Vitamin D after myocardial infarction fails even when the target is reached

Design

pragmatic randomised trial, targeted titration versus usual care, average follow-up 4.2 +/- 2.0 years (TARGET-D)

Population

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

Primary outcome

major adverse cardiovascular events: death, myocardial infarction, heart-failure hospitalisation or stroke

Effect

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

The standing defence of vitamin D in cardiovascular prevention has been that the negative trials used fixed doses and never confirmed that anyone reached a sufficient level. TARGET-D removed that defence. It randomised 630 patients after myocardial infarction to usual care or vitamin D3 with ongoing titration by algorithm to reach and hold a 25-hydroxyvitamin D level above 40 ng/mL, and followed them for an average of 4.2 years. Baseline levels were low, median 25 ng/mL, with 87% at or below 40, and over half started at 5000 IU daily.

Major adverse cardiovascular events, a composite of death, myocardial infarction, heart-failure hospitalisation and stroke, occurred in 15.7% on vitamin D and 18.4% on usual care: hazard ratio 0.85 (95% CI 0.58 to 1.24), P=0.40. Death was identical, 8.9% against 9.2%. Heart-failure hospitalisation and stroke were numerically higher on vitamin D.

One secondary endpoint was positive: myocardial infarction, 3.8% against 7.9%, hazard ratio 0.48, P=0.03. It is a single secondary outcome among several, in a trial whose primary endpoint was null and which was sized to accrue only 104 primary events. Treat it as a finding to be tested, not as a result.

In practice this closes a conversation rather than opening one. Correcting vitamin D deficiency remains reasonable for bone and muscle reasons where deficiency is documented, which in Indian practice is common. It is not a cardiovascular intervention, and a patient after myocardial infarction who asks about vitamin D should be told that titrating it to a target did not reduce cardiovascular events.

• Do not prescribe vitamin D after myocardial infarction with a cardiovascular benefit in mind
• Treat documented deficiency on its own merits, for bone and muscle, and say so plainly to the patient
• Stop ordering 25-hydroxyvitamin D as part of a cardiovascular risk panel
• When quoting the reduction in myocardial infarction, name it as one secondary endpoint in a trial whose primary endpoint was null
• Redirect the consultation to what does change outcomes after infarction: lipid lowering, blood pressure, antiplatelet therapy, smoking and cardiac rehabilitation

The statistics, in plain English

The confidence interval, 0.58 to 1.24, spans a plausible 42% reduction and a plausible 24% increase, so the honest conclusion is that this trial could not tell benefit from harm rather than that it proved no effect. With only 104 primary events it was small for a cardiovascular outcome trial, which widens that interval. The apparent halving of myocardial infarction is exactly the kind of result that turns up by chance when several secondary endpoints are tested: with four secondary outcomes, one reaching P=0.03 is unremarkable, and it did not translate into fewer deaths.

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