Dual Antiplatelet Therapy Prior to Expedited Carotid Surgery Reduces Recurrent Events Prior to Surgery without Significantly Increasing Peri-operative Bleeding Complications.

OBJECTIVE: A daily Rapid-Access TIA Clinic was introduced in 2008, where symptomatic patients were started on 75 mg aspirin + 40 mg simvastatin by the referring doctor, before attending the clinic. Following clinic assessment, patients with 50-99% stenoses were transferred to the vascular unit for carotid endarterectomy (CEA). In two audits (n = 212 patients), the median delay from transfer to the vascular unit to undergoing CEA was 3 days, during which time 28 patients (13%) suffered recurrent neurological events. It was hypothesized that early introduction of dual antiplatelet therapy (by adding clopidogrel 75 mg once parenchymal haemorrhage was excluded in the TIA clinic) might significantly reduce recurrent events between transfer to the surgical unit and undergoing CEA. METHODS: Prospective audit in 100 consecutive, recently symptomatic patients receiving dual antiplatelet therapy. Endpoints were: prevalence of recurrent events between transfer from the TIA clinic and undergoing CEA; rates of spontaneous embolization prior to undergoing CEA; and prevalence of haemorrhagic complications RESULTS: The median delay from symptom to CEA was 8 days (IQR 5-15). The median delay between transfer from the TIA clinic to CEA was 3 days (IQR 2-5), during which time three patients (3%) suffered recurrent TIAs. This represents a fivefold reduction compared with previous audit data (OR 4.9, 95% CI 1.5-16.6, p = .01) and was matched by a fourfold reduction in the prevalence of spontaneous embolization from 39/189 (21%) previously to 5/83 (5%) in the current audit (OR 4.1, 95% CI 1.5-10.7, p = .0047). The 30-day death/stroke rate was 1%. There were three haemorrhagic complications: stroke caused by haemorrhagic transformation of an infarct; exploration for neck haematoma; and debridement and skin grafting for spontaneous shin haematoma. CONCLUSION: Early introduction of dual antiplatelet therapy was associated with a significant reduction in recurrent neurological events and spontaneous embolization prior to CEA, without incurring a significant increase in major peri-operative bleeding complications.

Lipid profiles for nevirapine vs. atazanavir/ritonavir, both combined with tenofovir disoproxil fumarate and emtricitabine over 48 weeks, in treatment-naïve HIV-1-infected patients (the ARTEN study).

OBJECTIVES: Dyslipidaemic effects of antiretrovirals (ARVs) may contribute to increased cardiovascular risk (CR) in HIV-1-infected patients. The ARTEN (atazanavir/ritonavir on a background of tenofovir and emtricitabine vs. nevirapine on the same background, in naïve HIV-1-infected patients) study compared prospectively ritonavir-boosted atazanavir (ATZ/r) 300 mg/100 mg once daily (qd) with immediate release nevirapine (NVP) 200 mg twice daily or 400 mg qd, each combined with fixed-dose tenofovir 300 mg/emtricitabine 200 mg qd in 569 ARV-naïve HIV-1-infected patients. Lipid profiles and CR from baseline to week 48 are reported. METHODS: Changes from baseline to week 48 in fasting plasma levels of total cholesterol (TC), high-density lipoprotein cholesterol (HDL-c), low-density lipoprotein cholesterol (LDL-c), TC:HDL-c ratio, apolipoprotein A1 (ApoA1), apolipoprotein B (ApoB) and total triglycerides (TG) were determined. The Framingham algorithm was used to estimate CR. Analysis was by intention-to-treat (ITT) with last observation carried forward (LOCF) for missing data. RESULTS: At week 48, NVP treatment resulted in significantly greater mean increases from baseline in TC (24.4 vs. 19.6 mg/dL; P=0.038), HDL-c (9.7 vs. 3.9 mg/dL; P<0.0001), LDL-c (15.0 vs. 10.4 mg/dL; P=0.011) and ApoA1 (0.18 vs. 0.08 g/L; P<0.0001) but not ApoB (0.02 vs. 0.02 g/L) compared with ATZ/r treatment. ATZ/r use was associated with higher mean TG increases (27.80 vs. 0.02 mg/dL; P=0.0001). Significantly greater mean decreases in TC:HDL-c and ApoB/ApoA ratios were observed with NVP vs. ATZ/r (P=0.0001 and P=0.008, respectively). Framingham CR scores were low and comparable between the arms, with only a slight mean increase from baseline to week 48 of 0.70 for NVP and 0.80 for ATZ/r [difference -0.069; 95% confidence interval (CI) -0.61 to 0.46; P=0.80]. CONCLUSIONS: In ARV-naïve patients with low CR at the outset, NVP showed a potentially less atherogenic lipid profile compared with ATZ/r.

