Simvastatin in Colorectal Surgery

Study Overview
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Brief Summary
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Statins (HMG-CoA reductase inhibitors) are a widely used class of cholesterol-lowering drugs that have an established role in the medical management of cardiovascular disease. Their benefits have also been shown in the surgical setting with decreased cardiovascular complications and lower perioperative mortality following cardiac and vascular surgery. There is now considerable evidence showing statins have useful pleiotropic properties that extend beyond cholesterol lowering, including anti-inflammatory, anti-oxidant, immunomodulatory and fibrinolytic effects. Growing evidence suggests these effects may be useful in attenuating the proinflammatory and metabolic stress response to surgery and the benefit of statins may extend to other surgical settings such as abdominal surgery. Laboratory studies demonstrate the surgically-relevant benefits of statins and show they decrease peritoneal inflammation, reduce the severity of intestinal ischaemia-reperfusion injury, improve survival in models of abdominal sepsis, decrease the formation of postoperative intraperitoneal adhesions and improve the healing of colonic anastomoses. Retrospective clinical studies show statins improve outcomes in sepsis, reduce the postoperative systemic inflammatory response syndrome (SIRS) and are associated with decreased rates of surgical wound infections and postoperative respiratory complications following various non-cardiac general surgical procedures. However, no prospective studies have specifically evaluated the perioperative use of statins in abdominal surgery. Using colorectal surgery as a model for major abdominal surgery, the investigators will conduct a randomised controlled trial evaluating the effect of perioperative statin use on postoperative morbidity, local and systemic inflammatory response, and functional recovery after surgery.

Official Title
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Prospective, Double-Blinded, Multi-Centred, Randomised Controlled Trial of Perioperative Simvastatin Use in Elective Colorectal Surgery

Conditions
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Intestinal Neoplasm, Perioperative Care

Intervention / Treatment
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* Drug: Simvastatin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Consecutive consenting patients undergoing elective colectomy, rectal resection, and reversal of Hartmann's procedure at Middlemore Hospital, Manukau Surgery Centre, Auckland City Hospital, and North Shore Hospital. Exclusion criteria: Acute presentation Already taking statins or other lipid-lowering medication Known adverse reaction to statins Hepatic dysfunction Moderate to severe renal dysfunction Previous history of rhabdomyolysis On contraindicated medication Pregnancy Breastfeeding Patient choice.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 90 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Placebo tablets (Inert calcium lactate) | Drug: Placebo<br>* Placebo (Inert calcium lactate) tablets 3-7 days pre-op to 14 days post-op (as per experimental arm)<br>|
| Experimental: Simvastatin<br>40mg of Simvastatin given 3-7 days pre-op and continued till 14 days post-op | Drug: Simvastatin<br>* 40mg orally, given 3-7 days pre-op and continued till 14 days post-op<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total complications | Complications pre-defined and graded by the Clavien-Dindo classification | Up to post-operative day 30 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Peritoneal Cytokines |  | Postoperative Day 1 | 
| Serum cytokines |  | Post-operative Day 1 | 
| Change in serum C-reactive protein (CRP) |  | Baseline and Postoperative Day 1, 2 and 3 | 
| Change in functional recovery |  | Baseline and Postoperative Day 1, 3, 7, 14, and 30 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Statin, Colon, Colorectal, Intestinal Neoplasms, ERAS, Perioperative Care