#189 Moving along the management of constipation predominant IBS – Is it worth the cost?
CLINICAL QUESTION
What is the efficacy and safety of linaclotide in constipation predominant irritable bowel syndrome (IBS-C)?
BOTTOM LINE
Compared to placebo, for every seven patients treated with linaclotide one more will be a “responder” [30% improvement in pain and one additional “complete” spontaneous bowel movement (CSBM) per week for six weeks in 12]. Overall, patients experience ~3 additional “spontaneous” bowel movements (BM) per week, at the price of $15 per BM. For every 21 patients treated, one will stop due to diarrhea. Post-marketing surveillance should help clarify long-term safety.
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EVIDENCE
- Two multicentre, Randomized Controlled Trials (RCTs) (803 and 805 patients)1,2 comparing linaclotide 290 mcg to placebo in IBS-C, and three systematic reviews.3-5
- Both RCTs had strikingly similar baseline demographics and outcomes at 12 weeks:1,2
- Mean age 44, ~ 90% female, ~78% white.
- Baseline abdominal pain ~5.6 on 0-10 point scale, CSBM 0.2/week.
- Primary outcome:
- “Responder”: ≥30% reduction in abdominal pain and increase of one CSBM per week for six of the 12 weeks.1,2
- 34% linaclotide versus 14-21% placebo.1,2
- Combined number needed to treat=7.3,4
- Secondary outcomes:
- ~3 additional spontaneous BM per week (above placebo).1,2
- Average pain reduction in both trials was 1.9 linaclotide versus 1.1 placebo (0-10 scale).
- Minimally clinically important difference=2.2.6
- Adverse outcomes:
- Diarrhea resulting in discontinuation:1,2
- 4-6% linaclotide versus 0.2-0.3% placebo.
- Combined Number Needed to Harm=21.
- Diarrhea resulting in discontinuation:1,2
- Limitations: Unclear recruitment, run in excluded >40% of patients.
- Over 40 publications (abstract and peer-reviewed) on two RCTs with common author (employee of linaclotide manufacturer). Some inconsistent data between abstracts and peer-reviewed publications.3,7
- Both RCTs had strikingly similar baseline demographics and outcomes at 12 weeks:1,2
- One smaller RCT reported similar outcomes.8
- Publication bias likely: Two open-label, 52 and 78-week safety studies with 1,557 and 1,743 patients completed in 2012 and 2013 not fully published9-11 but have been evaluated by the FDA.12
- At least two other IBS-C drugs have been withdrawn due to safety concerns:
- Tegaserod: 5-HT4 antagonist due cardiovascular risk.13
- Alosetron: 5-HT3 antagonist due to ischemic colitis.14
- Linoclotide costs approximately $180 per month or ~$15 per additional BM.
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