Withdrawal of proliferation signal inhibitors due to adverse events in the maintenance phase of heart transplantation

doi:10.1016/j.healun.2011.10.011

The Journal of Heart and Lung Transplantation

Volume 31, Issue 3, March 2012, Pages 288-295

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https://doi.org/10.1016/j.healun.2011.10.011 Get rights and content

Background

The increasing use of proliferation signal inhibitors (PSIs) has raised the issue of their risk profile. We sought to determine the causes, incidence, risk factors, and consequences of withdrawal due to adverse events of PSIs in maintenance heart transplantation.

Methods

This was a retrospective study from 9 centers of the Spanish Registry for Heart Transplantation. Demographic, clinical, analytic, and evolution data were obtained for patients in whom a PSI (sirolimus or everolimus) was used between October 2001 and March 2009.

Results

In the first year, 16% of 548 patients could not tolerate PSIs. This incidence rate stabilized to 3% to 4% per year thereafter. The most frequent causes for discontinuation were edema (4.7%), gastrointestinal toxicity (3.8%), pneumonitis (3.3%), and hematologic toxicity (2.0%). In multivariate analysis, withdrawal of PSI was related to the absence of statin therapy (p = 0.006), concomitant treatment with anti-metabolites (p = 0.006), a poor baseline renal function (p = 0.026), and multiple indications for PSI use (p = 0.04). Drug discontinuation was associated with a decline in renal function (p = 0.045) but not with an excess in mortality (p = 0.42).

Conclusions

In this large cohort of maintenance heart transplant recipients taking a PSI, 16% withdrew treatment in the first year, and 25% had stopped PSI due to severe adverse events by the fourth year. This high rate of toxicity-related PSI withdrawal could limit the clinical utility of this otherwise novel class of immunosuppressive agents.

Section snippets

Materials and methods

This was an investigator-initiated, industry-independent, retrospective, multicenter study on an intention-to-treat basis. The coordination between the 9 participating centers across Spain, the adjudication process, and analyses were performed centrally according to the standards from the Spanish Registry of Heart Transplantation.¹⁶ The study protocol was approved by the Hospital Universitario Marques de Valdecilla Ethics Committee.

Results

Between October 2001 and March 2009, 548 patients were treated with a PSI, which represents 30.2% of all the HTx recipients on follow-up during the study period. Everolimus was used in 360 patients (65.7%) and sirolimus in 188 (34.3%). PSIs were used as substitutes for CNIs (conversion protocols) in 289 patients (52.7%) and in protocols aimed to minimize CNI exposure (minimization protocols) in 259 (47.3%). The main characteristics of the study population are summarized in Table 1, Table 2.

Discussion

The main findings in this large study addressing the problem of AEs related to the use of PSI in clinical practice can be summarized as follows:

1
The rate of PSI withdrawal due to AEs in maintenance HTx is substantial: close to 16% just within the first year, stabilizing thereafter to a rate of 3% to 4% per year in the next 3 years.
2
Edema, gastrointestinal intolerance, pneumonitis, and bone marrow depression are the most clinically significant AEs, accounting for 62.3% of all instances of PSI

Disclosure statement

Drs Gonzalez-Vilchez and Vázquez de Prada are partly supported by an unrestricted grant from the Instituto de Formación e Investigacion Marques de Valdecilla (IFIMAV), Santander, Spain. Drs Paniagua and Crespo-Leiro are supported by the Red Tematica de Investigacion en Enfermedades Cardiovasculares, Instituto de Salud Carlos III, Spanish Ministry of Health and Consumer Affairs (RECAVA), Madrid, Spain. Drs Delgado, Almenar, Martinez-Dolz, Pérez-Villa, Roig, Ruiz-Cano, Gomez-Bueno, and Segovia

