Recipients of kidney transplants for whom corticosteroids were withdrawn early after transplantation had a lower rate of cardiovascular (CV) events than patients with later withdrawal, even though the early-withdrawal group had more coronary artery disease before transplantation, according to results presented here at the American Transplant Congress (ATC) 2011.

The decrease in CV events became apparent only at 3 to 4 years posttransplant, Nicole Schmidt, PharmD, from the University of Cincinnati in Ohio, reported. However, she said there were no differences in overall patient survival or in CV-related deaths between the early corticosteroid withdrawal (ECSWD) and the chronic corticosteroid (CCS) immunosuppression maintenance groups.

In general, CV disease accounts for about 30% of deaths among kidney transplant recipients. Clinical trials and a recent metaanalysis have shown that corticosteroid avoidance or withdrawal has been associated with a decrease in CV risk factors, including new-onset diabetes, hypertension, hyperlipidemia, and weight gain. "However, we still have limited long-term studies that have actually translated this cardiovascular risk reduction into actual cardiovascular events and, ultimately, patient survival," Dr. Schmidt said.

The investigators evaluated 1004 patients who underwent kidney transplantation between 1998 and 2010 (ECSWD, n = 714; CCS, n = 290). Data had been collected prospectively and entered into an electronic database. ECSWD was defined as steroid withdrawal within 7 days of transplantation. This group tended to be older, had more men, had fewer African Americans, and had more coronary artery disease before transplantation.

The ECSWD group had fewer repeat transplants than the CCS group (9.5% vs 14.5%; P = .02), less delayed allograft function (7.7% vs 15.2%; P < .001), more mean human leukocyte antigen mismatches (3.3 vs 2.1; P < .001), but lower mean class II peak and current cytotoxic panel reactive antibodies (P < .001 for both).

In terms of immunosuppressive therapy, ECSWD patients had more use of tacrolimus (89.9% vs 51.7%; P < .001) and sirolimus (22.1% vs 0.3%; P < .001), and less use of cyclosporine (9.1% vs 48.3%; P < .001). Even though the use of mycophenolate mofetil was statistically different between the 2 groups (P = .02), at least 97.5% of each group received the drug. The CCS group received mean steroid doses of 8.6 mg/day at 6 months, and was still receiving 5.3 mg/day at 7 years.

Pretransplant mean total cholesterol was lower in the ECSWD group than in the CCS group (168.6 vs 178.2 mg/dL), as was posttransplant mean total cholesterol (172.9 vs 189.1 mg/dL; P ≤ .002). All other pre- and posttransplant cholesterol values, including low-density-lipoprotein cholesterol, did not differ significantly between the groups. Other CV risk factors were largely the same, except for posttransplant mean diastolic blood pressure (which was 1.9 mm Hg higher in the CCS group) and the mean number of antihypertensive medications (which was 1.9 in the ECSWD group and 1.7 in the CCS group). Median follow-up was 4.2 years in the ECSWD group and 5.9 years in the CCS group.

"Patients who received chronic steroid regimens experienced definitely more cardiovascular events than those who were withdrawn from steroids within 7 days of transplantation. . . . However, this decrease in cardiovascular events [in the ECSWD group] did not become apparent until about 3 to 4 years after transplantation," Dr. Schmidt said.

CV events occurred in 14% of the ECSWD group and in 24.5% of the CCS group (P < .001). The Kaplan–Meier model showed a predicted 10-year CV event rate of 24% and 35%, respectively (P = .02). The most common CV events experienced in both groups were angina.

"There was no significant difference between the 2 steroid groups in terms of patient survival. When we looked at just the . . . cardiovascular-related deaths, we found, again, that there was no significant difference between the 2 groups," Dr. Schmidt reported (P = .54).

Session cochair Ram Peddi, MD, a transplant nephrologist at California Pacific Medical Center in San Francisco, who was not involved with the study, wondered whether longer follow-up would change the outcomes. He noted that, in light of some baseline demographic differences between the groups, a multivariate analysis would be in order to adjust for the differences.

In fact, Dr. Schmidt did present such an analysis in a later session here at the ATC. It showed that ECSWD reduced the risk for CV events by 54% (odds ratio [OR], 0.459; P < .001).

