ABSTRACT
Background and aims
Heart transplantation is the preferred treatment for selected patients with end stage heart failure. Kidney function often declines after heart transplantation. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) slow the decline in eGFR in different populations. However, the effect of SGLT2i on kidney function in heart transplant recipients is unknown.
Methods
The Dapagliflozin for Renal protection in Heart Transplant recipients (DAPARHT) trial is an investigator initiated, double blind, randomized, placebo-controlled trial designed to assess dapagliflozin’s effect on kidney function in heart transplant recipients. Adults heart transplanted at least one year prior to randomization are eligible. Exclusion criteria include an estimated glomerular filtration rate (eGFR) <25 mL/min/1.73 m 2, diabetes type I, and contraindication to study medication. Four hundred and thirty patients will be randomized 1:1 to receive 12 months blinded treatment with dapagliflozin 10 mg o.d. or placebo, followed by 24-months open-label treatment. The primary endpoint is the chronic slope of the eGFR from two weeks to 12 months after starting randomized treatment. The open-label phase evaluates dapagliflozin’s long-term effects on kidney function, clinical outcomes, safety, and tolerability. Enrolment began in June 2022. As of December 18, 2024, 300 patients were enrolled. The mean baseline creatinine was 104 ± 28 µmol/L with corresponding eGFR of 66 ± 22 mL/min/1.73 m 2. Estimated last patient visit is in September, 2028.
Conclusion
The DAPARHT trial will test whether dapagliflozin improves eGFR slope compared to placebo during one year of follow-up, providing the first randomized evidence of the efficacy of SGLT2i in heart transplant recipients.
Trial Registration
Dapagliflozin for Renal protection in Heart Transplant recipients (DAPARHT), NCT05321706, clinicaltrials.gov.
Background
Heart transplantation is the treatment of choice for selected patients with end-stage heart failure. Worldwide, almost 9,000 procedures are performed annually. Whereas the first successful heart transplantation led to a mere 18 days’ prolongation of the recipient’s life, the median survival after transplantation in Western Europe now exceeds 14 years, ,, due to important surgical advances and optimal medical therapy. Beyond the first year, outcomes have improved only slightly over the last decades. There is a considerable burden of long-term side effects associated with immunosuppressive therapy. There is an increased risk of reduced kidney function after heart transplantation due to prior heart failure and operative trauma, , which is associated with severe kidney failure found in approximately 11% of heart transplant recipients during the first five years after transplantation. , A major cause of kidney injury is calcineurin inhibitor (CNI)-related nephrotoxicity. However, diabetes and hypertension, which can both be CNI induced, are also contributing factors to kidney injury.
The deterioration of kidney function after heart transplantation appears to be linear. In data from Sweden, the average drop in the estimated glomerular filtration rate (eGFR) was 2.2 ± 14.6 mL/min/1.73 m 2/y as compared with 0.5 to 1.0 mL/min/1.73 m 2/y in the general population In the NOrdic Certican Trial in HEart and lung Transplantation (NOCTET trial), which comprised 282 Scandinavian heart and lung transplant recipients who were randomized to treatment with a CNI or low-dose CNI and everolimus 1 to 10 years after transplantation, the measured mean glomerular filtration rate (GFR) declined 7.2 mL/min/1.73 m 2 during a mean follow-up of 5.6 years (i.e., 1.3 mL/min/1.73 m 2/y) independently of the time since transplantation and baseline eGFR.
Sodium-glucose cotransporter-2 inhibitors (SGLT2i) have been studied in several landmark trials in patients with cardiovascular disease, including in patients with type 2 diabetes, heart failure or chronic kidney disease. ,, In addition to improving cardiovascular outcomes, including death, SGLT2i significantly attenuate the slope in eGFR decline over time and reduce kidney failure events in populations at risk.
