[Shared decision-making in metaclinical medicine: from informed consent to shared probability]. / Il processo decisionale condiviso nella medicina metaclinica: dal consenso informato alla probabilità condivisa.

At the dawn of "metaclinical medicine" era, shared decision-making represents the overcoming of modern medicine guidelines and classical medicine experience. The patient's life plan, the doctor's health plan, the scientist's evidence-based plan, the administrator's plan and the beliefs of the society for healthcare options should be integrated into the shared decision-making process to avoid patient's unrealistic expectations, doctor's self-referential and defensive medicine, the science without compassion of the scientist, the administered medicine of the politician, the herd mentality of artificial intelligence. For a doctor who must evaluate according to science and conscience, it becomes difficult to make decisions about a patient who thinks that there can be "no decisions about me without me". It risks being a pure declamatory statement in the absence of clinical knowledge and the associated concept of probability. The idea of moving from informed consent to shared probability is convenient for both the doctor and the patient but not for litigation professionals. Even in metaclinical medicine, clinical decision support systems, if well governed, would facilitate the choice of the best treatment according to the definition of absolute risk reduction and the number of patients to be treated to avoid an event, leaving it up to the doctor-patient relationship the narrative and the choice of the most appropriate treatment, which also requires taking care of the emotional and compassionate aspects.

[Process to insulin for type 2 diabetes mellitus therapy]. / Processo all'insulina nella terapia del diabete mellito di tipo 2.

In type 1 diabetes mellitus and in symptomatic and critical hyperglycemic states, insulin is a lifesaving drug; however, its value in long-term type 2 diabetes therapy, which represents more than 90% of diabetes, has not been assessed. This happens despite the fact that, in randomized studies on type 2 diabetes, insulin is used in two-thirds of cases when intensive hypoglycemic treatment is needed and in half of the patients when treatment is the standard one. This is a major issue from a clinical, economic and social-health organization point of view as insulin therapy is expensive and needs a complex organization. Observational and retrospective studies from the scientific literature show that in this type of diabetes insulin treatment is associated with increased cardiovascular and all-cause mortality. It is not clear whether this is due to a greater severity of the clinical picture, to the therapeutic target of blood glucose that may induce hypoglycemia, or to the intrinsic pharmacological activity of the drug that beyond reducing hyperglycemia can cause hypoglycemia, water retention, weight gain and hyperinsulinemia with proatherogenic effects. In particular, in patients with heart failure at high cardiovascular risk or with high insulin resistance, these clues are supported by meaningful data. Although there is no definitive evidence (the so-called "smoking gun") from randomized controlled trials, the high degree of suspicion induces the preferential choice of other drugs such as sodium-glucose co-transporter 2 inhibitors, glucagon-like peptide-1 receptor agonists and metformin beyond avoiding glycemic targets that induce hypoglycemia, especially in frail, elderly patients, or patients with cardiovascular diseases. These drugs, for their proven efficacy and the easy use within an outpatient setting (that favors their prescription and improves the inertia of the doctor and the adherence of patients), could help a more effective treatment of patients, both for quality and life expectancy beyond mere glycemic control.

[Mitral mass and severe mitral regurgitation in a patient with heart failure: differential diagnosis]. / Massa mitralica ed insufficienza di grado severo in paziente con scompenso cardiaco: diagnosi differenziale.

We describe the case of an 84-year-old woman, hospitalized for acute heart failure, presenting with an intracardiac mass detected on echocardiography. The differential diagnosis and the usefulness of multimodality imaging are discussed.

[The patient in clinical research: disposable guinea pig or involved actor?] / Il paziente nella ricerca clinica: cavia a disposizione o attore interessato?

