Meta-analysis of large outcome trials of angiotensin receptor blockers in hypertension.

Angiotensin receptor blockers (ARBs), also known as sartans, block the activation of angiotensin type 1 receptors and have a recognised role in the treatment of heart failure and nephropathy. Since 2002, there have been three major outcome trials of ARBs in hypertension. We performed a meta-analysis to evaluate the impact of ARB on major outcomes. Randomised controlled trials of ARBs in hypertensive subjects with an average follow-up of at least 2 years and at least 100 major cardiovascular events were included. For each trial, the ARB used, number and characteristics of subjects, baseline and change in blood pressure, cardiovascular and noncardiovascular outcomes were recorded. Three trials involving 29 375 subjects were included in the meta-analysis. In Losartan Intervention For Endpoint (LIFE) and Study on Cognition and Prognosis in the Elderly (SCOPE) but not in Valsartan Antihypertensive Long-term Use Evaluation trial (VALUE), an ARB reduced the occurrence of the primary end point and stroke compared to control. Compared to other antihypertensive drugs, ARB treatment was associated with no significant change in all-cause mortality (relative risk ratio (RRR) 0.96, 95% CI: 0.88-1.06, P = 0.45). There was an increase in myocardial infarction (RRR, 1.12, 95% CI: 1.01-1.26, P = 0.041), but a decrease in new-onset diabetes mellitus (RRR, 0.80, 95% CI: 0.74-0.86, P < 0.0000001). In conclusion, the reduction in new-onset diabetes partly offsets any increase in the risk of myocardial infarction. Most hypertensive patients require more than one class of drugs. Small differences in treatment outcome should not over-ride the importance of good blood pressure control.

Long-term combination therapy with aspirin and clopidogrel.

The possible additive antiplatelet effects of aspirin and clopidogrel have been explored in the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) and Management of Atherothrombosis with Clopidogrel in High Risk Patients (MATCH) studies. To assess the overall absolute beneficial and/or harmful impact of aspirin and clopidogrel combination therapy compared with monotherapy with either drug, we analyzed the results from both trials in terms of number needed to treat per year. Treating between 35 and 204 at-risk patients for 1 year with combination therapy appeared to prevent 1 patient from experiencing an adverse primary cardiovascular outcome; whereas, about 1 in 63 such patients appeared liable to major bleeding during that period. We determined that the evidence to date indicates no overall advantage for combination therapy with anti-platelet drugs in preference to monotherapy.

Sequential combination chemotherapy in patients with advanced nonsmall cell lung carcinoma: carboplatin and gemcitabine followed by paclitaxel.

BACKGROUND: The objective of this Phase II study was to evaluate the concept of sequential chemotherapy in the treatment of patients with advanced nonsmall cell lung carcinoma (NSCLC) by the administration of carboplatin plus gemcitabine followed by of paclitaxel. METHODS: Patients with Stage IIIB (pleural effusion) or Stage IV NSCLC and a Southwest Oncology Group (SWOG) performance status (PS) of 0--2 were eligible. Therapy consisted of three cycles of carboplatin (area under the concentration-time curve = 5.5 mg/mL per minute) on Day 1 and gemcitabine 1000 mg/m(2) on Days 1 and 8 every 21 days followed by three cycles of paclitaxel 225 mg/m(2) every 21 days. RESULTS: Of the 37 eligible patients, 81% had Stage IV disease, and 27% had a PS of 2; all were assessable for survival and toxicity; 32 patients were assessable for response. After treatment with carboplatin plus gemcitabine, there were no complete responses (CRs) and eight partial responses (PRs) (response rate [RR], 25%; 95% confidence interval [95% CI], 11--43%). The best overall response was two CRs and eight PRs (RR, 31%; 95% CI, 16--50%). The median survival time was 9.5 months, the 1-year survival rate was 36% (95% CI, 26--44%), the 2-year survival rate was 11% (95% CI, 3--25%), and the median time to disease progression was 4.9 months. The median survivals were 11.2 months for patients with a PS of 0--1 and 6.4 months for patients with a PS of 2. Noncumulative, reversible thrombocytopenia was the principal toxicity with carboplatin/gemcitabine therapy. Paclitaxel therapy was well tolerated, and moderate (Grade 3) neutropenia was the primary toxic effect. One cardiac death occurred, possibly related to paclitaxel. CONCLUSIONS: This study is the first to evaluate planned sequential chemotherapy in patients with NSCLC. Carboplatin plus gemcitabine followed by paclitaxel was well tolerated and resulted in promising survival in this patient population. This pilot experience forms the basis for an ongoing SWOG trial. Cancer 2001;92:146-52. Published 2001 American Cancer Society.

