Clinical characteristics, management, and one-year risk of complications among patients with heart failure with and without type 2 diabetes in Spain.

OBJECTIVE: This work aims to describe the clinical characteristics and therapeutic management and to determine cardiovascular outcomes after one year of follow-up in a contemporaneous population with heart failure (HF) with and without type 2 diabetes in Spain. These factors were also analyzed in the DAPA-HF-like population (patients who met most inclusion criteria of the DAPA-HF trial) and in patients treated with SGLT2 inhibitors at baseline. METHODS: This work is an observational, retrospective, population-based study using the BIG-PAC database. The index date was January 1, 2019. People aged ≥ 18 years who received care for HF in 2019 were selected. Events that occurred in 2019 were analyzed. RESULTS: We identified 21,851 patients with HF (age 78.0 ± 11.3 years, 53.0% men, 50.9% with HF with reduced left ventricular ejection fraction, 44.5% in NYHA functional class II). HF prevalence was 1.88% and incidence was 2.83 per 1,000 person-years. Regarding HF treatments, 66.1% were taking renin-angiotensin system inhibitors, 69.4% beta blockers, 31.2% aldosterone antagonists, and 7.5% sacubitril/valsartan. During the year of follow-up, 29.8% had HF decompensation which led to hospitalization (mean time to first event of 120.9 ± 72.5 days), 12.3% died, and 8.1% died during hospitalization. Events were more common among patients with type 2 diabetes. Hospitalizations for HF were more common in the DAPA-HF-like population. CONCLUSIONS: In Spain, the population with HF is elderly and has many comorbidities. Approximately half of patients have HF with reduced left ventricular ejection fraction. There is room for improvement in HF management, particularly through the use of drugs that reduce both HF hospitalization and mortality, in order to reduce the burden of HF.

Consensus on improving the comprehensive care of patients with acute heart failure.

The latest acute heart failure (AHF) consensus document from the Spanish Society of Cardiology (SEC, for its initials in Spanish), Spanish Society of Internal Medicine (SEMI), and Spanish Society of Emergency Medicine (SEMES) was published in 2015, which made an update covering the main novelties regarding AHF from the last few years necessary. These include publication of updated European guidelines on HF in 2016, new studies on the pharmacological treatment of patients during hospitalization, and other recent developments regarding AHF such as early treatment, intermittent treatment, advanced HF, and refractory congestion. This consensus document was drafted with the aim of updating all aspects related to AHF and to create a document that comprehensively describes the diagnosis, treatment, and management of this disease.

Consensus on improving the comprehensive care of patients with acute heart failure. / Consenso para la mejora de la atención integral de los pacientes con insuficiencia cardíaca aguda.

The latest acute heart failure consensus document from the Spanish Society of Cardiology, Spanish Society of Internal Medicine, and Spanish Society of Emergency Medicine was published in 2015, which made an update covering the main novelties regarding acute heart failure from the last few years necessary. These include publication of updated European guidelines on heart failure in 2016, new studies on the pharmacological treatment of patients during hospitalization, and other recent developments regarding acute heart failure such as early treatment, intermittent treatment, advanced heart failure, and refractory congestion. This consensus document was drafted with the aim of updating all aspects related to acute heart failure and to create a document that comprehensively describes the diagnosis, treatment, and management of this disease.

Hyponatraemia and congestive heart failure refractory to diuretic treatment. Utility of tolvaptan. / Hiponatremia e insuficiencia cardiaca congestiva refractaria a tratamiento diurético. Utilidad del tolvaptán.

Heart failure (HF) is currently one of the most significant healthcare problems in Spain and has a continuously increasing prevalence. Advances in our understanding of the various biological responses that promote cardiac remodelling and pulmonary venous congestion constitute the basis of current treatment. This article, prepared by members of the HF groups of the Spanish Society of Cardiology and the Spanish Society of Internal Medicine, discusses the current therapeutic strategies for patients with congestion refractory to diuretic treatment. The article includes our clinical experience with the use of tolvaptan as an additional treatment for congestion associated with hyponatraemia. To this end, we propose an algorithm for the use of tolvaptan in patients with congestive HF, natraemia <130mEq/l and poor response to conventional diuretic treatment.

