Clinical Briefs

With Comments from Russell H. Greenfield, MD

Antibiotics for Cardiovascular Disease Prevention?

Source: Brown DL, et al. Clinical and biochemical results of the metalloproteinase inhibition with subantimicrobial doses of doxycycline to prevent acute coronary syndromes (MIDAS) pilot trial. Arterioscler Thromb Vasc Biol 2004;24:733-738.

Goal: To determine whether low-dose doxycycline reduces vascular inflammation, matrix metalloproteinase (MMP) activity, and improves short-term clinical outcome.

Design: Prospective, randomized, double-blind, placebo-controlled pilot trial.

Subjects: Fifty patients admitted to a single center with symptomatic coronary artery disease, 24 randomized to placebo and 26 to subantimicrobial doses of doxycycline (SDD).

Methods: Patients randomized to receive SDD took 20 mg doxycycline orally twice daily for six months. Subjects were interviewed or examined at three months, then contacted at the end of six months regarding clinical events. Clinical endpoint was a composite of sudden death, fatal or nonfatal myocardial infarction, or troponin-positive unstable angina. Markers of inflammation, including CRP and various interleukins, were measured at study entry and completion for a subset of patients willing to return for phlebotomy.

Results: At six months, high-sensitivity CRP was reduced by 47% in the SDD group as compared to the placebo group, where there was little change from pretreatment values. Plasma levels of MMPs did not differ pre- and post-trial, but zymographic (in vitro) assessment of MMP activity revealed a 38% decrease from baseline values in the SDD group (no change noted in the placebo group), and a 55% reduction after six months of treatment as compared with placebo. Clinical endpoints were rare, and the composite endpoint did not differ significantly between groups.

Conclusion: Treatment with SDD in subjects with established coronary artery disease lessens markers of inflammation, and so may help stabilize atherosclerotic plaque.

Study strengths: Eager to avoid confounding factors such as the treatment of Chlamydia pneumoniae, the researchers used a subantimicrobial dose; no subject was lost to clinical follow-up.

Study weaknesses: Twenty out of the 50 subjects randomized did not return for biochemical analysis at the end of the trial; no assessment made of compliance with regimen; use of additional medication was at the discretion of the attending physician and could conceivably have included other anti-inflammatory agents; the authors readily point out that their study was inadequately powered to detect differences in clinical outcomes associated with SDD therapy.

Of note: A total of 230 people were screened, but only 50 were randomized to participate in the trial (all of whom underwent angiography, and most of whom underwent angioplasty); IL-6 levels also were reduced compared with pretreatment levels in the SDD group, but levels were not significantly different between the two groups at trial’s end; there were two clinical events in the SDD group and none in the placebo group; subantimicrobial doses of doxycycline can enter arterial walls and inhibit cytokine and protease mediators of inflammation, and directly inhibit MMP.

We knew that: Vulnerable atherosclerotic plaque shows signs of significant inflammation, including the buildup of macrophages that are capable of secreting MMPs that degrade collagenous components of the fibrous cap, leading to rupture and thrombosis; increased levels of MMP-9 have been correlated with plaque rupture; recent trials suggest that treatment against C. pneumoniae does not reduce the incidence of coronary events; doxycycline has been shown to lessen expansion of abdominal aortic aneurysms.

Clinical import: While many have considered participation of pathogens in the development and progression of coronary artery disease, in this intriguing study the authors explore the use of subantimicrobial doses of a widely available, affordable medication (doxycycline) to lessen vascular inflammation. Why discuss this paper in Alternative Medicine Alert? Because the implications are enormous. What if the same study were performed using an anti-inflammatory diet instead of an antibiotic? Is there cause to administer probiotic therapy along with SDD? Could herbal anti-inflammatory agents offer similar biochemical results? And with much of the excitement having died down about microbes potentially contributing to ischemic heart disease, would it not be remarkable if an antibiotic proved beneficial in preventing acute coronary events? Alas, this pilot trial does not answer that question, but it does inspire the larger trials to come that will focus primarily on clinical outcome.

What to do with this article: Keep a copy on your computer.