I like how the veteran health journalist Andrew Holtz once explained the interesting concept of surrogate or intermediate endpoints for us dull-witted patients. He cites, for example, studies on patients with diabetes that included aggressive control of blood sugar, high blood pressure and cholesterol in people considered to be at very high risk for heart attacks. But oddly enough, this research showed that:
- strict management of blood sugar did not reduce heart attack deaths
- reduction in high blood pressure levels did not reduce heart attack deaths
- controlling high LDL cholesterol numbers with the use of statin drugs did not reduce heart attack deaths
Holtz explains that lab results may not actually be accurate predictors of mortality – they are merely intermediate or surrogate endpoints along the way.
And just because a drug improves lab test results doesn’t mean it saves lives – despite the efforts of Big Pharma to convince drug prescribers otherwise.
Similarly, clinical trials have shown that the statin drug simvastatin (Zocor) was effective in reducing cholesterol (the surrogate endpoint) without showing directly that simvastatin prevents actual cardiac events.
In fact, proof of Zocor’s efficacy in reducing cardiovascular disease was finally only presented by Norwegian researchers five years after its original introduction, and then only for secondary prevention in those already diagnosed with heart disease.(1)
To help doctors plow through the muck, Dr. John S. Yudkin, emeritus professor of medicine at University College, London wrote the following 10 Commandments for his colleagues (but according to Dr. Richard Lehman of the British Medical Journal(2), Dr. Yudkin was dissuaded from publishing them more widely due to American religious sensitivities).
Finally, with many thanks for this laymen’s translation into plain English(3) of Dr. Yudkin’s work by Dr. Alice Dreger and Dr. Aron Sousa, here are:
The New Therapeutics: Ten Commandments
1. Thou shalt treat according to the level of risk rather than level of risk factor. “In medicine, a risk factor is a trait that increases the likelihood of having something really bad happen to you. For example, having a high level of triglycerides is a risk factor for having a heart attack. (That means that having high triglycerides increases the likelihood you will suffer a heart attack.) But you want your doctor to try to prevent what’s really bad – the heart attack – not just treat your triglyceride level. Why? Because lowering your triglyceride level with some prescription drug won’t actually decrease your risk of a heart attack. Doctors need to treat what really matters to you, the patient, not what is merely measurable in you.”
2. Thou shalt exercise caution when adding drugs to existing polypharmacy. “It’s generally a bad idea to give a patient another drug when a patient is already on a drug. Doing so increases the risk of bad interactions between the drugs. It also increases patient confusion, thereby again increasing risk. So adding one drug doesn’t just introduce the risks named on the pamphlet you get with that drug, because the body is a complex machine, drug interactions are poorly understood, and humans on lots of drugs make mistakes in the use of those drugs.”
3. Thou shalt consider benefits of drugs as proven only by hard endpoint studies. “This is similar to the first commandment because it reminds the physician that what you really care about are “hard endpoints” – things like heart attacks and strokes, not things like levels of cholesterol and triglycerides. A particular drug might make your lab results look really great, but it’s not a good drug if it doesn’t actually improve your health in the ways that matter (for example, reduction of risk of a major disease, or reduction of risk of death.)
“A drug might increase your bone density, but if it doesn’t reduce your risk of fracture, who cares that your bones are denser?”
4. Thou shalt not bow down to surrogate endpoints, for these are but grave images. “Again, ‘surrogate endpoints’ are things like blood pressure readings, as opposed to ‘hard endpoints’ like heart attacks and strokes. It doesn’t actually matter what your blood pressure is if your blood pressure doesn’t hurt you. We use blood pressure readings as a surrogate for what we really care about. It’s worth measuring, but we should not treat high blood pressure with a drug unless that particular drug is shown to achieve what we really care about: reduction of risk of heart attacks and strokes.”
5. Thou shalt not worship Treatment Targets, for these are but the creations of Committees. “Sometimes consensus groups come up with ‘treatment targets’ that tell physicians what patients’ lab numbers should look like. But physicians need to take individual patients’ bodies, lives, and needs into account. An example: a consensus committee might issue a treatment target for glucose (blood sugar) control. They might say everyone should have low blood sugar. But imagine a patient who is an 80-year-old woman who has been falling a lot. Lowering that woman’s blood sugar could increase her risk of a big bone fracture from a fall. So she should NOT be treated glibly according to a Treatment Target that might be perfectly reasonable for an otherwise healthy 30-year-old woman.
“Physicians and patients should especially beware any consensus issued by a committee of people who have had financial ties to drug and device makers.”
