Prevalence and clinical predictors of inappropriate direct oral anticoagulant dosage in octagenarians with atrial fibrillation.

PURPOSE: Older age is associated with inappropriate dose prescription of direct oral anticoagulants. The aim of our study was to describe the prevalence and the clinical predictors of inappropriate DOACs dosage among octogenarians in real-world setting. METHODS: Data for this study were sourced from the multicenter prospectively maintained Atrial Fibrillation (AF) Research Database (NCT03760874). Of the AF patients aged ≥ 80 who received DOACs treatment, 253 patients were selected. Participants were categorized as appropriate dosage, overdosage, or underdosage. Underdosage and overdosage were, respectively, defined as administration of a lower or higher DOAC dose than recommended in the EHRA consensus. RESULTS: A total of 178 patients (71%) received appropriate DOACs dose and 75 patients (29%) inappropriate DOACs dose; among them, 19 patients (25.6%) were overdosed and 56 (74.4%) were underdosed. Subgroup analysis demonstrated that underdosage was independently associated with male gender [OR = 3.15 (95% IC; 1.45-6.83); p < 0.001], coronary artery disease [OR = 3.60 (95% IC 1.45-9.10); p < 0.001] and body mass index [OR = 1.27 (1.14-1.41); p < 0.001]. Overdosage was independently associated with diabetes mellitus [OR = 18 (3.36-96); p < 0.001], with age [OR = 0.76 (95% IC; 0.61-0.96; p = 0.045], BMI [OR = 0.77 (95% IC; 0.62-0.97; p = 0.043] and with previous bleedings [OR = 6.40 (0.7; 1.43-28); p = 0.039]. There wasn't significant difference in thromboembolic, major bleeding events and mortality among different subgroups. Underdosage group showed a significatively lower survival compared with appropriate dose group (p < 0.001). CONCLUSION: In our analysis, nearly one-third of octogenarians with AF received an inappropriate dose of DOAC. Several clinical factors were associated with DOACs' overdosage (diabetes mellitus type II, previous bleeding) or underdosage (male gender, coronary artery disease, and higher body mass index). Octogenarians with inappropriate DOACs underdosage showed less survival.

CHA2DS2-VASc Score Predicts Adverse Outcome in Patients with Simple Congenital Heart Disease Regardless of Cardiac Rhythm.

Adult patients with simple congenital heart disease (sACHD) represent an expanding population vulnerable to atrial arrhythmias (AA). CHA2DS2-VASc score estimates thromboembolic risk in non-valvular atrial fibrillation patients. We investigated the prognostic role of CHA2DS2-VASc score in a non-selected sACHD population regardless of cardiac rhythm. Between November 2009 and June 2018, 427 sACHD patients (377 in sinus rhythm, 50 in AA) were consecutively referred to our ACHD service. Cardiovascular hospitalization and/or all-cause death were considered as composite primary end-point. Patients were divided into group A with CHA2DS2-VASc score = 0 or 1 point, and group B with a score greater than 1 point. Group B included 197 patients (46%) who were older with larger prevalence of cardiovascular risk factors than group A. During a mean follow-up of 70 months (IQR 40-93), primary end-point occurred in 94 patients (22%): 72 (37%) in group B and 22 (10%, p < 0.001) in group A. Rate of death for all causes was also significantly higher in the group B than A (22% vs 2%, respectively, p < 0.001). Multivariable Cox regression analysis revealed that CHA2DS2-VASc score was independently related to the primary end-point (HR 1.84 [1.22-2.77], p = 0.004) together with retrospective AA, stroke/TIA/peripheral thromboembolism and diabetes. Furthermore, CHA2DS2-VASc score independently predicted primary end-point in the large subgroup of 377 patients with sinus rhythm (HR 2.79 [1.54-5.07], p = 0.01). In conclusion, CHA2DS2-VASc score accurately stratifies sACHD patients with different risk for adverse clinical events in the long term regardless of cardiac rhythm.

Tissue Doppler indices of diastolic function as prognosticator in patients without heart failure in primary care.

BACKGROUND: Tissue Doppler imaging (TDI) indices of left ventricular (LV) diastolic function provide incremental prognostic information on mortality and morbidity in the general population and in several clinical scenarios. Their independent, additional role in outpatients with normal LV ejection fraction (LVEF) and without heart failure (HF) is undefined. METHODS: We reviewed clinical and echocardiographic records of 2628 consecutive outpatients 52.8% male, median age 71 years) with LVEF > 50% without concurrent or prior HF, from the Cardiovascular Center of Trieste. We analyzed septal early mitral annular velocity (e') and its combination with mitral peak early filling velocity (E/e') in relation to the composite end-point of death and cardiovascular hospitalizations. RESULTS: During follow-up of 26 months (interquartile range: 12-41), 392 (15%) patients experienced the endpoint (88 deaths). Increasing E/e' showed an overall association with the clinical end-point (log rank p < 0.02), but with no prognostic difference between the middle and upper tertile. Decreasing e' also showed an association with the end-point, with a more balanced stepwise risk increase for increasing tertiles (log rank p < 0.01 for all contrasts). At multivariable analysis, E/e' (either in tertiles or dichotomized according to the threshold of 15) was no longer associated with clinical outcome, whereas e' independently predicted the combined endpoint [hazard ratio 0.73 (0.53-0.94), p = 0.04]. The prognostic value of e' was incremental to that of other clinical and echocardiographic variables (p = 0.04). CONCLUSIONS: In outpatients with normal LVEF and without HF, e' and E/e' are both associated with clinical end-points, though only e' is an independent and incremental predictor of outcome. These findings suggest a potential role for e' as a prognosticator, and spread a cautionary word about the utilization of septal E/e' alone as a surrogate for a comprehensive assessment of diastolic function in this context.

