An invasive management strategy is associated with improved outcomes in high-risk acute coronary syndromes in patients with chronic kidney disease.

INTRODUCTION: Chronic kidney disease (CKD) is associated with poor outcomes after acute coronary syndromes, yet selection for invasive investigation and management is low. METHODS: Patients presenting with ST segment elevation myocardial infarction (STEMI) or intermediate- to high-risk non-ST segment elevation acute coronary syndrome (NSTEACS) (n=2597) were stratified into groups based on kidney function, defined as normal (glomerular filtration rate (GFR)≥60mL/min/1.73m(2) ), moderate CKD (GFR 30-59mL/min/1.73m(2) ) and severe CKD (GFR <30mL/min/1.73m(2)). Based on these stratums of kidney function, incidence and outcome measures were obtained for: rates of angiography and revascularization; 6-month mortality; and the incidence and outcome of in-hospital acute kidney impairment (AKI). RESULTS: Patients with CKD were less likely to be offered coronary angiography after STEMI/NSTEACS (P<0.001); however, after selection, revascularization rates were similar (percutaneous coronary intervention (P=0.8); surgery (P=0.4)). Six-month mortality rates increased with CKD (GFR≥60, 2.8%; GFR 30-59, 9.9%; GFR<30, 16.5%, P≤0.001), as well as the combined efficacy/safety end-point (GFR≥60, 9.4%; GFR 30-59, 20.2%; GFR<30, 27.1%, P≤0.001). Six-month mortality was lower in patients who had received prior angiography (GFR≥60, 1.5% vs 3.6%, P=0.001; GFR 30-59, 5.1% vs 12.7%, P<0.001; GFR<30, 7.3% vs 18.5%, P=0.094). Risk of AKI increased with CKD (GFR≥60, 0.7%; GFR 30-59, 3.4%; GFR<30, 6.8%, P≤0.001), and was associated with high 6-month mortality (35.6% vs 4.1%, P<0.001). CONCLUSIONS: In patients with CKD after STEMI/NSTEACS, 6-month mortality and morbidity is high, selection for angiography is lower, yet angiography is associated with a reduced long-term mortality, and with comparable revascularization rates to those without CKD. In-hospital AKI is more common in CKD and predicts a high 6-month mortality.

Impact of acute and chronic risk factors on use of evidence-based treatments in patients in Australia with acute coronary syndromes.

OBJECTIVE: To determine whether acute risk factors (ARF) and chronic risk factors (CRF) contribute differently to the use of evidence-based treatments (EBT) for patients with acute coronary syndromes (ACS). DESIGN: Data were collected through a prospective audit of patients with ACS. Management was analysed by the presence of acute myocardial risk factors and chronic comorbid risk factors at presentation. SETTING: 39 hospitals across Australia. PATIENTS: 2599 adults presenting with ACS. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Use of EBT, in-hospital and 12-month death, recurrent myocardial infarction and bleeding. RESULTS: The number of ARF and CRF at presentation predicted in-hospital and 12-month death, recurrent myocardial infarction and bleeding. Patients with higher numbers of ARF were more likely to receive EBT (aspirin at presentation, 81.1% for zero ARF to 85.7% for > or =3 ARF, p<0.001; angiography 45.9% to 67.5%, p<0.001; reperfusion for ST elevation 50% to 70%, p = 0.392; beta blocker at discharge 66.5% to 74.4%, p<0.001). Patients with higher numbers of CRF were less likely to receive EBT (aspirin at presentation 90.4% for zero CRF to 68.8% for > or =4 CRF, p<0.001; angiography 78.8% to 24.7%, p<0.001; reperfusion for ST elevation 73.4% to 30%; p<0.001, beta blocker at discharge 75.2% to 55.6%; p<0.001). In multivariate regression analysis, ARF and CRF were the strongest predictors of receiving or failing to receive EBT, respectively. CONCLUSIONS: Patients presenting with many ARF are more likely to receive EBT, while patients presenting with many CRF are less likely to receive them. This has important implications for future quality-improvement efforts.

Current management of acute coronary syndromes in Australia: observations from the acute coronary syndromes prospective audit.

