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Medical Forum / General / Cardiology / March 2006Ezetimibe/Simvastatin Better Than a Statin Alone
I think this suggests the combination drug will lead to less events but does not prove it. Bill _____________________ Ezetimibe/Simvastatin Better Than a Statin Alone Charlene Laino Medscape Medical News 2006. © 2006 Medscape March 20, 2006 (Atlanta) - A combination of the cholesterol-lowering drugs ezetimibe and simvastatin is more effective at lowering C-reactive protein (CRP) levels than simvastatin alone, a post-hoc analysis of 3 randomized, placebo-controlled, double-blind studies suggests. A second study showed that ezetimibe/simvastatin was better than atorvastatin in lowering CRP, low-density lipoprotein (LDL) cholesterol, and apolipoprotein (ApoB) levels. "Ezetimibe/simvastatin provided enhanced lipid regulation and anti-inflammatory effects compared to simvastatin or atorvastatin alone," said Christie M. Ballantyne, MD, associate chief and professor of medicine in the section of atherosclerosis and lipoprotein research at Baylor College of Medicine in Houston, Texas. Dr. Ballantyne presented both studies here at the 55th annual scientific session of the American College of Cardiology (ACC). The first pooled analysis used data from 3 randomized, placebo-controlled trials that enrolled 3083 patients with hypercholesterolemia. In each of the studies, patients discontinued therapy for 4 to 6 weeks and then were randomized to placebo, ezetimibe (10 mg), ezetimibe/simvastatin (10/10, 20, 40, 80 mg), or simvastatin (10, 20, 40, 80 mg) for 12 weeks. Ezetimibe/simvastatin is sold as Vytorin. Overall results, which were pooled across the dose range, showed that CRP levels decreased 31% from baseline for patients receiving ezetimibe/simvastatin compared with 14.3% in patients receiving simvastatin (P < .001). Ezetimibe by itself did not significantly reduce levels of CRP, Dr. Ballantyne said. The pooled data also showed that the combination treatment reduced LDL cholesterol levels by 52.5% while simvastatin lowered LDL cholesterol levels by 38% (P < .001). The second study, a post-hoc analysis of the Vytorin Versus Atorvastatin (VYVA) study of 1902 patients with high cholesterol levels, showed that 32.5% of patients receiving ezetimibe/simvastatin achieved LDL cholesterol levels of less than 70 mg/dL and ApoB levels of less than 90 mg/dL compared with 16% of patients receiving atorvastatin alone (P < .001). Also, 20.7% of patients receiving ezetimibe/simvastatin achieved an LDL cholesterol level of less than 70 mg/dL and a CRP level of less than 2 mg/L compared with 9.8% of patients receiving atorvastatin (P < .001). All of the drugs were well tolerated. James H. Stein, MD, cochair of the scientific program committee for the ACC meeting and an associate professor of medicine at the University of Wisconsin Medical School in Madison, told Medscape that while interesting, the results will need to be confirmed in additional, prospective studies before changing clinical practice. ACC 55th Annual Scientific Session: Abstracts 808-5 and 981-194. Presented March 13, 2006. > I think this suggests the combination drug will lead to less events but does > not prove it. > > Bill If you buy that lower LDL and CRP means fewer events, that would be a reasonable hypothesis. If you think there is something unique about lowering cholesterol with statins (and there's a fair amount of evidence to suggest this is the case) then the lower LDL/CRP doesn't really tell us anything at all that is clinically important.  SignatureDavid Rind drind@caregroup.harvard.edu >If you buy that lower LDL and CRP means fewer events, that would be a >reasonable hypothesis. If you think there is something unique about >lowering cholesterol with statins (and there's a fair amount of evidence >to suggest this is the case) then the lower LDL/CRP doesn't really tell >us anything at all that is clinically important. Please tell me more! I've seen a lot of studies that suggested that LDL reduction is only loosely related to preventing CHD. But I've figured that inflammation (fairly well measured by CRP) was the missing piece of the puzzle. I've seen articles suggesting that the statins do most of their good by releiving inflammation. You seem to be saying that it isn't the LDL and it isn't the inflammation (or at least not as indicated by CRP.) I'd like to read more about this - where do I go? David Throop >>If you buy that lower LDL and CRP means fewer events, that would be a >>reasonable hypothesis. If you think there is something unique about [quoted text clipped - 13 lines] > > David Throop There are lots of hints that statins may have important effects independent of LDL lowering. These may include decreasing inflammation (which may or may not be appropriately measured by CRP) and stabilizing arterial plaques. All of this is difficult to separate out. Statins lower LDL and lower cardiac risk, and higher doses lower LDL more and lower