Comentários sobre WENBIT

Don't End It With WENBIT -- Details Needed on B Vitamins, Stroke, and Cancer
From Heartwire — a professional news service of WebMD
August 20, 2008 — The Western Norway B-Vitamin Intervention Trial (WENBIT), showing no benefit of either folate with vitamin B12 or vitamin B6 in patients with established heart disease, is now published in the August 20, 2008, issue of the Journal of the American Medical Association [1]. First presented at the European Society of Cardiology Congress 2007 by Dr Marta Ebbing (Haukeland University Hospital, Bergen, Norway), as reported by heartwire, the trial is the latest in a series of studies suggesting that B-vitamin supplementation is not justified as secondary prevention in heart disease and that its intended target, homocysteine, is a marker of coronary heart disease (CHD), rather than a "modifiable cause" of heart disease.
Commenting on the published study to heartwire, Ebbing pointed out that the rigorous design of the WENBIT study makes the results an important addition to the field. Patients underwent coronary angiography before entering the study, were not already taking B vitamins, and Norway, unlike many other countries, does not have folic-acid fortification of foods.
"WENBIT confirms and adds further evidence to results from previously published and similar homocysteine-lowering B-vitamin trials in populations with established or at increased risk of cardiovascular disease," she said.
WENBIT results
In WENBIT, 3096 CHD patients were randomized in a 2 x 2 factorial design to one of four groups to receive a daily oral dose of folic acid (0.8 mg) plus vitamin B12 (0.4 mg) and vitamin B6 (40 mg); folic acid with vitamin B12 alone; vitamin B6 alone; or placebo. Homocysteine levels declined by about 30% in the folic-acid/B12 group at one year; the trial, however, was terminated early after results from the Norwegian Vitamin (NORVIT) trial suggested a possible increase in cancer risk with B-vitamin supplementation. After a median follow-up of 38 months, there was no significant difference in the risk of death or major cardiovascular events among the four groups.
But like the NORVIT trial before it, WENBIT hinted at a possible cancer risk — a worrying trend, given that several Western countries have or are considering mandatory folic-acid fortification of staple foods, including cereals, spreads, and flour, to prevent neural-tube defects in babies.
"Both in NORVIT and in WENBIT there was a numerically larger incidence of cancer in the groups treated with folic acid and vitamin B12, and although this could be due to chance, the possible harmful effects of folic-acid treatment/supplementation on cancer development should be explored," Ebbing told heartwire. Researchers in NORVIT and WENBIT are currently working to provide combined results from an extended follow-up of the almost 7000 patients who participated in these trials to explore such possible harmful short- and long-term effects from the intervention.
Furthermore, she said, the B-Vitamin Trialists Treatment Collaboration is planning to collaborate on a meta-analysis of results from completed and ongoing B-vitamin intervention trials. "Incident cancers will be one of the clinical end points in this analysis," she said.
There is also some suggestion that the incidence of stroke is actually reduced by folic acid/vitamin B12, and this potential effect may also warrant further scrutiny, the WENBIT investigators note.
WENBIT: Percentage of patients with cardiovascular events
End point
Folic acid+B12+B6
Folic acid+B12
B6
Placebo
Primary end point
12.2
16.3
13.7
12.5
All-cause death
4.5
4.9
3.6
3.9
Acute MI
7.7
9.9
7.1
7.4
Unstable angina
2.9
3.8
3.1
3.5
Nonfatal thromboembolic stroke
1.4
2.2
2.6
2.4
Cancer
6.0
5.1
4.9
4.0
Dr Salim Yusuf (McMaster University, Hamilton, ON), who discussed the trial when it was first presented last year, pointed out that results from the VITAmins TO Prevent Stroke (VITATOPS) trial (8000 stroke patients) and the SEARCH trial in 12,000 heart-disease patients will more than double the total database on homocysteine lowering. Echoing Ebbing et al's conclusions, Yusuf stated: "There is no reason now to lower homocysteine levels, but it is still too early to write off the hypothesis completely."
This trial was funded by the Advanced Research Program and Research Council of Norway, the Norwegian Foundation for Health and Rehabilitation, the Norwegian Heart and Lung Patient Organisation, the Norwegian Ministry of Health and Care Services, the Western Norway Regional Health Authority, the Department of Heart Disease at Haukeland University Hospital, Locus for Homocysteine and Related Vitamins at the University of Bergen, Locus for Cardiac Research at the University of Bergen, the Foundation to Promote Research Into Functional Vitamin B12 Deficiency, Bergen, Norway, and Alpharma Inc, Copenhagen, Denmark.
One study author has disclosed that he is a member of the steering board of the nonprofit Foundation to Promote Research Into Functional Vitamin B12 Deficiency. Two study authors have received consulting fees from Nycomed. The remaining study authors have disclosed no relevant financial relationships.
Source
Ebbing M, Bleie Ø, Ueland PM, et al. Mortality and cardiovascular events in patients treated with homocysteine-lowering B vitamins after coronary angiography. A randomized controlled trial. JAMA. 2008;300:795-804

Vytorin e câncer: um caso para ser verificado

FDA investigating link between Vytorin and cancer.
The Wall Street Journal (8/22, B7, Favole, Mundy) reports that the Food and Drug Administration (FDA) "is reviewing a recent study, called SEAS, that found an increased risk of cancer and deaths from cancer in patients taking Vytorin (ezetimibe and simvastatin), compared with those given a placebo." The agency "expects to receive a final SEAS study report from the Merck/Schering-Plough joint venture in about three months and said it will likely take...six months to fully evaluate the data."
Investigators "involved in the SEAS study said during a July 21 press conference to discuss the data that the increased cases were likely due to chance,"
Bloomberg (8/22, Larkin, Pettypiece) adds. In order "to see if there was a risk, Richard Peto, professor of medical statistics and epidemiology at the University of Oxford, analyzed larger and longer studies of Vytorin that would be more likely to find one." But he "found no increase in cancers in those studies and concluded the SEAS finding was likely an anomaly."
The FDA "said patients should not stop taking Vytorin because the evidence of a cancer link is unclear," according to the AP (8/22, Alonso-Zaldivar, Johnson). The agency said that "while one recent clinical trial indicated higher rates of cancer for patients taking the medication, two studies currently under way have shown no increased risk." Meanwhile, "leaders of the powerful House Energy and Commerce Committee asked the companies for extensive data on the" SEAS trial. Rep. John D. Dingell (D-Mich.), who chairs the committee, "and Rep. Bart Stupak (D-Mich.), chairman of its Oversight and Investigations subcommittee, sent a letter to the chief executives of the drug companies, giving them two weeks to supply detailed information." The lawmakers "are investigating drug industry safety issues and marketing practices, and have been focusing increasingly on Vytorin." MedPage Today (8/21, Peck) and
WebMD (8/21, DeNoon) also covered the story.

