deterioration in ovarian function at 1 year, when compared with surgery. UAE is associated with a decrease in the duration of menstrual flow at 1 year.

Forced convective head cooling device reduces human cross-sectional brain temperature measured by magnetic resonance: a non-randomized healthy volunteer pilot study.

BACKGROUND: This pilot study in five healthy adult humans forms the pre-clinical assessment of the effect of a forced convective head cooling device on intracranial temperature, measured non-invasively by magnetic resonance spectroscopy (MRS). METHODS: After a 10 min baseline with no cooling, subjects received 30 min of head cooling followed by 30 min of head and neck cooling via a hood and neck collar delivering 14.5 degrees C air at 42.5 litre s(-1). Over baseline and at the end of both cooling periods, MRS was performed, using chemical shift imaging, to measure brain temperature simultaneously across a single slice of brain at the level of the basal ganglia. Oesophageal temperature was measured continuously using a fluoroptic thermometer. RESULTS: MRS brain temperature was calculated for baseline and the last 10 min of each cooling period. The net brain temperature reduction with head cooling was 0.45 degrees C (SD 0.23 degrees C, P=0.01, 95% CI 0.17-0.74 degrees C) and with head and neck cooling was 0.37 degrees C (SD 0.30 degrees C, P=0.049, 95% CI 0.00-0.74 degrees C). The equivalent net reductions in oesophageal temperature were 0.16 degrees C (SD 0.04 degrees C) and 0.36 degrees C (SD 0.12 degrees C). Baseline-corrected brain temperature gradients from outer through intermediate to core voxels were not significant for either head cooling (P=0.43) or head and neck cooling (P=0.07), indicating that there was not a significant reduction in cooling with progressive depth into the brain. CONCLUSIONS: Convective head cooling reduced MRS brain temperature and core brain was cooled.

Ankle brachial index combined with Framingham Risk Score to predict cardiovascular events and mortality: a meta-analysis.

CONTEXT: Prediction models to identify healthy individuals at high risk of cardiovascular disease have limited accuracy. A low ankle brachial index (ABI) is an indicator of atherosclerosis and has the potential to improve prediction. OBJECTIVE: To determine if the ABI provides information on the risk of cardiovascular events and mortality independently of the Framingham risk score (FRS) and can improve risk prediction. DATA SOURCES: Relevant studies were identified. A search of MEDLINE (1950 to February 2008) and EMBASE (1980 to February 2008) was conducted using common text words for the term ankle brachial index combined with text words and Medical Subject Headings to capture prospective cohort designs. Review of reference lists and conference proceedings, and correspondence with experts was conducted to identify additional published and unpublished studies. STUDY SELECTION: Studies were included if participants were derived from a general population, ABI was measured at baseline, and individuals were followed up to detect total and cardiovascular mortality. DATA EXTRACTION: Prespecified data on individuals in each selected study were extracted into a combined data set and an individual participant data meta-analysis was conducted on individuals who had no previous history of coronary heart disease. RESULTS: Sixteen population cohort studies fulfilling the inclusion criteria were included. During 480,325 person-years of follow-up of 24,955 men and 23,339 women, the risk of death by ABI had a reverse J-shaped distribution with a normal (low risk) ABI of 1.11 to 1.40. The 10-year cardiovascular mortality in men with a low ABI (< or = 0.90) was 18.7% (95% confidence interval [CI], 13.3%-24.1%) and with normal ABI (1.11-1.40) was 4.4% (95% CI, 3.2%-5.7%) (hazard ratio [HR], 4.2; 95% CI, 3.3-5.4). Corresponding mortalities in women were 12.6% (95% CI, 6.2%-19.0%) and 4.1% (95% CI, 2.2%-6.1%) (HR, 3.5; 95% CI, 2.4-5.1). The HRs remained elevated after adjusting for FRS (2.9 [95% CI, 2.3-3.7] for men vs 3.0 [95% CI, 2.0-4.4] for women). A low ABI (< or = 0.90) was associated with approximately twice the 10-year total mortality, cardiovascular mortality, and major coronary event rate compared with the overall rate in each FRS category. Inclusion of the ABI in cardiovascular risk stratification using the FRS would result in reclassification of the risk category and modification of treatment recommendations in approximately 19% of men and 36% of women. CONCLUSION: Measurement of the ABI may improve the accuracy of cardiovascular risk prediction beyond the FRS.

