Rapamycin powerfully inhibits the progression of antigen-activated T cells through the cell cycle. In animal heart transplantation models, rapamycin therapy has been associated with profound ...immunosuppressive effects on host humoral and cellular responses. In consequence, further studies have been conducted to evaluate the efficiency of rapamycin in preventing acute heart allograft rejection, treating refractory acute heart allograft rejection, inducing transplantation tolerance, and preventing and treating transplant coronary artery disease. The results of these studies indicated that rapamycin can effectively prevent acute graft rejection and inhibit refractory acute graft rejection in heart transplant recipients by exerting potent immunosuppressive and antiproliferative effects without adversely affecting renal function. This supports the use of rapamycin therapy in heart transplant recipients, especially in those with renal dysfunction, for whom treatment with calcineurin inhibitors is contraindicated. Rapamycin may also halt and even reverse the progression of cardiac allograft vasculopathy, which warrants further clinical trials in humans. Finally, rapamycin may be able to induce transplantation tolerance, thus making it one of the most promising modalities for improving the long-term survival of heart transplant recipients.
Abstract
Background
Studies of the repetitive use of intravenous levosimendan suggested a beneficial effect in patients with advanced heart failure (HF). It was the aim of the LeoDOR trial to test ...the efficacy and safety of intermittent levosimendan therapy in the vulnerable phase following a hospitalization for acute HF.
Methods
In this multicenter, double-blind, three-armed trial with an enrolment period from 3-2018 to 6-2021, patients with advanced HF were randomized 2:1 at the end of an index hospitalization for acute HF to intermittent levosimendan therapy or placebo for a period of 12 weeks. Levosimendan was administered according to center preference either as 6-hour infusion at a rate of 0.2 mcg/kg/min every 2 weeks, or as 24-hour infusion at a rate of 0.1 mcg/kg/min every 3 weeks. The primary efficacy assessment after 14 weeks was based on a global rank endpoint consisting of three hierarchical groups: Tier 1 = time to death or urgent heart transplantation or implantation of a ventricular assist device; Tier 2 = time to non-fatal HF requiring i.v. vasoactive therapy; Tier 3 = time-averaged proportional change in NTproBNP from baseline to week 14.
Results
Due to a forced interim interruption of the study as a result of the COVID-19 pandemic, the planned number of patients could not be recruited. The final modified intention-to-treat (mITT) analysis included 145 patients (93 in the combined levosimendan arm, 52 in the placebo arm). Patient characteristics were well balanced between treatment and placebo arms (mean age 69.3±9.7 vs 67.9±10.1, proportion of women 22.6% vs 21.2%, HF-hospitalizations in previous 12 months 1.9±1.4 vs. 1.7±1.1, NTproBNP at baseline 4740 ng/L (IQR 2235 – 9016) vs 5380 ng/L (IQR 2287 – 8204). There were no marked differences regarding HF medication and implanted devices.
Compared with placebo, intermittent levosimendan had no significant effect on the primary endpoint (mean rank score 71.8 for the levosimendan group vs 75.1 for the placebo group; p = 0.65). However, there was a strong signal towards a higher incidence of the individual clinical components of the primary endpoint (tier 1 plus tier 2) in the levosimendan group vs the placebo group both after 14 weeks (HR 2.94, 95%CI 1.13–7.70; p = 0.028) and 26 weeks (HR 1.65 95%CI 0.87 – 3.12; p = 0.123). The number of investigator-reported adverse events during and immediately after drug application was 12.4% in the levosimendan group vs 11.8% in the placebo group (p = 0.905).
Conclusion
Our findings do not support the use of intermittent levosimendan to improve post-hospitalization clinical stability in patients who were recently hospitalized with HF and reduced LVEF. Further studies are warranted to find the correct use of levosimendan in advanced heart failure patients.
To describe the baseline characteristics of patients with heart failure and preserved left ventricular ejection fraction enrolled in the PARAGON-HF trial (Prospective Comparison of Angiotensin ...Receptor Neprilysin Inhibitor With Angiotensin Receptor Blocker Global Outcomes in HFpEF) comparing sacubitril/valsartan to valsartan in reducing morbidity and mortality.
We report key demographic, clinical, and laboratory findings, and baseline therapies, of 4822 patients randomized in PARAGON-HF, grouped by factors that influence criteria for study inclusion. We further compared baseline characteristics of patients enrolled in PARAGON-HF with those patients enrolled in other recent trials of heart failure with preserved ejection fraction (HFpEF). Among patients enrolled from various regions (16% Asia-Pacific, 37% Central Europe, 7% Latin America, 12% North America, 28% Western Europe), the mean age of patients enrolled in PARAGON-HF was 72.7±8.4 years, 52% of patients were female, and mean left ventricular ejection fraction was 57.5%, similar to other trials of HFpEF. Most patients were in New York Heart Association class II, and 38% had ≥1 hospitalizations for heart failure within the previous 9 months. Diabetes mellitus (43%) and chronic kidney disease (47%) were more prevalent than in previous trials of HFpEF. Many patients were prescribed angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (85%), β-blockers (80%), calcium channel blockers (36%), and mineralocorticoid receptor antagonists (24%). As specified in the protocol, virtually all patients were on diuretics, had elevated plasma concentrations of N-terminal pro-B-type natriuretic peptide (median, 911 pg/mL; interquartile range, 464-1610), and structural heart disease.
PARAGON-HF represents a contemporary group of patients with HFpEF with similar age and sex distribution compared with prior HFpEF trials but higher prevalence of comorbidities. These findings provide insights into the impact of inclusion criteria on, and regional variation in, HFpEF patient characteristics.
