Immunosuppression With Prednisone for Restenosis Prevention
Immunosuppression With Prednisone for Restenosis Prevention
Drug-eluting stents have substantially reduced the recurrence of ischaemia at short-to mid-term, and this benefit is sustained also at 4–5 years compared with BMS. However, the need for repeated revascularization procedures in the same lesion (TLR) after DES implant increased in randomized studies from 7.2 and 11.6% for Cypher and Taxus at 1 year, up to 15 and 18% at 5 years, respectively, percentages that suggest a 'late catch-up phenomenon'. This process is even more evident in real-life settings that have demonstrated a sustained increment in new TLR after implantation of the first-generation DES of 2–3% per year. Also important is the need for new revascularization procedures after PCI driven by the progression of atherosclerosis in other than the initially treated sites, an eventuality that doubled the incidence of target vessel myocardial infarction and re-interventions from 10 to 11% at 1 year, to 20–21%, at 2 years of the index treatment in the Resolute AC trial, despite the use of second generation DES. In fact, the occurrence of neo-atherogenesis within DES, and atherosclerosis progression in other than the PCI-treated sites, are both strong determinants of the long-term clinical outcome of catheter-based revascularization techniques, despite the improved local efficacy and global safety of new generation DES. A subtle but progressive deterioration of the excellent early results of first-generation DES observed in large series, is confirmed in our study. Both, late DES restenosis and very late DES thrombosis accounted for most of these adverse events, in particular after the third year of follow-up. This happened despite the maintenance of optimal medical therapy during 4 years of regular medical controls, an attitude that may have contributed to improve the clinical outcome in all patients.
At 1 year, our study demonstrated that the addition of prednisone after BMS, or the implantation of DES, yielded similar event-free survival, and that both strategies performed significantly better than BMS alone. The analysis at the long term of the prednisone therapy after stenting, discloses the following principal observations.
First, the clinical benefits observed at 1 year remain almost unchanged at 4 years, with a very low incidence of cardiac events occurring between 1 and 4 years; (i.e. only one case of late restenosis, and none of late or very late stent thrombosis). Of note, these long-term results are almost identical to those previously reported following preliminary experiences with oral prednisone after BMS implantation in patients with single or with multi-vessel CAD at 5-year follow-up. Secondly, is that the use of a short, high-dose cycle of oral prednisone as in the IMPRESS and the CEREA studies does not correlate with the occurrence of other newly diagnosed diseases such as diabetes mellitus, gastric or suprarenal disorders or refractory hypertension; and thirdly, is the trend observed towards a lower need for new revascularizations at the long term, compared with the other two groups. This may suggest a beneficial effect of the immunosuppressive and/or anti-inflammatory cycle against atherosclerosis progression in the coronary vascular tree.
Other experiences with systemic drug therapy to prevent restenosis have been reported some years ago, in particular with the administration of oral rapamycin. Despite favourable short-term results, long-term clinical outcome has shown some reduced anti-restenotic efficacy compared with that observed at 1 year. Similarly to prednisone, the anti-proliferative efficacy of orally administered rapamycin is dose dependent, but unlike prednisone, it induces different effects in the reparative process that follows artery wall injury after stent implantation in the experimental model. Furthermore, it has a lower tolerability profile at the effective dose required in humans compared with prednisone.
It is unarguable that DESs are highly effective in reducing in-stent restenosis, intended as a local phenomenon, due to their potent anti-proliferative effect. Nevertheless, the need to re-intervene on the same vessel or on other vessels at long-term follow-up increases with time at a higher rate compared with BMS, likely because of a more intense induction of neoatherosclerosis that follows the implantation of the Taxus or Cypher stents, a permanent endothelial damage being considered to play a main role in this sustained plaque progression. A lower need for repeated interventions in different segments of the treated vessel and in other than the treated vessels (non-TLR+non-TVR) following immunosuppression with prednisone, may suggest a global beneficial effect of the treatment. This, if proved by adequately conceived investigations, may benefit patients undergoing PCI irrespective of the type of stent implanted. The anti-proliferative effectiveness of the steroid treatment mediated by persistent and effective inhibition of monocyte activation and cytokines release, as demonstrated in a subgroup of patients of the CEREA-DES, provides mechanistic support to this hypothesis. Furthermore, relatively short cycles of immunosuppression with steroids have shown similar efficacy at long term compared with prolonged steroid exposition in several diseases of known inflammatory nature, such as, cystic fibrosis, acute and recurrent pericarditis, retroperitoneal fibrosis, and kidney transplant patients, among others.
