Why are Cochrane hepato-biliary reviews undervalued by physicians as an aid for clinical decision-making?

BACKGROUND: Cochrane systematic reviews are of higher quality than reviews published in scientific journals, yet are used less than other sources for clinical decision-making. AIM: To assess whether the characteristics of the Cochrane systematic reviews can account for their scant use by physicians. MATERIALS AND METHODS: We analysed the 87 Cochrane hepato-biliary reviews dealing with therapeutic topics posted in the Cochrane Database of Systematic Reviews through December 2008, which we classified according to four characteristics: empty reviews; outdated reviews; content of reviews; implications for practice. RESULTS: Six empty reviews found no eligible randomised trials and six found one trial, precluding a systematic review; some empty reviews investigated irrelevant topics. Twenty-one reviews investigated outdated interventions, and thirteen of them were posted ten or more years after the publication of the most recent trial included. Most reviews were too lengthy (median: 40 pages) and their consultation was time-consuming with respect to clinical content. They generally compared two treatments, disregarding other options, and usually did not report any non-randomised (although convincing) evidence of potential use in clinical decision-making. CONCLUSIONS: If generalized to the entire Cochrane Database of Systematic Reviews, these characteristics may largely explain why physicians undervalue the Cochrane reviews as a source of evidence for clinical decision-making.

[Professional driving and safety, a target for occupational medicine]. / Guida professionale e sicurezza, un approccio obiettivo che coinvolge anche la medicina del lavoro.

BACKGROUND: Road traffic injuries constitute one of the main causes of death and disability in Italy and in the European Union. Occupational medicine should pay special attention to the field of road transport because every year a large number of road accidents occur with fatal outcomes. Via health surveillance the occupational physician can play an important role in the prevention of such events. OBJECTIVES: The aim of the article is to summarize the results of the most recent studies on the main risk factors for road transport safety and discuss possible strategies of health surveillance, according to the recent indications of the European Agency for Safety and Health at Work, Bilbao. METHODS: A review of the literature was made. RESULTS AND CONCLUSIONS: The scientific literature provides a large amount of interesting information on the most important risk factors for road accidents, such as drinking and drug abuse, sleepiness and other medical conditions, or excessive speed. The presence of numerous and varied hazards for road transport safety requires, as suggested by the Bilbao Agency, the adoption of occupational health measures, including risk assessment, health education, technical and environmental prevention, health surveillance and clinical interventions (diagnosis and rehabilitation of occupational accidents). Moreover, the paper stresses the need to strengthen collaboration between occupational health physicians and other medical specialists.

The Myocardial Performance Index detects chronic cardiac allograft dysfunction sooner than other methods.

AIM: Many noninvasive techniques have been proposed for the early detection of chronic heart graft dysfunction. Diastolic dysfunction may precede systolic dysfunction, and often is prominent; therefore, the aim of the study was to investigate the clinical and prognostic value of a Doppler-derived index of both systolic and diastolic function in heart transplanted patients (Myocardial Performance Index, MPI). METHODS: The MPI was measured in 63 consecutive patients (mean age 55 years, 49 men and 14 women) in sinus rhythm with an orthotopic heart transplantation for at least 1 year (mean 5.3 years) and in 63 age and sex-matched controls. A complete clinical examination was performed at the time of enrollment and was repeated after 3 months. RESULTS: At 3 months, 11 patients (17.5%) presented events (heart failure, hospitalisation or cardiac death). Patients were divided into 2 groups: Group A (52 patients) without events in the follow-up and Group B (11 patients) with events. The values of MPI in Group B (0.55+/-0.19) were significantly higher than values in Group A (0.34+/-0.18, P=0.001). Whereas the values of the index did not differ significantly between Group A and control group (0.34+/-0.18 vs 0.33+/-0.10, P=NS). In the univariate analysis, the population of heart transplanted patients was dichotomised in subgroups by a cut-off MPI of 0.47 and a cut-off ejection fraction (EF) of 50%. Nine patients (41%) with MPI=or>0.47 presented events, while only 2 patients (5%) with MPI<0.47 had any event (P<0.001; c2 12.9). Six patients (85%) with EF<50% had events, while only 5 patients (9%) with EF=or>50% had an event (P<0.001; c2 14). In the multivariate analysis only MPI (chi squared=22.6, P=0.018) and EF (chi squared=20.8, P=0.025) were significant independent predictors of heart failure or cardiac death. By looking at Kaplan-Meyer curves, MPI seems to be better than EF in the earlier detection of graft dysfunction. CONCLUSION: MPI, as a combined systolic and diastolic index, may detect graft dysfunction earlier than EF.