Clinical profile of direct oral anticoagulants versus vitamin K anticoagulants in octogenarians with atrial fibrillation: a multicentre propensity score matched real-world cohort study.

Atrial fibrillation (AF) is the most common arrhythmia in clinical practice and its prevalence increases with age. Few data are available about the clinical performance of direct oral anticoagulant (DOACs) in patients aged ≥ 80 years with AF. The aim of our propensity score matched cohort study was to compare the safety and efficacy of DOACs versus well-controlled VKA therapy among octogenarians with AF in real life setting. Data for this study were sourced from the multicenter prospectively maintained Atrial Fibrillation Research Database (NCT03760874), which includes all AF patients followed by the participating centers, through outpatient visits every 3 to 6 months. The database was queried for AF patients aged ≥ 80 years who received DOACs or VKAs treatment. The primary effectiveness endpoint was the occurrence of thromboembolic events (a composite of stroke, transient ischemic attack, systemic embolism); the primary safety endpoint was the occurrence of major bleeding; the secondary endpoint was all-cause mortality. The database query identified 774 AF patients aged ≥ 80 years treated with VKAs and 279 with DOACs. Propensity score (2:1) matching selected 252 DOAC and 504 VKA recipients. The mean follow-up was 31.07 ± 14.09 months. The incidence rate of thromboembolic events was 13.79 per 1000 person-years [14.80 in DOAC vs 13.34 in VKA group, Hazard Ratio 1.10; 95% confidence interval (CI) 0.49 to 2.45; P = 0.823]. The incidence rate of intracranial hemorrhage (ICH) was 8.06 per 1000 person-years (3.25 in DOAC vs 10.23 in VKA group, HR 0.33; 95% CI 0.07 to 1.45; P = 0.600). Through these incidence rates, we found a positive net clinical benefit (NCB) of DOACs over VKAs, equal to + 9.01. The incidence rate of all-cause mortality was 105.05 per 1000 person-years (74.67 in DOAC vs 118.67 in VKA group, Hazard Ratio 0.65; 95% CI 0.47 to 0.90; P = 0.010). The concomitant use of antiinflammatory drugs (HR 7.90; P < 0.001) were found to be independent predictor of major bleeding. Moreover, age (HR 1.17; P < 0.002) and chronic kidney disease (HR 0.34; P = 0.019) were found to be independently associated with thromboembolic events. In our study no significant difference in terms of both thromboembolic and major bleeding events, but a significant lower incidence of all-cause mortality, was detected in AF patients aged ≥ 80 years treated with DOACs vs VKAs.

Clinical Benefit of Direct Oral Anticoagulants Versus Vitamin K Antagonists in Patients with Atrial Fibrillation and Bioprosthetic Heart Valves.

PURPOSE: The use of direct oral anticoagulants (DOACs) in patients with atrial fibrillation (AF) and bioprosthetic heart valve is still controversial. The aim of this study was to compare the tolerability and effectiveness of treatment with DOACs versus vitamin K antagonists (VKAs) in patients with AF and a bioprosthetic heart valve in clinical practice. METHODS: Data for this study were sourced from the multicenter, prospectively maintained AF Research Database (NCT03760874), which includes all patients with AF undergoing follow-up at participating centers through outpatient visits every 3-6 months. The rates of occurrence of thromboembolic events (ischemic stroke, transient ischemic attack, systemic embolism), major bleed, and intracranial hemorrhage (ICH) were assessed. These data were used for quantifying the net clinical benefit (NCB) of DOACs versus VKAs, in accordance with the following formula: (Thromboembolic events incidence rate with VKAs - Thromboembolic events incidence rate with DOACs) - Weighting factor × (ICH rate with DOACs - ICH incidence rate with VKAs). The database was retrospectively queried for patients with AF who were prescribed a DOAC or VKA and had a history of bioprosthetic heart valve replacement. FINDINGS: A total of 434 patients with AF (DOACs, n = 211; VKAs, n = 223) were identified. Propensity score matching identified 130 patients prescribed DOACs (apixaban, 55.4%; rivaroxaban, 30.0%; dabigatran, 13.1%; edoxaban, 1.4%) and the same number of VKA recipients (warfarin, 89.2%; acenocoumarol, 10.8%). The mean (SD) duration of follow-up was 26.8 (2.3) months. The incidence rates of thromboembolic events were 1.3 per 100 person-years in the DOAC group versus 2.0 per 100 person-years in the VKA group (P = 0.14). The incidence rates of major bleed events were 2.6 per 100 person-years in the DOAC group versus 4.9 per 100 person-years in the VKA group (P = 0.47). The incidence rates of ICH were 0.38 per 100 person-years in the DOAC group versus 1.16 in the VKA group (hazard ratio = 0.33; 95% CI, 0.05-2.34; P = 0.3). A positive NCB of DOACs over VKAs of +1.87 was found. IMPLICATIONS: According to these data from clinical practice, DOACs seem to be associated with a greater NCB versus VKAs in patients with AF with a bioprosthetic heart valve, primarily due to lower rates of both major bleeds and thromboembolic events.

