Response to Letter by Obeid and Herrmann
We appreciate the interest and kind letter from Drs Obeid and Herrmann. They suggested that both hypercholesterolemia and hyperhomocysteinemia can synergistically accelerate atherosclerosis; therefore, treating both at the same time may enhance stroke prevention.
Effective strategies in stroke prevention include antithrombotic, lipid-lowering and antihypertensive therapy. The analysis of stroke outcomes in HOPE 2 suggests a 25% relative risk reduction with homocysteine-lowering therapy. This benefit remained on adjusting for concomitant medication-use at study entry, including antithrombotics, lipid-lowering treatment antihypertensives (hazard ratio 0.71; 95% CI, 0.56 to 0.91).1 Nonetheless, care is needed when interpreting the results of subgroup analyses, such as participants with elevated cholesterol, but not on lipid-lowering or antithrombotic therapy. HOPE 2 was not powered to detect a difference between these subgroups, and the probability value for interaction testing was not significant.1,2
Unfortunately, the results of randomized clinical trials of homocysteine-lowering therapy in vascular prevention tell us a “consistent inconsistency” story. What does it mean? The negative results of cardiovascular outcomes for homocysteine-lowering therapy was consistent throughout almost all randomized trials (HOPE 2, NORVIT, WAFACS and the unpublished results of SEARCH).2–4 The inconsistency refers to the possible differential effect when comparing cardiovascular and stroke outcomes.1,5
The results of HOPE 2 might be promising by adding another intervention (with a modest, but perhaps significant effect) for primary and secondary stroke prevention. Moreover, if proven effective homocysteine-lowering therapy is considered to be safe and inexpensive.
We believe that further studies using the appropriate dose of folic acid and B vitamin supplements are necessary to confirm the efficacy in reducing stroke risk and determine which patient subsets are most likely to achieve the greatest benefit from this treatment.
Saposnik G, Ray JG, Sheridan P, McQueen M, Lonn E. Homocysteine-lowering therapy and stroke risk, severity, and disability: additional findings from the hope 2 trial. Stroke. 2009; 40: 1365–1372.
Lonn E, Held C, Arnold JM, Probstfield J, McQueen M, Micks M, Pogue J, Sheridan P, Bosch J, Genest J, Yusuf S. Rationale, design and baseline characteristics of a large, simple, randomized trial of combined folic acid and vitamins B6 and B12 in high-risk patients: The Heart Outcomes Prevention Evaluation (HOPE)-2 trial. Can J Cardiol. 2006; 22: 47–53.
Albert CM, Cook NR, Gaziano JM, Zaharris E, MacFadyen J, Danielson E, Buring JE, Manson JE. Effect of folic acid and B vitamins on risk of cardiovascular events and total mortality among women at high risk for cardiovascular disease: A randomized trial. JAMA. 2008; 299: 2027–2036.