Increasing use of inhaled steroids associated with declining asthma mortality.

Increasing worldwide asthma prevalence and mortality has led to greater advocacy of inhaled agents, especially steroids. To determine whether corresponding drug usage trends had ensued locally, wholesale data (expressed as defined daily doses (DDDs)/1000 inhabitants/day) were compared for inclusive periods 1984-1986 and 1992-1994. Whereas absolute usage of anti-asthmatics increased by 79%, proportional inhaled usage increased markedly, especially of steroids (571%) and in hospitals. An odds ratio trend analysis revealed asthma mortality from 1992 onward had declined, particularly in males (p < 0.001). In Hong Kong, despite increasing asthma prevalence, more intensive use of anti-asthmatic drugs (especially inhaled steroids) was associated with declining asthma mortality.

A community study of sleep-disordered breathing in middle-aged Chinese men in Hong Kong.

BACKGROUND: Sleep-disordered breathing (SDB) in Asian populations is being increasingly recognized. This study investigated the prevalence of SDB in Chinese middle-aged office-based male workers in Hong Kong. METHODS: Sleep questionnaires were distributed to 1,542 men (age range, 30 to 60 years), and 784 questionnaires were returned. Subsequently, full polysomnographic (PSG) examinations were conducted in 153 questionnaire respondents. Subjects with an apnea-hypopnea index (AHI) > or =5 were recalled for clinical assessment. RESULTS: Questionnaire respondents were similar in age and body mass index (BMI) to the general community in the target age range and gender. Habitual snoring was reported by 23% of this cohort and was associated with excessive daytime sleepiness (EDS), hypertension, witnessed abnormal breathing pattern, BMI, and leg movements during sleep. Allowing for subject bias in undergoing PSG, the estimated prevalence of SDB and obstructive sleep apnea syndrome (OSAS) (defined as SDB in the presence of EDS) at various AHI cutoff threshold values was 8.8% and 4.1% (AHI > or =5), 6.3% and 3.2% (AHI > or =10), and 5.3% and 3.1% (AHI > or =15). Multiple stepwise logistic regression analysis identified BMI, habitual snoring, time taken to fall asleep, and age as predictors of SDB at AHI > or =5. Analysis of anthropometric parameters indicated that the relative risk of OSAS attributable to obesity was less than in white subjects. CONCLUSION: This community-based study of sleep apnea among middle-aged men in Hong Kong using full PSG demonstrated an estimated prevalence of OSAS (AHI > or =5 and EDS) at 4.1%. Increasing BMI and age were associated with SDB, although factors other than adiposity may also have an important pathogenic role in OSA in Chinese subjects.

Long-term culture of human immunodeficiency virus type 1 resulting in loss of glycosylation sites.

Cultures of human immunodeficiency virus type 1 (HIV-1) provided a model for the study of mutations in the absence of host antibodies. Replicate cultures of biological and molecular clones of HIV-1 were passaged weekly for 30 or 34 weeks. Eight regions of HIV-1 genomic RNA were analyzed by means of single-strand conformation polymorphism analysis and nucleotide sequencing. Six mutations were detected in the biological clones. Two were G-->A substitutions. The frequency of mutations was higher in V1 compared to that in other regions (P = 0.01). Three mutations involved loss of potential glycosylation sites in V1. These results show that mutations in the viral genome may result from selection by factors other than host immune pressures.