Real-life Performance of Edoxaban in Elderly Patients With Atrial Fibrillation: a Multicenter Propensity Score-Matched Cohort Study.

PURPOSE: The purpose of the current study was to compare the efficacy and safety of edoxaban versus vitamin K antagonist (VKA) therapy among a cohort of elderly patients (ie, those aged ≥75 years) with atrial fibrillation (AF) in a real-life setting. METHODS: A propensity score-matched cohort observational study was performed comparing the safety and efficacy of edoxaban versus VKA therapy among a cohort of elderly (aged ≥75 years) patients with AF in a real-life setting. Follow-up data were obtained through outpatient visits at 1, 3, and every 6 months. The primary safety outcome was major bleeding. The primary efficacy outcome was the composite of stroke, transient ischemic attack, and systemic embolism. FINDINGS: A total of 130 patients receiving edoxaban 60 mg (EDO) treatment were compared with the same number of VKA recipients. The mean follow-up was 16 (2.6) months. The cumulative incidence of thromboembolic events in the EDO and VKA groups was 1.5% (2 of 130) and 2.3% (3 of 130), respectively (P < 0.6). The cumulative incidence of major bleeding events was 1.5% (2 of 130) in the EDO group and 3.1% (4 of 130) in the VKA group (P < 0.4). The total anticoagulant therapy discontinuation rate was 2.3% (3 of 130) in the EDO group and 4.6% (6 of 130) in the VKA group (P < 0.3). A nonsignificant trend in improved adherence was observed between the EDO and VKA groups (81% vs 78%; P = 0.6). IMPLICATIONS: Edoxaban therapy showed a good real-life performance among elderly patients (aged ≥75 years) with AF.

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.

Are aortic coarctation and rheumatoid arthritis different models of aortic stiffness? Data from an echocardiographic study.

BACKGROUND: Patients who underwent a successful repair of the aortic coarctation (CoA) show high risk for cardiovascular (CV) events. Mechanical and structural abnormalities in the ascending aorta (Ao) might have a role in the prognosis of CoA patients. We analyzed the elastic properties of Ao measured as aortic stiffness index (AoSI) in CoA patients in the long-term period and we compared AoSI with a cohort of 38 patients with rheumatoid arthritis (RA) and 38 non-RA matched controls. METHODS: Data from 19 CoA patients were analyzed 28 ± 13 years after surgery. Abnormally high AoSI was diagnosed if AoSI > 6.07% (95th percentile of the AoSI detected in our reference healthy population). AoSI was assessed at the level of the aortic root by two-dimensional guided M-mode evaluation. RESULTS: CoA patients showed more than two-fold higher AoSI compared to RA and controls (9.8 ± 12.6 vs 4.8 ± 2.5% and 3.1 ± 2.0%, respectively; all p < 0.05 and in 5 of 19 patients with CoA (26%) AoSI was exceptionally high. The 5 patients with abnormally high AoSI were older with higher BP, LV mass and prevalence of LV diastolic dysfunction. Multiple linear regression analysis revealed that AoSI was independently related to the presence of LV hypertrophy and higher LV relative wall thickness. CONCLUSIONS: CoA patients have higher AoSI levels than RA patients and non-RA matched controls. AoSI levels are abnormally high in a small sub-group of CoA patients who show a very high-risk clinical profile for adverse CV events.

Prognostic role of cardiac calcifications in primary prevention: A powerful marker of adverse outcome highly dependent on underlying cardiac rhythm.

