The five statin mega-studies: a closer look
HPS. This study took place in the United Kingdom and was carried out on 20.536 adults ages forty to eighty at high risk for a heart attack (subjects had a previous diagnosis of coronary artery disease or diabetes). Patients were prescribed either 40 mg per day of a statin drug called Zocor of given a placebo pill over a period of five years, after which researchers determined that Zocor reduced a patient's risk of heart attack and stroke by approximately 25 percent. The LDL cholesterol was lowered in the Zocor group from an initial average of less than 116 mg/dL to less than 77 mg/dL in one subsection of the statin group and from about 156 g/dL to 117 mg/dL in the other subsection. This study proved that lowering LDL cholesterol 25 to 34 percent, with a statin drug, is a highly effective means of preventing heart attacks and stroke in a high-risk population.
ALLHAT-LLT. This trial drew patients from 513 community clinics in North America (United States, Puerto Rico, Canada, and the U.S. Virgin Islands). A total of 10,355 people at high risk for heart disease, age fifty-five or older with moderately high LDL cholesterol and high blood pressure, were recruited and randomized to either treatment with the statin drug Pravachol (40 mg/day) or to a "usual care" group. For purposes of the study, "usual care" was defined as treatment for high LDL according to the discretion of the subject's primary physician, which could include statin therapy. After four years, researchers found that LDL declined from 146 mg/dL to 102 mg/dL in the Pravachol group compared to 146 mg/dL to 122 mg/dL in the "usual care" group. No significant difference between the two groups was observed in terms of measured out-come (death rate from coronary artery disease or heart attacks). The problem with this study was that only 70 percent of the Pravachol group complied with their medication treatment and almost 30 percent in the "usual care" group took cholesterol - lowering drugs, factors that greatly diminish the ability to detect a difference between the two. However, the Pravachol group did exhibit an almost 10 percent reduction in heart attack risk, albeit this did not reach statistical significance. This finding suggests that the 20-point-lower LDL number confers greater protection. The authors of the study concluded that despite the small difference in outcome between the two groups, the results are still consistent with findings from other large-scale statin studies: lowering LDL is vital for the prevention and treatment of heart disease; the lower the LDL, the greater the reduction in risk.
ASCOT-LLA. This large-scale European trial recruited patients from several Nordic countries as well as the United Kingdom and Ireland. Researchers tested the impact of Lipitor in 10,305 people with high blood pressure. Patients were divided into two groups, one that took 10 mg of Lipitor per day and another that took a placebo. After just one year, and compared to the placebo group, the Lipitor group had an LDL cholesterol approximately 47 mg/dL lower (135 mg/dL versus 88 mg/dL). The study was designed to run for five years, but researchers saw such dramatic declines in death and disease that they chose to cut the study short after just three years and release the results: a 36 percent reduction in heart attack risk in patients taking Lipitor compared to the control group. Thus, getting LDL down to ultra-low values dramatically reduces risk of heart attack and stroke.
PROSPER. This study recruited 5,804 elderly individuals, ages seventy to eighty-two, from Scotland, Ireland, and the Netherlands, all at high risk for heart disease and stroke. The patients were randomly divided into two groups: those taking Pravachol (40 mg per day) or those given a placebo. After three years, it was found that Pravachol reduced LDL cholesterol by 34 percent (from 147 mg/dL to 97 mg/dL). Furthermore, death from heart disease fell by 24 percent in the group taking Pravachol compared to the control group. This study provides further evidence supporting the notion that the lowering of heart disease risk is roughly proportional to the reduction in LDL cholesterol.
PROVE IT - TIMI-22. This trial was undertaken by Harvard researchers and was designed to compare the effects of two different statin drugs, administered at different doses, to patients drawn from eight different countries. Bristol-Myers Squibb, the maker of the older statin drug Pravachol, wanted to prove that its statin medication reduced cholesterol as well as the newer drug that had grabbed the lion's share of the market (Lipitor, manufactured by Pfizer). In this study, 4,162 patients with a recent history of heart problems were randomly assigned to take either 40 mg of Pravachol or 80 mg of Lipitor per day. At the two-year follow-up, LDL had dropped dramatically in both groups, but to a greater extent in those taking the high dose of Lipitor (95 mg/dL versus 62 mg/dL, respectively). Regarding outcomes, it was found that 26 percent of those on Pravachol had a heart problem compared to 22 percent of those taking Lipitor and that the more intensive therapy resulted in a lower risk of death. Thus, these five studies provide powerful evidence supporting the government's new ultra-low LDL target goal of less than 70 mg/dL (for high-risk individuals) for maximum cardio protection.
