Clopidogrel, prasugrel or ticagrelor in patients with acute coronary syndromes undergoing percutaneous coronary intervention.

BACKGROUND: Guidelines recommend prasugrel or ticagrelor instead of clopidogrel in patients with acute coronary syndromes (ACS) undergoing percutaneous coronary interventions (PCI). AIM: We sought to describe the trends in uptake of the newer agents and analyse the clinical characteristics and short-term outcomes of patients treated with clopidogrel, prasugrel or ticagrelor. METHODS: We analysed the temporal trends of antiplatelet use since the availability of prasugrel (2009-2013) in patients with ACS from the Melbourne Interventional Group registry. To assess clinical characteristics and outcomes, we included 1850 patients from 2012 to 2013, corresponding to the time all three agents were available. The primary outcome was major adverse cardiovascular events (MACE). The safety end-point was in-hospital bleeding. RESULTS: For the period of 2009-2013, the majority of patients were treated with clopidogrel (72%) compared with prasugrel (14%) or ticagrelor (14%). There was a clear trend towards ticagrelor by the end of 2013. Patients treated with clopidogrel were more likely to present with non-ST-elevation ACS, be older, and have more comorbidities. There was no difference in unadjusted 30-day mortality (0.9 vs 0.5 vs 1.0%, P = 0.76), myocardial infarction (2 vs 1 vs 2%, P = 0.52) or MACE (3 vs 3 vs 4%, P = 0.57) between the three agents. There was no difference in in-hospital bleeding (3 vs 2 vs 2%, P = 0.64). CONCLUSION: Prasugrel and ticagrelor are increasingly used in ACS patients treated with PCI, predominantly in a younger cohort with less comorbidity. Although antiplatelet therapy should still be individualised based on the thrombotic and bleeding risk, our study highlights the safety of the new P2Y12 inhibitors in contemporary Australian practice.

Pre-treatment with dual antiplatelet therapy in patients with non-ST-segment elevation acute coronary syndromes undergoing percutaneous coronary intervention.

BACKGROUND: Although dual antiplatelet therapy is the standard of care in non-ST-segment elevation acute coronary syndromes (NSTEACS), it remains unclear when a second antiplatelet agent should be initiated. We sought to assess the safety and efficacy of pre-treatment with clopidogrel in patients with NSTEACS undergoing percutaneous coronary intervention (PCI). METHODS: We analysed baseline clinical and procedural characteristics of 6817 patients with NSTEACS who underwent PCI from the Melbourne Interventional Group registry from 2005 to 2012. Patients were included in the pre-treatment group if clopidogrel was administered prior to cardiac catheterisation. We assessed 30-day mortality, myocardial infarction (MI) and major adverse cardiovascular events. The safety endpoint was in-hospital bleeding. RESULTS: Of the 6817 patients, only 2951 (43%) received pre-treatment with clopidogrel. Patients in the pre-treatment group were more likely to present with unstable angina (70.8% vs 68.2%, P = 0.02) and have a history of MI (35.6% vs 23.6%, P < 0.01) but were less likely to have PCI within 24 h of admission (17.2% vs 25.2%, P < 0.01). There was no difference between the groups in 30-day mortality (0.9% vs 1.4%, P = 0.06), MI (2.0% vs 2.2%, P = 0.52) or major adverse cardiovascular event (3.7% vs 4.2%, P = 0.25). There was no difference in bleeding complications (1.9% vs 1.9%, P = 0.94). CONCLUSIONS: Pre-treatment with dual antiplatelet therapy in NSTEACS is not routine clinical practice in Australia. Pre-treatment appears safe but is not associated with improved short-term clinical outcomes.

Cost-efficacy modeling of catheter reuse for percutaneous transluminal coronary angioplasty.