Surrogate End-points: ENHANCE

Clinical Trials and Surrogate End Points: Lessons From the ENHANCE Trial
Posted 08/12/2008
John Alan Farmer, MDAuthor
The lipid hypothesis was originally proposed as a theory to explain the central role of dyslipidemia in the initiation and progression of atherosclerosis. The lipid hypothesis was supported by epidemiologic, pathologic and genetic observations. However, definitive proof of concept would require prospective clinical trial evidence that demonstrates that optimization of dyslipidemia would result in a reduction in risk from the complications of atherosclerosis. Epidemiologic studies that demonstrate a statistical correlation between dyslipidemia and atherosclerosis do not necessarily imply that pharmacologic modification of the lipid profile will alter the natural history of atherosclerosis. Early clinical trials that employed a variety of interventions did demonstrate that modification of dyslipidemia resulted in a modest decrease in the incidence of cardiovascular events. Clinical trials such as the Lipid Research Clinic Coronary Primary Prevention Trial, which utilized cholestyramine, and the Helsinki Heart Study, which analyzed gemfibrozil, demonstrated that these interventions did reduce cardiovascular event rates.[1,2] However, the interpretation and implication of these trials generated considerable controversy. The absolute degree of risk reduction was minimal and total mortality was not improved. The failure of pharmacologic therapy to reduce total mortality despite a decline in cardiovascular mortality implied a potential drug-mediated adverse effect of cholesterol lowering that would negate the vascular benefits. The early clinical trials were also hampered by problems in trial design and only a modest improvement in circulating lipid levels. The advent of pharmacologic agents that partially inhibit the key enzyme in cholesterol synthesis (3-hydroxy-3-methyl-glutaryl-CoA reductase) provided the ability to significantly reduce LDL levels. Statin therapy was originally approved by the US FDA solely with an indication to improve dyslipidemia since clinical trial evidence for event reduction was lacking at the time of approval. The role of statin therapy in cardiovascular risk reduction was subsequently studied in a variety of clinical trials that encompassed the spectrum of atherosclerosis. The role of cardiovascular risk factor modification in primary prevention (clinical absence of atherosclerosis) has been controversial owing to economic, efficacy and safety concerns. Primary prevention can be subdivided into high- and low-risk populations depending on the degree of dyslipidemia and extent of associated risk factors. Statin therapy was subsequently demonstrated to be efficacious in both high- and low-risk subgroups. The West of Scotland Coronary Primary Prevention Study analyzed the role of pravastatin therapy in a patient cohort characterized by significant dyslipidemia coupled with a high prevalence of other risk factors, such as tobacco usage.[3]
Pravastatin therapy demonstrated a clear reduction in the incidence of cardiovascular events. The Air Force/Texas Coronary Atherosclerosis Prevention Study evaluated the role of lovastatin therapy in a large cohort of both men and women with LDL-C levels that were considered to be within normal limits by contemporary guidelines.[4] The primary lipid abnormality was a reduced level of HDL. Lovastatin therapy significantly reduced the primary end point, which was a composite consisting of sudden death, fatal and nonfatal myocardial infarction and unstable angina. The role of statin therapy in secondary prevention (documented presence of atherosclerosis) was evaluated in patients who survived a myocardial infarction coupled with a significantly elevated LDL-C level in the Simvastatin Scandinavian Survival Study (4S).[5] Simvastatin therapy reduced not only cardiovascular but also total mortality. Additionally, pravastatin therapy was demonstrated to reduce cardiovascular events in survivors of a myocardial infarction whose total cholesterol levels were considered to be normal (<240 mg/dl) in the Cholesterol and Recurrent Events (CARE) study.[6] Analysis of secondary prevention studies demonstrated a linear reduction in cardiovascular event rates, which correlated with the degree of reduction in LDL-C levels (Figure 1). Additionally, multiple vascular imaging (angiography, intravascular ultrasound, B-mode ultrasound etc.) studies have analyzed the impact of modification of the lipid profile on the progression of coronary atherosclerosis. Intravascular ultrasound studies have been performed, which compared aggressive lipid-lowering strategies with a more conventional approach.[7] The intensive reduction of LDL-C has been correlated with reduced plaque volume. The controversy relative to the clinical benefits, which accrue from the reduction of LDL-C levels, appeared to have been resolved and the concept that ‘lower is better’ achieved widespread acceptance. Many experts felt that further clinical trials demonstrating the reduction of hard clinical end points following lipid-lowering therapy were no longer required owing to the extensive clinical trial experience involving thousands of patients. Clinical trials require large numbers of subjects followed for a period of years and are extremely expensive to perform. The problems associated with enrolment and funding of clinical trials has led to the concept of the substitution of surrogate markers a satisfactory means to demonstrate clinical benefit. However, the utilization of surrogate markers is problematic. The problems encountered by relying upon surrogate markers were emphasized in the recent clinical controversy surrounding the Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression (ENHANCE) study.

