The revolution of the anti-diabetic drugs in cardiology.

Beginning in December 2008, under the auspices of Food and Drug Administration, numerous controlled clinical trial were planned, and in part completed, concerning the cardiovascular (CV) effects of hypoglycaemic drug in patients with Type 2 diabetes mellitus. At least 9 studies have been concluded, 13 are still open, and 4 have been initiated and closed ahead of time. Of the nine completed studies, three concerned inhibitor of the dipeptidyl peptidase 4 (inhibitors of DPP-4), four the glucagon-like peptide 1 agonist (GLP-1 agonist), and two the inhibitor of sodium-glucose co-transporter-2 (inhibitors of SGLT-2). Only four studies demonstrated the superiority, and not the mere 'non-inferiority', of the anti-diabetic drugs compared to placebo, in addition to standard treatment, in terms of reduction of the primary endpoint (CV death, non-fatal myocardial infarction, and non-fatal stroke). Two of the four studies regarded GLP-1 analogues (liraglutide and semaglutide), and two inhibitors of SGLT-2 (empaglifozin and canaglifozin). As a whole, these studies provided solid data supporting major beneficial CV effects of anti-diabetic drugs. During the next 3-4 years, an equal number of studies will be completed and published, so we will soon have the 'final word' on this issue. In the meantime, the clinical cardiologist should become familiar with these drugs, selecting the patients able to gain the best clinical advantage from this treatment, also by establishing a close relationship with the diabetologist.

Detrimental Impact of Chronic Obstructive Pulmonary Disease in Atrial Fibrillation: New Insights from Umbria Atrial Fibrillation Registry.

Background and objectives: Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide. Among extra-pulmonary manifestations of COPD, atrial fibrillation (AF) is commonly observed in clinical practice. The coexistence of COPD and AF significantly affects the risk of cardiovascular morbidity and mortality. Nonetheless, the mechanisms explaining the increased risk of vascular events and death associated to the presence of COPD in AF are complex and not completely understood. We analyzed data from an Italian network database to identify markers and mediators of increased vascular risk among subjects with AF and COPD. Materials and Methods: Cross-sectional analysis of the Umbria Atrial Fibrillation (Umbria-FA) Registry, a multicenter, observational, prospective on-going registry of patients with non-valvular AF. Of the 2205 patients actually recruited, 2159 had complete clinical data and were included in the analysis. Results: the proportion of patients with COPD was 15.6%. COPD patients had a larger proportion of permanent AF when compared to the control group (49.1% vs. 34.6%, p < 0.0001) and were more likely to be obese and current smokers. Other cardiovascular risk factors including chronic kidney disease (CKD), peripheral artery disease and subclinical atherosclerosis were more prevalent in COPD patients (all p < 0.0001). COPD was also significantly associated with higher prevalence of previous vascular events and a history of anemia (all p < 0.0001). The thromboembolic and bleeding risk, as reflected by the CHA2DS2VASc and HAS-BLED scores, were higher in patients with COPD. Patients with COPD were also more likely to have left ventricular (LV) hypertrophy at standard ECG than individuals forming the cohort without COPD (p = 0.018). Conclusions: AF patients with COPD have a higher risk of vascular complications than AF patients without this lung disease. Our analysis identified markers and mediators of increased risk that can be easily measured in clinical practice, including LV hypertrophy, CKD, anemia, and atherosclerosis of large arteries.

Managing hypertension in 2018: which guideline to follow?

Hypertension is a global public health issue and a major cause of morbidity and mortality. Its prevalence is increasing in many Asian countries, with a number of countries with blood pressure above the global average. Although the average systolic blood pressure is decreasing worldwide since the 1980s at the rate of about 1 mm Hg systolic blood pressure per decade, it is increasing in low-income and middle-income countries, especially in the East and South Asian population. Of note, the much larger base Asian population results in a considerably larger absolute number of individuals affected. When compared with Western countries, hypertension among Asian populations has unique features in terms of its onset, clustering of associated cardiovascular risk factors, complications and outcomes. Moreover, only a minority of hypertensive individuals are receiving treatment and achieving control. Projected number of deaths related to hypertension dramatically increased in the last 25 years in some Asian regions with a disproportionately high mortality and morbidity from stroke compared with Western countries. The relation between blood pressure and the risk of stroke is stronger in Asia than in Western regions. Although new Guidelines for hypertension diagnosis and management have been recently released from Europe and North America, the unique features of Asian hypertensive patients raise concerns on the clinical applicability of Western Guidelines to Asian populations. To this purpose, we critically reviewed key elements from the most updated Guidelines. We also discussed their core concepts to verify the impact on hypertension prevention and management in Asian countries.

