CLEAN: intravenous nicorandil does not improve outcomes after primary PCI

Design

multicentre, randomised, double-blind, placebo-controlled trial at 49 hospitals in China

Population

1,503 patients aged 18–80 with STEMI within 12 hours of symptom onset undergoing primary PCI

Primary outcome

12-month composite of cardiovascular death, non-fatal MI, target-vessel revascularisation or unplanned heart failure hospitalisation

Effect

13.1% vs 13.1%; rate ratio 0.869 (95% CI 0.650–1.162), p=0.34

Microvascular obstruction persists in a large minority of STEMI patients after successful epicardial reperfusion, and nicorandil — an ATP-sensitive potassium channel opener with nitrate-like properties — has long been proposed as a way to limit it. CLEAN tested that properly: 1,503 patients at 49 hospitals in China, randomised double-blind to a 6 mg nicorandil bolus before reperfusion followed by 6 mg/h for 48 hours, or matching placebo, with oral nicorandil prohibited afterwards.

The 12-month composite of cardiovascular death, non-fatal myocardial infarction, target-vessel revascularisation or unplanned heart failure admission occurred in 13.1% of both arms (rate ratio 0.869, 95% CI 0.650–1.162, p=0.34). Adverse events did not differ.

The secondary outcomes will be quoted selectively, so handle them carefully. Cardiovascular death was 1.9% versus 3.6% (HR 0.515) and target-vessel revascularisation 1.1% versus 3.0% (HR 0.322). Both are nominal, in a trial whose primary endpoint was neutral, with no multiplicity adjustment. They are hypothesis-generating at best, and in a negative trial that phrase means what it says.

• Do not add intravenous nicorandil to the primary PCI pathway on the strength of this trial.
• The composite was driven by revascularisation and heart failure admission as much as by death — check which component any quoted benefit refers to.
• Nicorandil is available in India and widely used orally for angina; that use is unaffected by this trial, which studied intravenous peri-procedural administration.
• Microvascular obstruction remains without a proven pharmacological treatment — the gap this trial tried to fill is still open.

Why it matters

Another cardioprotective agent joins the long list that improved surrogate markers and changed nothing a patient experiences.

Don't overread it

The lower cardiovascular death rate is a nominal secondary finding in a trial that missed its primary endpoint — it does not establish a mortality benefit.

The statistics, in plain English

The primary confidence interval, 0.650 to 1.162, includes 1.0 and so is compatible with no effect, but it is also compatible with a 35% reduction — the trial was not large enough to rule out a real benefit, only large enough to fail to find one. The secondary reductions come from small numbers of events (1.9% versus 3.6% death) and, because the primary endpoint failed, carry no formal statistical protection. In a neutral trial, significant-looking secondary results are exactly what chance produces when you test enough of them.

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