Risk of mortality and cardiovascular disease associated with the ankle-brachial index: Systematic review.

OBJECTIVE: To determine the strength and consistency with which a low ankle brachial pressure index (ABI), measured in the general population, is associated with an increased risk of subsequent death and/or cardiovascular events. DESIGN: Systematic review. DATA SOURCES: Medline, Embase, reference lists and grey literature were searched; studies known to experts were also retrieved. MAIN OUTCOME MEASURES: All cause mortality, fatal and non-fatal coronary heart disease and stroke. REVIEW METHODS: Longitudinal studies in which participants were representative of the general population (all ages, either sex) and which used any standard method for measurement and calculation of the ABI. Studies in which participants were selected according to presence of pre-existing disease or were post intervention (e.g. angioplasty or peripheral arterial grafting) were excluded. RESULTS: 11 studies comprising 44,590 subjects from six different countries were included. Despite clinical heterogeneity between studies, the findings were remarkably consistent in demonstrating an increased risk of clinical cardiovascular disease associated with a low ABI. A low ABI (<0.9) was associated with an increased risk of subsequent all cause mortality (pooled RR 1.60, 95% CI 1.32-1.95), cardiovascular mortality (pooled RR 1.96, 95% CI 1.46-2.64), coronary heart disease (pooled RR 1.45, 95% CI 1.08-1.93) and stroke (pooled RR 1.35, 95% CI 1.10-1.65) after adjustment for age, sex, conventional cardiovascular risk factors and prevalent cardiovascular disease. CONCLUSIONS: The ABI may help to identify asymptomatic individuals in the general population who are at increased risk of subsequent cardiovascular events. Evaluation is now required of the potential of incorporating ABI measurement into cardiovascular prevention programmes.

The association between APOE epsilon4, age and outcome after head injury: a prospective cohort study.

Previous preliminary studies have suggested that possession of the APOE epsilon4 allele is associated with a poor outcome after head injury. This study was designed to confirm and extend those observations in a larger study with examination of additional variables. We prospectively identified admissions to a Neurosurgical Unit for head injury, collected demographic and clinical data, determined APOE genotypes and obtained follow-up information at 6 months. A total of 1094 subjects were enrolled (age range: 0-93 years, mean 37 years). Outcome was assessed using the Glasgow Outcome Scale. There was no overall association between APOE genotype and outcome, with 36% of APOE epsilon4 carriers having an unfavourable outcome compared with 33% of non-carriers of APOE epsilon4. However, there was evidence of an interaction between age and APOE genotype on outcome (P = 0.007) such that possession of APOE epsilon4 reduced the prospect of a favourable outcome in children and young adults. The influence of APOE genotype in younger patients after head injury can be expressed as, at age <15 years, carriage of APOE epsilon4 being equivalent to ageing by 25 years. This finding is consistent with experimental data suggesting that the effect of APOE genotype on outcome after head injury may be expressed through the processes of repair and recovery.

Myocardial viability as a determinant of the ejection fraction response to carvedilol in patients with heart failure (CHRISTMAS trial): randomised controlled trial.

