Dimitri P. Mikhailidis

ESVS Guidelines. Invasive Treatment for Carotid Stenosis: Indications, Techniques

The European Society for Vascular Surgery brought together a group of experts in the field of carotid artery disease to produce updated guidelines for the invasive treatment of carotid disease. The recommendations were rated according to the level of evidence. Carotid endarterectomy (CEA) is recommended in symptomatic patients with >50% stenosis if the perioperative stroke/death rate is <6% [A], preferably within 2 weeks of the patients last symptoms [A]. CEA is also recommended in asymptomatic men <75 years old with 70-99% stenosis if the perioperative stroke/death risk is <3% [A]. The benefit from CEA in asymptomatic women is significantly less than in men [A]. CEA should therefore be considered only in younger, fit women [A]. Carotid patch angioplasty is preferable to primary closure [A]. Aspirin at a dose of 75-325 mg daily and statins should be given before, during and following CEA. [A] Carotid artery stenting (CAS) should be performed only in high-risk for CEA patients, in high-volume centres with documented low peri-operative stroke and death rates or inside a randomized controlled trial [C]. CAS should be performed under dual antiplatelet treatment with aspirin and clopidogrel [A]. Carotid protection devices are probably of benefit [C].

Does severity of ischaemic coronary disease correlate with erectile function

An association between diminution in the quality of male sexual function and ischemic coronary disease has been suggested. Patients with ischemic heart disease who underwent coronary angiography participated in this study which aimed to document the impact of the extent of coronary disease upon sexual function in 40 patients (mean age 56.6 y). The 11-questions accepted questionnaire addressing sexual drive, erectile function, and ejaculation was used. Information regarding, age, medications, hypertension, diabetes, relevant risk factors, medical history, and the number of occluded coronary vessels was retrieved from the patients’ records. A statistically significant correlation was demonstrated between erectile function and the number of coronary vessels involved. Patients with one-vessel disease had more (P<0.04) and firmer erections (P<0.001) with fewer difficulties in achieving an erection (P<0.007) than men with two- or three-vessel disease. Age, diabetes, and hypertension also had a negative effect on the quality of the erection (P<0.05) in all patients.

Effect of multifactorial treatment on non-alcoholic fatty liver disease in metabolic syndrome: a randomised study

ABSTRACT Background: Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome (MetS). There is no established treatment for NAFLD. Aim: To evaluate a multifactorial intervention in the treatment of NAFLD. Methods: A prospective, open-label, randomised study in non-diabetic patients (n = 186) with MetS (follow-up: 54 weeks). All patients had both biochemical and ultrasonographic evidence of NAFLD at baseline. Other causes of liver disease were excluded. Patients received lifestyle advice and treatment for hypertension (mainly inhibitors of the renin–angiotensin system), impaired fasting glucose (metformin), obesity (orlistat) and dyslipidaemia [randomly allocated to atorvastatin 20 mg/day (n = 63) or micronised fenofibrate 200 mg/day (n = 62) or both drugs (n = 61)]. Liver ultrasonography was assessed at baseline and at the end of the study. Results: At the end of treatment, 67% of patients on atorvastatin, 42% on fenofibrate and 70% on combination treatment no longer had biochemical plus ultrasonographic evidence of NAFLD ( p < 0.05 vs. baseline for all comparisons). The percentage of patients who no longer had evidence of NAFLD was significantly higher ( p < 0.009) in the atorvastatin and combination groups compared with the fenofibrate group. This effect was independently related to drug treatment, as well as to reductions in high-sensitivity C-reactive protein, waist circumference, body weight, triglycerides, low-density lipoprotein-cholesterol, total cholesterol, systolic blood pressure and glucose. Four patients discontinued treatment because of adverse effects. Conclusions: Multifactorial intervention in MetS patients with both biochemical and ultrasonographic evidence of NAFLD offsets surrogate markers of NAFLD (i.e. elevated aminotransferase plus echogenic liver).

Effect of ethanol on vascular prostacyclin (prostaglandin I2) synthesis, platelet aggregation, and platelet thromboxane release

A series of experiments with platelets from healthy volunteers showed a concentration related inhibitory effect of ethanol on platelet aggregation and release of thromboxane A2. This effect was observed at blood alcohol concentrations ranging between 66 and 132 mg/dl (14.3 and 28.6 mmol/l), which are commonly found in alcoholics. Investigations carried out by incubating ethanol with platelet rich plasma in vitro also showed an inverse linear correlation between ethanol concentration and platelet thromboxane synthesis. In contrast, the incubation of a wide range of concentrations of ethanol with human endothelial cells and rat aortic rings did not alter the ability of these systems to synthesise prostacyclin (prostaglandin I2). This finding of a selective inhibition of thromboxane A2 synthesis and platelet aggregation without an alteration of prostaglandin I2 synthesis may provide an explanation for the reported ethanol mediated protection against vascular disease. This effect of ethanol may also be relevant to the induction of acute gastrointestinal haemorrhage that occurs after bouts of excessive alcohol consumption.