Consensus Document of the Spanish Society of Cardiology and the Spanish Society of Internal Medicine on the diagnosis and treatment of iron deficiency in heart failure. / Documento de consenso de la Sociedad Española de Cardiología y la Sociedad Española de Medicina Interna sobre el diagnóstico y tratamiento del déficit de hierro en la insuficiencia cardíaca.

Iron deficiency in patients with heart failure is a medical problem of recent particular interest. This interest has resulted from the publication of several clinical trials that demonstrated that the administration of intravenous iron to such patients improved their functional capacity and even reduced the number of hospitalisations for heart failure decompensation. However, applying the evidence from these studies in clinical practice is still controversial, both in terms of the diagnostic criteria for iron deficiency (absolute and functional) and the optimal method for iron replenishment. This article is a consensus document that integrates the recommendations of the Spanish Society of Internal Medicine and the Spanish Society of Cardiology. The article reviews the scientific evidence and proposes a diagnostic and therapeutic performance protocol for iron deficiency in heart failure.

Management of cytomegalovirus infection in solid organ transplant recipients: SET/GESITRA-SEIMC/REIPI recommendations.

Cytomegalovirus (CMV) infection remains a major complication of solid organ transplantation. Because of management of CMV is variable among transplant centers, in 2011 the Spanish Transplantation Infection Study Group (GESITRA) of the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC) developed consensus guidelines for the prevention and treatment of CMV infection in solid organ transplant recipients. Since then, new publications have clarified or questioned the aspects covered in the previous document. For that reason, a panel of experts revised the evidence on CMV management, including immunological monitoring, diagnostics, prevention, vaccines, indirect effects, treatment, drug resistance, immunotherapy, investigational drugs, and pediatric issues. This document summarizes the recommendations.

Contribution of Population Pharmacokinetics to Dose Optimization of Ganciclovir-Valganciclovir in Solid-Organ Transplant Patients.

Treatment of solid-organ transplant (SOT) patients with ganciclovir (GCV)-valganciclovir (VGCV) according to the manufacturer's recommendations may result in over- or underexposure. Bayesian prediction based on a population pharmacokinetics model may optimize GCV-VGCV dosing, achieving the area under the curve (AUC) therapeutic target. We conducted a two-arm, randomized, open-label, 40% superiority trial in adult SOT patients receiving GCV-VGCV as prophylaxis or treatment of cytomegalovirus infection. Group A was treated according to the manufacturer's recommendations. For group B, the dosing was adjusted based on target exposures using a Bayesian prediction model (NONMEM). Fifty-three patients were recruited (27 in group A and 26 in group B). About 88.6% of patients in group B and 22.2% in group A reached target AUC, achieving the 40% superiority margin (P< 0.001; 95% confidence interval [CI] difference, 47 to 86%). The time to reach target AUC was significantly longer in group A than in group B (55.9 ± 8.2 versus 15.8 ± 2.3 days,P< 0.001). A shorter time to viral clearance was observed in group B than in group A (12.5 versus 17.6 days;P= 0.125). The incidences of relapse (group A, 66.67%, and group B, 9.01%) and late-onset infection (group A, 36.7%, and group B, 7.7%) were higher in group A. Neutropenia and anemia were related to GCV overexposure. GCV-VCGV dose adjustment based on a population pharmacokinetics Bayesian prediction model optimizes GCV-VGCV exposure. (This study has been registered at ClinicalTrials.gov under registration no. NCT01446445.).

Health-related quality of life, social support, and caregiver burden between six and 120 months after heart transplantation: a Spanish multicenter cross-sectional study.

A multicenter cross-sectional study was conducted to determine the current heart transplant (HTx) outcomes in Spain. Clinical and functional status, health-related quality of life (HRQoL), social support, and caregiver burden were analyzed in 303 adult transplant recipients (77.9% males) living with one functioning graft. Mean age at time of HTx (SD) was 56.4 (11.4) years, and the reason for transplantation in all patients was congestive heart failure. All patients had received a first heart transplant 6 (± 1), 12 (± 2), 36 (± 6), 60 (± 10), or 120 (± 20) months previously. Participants completed the Kansas City Cardiomyopathy Questionnaire (KCCQ), the EQ-5D, the Duke-UNC Functional Social Support Questionnaire, and the Zarit Caregiver Burden Scale. Reasonable HRQoL, social support, and caregiver burden levels were found at all time points, although a slight decrease in HRQoL was recorded at 120 months (p ≤ 0.033). Multivariate regression analyses showed that complications, comorbidities, and hospitalizations were associated with HRQoL (EQ-5D: 48.4% of explained variance, F4,164 = 38.46, p < 0.001; KCCQ overall summary score: 45.0%, F3,198 = 54.073, p < 0.001). Patient functional capabilities and complications affected caregiver burden (p < 0.05). In conclusion, HTx patients reported reasonable levels of HRQoL with low caregiver burden. Clinical variables related to these outcomes included functional status, complications, and number of admissions.