Alcohol consumption as a risk factor for high blood pressure. Munich Blood Pressure Study.

The Munich Blood Pressure Study (MBS), a 1980-81 cross-sectional study (with follow-up) of a random sample of 3198 Munich citizens aged 30-69 years (response rate 69%), revealed hypertensive blood pressure (BP) values in 17.7% of men and 10.7% of women (WHO criteria). One of the main goals of the MBS was to search for social, behavioral, and environmental risk factors for hypertension. The relationship between BP and five possible risk factors--alcohol consumption (g/day), cigarette smoking, oral contraceptive use, years of education, obesity (BMI)--has been examined. The major emphasis of this report is the relationship of alcohol consumption to BP. Multiple linear and logistic regression analyses were run controlling for both age and sex. All second- and third-order interactions between the independent variables were tested during a backward-stepping procedure. Alcohol consumption appeared as a significant main effect in many of the analyses. The coefficient of the alcohol variable ranged from 0.02 to 0.06 for men and women in the separate linear regression analyses for systolic and diastolic BP. Thus, for example, according to the model, the daily consumption of 1 liter of beer (40 g alcohol) may cause an increase in diastolic BP in women of 2.4 mm Hg.

Short report: ramipril and hydrochlorothiazide combination therapy in hypertension: a clinical trial of factorial design. The East Germany Collaborative Trial Group.

OBJECTIVE: To identify appropriate dosages of ramipril and hydrochlorothiazide (HCT) when given in combination once a day for the treatment of essential hypertension. DESIGN: A 2- or 4-week placebo run-in followed by 6-week, double-blind, parallel-group phase: 4 x 3 factorial (2.5, 5 and 10 mg ramipril; 12.5 and 25 mg HCT; all six combinations; placebo). SETTING: Office practice (21 centres). PATIENTS AND PARTICIPANTS: Patients with mild-to-moderate essential hypertension (World Health Organization stage I-II; supine diastolic blood pressure 100-115 mmHg in last 2 weeks of run-in): 581 enrolled, 534 randomly assigned to double-blind therapy and 517 completed. MAIN OUTCOME MEASURES: Reduction in supine and standing blood pressure. RESULTS: In pairwise comparisons, the combinations of 5 mg ramipril with 12.5 and 25 mg HCT and 10 mg ramipril with 12.5 mg HCT consistently produced significantly greater blood pressure reductions than their respective components. Response surface analyses were performed, and a stairstep model was constructed to characterize the shape of the dose-response surface. The combinations involving 5 and 10 mg ramipril with 12.5 and 25 mg HCT were again more effective than their components. Withdrawals and adverse effects were minimal for all treatments. A large drop in serum potassium was observed on 25 mg HCT, but not on combination therapy. Addition of ramipril appeared to reduce the hyperuricaemic effect of HCT. CONCLUSIONS: Several dosage combinations of ramipril plus HCT produced significantly greater blood pressure reductions than the monotherapies at the same dosages. Overall, the combination of 5 mg ramipril and 25 mg HCT gave the best mean reduction. Combination therapy with ramipril plus HCT was safe and effective for patients with mild-to-moderate essential hypertension.

Tacrolimus induces increased expression of transforming growth factor-beta1 in mammalian lymphoid as well as nonlymphoid cells.

