Normohomocysteinaemia and vitamin‐treated hyperhomocysteinaemia are associated with similar risks of cardiovascular events in patients with premature peripheral arterial occlusive disease. A prospective cohort study

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Abstract
Objectives. Mild hyperhomocysteinaemia (HHC), fasting or after methionine loading, is associated with an increased risk and severity of atherosclerotic vascular disease. Post‐methionine and fasting HHC are responsive to treatment with vitamin B6 and folic acid. We performed a prospective cohort study amongst normohomocysteinaemic and vitamin‐treated (vitamin B6, 250 mg plus folic acid, 5 mg daily) hyperhomocysteinaemic patients with premature peripheral arterial occlusive disease and assessed the incidence of cardiovascular events. Design. We studied 273 consecutive patients with clinically manifest peripheral arterial occlusive disease with onset before the age of 56, 79 (28.9%) of whom had postmethionine HHC. Follow‐up was obtained in 232 (85%) patients. At baseline, 70 (30%) were hyperhomocysteinaemic after methionine loading and started treatment with vitamin B6 and folic acid; 162 (70%) were normohomocysteinaemic (reference group). Results. During the follow‐up period (median 20, range 1–63 months), 48 (29.6%) and 23 (32.9%) of the normo‐ and the hyperhomocysteinaemic patients, respectively, had a new cardiovascular event. Most (75%) involved the peripheral arterial system. The crude incidence rate for any cardiovascular event was 0.16 (95% CI, 0.12–0.21) per person per year in the normohomocysteinaemic and 0.16 (95% CI, 0.09–0.22) per person per year in the hyperhomocysteinaemic group. Multivariate Cox regression analyses showed that higher plasma homocysteine levels were associated with an increased risk of new cardiovascular events in the normohomocysteinaemic patients (relative risk [RR] per 1 µmol L–1, 1.17 [CI, 1.05–1.30] for fasting and 1.06 [CI, 1.01–1.12] for postmethionine levels), but not in the hyperhomocysteinaemic (vitamin‐treated) patients. The adjusted RR for new cardiovascular events in the hyper‐ as compared to the normohomocysteinaemic patients was 0.76 (CI, 0.33–1.74). Conclusions. These data are consistent with a protective effect of treatment with vitamin B6 and folic acid in patients with premature peripheral arterial occlusive disease and postmethionine HHC. Double‐blind randomized trials are necessary to confirm this.