Secondary prevention trials and LDL reduction.
The ENHANCE trial was designed to study the potential benefits of the addition of the cholesterol absorption inhibitor ezetimibe to maximum statin dosing on the progression of atherosclerosis.[8] The ENHANCE trial is a randomized, double-blind active comparator study, which employed a surrogate marker (B-Mode ultrasound) in lieu of clinical end points such as myocardial infarction. The progression of atherosclerosis was assessed by the utilization of B-mode ultrasonography imaging to calculate the intimal medial thickness of the carotid and femoral arteries.
The modification of intimal medial thickness is not recognized by the US FDA as an end point qualifying for drug approval or a new drug indication. The rationale for combination therapy lies in the fact that the greatest reduction in LDL-C occurs with the initial statin dose. Subsequent doubling of the dose results in approximately a 5-7% additive reduction in LDL reduction and is associated with an increased incidence of side effects.[9] The therapeutic rationale for the addition of ezetimibe is to further reduce circulating LDL levels as a means of achieving goals established by the National Cholesterol Education Program (NCEP). Ezetimibe lowers LDL by reducing the absorption of cholesterol from the gastrointestinal tract by binding to the Niemann-Pick C1-like 1 protein, which is the key transport mediator.[10] The reduction in the delivery of cholesterol to the liver results in a decrease in intrahepatic cholesterol followed by an upregulation of the LDL receptor. The increase in LDL-receptor activity is associated with enhanced plasma clearance of lipoproteins that carry ApoB or ApoE on their surface. The gastrointestinal absorption of cholesterol is at least partially under genetic control and the average individual absorbs approximately 55% of the cholesterol presented to the gastrointestinal tract. The administration of ezetimibe monotherapy results in a 15-20% reduction in LDL-C in the individual with normal absorptive capacity. The use of ezetimibe is associated with minimal systemic toxicity owing to the limited absorption and enterohepatic circulation. The ENHANCE study compared simvastatin 80 mg plus ezetimibe 10 mg versus simvastatin 80 mg alone on carotid and femoral intimal thickness. The study population was composed of 720 subjects with heterozygous familial hypercholesterolemia who were evaluated over a 24-month trial period. The trial was well designed and conducted by a research group that is highly experienced in the analysis of carotid intimal thickness. The baseline characteristics of the patients were well matched, with the exception of a higher prevalence of increased BMI in the simvastatin plus ezetimibe group.
Combination therapy resulted in a significant reduction in circulating lipid levels compared with the group who received simvastatin alone. The circulating levels of LDL-C decreased from 317.8 to 192.7 mg/dl in the simvastatin alone group. Combination therapy reduced circulating LDL-C levels from 319.0 to 141.3 mg/dl and represented a between-group difference of 16.5%, which was statistically significant. Combination therapy also resulted in a significant reduction in high-sensitivity C-reactive protein (hs c-RP) protein of 49% compared with 23% in the simvastatin monotherapy group. The primary end point of the EHANCE study was the change from baseline in the mean intimal thickness of the carotid artery. Combination therapy did not result in a significant alteration of the primary end point for simvastatin monotherapy (0.0058 ± 0.0037 versus 0.0111 ± 0.0038; p = 0.29). Additionally, a variety of secondary end points were not beneficially altered by combination therapy. New plaque formation, which was defined as intimal medial thickness in excess of 1.3 mm, was demonstrable in 2.8% of the monotherapy group and 4.7% of subjects who received combination therapy (p = 0.20). The addition of combination therapy also did not beneficially alter intimal thickness in the femoral arteries. The ENHANCE study thus evaluated three surrogate markers that have been correlated with risk for atherosclerosis (LDL-C, c-RP and carotid intimal thickness). The hypothesis that reduction of LDL-C and inflammatory markers would result in a beneficial duration of carotid intimal thickness was not verified. How can these surprising results be explained?
The possibility of technical problems in the assessment of carotid intimal thickness is highly unlikely. Physicians involved in the analysis of the images are considered to be world experts. Additionally, the research group that designed and performed the ENHANCE trial previously performed the well-regarded Atorvastatin Versus Simvastatin on Atherosclerosis Progression (ASAP) study. The ASAP and EHANCE studies both analyzed subjects with heterozygous familial hypercholesterolemia. The ASAP trial was designed to compare the effects of atorvastatin 80 mg with simvastatin 40 mg on carotid intimal thickness in 320 subjects over a 2-year period.[11] The study populations in the ASAP and ENHANCE trials was similar in age, lipid profile and method employed to quantitate carotid intimal thickness. The ENHANCE and ASAP trials both utilized the same central core laboratory for image evaluation. However, carotid intimal thickness at baseline was not the same in the two groups. The ASAP cohort had carotid intimal thickness of 0.925 mm compared with 0.695 mm in the ENHANCE cohort. The normal value for carotid intimal thickness in subjects 40-49 years of age is 0.64 mm at the bifurcation of the common carotid. The values for carotid intimal thickness in the ENHANCE study were essentially normal at baseline implying prior significant risk factor modification (especially considering the high-risk patient population, which was composed of heterozygous familial hypercholesterolemic subjects in their fifth decade of life) prior to the onset of the study.
The ASAP trial was begun in 1997 when aggressive therapy with statins was less prevalent. The number of patients in the ASAP trial who previously were treated with statins and the duration of therapy is not available. By contrast, 80% of subjects in the EHANCE study had previously received statin therapy and only a short washout period was employed. The possibility of a lengthy period of pretreatment with statins resulting in delipidation of the vasculature in the EHANCE cohort may have blunted potential benefits from a further 24-month treatment period.
Assuming that there were no technical problems encountered in the accumulation and analysis of the data, a major question to be answered is the validity of the surrogate end points that were analyzed in the ENHANCE trial as a means of predicting risk from atherosclerosis. The clinical utility of a surrogate marker would require confirmation that the substitution of a laboratory measurement (LDL-C, carotid intimal thickness etc.) is a substitute for clinically meaningful end points, such as reduction of cardiovascular events.
Thus, definite proof should be present to demonstrate the changes induced by any therapeutic intervention on a surrogate end point accurately predict a clinically meaningful outcome alteration. The ENHANCE trial is basically an analysis of several biomarkers on the process of atherosclerosis with carotid intimal thickness designated as the primary end point. LDL-C, c-RP and other lipid subfractions were significantly reduced. A major question is which of the analyzed surrogates is the most valid in predicting risk from atherosclerosis? The major lipid alteration in the ENHANCE trial was a highly significant reduction in LDL-C by the combination of simvastatin and ezetimibe of 51 mg/dl, which was statistically significant with a p-value of less than 0.01. LDL reduction has consistently been correlated with a decrease in cardiovascular event rates in multiple trials. LDL-C and c-RP have extensive databases that support their use as surrogate end points.[12] The utility of employing the rate of change in carotid intimal thickness is conceptually attractive as it directly analyzes vascular structure but lacks the robust database of LDL-C modification and clinical end point reduction. Modest positive statistical correlations between the degree of carotid intimal thickness and event rates have been demonstrated in 30 of 34 clinical studies.[13] The role of lipid therapy in the modification of carotid intimal thickness has been analyzed in 15 clinical studies and has demonstrated that high-dose statin therapy has slowed or caused regression of atherosclerosis.[14] However, studies with less than 2 years of follow-up have not demonstrated event reduction, which raises the possibility that short-term studies such as the ENHANCE trial may not be valid in the utilization of intimal thickness as a surrogate marker. A major clinical question that was raised by the ENHANCE trial also relates to the efficacy of ezetimibe. The result of the trial has been interpreted by some as evidence that the addition of ezetimibe provides no benefit in reducing the risk of atherosclerosis either in combination or monotherapy. Ezetimibe has been demonstrated to reduce the degree of atherosclerosis in experimental animals, which may not be applicable to human subjects. However, ezetimibe has been demonstrated to exhibit several proatherogenic effects, including inhibition of the scavenger receptor B1 and decreasing the activity of the ATP-binding cassette A1, which modulates the efflux of cholesterol from the lipid-laden macrophage.[15] However, for these mechanisms to exhibit clinically relevant proatherogenic activity, ezetimibe would require significant systemic activity and the drug is only minimally absorbed from the gastrointestinal lumen.
Additionally, LDL-lowering interventions (fibric acid derivatives, nicotinic acid, bile acid sequestrants, diet and ileal bypass) have all been demonstrated to reduce clinical events.
The major exception is the cholesterol ester transfer protein inhibitors, such as torcetrapib, which improved the lipid profile but demonstrated adverse affects such as the induction of hypertension. Ezetimibe has not been correlated with the worsening of any metabolic effects due to the lack of systemic absorption.
The controversy surrounding the ENHANCE trial may have been avoided by the formation and presence of an external advisory board to independently analyze the design of the trial with modification of the aforementioned problems. The null results of the trial are difficult to translate into clinical practice guidelines. The NCEP guidelines remain valid and appropriate LDL goals should still be attempted to be achieved. Statin therapy should remain the primary therapeutic intervention. If combination therapy is required, utilization of agents with a proven clinical efficacy should be employed. Ezetimibe therapy may still be added to achieve LDL goals when statin monotherapy is inadequate or associated with side effects such as myopathy. The clinical benefits of combination therapy utilizing statins and ezetimibe will await the results of the Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) trial, which will analyze the affect of combination therapy on hard end points.[16] The IMPROVE-IT trial will provide insight into the role of absolute LDL reduction in addition to clarification of the role and efficacy of the therapies employed to achieve LDL goals.