OBJECTIVES: Our goal was to provide the range of cost savings associated with various catheter reuse strategies. BACKGROUND: Percutaneous transluminal coronary angioplasty catheters are commonly reused in several countries outside the United States. However, the cost-effectiveness of such reuse strategies has not been evaluated. METHODS: Three theoretical models of catheter reuse were constructed using the actual costs for treating patients with coronary angioplasty at the Cleveland Clinic. Costs were calculated based on the number of balloon catheters, the amount of contrast agent used and the rates for urgent revascularization that were observed in a prospective Canadian study on catheter reuse. RESULTS: The median cost to treat a lesion by means of coronary angioplasty using new catheters was $8,800 per patient. In reuse models, the potential to reduce cost depended on the number of balloon catheters used and the rates of urgent revascularization. The "best care" scenario offered a potential savings of $480 (5.5% of total in-hospital cost), whereas the "worst case" scenario resulted in an increased cost of $1,075 (12.2% of total in-hospital cost) compared with the single-use strategy. Cost of the "likely case" scenario was similar to that of the single-use strategy. Sensitivity analyses identified the different rates of revascularization and cost of balloon catheters required to offset potential savings in each strategy. CONCLUSIONS: Although reusing coronary angioplasty catheters may reduce total in-hospital costs, even a modest increase in complications requiring urgent revascularization may offset any potential savings. However, if an increase in complications and procedure time can be avoided, the reuse strategy has significant economic potential and, ultimately, may be extended to other percutaneous coronary interventional equipment.

Ultrasonic coronary angioplasty during coronary artery bypass grafting.

This preliminary study in 20 patients demonstrated that ultrasonic coronary angioplasty in the setting of bypass grafting is feasible, safe, and able to recanalize atherosclerotic vessels. Shorter monorail probes were superior to longer probes without guidewires in terms of success of vessel recanalization; >95% of particle debris was <25 microm in size.

Impact of early percutaneous coronary intervention on short- and long-term outcomes in patients with cardiogenic shock after acute myocardial infarction.

This study assesses the impact of early percutaneous coronary intervention in patients presenting with cardiogenic shock after acute myocardial infarction. Predictors of in-hospital death include the need for intubation, cardiopulmonary resuscitation, and angiographic failure; long-term outcomes at 2 years in hospital survivors are favorable.

Results of the study to determine rotablator and transluminal angioplasty strategy (STRATAS).

Rotational atherectomy is used to debulk calcified or complex coronary stenoses. Whether aggressive burr sizing with minimal balloon dilation (<1 atm) to limit deep wall arterial injury improves results is unknown. Patients being considered for elective rotational atherectomy were randomized to either an "aggressive" strategy (n = 249) (maximum burr/artery >0.70 alone, or with adjunctive balloon inflation < or = 1 atm), or a "routine" strategy (n = 248) (maximum burr/artery < or =0.70 and routine balloon inflation > or =4 atm). Patient age was 62 +/- 11 years. Fifty-nine percent routine and 60% aggressive strategy patients had class III to IV angina. Fifteen percent routine and 16% aggressive strategy patients had a restenotic lesion treated; lesion length was 13.6 versus 13.7 mm. Reference vessel diameter was 2.64 mm. Maximum burr size (1.8 vs 2.1 mm), burr/artery ratio (0.71 vs 0.82), and number of burrs used (1.9 vs 2.7) were greater for the aggressive strategy, p <0.0001. Final minimum lumen diameter and residual stenosis were 1.97 mm and 26% for the routine strategy versus 1.95 mm and 27% for the aggressive strategy. Clinical success was 93.5% for the routine strategy and 93.9% for the aggressive strategy. Creatine kinase-myocardial band (CK-MB) was >5 times normal in 7% of the routine versus 11% of the aggressive group. CK-MB elevation was associated with a decrease in rpm of >5,000 from baseline for a cumulative time >5 seconds, p = 0.002. At 6 months, 22% of the routine patients versus 31% of the aggressive strategy patients had target lesion revascularization. Angiographic follow-up (77%) showed minimum lumen diameter to be 1.26 mm in the routine group versus 1.16 mm in the aggressive group, and the loss index 0.54 versus 0.62. Dichotomous restenosis was 52% for the routine strategy versus 58% for the aggressive strategy. Multivariable analysis indicated that left anterior descending location (odds ratio 1.67, p = 0.02) and operator-reported excessive speed decrease >5,000 rpm (odds ratio 1.74, p = 0.01) were significantly associated with restenosis. Thus, the aggressive rotational atherectomy strategy offers no advantage over more routine burr sizing plus routine angioplasty. Operator technique reflected by an rpm decrease of >5,000 from baseline is associated with CK-MB elevation and restenosis.

