Antiplatelet efficacy of ticagrelor versus clopidogrel in Mediterranean patients with diabetes mellitus and chronic coronary syndromes: A crossover pharmacodynamic investigation.

Introduction: Patients with diabetes mellitus (DM) have augmented platelet reactivity and diminished responsiveness to clopidogrel. Ticagrelor, a more potent P2Y12 inhibitor, is clinically superior to clopidogrel in acute coronary syndromes, although its role in chronic coronary syndromes (CCS) is still the subject of debate. The aim of this investigation was to compare the pharmacodynamic effectiveness of ticagrelor and clopidogrel in Mediterranean DM patients with CCS. Materials and methods: In this prospective, randomized, crossover study, patients (n = 20) were randomized (1:1) to receive, on top of aspirin therapy, either ticagrelor 180 mg loading dose (LD)/90 mg maintenance dose (MD) b.i.d. or clopidogrel 600 mg LD/75 mg MD o.d. for 1 week in a crossover fashion with a 2-4 week washout period between regimens. Platelet function measurements were performed at 4 timepoints in each period (baseline, 2 h and 24 h after LD, and 1 week), including light transmission aggregometry (LTA, primary endpoint), VASP assay, Multiplate and VerifyNow P2Y12. Results: The ticagrelor LD achieved greater platelet inhibitory effect than clopidogrel LD, assessed with LTA (20 µM ADP as agonist), at 2 h (34.9 ± 3.9% vs. 63.6 ± 3.9%; p < 0.001) and 24 h (39.4 ± 3.5% vs. 52.3 ± 3.8%; p = 0.014). After 1 week of therapy, platelet reactivity was again significantly inferior with ticagrelor compared to clopidogrel (30.7 ± 3.0% vs. 54.3 ± 3.0%; p < 0.001). The results were consistent with the other platelet function assays employed. Conclusion: In Mediterranean patients with DM and CCS, ticagrelor provides a more potent antiplatelet effect than clopidogrel after the LD and during the maintenance phase of therapy. Clinical trial registration: [ClinicalTrials.gov], identifier [NCT02457130].

Clinical correlates and prognostic impact of impaired iron storage versus impaired iron transport in an international cohort of 1821 patients with chronic heart failure.

AIMS: To define iron deficiency in chronic heart failure (CHF), both, ferritin<100µg/L (indicating reduced iron storage) and transferrin saturation (TSAT)<20% (indicating reduced iron transport) are used. The aim of the study was to evaluate clinical outcomes and prognosis of either low ferritin or low TSAT in patients with CHF. METHODS AND RESULTS: We evaluated the clinical impact of impaired iron storage (IIS) and impaired iron transport (IIT) either alone or in combination compared to patients with normal iron status (NIS), in an international cohort of 1821 patients with CHF with a mean age of 66±13years and mean left ventricular ejection fraction of 35%±15. Isolated IIS was observed in 219 patients (12%), isolated IIT in 454 (25%) and coexistence of both conditions (IIS+IIT) were seen in 389 (21%). In adjusted models we found that patients with IIS+IIT and patients with isolated IIT had higher NT-proBNP levels (OR 2.2 [1.6-3.1] and OR 2.1 [1.5-2.9] respectively) and worse quality of life (OR 1.8 [1.2-2.7] and OR 1.7 [1.2-2.5] respectively) compared with isolated IIS. Multivariate Cox analyses showed that IIS+IIT and isolated IIT were independently associated with all-cause mortality (OR 1.41 [1.06-1.86] and OR 1.47 [1.13-1.92] respectively). Patients with isolated IIS did not differ from NIS patients in terms of severity or outcomes. CONCLUSIONS: Impaired iron transport alone or in combination with impaired iron storage is associated with worse clinical profile and increased risk of mortality in patients with CHF. Patients with isolated impaired iron storage may have a milder form of iron deficiency.

Secondary prevention strategies after an acute ST-segment elevation myocardial infarction in the AMI code era: beyond myocardial mechanical reperfusion.