BACKGROUND: Increasing evidence exists regarding calcium detected in aortic cusps and/or mitral annulus (AOC_MAC) at transthoracic echocardiogram as a predictor of cardiovascular (CV) events and mortality. PURPOSE: To verify whether AOC_MAC has a prognostic role in the setting of primary prevention independently of the presence of atrial fibrillation (AF). METHODS: All subjects consecutively referred from January 2011 to October 2014 to the Cardiovascular Centre for CV risk assessment in primary prevention were selected. AOC_MAC was assessed by transthoracic echocardiography. Primary study endpoint was a composite of CV hospitalizations/all-cause death. RESULTS: The 1389 study patients were 70 years old, 43% males, 24% had diabetes mellitus, 75% arterial hypertension, 56% dyslipidaemia. Of all, 997 (72%) were in sinus rhythm (SR), 392 (28%) in AF. Patients with AF were older and more frequently males, with larger atria than SR subjects. During a median follow-up of 32 months, 165 patients (12%) were hospitalized for CV cause, 68 (5%) died. The primary endpoint occurred more frequently in patients with than without AOC_MAC (18% vs 11%, p < 0.001). AF patients showed higher event-rate compared with patients in SR (20% vs 10%, respectively; p < 0.01). AOC_MAC emerged as an independent prognosticator of primary endpoint in SR patients (HR 1.74 [1.07-2.82], p = 0.02), together with increasing age and left ventricular hypertrophy, while AOC_MAC had no prognostic relevance in AF patients. CONCLUSIONS: In subjects with multiple CV risk factors assessed in primary prevention, the presence of AF nullifies the prognostic power of AOC_MAC, on the contrary robustly confirmed in SR patients.

Nonvitamin K Antagonist Oral Anticoagulants Use in Patients with Atrial Fibrillation and Bioprosthetic Heart Valves/Prior Surgical Valve Repair: A Multicenter Clinical Practice Experience.

This is an observational study to investigate the efficacy and safety of nonvitamin K antagonist oral anticoagulants (NOACs) in atrial fibrillation (AF) patients with bioprosthetic valves or prior surgical valve repair in clinical practice. A total of 122 patients (mean age: 74.1 ± 13.2; 54 females) with bioprosthetic heart valve or surgical valve repair and AF treated with NOACs were included in the analysis. The mean CHA2DS2-VASc (Congestive heart failure, Hypertension, Age >75 years, Diabetes mellitus, prior Stroke or transient ischemic attack, Vascular disease) and HAS-BLED (Hypertension, Abnormal renal and liver function, Stroke, Bleeding, Labile INR [international normalized ratio], Elderly, Drugs or alcohol) score values were 3.6 ± 1.2 and 2.6 ± 1.4, respectively. Of the total study population, 28.6% was taking apixaban 5 mg twice daily (BID), 24.5% apixaban 2.5 mg BID, 18% dabigatran 150 mg BID, 13% dabigatran 110 mg BID, 9.8% rivaroxaban 20 mg daily (QD), and 5.7% rivaroxaban 15 mg QD. Also, 92% of the study population previously had warfarin replaced with NOACs due to lack compliance and labile INR control (time in therapeutic range < 60%). NOAC therapy for AF was started on average 934 ± 567 days after bioprosthetic heart valve implantation or surgical repair for an average duration of 835 ± 203 days. The study population included 24 (19.6%) patients with bioprosthetic mitral valve, 52 (43%) patients with bioprosthetic aortic valve, 41 (33.6%) patients with previous surgical mitral repair, 5 (4%) patients with previous surgical aortic repair, and concomitant use of NOACs. All patients were evaluated for thromboembolic events (ischemic stroke, transient ischemic attack, systemic embolism) as well as major bleeding events during the follow-up period. In our study population, we recorded a low mean annual incidence of thromboembolism (0.8%) and major bleeding (1.3%). According to our data, anticoagulation therapy with NOACs seems to be an effective and a safe treatment strategy for nonvalvular AF patients with bioprosthetic valves or prior surgical valve repair.

Predictive role of CHA2DS2-VASc score for cardiovascular events and death in patients with arterial hypertension and stable sinus rhythm.

Background The CHA2DS2-VASc score well stratifies the risk for thromboembolic events in non-valvular atrial fibrillation (NVAF) patients. This score may also predict thromboembolic events in sinus rhythm populations. Purpose The purpose of this study was to assess the prognostic role of CHA2DS2-VASc in a Caucasian community population of patients with arterial hypertension and sinus rhythm. Methods A total of 12,599 arterial hypertension residents not receiving anticoagulation were selected from a community population in Trieste between November 2009 and October 2014: 11,159 sinus rhythm and 1440 NVAF patients. We considered thromboembolic events, cardiovascular hospitalisation and all-cause death in all patients divided according to CHA2DS2-VASc. Results Sinus rhythm patients were 74 (interquartile range 65-81) years old, 50% were women, 32% with CAD, mean CHA2DS2-VASc 3.68 ± 1.47 points, significantly lower than NVAF patients (4.26 ± 1.50, P < 0.001). After 37 months follow-up, an increasing CHA2DS2-VASc corresponded to a higher rate of thromboembolic events in sinus rhythm patients, ranging from 0% in patients with a score of 1 or 2 to 2.6% in those with a score of 6 or greater ( P < 0.0001). A similar trend was found in the reference NVAF group. At Cox multivariable analysis, CHA2DS2-VASc predicted thromboembolic events (hazard ratio (HR) 2.12), cardiovascular hospitalisation (HR 1.55) and all-cause death (HR 1.57). The predictive accuracy of CHA2DS2-VASc was similar in sinus rhythm and NVAF patients for thromboembolic events, cardiovascular hospitalisation and all-cause death (area under the curve statistic 0.76 vs. 0.76, 0.68 vs. 0.66, 0.64 vs. 0.64, respectively). Conclusions In a community population of Caucasian arterial hypertension patients in sinus rhythm, CHA2DS2-VASc rather well stratifies for adverse clinical events at mid-term follow-up with a similar accuracy to NVAF patients. These results might be clinically relevant in this setting of sinus rhythm patients.