BACKGROUND: We and others have reported that cyclosporine (CsA) induces increased expression of transforming growth factor-beta1 (TGF-beta1) in vitro as well as in vivo. In view of similarities between tacrolimus and CsA with respect to immunosuppressive mechanisms, we determined whether tacrolimus, in a fashion similar to CsA, induces TGF-beta1 hyperexpression in mammalian cells. METHODS: We studied the induction of TGF-beta1 mRNA by tacrolimus using reverse transcription-polymerase chain reaction and Northern blot analysis in normal human T cells and A-549 cells (human lung adenocarcinoma cell line), a cell line used to study the biology of TGF-beta and the induction of TGF-beta1 by CsA. We also measured the induction of TGF-beta1 protein by tacrolimus in activated human T cells, peripheral blood mononuclear cells, and A-549 cells, using sandwich enzyme-linked immunosorbent assay. RESULTS: A significant increase in the TGF-beta1 mRNA expression was observed after treatment of T cells or A-549 cells. Tacrolimus treatment resulted also in heightened production of TGF-beta1 protein by activated T cells, A-549 cells, or peripheral blood mononuclear cells activated with anti-CD3, phytohemagglutinin, and concanavalin A. CONCLUSIONS: Our observations that tacrolimus stimulates TGF-beta1 hyperexpression in mammalian cells suggest a unifying mechanism for the immunosuppressive as well as nephrotoxic properties of tacrolimus, as the multifunctional TGF-beta1 is a potent immunosuppressive and fibrogenic cytokine.

Transforming growth factor (TGF)-beta mimics and anti-TGF-beta antibody abrogates the in vivo effects of cyclosporine: demonstration of a direct role of TGF-beta in immunosuppression and nephrotoxicity of cyclosporine.

BACKGROUND: Cyclosporine (CsA) has been shown to induce the expression of transforming growth factor (TGF)-beta both in vitro and in vivo. It is hypothesized that the efficacy as well as the side effects of CsA are mediated by TGF-beta. This study was planned to investigate whether anti-TGF-beta mitigated and TGF-beta reproduced the in vivo effects of CsA to directly prove this hypothesis. METHODS: B6AF1 (H2b/k.d) mice were divided into groups and received the following: CsA, vehicle (olive oil), CsA + anti-TGF-beta1 antibody, TGF-beta1, or vehicle phosphate-buffered saline/bovine serum albumin. All studies were carried out at 10 and 28 days after the last day of CsA administration with the exception of the exogenous TGF-beta experiments, which were performed 5 days after exogenous TGF-beta administration. The efficacy was studied by the anti-CD3-induced ex vivo proliferation of splenocytes measured by [3H]thymidine uptake; TGF-beta protein levels were quantified by ELISA. TGF-beta, collagen, and fibronectin gene expression was studied using reverse transcriptase-polymerase chain reaction, and histopathological analysis was made on periodic acid-Schiff- and trichrome C-stained thin kidney sections. RESULTS: CsA treatment resulted in decreased ex vivo proliferation of splenocytes, an increase in TGF-beta protein in the sera, and renal histopathological changes including tubular swelling, vacuolization, thrombotic microangiopathy, and increased expression of TGF-beta, collagen and fibronectin genes. All of these findings were blocked by anti-TGF-beta antibody. CONCLUSION: The study demonstrates the in vivo modulation of the effects of CsA by manipulating TGF-beta levels and suggests that TGF-beta at least in part mediates CsA's beneficial and detrimental effects.

A double-blind study to compare the efficacy, tolerance and safety of two doses of the angiotensin converting enzyme inhibitor ramipril with placebo.