The influence of L-tryptophan and monoamine oxidase inhibitors on catecholamine metabolism in rat brain.

1. L-Tryptophan (100 mg/kg) was administered to rats with or without pretreatment with a monoamine oxidase inhibitor and the concentration of 5-hydroxyindoleacetic acid, homovanillic acid, dihydroxyphenylacetic acid, 3-methoxy 4-hydroxyphenyl glycol, normetanephrine, noradrenaline and dopamine measured in whole brain one hour later. 2. L-Tryptophan increased the concentration of 5-hydroxyindoleacetic acid, homovanillic acid, dihydroxyphenylacetic acid, 3-methoxy 4-hydroxyphenyl glycol and normetanephrine. The concentration of noradrenaline did not change whilst that of dopamine increased significantly. 3. In animals pretreated chronically with a monoamine oxidase inhibitor, tryptophan increased the concentration of dihydroxyphenylacetic acid and homovanillic acid compared to monoamine oxidase alone. 4. The results suggest either a release of dopamine and noradrenaline by 5-hydroxytryptamine, with a compensatory increase in their synthesis, or an increase in the firing of dopaminergic and noradrenergic neurones after L-tryptophan.

Uptake of 5-hydroxytryptamine in the catecholamine containing areas of the hypothalamus of the rat after treatment with phenelzine and tryptophan.

1 Uptake of 5-hydroxytryptamine in the catecholamine containing nerve endings of the hypothalamus in the rat brain was found after intraperitoneal injection of phenelzine sulphate (25 mg/kg) and tryptophan (100 and 400 mg/kg). 2 The results were obtained by fluorescence microscopy and microspectrofluorimetry.

A comparison of D and L-tryptophan on the cerebral metabolism of 5-hydroxytryptamine and dopamine in the dog.

1 After D and L-tryptophan (50 mg/kg) were given intravenously in the dog, the concentration of the amino acid was increased in ventricular cerebrospinal fluid (CSF) during the subsequent 4 h or sampling, although the concentrations were significantly lower following the administration of the D-isomer. 2 There was no evidence that D-tryptophan increased the synthesis of 5-hydroxytryptamine (5-HT) in dog brain as judged by the failure to cause a change in 5-hydroxyindoleacetic acid (5-HIAA) concentrations in ventricular CSF different from that seen with controls. 3 There was no appreciable conversion of D-tryptophan to L-tryptophan in the dog. 4 D-tryptophan was cleared more rapidly from plasma than L-tryptophan. 5 No difference in plasma binding between D and L-tryptophan was detected.

Platelet intracellular calcium in patients with recurrent affective disorders.

Forty-four subjects with a history of a major recurrent affective disorder in remission and who were either on no medication or taking a single dose of psychotropic medication were conscripted together with matched controls. The fluorescent indicator fura 2 was used to measure intracellular calcium in platelets and estimations were made of total serum and ionised calcium as well as of whole blood serotonin. Intracellular calcium was measured in the resting state as well as after stimulation with thrombin, platelet activating factor and serotonin. No significant differences were found between the 17 subjects with a diagnosis of bipolar disorder or the 27 subjects with recurrent unipolar depression and their matched controls. Intracellular calcium measures were significantly higher in the lithium treated group after stimulation with 5HT, whereas the subjects taking tricyclic antidepressants did not differ significantly from their controls on any measure. Serum calcium was found to be significantly higher in those subjects taking lithium. These findings suggest that the measurement of intracellular calcium is not a useful trait marker in affective disorders. Lithium appears to enhance the 5HT induced rise of intracellular calcium.

Alaproclate--an open clinical study in depressive illness.

This open study of alaproclate points towards an antidepressant effect in a a relatively chronic and drug-resistant group of depressives. Five patients had an average improvement of more than 21 points on the Hamilton Rating Scale for Depression and six had an average improvement of seven points. Several patients had anticholinergic side effects, abnormal results in liver functional tests and faecal occult blood, but none were bad enough to require being taken off the drug and most side effects improved before the end of the trial. The biochemical results suggested that the responders and non-responders constituted two distinct biological groups. In the patients who responded well to treatment there were increases in Km values consistent with treatment. The Km and 5-HT values correlated strongly with plasma drug values. There was a strong correlation between Hamilton Rating scores in the 4th week and Km values in the 4th week, although there were only five cases. However, there were no significant relationships between improvement and any pretreatment value. These results are sufficiently promising to suggest that a controlled clinical trial would yield information on alaproclate as a therapeutic aid.