BACKGROUND: The request for informed consent to join a clinical trial often creates mistrust and hesitation in the patient who should be enrolled. In our study, we evaluated the reasons for refusing to participate in a clinical trial. METHODS: In the last 10 years of cardiovascular clinical research, we asked an informed consent to 2586 patients for intervention studies. Overall, 59% agreed to join clinical trials, 40% refused. The 1% initially accepted and then withdrew the consent. Those who refused were more frequently women, relatively younger (mean age 62 ± 5 vs 74 ± 9 years) and had a higher level of education and income. We asked all these patients who refused to answer a brief questionnaire about the reasons for rejection. RESULTS: Of 1031 patients, 629 (61%), accepted to answer the interview; 176 (28%) answered they refused on relatives', friends' or other doctors' advices, or after Internet searches; 157 (25%) answered they did not agree about how the trials were carried out (double-blind control procedure, use of placebo); 126 (20%) did not trust official medicine; 63 (10%) could not guarantee their presence at the follow-up visits; 69 (11%) did not want to undergo additional medical examinations; 31 (5%) had previous bad research experiences (feeling like a guinea pig); 7 (about 1%) refused for other reasons. CONCLUSIONS: Recruitment into clinical research studies is still a major challenge. Patients, due to a prevailing humanistic culture, are not fully aware of the importance of participation in clinical research, which is sometimes considered as exclusive economic or prestige interest. In our experience, people who refused participation in the trials were younger, with a high level of education and income, more frequently women. The researcher's task is to motivate the patient by emphasizing that participating in a study means being the actors of a treatment choice and that one is a guinea pig when taking untested therapies.

Stable atypical chest pain with negative anatomical or functional diagnostic test: Diagnosis no matter what or prevention at any cost?

BACKGROUND: Approximately 1% to 2% of patients with stable atypical chest pain (SACP) experienced a major coronary event, even after a negative functional or anatomical test. METHODS: Over the past 15 years, 1706 patients with SACP evaluated in our clinics underwent functional stress testing or coronary computed tomographic angiography (CTA). In these patients, we also assessed the presence of three major modifiable lifestyle-related risk factors (cigarette smoking, low intake of fruit and vegetables, and physical inactivity). Patients were stratified according to the presence of at least one risky lifestyle factor or no risky lifestyle factors. Functional or anatomical tests were positive in 170 patients (10%). We followed the remaining 1536 patients with negative tests for 1 year to evaluate the incidence of major coronary events. RESULTS: The percentage of patients reporting major coronary events was 1.2% in the group with risky lifestyles and 0.2% in the non-risky lifestyle group (P < .01). Events were more common in smokers. CONCLUSIONS: Patients with SACP, when functional or anatomical tests are negative, have a residual risk of fatal and non-fatal cardiovascular events of 1% at 1 year of follow-up. People with incorrect lifestyles, especially smokers, have a higher risk of events. We think that in this population, a more effective intervention on lifestyles could be the key to reduce major cardiovascular events.

Insulin treatment and clinical outcomes in patients with diabetes and heart failure with preserved ejection fraction.

AIMS: Insulin causes sodium retention and hypoglycaemia and its use is associated with worse outcomes in heart failure (HF) with reduced ejection fraction. We have investigated whether this is also the case in HF with preserved ejection fraction (HFpEF). METHODS AND RESULTS: We examined the association between diabetes/diabetes treatments and the risk of the primary composite of cardiovascular death or HF hospitalization, as well as other outcomes in adjusted analyses in CHARM-Preserved (left ventricular ejection fraction ≥ 45%), I-Preserve and TOPCAT (Americas) pooled. Of 8466 patients, 2653 (31%) had diabetes, including 979 (37%) receiving insulin. Patients receiving insulin were younger, had a higher body mass index, prevalence of ischaemic aetiology, N-terminal pro-B-type natriuretic peptide and use of diuretics, worse New York Heart Association class and signs and symptoms, and worse quality of life and renal function, compared to patients with diabetes not on insulin. Among the 1398 patients with echocardiographic data, insulin use was associated with higher left ventricular end-diastolic pressure and more diastolic dysfunction than in other participants. The primary outcome occurred at a rate of 6.3 per 100 patient-years in patients without diabetes, and 10.2 and 17.1 per 100 patient-years in diabetes patients without and with insulin use, respectively [fully adjusted hazard ratio (aHR) insulin-treated diabetes vs. other diabetes: 1.41, 95% confidence interval (CI) 1.23-1.63, P < 0.001]. The adjusted HR is 1.67 (95% CI 1.20-2.32, p = 0.002) for sudden death (insulin-treated diabetes vs. other diabetes). CONCLUSIONS: Insulin use is associated with poor outcomes in HFpEF. Although we cannot conclude a causal association, the safety of insulin and alternative glucose-lowering treatments in HF needs to be evaluated in clinical trials.

