The International Consortium on Primary Graft Dysfunction: Redefining Clinical Risk Factors in the Contemporary Era of Heart Transplantation.

BACKGROUND: Primary graft dysfunction (PGD) is the leading cause of morbidity and mortality early after heart transplantation (HT). The International Consortium on PGD is a multicenter collaboration dedicated to identifying the clinical risk factors for PGD in the contemporary era of HT. The objectives of the current report were (1) to assess the incidence of severe PGD in an international cohort; (2) to evaluate the performance of the most strongly validated PGD risk tool, the RADIAL score, in a contemporary cohort; and (3) to redefine clinical risk factors for severe PGD in the current era of HT. METHODS: This is a retrospective, observational study of consecutive adult HT recipients between 2010 and 2020 in 10 centers in the United States, Canada and Europe. Patients with severe PGD were compared to those without severe PGD (comprising those with no, mild and moderate PGD). The RADIAL score was calculated for each transplant recipient. The discriminatory power of the RADIAL score was evaluated using receiver operating characteristic (ROC) analysis, and its calibration was assessed by plotting the percentage of PGD predicted vs that which was observed. To identify clinical risk factors associated with severe PGD, we performed multivariable mixed-effects logistic regression modeling to account for among-center variability. RESULTS: A total of 2746 patients have been enrolled in the registry to date, including 2015 (73.4%) from North America, and 731 (26.6%) from Europe; 215 participants (7.8%) met the criteria for severe PGD. There was an increase in the incidence of severe PGD over the study period (P value for trend by difference sign test = 0.004). The Kaplan-Meier estimate for 1-year survival was 75.7% (95% CI 69.4-80.9%) in patients with severe PGD as compared to 94.4% (95% CI 93.5-95.2%) in those without severe PGD (log-rank P value < 0.001). The RADIAL score performed poorly in our contemporary cohort and was not associated with severe PGD; it had an AUC of 0.53 (95% CI 0.48-0.58). In the multivariable regression model, acute preoperative dialysis (OR 2.41, 95% CI 1.31-4.43), durable left ventricular assist device support (OR 1.77, 95% CI 1.13-2.77), and total ischemic time (OR 1.20 for each additional hour, 95% CI 1.02-1.41) were associated with an increased risk of severe PGD. CONCLUSIONS: Our consortium has identified an increasing incidence of PGD in the modern transplant era. We identified contemporary risk factors for this early post-transplant complication, which confers a high mortality risk. These results may enable the identification of patients at high risk for developing severe PGD in order to inform peri-transplant donor and recipient management practices.

Relationship between nutritional treatment compliance and nutritional status improvements in patients with gastrointestinal impairment taking an oral peptide-based supplement.

OBJECTIVES: Compliance in outpatients with gastrointestinal (GI) malabsorption is key in nutritional treatment. The objective of this study was to assess compliance in patients with GI impairment and malnutrition taking a high-calorie, high-protein, peptide-based oral nutritional supplement (ONS-PBD). METHODS: A prospective, multicenter, observational study was conducted in 19 medical sites in Spain where ONS-PBD were prescribed as standard of care. Patients consumed ONS-PBD daily for 12 wk. Compliance was calculated as the percentage consumed of the prescribed amount of ONS per day. RESULTS: A total of 90 adult patients were included in the study, of whom 64 completed the 12-wk regimine. Mean compliance was 78.8% ± 24.5%. Risk of malnutrition decreased in 56.3% of patients at 12 wk, as measured with the malnutrition universal screening tool. A reduction in abdominal pain was observed and stool consistency improved, with a mean of 54.7% and 27.5%, respectively. Improvements in quality of life and a decrease in percentage of patients with severe functional impairment were observed. CONCLUSIONS: These data show that ONS-PBD compliance in malnourished patients with GI symptoms is high, reducing GI symptoms and improving patients' nutritional status.

Changes in Pulmonary Function in Patients With Advanced Heart Failure Listed for Heart Transplantation.