Binding by serum IgA antibodies from patients with coeliac disease to monkey heart tissue.

BACKGROUND: The recently reported increased prevalence of coeliac disease in heart transplant candidates and in patients with autoimmune myocarditis may suggest an autoimmune process towards antigenic components of both myocardium and small bowel. The objective of this study was to determine the possible presence of IgA antibodies directed against heart tissue in sera from patients with coeliac disease. METHODS: Sera samples from 28 biopsy-proven coeliac disease patients and 81 controls (both healthy and diseased) were assessed by indirect immunofluorescence, with fluorescein isothiocyanate labelled rabbit anti-human IgA, on commercial monkey cardiac muscle sections. RESULTS: A strong fluorescence around heart muscle fibres was found in 13 out of 15 untreated patients but none in either those treated for coeliac disease or in controls. Pretreatment with tissue transglutaminase, a prominent coeliac auto-antigen, abolished the typical fluorescent pattern almost completely. CONCLUSIONS: Our study demonstrates that in untreated coeliac disease there is a reaction of IgA antibodies sera, yielding a strong fluorescence, with monkey heart structures, and that tissue transglutaminase is the target antigen in this reaction.

One year temporal pattern of neurohumoral factors and natriuretic peptides compared with clinical variables in patients with dilated cardiomyopathy.

BACKGROUND: Elevated levels of neuroendocrine peptides and hormones are some of the compensatory mechanisms activated in patients with congestive heart failure. The aim of this study was to describe their time related variability in clinically stable patients and to compare hormones and peptides levels to clinical variables. METHODS: Nineteen patients with history of congestive heart failure due to dilated cardiomyopathy and in sinus rhythm were recruited. At baseline, after 3 months, and at 1 year they underwent 6-min walk test, Minnesota Living with Heart Failure Questionnaire, and blood measurements of ANP, BNP, plasma renin activity, aldosterone, norepinephrine and epinephrine. RESULTS: After 1 year, 17 patients remained clinically stable, and did not change their therapy and functional class. Also echocardiographic data and neurohormonal parameters did not change significantly except for epinephrine that decreased significantly after 3 months and returned to a value similar to the basal one at 1 year. Two outliner values were observed for norepinephrine belonging to the only 2 patients that spontaneously withdrew the ace-inhibitor therapy during the follow-up. CONCLUSIONS: This study indicates that plasma concentration of neurohormones and peptides were fairly stable over 1 year interval in stable patients with mild-moderate heart failure due to dilated cardiomyopathy and that norepinephrine could be considered as the most sensible parameters to monitor therapy compliance.

GH-independent cardiotropic activities of hexarelin in patients with severe left ventricular dysfunction due to dilated and ischemic cardiomyopathy.