Donor-transmitted malaria after heart transplant managed successfully with artesunate.

Donor-transmitted malaria is a rare complication in solid organ transplantation, which causes high mortality. Data concerning the use of artesunate in solid organ transplant recipients are lacking. We report a heart transplant patient who developed donor-derived severe Plasmodium falciparum malaria, successfully treated with artesunate. Transmission of malaria to 2 of the other transplant recipients from the same donor was also documented.

Renal function improvement after conversion to proliferation signal inhibitors during long-term follow-up in heart transplant recipients.

INTRODUCTION: The use of proliferation signal inhibitors (PSIs) for calcineurin-inhibitor (CNI) minimization or conversion protocols has been promoted for heart transplantation (HT) in the contexts of renal insufficiency, cardiac allograft vasculopathy (CAV), or malignancy. We evaluated our experience with conversion of patients from a CNI-based to a PSI-based immunosuppressive regimen. We focused on improvement in renal function. METHODS: This prospective follow-up included 96 HT patients converted to a PSI-based regimen from 2001 to 2010. We evaluated changes in creatinine clearance (CrCl) prior to at 1 year and at the end of follow-up after conversion. RESULTS: Ninety-six patients including 86% men showed a mean age of 62 ± 8 years. They were converted to a PSI-based regimen at 6.3 ± 4 years post-HT due to the following causes: CNI toxicity (45%), CAV (16%), cancer (16%), CNI toxicity + CAV (17%), or CNI toxicity + cancer (6%). CNI withdrawal was achieved in 77 cases (80%) and minimization in 19 (20%). Everolimus was used in 54 (56%) and sirolimus in 42 (44%) cases. Median follow-up time was 3.8 years. PSI discontinuation due to side effects was common (38%). There were 43 deaths mainly due to cancer and CAV. CrCl improved albeit not significantly in the withdrawal group from a median of 51 mL/min preconversion to 59 mL/min at the last follow-up (P = .12). In the minimization group, median CrCl worsened from a median of 61 mL/min preconversion to 51 mL/min at the last follow-up (P = .001). In the 58 cases (61%) of CNI nephrotoxicity, median CrCl improved from a median of 41 mL/min preconversion to 49 mL/min at the last follow-up (P = .04). CONCLUSION: Despite high rates of discontinuation of PSIs during long-term follow-up, the conversion regimen seemed to be useful to diminish CNI-related renal insufficiency especially with CNI withdrawal.

Successful outcome of ganciclovir-resistant cytomegalovirus infection in organ transplant recipients after conversion to mTOR inhibitors.

Ganciclovir-resistant (GanR) cytomegalovirus (CMV) infection after organ transplantation is emerging as a significant therapeutic challenge. We report two cases of GanR CMV infection successfully managed by switching immunosuppression from calcineurin inhibitors to an mTOR inhibitor-based regimen. This salvage therapy should be considered when other options are not available.

Improvement in chronic renal failure after mycophenolate mofetil introduction and cyclosporine dose reduction: four-year results from a cohort of heart transplant recipients.

