Titrating vitamin D to target after infarction did not reduce events

Design

pragmatic randomised trial, usual care vs algorithm-titrated supplementation, average follow-up 4.2 (SD 2.0) years

Population

630 patients after myocardial infarction, median age 63, 78.1% men, median baseline 25(OH)D 25 ng/mL

Primary outcome

composite of death, myocardial infarction, heart failure hospitalisation and stroke

Effect

15.7% vs 18.4%; HR 0.85 (95% CI 0.58-1.24), P = 0.40

The standing objection to the neutral vitamin D trials has been that they used fixed doses and never confirmed anyone reached a therapeutic level. TARGET-D removed that objection. It randomised 630 patients after myocardial infarction to usual care or an algorithm that titrated vitamin D3 to reach and hold a 25-hydroxyvitamin D level above 40-80 ng/mL, and followed them an average 4.2 years. Baseline levels were low, median 25 ng/mL, with 87% at or below 40; over half started on 5,000 IU daily.

The composite of death, myocardial infarction, heart failure hospitalisation and stroke occurred in 15.7% against 18.4% (HR 0.85, 95% CI 0.58-1.24, P = 0.40). Among secondary endpoints, myocardial infarction alone was 3.8% against 7.9% (HR 0.48, P = 0.03), while death, heart failure hospitalisation and stroke all sat at or above 1.0.

That myocardial infarction result will be quoted, and it should not be. It is one of four secondary endpoints in a trial whose primary endpoint was neutral, with no correction for multiplicity. The honest summary is that correcting the deficiency properly still did not reduce events, which is now the third way of asking this question and getting the same answer.

• Do not start vitamin D after infarction for cardiovascular protection
• Treat documented deficiency for its bone and muscle indications, which are unaffected by this result
• Deficiency remains common in this population — 87% were at or below the target threshold at baseline
• If a patient raises the myocardial infarction subgroup figure, explain why a neutral primary endpoint outranks it

Why it matters

The 'the doses were wrong' defence of vitamin D in cardiovascular prevention has now been tested directly and did not hold.

Don't overread it

The lower rate of myocardial infarction is an unadjusted secondary endpoint in a trial that missed its primary — it is hypothesis-generating at best.

The statistics, in plain English

A hazard ratio of 0.85 with an interval of 0.58 to 1.24 includes 1.0, so no effect is entirely compatible with the data — and so is a 42% reduction, which is why the trial is uninformative rather than reassuring at this size. The myocardial infarction finding (HR 0.48, P = 0.03) is a secondary endpoint among four; with no multiplicity adjustment, one nominally significant result out of four is what chance alone produces reasonably often.

Read the rest in the app

You have read your two free briefings this month. The app carries all 27 specialties, every morning, free — and this finding is waiting in it.

Get Daily Doctor — free

Scan to keep reading on your phone. No account needed to start.