Are higher doses of cholesterol-lowering drugs worth the extra money? Only sometimes, U-M/VA study suggests

ANN ARBOR, MI – When it comes to cholesterol-lowering drugs, more is better. At least, that’s what heart doctors and heart patients have been hearing in recent years. And as a result, more patients are taking higher doses of drugs called statins – leading to lower heart and stroke risk, but also higher prescription drug costs and more frequent side effects.

Now, a new study looks at whether those higher doses, and higher costs, are really going to pay off for some patients. For those with a recent heart attack or what doctors call ‘acute coronary syndrome’, the answer is yes, the researchers say.

But the picture is less clear for those patients with known heart blockages who have stable symptoms. For them, the usual dose of their statin may provide adequate heart-protecting benefit, and the higher cost of high-dose statins may provide only marginal benefit at much greater cost, especially if they use generic statins.

The study, from a team at the University of Michigan Cardiovascular Center and the VA Ann Arbor Healthcare System, is published online in the journal Circulation, and will be in the May 8 print issue of the journal. It’s based on a sophisticated computer analysis of data from thousands of patients.

The team finds that patients with a recent history of acute coronary syndrome (ACS) – either a heart attack or hospital stay for chest pain – get so much benefit from higher statin doses (more than four additional quality-adjusted months of life) that the extra cost of an increased dose is worthwhile, even if the difference is a few dollars a day.

But for patients with stable coronary artery disease (CAD), whose arteries have been narrowed by plaque but who haven’t had a recent heart attack or hospitalization for chest pain, the much smaller gain (about 5 weeks of quality-adjusted life) from a higher dose of a statin may not be sufficient to outweigh the extra cost.

The researchers also point out that the type of analysis they performed for this study could be used to assess the cost-effectiveness of other medications and treatments. It could be especially useful when doctors, patients and insurers need to choose between two options that have different costs and benefits to particular patients.

“Clinical trials have effectively demonstrated that high-dose statins reduce cardiovascular endpoints in patients with established coronary artery disease. However, we found that whereas high-dose statin therapy reduced mortality in patients with acute coronary syndromes, patients with stable coronary artery disease had no mortality benefit from high-dose statins, but only reductions in stroke and repeat heart attack risk,” says Paul Chan, M.D., M.Sc., the study’s lead author and a fellow in cardiovascular medicine at the U-M Medical School.

“Our study illustrates that simply having a ‘positive’ clinical trial may not be as informative as reporting what the actual gains in life expectancy and quality of life are with positive trials, and we propose using decision analysis as a way to appreciate the impact of trials that use multiple end points that are dissimilar (e.g., death and rehospitalization),” says Chan, who is also a member of the VA Health Services Research and Development Center of Excellence at VA Ann Arbor.

The authors point out that one reason for the rapid rise in health care spending is the overuse of new drugs and technologies.

“Many times, clinical trials report a small but statistically significant benefit in an outcome, and this leads to widespread adoption of a treatment, even though the long-term benefits of using that treatment are small. Our methods of analyzing these results begin to address the question of where we really get value from medical care,” says Sandeep Vijan, M.D., the senior author and an associate professor of general internal medicine at U-M. “In this study, we found that intensive treatment with statins, a treatment with ‘proven’ effectiveness, has very different effects depending on who you are. If you are a very high-risk patient who was just in the hospital for a heart attack, you get lots of benefit from high doses of statins, and treatment is therefore cost-effective.”

But if you are a patient who has more stable heart disease, the benefit is much lower – only about one-quarter of that seen in the high-risk group – and the treatment is probably not cost-effective most of the time.

“This is further compounded by the fact that the higher-dose treatments are less well-tolerated, and my clinical experience is that once patients decide the drugs are hard to tolerate, they often won’t even take the lower dose drugs, which are enormously beneficial,” Vijan adds.

The team based its analysis on data from four very large clinical trials – those whose results led to recommendations of higher doses of statins for ACS and CAD patients. They combined those data with data on cost and a range of estimates about how long the drug’ beneficial effect would last.

In general, statin drugs lower the levels of cholesterol in the blood, which is thought to slow the formation of plaque along artery walls. But they also appear to play a role in reducing inflammation, which is also a major factor in heart disease. Studies that have compared high and standard doses of statins have shown significant differences in the risk of negative events among the patients taking the higher doses. And that has helped lead to the current recommendations by the federal National Cholesterol Education Program and others, which call for aggressive statin treatment.

But, the team says, the results from these studies are often expressed in terms of “composite end points” – for instance, the risk of death, heart attack and stroke put together, rather than the risk of each. That practice yields the most dramatic differences between high-dose and standard-dose statin treatment, but it masks the fact that there may not have been significant differences between the two groups in some of those individual events (death, heart attack or stroke). It also assumes that each of these events is viewed equally by doctors and patients, which is clearly not the case.

So, for the new study, the team pooled the clinical trial data from all patients with a history of ACS, and in a separate pool, all patients with CAD. They looked at all the differences between the high-dose and standard-dose patients in those pools, including their risk of cardiovascular events during the study period. They then used this information to create a computer model of hypothetical 60-year-olds taking different doses of statins, and calculated what reduction in risk might be related to those doses, any how many “quality adjusted life years” they might gain from that reduction in risk.

The researchers then calculated how much each of those life years would cost, given different costs of statins and differences in cost between the two possible doses of statins.

Cost-effectiveness is based on how many dollars each quality-adjusted life year costs. In the end, high-dose statins were cost effective for ACS patients, but they would be cost-effective for stable CAD patients only if the difference in cost between standard and high doses was small to moderate.

That’s an important point for insurers and patients, especially given that some popular statins have already become available in generic form or will soon do so, says Chan.

“As the generic statins continue to drop in price with the entry of even more generic manufacturers in the upcoming months, high-dose statin therapy may not remain cost-effective in patients with stable coronary artery disease,” he explains. For example, if the daily cost difference between a high and conventional statin dose exceeds $1.40 (or $500 per year), high-dose statin therapy may no longer be considered cost-effective in stable patients. “In contrast, because of the greater life gains in patients with acute coronary syndromes, high-dose statin therapy would remain cost-effective compared with conventional-dose statin therapy even when the cost difference was $3.50 a day or $1,280 per year,” he says.

This kind of analysis may be important as more new treatments come on the market and others become available in less-expensive generic form, the authors say.

In addition to Chan and Vijan, the study’s authors are Brahmajee Nallamothu, M.D., MPH, and Hitinder Gurm, M.D., both assistant professors of cardiovascular medicine; and Rodney Hayward, M.D., professor of general internal medicine and director of the VA HSR&D center. The study was supported by the National Institutes of Health.