Thalidomide may reverse ventricular remodeling, raise LVEF in HF

Thalidomide therapy appears to help prevent some of the myocardial changes that promote ventricular remodeling in patients with heart failure, according to a small but randomized, double-blind, placebo-controlled study The drug’s observed effects on remodeling, which included improved end-diastolic volumes and LVEF, were associated with suppression of matrix-degrading enzymes, write investigators in the November 29, 2005 issue of Circulation.

The study, from Dr Lars Gullestad (Rikshospitalet, Oslo, Norway) and associates, also challenged perceptions about some of thalidomide’s mechanisms of action. The drug’s reputation as an anti-inflammatory agent comes largely from observed suppression of tumor necrosis factor-alpha (TNF-) in laboratory and animal studies, according to the authors. But their data suggest that thalidomide actually increases levels of TNF-.The group randomized 56 clinically stable patients with HF who were on optimal standard medical therapy to receive either thalidomide, titrated to a target of 200 mg/day, or placebo. Among the 48 patients who completed the 12-week study, significant relative LVEF increases and reductions in left-ventricular end-diastolic volume (LVEDV) among those who were actively treated were accompanied by “a decrease in matrix metalloproteinase-2 without any changes in its endogenous tissue inhibitor, suggesting a matrix-stabilizing effect,” the authors write. The group also observed the following: – Thalidomide therapy appeared to reduce neutrophil counts, upregulate interleukin (IL)-8, and downregulate IL-10, which along with the climb in TNF- levels suggests the drug has both proinflammatory and anti-inflammatory effects, the authors write. – The handful of patients with nonischemic HF as compared with those with CAD were able to tolerate the drug at higher dosages and showed more pronounced LVEF increases. Overall, patients who could take thalidomide at higher levels showed greater changes in laboratory parameters. – Significantly more actively treated patients experienced adverse events or side effects (89% vs 57% for placebo, p<0.05), which included bradycardia, vertigo, and constipation. - The six patients with the greatest thalidomide-associated LVEF gains were followed off-drug for one year, by which time both LVEF and LVEDV had reverted to baseline levels or worse. Although the study is small and should be followed by more definitive ones to clarify the drug's safety and clinical efficacy, according to the authors, "these findings may suggest a role for thalidomide in the management of HF in addition to traditional cardiovascular medications."(Source: (1) Gullestad L, Ueland T, Fjeld JG, et al. Effect of thalidomide on cardiac remodeling in chronic heart failure. Results of a double-blind, placebo-controlled study. Circulation 2005; 112:3408-3414. PubMed: The Heart: December 2005.)