In a randomized, double-blind trial, 2 doses of ramipril (2.5 and 5 mg once daily) were compared with placebo in patients with mild to moderate essential hypertension. A 2-week placebo run-in phase was followed by 4 weeks of treatment. Eighty-six patients entered the study and 17 withdrew during the course of the study. Both doses of ramipril appeared to be more effective than placebo in reducing blood pressure, but significant differences between 2.5 mg of ramipril and placebo were not found in any statistical analyses. In the endpoint analyses (taking the last measurement from each patient), the patients receiving 5 mg of ramipril had significantly larger decreases in blood pressure than the patients receiving placebo (t tests: standing systolic, p less than 0.001; supine diastolic, p less than 0.05; standing diastolic, p less than 0.05) and also than the patients receiving 2.5 mg of ramipril (standing systolic, p less than 0.05). It appears from the results of this study that the minimum effective dosage of ramipril is 5 mg once daily. No clinically relevant side effects or clinically relevant changes in laboratory values were observed.

Oral contraceptive use and blood pressure in a German metropolitan population.

The relationship between blood pressure (BP) and oral contraceptive (OC) use in women has been examined with the data from the Munich Blood Pressure Study (MBS), a cross-sectional study with follow-up of a random sample of 3198 Munich citizens aged 30-69 (response rate 69.3%). Multiple linear and logistic regression analyses were run with BP as the dependent variable and age, OC use, obesity, alcohol consumption, and smoking habit as the independent variables. All second and third order interactions between the independent variables were tested during a backward stepping procedure. OC use appeared as a significant main effect in most of the analyses. The coefficient of the OC variable was about 3 in the linear regression analyses for both systolic BP and diastolic BP, indicating an increase of about 3 mmHg in the systolic and diastolic BP of the OC users. An analysis of the change in BP after one year in relation to change in OC user status has also been made. It was observed that women ceasing to use OC had a clear decrease in BP while those starting to use OC had on average an increase in BP.

PIP: A random sample of 3198 persons aged 30-69, as part of the Munich Blood Pressure Study, revealed that oral contraceptive use raises blood pressure. Data were collected from December 1980 to May 1981, and from January to March 1982, on the same subjects. Each participant was interviewed about risk factors for about 30 minutes in a sitting position, and his pressure measured 3 times afterward with the Hawksley Random Zero sphygmomanometer. There were 113 women using pills, 32 different brands. Multiple linear and logistic regression analyses were run with blood pressure as the dependent variable, and age, pill use, obesity, alcohol consumption, and smoking habit as the independent variables. Pill use appeared as a significant main effect in most of the analyses. Based on the coefficient of the pill variable in the linear regression, an increase of about 3 mm Hg in both systolic and diastolic pressures was demonstrated. It was observed that women stopping oral contraception had a clear decrease of 7.2 mm Hg systolic, and 2.8 mm Hg diastolic pressure, and those beginning oral contraception appeared to have an increase in pressure, if the results were adjusted for regression toward the mean. Even a slight increase of 3 or 4 mm Hg in blood pressure, when added to other risk factors such as obesity, smoking, and age, may increase the overall risk for cardiovascular disease considerably.

The stability of the symptom groupings in the Inpatient Multidimensional Psychiatric Scale (IMPS).

A full set of data has been gathered on admission of 1654 inpatients and included information on all 90 items from the Inpatient Multidimensional Psychiatric Scale (IMPS). The sample was divided into two by means of an odd-even split and principal component analyses with Varimax rotation as well as Ward hierarchical cluster analyses of symptoms were run on both subsamples. Comparisons of results were than made between the two subsamples, between the two methods of analysis, and with the studies of Lorr and Klett and Behrends et al. In general, earlier results concerning the structure of the symptom groupings have been confirmed. However, by comparing all the different sets of results, those symptom groupings that are particularly stable or unstable have been identified. In addition, comparisons have been made between the results from analyses using the full range of scores on the items and those using dichotomized scores in order to determine whether the use of different rating scales for different items has an effect on the resulting item groupings.

Combination of ramipril and hydrochlorothiazide in the treatment of mild to moderate hypertension: Part 1--A double-blind, comparative, multicenter study in nonresponders to ramipril monotherapy.