Value of Combined Circumferential and Longitudinal Left Ventricular Systolic Dysfunction to Predict Adverse Outcome in Patients with Asymptomatic Aortic Stenosis.

BACKGROUND AND AIM OF THE STUDY: Patients with asymptomatic aortic stenosis (AS) may have left ventricular systolic dysfunction (LVSD) defined as an impairment of the circumferential and/or longitudinal (C&L) myocardial fibers, despite a preserved left ventricular ejection fraction (LVEF). An assessment was made as to whether the combined LVSD of C&L fibers has a prognostic impact in asymptomatic AS. METHODS: A total of 200 asymptomatic AS patients was analyzed. Midwall shortening and mitral annular peak systolic velocity were considered as indices of C&L function and classified as low if <16.5% and <8.5 cm/s, respectively. The primary outcome was a composite of major cardiovascular events (MACE), including aortic valve-related and ischemic cardiovascular-related events. RESULTS: During a 25-month follow up period, MACE occurred in 69 patients (35%),while 46 of 72 patients (64%) had C&L LVSD and 23 of 128 patients (18%) had not (p <0.001). Cox analysis identified C&L LVSD as an independent MACE predictor, together with aortic transvalvular peak gradient, E/E' ratio and excessive left ventricular mass. C&L-LVSD also predicted the occurrence of aortic valve-related events and ischemic cardiovascular-related events analyzed separately. A receiver operating characteristic curve analysis showed that the area under the curve (AUC) for C&L LVSD in predicting MACE was 0.77, significantly higher (p = 0.002, z-statistic) than the AUCs of C&L fibers considered individually (0.64 and 0.63, respectively). CONCLUSION: C&L-LVSD provides additional prognostic information into traditional risk factors for patients with asymptomatic AS.

Reasons why patients suffering from chronic heart failure at very low risk for mortality die.

BACKGROUND: A proper prognostic stratification is crucial for organizing an effective clinical management and treatment decision-making in patients with chronic heart failure (CHF). In this study, we selected and characterized a sub-group of CHF patients at very low risk for death aiming to assess predictors of death in subjects with an expected probability of 1-year mortality near to 5%. METHODS: We used the Cardiac and Comorbid Conditions HF (3C-HF) Score to identify CHF patients with the best mid-term prognosis. We selected patients belonging to the lowest quartile of 3C-HF score (≤9 points). RESULTS: We recruited 1777 consecutive CHF patients at 3 Italian Cardiology Units (age 76±10years, 43% female, 32% with preserved ejection fraction). Subjects belonging to the lowest quartile of 3C-HF score were 609. During a median follow-up of 21 [12-40] months, 48 of these patients (8%) died, and 561 (92%) survived. The variables that contributed to death prediction by Cox regression multivariate analysis were older age (HR 1.03[CI 1.00-1.07]; p=0.04), male gender (HR 2.93[CI 1.50-5.51]; p=0.002) and a higher degree of renal dysfunction (HR 0.96[CI 0.94-0.98]; p<0.001). CONCLUSIONS: The prognostic stratification of CHF patients by 3C-HF score allows one to select patients at different outcome and to identify the factors associated with death in outliers with a very low mortality risk at mid-term follow-up. The reasons why these patients do not outlive the matching part of subjects who expectedly survive are related to a declined renal function and unmodifiable conditions including older age and male gender.

Echocardiographic markers of inducible myocardial ischemia at baseline evaluation preparatory to exercise stress echocardiography.

BACKGROUND: Tissue Doppler Imaging (TDI) is a sensible and feasible method to detect longitudinal left ventricular (LV) systolic dysfunction (LVSD) in patients with diabetes mellitus, hypertension or ischemic heart disease. In this study, we hypothesized that longitudinal LVSD assessed by TDI predicted inducible myocardial ischemia independently of other echocardiographic variables (assessed as coexisting potential markers) in patients at increased cardiovascular (CV) risk. METHODS: Two hundred one patients at high CV risk defined according to the ESC Guidelines 2012 underwent exercise stress echocardiography (ExSEcho) for primary prevention. Echocardiographic parameters were measured at rest and peak exercise. RESULTS: ExSEcho classified 168 (83.6 %) patients as non-ischemic and 33 (16,4 %) as ischemic. Baseline clinical characteristics were similar between the groups, but ischemic had higher blood pressure, received more frequently beta-blockers and antiplatelet agents than non-ischemic patients. The former had greater LV size, lower relative wall thickness and higher left atrial systolic force (LASF) than the latter. LV systolic longitudinal function (measure as peak S') was significantly lower in ischemic than non-ischemic patients (8.7 ± 2.1 vs 9.7 ± 2.7 cm/sec, p = 0.001). The factors independently related to myocardial ischemia at multivariate logistic analysis were: lower peak S', higher LV circumferential end-systolic stress and LASF. CONCLUSIONS: In asymptomatic patients at increased risk for adverse CV events baseline longitudinal LVSD together with higher LV circumferential end-systolic stress and LASF were the factors associated with myocardial ischemia induced by ExSEcho. The assessment of these factors at standard echocardiography might help the physicians for improving the risk stratification among these patients for ExSEcho.

