Folate Therapy and In-Stent Restenosis after Coronary Stenting
Helmut Lange, M.D., Harry Suryapranata, M.D., Giuseppe De Luca, M.D., Caspar Börner, M.D., Joep Dille, B.Sc., Klaus Kallmayer, M.D., M. Noor Pasalary, M.D., Eberhard Scherer, M.D., and Jan-Henk E. Dambrink, M.D.
Background Vitamin therapy to lower homocysteine levels hasrecently been recommended for the prevention of restenosis aftercoronary angioplasty. We tested the effect of a combinationof folic acid, vitamin B6, and vitamin B12 (referred to as folatetherapy) on the risk of angiographic restenosis after coronary-stentplacement in a double-blind, multicenter trial.
Methods A total of 636 patients who had undergone successfulcoronary stenting were randomly assigned to receive 1 mg offolic acid, 5 mg of vitamin B6, and 1 mg of vitamin B12 intravenously,followed by daily oral doses of 1.2 mg of folic acid, 48 mgof vitamin B6, and 60 µg of vitamin B12 for six months,or to receive placebo. The angiographic end points (minimalluminal diameter, late loss, and restenosis rate) were assessedat six months by means of quantitative coronary angiography.
Results At follow-up, the mean (±SD) minimal luminaldiameter was significantly smaller in the folate group thanin the placebo group (1.59±0.62 mm vs. 1.74±0.64mm, P=0.008), and the extent of late luminal loss was greater(0.90±0.55 mm vs. 0.76±0.58 mm, P=0.004). Therestenosis rate was higher in the folate group than in the placebogroup (34.5 percent vs. 26.5 percent, P=0.05), and a higherpercentage of patients in the folate group required repeatedtarget-vessel revascularization (15.8 percent vs. 10.6 percent,P=0.05). Folate therapy had adverse effects on the risk of restenosisin all subgroups except for women, patients with diabetes, andpatients with markedly elevated homocysteine levels (15 µmolper liter or more) at baseline.
Conclusions Contrary to previous findings, the administrationof folate, vitamin B6, and vitamin B12 after coronary stentingmay increase the risk of in-stent restenosis and the need fortarget-vessel revascularization.
Homocysteine is believed to be a risk factor for coronary arterydisease.1,2 Folate supplementation is a cost-effective way totreat hyperhomocysteinemia.3,4 Studies in animals have shownthat homocysteine levels are related to the risk of restenosisafter carotid angioplasty,5,6 because high levels promote thrombogenicity7,8and neointimal proliferation.9 In rats, folate supplementationlowered homocysteine levels and inhibited neointimal hyperplasiaafter carotid endarterectomy.10 In humans, data regarding homocysteinelevels and the risk of restenosis after coronary angioplastyhave been conflicting.11,12,13,14,15,16,17,18 The recent findingthat the rate of restenosis was significantly reduced aftercoronary angioplasty among patients who received folate in combinationwith vitamins B6 and B12 (referred to as folate therapy)19 hasled some interventionalists to adopt the use of folate therapyafter coronary interventions. However, in that trial, folatetreatment seemed to be more effective after balloon angioplastythan after coronary stenting; the latter is now the method ofchoice for the vast majority of patients undergoing coronaryintervention. We therefore evaluated the efficacy of vitamintherapy for the prevention of restenosis in patients undergoingcoronary stenting.