References
Rifkind BM: The Lipid Research Clinics Coronary Primary Prevention Trial: results and implications. Monogr. Atheroscler. 13, 74-84 (1985).
Frick MH, Elo O, Haapa K et al.: Helsinki Heart Study: primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia. Safety of treatment, changes in risk factors, and incidence of coronary heart disease. N. Engl. J. Med. 317(20), 1237-1245 (1987).
Shepherd J, Cobbe SM, Ford I et al.: Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group. N. Engl. J. Med. 333(20), 1301-1307 (1995).
Downs JR, Clearfield M, Weis S et al.: Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study. JAMA 279(20), 1615-1622 (1998).
Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 344(8934), 1383-1389 (1994).
Sacks FM, Pfeffer MA, Moye LA et al.: The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial investigators. N. Engl. J. Med. 335(14), 1001-1009 (1996).
Nissen SE, Tuzcu EM, Schoenhagen P et al.: Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial. JAMA 291(9), 1071-1080 (2004).
Kastelein JJ, Akdim F, Stroes ES et al.: Simvastatin with or without ezetimibe in familial hypercholesterolemia. N. Engl. J. Med. 358(14), 1431-1443 (2008).
Roberts WC: The rule of 5 and the rule of 7 in lipid-lowering by statin drugs. Am. J. Cardiol. 80(1), 106-107 (1997).
Altmann SW, Davis HR Jr, Zhu LJ et al.: Niemann-Pick C1 like 1 protein is critical for intestinal cholesterol absorption. Science 303(5661), 1201-1204 (2004).
Smilde TJ, van Wissen S, Wollersheim H, Trip MD, Kastelein JJ, Stalenhoef AF: Effect of aggressive versus conventional lipid lowering on atherosclerosis progression in familial hypercholesterolaemia (ASAP): a prospective, randomised, double-blind trial. Lancet 357(9256), 577-581 (2001).
Ridker PM: C-reactive protein and the prediction of cardiovascular events among those at intermediate risk: moving an inflammatory hypothesis toward consensus. J. Am. Coll. Cardiol. 49(21), 2129-2138 (2007).
Bots ML, Baldassarre D, Simon A et al.: Carotid intima-media thickness and coronary atherosclerosis: weak or strong relations? Eur. Heart J. 28(4), 398-406 (2007).
Zhao XQ, Yuan C, Hatsukami TS et al.: Effects of prolonged intensive lipid-lowering therapy on the characteristics of carotid atherosclerotic plaques in vivo by MRI: a case-control study. Arterioscler. Thromb. Vasc. Biol. 21(10), 1623-1629 (2001).
During A, Dawson HD, Harrison EH: Carotenoid transport is decreased and expression of the lipid transporters SR-BI, NPC1L1, and ABCA1 is downregulated in Caco-2 cells treated with ezetimibe. J. Nutr. 135(10), 2305-2312 (2005).
Greenland P, Lloyd-Jones D: Critical lessons from the ENHANCE trial. JAMA 299(8), 953-955 (2008).
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Folato, B-6 e B-12 como prevenção secundária

Mortality and Cardiovascular Events in Patients Treated With Homocysteine-Lowering B Vitamins After Coronary Angiography
A Randomized Controlled Trial
Marta Ebbing, MD; Øyvind Bleie, MD, PhD; Per Magne Ueland, MD, PhD; Jan Erik Nordrehaug, MD, PhD; Dennis W. Nilsen, MD, PhD; Stein Emil Vollset, MD, DrPH; Helga Refsum, MD, PhD; Eva Kristine Ringdal Pedersen, MD; Ottar Nygård, MD, PhD
JAMA. 2008;300(7):795-804.
ABSTRACT
Context Observational studies have reported associations between circulating total homocysteine concentration and risk of cardiovascular disease. Oral administration of folic acid and vitamin B12 can lower plasma total homocysteine levels.
Objective To assess the effect of treatment with folic acid and vitamin B12 and the effect of treatment with vitamin B6 as secondary prevention in patients with coronary artery disease or aortic valve stenosis.
Design, Setting, and Participants Randomized, double-blind controlled trial conducted in the 2 university hospitals in western Norway in 1999-2006. A total of 3096 adult participants undergoing coronary angiography (20.5% female; mean age, 61.7 years) were randomized. At baseline, 59.3% had double- or triple-vessel disease, 83.7% had stable angina pectoris, and 14.9% had acute coronary syndromes.
Interventions Using a 2 x 2 factorial design, participants were randomly assigned to 1 of 4 groups receiving daily oral treatment with folic acid, 0.8 mg, plus vitamin B12, 0.4 mg, plus vitamin B6, 40 mg (n = 772); folic acid plus vitamin B12 (n = 772); vitamin B6 alone (n = 772); or placebo (n = 780).
Main Outcome Measures The primary end point was a composite of all-cause death, nonfatal acute myocardial infarction, acute hospitalization for unstable angina pectoris, and nonfatal thromboembolic stroke.
Results Mean plasma total homocysteine concentration was reduced by 30% after 1 year of treatment in the groups receiving folic acid and vitamin B12. The trial was terminated early because of concern among participants due to preliminary results from a contemporaneous Norwegian trial suggesting adverse effects from the intervention. During a median 38 months of follow-up, the primary end point was experienced by a total of 422 participants (13.7%): 219 participants (14.2%) receiving folic acid/vitamin B12 vs 203 (13.1%) not receiving such treatment (hazard ratio, 1.09; 95% confidence interval, 0.90-1.32; P = .36) and 200 participants (13.0%) receiving vitamin B6 vs 222 (14.3%) not receiving vitamin B6 (hazard ratio, 0.90; 95% confidence interval, 0.74-1.09; P = .28).
Conclusions This trial did not find an effect of treatment with folic acid/vitamin B12 or vitamin B6 on total mortality or cardiovascular events. Our findings do not support the use of B vitamins as secondary prevention in patients with coronary artery disease