[Medical intensive care unit patients with hyperglycemia: is it possible a hypoglycemic risk close to zero?] / Il cardiopatico iperglicemico in area critica: è possibile un rischio ipoglicemico zero?

BACKGROUND: In patients with diabetic or stress hyperglycemia hospitalized for acute cardiovascular disease, the occurrence of hypoglycemia increases the risk of mortality and morbidity without this being counterbalanced by a reduction in events related to a tighter glycemic control. The guidelines on this topic agree in excluding intensive treatment, but are very discordant in recommending a conventional (<180 mg/dl) or milder (<200 mg/dl) blood glucose control. METHODS: In 1256 hyperglycemic patients (mean age 74 ± 12 years) admitted to the medical intensive care unit (MICU) for acute coronary syndrome or acute heart failure, we adopted a nurse-led protocol of mild blood glucose control with subcutaneous administration of insulin, called "BBC200" (basal-bolus correction insulin regimen with glycemic target <200 mg/dl), with the aim at maintaining average blood glucose <200 mg/dl and an indication for intravenous insulin only for blood glucose >350 mg/dl. A retrospective analysis was carried out for assessing the occurrence of hypoglycemic episodes (blood glucose <70 mg/dl) and therapeutic failure (persistent hyperglycemia with values >240 mg/dl). RESULTS: Mean blood glucose was 261 ± 72 mg/dl on admission and 173 ± 50 mg/dl during treatment. Five patients (0.2%) required intravenous insulin infusion. There was only one case of severe hypoglycemia (≤40 mg/dl) due to an error of administration, and 2 cases of moderate hypoglycemia (41-70 mg/dl), with a total hypoglycemia rate of 0.24%. Transient therapeutic failure occurred in 27% of cases. CONCLUSIONS: In MICU hyperglycemic patients, the simple, intuitive and economical "BBC200" protocol could lead to a hypoglycemic risk very close to zero (0.24%), with a significant reduction in hypoglycemia-related clinical events and a modest increase in persistent hyperglycemic phenomena.

Treatment with insulin is associated with worse outcome in patients with chronic heart failure and diabetes.

AIMS: Up to one-third of patients with diabetes mellitus and heart failure (HF) are treated with insulin. As insulin causes sodium retention and hypoglycaemia, its use might be associated with worse outcomes. METHODS AND RESULTS: We examined two datasets: 24 012 patients with HF from four large randomized trials and an administrative database of 4 million individuals, 103 857 of whom with HF. In the former, survival was examined using Cox proportional hazards models adjusted for baseline variables and separately for propensity scores. Fine-Gray competing risk regression models were used to assess the risk of hospitalization for HF. For the latter, a case-control nested within a population-based cohort study was conducted with propensity score. Prevalence of diabetes mellitus at study entry ranged from 25.5% to 29.5% across trials. Insulin alone or in combination with oral hypoglycaemic drugs was prescribed at randomization to 24.4% to 34.5% of the patients with diabetes. The rates of death from any cause and hospitalization for HF were higher in patients with vs. without diabetes, and highest of all in patients prescribed insulin [propensity score pooled hazard ratio for all-cause mortality 1.27 (1.16-1.38), for HF hospitalization 1.23 (1.13-1.33)]. In the administrative registry, insulin prescription was associated with a higher risk of all-cause death [odds ratio (OR) 2.02, 95% confidence interval (CI) 1.87-2.19] and rehospitalization for HF (OR 1.42, 95% CI 1.32-1.53). CONCLUSIONS: Whether insulin use is associated with poor outcomes in HF should be investigated further with controlled trials, as should the possibility that there may be safer alternative glucose-lowering treatments for patients with HF and type 2 diabetes mellitus.

Large Left Ventricular Aneurysm and Multifocal Myocardial Involvement in a Patient With Systemic Sclerosis.