Methods
Study Design
This double-blind, placebo-controlled, randomized trial, conductedin Germany and the Netherlands, was approved by the local ethicscommittees in each country, and written informed consent wasobtained from all patients. Between November 1998 and September2000, 636 patients who had undergone successful coronary stentingwere enrolled at two centers (446 in Bremen, Germany, and 190in Zwolle, the Netherlands). Exclusion criteria were in-stentrestenosis, significant left-main-artery stenosis and bifurcationlesions, myocardial infarction less than 24 hours before enrollment,renal dysfunction (defined by a serum creatinine level of morethan 1.3 mg per deciliter [115 µmol per liter]), and currentintake of vitamins. Patients were assigned to receive folatetherapy — an intravenous bolus injection of 1 mg of folicacid, 5 mg of vitamin B6, and 1 mg of vitamin B12, followedby daily oral administration of 1.2 mg of folic acid, 48 mgof vitamin B6, and 60 µg of vitamin B12 — or placebo.Study medication was provided at no charge by Medice. Plasmalevels of homocysteine were measured at baseline and at sixmonths in all patients after an overnight fast. Samples wereanalyzed by high-performance liquid chromatography. Patientswere followed by monthly telephone contact and were questionedabout adherence to the study regimen. Eighty patients agreedto return for laboratory follow-up at one month. All patientswere asked to return after six months for angiographic follow-up.If clinically indicated, follow-up angiography was performedearlier. Patients who underwent early follow-up angiography(within four months after the initial procedure) were askedto undergo the scheduled follow-up angiography after six monthsas well, if no restenosis was found. All investigators agreedto perform repeated target-lesion revascularization accordingto the following prespecified guidelines: if the degree of stenosiswas between 75 percent and 90 percent, the lesion was redilatedonly if clinically significant signs or symptoms of ischemiawere present, and if the degree of stenosis exceeded 90 percent,redilation was always encouraged. Adherence to the study medicationwas confirmed by a pill count at follow-up. The trial was coordinatedby Diagram (Zwolle, the Netherlands).
Coronary-Stent Placement
Coronary stents were placed according to standard techniques.Only bare-metal stents were used, and the choice of stent wasleft to the operator. All patients received 300 mg of clopidogrelorally immediately after the procedure, followed by 75 mg dailyfor four weeks, and 100 mg of aspirin daily. Procedural successwas defined as residual stenosis of less than 20 percent inthe absence of closure during the first 48 hours after the procedure.20
Quantitative Coronary Angiography
Coronary angiograms were obtained at baseline, immediately afterstenting, and at follow-up; two identical orthogonal views wereobtained after the intracoronary administration of nitratesand stored on digital CD-ROM. End-diastolic frames were chosenfor quantitative analysis, which was performed in a blindedfashion by an independent core laboratory (Diagram). The referencediameter, minimal luminal diameter, degree of stenosis, andlesion length were calculated as the average value of the twoorthogonal views. The same views and calibration were used atfollow-up angiography. Restenosis was defined as stenosis ofmore than 50 percent of the luminal diameter. Late luminal losswas defined as the difference between the minimal luminal diameterimmediately after the procedure and that at follow-up. Acutegain was defined as the difference between the minimal luminaldiameter before the procedure and that immediately after theprocedure. The loss index was calculated as late loss dividedby acute gain. The target lesion was defined as the segmentcovered by the stent plus the 5-mm segments adjacent to theproximal and distal edges of the stent.
End Points
The primary angiographic end point was the minimal luminal diameterwithin the target lesion at follow-up. Secondary end pointswere late luminal loss and restenosis. Primary clinical endpoints were events related to restenosis: death from cardiaccauses, target-vessel myocardial infarction (defined by an increasein the creatine kinase level to more than three times the normalvalue and electrocardiographic changes in the distribution ofthe target vessel), and target-vessel revascularization (definedas redilation owing to in-segment restenosis or bypass surgeryprompted by restenosis).
Statistical Analysis
We estimated that 622 patients would need to be enrolled forthe study to have the statistical power to detect a differencein late luminal loss of 0.13 mm between the two groups with90 percent power, assuming a standard deviation of 0.50 mm ineach group, using a two-group t-test and a two-sided significancelevel of 0.05. To account for the probability that some patientswould not complete the study protocol, we planned to enroll650 patients.
For continuous variables, differences between the two groupswere calculated by analysis of variance or Wilcoxon's rank-sumtest. For discrete variables, differences were analyzed withthe chi-square test or Fisher's exact test. The Breslow–Daytest was used to examine the statistical evidence of heterogeneityamong subgroups.
A multiple logistic-regression analysis was performed to identifyindependent variables associated with restenosis. The stepwiseselection of the variable and the estimation of significantprobabilities were performed by means of the maximum-likelihoodratio test. The chi-square value was calculated from the logof the ratio of maximum-partial-likelihood functions. The additionalvalue of each category of variables added sequentially was evaluatedon the basis of the increases in the overall likelihood statisticratio. The following variables, if significant on univariateanalysis, were included in the multivariate analysis: age; sex;the presence or absence of diabetes (defined by current useof insulin or oral hypoglycemic therapy), smoking, previousmyocardial infarction, previous bypass surgery, and use of glycoproteinIIb/IIIa inhibitors; baseline and follow-up levels of homocysteine,cholesterol, and triglycerides; lesion length; reference diameter;postprocedural minimal luminal diameter; and type of therapyat discharge (statins, beta-blockers, and angiotensin-converting–enzymeinhibitors).
