TOPPICCD · Surgery
Mercaptopurine versus placebo to prevent recurrence of Crohn's disease after surgical resection (TOPPIC): a multicentre, double-blind, randomised controlled trial
Mowat C, et al.
Lancet Gastroenterol Hepatol 2016 · PMID 28404197 (PubMed, opens in a new tab) · doi 10.1016/S2468-1253(16)30078-4 (full paper, opens in a new tab)
| Outcome | Mercaptopurine | Placebo | Estimate (confidence interval) | P |
|---|---|---|---|---|
| All patients, Primary analysis, adjusted (primary) | 16/128 (13%) | 26/112 (23%) | 0.54 (95% CI 0.27–1.06) | P=0.07 |
| All patients, Unadjusted | 0.53 (95% CI 0.28–0.99) | P=0.046 | ||
| Smokers, Subgroup | 3/29 (10%) | 12/26 (46%) | 0.13 (95% CI 0.04–0.46) | |
| Non-smokers, Subgroup | 13/99 (13%) | 14/86 (16%) | 0.90 (95% CI 0.42–1.94) |
The adjusted primary analysis crossed 1; the clear benefit sat in smokers, a subgroup result.
Source: Mowat 2016, abstract. Smoking was a planned subgroup analysis (interaction P=0.018).
Structured abstract
BackgroundPostoperative recurrence of Crohn's disease is common, and whether mercaptopurine prevents or delays clinical recurrence after resection was uncertain.
MethodsMulticentre, double-blind, placebo-controlled randomised trial (29 UK hospitals); 3-year follow-up. 240 patients. Primary endpoint: Clinical recurrence (CDAI above 150 with a rise of 100 points) needing anti-inflammatory rescue treatment or surgery.
ResultsPrimary result. 13% (16/128) with mercaptopurine vs 23% (26/112) with placebo; adjusted HR 0.54 (95% CI 0.27–1.06; P=0.07); unadjusted HR 0.53 (0.28–0.99; P=0.046).
Take-homePostoperative mercaptopurine did not clearly prevent clinical recurrence overall; the benefit was confined to smokers, and stopping smoking matters more.
| Patients | 240 |
|---|---|
| Population | Adults with Crohn's disease after intestinal resection (aged over 16 in Scotland, over 18 in England and Wales). |
| Comparison | Mercaptopurine 1 mg/kg daily, rounded to the nearest 25 mg (half dose if TPMT activity low; n=128) vs placebo (n=112) |
| Drugs | mercaptopurine |
| Classes | Thiopurine |
| Published | Mowat C, et al. Lancet Gastroenterol Hepatol 2016;1:273–82. |
Key points
- Smokers: recurrence 10% (3/29) with mercaptopurine vs 46% (12/26) with placebo; HR 0.13 (95% CI 0.04–0.46).
- Non-smokers: 13% (13/99) vs 16% (14/86); HR 0.90 (0.42–1.94). Interaction with smoking P=0.018.
- No significant effect in other planned subgroups (previous thiopurine, infliximab or methotrexate, previous surgery, disease duration, age at diagnosis).
- Adverse events led to stopping treatment in 30% (39/128) on mercaptopurine and 37% (41/112) on placebo.
Limitations
- Primary analysis (adjusted) did not reach significance.
- Clinical, not endoscopic, primary endpoint; no scheduled colonoscopy-guided step-up.
- The smoking result is a subgroup finding.
Commentary
TOPPIC is the largest placebo-controlled trial of a thiopurine after resection for Crohn’s disease. It is a useful counterweight to the idea that every patient needs a thiopurine after surgery: overall benefit was marginal, with a clear effect only in people who kept smoking.
Today postoperative care follows the POCER model: stratify risk, give prophylaxis to high-risk patients (anti-TNF therapy as in PREVENT, or vedolizumab as in REPREVIO), and perform ileocolonoscopy 6 to 12 months after surgery. Smoking raised recurrence in both POCER and TOPPIC; support cessation at every visit.
Journal club
Design
Multicentre, double-blind, placebo-controlled randomised trial (29 UK hospitals); 3-year follow-up. 240 patients.
Primary result. 13% (16/128) with mercaptopurine vs 23% (26/112) with placebo; adjusted HR 0.54 (95% CI 0.27–1.06; P=0.07); unadjusted HR 0.53 (0.28–0.99; P=0.046).
Validity and applicability
- Primary analysis (adjusted) did not reach significance.
- Clinical, not endoscopic, primary endpoint; no scheduled colonoscopy-guided step-up.
- The smoking result is a subgroup finding.
Where it sits now
Postoperative mercaptopurine did not clearly prevent clinical recurrence overall; the benefit was confined to smokers, and stopping smoking matters more.
- POCER (2015): After resection, treating by risk and scoping at 6 months with step-up for recurrence beats drug prophylaxis alone; this is why we do a postoperative colonoscopy.
- PREVENT (2016): In patients at increased risk, postoperative infliximab roughly halves endoscopic recurrence but did not significantly reduce clinical recurrence by week 76, so endoscopic monitoring is still needed.
- REPREVIO (2025): Starting vedolizumab within 4 weeks of ileocolonic resection reduces early endoscopic recurrence in patients at risk.
- SPICY (2024): Removing more mesentery at primary ileocolic resection did not reduce 6-month endoscopic recurrence, and leaks were numerically more common.
Questions for discussion
- The adjusted primary analysis missed significance (P=0.07) while the unadjusted analysis reached it (P=0.046). Which should you believe, and why?
- The benefit was confined to smokers. What makes a subgroup finding credible enough to change practice?
- After POCER, where does a thiopurine fit in postoperative care today?