Sudden Cardiac Death in Hypertensive Patients.

In patients with hypertension, but without established cardiovascular disease, predictive factors for sudden cardiac death (SCD) remain undefined. We followed for an average of 10.3 years a cohort of 3242 initially untreated hypertensive patients without evidence of coronary or cerebrovascular heart disease at entry. All patients underwent a complete clinical examination which included ECG and 24-hour ambulatory blood pressure monitoring. At entry, the mean age of patients was 50.0 years, 45% were women, and 6.1% had type 2 diabetes mellitus. Average office blood pressure was 154/96 mm Hg, and average 24-hour ambulatory blood pressure was 136/86 mm Hg. Prevalence of left ventricular hypertrophy at ECG was 13.9%. During follow-up, SCD occurred in 33 patients at a rate of 0.10 per 100 patient-years (95% CI, 0.07-0.14). The rate of SCD was 0.07 and 0.30 per 100 patient-years, respectively, in the cohort of patients without and with ECG left ventricular hypertrophy ( P<0.01). In a multivariable Cox model with Firth penalized maximum bias reduction method for rare outcome events, left ventricular hypertrophy almost tripled the risk of SCD (adjusted hazard ratio, 2.99; 95% CI, 1.47-6.09; P=0.002) after adjustment for age ( P<0.0001), sex ( P=0.019), diabetes mellitus ( P<0.0001), and 24-hour ambulatory pulse pressure ( P=0.036). For each 10 mm Hg increase in 24-hour ambulatory pulse pressure, the risk of SCD increased by 35%. The time-dependent area under the receiver operating characteristic curve was 0.85 (95% CI, 0.74-0.96). We conclude that in patients with hypertension without established cardiovascular disease, age, diabetes mellitus, ECG left ventricular hypertrophy, and 24-hour ambulatory pulse pressure are independent prognostic markers for SCD in the long-term.

European and US guidelines for arterial hypertension: similarities and differences.

Hypertension is one of the most common chronic diseases in adults and a leading cause of disability and mortality worldwide. Recently, new Guidelines for the diagnosis and management of hypertension have been released in Europe and in the United States, with changes regarding how to diagnose and treat the condition, and the extent to which intensive blood pressure control should be pursued. Important differences between the Guidelines exist in the classification of blood pressure levels and definition of treatment goals. Diagnosis of hypertension starts at 140/90 mmHg for the European Guidelines, and 130/80 mmHg for the US Guidelines. Besides, the European guidelines introduced the concept of "safety boundaries", consisting of BP thresholds not to be exceeded towards lower levels (120 mmHg for age < 65 years, 130 mmHg for older people) because of the fear of important adverse events associated with overtreatment. Such discrepancies can indeed have an impact on treatment attitudes and outcome incidence. Hence, we appraised facts in favor and against each of these controversial issues. In conclusion we believe that, instead of fixing rigid BP targets and boundaries, modern hypertension management should be aimed to achieve in each patient an optimal balance between intensive BP reduction and treatment safety.

Electrocardiography for diagnosis of left ventricular hypertrophy in hypertensive patients with atrial fibrillation.