AIM: To investigate acute cardiotropic activities of hexarelin in patients with severe left ventricular dysfunction due to ischemic (iCMP) and dilated cardiomyopathy (dCMP). METHODS AND RESULTS: We studied the effect of intravenous hexarelin administration on growth hormone (GH) levels and left ventricular ejection fraction (LVEF) evaluated by radionuclide angiography in eight patients with dCMP (age 53.0+/-2.8, LVEF 16.7+/-2.1%) and five patients with iCMP (age 52.0+/-2.8 years, LVEF 22.6+/-2.1). Results were compared with a group of seven normal subjects (age 37.4+/-3.4 years, LVEF 64.0+/-1.5%) and seven patients with severe growth-hormone deficiency (GHD; age 42.0+/-4.4 years, LVEF 50.0+/-1.9%) previously studied with the same methodology. In dCMP and iCMP patients hexarelin induced a similar significant (P<0.05) increase in GH levels. In iCMP patients hexarelin induced a LVEF increase (peak LVEF 26.2+/-2.5%, P<0.05) as observed in normals and GHD, while in dCMP LVEF was unchanged (peak LVEF 17.7+/-1.7, P=NS). In all groups other hemodynamic parameters were unchanged. CONCLUSIONS: Acute hexarelin administration increases LVEF in iCMP patients (as in normals and GHD) but not in dCMP patients in spite of a similar GH releasing effect and basal LVEF. A possible explanation of the positive inotropic effect of hexarelin in iCMP could be a direct stimulation on viable myocardium or myocardial contractile reserve.

Inaccuracy of four coronary surgery risk-adjusted models to predict mortality in individual patients.

OBJECTIVES: This study was undertaken to evaluate the accuracy of four different risk-adjusted models in predicting mortality in individual patients who are undergoing coronary artery by-pass graft surgery. In the last decade several models to stratify patients before open heart surgery, according to factors affecting mortality, were developed with the aim of retrospectively comparing outcomes of open heart surgery, based on reliable stratification of case-mix, and of prospectively identifying high risk patients as a basis for a meaningful informed consent for patients counseling. METHODS: The pre-operative risk of death was calculated with four different models in 418 consecutive patients who underwent coronary artery by-pass surgery and then compared with the actual outcome. To discriminate patients with favorable and unfavorable outcome, the logistic regression analysis and the areas under the receiver-operating-characteristic curves were applied. The accuracy score was used to evaluate the reliability of each score to predict the individual outcome. RESULTS: Seven deaths (1.7%) were observed within 30 days from the operation, and the overall incidence was similar to that predicted by all models. Only the NBI score was not able to discriminate survivors from patients who will die, and the areas under the curves were 0.596 for the Parsonnet score, 0.861 for the Cleveland Clinic Foundation score, 0.823 for the French score, and 0.806 for the EuroSCORE. The four models were highly accurate (between 0.97 and 0.98) to predict the overall mortality. In seven patients who died the mean predictive scores were very low and ranged between 2.1 and 4.6, but were significantly higher than those of patients who survived (between 1.1 and 2.2). CONCLUSIONS: The four pre-surgical predictive models were similarly able to discriminate favorable vs. unfavorable outcomes and highly accurate to predict overall mortality, but very inaccurate to predict mortality in individual patients.

Growth hormone-independent cardiotropic activities of growth hormone-releasing peptides in normal subjects, in patients with growth hormone deficiency, and in patients with idiopathic or ischemic dilated cardiomyopathy.

Growth hormone releasing peptides (GHRPs) are synthetic molecules endowed with potent neuroendocrine activities mediated by specific receptors in the pituitary and in the central nervous system. GHRPs receptors have been reported even in perpheral tissues, particularly in the myocardium, where they probably mediate growth hormone (GH)-independent activities. We studied in humans the cardiac effects of hexarelin administration in 7 normal adults, in 7 severe GH-deficient patients, and in 12 patients with severe dilated cardiomyopathy. Left ventricular ejection fraction (LVEF), mean blood pressure (MBP), heart rate (HR), and GH levels were evaluated at baseline and every 15 min up to 60 min after acute 2.0 microg/kg iv hexarelin administration. Basal LVEF in dilated cardiomyopathy was impaired and lower (p < 0.001) than in GH deficiency, in turn lower (p< 0.001) than in normal subjects. Hexarelin signficantly (p < 0.05) increased LVEF in normal and in GH-deficient subjects, but not in dilated cardiomyopathy, without significant variations in MBP and HR. Hexeralin significantly (p < 0.05) increased GH levels in normal subjects and in dilated cardiomyopathy but not in GH deficiency. These findings suggest that, in humans, the acute administration of hexarelin exerts a GH-independent positive inotropic effect likely mediated by specific GHRPs myocardial receptors.