BACKGROUND: The improvement in left-ventricular ejection fraction (LVEF) in response to beta blockers is heterogeneous in patients with heart failure due to ischaemic heart disease, possibly indicating variations in the myocardial substrate underlying left-ventricular dysfunction. We investigated whether improvement in LVEF was associated with the volume of hibernating myocardium (viable myocardium with contractile failure). METHODS: We did a double-blind, randomised trial to compare placebo and carvedilol for 6 months in individuals with stable, chronic heart failure due to ischaemic left-ventricular systolic dysfunction. We enrolled 489 patients, of whom 387 were randomised. Patients were designated hibernators or non-hibernators according to the volume of hibernating myocardium. The primary endpoint was change in LVEF, measured by radionuclide ventriculography, in hibernators versus non-hibernators, on carvedilol compared with placebo. Analysis was by intention to treat. RESULTS: 82 patients dropped out of the study because of adverse events, withdrawal of consent, or failure to complete the investigation. Thus, 305 (79%) were analysed. LVEF was unchanged with placebo (mean change -0.4 [SE 0.9] and -0.4 [0.8] for non-hibernators and hibernators, respectively) but increased with carvedilol (2.5 [0.9] and 3.2 [0.8], respectively; p<0.0001 compared with baseline). Mean placebo-subtracted change in LVEF was 3.2% (95% CI 1.8-4.7; p=0.0001) overall, and 2.9% (0.7-5.1; p=0.011) and 3.6% (1.7-5.4; p=0.0002) in non-hibernators and hibernators, respectively. Effect of hibernator status on response of LVEF to carvedilol was not significant (0.7 [-2.2 to 3.5]; p=0.644). However, patients with more myocardium affected by hibernation or by hibernation and ischaemia had a greater increase in LVEF on carvedilol (p=0.0002 and p=0.009, respectively). INTERPRETATION: Some of the effect of carvedilol on LVEF might be mediated by improved function of hibernating or ischaemic myocardium, or both. Medical treatment might be an important adjunct or alternative to revascularisation for patients with hibernating myocardium.

Angiotensin-converting enzyme inhibitors after myocardial infarction: indications and timing.

A number of major studies have examined the impact of angiotensin-converting enzyme inhibitors on mortality in patients with ischemic heart disease. However, in these studies, selection of patients, choice of agent and timing of treatment after myocardial infarction have differed. In the Second Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS II), all patients, unless hypotensive, were treated immediately after thrombolysis with placebo or intravenous enalaprilat followed by oral therapy. In contrast, in the Survival and Ventricular Enlargement (SAVE) study, patients were selected with a reduced radionuclide ejection fraction and without overt ongoing ischemia. Despite these different approaches, both studies were based on the rationale that angiotensin-converting enzyme inhibition would beneficially affect infarct expansion and subsequent remodeling. The SAVE study reported a significant reduction in mortality rate (19% risk reduction, 95% confidence interval [CI] 3% to 32%) over an average follow-up period of 42 months, but with no observable impact on mortality rate until almost 1 year into treatment. The CONSENSUS II trial closed prematurely, with no benefit (a 10% increase in risk, 95% CI 7% reduction to 29% increase) apparent from enalapril after 6 months of follow-up. The recently reported but unpublished findings of Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico (GISSI-3) and the Fourth International Study of Infarct Survival (ISIS-4) indicate a small benefit from early (within 24 h) short-term (4 to 6 weeks) treatment of all patients, unless hypotensive, after a myocardial infarction.(ABSTRACT TRUNCATED AT 250 WORDS)

Secondary hypertension in a blood pressure clinic.

The prevalence, reversibility, and mortality of secondary hypertension among 3783 patients with moderately severe nonmalignant hypertension attending the Glasgow (Scotland) Blood Pressure Clinic were assessed. Underlying causes of hypertension were found in 297 patients (7.9%). Eighty-seven patients (2.3%) were considered to have a potentially reversible cause for their hypertension, including the oral contraceptive pill (38 patients), renovascular disease (27 patients), and primary hyperaldosteronism (ten patients), but of these only 33 patients (0.9% of total clinic population) were cured by specific intervention. Two hundred ten patients (5.6%) had irreversible renal parenchymal disease and significantly higher mortality than men and women with other causes of hypertension. Excess deaths in the renal group were attributed to renal failure (International Classification of Diseases [ICD] 580 to 589) and vascular causes (ICD 390 to 458) but not to cancer (ICD 140 to 208; 235 to 239) or other nonvascular disease. These results suggest that investigation of hypertension for an underlying cause will reveal a small number of patients with treatable disorders, of whom only a few will be cured by specific intervention, and a moderate number with irreversible disease who are at high risk of myocardial infarction and stroke.