Left ventricular (LV) hypertrophy at electrocardiography (ECG) predicts incident atrial fibrillation (AF). However, the diagnostic performance of ECG for diagnosis of LV hypertrophy in patients with AF is still not well characterized. We analyzed 563 hypertensive patients enrolled in the Umbria-Atrial Fibrillation (Umbria-FA) registry, an ongoing prospective observational registry in patients with AF. All patients underwent ECG and standard echocardiography at their entry in the Register. Mean age was 74 years and 43% of patients were women. Prevalence of ECG-LV hypertrophy, defined by Perugia criterion corrected for body mass index, was 23%. Echocardiographic LV mass was the reference standard. Sensitivity, specificity and diagnostic accuracy of ECG-LV hypertrophy were 37.4% (95% confidence interval [CI]: 31.6-43.4), 90.0% (95% CI: 86.0-93.2) and 64.5% (95% CI: 60.4-68.3), respectively. Performance was comparable in patients with AF or sinus rhythm at ECG recording. The area under the receiver-operating characteristic (ROC) curve was 0.622 (95% CI: 0.580-0.664) in the group with AF and 0.662 (95% CI: 0.605-0.720) in that with sinus rhythm (p â€‹= â€‹0.266 for comparison). These data suggest that standard ECG is reliable for diagnosis of LV hypertrophy in patients with a history of AF, regardless of the presence of AF or sinus rhythm at the time of ECG recording.

Persistence on apixaban in atrial fibrillation patients: a retrospective multicentre study.

AIMS: Real-world data on treatment persistence, safety and effectiveness of non-Vitamin K antagonist oral anticoagulants (NOACs) play an important role in the assessment of risks and benefits of these drugs. Our aim was to evaluate persistence on treatment, incidence of major bleeding and incidence of a composite endpoint of major events, including all-cause death, myocardial infarction, stroke and systemic thromboembolism, during treatment with apixaban in a cohort of patients with nonvalvular atrial fibrillation (NVAF). METHODS: In this multicentre retrospective observational study, we retrieved data from medical records of five Italian hospitals on patients with a diagnosis of NVAF who initiated apixaban between 1 January 2014 and 31 March 2016 and had a first subsequent visit at the same hospital. RESULTS: We studied 766 patients with mean age of 74.2 (standard deviation 11.1) years and median CHADS2 and CHA2DS2VASc scores of 2.0 and 4.0, respectively. Over a median follow-up period of 339 days, persistence on treatment was 83.5% [95% confidence interval (95% CI) 75.5-89.1%]. The rate of major bleeding (per 100 person-years) was 1.15 (95% CI 0.39-1.90 per 100 person-years), while the cumulative incidence was 4.4% (95% CI 1.6-12.0). The rate of major events was 1.97 (95% CI 1.08-2.86) per 100 patient-years, with a cumulative incidence over the entire follow-up period of 7.7% (95% CI 4.6-12.8). CONCLUSION: In real-life conditions, NVAF patients treated with apixaban show rates of treatment discontinuation and major bleedings, which are comparable to those found in the ARISTOTLE pivotal study, thus supporting its external validity.

Long-term outcome in patients with non-valvular atrial fibrillation on dabigatran: a prospective cohort study.

INTRODUCTION: Most studies on thromboembolic and bleeding risk in patients with non-valvular atrial fibrillation (NVAF) exposed to non-vitamin K oral anticoagulants stem from interrogation of insurance databases. Areas covered: We studied 742 consecutive patients with NVAF who started treatment with dabigatran in three hospitals in Italy. Average follow-up was 1.80 years. Mean age was 76.2 years. CHA2DS2VASc score was 0-1 in 37 (5%), 2 in 97 (13%) and ≥ 3 in 604 (82%) patients. NVAF was permanent in 349 (48%). Overall, 76% of patients remained on treatment over the entire follow-up period. Among 180 patients who discontinued permanently, the most frequent reasons were dyspepsia (33.9%), bleeding (17.8%), and renal worsening (12.1%). About 48% and 74% of permanent discontinuations occurred during the first 6 and 12 months of treatment, respectively. Rates of major events (per 100 patient-years) were 0.75 for stroke, 0.31 for myocardial infarction, 1.50 for all-cause death, and 1.80 for major bleedings. The rate of intracranial bleedings was 0.45 and that of major gastrointestinal bleedings was 0.75. Expert opinion: This prospective cohort study confirms the low incidence of stroke, major bleeding and intracranial bleeding, and a 76% persistence with treatment, in patients with NVAF treated with dabigatran over about 2 years.

Impact of Chamber Dilatation on the Prognostic Value of Left Ventricular Geometry in Hypertension.

