The present work was carried out to produce real world evidence on the use and the efficacy-safety profile of post-transplant maintenance immunosuppressive therapies. To the best of our knowledge this is the first observational study of its kind conducted in Europe.
First, the study highlighted how the use of cyclosporine, both as monotherapy and in combination with other drugs, has been abandoned in clinical practice over the years. This result is consistent with numerous evidence in literature indicating TAC as the CNI of choice (13–15) and with consequent recommendations (5, 16); between those evidence, for example, a meta-analysis (17) including 16 RCTs and 3,813 patients showed that TAC significantly reduced the risks after LT of death, graft-loss, acute rejection and steroid resistant rejection.
On the other hand, during the observation time there has generally been a progressive increase of TAC in combination therapy, and an increase in mTORi use in the HCC sub-cohort, these two facts also seem consistent with the prescribers' consideration of the growing body of evidence supporting the use of combination therapy.
From the efficacy and safety analysis it emerged an increased risk of mortality associated with TAC-monotherapy in the cirrhosis sub-cohort, this finding did not come with an increased risk of rejection infections or MACE; a possible explanation is related to the nephrotoxic power of CNI inhibitors and thus the occurrence of renal dysfunction in these patients, a data that could not be traced in our study. In fact, one of the main reasons why an early introduction of MMF or mTORi is recommended is to allow the lowering of the TAC dose and the consequent sparing of renal function (9). Therefore, it would be interesting to integrate our results with data concerning kidney function and to investigate this outcome.
The increased risk of death found in the cirrhosis group does not arise in the HCC group on TAC-monotherapy, even though the guidelines advise against monotherapy also in these patients. We can hypothesize that this result does not emerge from our analysis because the population with HCC, compared to that with cirrhosis, exhibited lower MELD scores across all therapy groups and a reduced presence of clinical history with renal failure or dialysis (Table 1); hence, assuming that renal function plays an important role in determining death in this population it is possible that the HCC sub-cohort was less susceptible to this issue.
As pointed out in the results section, our analysis suggested an increased risk of mortality and cancer occurrence related to mTORi use in HCC group, although statistical significance is not reached in both cases. It is possible that these results were due to a bias by indication whereby patients using these drugs were at higher risk of developing de novo tumors or recurrence of HCC in the first place. Indeed, Table 1 shows that mTORi users were older (42.5% vs 47.4%) and received the organ from older donors (50.1% vs 66.9%). Previous findings have established that immunosuppression plays a crucial role in de novo tumorigenesis and mTORi correlate with a lower incidence of de novo malignancies, because of their antiproliferative properties (18–20); therefore, mTORi are recommended in patients at increased risk of developing tumors (21, 22). Although risks presented in our study was adjusted for measured characteristics, it is possible that additional factors, such as familiarity, risky behaviors (e.g., being a smoker or not) or clinical parameter may have influenced the choice of therapy.
Finally, in both cohorts the use of mTORi was associated with an increased risk of statin utilization; this result fits in with the well-known effect of these drugs of inducing alterations in lipid balance, leading clinicians to prescribe statins during mTORi therapy or before its initiation as a preventive measure. (22–24)
Based on the analysis of treatment changes over time, the study demonstrated a generally favorable therapy persistency rate (from 59–76%). However, it is noteworthy that switches from TAC-mono to TAC + MMF within the cirrhosis group and from TAC + MMF to TAC + mTORi within the HCC group occurred, which raises the need for further investigation into the potential impact of these switches on risk analysis. Moreover, the analysis of the time to switch (Figure S1A and S1B) suggests that the shift from TAC-mono to dual therapy, occurring at an earlier phase, is proactive and linked to the need to set up a combination therapy that carries a lower risk of adverse effects, aiming to stabilize patients. On the contrary, given they occurrence later in the treatment course, the switches from TAC + MMF and TAC + mTORi are more likely to be reactive responses to side effects or issues that emerged after the initial treatment plan was established. These variations in the timing of switches contribute to the complexity of comparing the different switchers.
The main strength of this study is the availability of data about immunosuppressive dispensation from four regions, representative of Northern, Central and Southern Italy and the possibility to have data both administrative data and national transplant information system.
The study has some limitations. Firstly, as immunosuppressive pattern relies on drugs reimbursed by the national healthcare system, this approach may lead to some inaccuracies, due to prescriptions from outside the region or medications purchased privately. Additionally, there might be an overestimation of drug usage if patients claimed the drugs at the pharmacy but do not actually take it. Nevertheless, it’s worth noting that the Italian National Health System offers comprehensive coverage of immunosuppressant drugs, which are rarely paid for by individual patients due to their high costs. Consequently, the proportion of patients purchasing these drugs privately can be considered negligible. Furthermore, investigations have demonstrated the Italian health information system’s effectiveness in capturing chronically used medications, such as immunosuppressants post-transplant. (25)
Second, as noted above, it would be important to supplement our results with data on renal function that would allow investigation of this outcome in the two cohorts.
With regard to the HCC cohort, given the administrative nature of the data, it was not possible to assess the incidence of recurrence of HCC and the association of this outcome with the different therapies. In fact, a recently published meta-analysis (26) points out that the choice of mTORi may be especially linked to its anti-proliferative effect, which, in addition to reducing the risk of new-onset cancers, also reduces the chance of disease recurrence. Since our data sources make it difficult to distinguish between HCC already existing at the time of transplantation and disease recurrence, we preferred not to investigate this aspect; however, future studies would be needed to evaluate this point.
Lastly, the administrative nature of the data requires taking into account the possibility of unobserved clinical factors influencing outcomes, the record linkage of data from the National Transplant Center (CNT) and the large enrolled cohort help to strengthen the observed evidence, but it would be of particular interest to integrate the data with clinical information related to patients' family history, etiology of hepatic disease, tumor staging and severity.