COURAGE: comentários Medscape

COURAGE Quality-of-Life Analysis: Slim Early Gains With PCI Soon Disappear
News Author: Steve StilesCME Author: Charles Vega, MD From Heartwire — a professional news service of WebMD
August 14, 2008 — The results of their quality-of-life (QoL) analysis from the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial [1] are consistent with the message from its primary outcomes [2] and other secondary results, conclude researchers. That message: Percutaneous coronary intervention (PCI) can often be deferred in patients with stable coronary artery disease (CAD) and significant coronary lesions without adding risk while optimal medical therapy (OMT) is given a chance to work, and it can be considered later if the patient still develops significant symptoms, according to the group.
In the trial's QoL analysis, published in the August 14, 2008 issue of the New England Journal of Medicine, OMT either with or without routine early PCI rapidly improved the patients' Seattle Angina Questionnaire (SAQ) scores for physical limitation, angina frequency, overall QoL, and other outcome domains.
The gains with routine PCI were significantly greater than those for OMT-only throughout the first one to two years of follow-up. But the PCI advantages had dissipated by three years, when no significant differences in QoL scores were seen between the two treatment strategies.
The new report does little to settle controversies ignited when the COURAGE primary outcome — similar composite rates of mortality or myocardial infarction (MI) over four to five years for the routine-PCI and OMT-only groups — became public last year. As extensively reported by heartwire, proponents of early routine intervention have questioned the quality of PCI in COURAGE, the relevance of the trial's exceptionally good medical therapy, its statistical power for prespecified end points, other ways it was designed and executed, the authors' interpretation of the data, and their conclusions; but both detractors and defenders of the trial abound.
No additional risk from deferring PCI
According to the QoL report's lead author, Dr William S Weintraub (Christiana Care Health System, Newark, DE), the new analysis is consistent with the trial's primary-outcomes message and the results of its "nuclear substudy" [3], which provided objective evidence that the early PCI strategy was better than first-line OMT at relieving myocardial ischemia. COURAGE, he told heartwire, shows that there is some relief of angina with routine early PCI and that about a third of OMT-only patients will cross over to invasive management. "But lots of patients get better without PCI. So it doesn't mean we shouldn't do PCI, it means that people will not be put at additional risk if PCI is deferred to see [whether] they get better with just medical therapy."
If the patient reports debilitating symptoms on OMT, Weintraub added, "it's reasonable" to go right to PCI. One finding of the study, he said, is that the QoL benefits of PCI were proportional to the severity of angina.
Weintraub had presented a preliminary version of the QoL subanalysis at the American College of Cardiology (ACC) 2007 Scientific Sessions, the meeting at which the trial's primary results were also first formally reported. Both analyses were covered at the time by heartwire.
Dr Sanjay Kaul (Cedars-Sinai Medical Center, Los Angeles, CA), who has defended COURAGE in the literature [4], said to heartwire that "the most remarkable observation from COURAGE is the stellar performance of optimal medical therapy, which not only affected hard outcomes, but more impressively affected outcomes for which PCI clearly was thought to have an advantage, which is relief of angina and ischemia."
Although PCI did show significant QoL advantages during the first two years, there is a "disconnect between statistical significance and clinical importance," Kaul said. "While the difference in health status and anginal frequency in COURAGE is unequivocally significant in favor of PCI plus OMT, it is likely too small to be judged as being clinically important."
He continued, "if OMT is just as good and doesn't have the drawbacks of being invasive and associated with some periprocedural complications and added cost, then it stands to reason that the initial treatment strategy should then be optimal medical therapy, failing which PCI can be considered."
Angina frequency: Mean SAQ scores* by randomization group in COURAGE
Follow-up time, mo
PCI + OMT
OMT
p
3
85
80
< 0.001
12
87
84
0.003
24
89
86
0.002
36
89
88
0.37SAQ=Seattle Angina Questionnaire. OMT=optimal medical therapy*No significant differences between groups at baseline
In an editorial accompanying the QoL analysis [5], Dr Eric D Peterson (Duke Clinical Research Institute, Durham, NC) and Dr John S Rumsfeld (University of Colorado Denver Health Sciences Center) also questioned the clinical importance of PCI's early edge. "Depending on the domain evaluated," they write, "the health-status advantages associated with PCI persisted for six to 24 months. However, although the benefits were significant, the comparative differences were small, leaving open the question of whether a PCI-first strategy is justified."
As most patients in the OMT-only group showed symptomatic improvement within three months while 21% crossed over to PCI, observe Peterson and Rumsfeld, "a very reasonable take-home message from the COURAGE trial is to pursue optimal medical therapy initially and if this is ineffective, turn to PCI."
But interpretations of the QoL analysis vary, as they did for the trial's primary outcomes. The QoL data, Dr Bonnie Weiner (Worcester Medical Center, MA) told heartwire, "clearly shows the symptomatic benefit and the quality-of-life benefit for PCI, and I think that's what the interventional community has been saying all along. I think that actually it's a positive trial from that perspective. . . . I think it reaffirms that patients with more frequent and more severe angina do better with PCI than those with little or no angina. I think that's always been the case, and I don't think any of us have suggested otherwise." Weiner is the immediate past-president of the Society for Cardiovascular Angiography and Interventions.
Stepping back a bit . . .
