Assault on Canada's #1 killer

Rosuvastatin reverses artery
plaque buildup

By Owen Dyer

The ASTEROID trial tested 40mg of rosuvastatin daily on 507 subjects at 53 centres in Canada, the US, Europe and Australia. This extremely aggressive statin therapy reduced low-density (LDL) or 'bad' cholesterol by, on average, slightly more than half. High-density (HDL) or 'good' cholesterol levels were raised by a mean average 14.7%, an unprecedented boost in a figure that's seen as practically impossible to budge.

The effects on atherosclerotic plaques were not as dramatic, but still highly significant. Lead author Dr Steven Nissen, of the University of Michigan Medical School, says he'd never seen regression of atherosclerotic plaques in his entire career before this trial. The findings appear in the March 13 issue of JAMA and are freely available online.

The ASTEROID (A Study to Evaluate the Effect of Rosuvastatin on Intravascular Ultrasound-Derived Coronary Atheroma Burden) trial lasted two years. Changes in atherosclerotic burden over time were measured with the relatively new technique of intravascular ultrasound that relies on a catheter to visualize the inner wall of blood vessels. Dr Nissen and his team found that total atheroma volume was reduced by an average of 6.8%, while atheroma volume in the most diseased 10mm subsegment fell by a mean average of 8.5%.

Of 507 patients who began the trial, 349 progressed to the end and had usable intravascular ultrasound rates. Their average age was 58, 70% were male and almost all were white. Most were taking concomitant medications including aspirin, beta-blockers and ACE inhibitors.

Dr Nissen said the high dropout rate wasn't due to poor tolerance of the high-dose statins. "Many subjects decided that they didn't feel like undergoing a second catheterization [at the end of the trial] for research purposes. We had to respect that decision," he explains.

The key finding of this study, said Dr Nissen, is that the regression of atheroma was only seen after patients' LDL cholesterol was pushed down farther than current guidelines recommend. "I recently did a study where we got cholesterol down to an average of two mmol/L (78 mg/dL), and we didn't see anything like this. Here we were getting cholesterol down to about 1.6 mmol/L (62 mg/dL). That's very aggressive treatment, but it seems to make a major difference."

WORTH 1,000 WORDS
The findings have caused widespread excitement among heart disease experts.

After studying an intravascular ultrasound image of a before-and-after atherosclerotic plaque from the study, Dr Jacques Genest, director of the cardiology division at the McGill University Health Centre, exclaims: "Wow, they really reduced the size. That's impressive."

Dr Sidney Blumenthal, a cardiologist from Johns Hopkins, points out in a JAMA commentary that the same photo showed that the lumen of the blood vessel — the actual cavity or channel — was actually no larger than before treatment. As the plaques disappear, instead of the hollow inside of the vessel growing wider, he suggested the elastic outer membrane may contract, leaving the lumen itself unchanged.

But he says the results were significant nonetheless. "While the lumen in a resting person might be the same diameter, lowering cholesterol this much will have a beneficial effect on the epithelium, improving its ability to dilate during stress or exercise." The structure of the plaque also becomes safer, he added."Lumen is not the critical issue in cardiac events," adds Dr Genest. "Breakdown of the atherosclerotic plaque is generally the trigger. Lowering LDL cholesterol not only reduces plaque size, it also stabilizes the plaque cap, reducing the chance of rupture."

So where do these disappearing plaque fibrins actually go? "They're removed to the liver by HDL cholesterol through the reverse cholesterol transport pathway, then excreted," explains Dr Nissen.

RISKS vs BENEFITS
The most feared side effect of statins is rhabdomyolysis — the breakdown of skeletal muscle that can lead to acute renal failure — but Dr Nissen saw no incidents in the ASTEROID trial. Concerns over rhabdomyolysis led Health Canada to recommend a low starting dose for patients taking rosuvastatin. Some at-risk groups, notably Asians and people with kidney problems, are advised to start at just 5mg.

Forty milligrams is the highest approved dose, but Health Canada says this dose should be avoided in people taking other lipid-lowering drugs, heavy drinkers, those with hypothyroidism or liver problems and Asians, in whom genetic differences cause the same dose to typically produce twice the serum levels.

Dr Nissen, however, says that his experience leads him to believe that a reassessment of the risks and benefits is in order. Dr Genest, who's participating in an FDA safety-monitoring program involving 50,000 statin users, agrees that the risk of rhabdomyolysis is remote. "At 40mg, rosuvastatin, like atorvastatin and simvastatin, does cause a few cases of myalgia [muscle pain], about one %. But rhabdomyolysis is exceedingly rare, occurring at a fairly constant rate of one per two million."

Dr Genest concludes that as a proof of concept, this study is a great success. But, he warns, cardiologists are always wary of studies with surrogate endpoints. "We want to see large, randomized studies with endpoints like mortality and cardiac events."