BACKGROUND: The different geometric patterns of the left ventricle may or may not coexist with chamber dilatation. The prognostic impact of such a combination is unclear. METHODS AND RESULTS: We studied a cohort of 2635 initially untreated patients with hypertension, mean age 50 years. At entry, 24-hour ambulatory blood pressure progressively increased across the patterns of normal geometry, concentric left ventricular (LV) remodeling, eccentric nondilated LV hypertrophy (LVH), eccentric dilated LVH, concentric nondilated LVH, and concentric dilated LVH. During a mean follow-up of 9.7 years, 360 patients developed a first major cardiovascular event at a rate (×100 patient-years) of 1.41. The event rate was 0.93 in the group with normal LV geometry, 1.10 in the group with LV concentric remodeling, 1.40 in the group with nondilated eccentric LVH, 2.10 in the group with eccentric dilated LVH, 2.34 in the group with nondilated concentric LVH, and 4.67 in the group with dilated concentric LVH (log-rank test: P<0.001). In a Cox model, after adjustment for several independent covariables (age, sex, diabetes mellitus, current smoking, total cholesterol, estimated glomerular filtration rate, and average 24-hour systolic blood pressure), concentric dilated LVH was associated with a 98% excess risk of cardiovascular events (P=0.0037). However, LV geometric pattern lost statistical significance when LV mass was entered into the model. CONCLUSIONS: In initially untreated patients with hypertension, LV dilatation adds an adverse prognostic burden to the patterns of eccentric and concentric LVH. This phenomenon is explained by the greater LV mass associated with LV chamber dilatation.

Permanent discontinuation of non vitamin K oral anticoagulants in real life patients with non-valvular atrial fibrillation.

BACKGROUND: Persistence to treatment affects clinical outcomes in patients with chronic disease such as atrial fibrillation (AF). METHODS: This prospective cohort study included consecutive non-valvular AF patients prescribed with non-vitamin K oral anticoagulants (NOACs) and investigated for any permanent discontinuation at 1-year of this therapy, as well as any reasons for discontinuation. RESULTS: Overall, 1305 patients were prescribed with dabigatran (N=473), rivaroxaban (N=425) or apixaban (N=407). Of these, 201 patients (15.4%) discontinued NOACs during the first year of treatment. More than 60% of these discontinuations occurred during the first 6months. Reasons for discontinuation included: dyspepsia or abdominal pain in 38 patients (2.9%) and bleeding in 59 (4.5%). Discontinuation for the former occurred earlier (50% within 2months) compared to the latter (66% after the first 4months). The prescription of reduced NOAC doses resulted being an independent predictor of discontinuation (OR 1.74, 95% CI 1.23-2.45, p=0.002). Regarding the use of dabigatran, rivaroxaban and apixaban, the following were observed: discontinuers were 22.0% (95% CI 18.5-25.9), 14.4% (95% CI 11.3-18.0) and 8.8% (95% CI 6.5-12.0), the risk of discontinuation associated with bleeding was 20.2%, 44.3% and 30.6% and dyspepsia or abdominal pain was 35.6%, 1.6% and 0%, respectively. CONCLUSION: Discontinuation of NOACs in AF patients was relatively common and more than often occurred in the first six months after prescription. Patients treated with reduced doses of NOACs had a higher probability to discontinue compared to those who were prescribed conventional doses.

[Blood pressure: the lower the better? Maybe yes]. / Pressione arteriosa: più bassa è, meglio è? Forse sì.