[The new limitations of the Italian Regulatory Agency on Drugs]. / Le nuove "note" limitative della Commissione Unica del Farmaco.

In Italy the reimbursement of few free-of-charge drugs is limited to subgroups of patients or to one of the approved indications. In February 2001 new rules will become mandatory for Italian physicians. The text of the new rules related to drugs mostly used by cardiologists (levocarnitine, ticlopidine, hypolipemic drugs) is reported.

Effect of digoxin on the somatotroph responsiveness to growth hormone-releasing hormone (GHRH) alone or combined with arginine in normal young volunteers.

BACKGROUND: The activity of the GH/IGF-I axis, known to play a major role in myocardial structure and function, has been reported to be altered in patients with chronic heart failure. AIM AND DESIGN OF THE STUDY: In order to evaluate the possibility that clinically used cardioactive drugs may exert neuroendocrine influences on somatotroph secretion, we studied the effects of pretreatment with enalapril (20 mg/day orally for 3 days), furosemide (20 mg i.v. as a bolus at -5 minutes) or digoxin (0.25 mg orally 4x/day for 3 days) on the GH response to growth hormone-releasing hormone (GHRH) (1.0 microg/ kg i.v. as a bolus at 0 minutes) in 12 healthy male adults (age [mean +/- SEM] 30.2 +/- 1.4 years; BMI 22.7 +/- 0.7 kg/ m2). In a subgroup of 8 subjects the same study was performed testing the GH response to GHRH + arginine (ARG; 0.5 g/kg i.v. from 0 to + 30 minutes). RESULTS The GH response to GHRH (1,304.1 +/- 248-5 microg/l/h) was not modified by enalapril (1,368.7 +/- 171.2 microg/l/h) or by furosemide (1,269.3 +/- 185.2 microg/l/h) but was significantly blunted by digoxin (613.6 +/- 73.2 microg/l/h, P < 0.05). On the other hand digoxin, enalapril and furosemide did not modify the GH response to GHRH +ARG. CONCLUSIONS: Digoxin, but not enalapril or furosemide, inhibits the GH response to GHRH in normal subjects. The blunting effect of digoxin on the GHRH-induced GH response is counteracted by arginine. These findings show that digoxin possesses an inhibitory effect on somatotroph secretion that may be mediated at the hypothalamic level.

[We, the Italian physicians, and statins]. / Noi, medici italiani, e le statine.

After marketing withdrawal of cerivastatin physicians asked several questions regarding the efficacy and safety of statins, the real risk of myopathy, the compared efficacy of all the statins, the reasons why severe adverse events could happen despite several long-term randomized controlled trials, the approval from regulatory agencies. This is the position statement of the Italian Federation of Cardiology. Synthetic answers to previous questions are addressed and few suggestions to avoid that similar conditions should occur again. Finally, the appropriate prescription of statins is recommended.

[Interaction between congestive heart failure and diabetes mellitus: critical review of the literature]. / Interazioni tra scompenso cardiaco e diabete mellito: revisione critica della letteratura.

It is known from the Framingham Heart Study that there is a relationship between congestive heart failure and diabetes mellitus. Diabetes can cause myocyte hypertrophy, interstitial fibrosis, impaired myocardial blood flow, increased turnover of free fatty acids, leading to the development of cardiomyopathy. On the other hand, heart failure increases catecholamine plasma levels and it may cause insulin resistance, leading to the development of diabetes. We report and discuss data from the literature: ACE-inhibitors do not alter glucose metabolism, non selective beta-blockers increase insulin resistance, while beta-blockers with vasodilating properties do not seem to alter insulin sensitivity, and high doses of diuretics seem to have a negative effect on glycemic parameters. Since diabetes has a high prevalence among patients with heart failure, it is clinically relevant to monitor glycemic parameters in such patients and also to evaluate changes in the therapy.