Combined Circumferential and Longitudinal Left Ventricular Systolic Dysfunction in Patients with Rheumatoid Arthritis without Overt Cardiac Disease.

BACKGROUND: Patients with rheumatoid arthritis have an increased risk for cardiovascular disease. Because of accelerated atherosclerosis and changes in left ventricular (LV) geometry, circumferential and longitudinal (C&L) LV systolic dysfunction (LVSD) may be impaired in these patients despite preserved LV ejection fraction. The aim of this study was to determine the prevalence of and factors associated with combined C&L LVSD in patients with rheumatoid arthritis. METHODS: One hundred ninety-eight outpatients with rheumatoid arthritis without overt cardiac disease were prospectively analyzed from January through June 2014 and compared with 198 matched control subjects. C&L systolic function was evaluated by stress-corrected midwall shortening (sc-MS) and tissue Doppler mitral annular peak systolic velocity (S'). Combined C&L LVSD was defined if sc-MS was <86.5% and S' was <9.0 cm/sec (the 10th percentiles of sc-MS and S' derived in 132 healthy subjects). RESULTS: Combined C&L LVSD was detected in 56 patients (28%) and was associated with LV mass (odds ratio, 1.03; 95% CI, 1.01-1.06; P = .04) and concentric LV geometry (odds ratio, 2.76; 95% CI, 1.07-7.15; P = .03). By multiple logistic regression analysis, rheumatoid arthritis emerged as an independent predictor of combined C&L LVSD (odds ratio, 2.57; 95% CI, 1.06-6.25). The relationship between sc-MS and S' was statistically significant in the subgroup of 142 patients without combined C&L LVSD (r = 0.40, F < 0.001), having the best fitting by a linear function (sc-MS = 58.1 + 3.34 × peak S'; r(2) = 0.19, P < .0001), absent in patients with combined C&L LVSD. CONCLUSIONS: Combined C&L LVSD is detectable in about one fourth of patients with asymptomatic rheumatoid arthritis and is associated with LV concentric remodeling and hypertrophy. Rheumatoid arthritis predicts this worrisome condition, which may explain the increased risk for cardiovascular events in these patients. NOTICE OF CLARIFICATION: The aim of this "notice of clarification" is to analyze in brief the similarities and to underline the differences between the current article (defined as "paper J") and a separate article entitled "Prevalence and Factors Associated with Subclinical Left Ventricular Systolic Dysfunction Evaluated by Mid-Wall Mechanics in Rheumatoid Arthritis" (defined as "paper E"), which was written several months before paper J, and recently accepted for publication by the journal "Echocardiography" (Cioffi et al. http://dx.doi.org/10.1111/echo.13186). We wish to explain more clearly how the manuscript described in "paper J" relates to the "paper E" and the context in which it ought to be considered. Data in both papers were derived from the same prospective database, so that it would appear questionable if the number of the enrolled patients and/or their clinical/laboratory/echocardiographic characteristics were different. Accordingly, both papers reported that 198 patients with rheumatoid arthritis (RA) were considered and their characteristics were identical, due to the fact that they were the same subjects (this circumstance is common and mandatory among all studies in which the patients were recruited from the same database). These are the similarities between the papers. In paper E, which was written several months before paper J, we focused on the prevalence and factors associated with impaired circumferential left ventricular (LV) systolic function measured as mid-wall shortening (corrected for circumferential end-systolic stress). We found that 110 patients (56% of the whole population) demonstrated this feature. Thus, these 110 patients were the object of the study described in paper E, in which we specifically analyzed the factors associated with the impairment of stress-corrected mid-wall shortening (sc-MS). The conclusions of that paper were: (i) subclinical LV systolic dysfunction (LVSD) is detectable in more than half RA population without overt cardiac disease as measured by sc-MS, (ii) RA per se is associated with LVSD, and (iii) in RA patients only LV relative wall thickness was associated with impaired sc-MS based upon multivariate logistic regression analysis. Differently, in the paper J, we focused on the prevalence and factors associated with combined impairment of circumferential and longitudinal shortening (C&L) in 198 asymptomatic patients with RA. We found that 56 patients (28% of the whole population) presented this feature. Thus, these 56 patients were analyzed in detail in this study, as well as the factors associated with the combined impairment of C&L shortening. In paper J, we evaluated sc-MS as an indicator of circumferential systolic LV shortening, and we also determined the average of tissue Doppler measures of maximal systolic mitral annular velocity at four different sampling sites ( S') as an indicator of longitudinal LV systolic shortening. This approach clearly demonstrates that in paper J, we analyzed data deriving from the tissue Doppler analysis, which were not taken into any consideration in paper E. The investigation described in paper J made evident several original and clinically relevant findings. In patients with RA: (i) the condition of combined C&L left ventricular systolic dysfunction (LVSD) is frequent; (ii) these patients have comparable clinical and laboratory characteristics with those without combined C&L LVSD, but exhibit remarkable concentric LV geometry and increased LV mass, a phenotype that can be consider a model of compensated asymptomatic chronic heart failure; (iii) RA is an independent factor associated with combined C&L LVSD; (iv) no relationship between indexes of circumferential and longitudinal function exists in patients with combined C&L LVSD, while it is statistically significant and positive when the subgroup of patients without combined C&L LVSD is considered, having the best fitting by a linear function. All these findings are unique to the paper J and are not presented (they could not have been) in paper E. It appears clear that, starting from the same 198 patients included in the database, different sub-groups of patients were selected and analyzed in the two papers (they had different echocardiographic characteristics) and, consequently, different factors emerged by the statistical analyses as covariates associated with the different phenotypes of LVSD considered. Importantly, both papers E and J had a very long gestation because all reviewers for the different journals found several and important issues that merited to be addressed: a lot of changes were proposed and much additional information was required, particularly by the reviewers of paper E. Considering this context, it emerges that although paper E was written well before paper J, the two manuscripts were accepted at the same time (we received the letters of acceptance within a couple of weeks). Thus, the uncertainty about the fate of both manuscripts made it very difficult (if not impossible) to cite either of them in the other one and, afterward, we just did not think about this point anymore. Of note, the idea to combine in the analysis longitudinal function came therefore well after the starting process of revision of the paper E and was, in some way inspired by a reviewer's comment. That is why we did not put both findings in the same paper. We think that our explanations provide the broad audience of your journal a perspective of transparency and our respect for the readers' right to understand how the work described in the paper J relates to other work by our research group. Giovanni Cioffi On behalf of all co-authors Ombretta Viapiana, Federica Ognibeni, Andrea Dalbeni, Davide Gatti, Carmine Mazzone, Giorgio Faganello, Andrea Di Lenarda, Silvano Adami, and Maurizio Rossini.

