The Journal of Informed Pharmacotherapy 2003;12:200.
Reviewer: Peter Loewen, PharmD
Reviewer’s e-mail address: email@example.com
Reviewer's profession/specialty: Pharmacotherapeutic Specialist - Internal Medicine
Schnyder G, Roffi M, Flammer Y, Pin R, Hess OM. Effect of homocysteine-lowering therapy with folic acid, vitamin B12, and vitamin B6 on clinical outcome after percutaneous coronary intervention: the Swiss Heart study: a randomized controlled trial. JAMA 2002;288:973-979 PubMed Citation
The objective of this study was to confirm that the benefits of 6 months of homocysteine-lowering therapy following percutaneous coronary intervention (PCI) were persistent at 1 year following the procedure. (1) The sample included 553 Swiss patients who underwent successful coronary angioplasty of at least one significant coronary stenosis and had normal baseline serum homocysteine levels (mean 11.2 µmol/L). Patients had a typical range of cardiovascular risk factors and most were concurrently treated with standard secondary preventative therapies (i.e. ASA, a beta-blocker, a lipid-lowering agent, clopidogrel/ticlopidine and an ACE inhibitor). Patients were randomized to receive oral therapy consisting of a combination of folic acid (1 mg/d) plus vitamin B12 (400 mcg/d) plus vitamin B6 (10 mg/d), or placebo in double-blind fashion for 6 months. The primary outcome variable was a composite of death, myocardial infarction (MI), or repeat revascularization at 1 year.
1. Was assignment of patients randomized?
2. Were all patients who entered the trial properly accounted for and attributed at its conclusion?
All patients were accounted for. Eighty-seven percent of randomized patients completed the study, but all randomized patients were included in the primary analysis, according to the intention-to-treat principle.
1. How large was the treatment effect?
All outcomes were assessed at 1 year. After a mean follow up of 11 (SD 3) months, the composite primary endpoint was reached in 15.4% vs. 22.8% of patients, favouring vitamin therapy (RRR 32%, ARR 7.4%, NNT (for 12 months) 14, p=0.03). Death occurred in 1.5% study drug recipients vs. 2.8% of those patients receiving placebo (95% CI 0.16-1.70, p=0.27). Nonfatal MI: 2.6% vs. 4.3% (95% CI 0.24-1.51, p=0.27). Repeat target lesion revascularization: 9.9% vs. 16.0% favouring vitamin therapy (RR 0.62; 95%CI 0.40-0.97; p=0.03).
2. How precise was the estimate of the treatment effect?
The 95% CI around the primary endpoint RR of 0.68 are (0.48 - 0.96). The 95% CI around the primary endpoint ARR of 7.4% are (0.82 - 13.9). This translates to a 95%CI around the NNT of (8 - 123).
2. Were all clinically important outcomes considered?
Yes. The outcomes evaluated in this trial are certainly the most important endpoints of interest in patients with CAD. It is worth noting that the mean homocysteine level assessed at 6 months was lower in the treated group than in the placebo group (7.5 vs. 10.1 µmol/L), lending support to the hypothesis that homocysteine mediated the difference in clinical endpoints seen.
Yes. The only adverse event reported was pruritis (2 cases) and these occurred in group receiving the vitamin preparations. Thus, there appears to virtually no toxicity with the vitamin regimen. The regimen is also very inexpensive, relative to other drugs used for secondary prevention. Thus, it appears that the benefits, the magnitude of which exceed that of other drug therapies, vastly outweigh the harms and costs.
The importance of homocysteine in producing the full spectrum of vascular dysfunction (deep vein thrombosis, stroke, MI, peripheral embolism) has been suggested by a multitude of epidemiologic studies over the past decade. The efficacy of folate alone or in combination with vitamins B6 and B12 is also extremely well documented. This paper describes the results of one the first prospective trials aimed at validating the "homocysteine hypothesis" that homocysteine is a causative agent in vasculopathy and that lowering it produces clinical benefits. This trial appears to support the hypothesis. It is important to note that it does not, however, prove that changes in homocysteine alone are responsible for this clinical benefit since folate therapy could achieve its beneficial effects through an independent mechanism and homocysteine may, in fact, only be an "innocent bystander". From a clinicians viewpoint, this is somewhat irrelevant. Folate plus B6 plus B12 following PCI substantially reduces the chances mainly of repeat revascularization of the initial lesion with minimal toxicity and cost.
In practice, restricting vitamin therapy to hyperhomocysteinemic patients may not be necessary since the patients enrolled in this trial had mean levels considered within the "normal range" and were selected without regard to their actual baseline level. It is possible that the "target level" of serum homocysteine while on treatment will also be adjusted downward on the basis of this trial and its successors.
Numerous trials in other populations aimed at further exploring the benefits of homocysteine lowering are ongoing and are expected to clarify this issue further (e.g. HOPE-TOO, VISP, NORVIT, WENBIT, PACIFIC, SEARCH trials) . In the meantime, it appears advisable to implement this safe, inexpensive therapy for at least 6 months following PCI.
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