Urate-lowering therapy with allopurinol did not significantly reduce blood pressure among normotensive or mildly hypertensive young adults, despite beneficial effects being seen for endothelial function, a randomized crossover trial found. During a 4-week period of treatment with allopurinol, the 24-hour ambulatory systolic blood pressure declined by 1.39 mm Hg from baseline (P=0.23) and during the 4-week placebo period, the decrease from baseline was 1.06 mm Hg (P=0.33), which represented a nonsignificant between-period difference (P=0.83), according to Angelo L. Gaffo, MD, and colleagues from the University of Alabama at Birmingham. There was, however, a significant improvement in endothelial function estimated by flow-mediated dilation during the allopurinol phase but not during the placebo phase (2.5% vs -0.1%, P<0.001), the researchers reported online in Arthritis & Rheumatology. "Our findings do not support the use of urate-lowering therapy with allopurinol to reduce blood pressure in young adults," they concluded. Besides its clear causative role in gout, serum urate has also been linked with cardiovascular disease and hypertension. It's unclear precisely how urate might influence blood pressure, but possible explanations have included effects on endothelial function and systemic inflammation. Previous studies of urate-lowering therapies for hypertension have had conflicting results, with improvements being observed in trials of children, adolescents, and young adults but not among older adults. "We hypothesized that serum urate lowering would be an effective approach for blood pressure reduction in young adults, before arterial stiffness and plaque are fully developed," Gaffo and colleagues wrote. To explore this possibility and to consider possible mechanisms, the investigators conducted the Serum Urate Reduction to Prevent Hypertension trial, which was a single-center, double-blind crossover trial in which each patient served as his or her own control. The treatment regimen consisted of 300 mg oral allopurinol per day or a matched placebo, with a 2-week washout period before crossover to the other group. Eligible patients had to have systolic blood pressure between 120 and 160 mm Hg or diastolic blood pressure between 80 and 100 mm Hg. A total of 99 patients were enrolled. Their mean age was 28, almost two-thirds were men, and 40% were African American. Body mass index was approximately 31. Baseline mean systolic blood pressure was 127 mm Hg, while diastolic was 81 mm Hg. None of the patients had gout: serum urate levels were 6.4 mg/dL among men and 4.9 mg/dL among women. No changes in diastolic blood pressure or mean arterial pressures were observed during either the allopurinol or placebo phases. Serum urate declined from baseline by 1.33 mg/dL during the active treatment phase (P<0.001) but not during the placebo phase (-0.04 mg/dL). In subgroup analyses, blood pressure decreases were seen during the allopurinol phase among patients who had elevated serum urate at baseline and among those who were ages 28 to 40, but these were not statistically significant and "were of unclear clinical significance," according to the investigators. Small nonsignificant increases in C-reactive protein were observed during the allopurinol phase but no difference was seen during the placebo phase. This suggested that systemic inflammation was unlikely to play a pathophysiologic role. Adverse events included one case of systolic blood pressure rising above 160 mm Hg during the allopurinol phase, two cases of leukopenia in the placebo phase, and one case of elevated liver enzymes during the allopurinol phase. These were considered moderate; all other adverse events such as fatigue, nausea, and itching were mild. As to why these young adults did not show beneficial blood pressure effects, the investigators wrote, "It is possible that adults, even at a young age, quickly lose responsiveness to urate-mediated mechanisms proposed to affect blood pressure, namely effects on the renin-angiotensin system and generation of reactive oxidant species that adversely affect endothelial function." In an accompanying editorial, Edward Roddy, MD, of Keele University in the U.K. and Nicola Dalbeth, MD, of the University of Auckland in New Zealand, noted that the study findings do not support avoidance of allopurinol. "While the collective findings of these trials do not support the use of urate-lowering therapy to lower blood pressure in young to middle-aged adults, clinicians should not be deterred from prescribing urate-lowering therapies such as allopurinol for people with gout where clinically indicated. Treat-to-target urate-lowering therapy remains a highly effective treatment strategy to reduce the substantial pain, disability, and impairment of quality of life experienced by people with gout." Potential limitations of the study, according to the authors, included the use of allopurinol at dosages of only 300 mg per day and the relatively short duration of treatment. Source