Heart transplant recipients have many common features with these populations including hypertension, diabetes mellitus, overweight, a propensity for coronary disease in the form of allograft vasculopathy, and progressive kidney failure. On the other hand, heart transplant recipients face an increased risk of infections due to their immunosuppressive therapy, and SGLT2i are associated with an elevated risk of genital infections. SGLT2i are already prescribed in heart transplant recipients for type 2 diabetes, but beyond small case series, robust scientific evidence to support its routine use in this patient category is lacking. The role of these drugs in heart transplant recipients remains uncertain, providing a strong rationale for evaluating SGLT2i in this population in a randomized clinical trial.
Trial design
Overview
The Dapagliflozin for Renal protection in Heart Transplant recipients (DAPARHT) trial (ClinicalTrials.gov Identifier. NCT05321706) is an investigator initiated, double blind, randomized, parallel group, placebo-controlled trial designed to assess the effect of dapagliflozin on the slope of kidney function in heart transplant recipients.
Participants are randomized in a 1:1 ratio to receive oral dapagliflozin 10 mg or matching placebo once daily for 12 months blinded treatment. After 12 months, patients who were allocated to dapagliflozin will transition to open-label treatment with dapagliflozin for another 24 months. Patients originally allocated to placebo will receive standard of care without SGLT2 inhibition for the duration of the two-year open-label extension period, irrespective of the results from the blinded phase, unless a safety concern necessitates stopping the trial early. An overview of the trial design is provided in Figure 1 .
The DAPARHT trial is a randomized, controlled, double blind, parallel group trial with an open-label extension phase. The primary endpoint is the slope of the eGFR measured from 2 weeks after randomization and start of treatment to 12 months after start of treatment. The trial subjects immediately continue into the open-label phase. In this phase, patients assigned to dapagliflozin continue treatment for another 24 months. The primary endpoint of the open-label extension is the baseline-adjusted eGFR measured one month after the end of treatment, 37 months after randomization.
Site selection
Currently, the trial is recruiting at six heart transplant centres across Northern Europe: Oslo University Hospital, Rikshospitalet, Oslo; Erasmus University Medical Centre Rotterdam, Rotterdam, The Netherlands; University Medical Center Groningen, Groningen, The Netherlands; University Medical Center Utrecht, Utrecht, The Netherlands; Skåne University Hospital, Lund, Sweden, and Karolinska University Hospital, Stockholm, Sweden. Together these centres have approximately 1,400 heart transplant recipients under follow-up.
Patient population
Patients ≥18 years of age who have been a heart transplant recipient for ≥1 year and have an eGFR ≥25 mL/min/1.73 m 2 as assessed by the simplified Modified Diet in Renal Disease (sMDRD) formula at baseline will be included. The key exclusion criteria are current (treatment for) malignancy, type 1 diabetes or recent or concomitant use of SGLT2i. A full list of exclusion criteria is provided in Table 1 . Baseline characteristics of the first 300 trial participants are presented for context ( Table 2 ).
Table 1
Inclusion and exclusion criteria.
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Table 2
Baseline characteristics.
| Patients ( N = 300) | |
|---|---|
| Demography | |
| Age, y | 53 ± 15 |
| Sex, male | 213 (71) |
| Body mass index, kg/m 2 | 25.5 ± 4.5 |
| Systolic blood pressure, mmHg | 135 ± 22 |
| Time since heart transplant, y | 8.7 ± 7.5 |
| Medical history | |
| Ischemic heart disease | 45 (15) |
| Dilated cardiomyopathy | 184 (61) |
| Diabetes type II at baseline | 38 (12) |
| Medication | |
| Calcineurin inhibitors | 256 (85) |
| Everolimus | 67 (22) |
| Mofetil mycophenolate | 226 (75) |
| Prednisolone | 224 (75) |
| Statin | 283 (94) |
| Angiotensin converting enzyme inhibitor or angiotensin receptor blocker | 120 (40) |
| Biochemistry | |
| N-terminal pro-B-type natriuretic peptide, ng/L | 172 (66-394) |
| Troponin T, ng/L | 12 (8-18) |
| Creatinine, µmol/L | 104 ± 28 |
| eGFR, mL/min/1.73 m 2 | 66 ± 22 |
| HbA 1c , mmol/mol | 39 ± 9 |
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