Chronic renal failure (CRF) due to calcineurin inhibitor (CNI) nephrotoxicity is a frequent complication among heart transplant (HT) recipients. Small studies have suggested that the introduction of mycophenolate mofetil (MMF) can help to reduce CNI doses thereby to maintaining or improving renal function. We conducted a 4-year, prospective, multicenter study in 89 maintenance HT recipients at 5.6 ± 2.7 years postgrafting who displayed CRF (serum creatinine > 1.4 mg/dL) and were undergoing treatment with cyclosporine and prednisone ± azathioprine. We introduced MMF and reduced cyclosporine to level below 100 ng/mL. Creatinine clearance (CrCl), acute rejection episodes, and survival were through retrospectively compared with a contemporary cohort of HT recipients who were not treated with MMF (control group; n = 38). After conversion to MMF, a rapid increase was observed in the CrCl, which was maintained over the follow-up: namely, CrCl at month 6 and at 4 years were 51.0 ± 15.6 and 54.1 ± 15.6 mL/min versus 41.9 ± 11.1 mL/min at baseline (P < .0001). No renal function changes were observed among the control group. Acute rejection rates were 5.6% and 2.6% in the MMF versus control groups (P = NS) with 4-year survivals >85%. In conclusion, the introduction of MMF allowed a safe reduction of cyclosporine and significantly improved renal function after 4 years.

Risk factors associated with cytomegalovirus infection in heart transplant patients: a prospective, epidemiological study.

BACKGROUND: The objectives of this epidemiological, prospective study were to describe the characteristics of cytomegalovirus (CMV) infection in heart transplant (HT) recipients and to identify the variables that may influence the development of CMV viremia and CMV disease in these patients. METHODS: HT recipients ≥18 years of age (n=199) were included in the study. Variables studied included CMV serostatus, immunosuppressive treatment, and administration of anti-CMV prophylaxis. RESULTS: The mean age of the population was 52 years, and 84% were males. Immunosuppressive regimens were administered as induction therapy to 92.5% of patients; 88.5% of patients received calcineurin inhibitors as maintenance therapy. Anti-CMV treatment was given to 59% of 199 patients as prophylaxis (70%), preemptive therapy (10%), or to treat CMV infection (20%). Overall, 43% of patients had at least 1 positive viremia test. No patient with a high-risk serostatus (donor+/recipient-) receiving prophylaxis developed CMV syndrome, and only 2.5% of 199 patients developed CMV invasive disease. Multivariate analysis showed that having a positive donor CMV serostatus was associated with an increased risk of developing CMV viremia (P<0.012), while use of mammalian target of rapamycin (mTOR) inhibitors was associated with a decreased risk (P=0.005). CONCLUSIONS: In a population of HT recipients, the CMV infection rate was similar to that seen in previous studies, but the progression to overt CMV disease was very low. Having a CMV-positive donor was identified as an independent risk factor for developing CMV viremia, while the use of mTOR inhibitors was protective against viremia.

Incidence and risk factors for nonmelanoma skin cancer after heart transplantation.

INTRODUCTION: The incidence of skin cancer in heart transplant (HT) patients is higher than in the general population, reversing the proportion of cutaneous squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) with a predominance of the former. The etiologic role of new immunosuppressants is not well known. We sought to ascertain the incidence of SCC and BCC in HT patients and the risk factors for its occurrence. PATIENTS AND METHODS: We report the incidence of all types of post-HT skin cancer, SCC, and BCC among adult HT patients in Spain (4089 subjects) as well as the influence of gender, age at heart transplant, immunosuppression, and sunlight exposure. RESULTS: The incidence rates of SCC and BCC, per 1000 persons/year, were 8.5 and 5.2, respectively. Males had a higher risk of SCC but not BCC. Induction therapy increased the risk of SCC and BCC. The relative risk of mycophenolate mofetil (MMF) was 0.3 (0.2-0.6; P<.0005) and azathioprine (AZA) 1.8 (1.2-2.7; P<.0032) for SCC, whereas tacrolimus and cyclosporine showed no difference. The relative risk of BCC was not affected by any immunosuppressant. CONCLUSION: Age at transplantation>45 years, induction therapy use, and high sunshine zone were risk factors for both SCC and BCC. Different immunosuppressive agents have different risks of nonmelanoma skin cancer, as AZA increases the risk of SCC and MMF is a protective factor. The relative risk of BCC was not affected by any immunosuppressor.

Sequential treatment of cytomegalovirus infection or disease with a short course of intravenous ganciclovir followed by oral valganciclovir: efficacy, safety, and pharmacokinetics.