BACKGROUND: Pulmonary function tests (PFTs) are often impaired in patients with advanced heart failure. There is limited data about their impact on survival after heart transplantation (HT). We sought to assess the prevalence and type of PFT abnormalities in patients on HT waiting list and their impact on outcomes. METHODS: We performed a retrospective analysis of a prospective registry of consecutive patients undergoing HT between 2012 and 2018. Patients were classified into 4 groups according to pre-HT PFT results: 1. normal pattern: forced vital capacity (FVC) ≥ 80% and forced expiratory volume in 1 second (FEV1) to FVC ratio (FEV1/FVC) ≥ 0.7; 2. obstructive: FEV1/FVC < 0.7; 3. nonobstructive: FEV1/FVC ≥ 0.7 and FVC < 80% when total lung capacity value was not available; and 4. restrictive: FEV1/FVC ≥ 0.7 and total lung capacity < 80%. The prevalence of impaired carbon monoxide diffusing capacity corrected for hemoglobin < 80% and FEV1 < 70% was also analyzed. High-urgency HT patients and those referred from other centers without quantitative pulmonary evaluation were excluded. RESULTS: Among 123 patients who underwent HT, 83 patients with complete PFT were included. Median follow-up was 2.7 ± 1.9 years. Of these, 29 (34.9%) had an obstructive pattern, 20 (24.1%) a nonobstructive, 18 (21.7%) a restrictive, and 16 (19.3%) a normal pattern. Fifty-one (61.4%) patients had FEV1 < 70% and 58 (69.9%) a carbon monoxide diffusing capacity corrected for hemoglobin < 80%. There was a tendency to lower survival in all altered PFT groups compared with normal (P = .054) but not within the other groups. Patients with an impaired FEV1 had significantly higher mortality than patients with normal values (P = .008). Area under receiver operating characteristic curve for FEV1 was 0.73 (95% confidence interval [0.60-0.86]). A cutoff value of FEV1 (60.5) predicts mortality with 66% sensitivity and 64% specificity. CONCLUSIONS: PFT alterations have a very high prevalence on HT waiting list patients. Patients with impaired FEV1 had worse outcomes after heart transplantation.

Data on clinical characteristics of a heart failure patients' cohort with reduced ejection fraction and analysis of the circulating values of five different heart failure biomarkers; high sensitivity troponin T, galectin-3, C-terminal propeptide of type I procollagen, soluble AXL and BNP.

In this article, the full description of a heart failure with reduced ejection fraction (HF_REF) cohort of 192 patients is provided. Tables with the baseline demographic, prior history, ECG parameters, echocardiographic parameters, laboratory values and pharmacological treatment of these patients are included. Also, the quartile values of the analyzed circulating biomarkers: high sensitivity Troponin T (hs-TnT), galectin-3 (Gal-3), C-terminal propeptide of type I procollagen (CICP), soluble AXL (sAXL) and Brain Natriuretic Peptide (BNP) are given. The main demographic and clinical features of the patients' subgroups that have hs-TnT, Gal-3, CICP or BNP above the third quartile are described. Tables with Pearson correlation analysis of the HF_REF patients' biomarker levels are included. And Pearson correlation analysis of the HF_REF patients' hs-TnT, Gal-3, CICP levels with patients' biochemical parameters, blood count and inflammation parameters are also described. These data are related to the research articles (AXL receptor tyrosine kinase is increased in patients with heart failure (M. Batlle, P. Recarte-Pelz, E. Roig, M.A. Castel, M. Cardona, M. Farrero, et al., 2014) [1] and Use of serum levels of high sensitivity troponin T, galectin-3 and C-terminal propeptide of type I procollagen at long term follow-up in Heart Failure patients with reduced ejection fraction: comparison with soluble AXL and BNP (M. Batlle, B. Campos, M. Farrero, M. Cardona, B. González, M.A. Castel, et al., 2016) [2].

Use of serum levels of high sensitivity troponin T, galectin-3 and C-terminal propeptide of type I procollagen at long term follow-up in heart failure patients with reduced ejection fraction: Comparison with soluble AXL and BNP.

BACKGROUND: Prognostic biomarkers are needed to improve the management of the heart failure (HF) epidemic, being the brain natriuretic peptides the most valuable. Here we evaluate 3 biomarkers, high sensitivity troponin T (hs-TnT), galectin-3 (Gal-3) and C-terminal propeptide of type I procollagen (CICP), compare them with a recently described new candidate (sAXL), and analyze their relationship with BNP. METHODS: HF patients with reduced ejection fraction (n=192) were included in this prospective observational study, with measurements of candidate biomarkers, functional, clinical and echocardiographic variables. A Cox regression model was used to determine predictors for clinical events, i.e. all-cause mortality and heart transplantation. RESULTS: Hs-TnT circulating values were correlated to clinical characteristics indicative of more advanced HF. When analyzing the event-free survival at a mean follow-up of 3.6years, patients in the higher quartile of either BNP, hs-TnT, CICP and sAXL had increased risk of suffering a clinical event, but not Gal-3. Combination of high sAXL and BNP values had greater predictive value (HR 6.8) than high BNP alone (HR 4.9). In a multivariate Cox regression analysis, BNP, sAXL and NYHA class were independent risk factors for clinical events. CONCLUSIONS: In this HF cohort, hs-TnT is a good HF marker and has a very significant prognostic value. The prognostic value of CICP and sAXL was of less significance. However, hs-TnT did not add predictive value to BNP, while sAXL did. This suggests that elevated troponin has a common origin with BNP, while sAXL could represent an independent pathological mechanism.