The comprehensive interpretation of these observations, and their potential clinical impact, raises important questions that warrant further investigation.
Our study shows that a relatively short cycle of high-dose prednisone treatment given orally after BMS implantation in non-diabetic patients with advanced CAD, improves the clinical outcome of PCI performed in patients receiving BMS, by reducing the cumulative incidence of MACE at long term. The significant clinical benefit observed at 1 year (HR: 0.505; 95% CI: 0.260–0.981) was further incremented along time up to 4 years (HR: 0.447; 95% CI: 0.249–0.803) without the occurrence of undesirable adverse effects that may be attributable to the steroid treatment itself. The strategy of using prednisone, on top of optimal medical therapy, after BMS implantation in patients without contraindications, may prove particularly suited in suboptimal candidates for prolonged intense anti-platelet therapy. Furthermore, the present study, as well as other previous experiences, has shown that the systemic effect of the drug provides restenosis protection also in complex patients with diffuse disease, long lesions, or bifurcations treated with balloon angioplasty and spot and provisional stenting. Furthermore, due to the irrelevant economic cost of the drug, this strategy may help patients (and doctors) in situations of economic restrictions wherever the cost of DES is still an issue.
The study was designed as a superiority trial, to compare DES, and BMS plus prednisone, with BMS. The direct comparison of the two study groups (DES vs. prednisone) as a non-inferiority trial would be of greater interest. However, the sample size required for a pairwise comparison of the three groups is beyond the possibility of an investigator-initiated study. Indeed, even keeping the non-inferiority margin as high as 25%, 2507 patients per arm would be required in order to obtain an 80% power. Under a clinical standpoint, prednisone treatment and dual anti-platelet therapy require accurate monitoring of side-effects, and this has precluded the possibility of performing the study in a blinded fashion. The exclusion of diabetic patients is a main limitation to the applicability of this treatment and a possible determinant of the global incidence of MACEs. Finally, our DES patients underwent Cypher and Taxus implantation, new generation DES may permit shorter periods of dual anti-platelet therapy with better safety profile.
Discussion
Drug-eluting stents have substantially reduced the recurrence of ischaemia at short-to mid-term, and this benefit is sustained also at 4–5 years compared with BMS. However, the need for repeated revascularization procedures in the same lesion (TLR) after DES implant increased in randomized studies from 7.2 and 11.6% for Cypher and Taxus at 1 year, up to 15 and 18% at 5 years, respectively, percentages that suggest a 'late catch-up phenomenon'. This process is even more evident in real-life settings that have demonstrated a sustained increment in new TLR after implantation of the first-generation DES of 2–3% per year. Also important is the need for new revascularization procedures after PCI driven by the progression of atherosclerosis in other than the initially treated sites, an eventuality that doubled the incidence of target vessel myocardial infarction and re-interventions from 10 to 11% at 1 year, to 20–21%, at 2 years of the index treatment in the Resolute AC trial, despite the use of second generation DES. In fact, the occurrence of neo-atherogenesis within DES, and atherosclerosis progression in other than the PCI-treated sites, are both strong determinants of the long-term clinical outcome of catheter-based revascularization techniques, despite the improved local efficacy and global safety of new generation DES. A subtle but progressive deterioration of the excellent early results of first-generation DES observed in large series, is confirmed in our study. Both, late DES restenosis and very late DES thrombosis accounted for most of these adverse events, in particular after the third year of follow-up. This happened despite the maintenance of optimal medical therapy during 4 years of regular medical controls, an attitude that may have contributed to improve the clinical outcome in all patients.
At 1 year, our study demonstrated that the addition of prednisone after BMS, or the implantation of DES, yielded similar event-free survival, and that both strategies performed significantly better than BMS alone. The analysis at the long term of the prednisone therapy after stenting, discloses the following principal observations.