In a parallel-group multicenter study, the efficacy and safety of combination therapy with ramipril 5 mg plus hydrochlorothiazide 25 mg were compared double-blind with those of 5 mg and 10 mg ramipril monotherapy in patients with mild to moderate hypertension who had not responded adequately to ramipril 5 mg alone. Patients were initially treated single-blind for 1 week with ramipril 2.5 mg and 3 weeks with ramipril 5 mg. Of 240 patients enrolled, 165 were subsequently classed as nonresponders (diastolic blood pressure > 90 mmHg) and were randomized to one of the three double-blind treatments for a further 4 weeks. In the double-blind phase, the mean reductions in supine systolic and diastolic blood pressures at end point were significantly greater in the 5 mg plus 25 mg combination group (11.6/10.6 mmHg) than in the groups receiving ramipril 5 mg (6.2/5.9 mmHg; both p < 0.01) and ramipril 10 mg (7.4/7.1 mmHg; both p < 0.05). The proportion of responders at end point was also higher for combination therapy (72%) than for monotherapy (48% for ramipril 5 mg and 62% for ramipril 10 mg). All three treatments were well tolerated. Analysis of laboratory values revealed no clinically important changes.

Combination of ramipril and hydrochlorothiazide in the treatment of mild to moderate hypertension--Part 2: An open long-term study of efficacy and safety.

In an open, multicenter extension of a short-term study, 159 patients with mild to moderate hypertension were treated with either ramipril monotherapy or a combination of ramipril and hydrochlorothiazide for up to 1 year. Patients started with either 5 mg ramipril once daily (responders in the short-term study) or a combination of ramipril 5 mg plus hydrochlorothiazide 25 mg once daily. The dose could be adjusted and nonresponders to ramipril monotherapy could have hydrochlorothiazide added. In the 38 patients treated with ramipril monotherapy, the largest drop in mean blood pressure (BP) had already occurred in the previous short-term study; from Week 2 in the long-term study, the BP remained stable with means below 150/90 mmHg. In the 83 patients treated with the combination for 50 weeks or more, mean BP continued to decrease until around Week 10 in the long-term study while therapy was being adjusted. Thereafter, it also remained stable with means below 150/85 mmHg. Both treatment groups showed good mean reductions at end point, as did the group of 38 patients treated with the combination for less than 50 weeks. High response rates (84-95%) were seen in all groups at end point. The combination was well tolerated and the efficacy of ramipril in combination with hydrochlorothiazide was maintained over the 1-year period of investigation.

Carcinogenic and genotoxic activity of extracts from contaminated sediments in western Lake Ontario.

In order to investigate the putative association between chemical contamination in western Lake Ontario and high prevalences of fish tumors, sediments from Hamilton Harbour and Oakville Creek in Lake Ontario and reference sites in non-polluted areas of Ontario, Canada were collected and extracted for organic contaminants. Sediment extracts from Hamilton Harbour had the highest concentrations of polychlorinated biphenyls and organochlorine insecticides (ppb) and contained very high concentrations of polynuclear aromatic hydrocarbons (ppm); although the levels of these compounds varied widely with sampling location in the harbor. A sediment extract from Hamilton Harbour was mutagenic in the Ames bacterial assay, both with and without microsomal activation. High levels of aromatic DNA adducts were induced in cultured mouse C3H1OT1/2 cells after in vitro exposure to Hamilton Harbour sediment extract. In two separate carcinogenicity experiments involving a sac fry microinjection assay with rainbow trout (Oncorhynchus mykiss), Hamilton Harbour sediment extract induced hepatocellular carcinomas in fish. No hepatic neoplasms were observed in fish that had been treated with sediment extract from Oakville Creek, or with extract from a reference sediment. The significance of these results is discussed in relation to the distribution of neoplasms in feral fish within western Lake Ontario.

Plotting n-dimensional psychiatric data in 2 dimensions using Andrews' method.