The prevalence of the metabolic syndrome using the National Cholesterol Educational Program and International Diabetes Federation definitions

ABSTRACT Objective: The prevalence of metabolic syndrome (MetS), using the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) and International Diabetes Federation (IDF) definitions, was compared in 9669 subjects, representing the Greek population. Results: The age-adjusted prevalence of NCEP ATP III-defined MetS was 24.5% whereas that of IDF-defined MetS was 43.4% (+77%, p < 0.0001). The majority (up to 69%) of older age groups had IDF-defined MetS. The calculated vascular event risk was low (6.1% and 7.2% using the Framingham and PROCAM calculation, respectively) in those with IDF-defined MetS when compared with those with NCEP ATP III MetS (11.3% and 13.7%, respectively) ( p < 0.0001 for both comparisons). Conclusion: MetS could be considered as a ‘normal’ variant if it was present in the majority of the population. Moreover, the vascular risk associated with IDF-defined MetS could be low, raising cost-effectiveness issues. Alternatively, the new IDF definition may realistically reflect the current MetS epidemic. More studies are required to support or refute those interpretations.

Orlistat-Associated Adverse Effects and Drug Interactions A Critical Review

Orlistat, an anti-obesity drug, is a potent and specific inhibitor of intestinal lipases. In light of the recent US FDA approval of the over-the-counter sale of orlistat (60 mg three times daily), clinicians need to be aware that its use may be associated with less well known, but sometimes clinically relevant, adverse effects. More specifically, the use of orlistat has been associated with several mild-to-moderate gastrointestinal adverse effects, such as oily stools, diarrhoea, abdominal pain and faecal spotting. A few cases of serious hepatic adverse effects (cholelithiasis, cholostatic hepatitis and subacute liver failure) have been reported. However, the effects of orlistat on non-alcoholic fatty liver disease are beneficial. Orlistat-induced weight loss seems to have beneficial effects on blood pressure. No effect has been observed on calcium, phosphorus, magnesium, iron, copper or zinc balance or on bone biomarkers. Interestingly, the use of orlistat has been associated with rare cases of acute kidney injury, possibly due to the increased fat malabsorption resulting from the inhibition of pancreatic and gastric lipase by orlistat, leading to the formation of soaps with calcium and resulting in increased free oxalate absorption and enteric hyperoxaluria. Orlistat has a beneficial effect on carbohydrate metabolism. No significant effect on cancer risk has been reported with orlistat.Orlistat interferes with the absorption of many drugs (such as warfarin, amiodarone, ciclosporin and thyroxine as well as fat-soluble vitamins), affecting their bioavailability and effectiveness.This review considers orlistat-related adverse effects and drug interactions. The clinical relevance and pathogenesis of these effects is also discussed.

Statin-fibrate combination therapy for hyperlipidaemia: a review

SUMMARY Statins and fibrates are well-established treatments for hyperlipidaemias and the prevention of vascular events. However, fibrate + statin therapy has been restricted following early reports of rhabdomyolysis that mainly involved gemfibrozil, originally with lovastatin, and recently, with cerivastatin. Despite this limitation, several reports describing combination therapy have been published. This review considers these studies and the relevant indications and contraindications. Statin + fibrate therapy should be considered if monotherapy or adding other drugs (e.g. cholesterol absorption inhibitors, omega-3 fatty acids or nicotinic acid) did not achieve lipid targets or is impractical. Combination therapy should be hospital-based and reserved for high-risk patients with a mixed hyperlipidaemia characterised by low density lipoprotein cholesterol (LDL) > 2.6 mmol/l (100 mg/dl), high density lipoprotein cholesterol (HDL) < 1.0 mmol/l (40 mg/dl) and/or triglycerides > 5.6 mmol/l (500 mg/dl). These three ‘goals’ are individually mentioned in guidelines. Patients should have normal renal, liver and thyroid function tests and should not be receiving therapy with cyclosporine, protease inhibitors or drugs metabolised through cytochrome P450 (especially 3A4). Combination therapy is probably best conducted using drugs with short plasma half-lives; fibrates should be prescribed in the morning and statins at night to minimise peak dose interactions. Both drug classes should be progressively titrated from low doses. Regular (3-monthly) monitoring of liver function and creatine kinase is required. In conclusion, fibrate + statin therapy remains an option in high-risk patients. However, long-term studies involving safety monitoring and vascular endpoints are required to demonstrate the efficacy of this regimen.