BACKGROUND: Acute coronary syndromes (ACS) management is now well informed by guidelines extrapolated from clinical trials. However, most of these data have been acquired outside the local context. We sought to describe the current patterns of ACS care in Australia. METHODS: The Acute Coronary Syndrome Prospective Audit study is a prospective multi-centre registry of ST-segment elevation myocardial infarction (STEMI), high-risk non-ST-segment elevation ACS (NSTEACS-HR) and intermediate-risk non-ST-segment elevation ACS (NSTEACS-IR) patients, involving 39 metropolitan, regional and rural sites. Data included hospital characteristics, geographic and demographic factors, risk stratification, in-hospital management including invasive services, and clinical outcomes. RESULTS: A cohort of 3402 patients was enrolled; the median age was 65.5 years. Female and non-metropolitan patients comprised 35.5% and 23.9% of the population, respectively. At enrolment, 756 (22.2%) were STEMI patients, 1948 (57.3%) were high-risk NSTEACS patients and 698 (20.5%) were intermediate-risk NSTEACS patients. Evidence-based therapies and invasive management use were highest among suspected STEMI patients compared with other strata (angiography: STEMI 89%, NSTEACS-HR 54%, NSTEACS-IR 34%, P < 0.001) (percutaneous coronary intervention: STEMI 68.1%, NSTEACS-HR 22.2%, NSTEACS-IR 8.1%, P < 0.001). In hospital mortality was low (STEMI 4.0%, NSTEACS-HR 1.8%, NSTEACS-IR 0.1%, P < 0.001), as was recurrent MI (STEMI 2.4%, NSTEACS-HR: 2.8%, NSTEACS-IR 1.2%, P = 0.052). CONCLUSION: There appears to be an 'evidence-practice gap' in the management of ACS, but this is not matched by an increased risk of in-hospital clinical events. Objective evaluation of local clinical care is a key initial step in developing quality improvement initiatives and this study provides a basis for the improvement in ACS management in Australia.

Effects of the CRF(1) receptor antagonist, CP 154,526, in the separation-induced vocalization anxiolytic test in rat pups.

CRF(1) receptor antagonists have been proposed as novel pharmacological treatments for depression, anxiety and stress disorders. The primary goal of the present study was to evaluate the effects of the CRF(1) receptor antagonist, CP 154,526, in the separation-induced vocalization (SIV) model of anxiety. Nine- to 11-day-old rat pups were separated from their litter and the effects of intraperitoneally administered test compounds on the elicited ultrasonic vocalizations were measured. Side-effect potential was assessed using a modified inclined plane test ('time on an inclined plane', or TIP), and using negative geotaxis. SIV was reduced by CP 154,526 at doses that did not affect TIP or negative geotaxis, a profile like that of the 5-HT(1A) partial agonist buspirone. The benzodiazepine anxiolytic, diazepam, decreased SIV but also produced significant side effects at one to three-fold higher doses. Additional pharmacological characterization of SIV demonstrated anxiolytic-like effects of the atypical antipsychotic, clozapine, but not the typical antipsychotic, haloperidol, and of the serotonin reuptake inhibitor, zimelidine, but not the norepinephrine reuptake inhibitor, desipramine. In summary, the data support the conclusion that selective CRF(1) receptor antagonists may have utility in anxiety and stress disorders. The data further support the use of separation-induced vocalizations for identifying mechanistically diverse compounds with anxiolytic actions in man.

Risk factors for development of hepatocellular carcinoma among Australians with hepatitis C: a case-control study.