Cost-effectiveness analysis of applying the Cholesterol and Recurrent Events (CARE) study protocol in Hong Kong.

OBJECTIVE: To determine the cost-effectiveness of secondary prevention with pravastatin in Hong Kong patients with coronary heart disease and average cholesterol levels. DESIGN: Cost-effectiveness analysis based on published results of the CARE study. PATIENTS: Men and women post-myocardial infarction with average cholesterol levels. MAIN OUTCOME MEASURES: Cost-effectiveness analysis: cost per life saved, cost per fatal or non-fatal coronary event prevented, cost per procedure prevented, and cost per fatal or non-fatal stroke prevented. Cost-utility analysis: gross cost and net cost per quality-adjusted life year gained calculated using two alternative models. RESULTS: Cost per life saved or death prevented was HK$4,442,350 (non-discounted); cost per fatal or non-fatal cardiac event prevented HK$1,146,413; cost per procedure prevented HK$732,759; and cost per fatal or non-fatal stroke prevented HK$2,961,566. Net cost per quality adjusted life year gained was HK$73,218 and HK$65,280 non-discounted, respectively using the two alternative models. CONCLUSIONS: The results of this study can assist in prioritising the use of health care resources in Hong Kong but should be considered alongside the benefits and costs of alternative interventions for coronary heart disease.

The impact of chronic diseases on the health-related quality of life (HRQOL) of Chinese patients in primary care.

BACKGROUND: Ageing of the population results in an increasing number of people living with chronic diseases that can adversely affect their quality of life. Information on the impact of chronic diseases on quality of life can make health services more patient-centred. OBJECTIVES: The aim of this study was to determine the impact of eight chronic diseases on the health-related quality of life (HRQOL) of Chinese patients. METHODS: A cross-sectional case-control study was carried out on 760 adult Chinese patients of a family medicine clinic in Hong Kong. Each subject answered the COOP/WONCA charts and a standard questionnaire on demographic and morbidity data. The likelihood of sub-optimal COOP/WONCA scores of each disease group was compared with that of patients without any of the surveyed diseases. The independent effects of each disease on the COOP/WONCA scores were analysed by multivariate logistic regression, controlling for demographic variables and co-morbidity. RESULTS: Depression increased the risks for sub-optimal scores in all but one COOP/WONCA chart with odds ratios (OR) ranging from 2.1818 to 3.8645. Hypertension increased the risk of a sub-optimal physical fitness score (OR 1.7263). Increased risk of limitations in daily activities was associated with stroke (OR = 1.8771), osteoarthritis of the knee (OR = 1.5867), diseases of joints other than the knees (OR 2.0187) and asthma/COPD (OR 2.1679). Osteoarthritis of the knees also increased the risk of sub-optimal overall health (OR = 1.7927). CONCLUSIONS: Depression was the most disabling disease, and osteoarthritis of the knee had more impact on the HRQOL than many other chronic diseases. The lack of adverse effects of diabetes mellitus and heart disease on the HRQOL of Chinese patients deserves further studies.

Early detection of hepatocellular carcinoma increases the chance of treatment: Hong Kong experience.