Elevated Baseline C-Reactive Protein as a Predictor of Outcome After Aneurysmal Subarachnoid Hemorrhage: Data From the Simvastatin in Aneurysmal Subarachnoid Hemorrhage (STASH) Trial.

BACKGROUND: There remains a proportion of patients with unfavorable outcomes after aneurysmal subarachnoid hemorrhage, of particular relevance in those who present with a good clinical grade. A forewarning of those at risk provides an opportunity towards more intensive monitoring, investigation, and prophylactic treatment prior to the clinical manifestation of advancing cerebral injury. OBJECTIVE: To assess whether biochemical markers sampled in the first days after the initial hemorrhage can predict poor outcome. METHODS: All patients recruited to the multicenter Simvastatin in Aneurysmal Hemorrhage Trial (STASH) were included. Baseline biochemical profiles were taken between time of ictus and day 4 post ictus. The t-test compared outcomes, and a backwards stepwise binary logistic regression was used to determine the factors providing independent prediction of an unfavorable outcome. RESULTS: Baseline biochemical data were obtained in approximately 91% of cases from 803 patients. On admission, 73% of patients were good grade (World Federation of Neurological Surgeons grades 1 or 2); however, 84% had a Fisher grade 3 or 4 on computed tomographic scan. For patients presenting with good grade on admission, higher levels of C-reactive protein, glucose, and white blood cells and lower levels of hematocrit, albumin, and hemoglobin were associated with poor outcome at discharge. C-reactive protein was found to be an independent predictor of outcome for patients presenting in good grade. CONCLUSION: Early recording of C-reactive protein may prove useful in detecting those good grade patients who are at greater risk of clinical deterioration and poor outcome.

Similarity of idiopathic aldosteronism and essential hypertension. A statistical comparison.

There is clinical, biochemical, and pathological evidence that idiopathic aldosteronism is part of a continuum which includes low-renin and normal-renin essential hypertension. In a retrospective statistical study, 89 patients with essential hypertension have been compared with 22 cases of idiopathic aldosteronism and 34 cases of aldosterone-secreting adrenal adenomas. Measurements of serum sodium, potassium, bicarbonate, and plasma angiotensin II concentrations and estimates of exchangeable sodium and potassium were obtained for individual patients. By using various combinations of these biochemical variables, a statistic, the Mahalanobis distance, was described for each of the three populations, essential hypertension, idiopathic aldosteronism, and adrenal adenomas. For each combination of variables, the distribution of the idiopathic aldosteronism group resembled that of the essential hypertension group more closely than that of the aldosterone-secreting adrenal adenoma group. Thus, the use of this statistical technique provides further evidence of the similarity of essential hypertension and idiopathic aldosteronism.

Low blood pressure in Down's syndrome, A link with Alzheimer's disease?

Low blood pressure is reported in Down's syndrome (DS). To assess this and determine whether low pressure results from the disease or from long-term residence in hospital, we measured blood pressure with a random-zero sphygmomanometer in three groups of patients: 52 DS inpatients, 62 DS outpatients, and 60 outpatients with other forms of mental handicap. Relative to normal reference populations, blood pressure was low in both DS inpatients (systolic, score -33 mm Hg, P < .0001) and DS outpatients (-25 mm Hg, P < .0001). It was normal in non-DS outpatients (-4.0 mm Hg, P = .3). Blood pressure rose normally with age in the non-DS group but not in the DS group. We conclude that blood pressure is low in DS and that this is a feature of the disease rather than of the protected environment in which patients live. A mechanism related to trisomy 21 is likely, and there may be a link with Alzheimer's disease (AD) because blood pressure is also low in Alzheimer's and a high proportion of Ds patients develop this disease. If, as is likely, blood pressure is lowered in Alzheimer's by the neuropathy, the same neuropathy developing early in DS may also reduce blood pressure.

Haemostatic abnormalities and outcome in patients with operable breast cancer.