Oral (p.o.) or intravenous (IV) ganciclovir (GCV) has been the first-line agent for prevention and treatment of cytomegalovirus (CMV) infection and disease in solid organ transplantation (SOT). The introduction of p.o. valganciclovir, with higher bioavailability than p.o. GCV, has proven to be a suitable approach toward outpatient p.o. therapy for CMV infection/disease. The present single-arm, exploratory pilot trial performed with 21 patients investigates the efficacy and safety of a short therapeutic course (21 days) based on an initial IV treatment with GCV (5 mg/kg twice daily, for 5 days) followed by p.o. valganciclovir (900 mg twice daily, for 16 days) for CMV infection/disease in SOT patients. In all cases, doses were adjusted for renal function. Moreover, the study allowed comparison of exposure to GCV after p.o. valganciclovir with respect to IV GCV in the same patients. Response to treatment was monitored until day 180. Viral load eradication was achieved in 66.7% of patients, on day 21. Although not statistically significant, a trend was seen toward increased persistence of viral load on day 21 for patients with donor positive/recipient negative CMV serostatus or receiving either anti-rejection therapy or polyclonal anti-thymocyte globulin. CMV clinical infection recurred in 14.3% of patients, with higher recurrence rates in patients with risk factors for persistence of viremia. Exposures to GCV after using IV GCV or p.o. valganciclovir showed comparable values (P=0.054). This short course, combining initial IV GCV and subsequent p.o. valganciclovir, may provide effective exposure and therapeutic response in the treatment of CMV infection in SOT patients with adequate drug exposure and with the additional potential benefit of shortening the length of hospital stay, which may result in cost reduction and improved patient comfort.

Usefulness of sirolimus as rescue therapy in heart transplant recipients with renal failure: analysis of the Spanish Multicenter Observational Study (RAPACOR).

BACKGROUND: Chronic renal failure is a common complication of heart transplantation. Sirolimus (SRL) is an immunosuppressive drug that, unlike calcineurin inhibitors (CNIs), is not associated with nephrotoxicity. METHODS: We collected efficacy and safety data from a Spanish registry of heart transplant recipients who were switched from a CNI to SRL due to renal failure. Patients were included if the serum creatinine level before switching was >1.5 mg/dL and/or the estimated creatinine clearance level was below 50 mL/min. RESULTS: Ninety-seven patients started SRL due to renal impairment. When SRL was started, CNIs were progressively tapered and in some cases withdrawn. Mean baseline creatinine level was 2.5 mg/dL and mean creatinine clearance level was 39 mL/min. Only 1 episode of acute rejection was observed in a patient receiving SRL plus cyclosporine (CsA) but the eventual allograft function remained stable. Compared with baseline, a significant improvement in renal function was observed at 6 months among patients who stopped CNIs before the third month after SRL was started, although not among those who continued taking CNIs. Upon multivariate analysis, no predictors of response were observed. SRL was withdrawn in 18% of patients due to adverse events. CONCLUSIONS: Switching to SRL was safe in heart allograft recipients, improving renal function among those previously receiving a CNI. Renal function improves if CNIs are withdrawn soon after starting SRL.

Recovery of ventricular function with a left ventricular axial pump in a patient with end-stage toxic cardiomyopathy not a candidate for heart transplantation: first experience in Spain.

BACKGROUND: Toxic cardiomyopathies are rare and the most frequent cause are anthracycline compounds. Early acute toxicity can be reversible, but at present the only effective therapy for late end-stage anthracycline cardiomyopathy seems to be a heart transplantation. Currently, this transplantation is contraindicated in cases of cancer, at least during the first 4 or 5 years. Recently, implantable axial pumps have shown good results and are used with increasing frequency as destination therapy. METHODS: We present a case of end-stage heart failure due to a toxic cardiomyopathy after a bilateral breast cancer treated with resection and chemotherapy (doxorubicin and trastuzumab). Ejection fraction was 23% with dobutamine. A left ventricular axial pump (Incor) was implanted. RESULTS: The immediate postoperative course was uneventful. The left ventricular function improved and on the fourth month the ejection fraction was 55%. On postoperative day 135, the pump was explanted. After 1.5 years, the patient is doing well, with an ejection fraction of 57%. CONCLUSION: This is the first application of an implantable axial pump in Spain. Although toxic cardiomyopathies are rare, in cases of late end-stage left ventricular failure and when the heart transplantation is contraindicated, the implantation of an axial pump can be the solution. The results in previous cases are unknown, although it is possible, as in our case.