A 43-year-old man with systemic sclerosis and chest pain had negative T waves in precordial electrocardiographic leads. The echocardiogram showed a large left ventricular apical accessory chamber. The coronary arteries were normal. Cardiac magnetic resonance imaging (MRI) showed a large fibrotic aneurysm and a small patch of midwall late enhancement in the septum. The aneurysm was surgically removed. At the 8-month follow-up, cardiac MRI showed the appearance of a new nodular lesion in the anterior wall, causing a localized wall motion abnormality. Myocardial involvement in patients with systemic sclerosis can be severe, and cardiac MRI evaluation is fundamental.

[Digitalis, a drug to be scrapped?] / La digitale: un farmaco da rottamare?

We performed a comprehensive review of the scientific literature on the use of digoxin in heart failure and atrial fibrillation. In congestive heart failure (CHF) there is only one randomized trial with a statistical sample sufficiently large. In this trial (DIG trial), which enrolled patients with systolic left ventricular dysfunction in sinus rhythm, digoxin had a neutral action on mortality and modestly reduced the overall need of hospitalization. The study was conducted in the pre-beta-blocker era and, therefore, it has a doubtful application to the current clinical context. There are no randomized trials on atrial fibrillation, either with or without heart failure. Several observational and retrospective studies and meta-analysis have shown an association between the use of digoxin and increased mortality about 20%. Both in the European and American guidelines, even in class I recommendations, evidence is not supported by randomized or observational trials, but just by experts' opinions. Digoxin use in CHF and atrial fibrillation is related to the physician's clinical judgment, based more on consolidated custom that on established scientific evidence. In our opinion, this therapy should be withdrawn until new randomized controlled trials will provide evidence of its efficacy. Two trials have been planned to this aim. Also the issue of toxicity threshold is still unresolved; digoxinemia values should be <1 ng/ml if digoxin is used, to avoid overdosing and toxicity with increased mortality.

Regular wine consumption in chronic heart failure: impact on outcomes, quality of life, and circulating biomarkers.

BACKGROUND: Moderate, regular alcohol consumption is generally associated with a lower risk of cardiovascular events but data in patients with chronic heart failure are scarce. We evaluated the relations between wine consumption, health status, circulating biomarkers, and clinical outcomes in a large Italian population of patients with chronic heart failure enrolled in a multicenter clinical trial. METHODS AND RESULTS: A brief questionnaire on dietary habits was administered at baseline to 6973 patients enrolled in the Gruppo Italiano per lo Studio della Sopravvivenza nell'Insufficienza Cardiaca-Heart Failure (GISSI-HF) trial. The relations between wine consumption, fatal and nonfatal clinical end points, quality of life, symptoms of depression, and circulating biomarkers of cardiac function and inflammation (in subsets of patients) were evaluated with simple and multivariable-adjusted statistical models. Almost 56% of the patients reported drinking at least 1 glass of wine per day. After adjustment, clinical outcomes were not significantly different in the predefined 4 groups of wine consumption. However, patients with more frequent wine consumption had a significantly better perception of health status (Kansas City Cardiomyopathy Questionnaire score, adjusted P<0.0001), less frequent symptoms of depression (Geriatric Depression Scale, adjusted P=0.01), and lower plasma levels of biomarkers of vascular inflammation (osteoprotegerin and C-terminal proendothelin-1, adjusted P<0.0001, and pentraxin-3, P=0.01) after adjusting for possible confounders. CONCLUSIONS: We show for the first time in a large cohort of patients with chronic heart failure that moderate wine consumption is associated with a better perceived and objective health status, lower prevalence of depression, and less vascular inflammation, but does not translate into more favorable clinical 4-year outcomes. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT0033633.

[Metformin and insulin in chronic heart failure: contraindications not contraindicated and indications not indicated]. / Metformina e insulina nell'insufficienza cardiaca cronica: controindicazioni non controindicate e indicazioni non indicate.