Distribution of O-acetylated sialomucin in the normal and diseased gastrointestinal tract shown by a new monoclonal antibody.

AIMS: To produce and characterise a monoclonal antibody specific for O-acetylated sialomucin and to assess its use in immunohistochemistry on a panel of normal and diseased intestinal tissue samples. METHODS: Mouse monoclonal antibodies were developed following immunisation with highly purified human colonic mucin. One of these (MMM-17) showed strong binding to mucin throughout the normal colon with relative lack of binding to colon cancer tissue. The binding epitope of MMM-17 was then characterised by screening for agglutination activity against a panel of human and animal erythrocytes and by assessment of its binding to a range of normal and chemically treated slot blotted mucins. Further immunohistochemical studies were then performed on formalin fixed, normal, and diseased human intestinal samples. RESULTS: Binding of MMM-17 to slot blotted human colonic mucin was reduced by 38 (SD 14%) (n = 4) by alkali treatment of the mucin, sequential alkali and sialidase treatment completely abolished binding. Sialidase treatment alone, however, caused only an 11 (11%) reduction in binding. MMM-17 failed to agglutinate any human, rabbit, rat or mouse erythrocytes. These findings were compatible with specificity of MMM-17 for sialomucins O-acetylated at the C-7 or C-8 positions on the sialic acid. Strong staining by MMM-17 was found in all goblet cells throughout all 40 normal colonic and rectal samples studied, but staining was absent in seven of 13 colorectal carcinomas. Normal duodenum (n = 16) and normal ileum (n = 3) all showed occasional positive goblet cells. The normal gastric antral mucosa was generally negative B MMM-17, but in all of 15 cases of gastritis with intestinal metaplasia the metaplastic glands were strongly positive for MMM-17. CONCLUSION: Monoclonal antibody MMM-17 has specificity for O-acetylated sialomucins and its binding depends both on the position of O-acetylation and on the adjacent oligosaccharide structure. Preliminary studies using the antibody on archival tissue samples support the previous reports of reduced O-acetylation in colon cancer demonstrated by indirect histochemistry and show the neo-formation of O-acetylated sialomucin in intestinal metaplasia in the stomach.

Interactions between serotonergic and dopaminergic systems in rat brain demonstrated by small unilateral lesions of the raphe nuclei.

Unilateral lesions in the dorsal raphe (DR) resulted in decreased concentrations of 5-hydroxytryptamine and 5-hydroxyindoleacetic acid and increases in homovanillic acid and 3,4-dihydroxyphenylacetic acid in the ipsilateral substantia nigra (SN). Unilateral lesions in the median raphe (MR) caused similar biochemical changes in the corpus striatim (CS). Apomorphine and amphetamine caused turning behaviour in the lesiond animals which was ipsiversive after DR lesions but contraversive after MR damage. The animals turned in the opposite direction to that induced by these drugs after treatment with 5-methoxy-N,N-dimethyltryptamine and in the same direction after treatment with phenelzine plus L-tryptophan. All the drug-induced turning behaviour was blocked by haloperidol. The turning induced by 5-methoxy-N,N-dimethyltryptamine and in the same direction after treatment with phenelzine plus L-tryptophan. All the drug-induced turning behaviour was blocked by haloperidol. The turning induced by 5-methoxy-N,N-dimethyltryptamine was blocked by methysergide. This work suggested that the DR and MR nuclei send projections differentially to SN and CS respectively. These projections may exert a tonically active inhibition of dopamine metabolism in their respective terminal areas.

5-HT receptor binding in post-mortem brain from patients with affective disorder.

