Vitamin D Supplementation for COPD: Hype or Hope?
This is Andy Shorr from the Washington Hospital Center with a pulmonary and critical care literature update. I would like to point out a recent article in the Annals of Internal Medicine by Lehouck and colleagues that focused on vitamin D supplementation for the prevention of chronic obstructive pulmonary disease (COPD) exacerbations.

COPD exacerbations remain associated with substantial morbidity and mortality and, therefore, have become a major focus as an endpoint in recent clinical trials. In the past, we have only addressed forced expiratory volume in 1 second (FEV₁) or other markers of lung function. Now we have come to realize that COPD exacerbations have important impacts on quality of life and outcomes for our patients and that they need to be a specific and focused endpoint in clinical trials.

A number of novel therapies focus on this endpoint. Recent trials looked at the use of daily macrolides or daily azithromycin therapy for the prevention of COPD exacerbations. The article [that we are discussing today] focused on vitamin D supplementation as a means of preventing COPD exacerbations. A number of studies have documented that many patients with COPD are vitamin D deficient. Vitamin D has a number of extraskeletal effects (particularly on the immune system) that might play a role pathophysiologically in the evolution of COPD exacerbations.

Some observational data suggest a relationship between vitamin D levels and lung function. Therefore, the authors sought to specifically test the value of vitamin D supplementation for the prevention of COPD exacerbations. They conducted a double-blind, randomized controlled trial with approximately 182 patients who were randomly assigned to either placebo or 100,000 IU of vitamin D given every 4 weeks. On average, patients were followed for over 1.5 years.

The primary endpoint for this trial was time to first COPD exacerbation. I think it's important to understand how the authors defined COPD exacerbation. We don't have a very good, strong, objective definition of COPD exacerbation, so comparing trials becomes challenging. The authors defined a COPD exacerbation as any change in baseline respiratory status that required treatment with either antibiotics or steroids. They did not require hospitalization. The criteria for antibiotic or steroid administration were not objectively defined, and they also looked at the development of at least one of the Anthonisen criteria, which have been used in other COPD exacerbation trials. As a reminder, the criteria are change in sputum purulence, change in dyspnea, and change in the amount of sputum. In the past, we had to meet at least 2 of the 3 criteria for us to call it a substantial COPD exacerbation. The authors of this study only required 1.

Of the 182 patients who were enrolled, most were vitamin D deficient and many had advanced COPD. Most were GOLD stage 3 and a good portion were GOLD stage 4. The average BODE score was about 4 in both groups, and 80% of the patients were on triple inhaled therapy: a LABA, an inhaled corticosteroid, and a LAMA.

For the time to first exacerbation, there was absolutely no difference [between the 2 groups]. For the time to second exacerbation, there was absolutely no difference. For the rate of exacerbations per year, there was absolutely no difference -- about 3 in each arm. This was a negative study. There was no difference in mortality between the 2 arms, and the vitamin D supplementation was very well tolerated. There were no adverse events and the vitamin D levels increased when they were measured serially. Therefore, it wasn't as if the dose was not enough to raise the level of vitamin D.

It is interesting that the authors chose to look at a subgroup of patients with quite severe vitamin D deficiency (ie, levels below 10 ng/mL). In those patients, they saw a difference in the rate of exacerbations favoring vitamin D supplementation. They did not see a difference in time to first or second exacerbation. Remember, time to first exacerbation is the primary endpoint. In a small subgroup of about 30 patients in a post hoc analysis, they saw a difference in the secondary endpoint, so this was purely, at best, hypothesis-generating and not at all supportive of the relationship between vitamin D supplementation and outcome. In the end, this was a negative study.

An accompanying editorial reviewed the trial and said that the trial does not refute the potential benefit of vitamin D supplementation. That is a very odd way to write an editorial because you would think that the burden of proof lies on those who advocate for vitamin D supplementation. The hypothesis needs to be tested, and that hypothesis was not supported by these data. Providing data that fail to support your hypothesis is a weak argument for suggesting that we need to devote lots of resources to understanding this issue.

There is a large, ongoing trial that is looking at this over a longer period of time. It may be that the vitamin D supplementation, which was given every 4 weeks, was not the right way to do it. Maybe it should have been given daily. Maybe they need to enroll different groups of patients in terms of the phenotype for the COPD exacerbation, because we know that some patients have frequent exacerbations regardless of their FEV₁ vs those who don't have frequent exacerbations.

However, in this trial with a moderate-term follow-up in 180 patients -- which in COPD exacerbation studies is not unreasonable -- the weight of the evidence does not suggest a potential benefit. It does not even suggest that you should be giving vitamin D or considering measuring vitamin D levels in patients with COPD. If a patient has an indication for vitamin D supplementation otherwise, that is appropriate.

I think this evidence suggests that there isn't a signal here despite what we would hope for pathophysiologically and despite what has been shown in observational data. It is actually consistent with what we have seen in a number of vitamin supplementation trials where, whether it's vitamin D or otherwise, there really isn't a benefit despite all the potential benefits that people might suggest based on observational data.

Again, the article was recently in the Annals of Internal Medicine. This is Andy Shorr at the Washington Hospital Center.