Adverse events during follow-up were analyzed by the Kaplan–Meiermethod. Differences in the event-free survival curves betweenthe two groups were compared with the use of the log-rank test.Data analysis was performed by an independent core laboratory(Diagram). The investigators initiated the study, wrote thearticle, and had full access to the data.
Results
A total of 636 patients were enrolled: 316 were randomly assignedto receive folate therapy, and 320 to receive placebo. All 636patients were included in the analysis of clinical end points.During follow-up, 91 patients discontinued treatment: 42 (13.3percent) in the folate group and 49 (15.3 percent) in the placebogroup (P=0.47); in no case was treatment discontinued becauseof side effects. The remaining 545 patients completed the study.No follow-up angiography was obtained in 62 patients (60 declined,and 2 died), leaving 483 patients (242 [76.6 percent] in thefolate group and 241 [75.3 percent] in the placebo group, P=0.71)with angiographic follow-up. The rate of statin use at the six-monthfollow-up visit was 40.6 percent in the folate group and 45.5percent in the placebo group (P=0.22).
Clinical and Laboratory Characteristics
Clinical and laboratory data were similar in the groups at baseline(Table 1). Homocysteine levels decreased significantly at bothone month (from a mean of 12.2 µmol per liter at baselineto 8.7 µmol per liter, P<0.001) and six months (9.0µmol per liter, P<0.001) in the folate group, but notin the placebo group.
Table 1. Baseline Characteristics and Laboratory Findings.
Angiographic Analysis
The characteristics of the target lesion were well matched inthe two study groups (Table 2). The mean (±SD) durationof angiographic follow-up was 210±20 days.
Table 2. Angiographic Results for 521 Lesions in 483 Patients with Angiographic Follow-up.
The primary angiographic end point — minimal luminal diameter— was significantly smaller in the folate group than inthe placebo group at follow-up (1.59±0.62 vs. 1.74±0.64mm, P=0.008). Conversely, the extent of late luminal loss wassignificantly greater in the folate group than in the placebogroup (0.90±0.55 vs. 0.76±0.58 mm, P=0.004), aswas the loss index (late luminal loss divided by acute gain)(0.61±0.38 vs. 0.51±0.41, P=0.006). The restenosisrate was higher in the folate group than in the placebo group(34.5 percent vs. 26.5 percent; relative risk, 1.30; 95 percentconfidence interval, 1.00 to 1.69; P=0.05). The cumulative distributioncurves of the minimal luminal diameter are shown in Figure 1.At follow-up, the curve showed a significant leftward shiftin the folate group, indicating a higher frequency of smallerluminal diameters (P=0.004).
Figure 1. Cumulative Distribution of the Minimal Luminal Diameter before and Immediately after Stent Implantation and at Follow-up Angiography in the Folate Group and the Placebo Group.
A significant shift to the left is seen at follow-up in the folate group, indicating that the minimal luminal diameter was smaller in this group than in the placebo group.
We performed subgroup analyses of the relative risk of restenosisin order to evaluate whether the increase in restenosis wasdistributed evenly across subgroups (Figure 2). The point estimatesshowed that folate therapy reduced the risk of restenosis, butnot significantly so, among women (relative risk, 0.67; 95 percentconfidence interval, 0.39 to 1.14; P=0.13; P for heterogeneity= 0.002), and among patients with diabetes, as compared withpatients without diabetes (relative risk, 0.71; 95 percent confidenceinterval, 0.44 to 1.15; P=0.16; P for heterogeneity = 0.02).Likewise, patients with baseline homocysteine levels of 15 µmolper liter or more had a decreased risk of restenosis with theuse of folate therapy (relative risk, 0.86; 95 percent confidenceinterval, 0.49 to 1.52; P=0.61), whereas those with lower levelsof homocysteine had an increase in risk (relative risk, 1.42;95 percent confidence interval, 1.05 to 1.92; P=0.02; P forheterogeneity = 0.12). The adverse effect of folate therapywas most pronounced in patients who had vessels with a referencediameter of 3 mm or more (relative risk, 2.02; 95 percent confidenceinterval, 1.18 to 3.48; P=0.008).