Meta-analysis of the cholesterol-lowering effect of ezetimibe added to ongoing statin therapy

ABSTRACT Objective: To review and analyse the evidence for the cholesterol-lowering effect of ezetimibe in adult patients with hypercholesterolaemia who are not at low-density lipoprotein cholesterol (LDL‑C) goal on statin monotherapy. Research design: Systematic review and meta-analysis. Methods: MEDLINE and EMBASE were searched to identify ezetimibe randomised controlled trials (RCTs) published between January 1993 and December 2005. The meta-analysis combined data from RCTs, with a minimum treatment duration of 6 weeks, that compared treatment with ezetimibe 10 mg/day or placebo added to current statin therapy. The difference between treatments was analysed for four co-primary outcomes: mean percentage change from baseline in total cholesterol (TC), LDL‑C, and high-density lipoprotein cholesterol (HDL‑C), and number of patients achieving LDL‑C treatment goal. Meta-analysis results are presented for a modified version of the inverse variance random effects model. Results: Five RCTs involving a total of 5039 patients were included in the meta-analysis. The weighted mean difference (WMD) between treatments significantly favoured the ezetimibe/statin combination over placebo/statin for TC (–16.1% (–17.3, –14.8); p < 0.0001), LDL‑C (–23.6% (–25.6, –21.7); p < 0.0001) and HDL‑C (1.7% (0.9, 2.5); p < 0.0001). The relative risk of reaching the LDL‑C treatment goal was significantly higher for patients on ezetimibe/statin relative to those on placebo/statin (3.4 (2.0, 5.6); p < 0.0001). In pre-defined sub-group analyses of studies in patients with coronary heart disease, the WMD between treatments remained significantly in favour of ezetimibe/statin ( p < 0.0001) for TC and LDL‑C but was no longer significant for HDL‑C. Elevations in creatine kinase, alanine aminotransferase or aspartate aminotransferase that were considered as an adverse effect did not differ significantly between treatments. Conclusions: The meta-analysis we performed included only five studies and was restricted to analysis of the changes in cholesterol levels relative to baseline. However, the results suggest that ezetimibe co-administered with ongoing statin therapy provides significant additional lipid-lowering in patients not at LDL‑C goal on statin therapy alone, allowing more patients to reach their LDL‑C goal.

Intraplatelet serotonin in patients with diabetes mellitus and peripheral vascular disease

Abstract Intraplatelet serotonin (5‐HT) content was determined in 23 patients with type I (insulin‐dependent) diabetes mellitus (IDDM), 23 patients with type II (non‐insulin‐dependent) diabetes mellitus (NIDDM), 29 patients with peripheral vascular disease (PVD) and 34 age‐matched normal subjects. Intraplatelet 5‐HT content in normal subjects showed an age‐related decline (r=–0·45; P < 0·008), as has been previously demonstrated. The median 5‐HT content in platelets of the young normal subjects was 4·36 (range: 3·62–6·79) nmol 10‐9platelets, while that in the elderly normal subjects was 3·87 (range: 2·8–6·0) nmol 10‐9platelets and that in young+elderly subjects was 4·05 (range: 2·8–6·8) nmol 10‐9platelets. The median intraplatelet 5‐HT content was significantly lower (P < 0·002) in IDDM patients: 3·0 (range 1·3–6·3), NIDDM patients: 2·5 (range 1·7–5·8), PVD patients: 2·42 (range 0·94–4·98) nmol 10‐9platelets than that in all young+elderly healthy subjects. The presence of hypertension in DM patients caused a small but significant (P < 0·05) decrease in intraplatelet 5‐HT content, whilst its presence had no effect in PVD patients. In a smaller study, it was established that NIDDM and PVD patients have significantly (P < 0·002) greater plasma 5‐HT concentrations than controls. Insulin‐dependent diabetes mellitus patients had greater plasma 5‐HT concentrations but this did not achieve statistical significance despite a 66% increment in its value. We conclude that the diminished 5‐HT content in platelets and the increased plasma levels may reflect enhanced release of 5‐HT by hyperactive platelets. This increase in plasma 5‐HT may contribute to the pathogenesis of atherosclerosis and vasospasm.

The GREek Atorvastatin and Coronary-heart-disease Evaluation (GREACE) Study

BACKGROUND Metabolic syndrome (MetS) is associated with increased risk for both vascular and chronic kidney disease. Whether statins ameliorate these risks is not established. METHODS This post hoc analysis of the GREek Atorvastatin and Coronary heart disease (CHD). Evaluation (GREACE) examines the effect of statins on estimated glomerular filtration rate (e-GFR) and serum uric acid (SUA) levels and their relation to vascular events in CHD patients with MetS. MetS patients were divided into two groups: Group A (n = 365) received lifestyle advice, target-driven treatment with statins (mainly atorvastatin) and treatment for hypertension and elevated glucose. Group B (n = 347) received the same except for statins. Patients without MetS were divided into those who received treatment similar to Group A and Group B [Groups C (n = 504) and D (n = 384), respectively]. All patients were followed for 3 years. RESULTS A total of 12.1% of patients in Group A experienced a vascular event vs 28% in Group B; risk ratio (RR) 0.43, 95% confidence interval (CI) 0.20-0.64, P < 0.0001, while in those without MetS (Group C vs Group D), the respective RR was 0.59, 95% CI 0.41-0.79, P < 0.0001. In Group A, e-GFR increased by 13.7% and SUA levels fell by 8.9%, while in Group B e-GFR was reduced by 5.8% and SUA increased by 4.3% (P < 0.005). Stepwise regression analysis showed that these changes were independently related to vascular events. CONCLUSION Among CHD patients, those with MetS benefited more from statin treatment than those without MetS. This benefit could be partially attributed to favourable changes in e-GFR and SUA levels probably induced by statin treatment.