BACKGROUND: The AMI code is a regional network enhancing a rapid and widespread access to reperfusion therapy (giving priority to primary angioplasty) in patients with acute ST-segment elevation myocardial infarction (STEMI). We aimed to assess the long-term control of conventional cardiovascular risk factors after a STEMI among patients included in the AMI code registry. DESIGN AND METHODS: Four hundred and fifty-four patients were prospectively included between June-2009 and April-2013. Clinical characteristics were collected at baseline. The long-term control of cardiovascular risk factors and cardiovascular morbidity/mortality was assessed among the 6-months survivors. RESULTS: A total of 423 patients overcame the first 6 months after the STEMI episode, of whom 370 (87%) underwent reperfusion therapy (363, 98% of them, with primary angioplasty). At 1-year follow-up, only 263 (62%) had adequate blood pressure control, 123 (29%) had LDL-cholesterol within targeted levels, 126/210 (60%) smokers had withdrawn from their habit and 40/112 (36%) diabetic patients had adequate glycosylated hemoglobin levels. During a median follow-up of 20 (11-30) months, cumulative mortality of 6 month-survivors was 6.1%, with 9.9% of hospital cardiovascular readmissions. The lack of assessment of LDL and HDL-cholesterol were significantly associated with higher mortality and cardiovascular readmission rates. CONCLUSIONS: Whereas implementation of the AMI code resulted in a widespread access to rapid reperfusion therapy, its long-term therapeutic benefit may be partially counterbalanced by a manifestly suboptimal control of cardiovascular risk factors. Further efforts should be devoted to secondary prevention strategies after STEMI.

Iron Deficiency Is a Determinant of Functional Capacity and Health-related Quality of Life 30 Days After an Acute Coronary Syndrome.

BACKGROUND AND OBJECTIVES: Iron deficiency (ID) is a prevalent condition in patients with ischemic heart disease and heart failure. Little is known about the impact of ID on exercise capacity and quality of life (QoL) in the recovery phase after an acute coronary syndrome (ACS). METHODS: Iron status and its impact on exercise capacity and QoL were prospectively evaluated in 244 patients 30 days after the ACS. QoL was assessed by the standard EuroQoL-5 dimensions, EuroQoL visual analogue scale, and Heart-QoL questionnaires. Exercise capacity was analyzed by treadmill/6-minute walk tests. The effect of ID on cardiovascular mortality and readmission rate was also investigated. RESULTS: A total of 46% of the patients had ID. These patients had lower exercise times (366±162 vs 462±155seconds; P<.001), metabolic consumption rates (7.9±2.9 vs 9.3±2.6 METS; P=.003), and EuroQoL-5 dimensions (0.76±0.25 vs 0.84±0.16), visual analogue scale (66±16 vs 72±17), and Heart-QoL (1.9±0.6 vs 2.2±0.6) scores (P<.05). ID independently predicted lower exercise times (OR, 2.9; 95%CI, 1.1-7.6; P=.023) and worse QoL (OR, 1.9; 95%CI, 1.1-3.3; P<.001) but had no effect on cardiovascular morbidity or mortality. CONCLUSIONS: ID, a prevalent condition in ACS patients, results in a poorer mid-term functional recovery, as measured by exercise capacity and QoL.

Iron Status in Chronic Heart Failure: Impact on Symptoms, Functional Class and Submaximal Exercise Capacity.

INTRODUCTION AND OBJECTIVES: To evaluate the effect of iron deficiency and anemia on submaximal exercise capacity in patients with chronic heart failure. METHODS: We undertook a single-center cross-sectional study in a group of stable patients with chronic heart failure. At recruitment, patients provided baseline information and completed a 6-minute walk test to evaluate submaximal exercise capacity and exercise-induced symptoms. At the same time, blood samples were taken for serological evaluation. Iron deficiency was defined as ferritin < 100 ng/mL or transferrin saturation < 20% when ferritin is < 800 ng/mL. Additional markers of iron status were also measured. RESULTS: A total of 538 heart failure patients were eligible for inclusion, with an average age of 71 years and 33% were in New York Heart Association class III/IV. The mean distance walked in the test was 285 ± 101 meters among those with impaired iron status, vs 322 ± 113 meters (P=.002). Symptoms during the test were more frequent in iron deficiency patients (35% vs 27%; P=.028) and the most common symptom reported was fatigue. Multivariate logistic regression analyses showed that increased levels of soluble transferrin receptor indicating abnormal iron status were independently associated with advanced New York Heart Association class (P < .05). Multivariable analysis using generalized additive models, soluble transferrin receptor and ferritin index, both biomarkers measuring iron status, showed a significant, independent and linear association with submaximal exercise capacity (P=.03 for both). In contrast, hemoglobin levels were not significantly associated with 6-minute walk test distance in the multivariable analysis. CONCLUSIONS: In patients with chronic heart failure, iron deficiency but not anemia was associated with impaired submaximal exercise capacity and symptomatic functional limitation.

