Homocysteine lowering therapy and stroke risk

Original HOPE study (1):

• designed to investigate the effects of taking an ACE inhibitor ramipril and/or vitamin E for at least 4 years, on a wide range of vascular endpoints
  
  
• total of 9541 patients (men and women) older than 55 years took part in study
  
  
• patients were included if they were at high risk of cardiovascular events due to history of diabetes, previous ischaemic heart disease, peripheral vascular disease or stroke
  
  
• treatment benefits of ramipril were seen across all patient groups - these benefits occurred within 3 to 4 months of starting treatment with ramipril
  
  
• results revealed that the combined reduction in myocardial infarction, cardiovascular death and stroke at 5 years was 22 % in the ramipril treatment group; there was a 17% reduction in all cause mortality in the ramipril treatment group; no effect on stated endpoints occurred with patients treated with vitamin E
  
  
• the study investigators do not attribute treatment benefits accrued with ramipril to be because of an impact on blood pressure - the baseline blood pressure had a mean level of 139/79 mmHg - by the end of the trial there had only been a small further decline

HOPE follow-up study (2):

• a follow-up study based on the HOPE study population has been undertaken
  • 4,528 patients agreed to further follow-up (median follow-up period 2.6 years)
    • rates of use of angiotensin-converting-enzyme inhibitors (ACEIs) in the 2 groups (72% ramipril versus 68% placebo) were similar after the end of the trial
    • during the post-trial follow-up, patients allocated to ramipril had a 19% further lower relative risk (RR) of myocardial infarction (MI), a 16% lower RR of revascularization, and a 34% lower RR of a new diagnosis of diabetes
      • RR reductions in vascular events were observed during and after the active phase of the trial, regardless of baseline risk (RR of 0.76, 0.89, and 0.83 for low-, medium-, and high-risk patients, respectively) or ancillary treatments (RR of 0.90 for aspirin, 0.76 for beta-blockers, and 0.84 for lipid-lowering medication)
  • the study authors noted that the benefits of ramipril observed during the active period of the HOPE trial were maintained during post-trial follow-up for cardiovascular death, stroke, and hospitalisation for heart failure
    • additional reductions in MI, revascularization, and the development of diabetes were observed during the follow-up phase despite similar rates ACEI use in the 2 randomized groups
    • benefits associated with ACEI use were consistent regardless of patient risk or ancillary treatments
    • the benefits observed in the study extension data indicate that the 4.5 years of initial, "earlier" use of ramipril therapy provided a longer-term protective effect compared with later initiation
    • during the follow-up period, there was not observed an additional treatment effect for stroke
      • blood pressure was similar during the post-trial follow-up and suggests that an important mechanism by which strokes may have been reduced during the blinded part of the study (where there was a modest difference in blood pressure of 3/2 mm Hg) was blood pressure lowering
    • the study authors concluded that ACE inhibitor therapy should be used in most patients with vascular disease or diabetes and additional CV risk factors

Vitamin E in the prevention of cardiovascular disease:

• study evidence (1,3) has provided no evidence of benefit of vitamin E supplementation in the prevention of the development cardiovascular disease

Vitamin C supplementation in the prevention of cardiovascular disease:

• in a large, long-term trial of male physicians, neither vitamin E nor vitamin C supplementation reduced the risk of major cardiovascular events (3)

Homocysteine lowering therapy and stroke risk (4)

• HOPE 2 investigators have analyzed stroke outcomes among participants of the HOPE 2 trial that randomized 5522 adults with known cardiovascular disease to a daily combination of 2.5 mg of folic acid, 50 mg of vitamin B6, and 1 mg of vitamin B12, or matching placebo, for 5 years
  • among 5522 participants, stroke occurred in 258 (4.7%) individuals during a mean of 5 years of follow-up. The geometric mean homocysteine concentration decreased by 2.2 micromol/L in the vitamin therapy group and increased by 0.80 micromol/L in the placebo group
  • the incidence rate of stroke was 0.88 per 100 person-years in the vitamin therapy group and 1.15 per 100 person-years in the placebo group - the hazard ratio [HR], 0.75; 95% (CI, 0.59-0.97) was significant
  • vitamin therapy also significantly reduced the risk of nonfatal stroke (HR, 0.72; 95% CI, 0.54-0.95) but did not impact on neurological deficit at 24 hours (P=0.45) or functional dependence at discharge or at 7 days (OR, 0.95; 95% CI, 0.57-1.56)
  • this study data suggests that homocysteine lowering therapy may have a role in lowering stroke risk
  • a meta-analysis has suggested that folic acid reduces risk of stroke (5)

Reference:

• 1. New England Journal of Medicine 2000; 342: 145-53.
• 2. Bosch J et al. Long-term effects of ramipril on cardiovascular events and on diabetes: results of the HOPE study extension.Circulation. 2005 Aug 30;112(9):1339-4
• 3. Sesso HD et al.Vitamins E and C in the prevention of cardiovascular disease in men: the Physicians' Health Study II randomized controlled trial. JAMA. 2008 Nov 12;300(18):2123-33.
• 4. Saposnik G et al.; Heart Outcomes Prevention Evaluation 2 Investigators. Homocysteine-lowering therapy and stroke risk, severity, and disability: additional findings from the HOPE 2 trialStroke. 2009 Apr;40(4):1365-72.
• 5) Wang X et al.Efficacy of folic acid supplementation in stroke prevention: a meta-analysis.Lancet. 2007 ;369:1876-82.