Andrews' method of plotting n-dimensional data in 2 dimensions allows one to summarize all the data on one patient using a single curve. Comparisons have been made between different diagnostic groups on the basis of the 12 scales from the In-patient Multidimensional Psychiatric Scale (IMPS) using data from a sample of 787 newly admitted in-patients. For each diagnostic group, a figure was produced containing the Andrews' curves from all the patients in the group. Those groups that were particularly homogeneous or heterogeneous were noted. The main features of the different groups could be discerned.

Providing evidence of efficacy for a new drug.

There are many issues to consider when designing an efficacy package for drug registration. Generally in Europe and the United States, two or more confirmatory trials demonstrating efficacy (p < 0.025, one-tailed) of the test treatment versus a suitable control group must be conducted with a priori definition of a primary efficacy endpoint. Exceptions are possible, and there is always extensive discussion whenever less is proposed or more is required. Every aspect of the basic requirement can be questioned: number of trials; choice of control groups; selection of primary efficacy variables(s); levels of significance; one-tailed versus two-tailed test. These issues will be discussed, and justification is given when proposals are made for deviations from standard practice. Differences between Europe and the U.S. are discussed for certain disease entities. Because the assessment of the weight of evidence in favour of a drug effect is difficult to quantitate, if not impossible, no definitive guidance can be given that is suitable for all circumstances and countries.

[Office visits and physical well-being of hypertensive patients. Results of the Munich blood pressure study]. / Arztbesuche und physisches Befinden von Hypertonikern.

The relationship between the frequency of physician visits, self-reported health of hypertensives and the awarenes, treatment and control of hypertension has been investigated, using data from the Munich Blood Pressure Study I (1980/81), a study with 2216 participants of a random sample of the adult population of Munich (30-69 y.). As hypothesized, the chance of detecting and treating high blood pressure increased with the frequency of physician visits. However, frequent physician visits did not guarantee an effective treatment of hypertension. 33% of the treated hypertensives who visited their physicians more than ten times in the preceding year failed to show normotensive or borderline blood pressure values. Additionally it could be seen that the awareness, treatment and control of hypertension was closely related to the number of self-reported chronic diseases and self-reported physical well-being. A relationship between social variables and treatment status was only observed for men: among hypertensive men, the proportion who were treated increased with the number of years of education but decreased with the number of household members.

Factors contributing to the length of general practice consultations.

Ten general practitioners in a study of general practice consultations were shown to differ significantly in the time they spent in their consultations. Patient demographic characteristics contributed little to differences in consultation time. Consultations in which (a) there was a diagnosis of psychological disorder, (b) the practitioner and the patients focused attention on psychosocial matters, and (c) psychotropic drugs were prescribed, were found to be associated with increased length of consultation time.

Design, development and use of a standardized interview to assess social maladjustment and dysfunction in community studies.

A standardized social interview, designed to assess social maladjustment and dysfunction is described. The interview is composed of items grouped under the 3 headings of Material conditions, Social management and Satisfaction. Ratings are made on a 4-point scale by interviewers standardized in its use. The interview, which takes approximately 45 minutes to administer, covers housing, finance, occupation, social and leisure activities, and relationships with significant individuals in the subject's life. The inter-rater reliability is assessed and principal component analyses performed, and the results of these are provided and dicussed. Various methods of scoring are examined and the use of the schedule in a number of studies in the setting of general practice is described.

The analysis of a multiple-dose, combination-drug clinical trial using response surface methodology.

We consider the situation where a multiple-dose, combination-drug clinical trial is conducted to identify one or more combinations that satisfy regulatory requirements. Generally, these requirements involve a compound hypothesis with multiple comparisons. The min test has been shown to be an optimal alpha-level test for testing a single combination drug. Analysis procedures in a multiple-dose, combination-drug study have typically involved classical ANOVA models or multiple regression models in a response surface methodology (RSM) framework. An inferential procedure based on an ANOVA model uses a screening test to address multiple comparison issues and multiple min tests to explicitly identify combinations satisfying regulatory requirements. An exploratory procedure based on RSM modeling is used to build a segmented linear model and a stairstep linear model to describe dose-response relationships. The two procedures are mutually supportive of one another in providing a broader assurance in the identification of effective combinations.