Statins lower LDL
In 2003, a group of British scientists performed three meta-analyses to answer the question "What is the effect of statins on LDL cholesterol, heart disease, and stroke?" The results showed that statin drugs are highly effective medications that significantly lower LDL cholesterol levels by an average of 70 mg/dL and, by doing so, reduce the risk of a heart attack by about 60 percent and stroke by 17 percent. What's more, the researchers analyzed a number of studies that employed different methods of lowering LDL cholesterol (other than statins) and found a similar reduction in heart attack risk. This finding suggests that the reduction in heart attack risk is attributable to the reduction in LDL cholesterol and not necessarily to the drugs themselves. This is why the LDL - lowering combination of diet and exercise in the Cholesterol Down Plan is able to achieve LDL reduction results comparable to those of a statin drug starting dose, and why the plan can be a great supplement for high-risk individuals undergoing statin treatment.
LDL: It's the end result and not the means that counts
Statins have additional healthful cardiovascular side effects beyond just LDL cholesterol reduction, termed "pleiotrophic effects." For example, statins decrease inflammation, modulate immune system response, protect against blood clots, and potentially stabilize plaque so that it is less likely to rupture and cause a heart attack. Therefore, should you take a statin drug in lieu of diet and exercise to obtain any additional cardiovascular risk reduction that these medications may possibly have to offer?
A meta-analysis showed that it is not the statin drug but the actual decrease in the LDL cholesterol number that confers these additional cardiovascular risk reductions. As such, statins do not appear to offer patients any additional risk reduction benefits beyond those observed in patients lowering LDL cholesterol via non-statin alternatives.
Sources: Jane Rutishauser, "The role of statins in clinical medicine - LDL - cholesterol lowering and beyond," Swiss Medical Weekly 136 (2006): 41-49; Jennifer G. Robinson et al, "Pleiotrophic effects of statins: benefit beyond cholesterol reduction? A meta-regression analysis," Journal of the American College of Cardiology 46 (2005): 1855-1862.
The end of atherosclerosis?
Can lowering LDL to extremely low values actually stop the progression of atherosclerosis or even promote regression of plaque? Some of the most compelling evidence to date suggesting that lower is better comes from a study of 654 people with diagnosed heart disease, termed the Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) trial. Researchers randomly assigned subjects to receive either a very high dose of Lipitor (80 mg/day) or a more moderate 40 mg/day dose of Pravachol for a period of eighteen months. Results demonstrated that the high-dose Lipitor group effectively lowered LDL to an average value of 79 mg/dL (a 49 percent reduction). In contrast, the 40 mg daily dose of Pravachol resulted in a mean LDL value of 110 mg/dL (a 28 percent decline). The subjects in the high-dose Lipitor group (who attained a mean LDL of 79) showed a complete halting of the atherosclerotic process and even demonstrated a slight regression of plaque diameter compared with a slight increase in plaque size in the 40 mg Pravachol group.
The results from an international study called the ASTEROID trial (A Study to Evaluate the Effect of Rosuvastatin on Intravascular Ultrasound - Derived Coronary Atheroma Burden), involving 507 patients taking a high dose of the powerful statin drug Crestor, adds to the growing body of evidence that the lower the LDL value, the better. Patients from the United States, Australia, Canada, and Europe with previously diagnosed heart disease were prescribed a daily dose of 40 mg of Crestor. After a period of two years, LDL cholesterol dropped by 53 percent and HDL cholesterol rose by 15 percent. Furthermore, researchers demonstrated an actual reversal of plaque buildup (regression) within arterial walls.
Thus these new data have established beyond a shadow of a doubt that taking aggressive measures to lower the level of LDL cholesterol saves lives. The vital message from both the new research findings and the rush to update the ATP III report is that reducing LDL cholesterol to new lows halts the progression of atherosclerosis (plaque buildup) in the arteries and prevents death from cardiovascular disease. This finding pertains to those people with high cholesterol, moderate levels, and even what was once considered low LDL cholesterol values.
Source: Cholesterol Down, Foreword by Jennifer H. Mieres, M.D. |