URL: https://www.clinicaltrials.gov. Unique identifier: NCT01920711.
Abstract Levosimendan is a positive inotrope with vasodilating properties (inodilator) indicated for decompensated heart failure (HF) patients with low cardiac output. Accumulated evidence supports ...several pleiotropic effects of levosimendan beyond inotropy, the heart and decompensated HF. Those effects are not readily explained by cardiac function enhancement and seem to be related to additional properties of the drug such as anti-inflammatory, anti-oxidative and anti-apoptotic ones. Mechanistic and proof-of-concept studies are still required to clarify the underlying mechanisms involved, while properly designed clinical trials are warranted to translate preclinical or early-phase clinical data into more robust clinical evidence. The present position paper, derived by a panel of 35 experts in the field of cardiology, cardiac anesthesiology, intensive care medicine, cardiac physiology, and cardiovascular pharmacology from 22 European countries, compiles the existing evidence on the pleiotropic effects of levosimendan, identifies potential novel areas of clinical application and defines the corresponding gaps in evidence and the required research efforts to address those gaps.
Even though gender-specific differences in ventricular repolarization have gained wide recognition, the underlying mechanisms remain unknown. Because estrogen hormones may represent a causative ...factor for the changes in ventricular repolarization in women, this study evaluates a potential impact of estrogen replacement therapy on ventricular repolarization dynamics. Beat-to-beat QT and RR interval variability and QT/RR relationship during 5 minute resting high-resolution electrocardiogram recordings were measured in 30 healthy postmenopausal women (mean age 54.5 years) before and after 10 weeks of estrogen replacement therapy (ERT) with estradiol 2 mg/day. The 2 control groups included 12 healthy postmenopausal women of the similar age, who did not receive ERT, and 11 comparably healthy age-matched men. To evaluate ventricular repolarization dynamics, QT/RR linear regression slopes were calculated. After the 10-week period, the QT/RR regression slope increased by 93% in the ERT group (P lt .001), but no alterations were noted in either the male or female controls. The overall variability of RR and QT intervals did not change in any of the groups studied. Our results suggest that ERT causes alterations in ventricular repolarization dynamics without significantly affecting the autonomic nervous tone.
Abstract Patients in the latest stages of heart failure are severely compromised, with poor quality of life and frequent hospitalizations. Heart transplantation and left ventricular assist device ...implantation are viable options only for a minority, and intermittent or continuous infusions of positive inotropes may be needed as a bridge therapy or as a symptomatic approach. In these settings, levosimendan has potential advantages over conventional inotropes (catecholamines and phosphodiesterase inhibitors), such as sustained effects after initial infusion, synergy with beta-blockers, and no increase in oxygen consumption. Levosimendan has been suggested as a treatment that reduces re-hospitalization and improves quality of life. However, previous clinical studies of intermittent infusions of levosimendan were not powered to show statistical significance on key outcome parameters. A panel of 45 expert clinicians from 12 European countries met in Rome on November 24–25, 2016 to review the literature and envision an appropriately designed clinical trial addressing these needs. In the earlier FIGHT trial (daily subcutaneous injection of liraglutide in heart failure patients with reduced ejection fraction) a composite Global Rank Score was used as primary end-point where death, re-hospitalization, and change in N-terminal-prohormone-brain natriuretic peptide level were considered in a hierarchical order. In the present study, we tested the same end-point post hoc in the PERSIST and LEVOREP trials on oral and repeated i.v. levosimendan, respectively, and demonstrated superiority of levosimendan treatment vs placebo. The use of the same composite end-point in a properly powered study on repetitive levosimendan in advanced heart failure is strongly advocated.
We compared the use of intravenous ganciclovir and cytomegalovirus hyperimmune globulin (CMVIG) as a pre-emptive treatment for cytomegalovirus (CMV)-positive heart transplant recipients.
Of 59 ...CMV-seropositive adult heart transplant recipients enrolled in Group 1, 37 tested positive for pp65 antigen within 12 weeks post-transplantation. These patients were randomized to receive either intravenous ganciclovir (
n = 23) or CMVIG (
n = 14). Group 2 included 133 CMV-seropositive heart transplant recipients who were not tested for CMV antigenemia and who received no anti-CMV therapy.
CMV disease developed in 0 of 59 patients from Group 1, and in 27 of 133 patients (20%) in Group 2 (
p = 0.0001). The incidence of superinfections was lower in Group 1 (0.28 ± 0.46) than in Group 2 (1.10 ± 1.33) (
p = 0.01). The 2 groups did not differ with regard to incidence of rejection (0.7 ± 0.9 in Group 1 vs 1.0 ± 1.2 in Group 2;
p = NS), transplant coronary artery disease at 1 year (14% in Group 1 vs 16% in Group 2;
p = NS) or post-transplant lymphoproliferative disease (0% in Group 1 vs 2% in Group 2;
p = NS). Ganciclovir and CMVIG therapies were associated with similar rates of rejection (0.52 ± 0.6 with ganciclovir vs 0.50 ± 0.60 with CMVIG;
p = NS), superinfection (0.30 ± 0.48 with ganciclovir vs 0.25 ± 0.46 with CMVIG;
p = NS), and transplant coronary artery disease at 1 year (13% with ganciclovir vs 14% with CMVIG,
p = NS).
The pre-emptive anti-CMV approach is superior to prophylaxis in CMV-seropositive heart transplant recipients. Both ganciclovir and CMVIG are equally effective.
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