cardiac risk more. That does not mean that it's the LDL lowering that reduces the cardiac risk, but it certainly could be. In any case, there are no published trials showing that ezetimibe has any beneficial effects on clinical endpoints (like lowering cardiac events), just that it lowers cholesterol. In the absence of such trials, I'm more comfortable with statins, the only class of lipid lowering drugs that has consistently shown clinical benefits. SignatureDavid Rind drind@caregroup.harvard.edu David Rind <drind@caregroup.harvard.edu> wrote in part: >All of this is difficult to separate out. Statins lower LDL and lower >cardiac risk, and higher doses lower LDL more and lower cardiac risk >more. That does not mean that it's the LDL lowering that reduces the >cardiac risk, but it certainly could be. Well, all we need to do then, is to run a study that compares a statin with another drug that lowers LDL by 50% or so. Oh ... right. ;-) -- Jim Chinnis Warrenton, Virginia, USA > David Rind <drind@caregroup.harvard.edu> wrote in part: > [quoted text clipped - 5 lines] > Well, all we need to do then, is to run a study that compares a statin with > another drug that lowers LDL by 50% or so. Oh ... right. ;-) Actually, I've heard that there is a trial out there looking at clinical outcomes comparing atorvastatin alone with simvastatin/ezetimibe with the LDL goal the same in both arms. This should give us some additional information about whether it's the statin or the achieved LDL that matters. SignatureDavid Rind drind@caregroup.harvard.edu David Rind <drind@caregroup.harvard.edu> wrote in part: >> David Rind <drind@caregroup.harvard.edu> wrote in part: >> [quoted text clipped - 10 lines] >the LDL goal the same in both arms. This should give us some additional >information about whether it's the statin or the achieved LDL that matters. I also have read a report on a study that compared CAD outcome rates in people with different gene sequences known to affect their LDL level. I'd post a reference, but I don't remember it! It may have been released today. Just one more way to get a little more triangulation. -- Jim Chinnis Warrenton, Virginia, USA Jim Chinnis <jchinnis@SPAMalum.mit.edu> wrote in part: >David Rind <drind@caregroup.harvard.edu> wrote in part: > [quoted text clipped - 17 lines] >post a reference, but I don't remember it! It may have been released today. >Just one more way to get a little more triangulation. Here's the study: N Engl J Med. 2006 Mar 23;354(12):1264-72. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. Cohen JC, Boerwinkle E, Mosley TH Jr, Hobbs HH. Donald W. Reynolds Cardiovascular Clinical Research Center, University of Texas Southwestern Medical Center, Dallas, TX 75390-9046, USA. BACKGROUND: A low plasma level of low-density lipoprotein (LDL) cholesterol is associated with reduced risk of coronary heart disease (CHD), but the effect of lifelong reductions in plasma LDL cholesterol is not known. We examined the effect of DNA-sequence variations that reduce plasma levels of LDL cholesterol on the incidence of coronary events in a large population. METHODS: We compared the incidence of CHD (myocardial infarction, fatal CHD, or coronary revascularization) over a 15-year interval in the Atherosclerosis Risk in Communities study according to the presence or absence of sequence variants in the proprotein convertase subtilisin/kexin type 9 serine protease gene (PCSK9) that are associated with reduced plasma levels of LDL cholesterol. RESULTS: Of the 3363 black subjects examined, 2.6 percent had nonsense mutations in PCSK9; these mutations were associated with a 28 percent reduction in mean LDL cholesterol and an 88 percent reduction in the risk of CHD (P=0.008 for the reduction; hazard ratio, 0.11; 95 percent confidence interval, 0.02 to 0.81; P=0.03). Of the 9524 white subjects examined, 3.2 percent had a sequence variation in PCSK9 that was associated with a 15 percent reduction in LDL cholesterol and a 47 percent reduction in the risk of CHD (hazard ratio, 0.50; 95 percent confidence interval, 0.32 to 0.79; P=0.003). CONCLUSIONS: These data indicate that moderate lifelong reduction in the plasma level of LDL cholesterol is associated with a substantial reduction in the incidence of coronary events, even in populations with a high prevalence of non-lipid-related cardiovascular risk factors. Copyright 2006 Massachusetts Medical Society. PMID: 16554528 [PubMed - in process] -- Jim Chinnis Warrenton, Virginia, USA Did this study account for CRP markers as well or only LDL levels? It is still hard to tell whether the increased protective effect is due to the LDL decrease or the CRP decrease. There are new drugs in the works trying to target CRP only, when they come out we may have an answer in 10 to 30 years as to which one is the better choice for therapy. Although I would venture we will just prescribe both unless one or the other is contraindicated in certain populations. |
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