POSCH trial 25-year follow-up results: latest news ...

4 downloads 0 Views 301KB Size Report
tion in cholesterol absorption by ileal bypass [1]. The proposed procedure excludes the distal third or the .... Effect of partial ileal bypass surgery on mortality and ...
Priority Paper Evaluation For reprint orders, please contact: [email protected]

POSCH trial 25-year follow-up results: latest news from an old kid on the block Evaluation of: Buchwald H, Rudser KD, Williams SE, Michalek VN, Vagasky J, Connett JE: Overall mortality, incremental life expectancy and cause of death in the Program on the Surgical Control of the Hyperlipidemia. Annal. Surg. 241, 1034–1040 (2010). The Program on the Surgical Control of the Hyperlipidemia (POSCH) trial was designed aiming to evaluate the effect of cholesterol reduction by ileal bypass on mortality in patients with previous myocardial infarction. The surgical procedure increases fecal loss of bile acids, promoting hepatocellular cholesterol deprivation and, as a result, induces an average 38% reduction of LDL‑C and 4% increase in HDL‑C, which held constant throughout the follow-up. In the last report, an analysis of the study after 25 years of follow-up demonstrated the persistence of the reduction of total and cardiovascular mortality in the surgical group, which were 18 and 8% lower, respectively, compared with the control group. Furthermore, cancer mortality was not different between groups, opposing the hypothesis of a causal association between cholesterol lowering and increases in the incidence of cancer. In this article, we discuss the rationale and findings of the POSCH trial over the past 25 years and their clinical and mechanistic implications. Keywords: follow-up

n

lipid lowering n mortality n POSCH trial

Riobaldo R Cintra1 & Andrei C Sposito† University of Brasilia Medical School, Brasilia, Brazil † Author for correspondence: Cardiology Division, Faculty of Medical Sciences, State University of Campinas (Unicamp), 13084-971, Campinas, Sao Paulo, Brazil Tel.: +55 61 3442 8439 Fax: +55 61 3442 8489 [email protected] 1

Summary of the rationale & methods The Program on the Surgical Control of Hyperlipidemia (POSCH) was first established in 1975 with the proposal of obtaining a reduction in cholesterol absorption by ileal bypass [1] . The proposed procedure excludes the distal third or the distal 200 cm of small intestine, whichever length is greater [2] . The loss of bile acids decreases the formation of micelles and thus reduces the emulsification and absorption of intestinal cholesterol. In parallel, the interruption of the enterohepatic circulation increases the fecal loss of bile acids and, by this way, increases the hepatocellular consumption of its substrate, the cholesterol, via the derepression of the activity of the rate-limiting enzyme cholesterol 7-hydroxylase [3] . The cellular cholesterol deprivation increases the transcription of a set of genes related to cholesterol synthesis or extracellular uptake. In hepatocytes, there is increased transcription of the LDL receptor gene, resulting in an average reduction of 37.7% of the plasma concentration of LDL‑C [1] . Furthermore, the authors observed an average increase of 4.3% in HDL‑C and of 19.8% in triglyceride levels. Ileal exclusion may induce hepatic secretion of

triglyceride-rich VLDL, which may underlie the increase in triglycerides [4] . However, the increase in HDL remains poorly understood. In the POSCH trial, the procedure was tested as a strategy for secondary prevention of cardiovascular disease in 838 patients who manifested myocardial infarction and had average LDL‑C levels of 179 mg/dl. Patients were randomized to dietary advice with or without the addition of surgery. The primary outcome was total mortality.

10.2217/CLP.10.58 © 2010 Future Medicine Ltd

Clin. Lipidol. (2010) 5(5), 651–653

Summary of the findings Given the invasive nature of the procedure, the sample size was limited, and it took a long followup period to record 296 deaths, which allows statistical power to test the main hypothesis of the study. Thus, 20 years after the randomization, the benefit in reducing total mortality in the surgical group was verified by reaching statistical significance (p = 0.043). This finding is probably still underestimated. During the follow-up, the use of statins was approximately eight‑times higher in the control group (up to 31%) than in the surgical group (up to 3.7%). After completing 25 years of follow-up, the difference remained significantly in favor of the surgical group [5] . ISSN 1758-4299

651

Priority Paper Evaluation | Cintra & Sposito However, at 10 years of follow-up, the overall mortality in patients with ejection fractions (EFs) of the left ventricle of more than 50% had already been demonstrated to be reduced by 36% (p = 0.021). In the same subgroup, the combined end point of mortality and fatal or nonfatal myocardial infarction was reduced by 35% (p