Figure 2. Relative Risk of Restenosis with Folate Therapy, According to Baseline Characteristics.
Squares indicate means, and horizontal lines 95 percent confidence intervals. Folate therapy did not uniformly increase the risk of restenosis. Women (P for heterogeneity = 0.002), patients with diabetes (P for heterogeneity = 0.02), and patients with high baseline homocysteine levels tended to have a lower risk of restenosis with folate therapy. LAD denotes left anterior descending coronary artery, CCA circumflex coronary artery, and RCA right coronary artery.
Variables related to restenosis on univariate analysis werelesion length (P=0.001) and the minimal luminal diameter afterthe procedure (P=0.003). There were no significant differencesbetween patients with and those without restenosis in homocysteinelevels at baseline (P=0.71) or follow-up (P=0.52) or in statinuse (42.1 percent vs. 41.7 percent, P=0.93). On multivariateanalysis, only the lesion length (P=0.002) and the minimal luminaldiameter after the procedure (P=0.001) significantly affectedthe risk of restenosis.
Clinical End Points
Table 3 summarizes the clinical end points in the two groupsafter 165 days of follow-up (before the planned angiographicfollow-up) and after 250 days of follow-up (after the 6-monthangiographic follow-up). The analysis of target-vessel revascularizationat 165 days, which included only clinically driven reinterventions,showed that 24 patients (7.6 percent) in the folate group and14 patients (4.4 percent) in the placebo group underwent target-vesselrevascularization (P=0.09). By 250 days of follow-up, an analysisthat included clinically and angiographically driven reinterventionsshowed that 50 patients (15.8 percent) in the folate group and34 patients (10.6 percent) in the placebo group had requireda second revascularization procedure (P=0.05). The incidenceof death and myocardial infarction did not differ significantlybetween the two groups at either 165 or 250 days. The use ofstatin therapy did not affect the rate of target-vessel revascularization(14.5 percent among patients who received statin therapy, ascompared with 12.4 percent among those who did not receive statintherapy; P=0.46).
We found that therapy with folate, vitamin B6, and vitamin B12had an adverse effect on the risk of restenosis among patientswho had received a coronary stent, even though it profoundlylowered plasma homocysteine levels. Despite the fact that hyperhomocysteinemiahas been shown to promote the restenotic process after coronaryangioplasty in animals,7,8,9,21,22,23 the extent of the roleof homocysteine levels in the risk of restenosis in humans hasbeen a subject of controversy.
In accordance with several previous studies,16,17,18 but incontrast to others,11,12,13,14,15 we did not find that the homocysteinelevel was a predictor of restenosis. With respect to the effectof folate, Schnyder et al.19 reported that folate therapy resultedin an impressive reduction in the rate of restenosis (from 37.6percent in the control group to 19.6 percent in the folate group),as well as in the need for target-lesion revascularization (from22.3 percent to 10.8 percent). Our trial differed in severalrespects from that of Schnyder et al. First, only approximatelyhalf of their patients received stents, and the benefits offolate therapy were evident predominantly in patients who weretreated with balloon angioplasty alone. The proliferation ofsmooth-muscle cells and matrix formation are the most importantmechanisms leading to restenosis after coronary stenting,24whereas after balloon angioplasty, thrombus formation withinintimal cracks and vascular remodeling are of predominant importanceto the process of restenosis; the latter changes are potentiallymore susceptible to the folate-induced effects of homocysteinelowering. Second, the dose of pyridoxal phosphate (vitamin B6)that we administered was nearly five times as high as that inthe study by Schnyder et al. (48 mg vs. 10 mg). Third, noneof their patients had homocysteine levels of more than 13.5µmol per liter at baseline, and no subgroup analysis wasperformed according to baseline homocysteine levels.