The SPRINT study tested the hypothesis that hypertensive patients randomized to a more intensive treatment, aimed at lowering systolic blood pressure (BP) below 120 mmHg have a lower incidence of major cardiovascular events when compared to patients randomized to a less intensive treatment (systolic BP reduction below 140 mmHg). Overall, 9361 patients were randomized to the more intensive (n=4678) or less intensive (n=4683) antihypertensive treatment. The study was prematurely interrupted because of an excess benefit in the more intensive arm. Indeed, the group randomized to the more intensive arm showed, when compared to the group randomized to the less intensive arm, a 25% reduction in the primary endpoint (1.65 vs 2.19% per year; p<0.001), a 43% reduction in cardiovascular death (0.25 vs 0.43%; p=0.005), a 27% reduction in all-cause death (1.03% vs 1.40%; p=0.003) and a 38% reduction in hospitalizations for heart failure (0.41 vs 0.67%; p<0.002). Unexpectedly, there was no significant reduction in the risk of stroke (not significant 11% reduction). The SPRINT study unequivocally shows that, in hypertensive patients with systolic BP ≥130 mmHg and no history of diabetes, previous stroke and polycystic renal disease, we should try to lower systolic BP to levels below 120 mmHg with the objective to lower the incidence of heart failure in addition to all-cause and cardiovascular death. Future guidelines on the management of patients with hypertension should implement the results of the SPRINT study.

Why switch from warfarin to NOACs?

Several patients with non-valvular atrial fibrillation treated with warfarin or other vitamin-K antagonists (VKA) might benefit from switching to an oral non vitamin-K antagonist anticoagulant (NOAC). In the absence of randomised comparative trials of switching to NOACs versus maintaining VKA treatment, several considerations argue in favour of a switching strategy. First, there is conclusive evidence that haemorrhagic strokes and intracranial bleedings are much fewer in number with NOACs than with warfarin. The risk of intracranial bleeding is 52 % lower with NOACS than with warfarin, with extremes ranging from 33 to 70 %. Such benefit is applicable to different NOACs, and independent of the time-in-therapeutic range under warfarin. Patients at increased risk for intra-cranial bleeding (renal dysfunction, or prior stroke or intra-cranial bleeding) should benefit most from switching to NOACs. Patients with labile International Normalized Ratio are also considered good candidates for switching because of their increased risk of stroke, and the lack of interactions between the effects of NOACs versus warfarin and the time-in-therapeutic range. Furthermore, some NOACs proved to be superior to warfarin in reducing the risk of thromboembolic complications even in intention-to-treat analyses. As further advantage, NOACs show fewer drug-drug and drug-food interactions when compared with warfarin. Last, but not least, NOACs do not need frequent blood drawings except in patients with moderate renal dysfunction, in whom periodic controls of serum creatinine are generally advised. The higher cost remains a barrier to a wider use of NOACs, especially in low-income settings.

Left ventricular hypertrophy and obesity: only a matter of fat?

Obesity can be regarded as an energy balance disorder in which inappropriate expansion and dys-function of adipose tissue lead to unfavorable outcomes. Even in the absence of hypertension, adiposity induces structural and functional changes in the heart through hemodynamic and non hemodynamic factors. In the "obese" heart, besides the growth of cardiomyocytes, interstitial fat infiltration and triglyceride accumulation in the contractile elements importantly contribute to left-ventricular mass (LVM) accrual, hypertrophy (LVH) and geometric pattern. In harmony with this, the likelihood of LVH is greater in either obese normotensive or hypertensive individuals than in their non-obese counterparts. Interestingly, recent observations highlight the increasing prevalence of the "concentric" (ie, combined remodeling and hypertrophy), rather than "eccentric" pattern of LV geometry in obesity. Nonetheless, obesity is linked with lack of decrease, or even increase, of LVM over time, independently of blood pressure control and hypertensive treatment. Although obesity-related LV changes result in progressive systolic and diastolic heart failure, the assessment of LVM and LVH in obese individuals still remains a difficult task. In this scenario, it is tempting to speculate that therapeutic interventions for reversal of LVH in obesity should either overcome the "non-hemodynamic" factors or reduce the hemodynamic load. Indeed, weight loss, either achieved by lifestyle changes or bariatric procedures, decreases LVM and improves LV function regardless of blood pressure status. These and other mechanistic insights are discussed in this review, which focuses on "adipose dysfunction" as potential instigator of, and putative therapeutic target for, LVH regression in the setting of obesity.

Detrimental Effects of Hyperglycemia in Acute Coronary Syndromes: from Pathophysiological Mechanisms to Therapeutic Strategies.