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El Registro Español de Trasplante Cardiaco cumple 24 años de actividad. En el presente artículo se hace referencia histórica a su evolución hasta el presente, incluyendo su organización, los resultados de su actividad y sus potencialidades.
The Spanish Heart Transplantation Registry has been in existence for 24 years. This article provides a historical perspective on the development of the Registry up to the present day and discusses its organization, achievements and future potential.
Incidence and treatment of lymphedema in heart transplant patients treated with everolimus
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Because of the small sample size, especially of patients developing peripheral edema, it was not possible to establish whether there was an EVE level predicting edema appearance. These results replicate those of several clinical trials [4–6] and single-center trials [7–14]. Although a similar discontinuation occurrence has been observed for other immunosuppressive drugs, it can be concluded that EVE suspension is not a so rare event.
Proliferation signal inhibitors are increasingly used as immunosuppressive drugs in solid organ transplantation. Among their side effects peripheral lymphedema is rarely described in literature.
All heart transplant patients treated with everolimus (de novo or maintenance) at our center (135 patients: age 50.72 ± 11.1 y, 115 male) were retrospectively analyzed. We considered the incidence of adverse events, particularly the appearance of peripheral edema (13 patients, 9.6%), and the correlation with preoperative characteristics, concomitant medications, other possible causes of edema, as well as all the measures developed for its therapeutic treatment.
Edema appearance, especially in lower limbs, was considered to be one of the most frequent side effects in heart transplant patients treated with everolimus. In some cases its regression was possible with an adjustment of drug dosages associated with diuretics and lymphatic drainage, but more often a suspension of the drug itself was required for complete regression of the symptoms.
A contemporary review of adult heart transplantation: 2012 to 2013
2014, Journal of Heart and Lung Transplantation
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Challenges with proliferation signal inhibitors (PSI) included a 16% withdrawal rate within the first year after conversion due to adverse events (25% within 4 years), including edema (4.7%) and gastrointestinal toxicity (3.8%).24 This Spanish Registry study found higher rates of PSI withdrawal in patients not on statin therapy (p = 0.006), those treated with concomitant anti-metabolites (p = 0.006), and in patients with poor baseline renal function (p = 0.026).24 Long-term outcomes in recipients with transplant coronary artery disease stratified by those who develop in-stent restenosis after percutaneous coronary intervention found that in-stent stenosis is a marker of poor long-term prognosis.25
Important developments have occurred during the past 2 years in the field of heart transplantation. These include refinements in donor management, preservation, and allocation, and evaluation of immunosuppression strategies for rejection and for allograft vascular disease. Finally, long-term outcomes addressing areas of significant morbidity for patients, including renal dysfunction and cancer, have seen important advances. This contemporary review will highlight the key articles for 2012 to 2013.
Prospective study of everolimus with calcineurin inhibitor-free immunosuppression after heart transplantation: Results at four years
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By the final evaluation, 6 patients (∼12.5%) who had been switched to everolimus were again on a CNI-based regimen, due to adverse events over the course of the 48-month follow-up. This experience is consistent with reconversion rates in other studies [21, 26, 27]. The rate of CNI reintroduction may be reduced by refining patient selection for everolimus therapy, particularly by excluding patients undergoing re-transplantation and those older than 65 years.
Immunosuppression is necessary after transplantation but it is associated with distinct adverse side effects. These negative effects could at least partially be overcome with the mammalian target of Rapamycin (mTOR) inhibitor everolimus. Few studies have examined everolimus therapy with calcineurin inhibitor (CNI) withdrawal in maintenance heart transplant patients (HTx).
In this prospective, single-arm, single-center study, maintenance patients after HTx were converted from CNI to everolimus. They were followed for 48 months. Primary endpoints were kidney-function and arterial hypertension.
Forty-eight patients were recruited (mean post-transplant time 5.4 ± 3.5 years). Of these, 36 were followed for the entire 4-year period. Median calculated glomerular filtration rate increased from 40.7 (32.4 to 59.1) mL/minute at baseline to 48.9 (29.7 to 67)) mL/minute at month 48 (p = not significant). Median systolic and diastolic blood pressure, triglycerides, and high-density lipoprotein and low-density lipoprotein cholesterol, did not change significantly in a comparison of the values at baseline and at 48 months. Early resolution of most non-renal CNI-related adverse events was sustained. Due to adverse events, CNI therapy had to be reintroduced in 6 patients (12.5%). No significant changes in cardiac function parameters were observed.
Calcineurin inhibitor-free immunosuppression with everolimus is an effective and safe option in selected maintenance HTx patients. Most adverse effects under everolimus occurred early after conversion and in most cases resolved without intervention within a few weeks. Refining selection criteria may help both in identifying patients who will profit most from switching and in alleviating the need to reintroduce CNI therapy.
Use of mTOR inhibitors in chronic heart transplant recipients with renal failure: Calcineurin-inhibitors conversion or minimization?
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A somewhat worrisome fact with the use of mTOR-i in heart transplantation is the safety profile of these drugs. A high rate of drug-related adverse effects, sometimes leading to drug withdrawal is a major limiting factor for the clinical usefulness of both sirolimus and everolimus [44]. Our results confirm that the adverse event-related drug withdrawal affects similarly both conversion and minimization strategies and that represent the most powerful factor influencing the evolution of renal function after mTOR-i switching.
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.
In a retrospective multi-center cohort of 394 maintenance cardiac recipients with renal failure (GFR < 60 mL/min/1.73 m²), 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.
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 5 years 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).
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Original clinical scienceWithdrawal of proliferation signal inhibitors due to adverse events in the maintenance phase of heart transplantation

Background

Methods

Results

Conclusions

Section snippets

Materials and methods

Results

Discussion

Disclosure statement

Am J Transplant

J Heart Lung Transplant

J Heart Lung Transplant

J Heart Lung Transplant

Am J Transplant

Transplant Proc

Rev Esp Cardiol

J Heart Lung Transplant

J Heart Lung Transpl

Original clinical science
Withdrawal of proliferation signal inhibitors due to adverse events in the maintenance phase of heart transplantation