Cost-Effectiveness of Highly Sensitive Cardiac Troponin T to Rule Out Acute Rejection After Heart Transplantation.

BACKGROUND: Endomyocardial biopsy (EMB) remains the gold standard for detecting acute rejection (AR) after heart transplantation (HTx). Non-invasive detection of AR thus far remains a challenge. Several studies have demonstrated that highly sensitive cardiac troponin T (hs-cTnT) concentrations have a low positive predictive value for diagnosing AR. Nevertheless, hs-cTnT proved to be useful for ruling out AR after HTx. An hs-cTnT concentration <17 ng/L, a value close to that used for rule-in or rule-out myocardial infarction, was associated with a 100% negative predictive value of AR. However, the cost-effectiveness of a strategy with the use of hs-cTnT for ruling out AR in HTx patients remains to be proven. METHODS: The cost-effectiveness of hs-cTnT determination for ruling out AR was assessed, comparing the costs of hs-cTnT measurements in 305 blood samples obtained at the time of EMB. Eighteen samples were excluded because the EMB was not assessable. RESULTS: Hs-cTnT determination cost 16.00€ per sample, whereas EMB cost 1752.00€ per biopsy; cost estimations included direct and indirect (30%) charges. Thirty-nine (13.6%) of the 287 blood samples presented hs-cTnT concentrations <17 ng/L; in none of them was an AR >2R degree found in the EMB. The cost of the assessment in the 287 blood samples and biopsies was of 4592.00€ for hs-cTnT and 502,824.00€ for EMB. Hs-cTnT systematic measurement would have avoided 39 EMB, with a saving of 68,328.00€, which represents the 13.5% of the total budget expended in these cases. CONCLUSIONS: The use of hs-cTnT values to rule out the need of EMB for AR diagnosis after HTx appears to be a cost-effective procedure.

AXL receptor tyrosine kinase is increased in patients with heart failure.

BACKGROUND: AXL is a membrane receptor tyrosine kinase highly expressed in the heart and has a conspicuous role in cardiovascular physiology. The role of AXL in heart failure (HF) has not been previously addressed. METHODS AND RESULTS: AXL protein was enhanced 6-fold in myocardial biopsies of end-stage HF patients undergoing heart transplantation compared to controls from heart donors (P<0.0001). Next, we performed a transversal study of patients with chronic HF (n=192) and a group of controls with no HF (n=67). sAXL and BNP circulating levels were quantified and clinical and demographic data were collected. sAXL levels in serum were higher in HF (86.3 ± 2.0 ng/mL) than in controls (67.8 ± 2.0 ng/mL; P<0.0001). Also, sAXL correlated with several parameters associated with worse prognosis in HF. Linear regression analysis indicated that serum creatinine, systolic blood pressure and atrial fibrillation, but not BNP levels, were predictive of sAXL levels. Cox regression analysis indicated that high sAXL values at enrollment time were related to the major HF events (all-cause mortality, heart transplantation and HF hospitalizations) at one year follow-up (P<0.001), adding predictive value to high BNP levels. CONCLUSIONS: Myocardial expression and serum concentration of AXL is elevated in HF patients compared to controls. Furthermore, peripheral sAXL correlates with parameters associated with the progression of HF and with HF events at short term follow-up. All together these results suggest that sAXL could belong to a new molecular pathway involved in myocardial damage in HF, independent from BNP.

Use of mTOR inhibitors in chronic heart transplant recipients with renal failure: calcineurin-inhibitors conversion or minimization?