[Cardiologists and limitations of statins reimbursement]. / I cardiologi e la limitazione della rimborsabilità delle statine.

BACKGROUND: In Italy of five approved HMG-CoA reductase inhibitors (atorvastatin, cerivastatin, fluvastatin, pravastatin, and simvastatin) only the last two are reimbursed by the National Health System for secondary prevention of coronary artery disease. METHODS: During the 1999 Annual Meeting of the National Association of Hospital Cardiologists (ANMCO) a questionnaire was included in the meeting material. The aim was two-fold: 1) to evaluate whether Italian cardiologists approve the National Health System policy to reimburse only pravastatin and simvastatin for secondary prevention, and 2) to assess which end-points are considered sufficient to grant the reimbursement of additional HMG-CoA reductase inhibitors. RESULTS: Two hundred and thirty-two completed questionnaires were collected and analyzed: 90.1% (95% confidence interval-CI between 85.1 and 93.6%) of cardiologists agree that only HMG-CoA reductase inhibitors with evidence-based mortality reduction should be reimbursed in Italy for secondary prevention; 75.0% (95% CI between 69.4 and 80.6%) follow the State guidelines in order to choose the approved HMG-CoA reductase inhibitors and 69.4% (95% CI between 63.5 and 75.3%) judge that at least the demonstration of coronary artery plaque reduction should be considered as an evidence-based decision to include new HMG-CoA reductase inhibitors for reimbursement. CONCLUSIONS: Most of Italian cardiologists who answered the questionnaire agreed with the limitation of reimbursement to only HMG-CoA reductase inhibitors with evidence-based demonstration of mortality reduction and asserted that the only reduction in blood cholesterol levels should not be considered proof of efficacy.

Normal IGF-I and enhanced IGFBP-3 response to very low rhGH dose in patients with dilated cardiomyopathy.

Well-nourished patients with dilated cardiomyopathy (DCM) show slight reduction of mean basal IGF-I levels which, however, display a response to a rhGH dose as low as 5.0 microg/kg/day similar to that of age-matched control subjects (CS). To further investigate peripheral GH sensitivity, we studied the IGF-I and IGFBP-3 responses to 4-day s.c. 2.5 microg/kg/day rhGH administration, the lowest effective dose able to increase IGF-I levels in normal subjects, in 10 DCM patients [age (mean+/-SE): 57.6+/-1.0 yr, body mass index (BMI): 24.0+/-1.2 kg/m2, left ventricular ejection fraction: 26.2+/-3.2%, NYHA (New York Heart Association): I/0, II/4, III/4, IV/2] and in 9 age-matched healthy CS (age: 55.3+/-1.2 yr, BMI: 23.7+/-1.8 kg/m2). Basal IGF-I levels in DCM were lower though not significantly than those in CS (147.7+/-9.8 vs 174.7+/-17.0 microg/l). Basal IGFBP-3 levels in DCM were similar to those in CS (3.1+/-0.3 vs 2.7+/-0.2 mg/l). In CS 4-day rhGH increased IGF-I levels (222.4+/-14.9 microg/l; p<0.01 vs baseline) but did not modify IGFBP-3 levels (3.0+/-0.2 mg/l). In DCM IGF-I levels were increased by 4-day rhGH administration (175.7+/-11.0 microg/l; p<0.05 vs baseline) with a similar percent extent than in CS. On the other hand, in DCM, but not in CS, 4-day rhGH significantly increased IGFBP-3 levels (3.5+/-0.3 mg/l; p<0.05 vs baseline). Therefore, in conclusion, testing with the lowest effective rhGH dose further suggest that peripheral GH sensitivity in well-nourished DCM is preserved. On the other hand, DCM patients show enhanced IGFBP-3 sensitivity to stimulation by rhGH.