Prevalence and Factors Associated with Subclinical Left Ventricular Systolic Dysfunction Evaluated by Mid-Wall Mechanics in Rheumatoid Arthritis.

OBJECTIVE: Patients with rheumatoid arthritis (RA) have an increased cardiovascular event rate, mainly due to the arterial stiffness which leads to coronary atherosclerosis and concentric left ventricular (LV) geometry. These conditions predispose to LV systolic dysfunction (LVSD), which can be detected by stress-corrected mid-wall shortening (sc-MS), an early prognosticator of cardiovascular events in asymptomatic patients with arterial hypertension and/or diabetes. In these subjects, sc-MS is frequently impaired even though LV ejection fraction (LVEF) is preserved. In this study, we analyzed the prevalence and the factors associated with asymptomatic LVSD measured by sc-MS among patients with RA and verified whether RA per se was independently related to LVSD. METHODS: We prospectively recruited 198 outpatients with RA without overt cardiac disease between January and June 2014 and compared them to 198 controls matched for age, gender, body mass index, and prevalence of hypertension and diabetes. sc-MS was taken as index of LVSD and considered impaired if <86.5%. RESULTS: Impaired sc-MS was detected in 110 (56%) RA patients and in 30 (15%) controls (P < 0.001), whereas LVEF was impaired (value <50%) in six (3%) RA patients and in two (1%) controls (P = ns). Multiple logistic regression analysis revealed that RA was independently associated with impaired sc-MS (Exp ß 2.01 [CI 1.12-3.80], P = 0.02) together with increased LV mass and concentric geometry. CONCLUSIONS: More than half RA patients without overt cardiac disease have LVSD detectable by sc-MS. RA emerges as a condition closely related to LVSD. These findings might explain the high risk for adverse cardiovascular events in RA patients.

Insights from Cardiac Mechanics after Three Decades from Successfully Repaired Aortic Coarctation.