COURAGE had randomized 2287 patients with stable CAD, at least one angiographically significant coronary stenosis, and inducible ischemia to either OMT plus PCI or OMT alone at centers in the US and Canada. Stents were used in the overwhelming majority of PCI cases, and they were bare-metal stents in all but a handful. OMT consisted of agents typical of today: nitrates, beta blockers, calcium-channel blockers, statins, and ACE inhibitors or angiotensin-receptor blockers.
With 1149 patients assigned to early PCI, the 1138 randomized to OMT-only went to revascularization if their angina failed to respond "or when there was objective evidence of worsening ischemia on noninvasive testing, at the discretion of the patient's physician," the primary report notes [2].
The groups didn't differ significantly in the primary end point of death or MI over a median follow-up of 4.6 years; it was 19.0% for early PCI and 18.5% for first-line OMT (p=0.62).
In the trial's 313-patient nuclear imaging substudy [3], the PCI-based approach significantly reduced the total burden of ischemia as judged by stress-single photon emission computed tomography (SPECT) myocardial perfusion imaging. The difference was most profound among patients initially with moderate-to-severe ischemia.
Quality of life: Mean SAQ scores* by randomization group in COURAGE
Follow-up time, mo
PCI + OMT
OMT
p
3
73
68
< 0.001
12
76
73
0.008
24
77
76
0.10
36
79
77
0.32SAQ=Seattle Angina Questionnaire. OMT=optimal medical therapy*No significant differences between groups at baseline
In the current analysis, SAQ scores for the two groups were similar at baseline for all domains and improved significantly by one to three months (p<0.001 for all improvements), write Weintraub et al. "This finding with respect to the benefit of OMT alone shows that PCI is not always essential for the relief of symptoms in patients with stable angina."
That observation also intrigued the editorialists. "A remarkable finding from the COURAGE study was the rapidity of improvement in health status in both treatment groups. This should serve as encouraging news to patients with coronary disease," they write.
"With contemporary treatment, the majority of patients had substantial improvements in health status that were sustained for several years. At the same time, the rapid improvement with optimal medical therapy alone suggests that antianginal medications are underused in practice."
According to Weintraub et al, "Scores were higher in the PCI group than in the medical-therapy group for six to 24 months, depending on the domain. By 36 months, the addition of PCI to optimal medical therapy no longer provided a significant advantage for any domain."
That eventual QoL parity between COURAGE groups also has more than one interpretation. While some see it as evidence for only a slim practical difference between the strategies, if any, others point to PCI's early advantage as fundamental to the study's message.
PCI's performance in COURAGE was attenuated because DES were only rarely used, observed Weiner. "But for two years or more, the PCI patients felt better, had fewer symptoms, and had a better quality of life," she said. "I do think that's a significant finding."
"Bad PCI and unrealistically good medicine"
PCI didn't surpass OMT more decisively because the trial used "bad PCI and unrealistically good medicine," Dr Dean J Kereiakes (Christ Hospital Heart and Vascular Center, Cincinnati, OH), coauthor of a published critique of the trial's methods [6], told heartwire.
Physical limitation: Mean SAQ scores* by randomization group in COURAGE
Follow-up time, mo
PCI + OMT
OMT
p
3
76
72
0.004
12
75
73
0.21
24
74
72
0.16
36
74
74
0.68SAQ=Seattle Angina Questionnaire. OMT=optimal medical therapy*No significant differences between groups at baseline
"I'm amazed PCI as performed in this trial maintained superiority through two years, because of the extremely high frequency of bare-metal stents, high frequency of standard balloon angioplasty, and the incomplete revascularization in the PCI cohort," Kereiakes said.
According to the trial's primary report, "complete revascularization was performed as clinically appropriate." But it also notes that 69% and 70% of routine-PCI and OMT-only patients, respectively, had two- or three-vessel disease, whereas only 41% of routine-PCI patients received more than one stent [2]. Only 31 patients received DES, which for most of the study had yet to become available, the report notes.
"Think of what could have been achieved if more complete PCI had been performed, with optimal technology — that is, with drug-eluting stents. You would have had a more durable benefit of PCI," Kereiakes said.
Excellent medical therapy and a high level of compliance within the confines of the clinical trial also narrowed the outcomes gap between the two patient groups, Kereiakes said. "The level of medication and even the goals achieved, as far as blood-pressure control, cholesterol levels, etc, were truly remarkable in this trial. It's admirable, I think it's inspirational, but it's unrealistic."
In the eye of the beholder
He added, "Patients with objective evidence of ischemia, absolutely, if feasible, should have PCI plus OMT, unless there are mitigating circumstances." PCI wouldn't be required, he said, if medication completely controls both symptoms and objectively documented ischemia, whether symptomatic or silent.
"These data contribute to my enthusiasm for doing PCI better than was done in this trial," Kereiakes said. "Still giving optimal medications to the extent that they're tolerated and the patients are compliant, I have no doubt that a strategy of complete revascularization with optimal technologies would provide a significantly greater gap than was demonstrated to two years in this trial and would extend that benefit beyond two years."
On the latter point, Weiner seemed to agree. If recurrent symptoms after PCI are often due to restenosis and DES can "virtually eliminate" restenosis — both ideas are borne out by the data — and then if DES are used in COURAGE-like patients, "it's not unreasonable to think that the separation between the two groups would be wider, and it would be maintained for a longer period of time," she said.
More conservative about when to perform PCI in COURAGE-like patients, Kaul outlined a scenario he thinks might indicate invasive management. "If on objective assessment you demonstrate a substantial degree of myocardial ischemia in association with reduced LV [left ventricular] systolic function, that would be a case where I could justify an initial PCI strategy," he said.
