JUPITER: Randomized Clinical Trial, double blinded, placebo controlled. 1315 sties in 26 countries. To see if cardiovascular naïve people with high hsCRP will have less CV events on Crestor.
drjohnhong 
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Vytorin has been in the news since January 14, 2008 due to the announcement of the ENHANCE trial. Vytorin is a combo pill of simvastatin (Brand name was Zocor) and Zetia. Simvastatin was shown in the Heart Protection to reduce cardiovascular deaths. However, Zetia has not been proven to reduce heart attack, strokes, or cardiovascular deaths. But Zetia has been shown to lower LDL – bad cholesterol that is associated with cardiovascular disease.
Back in 2001 a medical journal (Lancet) published the ASAP trial. It looked at a rare population of people with Heterozygous Familial Hypercholesterolemia, a genetic disorder seen in 0.2% of people with high cholesterol. The ENHANCE trial looked at the same group of folks. In the ASAP trial Zocor and Lipitor were compared to see reduction in carotid intima media artery thickness (IMT). IMT is measured simply by ultrasound. It is a clinical predictor of coronary artery disease. I never understood this study because the dose of Lipitor was 80mg (the highest dose) but Zocor was 40mg (though 80mg is the highest dose). So in the end of ASAP, Lipitor reduced IMT (which is good) but Zocor showed an increase in IMT (bad).
The ENHANCE trial basically did the same study as the ASAP but compared simvastatin (AKA Zocor) vs. Vytorin. This time though, the ENHANCE used 80mg of Zocor instead of 40mg in ASAP. Also the Vytorin group got the standard 10mg of Zetia and 80mg of Zocor.
The 720 folks with Heterozygous Familial Hypercholesterolemia had really high LDL levels, way higher than most people have. I would say in my practice, a person with an LDL 200 or more is pretty unusual. In the ENHANCE trial the average LDL at the start of the study was 319 in the group whom received Vytorin and 318 in the simvastatin group. Pretty darn high—ouch!
The IMT baseline means were 0.68mm (Vytorin group) and 0.69mm (simvastatin group). After 2 years of the trial, there was an increase of 0.0111mm in Vytorin group and 0.0058 in simvastatin group. If I did my math right, that means the end mean IMTs were 0.6911 in Vytorin and 0.6958 in simvastatin. Statistically it was not significant meaning they were basically the same from what we can tell. What is normal carotid IMT? It depends on your age, sex, and risk factors. Also I don’t know if they did this study in kids or not. Sigh.
So what does the IMT increase mean? The inner layer of the artery can become plump from cholesterol buildup. For adults, there is a moderate graded positive association between the carotid IMT and CAD (coronary artery disease). A meta-analysis of 8 studies showed: 15% increased risk of heart attack and 18% increased risk of stroke for every 0.10mm increase in carotid IMT.
Now I don’t have the real paper article. Because of the MEDIA not waiting for physicians to be able to critically appraise the study, I am forced to make my assessment from the literature in the papers, including Merck/Schering-Plough, CNN, AHA, and ACC. It doesn’t look like Vytorin is a dangerous drug compared to a plain statin like simvastatin alone and we have always known a very small increased risk of liver toxicity (2.8% Vytorin vs. 2.2% simvastatin) and muscle breakdown (2.2% Vytorin and 1.1% simvastatin). The problem is…how does this relate to reducing real heart attack and strokes in people who don’t have a genetic high cholesterol disorder as in the ENHANCE study? I don’t know. There isn’t a research trial to show this. I will say it is not great news the IMT didn’t improve but got worse with both simvastatin and Vytorin. But then again in the ASAP simvastatin had worsening IMT but the Heart Protection Study shows the benefits of simvastatin. This to me means more research needs to be done, but at this point it won’t make me take anyone off Vytorin and Zetia or stop it in my patients
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Effect of Rosiglitazone on the Risk of Myocardial Infarction and Death from Cardiovascular Causes. NEJM 5/21/07; 356
Avandia (generic name rosiglitazone) is a thiazolidinedione medication for type II diabetes. It is an agonist for peroxisome-proliferator-activated receptor gamma (PPAR-gamma) and has been around since 1999.
In diabetics, 65% of deaths are cardiovascular related. The meta-analysis of this study was done to increase the power to see what are the cardiovascular outcomes.
116 studies were investigated and 42 studies were analyzed for this meta-analysis. Criteria for entry included more than 24 weeks of drug exposure, randomized studies, MI (heart attack) or cardiovascular deaths had to be reported. Outcomes: MI. Cardiovascular Deaths.
15,560 people were in the Avandia treatment group and 12,283 in the control group (control group were divided into those taking insulin, sulfonylurea, metformin, and placebo). Most of the subjects were men around 57 years old, and diabetes control was relatively poor in both groups (HbA1C average 8.2%)
The trials had very few MIs or cardiovascular deaths, so they used some statistical method I have never heard of, the Peto Method. I’m not sure how they determined what would be clinically significant and statistically significant between Avandia group and control group.
Results are pretty similar. In the Avandia group, there were 86 MIs (0.55%) and in the Control group 72 MIs (0.58%). For cardiovascular deaths, the Avandia group had 39 deaths (0.25%) and the Control group had 22 deaths (0.18%).
So for MIs, Avandia had a 1.43 times increased risk of MI compared to control (43%) that is statistically significant. But in epidemiology, 43% increase risk is a weak to mild association. You need more of a 200-300% increase risk to be a strong association. Also if you just look at the numbers, 86 heart attacks out of 15,560 isn’t a whole lot in particular vs. 72 heart attacks out of 12,283 controls.
For cardiovascular, there is no increased risk of cardiovascular death that is statistically proven.
I think the findings are interesting but it is too soon to “jump the gun” like the media is doing. A study needs to be done and powered correctly to see if Avandia does indeed cause heart attacks and/or cardiovascular deaths. But I don’t think anyone can say for sure at this point that Avandia does cause heart attacks. We do know Avandia can’t be used in Stage III or IV congestive heart failure and I wonder if the heart attacks were due to this. Many questions have been raised from this meta-analysis.
© John S. Hong, MD, MS May 22, 2007
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