BACKGROUND AND AIMS: Patients who underwent a successful repair of the aortic coarctation show chronic hyperdynamic state and normal left ventricular (LV) geometry; however, there are few data regarding the LV systolic function in the long term. Accordingly, we assessed LV systolic mechanics and factors associated with LV systolic dysfunction (LVSD) in patients with repaired CoA. METHODS: Clinical and echocardiographic data from 19 repaired CoA were analyzed 28 ± 13 years after surgery. Stress-corrected midwall shortening (sc-MS) and mitral annular peak systolic velocity (S') were analyzed as indexes of LV circumferential and longitudinal systolic function, respectively. Echocardiographic data of CoA patients were compared with 19 patients matched for age and hypertension and 38 healthy controls. Sc-MS was considered impaired if <89%, S' if <8.5 cm/s (10th percentiles of healthy controls, respectively). RESULTS: There were no statistical differences between study groups in LV volumes, mass and geometry. LV ejection fraction and Sc-MS were similar in all groups, however, CoA group had a significantly lower peak S' in comparison with matched and healthy controls (7.1 ± 1.3, 10.3 ± 1.9, and 11.1 ± 1.5, respectively; all P < 0.001). Prevalence of longitudinal LVSD defined as low S' was 84% in CoA, 13% in matched, and 5% in healthy control group (all P<0.05). Multivariate logistic regression analysis revealed that low peak S' was independently related to higher E/E' ratio and the presence of CoA. CONCLUSIONS: Patients who underwent a successful repair of CoA commonly show asymptomatic longitudinal LVSD associated with worse LV diastolic function in the long-term follow-up.

Clinical implications of the CKD epidemiology collaboration (CKD-EPI) equation compared with the modification of diet in renal disease (MDRD) study equation for the estimation of renal dysfunction in patients with cardiovascular disease.

The CKD-EPI equation is more accurate than the MDRD equation in the general population. We performed this study to establish whether chronic kidney disease (CKD) is commonly recognized by clinicians and whether the CKD-EPI equation improves prognosis estimation in patients with chronic cardiovascular disease (CVD). We analyzed data on 12394 CVD patients consecutively examined at the Cardiovascular Center of Trieste (Italy) between November 2009 and October 2013. The outcomes were all-cause death and a composite outcome of death/hospitalization for CV events (D+cvH). CKD-EPI formula reclassified 1786 (14.4 %) patients between KDIGO categories compared to the MDRD: 2.3 % (n = 280) placed in a lower risk and 12.1 % (n = 1506) into a higher risk group. CKD, defined as eGFR-CKD-EPI formula <60 ml/min, was present in 3083 patients (24.9 %) but not recognized by clinicians in 1946 (63.1 % of patients with CKD). The lack of recognition of CKD was inversely proportional to the KDIGO class for both equations. There were 986 deaths and 2726 D+cvH during 24 months follow-up. The incidence of death and D+cvH was about twice as high in patients with unrecognized CKD than in those with normal renal function (31 % vs. 17.1 %, aHR: 1.35, 95 % CI: 1.15 to 1.60), even in those patients with eGFR-MDRD >60 but eGFR-CKD-EPI formula <60 (31.1 % vs 17.1 %, p < 0.001). CKD-EPI equation provides more accurate risk stratification than MDRD equation in patients with CVD. CKD was unrecognized in nearly two-thirds of these patients but clinical outcomes were similar in those for patients with recognized CKD.

[Nonvalvular atrial fibrillation: data from the Observatory of Cardiovascular Diseases in the province of Trieste (Italy)]. / La fibrillazione atriale non valvolare: dati dall'Osservatorio delle Malattie Cardiovascolari della provincia di Trieste.

BACKGROUND: Nonvalvular atrial fibrillation (NVAF) is the most common arrhythmia in outpatients and is associated with increased mortality, thromboembolic and hemorrhagic events. Although several international studies have evaluated its prognostic impact in the real world, Italian data are still lacking. Our aim was to define the prevalence, comorbidity, treatment and outcome in a population of "real-life" outpatients with NVAF. METHODS: From 2009 to 2013, 21 282 consecutive patients referred to the Cardiovascular Center of Trieste were enrolled in the study. NVAF was defined in the absence of moderate-to-severe valvular disease, valvular interventions, rheumatic heart disease. Events evaluated in the follow-up included mortality, hospitalizations, thromboembolism and hemorrhage. Clinical data and events were derived from the cardiac regional electronic patient records and the ICD-9 hospital discharge records. RESULTS: 3379 patients (15.8%) had NVAF (35.6% paroxysmal, 34.5% persistent, 29.9% permanent); compared to the general population these patients were older, predominantly male, with hypertension, diabetes and history of stroke/transient ischemic attack and heart failure. Oral anticoagulant therapy was prescribed in 54% of cases, above all in persistent or permanent forms, in patients with higher CHA2DS2-VASc score and younger age. The rate of all-cause mortality, cardiovascular hospitalization, thromboembolic and hemorrhagic events during follow-up was higher in patients with NVAF than in the general population. The use of oral anticoagulant therapy reduced the incidence of thromboembolic events. CHA2DS2-VASc score emerged as an independent predictor of thromboembolic events in patients with paroxysmal (35% higher risk), persistent (40% higher risk) and permanent atrial fibrillation (34% higher risk than patients without atrial fibrillation). CONCLUSIONS: In "real-life" outpatients NVAF is associated with older age, more comorbidities and increased cardiovascular events. CHA2DS2-VASc and HAS-BLED scores predict accurately the risk for thromboembolic and hemorrhagic events. Oral anticoagulation reduces thromboembolic events, but its use is limited to just half of the patients.