BACKGROUND: In the last decade, mTOR inhibitors (mTOR-is) have become the cornerstone of the calcineurin inhibitor (CNI)-reduced/free regimens aimed to the preservation of post-transplant renal function. We compared utility and safety of the total replacement of calcineurin inhibitors with a mTOR-i with a strategy based on calcineurin inhibitor minimization and concomitant use of m-TOR-i. METHODS: In a retrospective multi-center cohort of 394 maintenance cardiac recipients with renal failure (GFR<60 mL/min/1.73 m(2)), we compared 235 patients in whom CNI was replaced with a mTOR-i (sirolimus or everolimus) with 159 patients in whom mTOR-is were used to minimize CNIs. A propensity score analysis was carried out to balance between group differences. RESULTS: Overall, after a median time of 2 years from mTOR-i initiation, between group differences for the evolution of renal function were not observed. In a multivariate adjusted model, improvement of renal function was limited to patients with mTOR-i usage within 5years after transplantation, particularly with the conversion strategy, and in those patients who could maintain mTOR-i therapy. Significant differences between strategies were not found for mortality, infection and mTOR-i withdrawal due to drug-related adverse events. However, conversion group tended to have a higher acute rejection incidence than the minimization group (p=0.07). CONCLUSION: In terms of renal benefits, our results support an earlier use of mTOR-is, irrespective of the strategy. The selection of either a conversion or a CNI minimization protocol should be based on the clinical characteristics of the patients, particularly their rejection risk.

Primary immunosuppression and outcome differences after heart transplantation: tacrolimus versus cyclosporine.

BACKGROUND: The superiority of tacrolimus (Tac) as primary immunosuppression for heart transplantation (HT) compared with cyclosporine (CsA) is still under debate. Outcomes of comparison studies are not consistent; the duration of these studies has been limited. The aim of this study was to evaluate long-term outcomes of patients undergoing HT based on primary immunosuppression regime. METHODS AND RESULTS: We analyzed a single-center registry of all HT patients between 1998 and 2009, comparing outcomes based on primary immunosuppressions (Tac or CsA). Patients who died before starting immunosuppression were excluded. A total of 197 patients entered the study; 103 received Tac and 94 CsA. There were no differences between groups in baseline characteristics, United Network for Organ Sharing status 1A or ventricular assist device use, except for ischemia time (195 ± 50 min in Tac group vs 182 ± 55 min in CsA; P = .08) and days on waiting list (164 ± 155 vs 100 ± 73; P < .001). After mean follow-ups of 4.5 ± 2.3 years in the Tac group and 6.3 ± 4.3 years in the CsA group, there were 19 and 36 deaths, respectively. Kaplan-Meier analysis showed increased survival for the Tac group (log rank P = .04). Tac also was significantly superior to CsA regarding mortality (relative risk 0.55; 95% confidence interval, 0.31-0.98; P = .04). CONCLUSIONS: In our series the use of tacrolimus resulted in improved long-term survival compared with cyclosporine. At 1-year follow-up, there were no differences in acute rejection episodes or the appearance of vasculopathy.

[Detecting adverse drug events during the hospital stay]. / Detección de acontecimientos adversos producidos por medicamentos durante la estancia hospitalaria.

INTRODUCTION: The principal objective was to determine the incidence rate of adverse drug events (ADEs) in hospitalised patients and evaluate the event prevention percentage. METHODS: Multi-centre, prospective observational study lasting four months, performed in five hospitals providing different levels of care. We included all adult patients who were admitted to one of the selected centres for longer than 48 hours and who required pharmacological treatment. ADEs were identified by direct observation and the use of previously defined alarm signals. The Karch-Lasagna scale was used to determine the causality relationship, and the Schumock and Thornton questionnaire adapted by Otero was used to evaluate ADE preventability. Preventable drug-induced adverse events were classified according to the taxonomy that the Ruiz-Jarabo 2000 group defined, and coordinated by ISMP-Spain. RESULTS: We included 1,550 patients, 159 of whom experienced at least one ADE (10.3 %). The preventability percentage was 51.6 %, which represented 5.3 % of the total sample. The endocrine system (34.8 %) and the cardiovascular system (20.7 %) were the most affected by preventable ADEs. Antibiotics were responsible for 16.5 % of all ADEs. 9.3 % of all preventable ADEs were triggered by use of opiates. The vast majority of preventable ADEs (36.3 %) resulted from omitting a necessary medication. Only 4.4 % of preventable ADEs are considered to be serious. CONCLUSIONS: There is a high incidence rate of ADEs during patients' hospital stay (10.3 %), and half of them (51.6 %) could have been prevented. Implementation of an automatic alarm system and certain best practices for problem spots along the care circuit will help detect and avoid preventable ADEs.