First, the clinical benefits observed at 1 year remain almost unchanged at 4 years, with a very low incidence of cardiac events occurring between 1 and 4 years; (i.e. only one case of late restenosis, and none of late or very late stent thrombosis). Of note, these long-term results are almost identical to those previously reported following preliminary experiences with oral prednisone after BMS implantation in patients with single or with multi-vessel CAD at 5-year follow-up. Secondly, is that the use of a short, high-dose cycle of oral prednisone as in the IMPRESS and the CEREA studies does not correlate with the occurrence of other newly diagnosed diseases such as diabetes mellitus, gastric or suprarenal disorders or refractory hypertension; and thirdly, is the trend observed towards a lower need for new revascularizations at the long term, compared with the other two groups. This may suggest a beneficial effect of the immunosuppressive and/or anti-inflammatory cycle against atherosclerosis progression in the coronary vascular tree.
Other experiences with systemic drug therapy to prevent restenosis have been reported some years ago, in particular with the administration of oral rapamycin. Despite favourable short-term results, long-term clinical outcome has shown some reduced anti-restenotic efficacy compared with that observed at 1 year. Similarly to prednisone, the anti-proliferative efficacy of orally administered rapamycin is dose dependent, but unlike prednisone, it induces different effects in the reparative process that follows artery wall injury after stent implantation in the experimental model. Furthermore, it has a lower tolerability profile at the effective dose required in humans compared with prednisone.
It is unarguable that DESs are highly effective in reducing in-stent restenosis, intended as a local phenomenon, due to their potent anti-proliferative effect. Nevertheless, the need to re-intervene on the same vessel or on other vessels at long-term follow-up increases with time at a higher rate compared with BMS, likely because of a more intense induction of neoatherosclerosis that follows the implantation of the Taxus or Cypher stents, a permanent endothelial damage being considered to play a main role in this sustained plaque progression. A lower need for repeated interventions in different segments of the treated vessel and in other than the treated vessels (non-TLR+non-TVR) following immunosuppression with prednisone, may suggest a global beneficial effect of the treatment. This, if proved by adequately conceived investigations, may benefit patients undergoing PCI irrespective of the type of stent implanted. The anti-proliferative effectiveness of the steroid treatment mediated by persistent and effective inhibition of monocyte activation and cytokines release, as demonstrated in a subgroup of patients of the CEREA-DES, provides mechanistic support to this hypothesis. Furthermore, relatively short cycles of immunosuppression with steroids have shown similar efficacy at long term compared with prolonged steroid exposition in several diseases of known inflammatory nature, such as, cystic fibrosis, acute and recurrent pericarditis, retroperitoneal fibrosis, and kidney transplant patients, among others.
The comprehensive interpretation of these observations, and their potential clinical impact, raises important questions that warrant further investigation.
Clinical Implications and Conclusions
Our study shows that a relatively short cycle of high-dose prednisone treatment given orally after BMS implantation in non-diabetic patients with advanced CAD, improves the clinical outcome of PCI performed in patients receiving BMS, by reducing the cumulative incidence of MACE at long term. The significant clinical benefit observed at 1 year (HR: 0.505; 95% CI: 0.260–0.981) was further incremented along time up to 4 years (HR: 0.447; 95% CI: 0.249–0.803) without the occurrence of undesirable adverse effects that may be attributable to the steroid treatment itself. The strategy of using prednisone, on top of optimal medical therapy, after BMS implantation in patients without contraindications, may prove particularly suited in suboptimal candidates for prolonged intense anti-platelet therapy. Furthermore, the present study, as well as other previous experiences, has shown that the systemic effect of the drug provides restenosis protection also in complex patients with diffuse disease, long lesions, or bifurcations treated with balloon angioplasty and spot and provisional stenting. Furthermore, due to the irrelevant economic cost of the drug, this strategy may help patients (and doctors) in situations of economic restrictions wherever the cost of DES is still an issue.
Study Limitations
The study was designed as a superiority trial, to compare DES, and BMS plus prednisone, with BMS. The direct comparison of the two study groups (DES vs. prednisone) as a non-inferiority trial would be of greater interest. However, the sample size required for a pairwise comparison of the three groups is beyond the possibility of an investigator-initiated study. Indeed, even keeping the non-inferiority margin as high as 25%, 2507 patients per arm would be required in order to obtain an 80% power. Under a clinical standpoint, prednisone treatment and dual anti-platelet therapy require accurate monitoring of side-effects, and this has precluded the possibility of performing the study in a blinded fashion. The exclusion of diabetic patients is a main limitation to the applicability of this treatment and a possible determinant of the global incidence of MACEs. Finally, our DES patients underwent Cypher and Taxus implantation, new generation DES may permit shorter periods of dual anti-platelet therapy with better safety profile.
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