[Surrogate end points]. / Gli end point surrogati.

In order to evaluate the efficacy of a treatment, "minor" end points (the reduction in serum cholesterol, blood pressure, serum creatinine) that have a pathophysiological or statistical relationship with the true end points (reduction in mortality, incidence of myocardial infarction, or surgical procedures) are often adopted. They are called surrogate end points because they are used instead of true end points. In cardiology the results of clinical trials with clofibrate, milrinone, flecainide and more recently with doxazosine have demonstrated that the reduction of a surrogate end point does not correspond to the reduction of mortality. To define a treatment for a patient, clinicians should distinguish surrogate from true end points choosing evidence-based treatments and avoiding those that are supported only by pathophysiological assumptions.

Patients with dilated cardiomyopathy show reduction of the somatotroph responsiveness to GHRH both alone and combined with arginine.

OBJECTIVE: Altered function of the GH/IGF-I axis in patients with dilated cardiomyopathy (DCM) has been reported. In fact, DCM patients show reduction of IGF-I levels, which could reflect slight peripheral GH resistance or, alternatively, reduced somatotroph secretion. Spontaneous GH secretion has been reported to be altered by some but not by other authors, whereas the GH response to GHRH, but not that to GH-releasing peptides, seems reduced in DCM patients. On the other hand, it is well known that the GH response to GHRH in humans is markedly potentiated by arginine (ARG), which probably acts via inhibition of hypothalamic somatostatin release; in fact the GHRH+ARG test is known as one of the most reliable to evaluate the maximal secretory capacity of somatotroph cells. METHODS: In order to further clarify the somatotroph function in DCM, in well-nourished patients with DCM (34 male, 4 female; age (mean+/-s.e. m.) 57.8+/-1.1 years; body mass index (BMI) 24.6+/-0.6kg/m(2); left ventricular ejection fraction 23.2+/-1.6%; New York Heart Association classification I/1, II/17, III/18, IV/2) we studied the GH response to GHRH (1.0 microgram/kg i.v.) alone or combined with ARG (0.5g/kg i.v.). The results in DCM patients were compared with those in age-matched control subjects (CS) (39 male, 7 female; age 58.9+/-1.0 years; BMI 23.2+/-0.3kg/m(2)). RESULTS: Mean IGF-I levels in DCM patients were lower than in CS (144.3+/-6.9 vs 175.1+/-8. 4 microgram/l, P<0.05) whereas basal GH levels were similar in both groups (1.7+/-0.3 vs 1.7+/-0.3 microgram/l). The GH response to GHRH in DCM patients was lower (P<0.05) than that in CS (GH peak 6.5+/-1.2 vs 10.7+/-2.1 microgram/l). In both groups the GH response to GHRH+ARG was higher (P<0.001) than that to GHRH alone. However, the GH response to GHRH+ARG in DCM patients remained clearly lower (P<0.01) than that in CS (18.3+/-3.2 vs 34.1+/-4.6 microgram/l). The GH response to GHRH alone and combined with ARG was not associated with the severity of the disease. CONCLUSION: DCM patients show blunted GH responses to GHRH both alone and combined with ARG. Evidence that ARG does not restore the GH response to GHRH in DCM patients makes it unlikely that the somatotroph hyporesponsiveness to the neurohormone reflects hyperactivity of hypothalamic somatostatinergic neurons.

Cholesterol and long-term mortality after acute myocardial infarction in elderly patients.

METHOD: We investigated the association of total serum cholesterol concentrations and subsequent overall and coronary mortality in 304 patients aged > or =65 discharged from hospital after acute myocardial infarction. RESULTS: There was no association between total cholesterol concentrations and mortality due to either coronary heart disease or to all causes in all patients or, separately, in men, women, patients younger than 75 and patients aged 75 years and older.