The prognosis for patients with hepatocellular carcinoma (HCC) is poor because of the low chance of curative treatment. To increase the chance of intervention and to improve survival, early detection of subclinical HCC (SCHCC) by alpha-fetoprotein (AFP) and/or ultrasonography (USG) screening is implemented in many countries. Three hundred six Chinese patients with HCC diagnosed between January 1995 and December 1997 were recruited. They were categorized into two groups: 142 patients (group 1) had SCHCC diagnosed by screening (AFP and/or USG), and 164 patients (group 2) presented with symptomatic HCC. The tumor size was significantly smaller in group 1 compared with that of group 2 (3.5 cm vs. 8.1 cm; P <.0001). A significantly higher proportion of patients had bilobar involvement, multifocal HCC, diffuse-type HCC, portal vein infiltration, and distant metastasis in group 2 when compared with group 1. Operability and feasibility of treatment by transcatheter intra-arterial chemoembolization (TACE) in group 1 patients (26.8% and 45.1%, respectively) were significantly better than in group 2 patients (7.9% and 32.3%, P <.0001 and P =.03, respectively). The cumulative survival rate was significantly higher in group 1 than in group 2 (P <.0001). For those who had surgical resection and those who had TACE, group 1 patients had a higher cumulative survival rate compared with that of group 2 patients (P =.04 and P =.0003, respectively). Screening for HCC by AFP and/or USG can identify tumors at an early stage, resulting in a higher chance of receiving treatment. Whether it can improve survival requires a further prospective, randomized study.

How does a change in the administration method affect the reliability of the COOP/WONCA Charts? World Organization of National Colleges, Academies and Academic Associations of General Practitioners/Family Physicians.

BACKGROUND: An interviewer is often needed to administer the COOP/WONCA Charts to Chinese patients, and this may affect the reliability of results. OBJECTIVES: We aimed to find out the reliability of the COOP/WONCA Charts administered by an interviewer, and whether a change in the interviewer or administration method would affect the results. METHODS: We carried out a cross-sectional test-retest study on 487 Chinese adult patients attending a family medicine clinic in Hong Kong. The COOP/WONCA Charts were administered by the same interviewer, two different interviewers or self-completion and interviewer administration, on test and retest. The random, inter-observer and inter-method variances were compared with the inter-subject variance. The reliability coefficient of each COOP/WONCA Chart was calculated for each method of administration. RESULTS: Random errors could change the scores by 0.57-1.04, inter-observer variations could change the scores of four charts by 0.72-0.80, and a change in the method could change the physical fitness score by 1.79 and the daily activities score by 1.31, on a five-point scale. The reliability coefficients of the six COOP/WONCA Charts were 0.68-0.92 for one interviewer, 0.59-0.82 for two interviewers and 0.46-0.81 for two methods. CONCLUSION: The Chinese COOP/WONCA Charts were reliable in detecting real differences when administered by an interviewer. A change in the method of administration significantly decreased the reliability of the results. The use of more than one method of data collection in the same survey should be discouraged.

Cytochrome P4502D6 (debrisoquine 4-hydroxylase) and Parkinson's disease in Chinese and Caucasians.

Four polymorphic sites (C/T188, C/T2938, G/C4268, G/A1934) in the cytochrome P4502D6 (debrisoquine 4-hydroxylase) gene were investigated for their association with sporadic Parkinson's disease (PD). Three mutant alleles (C/T188, C/T2938 and G/C4268) result in amino acid changes which could alter the substrate specificity or alter its ability to metabolize their substrates; the fourth (G/A1934) causes a loss of enzyme activity. The study was carried out in two ethnically homogenous populations: Chinese (123 PD patients, 124 controls); and Caucasian (95 PD patients, 62 controls). Haplotype status, which took into account amino acid changes at three polymorphic sites, was deduced from genotyping results in order to investigate whether substrate specificity was important rather than loss of enzyme activity. There was no gender difference in the distribution of the alleles in either race. There was, however, significant association among the three polymorphic sites (C/T188, C/T2938, G/C4268) in both ethnic groups. T/T188:C/C2938:C/C4268 is the most common genotype in the Chinese population, in contrast to C/C188:C/T2938:C/G4268 (followed by C/C188:C/C2938:G/G4268) in Caucasians. All 69 of the sub-group of Chinese patients tested were homozygous for the wild-type allele at the G/A1934 polymorphic site. Neither the CYP2D6 allele nor haplotype was associated with PD in either ethnic group.

Knowledge of stroke in Hong Kong Chinese.