Post-mortem brain tissue was obtained from a group of patients with well documented clinical histories of affective disorder. 5-Hydroxytryptamine-1 (5-HT1) and 5-HT2 receptor binding to homogenates of frontal cortex (Brodmann area 10) was measured using tritiated 5-HT and tritiated ketanserin respectively. 5-Hydroxyindoleacetic acid (5-HIAA) levels from the same brain samples were measured by reverse-phase high performance liquid chromatography with electrochemical detection. A tendency towards increased 5-HT receptor binding density in patients with major affective disorder was found compared to dysthymic disorder patients and normal controls. No relationship was found between receptor binding densities and metabolite values, nor were the differences in 5-HT binding correlated with time to autopsy, storage time prior to assay, or to clinical variables including DSM-III psychoticism/non-psychoticism and melancholia. Previous antidepressant drug histories were similar in the two patient groups and are unlikely to account for the findings. An increase in postsynaptic 5-HT2 receptor binding in major affective disorder is a possible pathophysiological mechanism which is compatible with the observed down-regulatory effect of antidepressant drugs (although not electroconvulsive therapy) on 5-HT2 sites. The methodological problems inherent in post-mortem studies in affective disorder are discussed.

Treatment, prediction of relapse and prognosis of chronic primary major depression.

Our study of chronic and non-chronic depressive patients suggests that the following individual factors may predispose a patient to develop chronicity: unipolar depression, neurotic premorbid personality, high familial loading for affective disorder and multiple life events before and after the onset of the illness episode. It is interesting to note that bipolar disorders appear to be under-represented. This may be due to symptomatic chronicity in bipolar illness being more often represented by rapid cycling disorder. Evidence from a group of prospectively ascertained depressives with a median duration of illness of one year showed that apparently 75% of the variance in length of illness episode can be explained. Thus time taken to introduce active treatments, premorbid neuroticism, the occurrence of life events before and after the onset of illness, age at onset of first illness episode and family history of affective disorders were confirmed as important predictor variables. The fact that 85% of patients who develop chronic primary major depressive disorders have previously had an episode of affective illness tends to militate against the stereotype of these patients having a personality disorder. In future, it is important that biological research (for example, neuroendocrine studies) is directed towards chronically depressed patients. In the past, these patients have tended to be excluded from such studies as they represent an atypical population. It is therefore quite clear that future research should be directed towards not only pharmacological but also psychological and social mechanisms which lead to the perpetuation of depressive illness.

The Newcastle chronic depression study: results of a treatment regime.

A trial is described of new therapeutic approaches in treatment-resistant chronic depression. Phenelzine, L-tryptophan and lithium ("5HT-cocktail") was used as the major pharmacological strategy, and a regime aimed at reducing vanadium concentrations was added in the second part of the trial. Patients were randomly assigned to cognitive behaviour therapy in addition. All but 1 of the patients who ultimately entered the trial were unipolar depressives; 2 bipolar patients were withdrawn in the initial drug-free period because of the development of mixed affective states. Eleven of 20 patients showed an improvement to less than 50% of their initial scores on the Hamilton Rating Scale for Depression, and all those who improved did so in the first 6 weeks. Cognitive behaviour therapy did not seem to influence the response, but it is recognized that the short duration of therapy may be inadequate in these circumstances. It is suggested that intensive drug treatment is a necessary preliminary in management and may allow the effective use of rehabilitation aimed at the secondary handicaps of chronic depression.

Five-minute heart rate variability can predict obstructive angiographic coronary disease.

OBJECTIVE: Obstructive coronary artery disease (CAD) is evident in only half of patients referred for diagnostic angiography. Five-minute heart rate variability (HRV) is a non-invasive marker for autonomic control of the vasculature, which this study hypothesised could risk-stratify cardiac patients and reduce unnecessary angiograms. DESIGN: A prospective observational study (the Alternative Risk Markers in Coronary Artery Disease (ARM-CAD) study). SETTING: Three cardiac centres in Melbourne, Australia. PATIENTS: 470 consecutive patients undergoing elective angiography (with predominantly normal cardiac rhythm), regardless of co-morbidity. MAIN OUTCOME MEASURES: The presence of obstructive CAD (≥50% stenosis) on angiography. RESULTS: Patients with obstructive CAD had significantly reduced HRV, particularly in the low frequency (LF) range (median 180 vs 267 ms(2) without CAD; p<0.001). There was a linear trend with the severity of CAD; median LF power (IQR) in patients with normal coronaries was 275 (612), with minor coronary irregularities 255 (400), single-vessel CAD 212 (396) and more severe disease 170 (327) ms(2); p value for trend 0.003. There was a similar reduction in LF power regardless of the anatomical location of coronary stenoses. Comparing patients with LF less than 250 and 250 ms(2) or greater, the adjusted OR for obstructive CAD using multivariate regression was 2.42, 95% CI 1.33 to 4.38 (p=0.004). No interactions were noted in subgroup analysis and HRV added to risk prediction irrespective of the baseline Framingham risk (p<0.0001). CONCLUSION: Low HRV is strongly predictive of angiographic coronary disease regardless of other co-morbidities and is clinically useful as a risk predictor in patients with sinus rhythm. CLINICAL TRIAL REGISTRATION INFORMATION: http://clinicaltrials.gov/ct2/show/NCT00403351 www.armcad.com.

