Before a physician prescribes a medication, she should know exactly how safe and effective it is. And before a patient swallows any pill he should also know precisely how safe and effective it is. You don’t get any more basic than that. Before many people buy a car, a TV or an appliance, they do their homework. They may check Consumer Reports, or get a mechanic to inspect a used car to make sure they aren’t buying a lemon. When it comes to medicine, however, there is no easy way to determine how safe and effective a drug will be for you. This reader asked what on the surface seemed like a simple question.
What Does Safe and Effective Really Mean?
A reader recently asked us a very basic question:
“Is there any place a consumer can go to find the effectiveness of a drug that has been prescribed? And along the same lines, how can he/she determine the frequency and severity of that drug’s side effects?”
This is the homework anyone would want to do before taking a new medicine. In fact, any physician prescribing drugs should be able to find such information easily. In truth, these essential data are more difficult to locate than they should be.
The FDA Has Unique Definitions for “Safe” and “Effective”
The FDA has two criteria for approving a new medicine. It has to be effective and it must be safe. Sadly, though, the definitions of effective and safe are hard to pin down.
How does the FDA determine that a drug works? It requires the manufacturer to demonstrate that the medication is better than an inactive placebo. It doesn’t have to be a lot better; it only has to demonstrate statistical significance.
The FDA also relies on something called surrogate endpoints. In other words, if a drug lowers blood sugar, that is good enough for the agency to grant approval. The drug doesn’t have to prove that it reduces bad outcomes from diabetes or prolongs life. As long as the needle moves on some lab test, that is often good enough.
As for safety, all you have to do is turn on your television to realize that many FDA-approved drugs can cause serious or even life-threatening side effects. The FDA considers a drug safe even if it causes heart attacks, strokes, liver failure, kidney disease, cancer or death in some patients. We don’t know about you, but that doesn’t seem very safe to us.
What About Atorvastatin (Lipitor)?
For example, atorvastatin (Lipitor) is the most frequently prescribed cholesterol-lowering drug. Many doctors think of it as a life saver. And in fact, during a clinical trial fewer people taking the statin died of a heart attack (1.9 percent) than those taking placebo (3 percent).
This means that roughly one person out of 100 people taking Lipitor escaped a fatal heart attack. That is statistically significant, but it also means that 99 people taking the drug did not get that benefit.
Death, The Ultimate Statistic!
When measuring the effectiveness of any drug you have to ask a fundamental question. Effective for what? If you have a bad headache, you would determine the effectiveness of Advil, aspirin or Tylenol by how fast the headache completely goes away.
When it comes to statin-type cholesterol-lowering drugs, the most important metric is mortality. Did the drug prolong life? Yes, avoiding a heart attack is important. Ultimately, though, people want to know if their medicine will extend their lives.
It comes as a great shock to many physicians to learn that many randomized clinical trials of statins did not lead to a mortality benefit. Here are some examples:
In 2005 the TNT (Treating to New Targets) study was published in the New England Journal of Medicine (April 7, 2005). Over 10,000 patients with coronary heart disease were randomized to either 10 mg of atorvastatin or 80 mg of atorvastatin. There was a 2.2% reduction in major cardiovascular events in the intensive treatment group, but:
“There was no difference between the two treatment groups in overall mortality.”
In theory, the people getting 80 mg of atorvastatin should have done far better than those on 10 mg. Hmmm, what went wrong?
The IDEAL study involved 8,888 patients who had already had a heart attack (JAMA, Dec. 28, 2005). Half got 20 mg of simvastatin and the other half got 80 mg of atorvastatin. The expectation was that the intensive atorvastatin treatment would produce dramatic results. The conclusions:
“In this study of patients with previous MI [myocardial infarction or heart attack], intensive lowering of LDL-C did not result in a significant reduction in the primary outcome of major coronary events…There were no differences in cardiovascular or all-cause mortality.”
You might argue that the TNT and IDEAL study were not a comparison of statin to placebo. You would be right. They compared aggressive statin therapy that really lowered LDL cholesterol dramatically, to much more modest treatment. One might suggest that any statin treatment (low or high dose) produces substantial benefit. That’s why the ASPEN trials is so important.
ASPEN stands for Atorvastatin Study for Prevention of Coronary Heart Disease Endpoints (Diabetes Care, July, 2006). The investigators selected 2,410 subjects with type 2 diabetes. These people are like canaries in the coal mines. They are highly susceptible to heart attacks and early death from cardiovascular disease.
In this study patients received either 10 mg of atorvastatin or placebo. LDL cholesterol was lowered 29% in the statin group. After four years, however, there was no statistical difference in outcomes between the patients on atorvastatin and placebo. In other words, there were no meaningful reductions in heart attacks, strokes, bypass surgery or heart symptoms in the group on statins. Most important, there was no mortality benefit.
Putting Effectiveness into Perspective:
It’s not that statins are ineffective. There are other clinical trials that show a reduction in heart attacks and strokes and a mortality benefit.
How much of a mortality benefit? One of the most famous statin studies was called 4S. After almost six years of simvastatin use, the survival gain was less than a month (27 days to be precise)(BMJ Open, Sept. 24, 2015). These were very high-risk patients. They had either experienced a heart attack or were having serious symptoms of heart disease.
The trouble is that randomized clinical trials have produced contradictory and confusing results. It becomes very hard to say how effective statins are in preventing any given individual from experiencing a heart attack, a stroke or extending life.
How To Discover How Safe and Effective Your Drug Is:
Where do you find this information? For many drugs, the best place is DailyMed. https://dailymed.nlm.nih.gov/ This online resource contains the information that FDA and the drug companies think is essential for doctors as well as patients. Section 14 on Clinical Studies describes the results from the trials presented to support the drug’s approval. Trying to make sense of the statistics can be challenging, but that is one of the few places to check actual effectiveness.
What About Safety?
Assessing safety can be even more daunting. DailyMed also has the official prescribing information in its adverse reactions section (Number 6 Adverse Reactions). Here too the drug is compared to placebo.
If you look up the weight loss drug Contrave (naltrexone and bupropion), you will discover a black box warning. This is the closest thing the FDA has to waving a red flag to signal serious danger.
In the case of Contrave, the warning reads:
“In patients of all ages who are started on CONTRAVE, monitor closely for worsening, and for the emergence of suicidal thoughts and behaviors.”
In addition, Contrave causes nausea in about one third of patients. That compares to seven percent of those on placebo. Constipation, headache, vomiting and dizziness are also significant side effects along with insomnia, dry mouth and diarrhea.
The official prescribing information is a good first step but it does not always represent the final word on effectiveness or safety. Important adverse reactions are often discovered many years after the drug was approved.
One place to look for such information is PubMed.
This service of the US National Library of Medicine gives everyone access to brief summaries published in medical journals. Learning to use these resources is the first step to understanding how safe and effective your medicine may be.