Risk factors for CV events were pretransplant diabetes mellitus (OR, 2.69; P < .001) and smoking (OR, 1.88; P = .0024). The investigators concluded that when adjusted for multiple risk factors, this 12-year experience provides strong evidence of a protective effect of ECSWD on CV events.

A third analysis from the same group of investigators showed that at 10 years, patient survival was 76% in both groups, and CV-related deaths were 15% in both.

Dr. Peddi said that it has long been recognized that patients can benefit in terms of CV disease if corticosteroids are withdrawn early. "I think we all are aware of the cardiovascular risks associated with corticosteroids, but [early withdrawal] is now possible with the newer immunosuppressive drugs that are available because, especially the tacrolimus and mycophenolate, and also the induction therapy, offer better immunosuppression, which is enabling us to take the patients off steroids," he said.

Dr. Schmidt and Dr. Peddi have disclosed no relevant financial relationships.

American Transplant Congress (ATC) 2011. Concurrent Session 4: Cardiovascular. Presented May 1, 2011.

  俄亥俄州辛辛那提大學的Nicole Schmidt藥學博士在報告時指出,心血管事件的降低只有在移植後3到4年變得明顯,不過,在提早停用皮質類固醇組(ECSWD)和長期皮質類固醇免疫抑制維持組(CCS)之間,心血管相關死亡或整體病患存活並無差異。
  ECSWD組的再度移植率比CCS組少(9.5% vs 14.5%;P= .02)、移植物功能比較不會延遲(7.7% vs 15.2%;P< .001)、人類白血球抗原錯配平均值較多(3.3 vs 2.1;P< .001),但是,平均第二類尖峰值和目前的細胞毒性群組反應性抗體都比較低(兩項之P< .001)。
  就免疫抑制治療而言,ECSWD組病患比較多人使用tacrolimus (89.9% vs 51.7%;P< .001)與sirolimus (22.1% vs 0.3%;P< .001),比較少使用cyclosporine (9.1% vs 48.3%;P< .001),即使兩組使用mycophenolate mofetil 的比率有統計上的差異(P= .02),但每組都各至少有97.5%使用該藥,CCS組在6個月時平均使用的類固醇劑量為每天8.6 mg,7年時依舊接受每天5.3 mg的劑量。
  ECSWD組的移植前平均總膽固醇值較CCS組低(168.6 vs 178.2 mg/dL),移植後平均總膽固醇也是(172.9 vs 189.1 mg/dL;P≦ .002),至於其他膽固醇值,包括低密度脂蛋白膽固醇,兩組在術前術後並無顯著差異;其他心血管風險因素大部分都相同,除了移植後平均舒張壓(CCS組高1.9 mmHg),降壓藥物平均數量(ECSWD組為1.9種,CCS組為1.7種),追蹤期間中位數在ECSWD組為4.2年,CCS組為5.9年。 
  心血管事件佔ECSWD組的14%,CCS組的24.5% (P< .001),使用Kaplan–Meier模組分析顯示,預測10年心血管事件比率分別是24%和35%(P= .02),這兩組最常見的心血管事件都是心絞痛。
  Schmidt藥學博士報告指出,就病患存活率而言,兩組並無顯著差異,如果只是探討心血管相關死亡時,我們發現,兩組之間依舊沒有顯著差異(P= .54)。
  小組共同主席、舊金山加州太平洋醫學中心移植腎臟科、未參與這篇研究的Ram Peddi醫師表示,如果有更長的追蹤是否會改變這些結果,他指出,就這兩組原本的人口統計學差異看來,應進行多變項分析來校正這些差異。
  事實上,Schmidt藥學博士在ATC稍後的小組報告中發表了這類分析,顯示ECSWD組降低心血管事件風險達54% (勝算比[OR])為0.459;P<.001)。
  心血管事件的風險因素為移植前糖尿病(OR為2.69;P< .001)與抽菸(OR為1.88;P= .0024),研究人員結論表示,校正多項風險因素時,這12年的資料提供了ECSWD對於心血管事件之保護效果的有力證據。


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