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Pasireotide decreases incidence of postoperative fistula


 

FROM NEJM

The somatostatin analogue pasireotide reduced postoperative pancreatic fistula leak or abscess by 56%, compared with placebo, a randomized study has determined.

Pasireotide (Signifor) was effective after both pancreaticoduodenectomy and distal pancreatectomy, whether or not the pancreatic duct was dilated, Dr. Peter J. Allen and his colleagues wrote in the May 21 issue of the New England Journal of Medicine (N. Engl. J. Med. 2014;370:2014-22).

In those patients who did develop fistulas or leaks, pasireotide was associated with fewer grade 3 occurrences.

"These results suggest that ... not only were many leaks and fistulas prevented, but when they did occur they were less clinically relevant," wrote Dr. Allen of the Memorial Sloan Kettering Cancer Center, New York, and his coauthors.

The study randomized 300 patients to subcutaneous injections of either placebo or pasireotide twice daily for 7 days after pancreatic surgery. The primary endpoint was the development of a pancreatic leak, fistula, or abscess of at least grade 3. Secondary endpoints included the overall rate of pancreatic complications (all grades) and the rate of grade B or grade C pancreatic fistula.

Patients were a mean of 64 years old. Most (73%) underwent a pancreaticoduodenectomy. The average length of stay for these patients was about 10 days. The active group received 900 mcg of pasireotide subcutaneously twice daily for 7 days, beginning on the morning of surgery.

Mean postoperative serum glucose levels were significantly higher in patients taking pasireotide (258 mg/dL vs. 215 mg/dL). Readmission occurred in significantly fewer pasireotide patients (17% vs. 29%).

Significantly fewer of those taking the active drug were able to finish the entire course of 14 doses (76% vs. 86% given placebo). The lower completion rate was mostly due to nausea and vomiting, which caused 26 patients in the active group and 3 in the placebo group to withdraw from the study.

A leak or fistula of grade 3 or higher developed in 45 patients. The outcome was significantly less common among those taking pasireotide than among those on placebo (9% vs. 21%; relative risk, 0.44). "This corresponded to an absolute risk reduction of 11.7 percentage points," with a number needed to treat of 8, the investigators said.

Pasireotide was significantly more effective than placebo in surgical subgroups, including pancreaticoduodenectomy (RR, 0.49) and distal pancreatectomy (RR, 0.32). The effect was also positive whether the pancreatic duct was dilated (RR, 0.11) or nondilated (RR, 0.55).

The secondary outcome (grade B or C postoperative fistula) occurred in 37 patients (12%). In the pasireotide group, there were 12 grade B fistulas and no grade C fistulas. In the placebo group, there were 20 grade B and 5 grade C fistulas.

Overall 60-day mortality was 0.7% (one death in each treatment group). Grade 3 and 4 complications were common, occurring in 92% of the pasireotide group and 90% of the placebo group. Most of these were expected postoperative serum abnormalities.

The investigators said that the other approved somatostatin analogue, octreotide, has not been clearly associated with pancreatic leak reduction. They suggested that pasireotide may be more effective because it has a longer half-life and binds to four of the five somatostatin-receptor subtypes, rather than just two, as octreotide does.

They added that the octreotide studies were conducted before 2005, when there was no consistent definition of postoperative pancreatic fistula. Therefore, they concluded, the extant data cannot be used to identify octreotide efficacy in this application.

Pasireotide, which is made by Novartis Pharmaceuticals, is currently approved as an injection for the treatment of Cushing’s disease patients who cannot be helped through surgery.

Novartis Pharmaceuticals sponsored the trial. Dr. Allen received Novartis grant funding but had no other financial ties with the company.

msullivan@frontlinemedcom.com

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