Outcomes of heart transplantation for cardiac amyloidosis: subanalysis of the spanish registry for heart transplantation.

Amyloidosis (Am), a systemic disease, has poor prognosis because of organ damage produced by protein deposition in the extracellular space. Although heart transplantation (HTx) is possible, donor availability concerns and high mortality make this approach controversial. The Spanish Registry for Heart Transplantation includes 25 Am patients (54 +/- 9 years): 13 with AL type, 2 with AA and 10 with TTR mutation. Fifteen patients (60%) died during follow-up (4.9 +/- 1.3 years): 9 AL-Am patients, both AA-Am patients and 4 with TTR-Am. HTx survival for Am patients was similar to patients without Am at 1 month but significantly worse at 5 years: 46% versus 78% (p < 0.02). Of 10 AL-Am patients undergoing successful HTx, 4 died of systemic Am. Stem cell transplantation was performed in 3 (1 died of acute rejection). Five of 10 patients with TTR-Am underwent liver transplant; 4 remained alive at the last follow-up. Findings include poor outcome for AL-Am patients despite HTx and better survival for TTR-Am patients if HTx is associated with liver transplantation. Given the shortage of donors and poor outcome for Am patients, we would recommend that HTx be reserved for patients without or with mild systemic Am and be supplemented by additional therapies as indicated.

Malignancy after heart transplantation: incidence, prognosis and risk factors.

The Spanish Post-Heart-Transplant Tumour Registry comprises data on neoplasia following heart transplantation (HT) for all Spanish HT patients (1984-2003). This retrospective analysis of 3393 patients investigated the incidence and prognosis of neoplasia, and the influence of antiviral prophylaxis. About 50% of post-HT neoplasias were cutaneous, and 10% lymphomas. The cumulative incidence of skin cancers and other nonlymphoma cancers increased with age at HT and with time post-HT (from respectively 5.2 and 8.9 per 1000 person-years in the first year to 14.8 and 12.6 after 10 years), and was greater among men than women. None of these trends held for lymphomas. Induction therapy other than with IL2R-blockers generally increased the risk of neoplasia except when acyclovir was administered prophylactically during the first 3 months post-HT; prophylactic acyclovir halved the risk of lymphoma, regardless of other therapies. Institution of MMF during the first 3 months post-HT reduced the incidence of skin cancer independently of the effects of sex, age group, pre-HT smoking, use of tacrolimus in the first 3 months, induction treatment and antiviral treatment. Five-year survival rates after first tumor diagnosis were 74% for skin cancer, 20% for lymphoma and 32% for other tumors.

Clinical evolution of heart transplantation in patients with previous valvular cardiomyopathy.

OBJECTIVE: Heart transplantation (HT) due to valvular cardiomyopathy is rare, namely, about 3% of cases in the Registry of the International Society for Heart and Lung Transplantation (ISHLT). Usually, these patients present some risk factors such as previous valvular operations and pulmonary hypertension. Since there are few studies in the literature, we retrospectively analyzed our early and long-term results. MATERIALS AND METHODS: We studied our experience in 22 HT cases for valvular cardiomyopathy (9.3% of our total experience), namely, 12 men and 10 women, of overall mean age of 52.6 +/- 10 years. Five patients had mitral; 8, aortic; and 1, tricuspid valve disease; 7 had double valve disease and 1, triple valve disease. Nineteen patients (87%) had been operated previously between 1 and 4 times. The mean ejection fraction was 23% +/- 7.3% and the mean New York Heart Association (NYHA) functional class was 3.7. Fifty-three percent of the patients had pulmonary hypertension. Two patients were operated as an emergency "O." We used the standard HT technique. RESULTS: Four patients (18%) were reoperated due to hemorrhage. The hospital mortality was 2 cases (9%). Another patients (9%) died on follow-up due to cardiac allograft vasculopathy. All surviving patients have been followed to the end of 2006. The mean follow-up has been 72 +/- 53 months. They are functional class I or II. CONCLUSIONS: HT for this indication was more frequent in our experience than in the Registry of the ISHLT. The immediate and long-term results were good, with an 82% mean survival at 6 years. HT can be a good treatment for patients with valvular cardiomyopathy and bad ventricular function and/or multiple valvular reoperations.