Characterization of the nodal slow pathway in patients with nodal reentrant tachycardia: clinical implications for guiding ablation.

INTRODUCTION AND OBJECTIVES: Nodal slow pathway ablation is the treatment of choice for nodal reentrant tachycardia. No demographic, anatomic, or electrophysiologic variables have been reported to predict an exact location of the slow pathway in the atrioventricular node or its proximity to the fast pathway. The purpose of this study was to analyze these variables. METHODS: The study prospectively included 54 patients (17 men; mean age, 55 [16] years) who had undergone successful slow pathway ablation. The refractory periods of both pathways and their differential conduction time were measured, and calculations were performed to obtain the distance from the His-bundle region (location of the fast pathway) to the coronary sinus ostium (to estimate the anteroposterior length of the triangle of Koch) and to the slow pathway area. RESULTS: The differential conduction time (139 [98] ms) did not correlate with the His-coronary sinus distance (19 [6] mm; P=.6) or the His-slow pathway distance (14 [4] mm; P=.4). When the His-coronary sinus distance was larger, the His-slow pathway distance was also larger (r=0.652; P<.01) and the anatomic correlation between the triangle dimensions and the separation between the two pathways was confirmed. In patients older than 70 years, smaller triangle sizes and a shorter distance between both pathways were observed (P<.001). CONCLUSIONS: A greater anteroposterior dimension of the triangle of Koch is associated with a slow-pathway location farther from the fast pathway. In elderly patients the two pathways are closer together (higher risk of atrioventricular block).

Differences in neurohormonal activity partially explain the obesity paradox in patients with heart failure: The role of sympathetic activation.

BACKGROUND: Obese patients with chronic Heart Failure (HF) have better outcome than their lean counterparts, although little is known about the pathophysiology of this obesity paradox. Our aim was to evaluate the hypothesis that patients with chronic HF and obesity (defined as body mass index (BMI)≥30kg/m(2)), may have an attenuated neurohormonal activation in comparison with non-obese patients. METHODS AND RESULTS: The present study is the post-hoc analysis of a cohort of 742 chronic HF patients from a single-center study evaluating sympathetic activation by measuring baseline levels of norepinephrine (NE). Obesity was present in 33% of patients. Higher BMI and obesity were significantly associated with lower NE levels in multivariable linear regression models adjusted for covariates (p<0.001). Addition to NE in multivariate Cox proportional hazard models attenuated the prognostic impact of BMI in terms of outcomes. Finally, when we explored the prognosis impact of raised NE levels (>70th percentile) carrying out a separate analysis in obese and non-obese patients we found that in both groups NE remained a significant independent predictor of poorer outcomes, despite the lower NE levels in patients with chronic HF and obesity: all-cause mortality hazard ratio=2.37 (95% confidence interval, 1.14-4.94) and hazard ratio=1.59 (95% confidence interval, 1.05-2.4) in obese and non-obese respectively; and cardiovascular mortality hazard ratio=3.08 (95% confidence interval, 1.05-9.01) in obese patients and hazard ratio=2.08 (95% confidence interval, 1.42-3.05) in non-obese patients. CONCLUSION: Patients with chronic HF and obesity have significantly lower sympathetic activation. This finding may partially explain the obesity paradox described in chronic HF patients.

Iron deficiency is a key determinant of health-related quality of life in patients with chronic heart failure regardless of anaemia status.

AIMS: To evaluate the effect of iron deficiency (ID) and/or anaemia on health-related quality of life (HRQoL) in patients with chronic heart failure (CHF). METHODS AND RESULTS: We undertook a post-hoc analysis of a cohort of CHF patients in a single-centre study evaluating cognitive function. At recruitment, patients provided baseline information and completed the Minnesota Living with Heart Failure questionnaire (MLHFQ) for HRQoL (higher scores reflect worse HRQoL). At the same time, blood samples were taken for serological evaluation. ID was defined as serum ferritin levels <100 ng/mL or serum ferritin <800 ng/mL with transferrin saturation <20%. Anaemia was defined as haemoglobin ≤12 g/dL. A total of 552 CHF patients were eligible for inclusion, with an average age of 72 years and 40% in NYHA class III or IV. The MLHFQ overall summary scores were 41.0 ± 24.7 among those with ID, vs. 34.4 ± 26.4 for non-ID patients (P = 0.003), indicating worse HRQoL. When adjusted for other factors associated with HRQoL, ID was significantly associated with worse MLHFQ overall summary (P = 0.008) and physical dimension scores (P = 0.002), whereas anaemia was not (both P > 0.05). Increased levels of soluble transferrin receptor were also associated with impaired HRQoL (P ≤ 0.001). Adjusting for haemoglobin and C-reactive protein, ID was more pronounced in patients with anaemia compared with those without (P < 0.001). CONCLUSION: In patients with CHF, ID but not anaemia was associated with reduced HRQoL, mostly due to physical factors.