BACKGROUND: Older patients with cirrhosis due to hepatitis C are at risk of developing hepatocellular carcinoma (HCC), but additional risk factors may vary between countries. AIM: In the present study, we sought to identify additional risk factors for HCC among a cohort of Australian patients with chronic hepatitis C. METHODS: Case-control study of patients with advanced fibrosis stage hepatitis C who developed HCC during five-year follow up at a referral liver clinic. Cases were compared to twice the number of age-matched patients with chronic hepatitis C of similar fibrotic severity who did not develop HCC over a similar interval, using conditional logistic regression analysis (CLRA) and multivariate analysis. The main outcome measures were demographic and disease-related variables at first presentation in relation to the development of HCC. RESULTS: HCC developed in 17 cases, an annual incidence among those considered to be at risk of 2%. The duration of follow up since first assessment was comparable among the cases and 34 selected age-matched controls (4.1 and 5.2 years respectively, p=0.5). Cases were more often male (p=0.03), born in Asia (p=0.05), and had poorer liver function as indicated by serum albumin concentration (p=0.02). Anti-hepatitis B core-antibody (anti-HBc) was detected in 59% (ten/17) of cases, compared to 21% (seven/34) of the controls (p=0.01). No patient with a sustained response to interferon developed HCC during follow up. There were no significant differences in the mode of HCV transmission, HCV genotype, alcohol exposure, serum bilirubin level or prothrombin time between the cases and the controls. Although the data set was small, multivariate CLR analysis identified serum albumin < or = 35 g/L and anti-HBc positivity to be independent risk factors for development of HCC. CONCLUSIONS: Among older Australian patients (over the age of 40 years) with advanced fibrosis stage hepatitis C, the annual incidence of HCC is about 2%. Those who have low serum albumin and evidence of previous exposure to hepatitis B virus (anti-HBc positivity) appear to have the highest risk of developing HCC during follow up, but males and those born in Asia could also be at increased risk.

Molecular epidemiology of hepatitis C in Australia.

The aim of this study was to determine the distribution of hepatitis C virus (HCV) genotypes in Australian patients with hepatitis C and to identify factors associated with particular genotypes. Serum isolates of HCV-RNA were genotyped using a commercial oligonucleotide hybridization (line probe) assay. Relationships between demographic factors, mode of HCV transmission and HCV genotype were assessed by logistic regression analysis. Among 463 patients with hepatitis C, 425 tested positive for HCV-RNA and a single HCV genotype was identified in 420 cases. The patients' places of birth were Australia or New Zealand (62%), Asia (13%), Europe (12%), Mediterranean (6%), Middle East (6%) and other countries (< 1%). The most common genotypes were type 1 (52%) or type 3 (32%); type 2 (9.3%), type 4 (5.5%) and type 6 (1.7%) were less common. Patients with genotype 1b were older (48 +/- 13 years, P< 0.001) and patients with genotype 3 were younger than the remaining patients (37 +/- 11 years vs 42 +/- 12 years, P< 0.001). Among type 1 isolates, 1b was more common for patients born outside Australia compared with those born in Australia (50% vs 13%, P< 0.001) whereas non-1b subtypes were more common among Australian-born patients. Likewise, 21 of 23 (91%) patients with type 4 were from Egypt and six of seven (86%) with type 6 were from Vietnam. The relative importance of parenteral risk factors for HCV also varied according to geographic origin. Thus, a definite risk factor for HCV acquisition was identified in > 95% of Australian-born patients, but in only 33% of Asian or Mediterranean-born patients. Logistic regression analysis indicated that region of birth and risk factor (intravenous drug use or not) would allow 98% of type 4 cases and 76% of type 1b cases to be identified correctly. In summary, region of birth, patterns of migration over time and risk factors for transmission of HCV interact to determine the distribution of HCV genotypes in a multi-racial community like Australia.

Effects of hepatitis G virus coinfection on severity of hepatitis C: relationship to risk factors and response to interferon treatment.

The aims of the present study were to identify characteristics that are more often associated with hepatitis G virus (HGV) coinfection in Australian patients infected with the hepatitis C virus (HCV) and to investigate the effects of HGV on the histological and functional severity of chronic hepatitis C. Serum samples from 209 patients with chronic hepatitis C were tested for HGV-RNA using single-round reverse transcriptase-polymerase chain reaction to primers directed at the NS5 region of the HGV genome. Hepatitis G virus RNA was detected in 40 cases (19%). Hepatitis G virus-coinfected patients tended to be younger and parenteral risks could be identified in all but six. Although country of birth did not differ significantly between the coinfected and HCV-alone groups, HGV-positive patients appeared to be less likely to have originated from Asia. On logistic regression analysis, HCV genotype 3a was found in a significantly higher proportion of patients with HGV coinfection than other genotypes (P < 0.01). Liver histology and response to interferon were similar in the HGV-coinfected and HCV-alone groups and liver-related complications appeared to occur less frequently in patients with both HGV and HCV. On univariate analysis, antipyrine clearance was found to be higher in the coinfected group (P < 0.05), implying better preservation of hepatic metabolic function, but this difference was lost when adjusted for HCV genotype. In conclusion, coinfection with HGV was more commonly associated with HCV genotype 3a, a genotype associated with injection drug use in younger patients. However, the presence of HGV coinfection did not adversely affect liver disease or the response to interferon treatment in patients with chronic hepatitis C.