"I would say, high-risk anatomy and a high-risk functional stress test — a large amount of myocardial ischemia and compromised LV function — those would be reasons why I would offer PCI over medical therapy [only]."
Editorialists Peterson and Rumsfeld emphasize that OMT and PCI aren't actually competitors. "The COURAGE trial redefines the contemporary roles of optimal medical therapy and PCI in the management of patients with stable angina. Rather than one victor, COURAGE demonstrates that both treatment strategies can have a profoundly positive effect on patients' health status and suggests complementary roles — optimal medical therapy as first-line therapy, with PCI reserved for patients who do not have a response or who have severe baseline symptoms."
Dr. Weintraub has received consulting fees from sanofi-aventis, GlaxoSmithKline, Indigo Pharmaceuticals, and CV Therapeutics and grant support from sanofi-aventis, AstraZeneca, Otsuka, and Bristol-Myers Squib; disclosures for the other COURAGE coauthors and for the 2 editorialists are listed in the original article. Drs. Kaul and Weiner have disclosed no relevant financial relationships. Dr. Kereiakes has disclosed various financial relationships with Abbott/Bioabsorbable Vascular Solutions, Amylin Pharmaceuticals, Cordis/Johnson & Johnson, Boston Scientific, Medtronic, Daiichi Sanyko, Devax, Eli Lilly, and Medpace.
Sources
Weintraub WS, Spertus JA, Kolm P, et al. Effect of PCI on quality of life in patients with stable coronary disease. N Engl J Med. 2008;359:677-687. http://content.nejm.org/cgi/content/short/359/7/677
Boden WE, O'Rourke RA, Teo KK, et al. Optimal medical therapy with or without PCI for stable coronary disease. N Engl J Med. 2007;356:1503-16.
Shaw LJ, Berman DS, Maron DJ, et al. Optimal medical therapy with or without percutaneous coronary intervention to reduce ischemic burden: results from the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial nuclear substudy. Circulation. 2008;117:1283-1291. PMID: 18268144.
Diamond GA, Kaul S. COURAGE under fire. On the management of stable coronary disease. J Am Coll Cardiol. 2007;50:1604-1609. DOI:10.1016/j.jacc.2007.08.010.
Peterson ED, Rumsfeld JS. Finding the courage to reconsider medical therapy for stable angina. N Engl J Med. 2008;359:751-753. http://content.nejm.org/cgi/content/short/359/7/751
Kereiakes DJ, Teirstein PS, Sarembock IJ, et al. The truth and consequences of the COURAGE trial. J Am Coll Cardiol. 2007;50:1598-1603. DOI:10.1016/j.jacc.2007.07.063.
The complete contents of Heartwire, a professional news service of WebMD, can be found at www.theheart.org, a Web site for cardiovascular healthcare professionals.
Clinical Context
The COURAGE trial previously demonstrated that PCI may not improve cardiovascular or mortality outcomes in patients with stable angina and coronary artery disease. In this trial, patients were randomly assigned to undergo PCI plus OMT vs OMT alone. The main result of this trial, which was published in the April 12, 2007, issue of the New England Journal of Medicine, was that there were no significant differences between the group undergoing PCI plus medical therapy and the group that received medical therapy alone in the composite outcome of death, myocardial infarction, and stroke. In addition, rates of hospitalization for acute coronary syndrome and myocardial infarction were similar between treatment groups.
QoL is another important outcome for patients with coronary artery disease. The current report from the COURAGE trial examines QoL across multiple domains among randomized groups.
Study Highlights
Patients eligible for study participation had stenosis of at least 70% in at least 1 epicardial coronary artery or stenosis of at least 80% in 1 coronary artery plus classic angina symptoms.
Participants were randomly assigned to receive PCI plus OMT or OMT alone. Medical therapy conformed to standard best treatment for secondary prevention of coronary events.
The main outcomes of the study were the 19-item SAQ along with the Research and Development 36-Item Health Survey. These questionnaires were completed at baseline; at 1, 3, 6, and 12 months; and then annually thereafter. Both surveys use a scale of 0 to 100, with a higher score indicating better QoL.
2287 patients underwent randomization. The median follow-up period was 4.6 years.
88% of participants were experiencing angina at the time of baseline testing. However, the percentage of subjects with angina improved in both randomization groups after 1 month and continued to improve thereafter.
PCI plus OMT was superior to OMT alone in the percentage of angina-free patients at 24 months but not at 36 months.
The mean baseline scores on the SAQ were 66 for physical limitation, 54 for angina stability, 69 for angina frequency, 87 for treatment satisfaction, and 51 for QoL.
At 3 months, all of these values were superior in the group undergoing PCI plus OMT vs the group receiving OMT alone (76 vs 72 for physical limitations, 77 vs 73 for angina stability, 85 vs 80 for angina frequency, 92 vs 90 for treatment satisfaction, and 73 vs 68 for QoL, respectively).
Participants with more severe angina at baseline were particularly more likely to benefit from PCI plus OMT vs OMT alone.
PCI conferred an incremental benefit on QoL from 6 to 24 months. However, this benefit was not significant at 36 months.
Responses to the Research and Development 36-Item Health Survey improved in both groups between 1 and 3 months, although the group undergoing PCI plus OMT improved to a larger degree than the group receiving OMT alone at 3 months. This difference between groups in this outcome disappeared by 12 months.
The authors conclude that 12.5 patients would need to be treated with PCI in addition to OMT to achieve 1 additional significant improvement in QoL.
Pearls for Practice
A previous report from the COURAGE trial demonstrated no significant difference between PCI plus OMT and OMT alone in the composite outcome of death, myocardial infarction, and stroke. In addition, rates of hospitalization for acute coronary syndrome and myocardial infarction were similar between treatment groups.
In the current study of the COURAGE trial, PCI in addition to OMT improved QoL through 24 but not 36 months. Patients with more severe angina were likely to benefit from the addition of PCI to OMT