A random telephone survey on knowledge of stroke was conducted in 1, 238 Hong Kong Chinese. Most respondents realized that effective treatment was available, that stroke was preventable and that it could be fatal or disabling. Sudden unilateral limb weakness, sudden speech and language disturbances, and sudden vertigo and clumsiness were better recognized than other warning symptoms of stroke. A slightly better recognition of symptoms of stroke was seen in those with a belief of knowing about stroke, providing a correct description of stroke, those with a positive household history of stroke and those with a better knowledge of potential risk factors. Most respondents would choose desirable actions if stroke was suspected in their family members or themselves. Friends and relatives, newspapers and magazines, and mass media provided the major sources of their knowledge.

Tumour markers and their prognostic value in adenocarcinoma of the cervix.

Ninety-one patients with adenocarcinoma of the cervix had 4 tumour markers (TMs) assayed before treatment. Serum squamous cell carcinoma antigen (SCC) (n = 91) was raised in 25%; tissue polypeptide antigen (TPA) (n = 78) was raised in 35%; carcinoembryonic antigen (CEA) (n = 34) was raised in 26% and CA 125 (n = 64) was raised in 27% of these patients. In 47 of these 91 patients (52%), 1 or more of the markers were raised. The percentage of patients with raised TM increased with advancing stage. Univariate survival analysis showed that age, stage, raised TPA, raised CA 125, and raised TMs (any one or more) were of prognostic significance. When multivariate analysis was done and each TM was individually analysed, only age, stage and raised CA 125 were of prognostic significance. Rising SCC or TPA or CA 125 levels in serial estimations correlated well with the occurrence of recurrence. Thus, pretreatment estimation of SCC, TPA and CA 125 can be used to identify the patients who can subsequently be monitored by serial TM estimation.

Bronchodilator responses to salbutamol using diskhaler versus metered-dose inhaler.

In adults inhaling salbutamol via metered-dose inhalers (MDls) 200 microg doses are recommended, but with diskhalers the manufacturer advocates 400 rather than 200 microg doses. To assess this advice, a partially double-blind, placebo-controlled salbutamol dose response, crossover study (also incorporating MDI doses) was conducted in 12 mild/moderate asthmatics. After active treatment, mean peak expiratory flow rate (PEFR) increments yielded no clinically or statistically significant differences; compared to placebo, respective median differences in PEFR increments (95% Cls) were 10 (-10, 50), 20 (0, 50), and 15 (0, 30) following 400 and 200 microg via diskhalers and 200 microg via MDls. Diskhalers are a suitable alternative for patients with poor MDI technique, but the use of 400 rather than 200 microg salbutamol doses is not supported by evidence.

Selection of appropriate HIV-1 genomic regions for single-strand conformation polymorphism analysis of the diversity, modification, and transmission of HIV-1 quasispecies.

Single-strand conformation polymorphism (SSCP) analysis is a useful tool for studying viral quasispecies. Four regions within the HIV-1 genome were studied by means of SSCP analysis with the aim of determining which regions were the most informative for the study of HIV-1 transmission or for detection of changes in HIV-1 quasispecies populations. Nested polymerase chain reaction (PCR) was used to amplify V1, V2, V3 of the env gene, and the p2 region in the gag gene. In total, 114 plasma specimens from 79 individuals were tested, including serial specimens from 10 mother-infant pairs that were provided by the Women and Infants Transmission Study (WITS). HIV-1 in specimens that were PCR-positive with primer pair SK38/SK39 showed different percentages of positive signals with primer pairs for the four regions: V1, 63%; V2, 83%; V3, 88%, and p2, 100%. HIV-1 sequences in the p2 target region displayed the greatest degree of polymorphism. Analysis of serial specimens showed that the V1 target region was the most variable of the four regions studied and was the most appropriate region for monitoring changes in quasispecies populations. Of the four regions studied, p2 was the most informative for the study of HIV transmission, as shown by analysis of samples from documented cases of mother to infant HIV-1 transmission.