Effects of preoperative intravenous erythropoietin plus iron on outcome in anemic patients after cardiac valve replacement.

Preoperative anemia is a risk factor for postoperative morbidity and in-hospital mortality in cardiac surgery. However, it is not known whether treatment of anemia before cardiac surgery by administering recombinant human erythropoietin (rhEPO) plus iron improves postoperative outcomes and decreases red blood cell transfusions in these patients. In 1998 a collection of consecutive data for patients who underwent valve replacement was initiated and the inclusion criterion was anemia. Treatment with rhEPO was given at a dose of 500 IU/kg/day every week for 4 weeks and the fifth dose 48 hours before valve replacement. During each rhEPO session, patients received intravenous iron sucrose supplementation. The intervention cohort (2006 to 2011) included 75 patients and the observation cohort was composed of 59 patients who did not receive any treatment (1998 to 2005). Multivariable logistic regression analysis showed that administration of combined therapy was independently associated with decreased postoperative morbidity (odds ratio [OR] 0.13, 95% confidence interval [CI] 0.03 to 0.59 p = 0.008) and in-hospital mortality (OR 0.16, 95% CI 0.28 to 0.95 p = 0.04) after adjusting for logistic European System for Cardiac Operative Risk Evaluation score, type of intervention, time of cardiopulmonary bypass, and year of surgery. Individually, this treatment also decreased postoperative renal failure (OR 0.23, 95% CI 0.06 to 0.88, p = 0.03). Rate of red blood cell transfusion decreased from 93% in the observation cohort to 67% in the intervention cohort as did days of hospitalization (median, 15 days, 10 to 27, versus 10 days, 8 to 14, respectively, p = 0.01 for all comparisons). In conclusion, administration of intravenous rhEPO plus iron in anemic patients before valve replacement improves postoperative survival, decreases blood transfusions, and shortens hospitalization.

In-hospital acquired anemia in acute coronary syndrome. Predictors, in-hospital prognosis and one-year mortality.

INTRODUCTION AND OBJECTIVES: Anemia at hospital admission predicts a poor outcome in patients presenting with acute coronary syndrome. It remains unclear whether in-hospital hemoglobin levels decrease (nosocomial anemia) not related to bleeding also implies a poor prognosis. We aimed to identify predictors of nosocomial anemia and its prognostic significance. METHODS: We prospectively included 221 acute coronary syndrome patients admitted in our institution during the years 2009-2010, with normal hemoglobin levels at admission. Nosocomial anemia was defined as a decrease in hemoglobin levels to <13 g/dL in men and <12 g/dL in women in the absence of apparent bleeding. Clinical variables and hematological inflammatory parameters were assessed in order to identify predictors for the development of nosocomial anemia. We compared the clinical outcome after a 1-year follow-up period of patients without anemia as opposed to those who developed nosocomial anemia. RESULTS: Nosocomial anemia was registered in 25% of study patients. A >3.1 mg/dL value of C-reactive protein was highly predictive of developing nosocomial anemia (odds ratio=5.9; 95% confidence interval, 2.6-13.4; P<.001). The incidence of mortality and cardio-vascular morbidity was higher in the patients who developed nosocomial anemia (34.5% vs 9%; P<.001). Nosocomial anemia was a strong predictor of cardio-vascular morbidity and mortality in the long-term follow-up (hazard ratio=2.47; 95% confidence interval, 1.23-4.96; P=.01). CONCLUSIONS: Nosocomial anemia predicts a poorer outcome in patients with acute coronary syndrome. Increased C-reactive protein levels, indicating inflammatory state, are predictive of developing in-hospital anemia unrelated to apparent bleeding.