Hyperglycemia recognized during hospitalization for acute coronary syndromes (ACS) is common. It is a powerful predictor of worse prognosis in patients both with and without previously known diabetes mellitus. Hyperglycemia during ACS is caused by an inflammatory and adrenergic response to ischemic stress, when catecholamines are released and glycogenolysis induced. The link between hyperglycemia and prognosis in ACS patients is multi-factorial. Hyperglycemia exerts detrimental effects on left ventricular and platelet function and it also activates other systemic pathological processes that contribute to cellular and tissue injury such as increasing oxidative stress and worsening endothelial function. Glucose management strategies in ACS may improve outcome in patients with hyperglycemia, by reducing inflammatory and clotting mediators, by improving endothelial function and fibrinolysis and by reducing infarct size. Most of available oral anti-diabetic drugs are contraindicated for the increased risk of hypoglycemia. Thus, insulin is the preferred agent for glycemic control in ACS and conversion from intravenous to subcutaneous therapy commonly occurs when the critical acute phase of ACS resolves. Pharmacodynamics of insulin allows it to be adaptable to the changing physiology of the ACS patient, is easily titrated and has no dosage threshold. Nevertheless, findings concerning the effect on ACS-related mortality of the control of glucose levels by intravenous infusion of insulin have been conflicting and intervention trials are needed to optimize the definition of hyperglycemia and to establish appropriate modalities and goals of glucose lowering treatment. In particular, the clinical benefit of an aggressive treatment with insulin is yet unproved.

Safety and efficacy of non-vitamin K oral anticoagulants in non-valvular atrial fibrillation: a Bayesian meta-analysis approach.

INTRODUCTION: Choosing between different non-vitamin K antagonist oral anticoagulants (NOACs) in non-valvular atrial fibrillation (NVAF) is difficult due to the absence of head to head comparative studies. We performed a Bayesian meta-analysis to explore similarities and differences between different NOACs and to rank treatments overall for safety and efficacy outcomes. AREAS COVERED: Through a systematic literature search we identified randomized controlled Phase III trials of dabigatran, rivaroxaban, apixaban, and edoxaban versus adjusted-dose warfarin in patients with NVAF. EXPERT OPINION: Warfarin ranked worst for all-cause mortality and intracranial bleedings and had a nil probability of ranking first for any outcome. The risk of major bleeding versus warfarin was lower with apixaban, dabigatran 110 mg, and both doses of edoxaban. All agents reduced the risk of intracranial bleeding versus warfarin. Edoxaban 30 mg was the best among the treatments being compared for major and gastrointestinal bleeding. Dabigatran 150 mg was the best for stroke and systemic embolism. This study suggests that NOACs are generally preferable to warfarin in patients with NVAF. However, safety and efficacy differences do exist among NOACs, which might drive their use in specific subsets of AF patients, allowing prescribers to tailor treatment to distinct patient profiles.

Safety of dabigatran in an elderly population: single center experience in Italy.

In clinical practice, adherence to drugs and their safety may differ from randomised controlled trial settings. This study was undertaken to investigate the adherence to dabigatran, a direct thrombin inhibitor, and its safety in a real-world setting. We studied a prospective cohort of 114 elderly consecutive patients with non valvular atrial fibrillation (AF) who were treated with dabigatran 150 mg twice-daily (N=39) or 110 mg twice-daily (N=76). These patients were studied at baseline and after an average of 6 months. Mean age was 80 years and 53% were women. At entry, the average CHA2DS2VASc score was 4 and the HAS-BLED score was 2. AF was permanent in 49% of patients, persistent in 30%, paroxysmal in 12% and new-onset in 24%. In the follow-up clinical visit we ascertained vital status, adherence to treatment according to refill prescription orders, and side effects. Adherence was ≥80% in 76.5% of patients. Heartburn, the most frequent adverse effect, was reported by 25 patients (22%). Major and minor bleedings were experienced by 2 (1.8%) and 9 (7.9%) patients, respectively. Permanent discontinuation occurred in 18 patients (16%). The most frequent cause of permanent discontinuation was heartburn (10 patients). This real-life study suggests that safety of dabigatran and adherence to this drug in an elderly cohort of AF patients at high or very high risk of thromboembolism are generally good. Heartburn is the main cause of treatment discontinuation.