Glucose-lowering treatment in patients with type 2 diabetes and heart failure is controversial. Metformin is clearly contraindicated when such diseases coexist. Conversely, no contraindications have been established for insulin in this subset of patients, even though several observational and retrospective studies have shown increased mortality and worsening heart failure. Data from the literature have demonstrated that in this patient population, which accounts for one third of all cases of heart failure, metformin reduces mortality by 14-35%. In patients with a glomerular filtration rate >30 ml/min who do not show dehydration, shock, sepsis, severe liver disease or hypoxemia, the administration of metformin doses <2 g/day was associated with a null risk of lactic acidosis. The positive effects of metformin are correlated with the reduction in insulin resistance, which is responsible for both the onset and development of heart failure in diabetic patients. Insulin can provoke severe hypoglycemia and fluid retention, resulting in negative effects. Further randomized and prospective studies are warranted to address these controversial issues in such a large population with high mortality and morbidity rates. Longitudinal studies would be crucial to the understanding of the optimal therapy and for stratification of patients according to the severity of heart failure.

[Hypoglycemic therapy in heart disease patients with type 2 diabetes mellitus]. / Il trattamento ipoglicemizzante nel paziente cardiopatico con diabete mellito di tipo 2.

In type 1 diabetes, insulin treatment reduces complications related to microvascular disease and atherosclerosis. The same holds true in patients with short duration of type 2 diabetes, treated either with oral antidiabetic drugs or with insulin. Conversely, in patients with long-standing type 2 diabetes, advanced age or history of cardiovascular disease, treatment with oral diabetic drugs or insulin must be given with caution because of the unfavorable risk-benefit profile when these drugs are used with too aggressive aims. In the last year, several studies have clearly demonstrated that an excessive reduction of glycated hemoglobin exposes the patient at risk of hypoglycemia and fattening, with neutral results about clinical events or even with a paradoxical increase of cardiovascular events (hospitalization and mortality). The glycemic goal in heart disease and diabetic patients should be settled on higher values (probably 7-8%). There are no significant differences among drugs that reduce insulin resistance and drugs that stimulate its secretion. The only drug that proved to be effective in reducing cardiovascular events is metformin, which increases AMP-activated protein kinase activity and has a potent cardioprotective effect against ischemia-reperfusion injury. These findings should be confirmed in larger longitudinal studies in heart disease patients. Patients in intensive care units should be treated with intravenous insulin with a glycemic target <180 mg/dl (mean 142 mg/dl) because more aggressive goals may lead to increased mortality. These results demand important considerations about the management of heart disease patients with type 2 diabetes, also because self-monitoring of blood glucose concentration seems to induce an increase in depression. Conversely, an aggressive multifactorial intervention (improvement of lifestyle, blood pressure and dyslipidemia control, platelet aggregation inhibitors in secondary prevention) reduces effectively cardiovascular events and mortality.

[Obstructive sleep apnea syndrome and cardiovascular diseases]. / Sindrome dell'apnea ostruttiva notturna e malattie cardiovascolari.

Obstructive sleep apnea (OSA) syndrome is one of the most common respiratory disorders in humans. There is emerging evidence linking OSA to vascular disease, particularly hypertension. The underlying pathophysiological mechanisms that link OSA to cardiovascular diseases such as hypertension, congestive heart failure and atrial fibrillation are not entirely understood, although they certainly include mechanical events, increased sympathetic activity and oxidative stress. This review will examine the evidence and mechanisms linking OSA syndrome to cardiovascular disease.

[Insulin therapy may hasten congestive heart failure in cardiac patients: case series and review of the literature]. / Terapia insulinica quale fattore precipitante lo scompenso cardiaco congestizio: presentazione di casi clinici e revisione della letteratura.

We describe the appearance, within a few weeks from the beginning of insulin therapy, of signs and symptoms of congestive heart failure in three diabetic patients with known cardiac disease (one with aortic stenosis, one with hypertensive heart disease and one with ischemic heart disease), who however had never previously shown signs of heart failure. Reduction of the dose of insulin, along with a moderate diuretic therapy, led to resolution of clinical condition. Sodium retention and increased vascular permeability by insulin could be the causes of this phenomenon. In clinical practice it is necessary to remember that the beginning of insulin treatment could exacerbate left ventricular dysfunction to an overt heart failure. Future studies should evaluate whether insulin therapy plays a negative role in the long-term prognosis of patients with asymptomatic left ventricular dysfunction, as it has already been hypothesized in those with overt heart failure.