The predictive value for cancer recurrence of five measurements of haemostatic activity was studied in 89 patients with operable breast cancer. Neither preoperative nor sequential measurements up to 9 months postoperatively of fibrinopeptide A, fibrin fragment B beta 15-42, fibrinogen and serum fibrin(ogen) degradation products nor the fibrin plate lysis assay correlated with early recurrent disease. B beta 15-42 values were higher preoperatively in patients with oestrogen receptor positive tumours (P = 0.017). Mean B beta 15-42 values rose postoperatively (P = 0.003), largely because of an increase in patients with oestrogen receptor negative tumours.

Long-term prognostic significance of thymidine labelling index in primary breast cancer.

Tumour growth rates, as measured by incorporation of tritiated thymidine, have been reported as being of prognostic importance in breast cancer. We have measured the thymidine labelling index (TLI) of 185 early breast cancers, followed-up for a minimum of 8 years. Above median TLI was associated with higher tumour grade, but not with other prognostic factors. TLI was not predictive of survival in either univariate or multivariate analysis. The inter- and intra-observer reproducibilities of TLI measurements were poor, which may be a factor limiting its usefulness as a prognostic indicator in breast cancer.

International study of ketanserin in Raynaud's phenomenon.

PURPOSE: The effects of ketanserin on primary or secondary Raynaud's phenomenon due to connective tissue disease were studied in a large, international group of patients. PATIENTS AND METHODS: The study population consisted of 222 patients from 10 countries. After a run-in period of one month of placebo therapy, patients were randomly assigned in a double-blind manner to receive ketanserin 40 mg three times daily (n = 113) or placebo (n = 109) for three months. Total finger blood flow was measured in 41 patients in a warm and cool room before and during treatment. Vasospastic episodes were assessed by diaries and global evaluations. RESULTS: A significant reduction of 34% in frequency of episodes occurred with ketanserin, compared to 18% with placebo (p = 0.011). There was a 1% reduction in duration of episodes with ketanserin therapy, compared to a 2% increase with placebo therapy, but this finding was not statistically significant (p = 0.29). No difference was observed in severity of attacks. Global evaluations by investigators (p = 0.03) and patients (p less than 0.01) showed an overall benefit with ketanserin compared to that seen with placebo. Patients with primary or secondary Raynaud's phenomenon responded similarly to treatment. No changes in total finger blood flow were found. CONCLUSION: Ketanserin significantly improves the subjective symptoms of patients with primary or secondary Raynaud's phenomenon and is an appropriate agent to use in this disease when conservative measures fail.

Enalapril in treatment of hypertension with renal artery stenosis. Changes in blood pressure, renin, angiotensin I and II, renal function, and body composition.

The converting enzyme inhibitor enalapril, in single daily doses of 10 to 40 mg, was given to 20 hypertensive patients with renal artery stenosis. The decrease in blood pressure six hours after the first dose of enalapril was significantly related to the pretreatment plasma concentrations of active renin and angiotensin II, and to the concurrent decrease in angiotensin II. Blood pressure decreased further with continued treatment; the long-term decrease was not significantly related to pretreatment plasma renin or angiotensin II levels. At three months, 24 hours after the last dose of enalapril, blood pressure, plasma angiotensin II, and converting enzyme activity remained low, and active renin and angiotensin I high; six hours after dosing, angiotensin II had, however, decreased further. The increase in active renin during long-term treatment was proportionately greater than the increase in angiotensin I; this probably reflects the diminution in renin substrate that occurs with converting enzyme inhibition. Long-term enalapril treatment increased renin secretion by more than 10-fold, and renal venous and peripheral plasma renin concentration by more than 20-fold; however, the mean renal venous renin ratio was not changed. Enalapril caused a reduction in effective renal plasma flow via the affected kidney but a marked and consistent increase on the contralateral side, where renal vascular resistance decreased. The overall increase in effective renal plasma flow was significantly related to the decrease in angiotensin II. Overall glomerular filtration rate was lowered, and serum creatinine and urea increased. Enalapril alone caused a long-term reduction in exchangeable sodium, with slight but distinct increases in serum potassium. In five patients with bilateral renal artery lesions, enalapril given alone for three months did not cause renal function to deteriorate. Enalapril was well tolerated and provided effective long-term control of hypertension; only two of the 20 patients studied required concomitant diuretic treatment.