Growth hormone treatment increases cytochrome P450-mediated antipyrine clearance in man.

We used the antipyrine clearance test (APC) to examine the effect of growth hormone (GH) therapy on hepatic cytochrome P450 (CYP) enzyme activity. Eleven GH deficient adults were randomized to receive GH or placebo for 6 months, all subjects subsequently received GH. Before treatment, APC was below the normal range in six subjects. We found an increase in APC in the subjects randomized to receive GH compared to those on placebo (median change +0.14 ml/min/kg [range + 0.04 to + 0.20]vs -0.04 ml/min/kg [range -0.07 to + 0.04], p = 0.011). The stimulatory effect of GH on drug metabolism was confirmed by the data for 3 months GH treatment in all 11 subjects, with APC increasing from 0.33 ml/min/kg (range 0.22 to 0.69) to 0.50 ml/min/kg (range 0.27 to 0.83), p = 0.018). These data indicate that GH modulates hepatic CYP activity. This has important clinical implications, as the hepatic metabolism of drugs and hormones may be altered in patients undergoing GH therapy.

Sequential changes in serum levels of individual bile acids in patients with chronic cholestatic liver disease.

In order to determine the value of serum bile acids in predicting the course of chronic cholestatic liver diseases, we measured individual serum bile acids serially, using high-performance liquid chromatography, over a 4 year observation period in 12 patients with primary biliary cirrhosis and six patients with primary sclerosing cholangitis. The changes in individual serum bile acids and the ratios thereof, conventional liver tests and Child-Turcotte and Mayo scores were compared between survivors (n = 10) and patients who underwent liver transplantation for (n = 3) or died of the liver disease (n = 5). Patients with a serum total chenodeoxycholic acid concentration at study entry that exceded 15 mumol/L were 10 times more likely to die or need a liver transplant in the following 4 years than those with chenodeoxycholic acid levels < 15 mumol/L (P < 0.05). None of the other biochemical parameters or clinicopathological scores could similarly discriminate between the two groups at entry. Time-dependent analyses for the cholic acid/chenodeoxycholic acid ratio, serum total bilirubin and albumin concentrations and Child-Turcotte and Mayo scores were able to differentiate between primary sclerosing cholangitis patients who died or were transplanted and those who were not, whereas age of the patients and other parameters did not. The taurocholic acid/taurochenodeoxycholic acid ratio fell during progression of primary biliary cirrhosis but rose in temporal relationship with primary sclerosing cholangitis. This differential pattern of change was unique compared with other clinical and laboratory indices. In conclusion, serum chenodeoxycholic acid levels and the cholic acid/chenodeoxycholic acid ratio in both diseases were independent indices that allowed for the prediction of survival or the need for liver transplantation. These indices are worthy of further examination in a larger group of patients as prognostic criteria for chronic cholestatic liver disease and in the assessment of the efficacy of therapeutic interventions, including liver transplantations.

Antipyrine clearance and response to interferon treatment in patients with chronic active hepatitis C.

To determine whether hepatic metabolic function affects the response to interferon treatment, we measured antipyrine clearance (APC) in 85 patients with chronic active hepatitis C and compared the results with treatment outcome. Among 55 patients who responded to interferon by normalization of alanine transaminase (ALT), median APC before treatment was 0.47 (range, 0.12 to 0.98; normal range, 0.34 to 1.02 mL/min/kg body wt), a value that was significantly greater than in 30 nonresponders (0.23; 0.08 to 0.67 mL/min/kg body wt, P < .001). APC was closely associated with response to interferon. The response rate among cases with values > 0.25 mL/min/kg body weight was 79%, the same as in cases without cirrhosis. Cases without cirrhosis and with APC of > 0.25 mL/min/kg body weight had an 85% chance of responding to interferon; this was unlikely a simple reflection of histological activity, because the correlation with Scheuer score was poor in this subgroup (r = -.31, P < .05). A second, independent group of 43 patients was used to test the predictive value of APC (using 0.25 mL/min/kg body wt as a cut-off) for response to interferon treatment. In this group, APC correctly predicted positive response to interferon in 75% of cases. APC was also used to measure the effects of treatment on hepatic metabolic function. Regardless of outcome, there was no change in APC at the end of a 6-month course of interferon treatment. Six months later, however, improvement in APC (14%; P < .05) was evident among responders but not in those who had failed to respond to interferon.(ABSTRACT TRUNCATED AT 250 WORDS)

Non-alcoholic steatohepatitis: impaired antipyrine metabolism and hypertriglyceridaemia may be clues to its pathogenesis.