Interleukin-17 Expression in the Barrett's Metaplasia-Dysplasia-Adenocarcinoma Sequence.

Introduction. This pilot study evaluated the expression of the proinflammatory cytokine IL-17 along the Barrett's metaplasia-dysplasia-adenocarcinoma sequence by establishing the expression levels of IL-17 in columnar epithelium, intestinal metaplastic cells, and dysplastic/glandular neoplastic cells. Immunohistochemical techniques were used to examine the accumulation of the proinflammatory cytokine IL-17 in forty (n = 40) formalin-fixed, paraffin-embedded oesophageal archived specimens across a range of endoscopic diagnostic categories, and a highly significant difference was found, where P ≤ 0.001, in IL-17 expression (Kruskall Wallis and Mann-Whitney U) between all the cell types examined. There was also a strong positive correlation (Spearman's rank correlation) between disease progression and IL-17 expression (r s = 0.883, P < 0.001, n = 29), IL-17 expression was absent or absent/weak in columnar epithelium, weak to moderate in columnar metaplastic cells, and moderate to strong in dysplastic/neoplastic cells, which demonstrated that the elevation of IL-17 expression occurs in the progression of the disease. Understanding the differential expression of IL-17 between benign and malignant tissue potentially has a significant diagnostic, prognostic, and therapeutic value. Ultimately, this selective biomarker may be employed in routine clinical practice for the screening of oesophageal adenocarcinoma.

Clinical outcomes of drug-eluting stent use in patients with ST elevation myocardial infarction.

AIM: Randomised trials using drug-eluting stents (DES) in ST elevation myocardial infarction (STEMI) have shown mixed results, and excluded patients at the highest risk of adverse outcomes. We aimed to determine the real world clinical outcomes of DES and compare these with bare-metal stents (BMS) in an unrestricted observational study of patients presenting with STEMI. METHODS: 564 consecutive patients undergoing primary PCI for STEMI were prospectively enrolled in the Melbourne Interventional Group registry (August 2004 to May 2006). The choice of using DES was at the operator's discretion, yet restricted to patients considered at highest risk of restenosis [e.g. diabetes, long lesions (>20 mm) and small target vessels (<2.5 mm)]. Clinical, procedural, and 12-month outcomes of patients receiving DES were evaluated and compared to BMS. RESULTS: DES were used in 45% of patients presenting with STEMI. The rates of cardiogenic shock were similar in the DES and BMS groups (10.2 vs. 11%, p=0.71). In-hospital outcomes were not significantly different with respect to death (4.7 vs. 7.2%, p=0.23), major adverse cardiac events (MACE) (10.6 vs. 11.3%, p=0.80) or stent thrombosis (1.7 vs. 0.3%, p=0.71). At 12 months, target vessel revascularisation (TVR) in patients with DES was 10.2% vs. 7.2% in BMS (p=0.22). On propensity score adjusted multivariate analyses, the only independent predictor of 12-month MACE was presentation with cardiogenic shock (OR 2.59, 95% C.I 1.04-6.45), and the only predictor of 12-month TVR was reference vessel diameter ≤2.5 mm (OR 2.16, 95% C.I 1.06-4.33). DES use was not independently predictive of lower TVR, MACE rates or mortality. Late stent thrombosis rates were similar (DES 3.2 vs. BMS 3.8%, p=0.65). CONCLUSIONS: Drug-eluting stents are frequently used in Australia in the high-risk setting of STEMI. While target vessel revascularisation rates were moderate in this high-risk group, there was no increased mortality, reinfarction or stent thrombosis compared to bare-metal stents.