Tibolona na pós-menopausa

The Effects of Tibolone in Older Postmenopausal Women
Steven R. Cummings, M.D., Bruce Ettinger, M.D., Pierre D. Delmas, M.D., Ph.D., Peter Kenemans, M.D., Ph.D., Victoria Stathopoulos, Ph.D., Pierre Verweij, Ph.D., Mirjam Mol-Arts, M.D., Lenus Kloosterboer, Ph.D., Lori Mosca, M.D., Ph.D., M.P.H., Claus Christiansen, M.D., John Bilezikian, M.D., Eduardo Mario Kerzberg, M.D., Susan Johnson, M.D., Jose Zanchetta, M.D., Diederich E. Grobbee, M.D., Ph.D., Wilfried Seifert, Ph.D., Richard Eastell, M.D., for the LIFT Trial Investigators

ABSTRACT
Background Tibolone has estrogenic, progestogenic, and androgenic effects. Although tibolone prevents bone loss, its effects on fractures, breast cancer, and cardiovascular disease are uncertain.
Methods In this randomized study, we assigned 4538 women, who were between the ages of 60 and 85 years and had a bone mineral density T score of –2.5 or less at the hip or spine or a T score of –2.0 or less and radiologic evidence of a vertebral fracture, to receive once-daily tibolone (at a dose of 1.25 mg) or placebo. Annual spine radiographs were used to assess for vertebral fracture. Rates of cardiovascular events and breast cancer were adjudicated by expert panels.
Results During a median of 34 months of treatment, the tibolone group, as compared with the placebo group, had a decreased risk of vertebral fracture, with 70 cases versus 126 cases per 1000 person-years (relative hazard, 0.55; 95% confidence interval [CI], 0.41 to 0.74; P<0.001), and a decreased risk of nonvertebral fracture, with 122 cases versus 166 cases per 1000 person-years (relative hazard, 0.74; 95% CI, 0.58 to 0.93; P=0.01). The tibolone group also had a decreased risk of invasive breast cancer (relative hazard, 0.32; 95% CI, 0.13 to 0.80; P=0.02) and colon cancer (relative hazard, 0.31; 95% CI, 0.10 to 0.96; P=0.04). However, the tibolone group had an increased risk of stroke (relative hazard, 2.19; 95% CI, 1.14 to 4.23; P=0.02), for which the study was stopped in February 2006 at the recommendation of the data and safety monitoring board. There were no significant differences in the risk of either coronary heart disease or venous thromboembolism between the two groups.
Conclusions Tibolone reduced the risk of fracture and breast cancer and possibly colon cancer but increased the risk of stroke in older women with osteoporosis.

Anticoagulação na angioplastia para angina

Bivalirudin versus Unfractionated Heparin during Percutaneous Coronary Intervention
Adnan Kastrati, M.D., Franz-Josef Neumann, M.D., Julinda Mehilli, M.D., Robert A. Byrne, M.B., M.R.C.P.I., Raisuke Iijima, M.D., Heinz Joachim Büttner, M.D., Ahmed A. Khattab, M.D., Stefanie Schulz, M.D., James C. Blankenship, M.D., Jürgen Pache, M.D., Jan Minners, M.D., Melchior Seyfarth, M.D., Isolde Graf, Pharm.D., Kimberly A. Skelding, M.D., Josef Dirschinger, M.D., Gert Richardt, M.D., Peter B. Berger, M.D., Albert Schömig, M.D., for the ISAR-REACT 3 Trial Investigators
ABSTRACT
Background Whether bivalirudin is superior to unfractionated heparin in patients with stable or unstable angina who undergo percutaneous coronary intervention (PCI) after pretreatment with clopidogrel is unknown.
Methods We enrolled 4570 patients with stable or unstable angina (with normal levels of troponin T and creatine kinase MB) who were undergoing PCI after pretreatment with a 600-mg dose of clopidogrel at least 2 hours before the procedure; 2289 patients were randomly assigned in a double-blind manner to receive bivalirudin, and 2281 to receive unfractionated heparin. The primary end point was the composite of death, myocardial infarction, urgent target-vessel revascularization due to myocardial ischemia within 30 days after randomization, or major bleeding during the index hospitalization (with a net clinical benefit defined as a reduction in the incidence of the end point). The secondary end point was the composite of death, myocardial infarction, or urgent target-vessel revascularization.
Results The incidence of the primary end point was 8.3% (190 patients) in the bivalirudin group as compared with 8.7% (199 patients) in the unfractionated-heparin group (relative risk, 0.94; 95% confidence interval [CI], 0.77 to 1.15; P=0.57). The secondary end point occurred in 134 patients (5.9%) in the bivalirudin group and 115 patients (5.0%) in the unfractionated-heparin group (relative risk, 1.16; 95% CI, 0.91 to 1.49; P=0.23). The incidence of major bleeding was 3.1% (70 patients) in the bivalirudin group and 4.6% (104 patients) in the unfractionated-heparin group (relative risk, 0.66; 95% CI, 0.49 to 0.90; P=0.008).
Conclusions In patients with stable and unstable angina who underwent PCI after pretreatment with clopidogrel, bivalirudin did not provide a net clinical benefit (i.e., it did not reduce the incidence of the composite end point of death, myocardial infarction, urgent target-vessel revascularization, or major bleeding) as compared with unfractionated heparin, but it did significantly reduce the incidence of major bleeding. (ClinicalTrials.gov number, NCT00262054 [ClinicalTrials.gov] .)

COURAGE: angioplastia e qualidade de vida na angina do peito

Effect of PCI on Quality of Life in Patients with Stable Coronary Disease
William S. Weintraub, M.D., John A. Spertus, M.D., M.P.H., Paul Kolm, Ph.D., David J. Maron, M.D., Zefeng Zhang, M.D., Ph.D., Claudine Jurkovitz, M.D., M.P.H., Wei Zhang, M.S., Pamela M. Hartigan, Ph.D., Cheryl Lewis, R.N., Emir Veledar, Ph.D., Jim Bowen, B.S., Sandra B. Dunbar, D.S.N., Christi Deaton, Ph.D., Stanley Kaufman, M.D., Robert A. O'Rourke, M.D., Ron Goeree, M.S., Paul G. Barnett, Ph.D., Koon K. Teo, M.D., William E. Boden, M.D., for the COURAGE Trial Research Group
ABSTRACT
Background It has not been clearly established whether percutaneous coronary intervention (PCI) can provide an incremental benefit in quality of life over that provided by optimal medical therapy among patients with chronic coronary artery disease.
Methods We randomly assigned 2287 patients with stable coronary disease to PCI plus optimal medical therapy or to optimal medical therapy alone. We assessed angina-specific health status (with the use of the Seattle Angina Questionnaire) and overall physical and mental function (with the use of the RAND 36-item health survey [RAND-36]).
Results At baseline, 22% of the patients were free of angina. At 3 months, 53% of the patients in the PCI group and 42% in the medical-therapy group were angina-free (P<0.001). Baseline mean (±SD) Seattle Angina Questionnaire scores (which range from 0 to 100, with higher scores indicating better health status) were 66±25 for physical limitations, 54±32 for angina stability, 69±26 for angina frequency, 87±16 for treatment satisfaction, and 51±25 for quality of life. By 3 months, these scores had increased in the PCI group, as compared with the medical-therapy group, to 76±24 versus 72±23 for physical limitation (P=0.004), 77±28 versus 73±27 for angina stability (P=0.002), 85±22 versus 80±23 for angina frequency (P<0.001), 92±12 versus 90±14 for treatment satisfaction (P<0.001), and 73±22 versus 68±23 for quality of life (P<0.001). In general, patients had an incremental benefit from PCI for 6 to 24 months; patients with more severe angina had a greater benefit from PCI. Similar incremental benefits from PCI were seen in some but not all RAND-36 domains. By 36 months, there was no significant difference in health status between the treatment groups.
Conclusions Among patients with stable angina, both those treated with PCI and those treated with optimal medical therapy alone had marked improvements in health status during follow-up. The PCI group had small, but significant, incremental benefits that disappeared by 36 months.