Non-alcoholic steatohepatitis resembles alcoholic liver disease in hepatic morphology but appears to have a different natural history. We sought to assess the nature of non-alcoholic steatohepatitis by a prospective study of its clinical progression and the relationship of biochemical abnormalities to changes in serum lipids among 15 patients with this disorder. In addition, antipyrine clearance (Cl-AP), which reflects hepatic microsomal oxidative capacity, was measured serially. Although initial liver histology included micronodular cirrhosis in five cases and bridging fibrosis in another three, only one patient developed a hepatic complication during 1-10 years (median: 3.7) of follow up. This confirms the relatively benign nature of non-alcoholic steatohepatitis. Moreover, Cl-AP, which was below the normal range in 13 patients, did not change significantly during 10-40 months of follow up. However, compared with other chronic liver diseases, the reduced Cl-AP was disproportionately low relative to the uniformly normal serum albumin concentration and other indices of hepatic metabolic function. This is consistent with selective impairment of endoplasmic reticular drug oxidizing enzymes. Hyperlipidaemia was present in 11 patients. In three of these, diet-induced correction of serum triglyceride elevation was associated with reduction of hepatocellular damage as indicated by serum enzyme levels. A hypothesis that unites these and earlier findings is that release of cytokines may occur in non-alcoholic steatohepatitis and produce accumulation of free fatty acids in the liver, leading to focal necro-inflammatory lesions and the destruction or down-regulation of cytochrome P450.

Prediction of response to interferon in patients with chronic active hepatitis C, and evidence that this improves hepatic metabolic function.

We sought to ascertain whether response to alpha interferon treatment could be predicted among patients with chronic active hepatitis C, and whether antipyrine clearance estimations would determine changes in liver function with this disease. The patients came from a randomized controlled trial, with patients who were initially untreated eventually being offered interferon treatment. Among 28 patients treated with interferon 18 (64%) responded with normalization of serum aminotransferase levels. Responders were less likely to have acquired hepatitis C by blood transfusion and more likely to have acquired it by intravenous drug abuse (P less than 0.05). All 13 patients with less severe chronic active hepatitis responded to interferon but only 5 of 15 patients with progressive fibrosis or cirrhosis responded (P less than 0.01). During 8-39 (median 19) months of observation of 16 untreated patients, there was a significant fall in antipyrine clearance (Cl-Ap) but no change in serum albumin. Among interferon-treated patients, Cl-Ap improved in 9 of 16 compared with 1 of 14 controls observed for the same time period (P less than 0.02). It is concluded that Cl-Ap is a sensitive test for detecting changes in liver function during chronic hepatitis. Without treatment, deterioration is evident at 18 months in 50% of patients with chronic active hepatitis C. Conversely, normalization of serum aminotransferase levels by interferon is associated with improvement of Cl-Ap.(ABSTRACT TRUNCATED AT 250 WORDS)

The importance of suspecting sleep apnoea as a common cause of excessive daytime sleepiness: further experience from the diagnosis and management of 19 patients.

Over an 18 month period, 19 patients were referred for assessment of excessive daytime sleepiness and/or loud snoring. Respiratory studies during sleep were performed in 14 of these patients with additional features such as disturbed sleep, observed apnoea during sleep, morning headache, mental and personality changes, hypertension and cardiac failure. Nocturnal respiratory studies undertaken for periods of 4-8 hours confirmed a diagnosis of the Sleep Apnoea Syndrome in eight patients. In these patients apnoeas, lasting from 30-144 seconds, occurred frequently during sleep (from 35-291 episodes per patient). In one severely affected patient, tracheostomy abolished all symptoms. The use of conservative therapy such as weight loss, protriptyline or a neck collar, highlighted the inadequacies of current medical treatment. Awareness of the symptom complex and potential complications of the Sleep Apnoea Syndrome is important because the diagnosis may easily be missed if the patient presents with one or two isolated complaints.