Folate may play a crucial role in the synthesis of DNA and RNA.25The administration of high doses of folate vigorously promotesthe growth of neointimal cells by providing large amounts ofthe biochemical precursors needed for cell replication.26 Becauseit converts homocysteine to methionine, folate is essentialfor the formation of S-adenosylmethionine, the universal methyldonor and coenzyme for a large number of cell reactions.27 Thehomocysteine precursor S-adenosylhomocysteine is a powerfulcompetitive inhibitor of S-adenosylmethionine–dependentmethyltransferases.28 Therefore, by decreasing homocysteinelevels, folate can favorably influence the ratio of S-adenosylmethionineto S-adenosylhomocysteine and increase the availability of methylgroups for DNA methylation.29 Homocysteine is metabolized bytwo main pathways, the vitamin B6–dependent transsulfurationpathway and the folate-dependent remethylation pathway. Therelatively high dose of vitamin B6 given in our study (48 mg)may have led the transsulfuration pathway to predominate, therebyfurther decreasing the inhibition of S-adenosylhomocysteineas well as S-adenosylmethionine and contributing to increasedDNA methylation.
Experiments in animals have shown that folate can promote tumorgrowth.30 In transgenic mice with a folate deficiency, folatesupplementation significantly increased the induction of breastcancer.31 A recent study demonstrated that folate can inhibitintimal hyperplasia induced by a high-homocysteine diet in arat model of carotid endarterectomy.10 However, a folate-richdiet in the absence of hyperhomocysteinemia is associated withincreased intimal hyperplasia. In fact, vitamin therapy shouldbe considered a double-edged sword in patients who have receivedcoronary stents, since the beneficial antiproliferative effectsof folate, vitamin B6, and vitamin B12 — exerted by virtueof their ability to reduce homocysteine levels — mustbe weighed against their potential adverse proliferative effects.We found that folate therapy lowered the rates of restenosisamong women, patients with diabetes, and those with a markedlyelevated plasma level of homocysteine (15 µmol per literor more). Thus, homocysteine levels may play a greater rolein the development of restenosis in women and patients withdiabetes than in other subgroups of patients. With respect topatients with hyperhomocysteinemia, it is plausible that, givenits mechanism of action, folate therapy inhibits rather thanpromotes the development of restenosis.
A major limitation of our study is that, although the rate ofangiographic follow-up was similar in the two groups, follow-upangiography was performed in only 76 percent of patients, mainlybecause of the exclusion of patients who discontinued treatment,rather than because of any influence of the patients' symptoms.32Restenosis was evaluated by means of quantitative coronary angiography.The use of intravascular ultrasonography would have enhancedthe value of our study. Finally, there was a relatively lowrate of statin use in our population. However, statins havenot been shown to have any effect on the risk of target-vesselrevascularization after stent implantation.33,34
Our data do not provide any evidence that folate therapy forthe primary or secondary prevention of coronary artery diseaseis potentially harmful, since the folate group did not havean increased incidence of death or infarction. Our data cannotbe interpreted to mean that multivitamin supplementation shouldbe discontinued in patients after coronary stenting. The oraldose of folate that we used — 1.2 mg — is threetimes the recommended daily dose for vitamin supplements. If,however, physicians decide to administer folate therapy to patientswith coronary artery disease and moderate hyperhomocysteinemiaeven before the results of prospective prevention studies areknown, they should exercise caution in the use of this therapyfor patients who have just received a stent.
Funded in part by Medice, Iserlohn, Germany.
We are indebted to Vera Derks for editorial assistance and toEvelien Kolkman, Diny Amo, and Edwin Nibbering (Diagram, Zwolle,the Netherlands) for their core-laboratory and statistical expertise.
Source Information
From the Kardiologische Praxis, Klinikum Links der Weser, Heart Center, Bremen, Germany (H.L., C.B., K.K., M.N.P., E.S.); Isala Klinieken, Hospital De Weezenlanden, Zwolle, the Netherlands (H.S., G.D., J.-H.E.D.); and Diagram, Zwolle, the Netherlands (J.D.).
Address reprint requests to Dr. Suryapranata at the Department of Cardiology, Isala Klinieken, Hospital De Weezenlanden, Groot Wezeland 20, 8011 JW Zwolle, the Netherlands, or at h.suryapranata{at}diagram-zwolle.nl.
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