6. Thou shalt apply a pinch of salt to Relative Risk Reductions, regardless of P values, for the population of their provenance may bear little relationship to they daily clientele. “This is a complicated way of again reminding physicians what should matter: actual reduction of risk of the things their own real patients really care about and are really likely to suffer from. Relative Risk Reduction is another way drug companies often fool physicians and patients into thinking a drug is better than it really is.”
7. Thou shalt honour the Numbers Needed to Treat, for therein rest the clues to patient-relevant information and to treatment costs. “The phrase ‘numbers needed to treat’ refers to how many patients a doctor needs to treat with a particular intervention in order to have one patient’s outcome improve. This concept acknowledges that not every intervention benefits every patient. In fact, there’s a ‘number needed to harm’ for each drug, too, but you don’t often hear about either stat from your doctor. Yet for many medical interventions, you have to treat a relatively large number of people to benefit just one, but you’re introducing ALL of them to the risks of that intervention. You might think from pharmaceutical ads that a drug for heartburn will lower your risk of esophageal cancer. But the truth is that probably dozens if not hundreds of people will have to take the drug before just ONE of those people has cancer prevented by the drug, while ALL of you on the drug will bear all of the risks of the drug.
“Note that this commandment also refers to treatment cost, an idea that is supposed to offend us. But the truth is that it would be better if we thought rationally about how much money it makes sense to prevent, say, one death from cancer. If we keep ignoring that calculation, we’ll kill a lot more people than we save.”
8. Thou shalt not see detailmen (drug reps), nor covet an Educational Symposium in a luxury setting. “These days, detailmen are actually often women – perky, young, blonde women chosen because they still carry their cheerleader looks from high school. They are the representatives from drug and device makers who come to seduce your doctor into using their products on your body, so that profit can ensue. Drug and device makers also like to whisk your doctor off to ‘educational symposia’ where they are wined, dined, and sold the idea of using more of the companies’ products. Profit is the only endpoint these companies really care about, so they will take all the risks they need to in order to achieve that endpoint, including treating your life as an acceptable risk. If you are at your doctor’s office and you see detailmen or their paraphernalia (pens, mugs, posters, videos, etc. produced by these companies), you can assume your body is being used as an endpoint by a corporation that doesn’t care what really happens to you. So ask yourself: how much does your doctor really care about you?”
9. Thou shalt share decisions on treatment options with the patient in the light of estimates of the individual’s likely risks and benefits. “Your doctor needs to talk to you about what YOU are trying to achieve with your medical care. Then she or he needs to discuss with you the reasons and evidence for the options being offered to you. She or he really should be educating you about all the things we’ve covered so far: risk factor versus risk, surrogate endpoints, unknown drug interactions, etc. You can start this conversation by telling your doctor about what exactly you’re trying to achieve in a given office visit.
“For example, you might say in a yearly exam, ‘I would rather live a healthy life than a longer life, so I’m only interested in tests, procedures, and interventions that are likely to give me good health, not those that will necessarily keep me alive longer but make me feel unhealthy during those years.’ Or at a sick visit, you might say, ‘I didn’t come for a prescription. I came to try to figure out why I feel sick, and what I can expect in terms of healing. I only want a prescription if I really need one to get better. I would rather suffer the symptoms of this thing than take the risk of a drug that’s just going to treat the symptoms and increase my risk of side effects.’ “
10. Honour the elderly patient, for although this is where the greatest levels of risk reside, so do the greatest hazards of many treatments. “This one is self-explanatory, but too often ignored.”
- Your Health, Ball Possession, and the World Cup (about surrogate endpoints)
- How Did This Heart Drug Get Approved In the First Place?
- Doctor’s Kiss and Tell Tale: “My 1-Year Career as a Wyeth Drug Rep”
- Is Your Doctor a “Thought Leader”?
- NEJM Editor: “No Longer Possible to Believe Most Clinical Research Published”
- Say What? Do Patients Really Hear What Doctors Tell Them?
- Be Suspicious of Research Presented at Scientific Meetings
- Things Your Doctor May Not Know
- How to Turn a Condition into a Disease by “Selling Sickness”
- Nagging 101: (our basic glossary of clinical and research terminology)
(1) Pedersen TR, Olsson AG, Faergeman O, et al. (1998). “Lipoprotein changes and reduction in the incidence of major coronary heart disease events in the Scandinavian Simvastatin Survival Study (4S)”. Circulation 97 (15): 1453–1460.
(2) BMJ 2011; 343:d7995doi: 10.1136/bmj.d7995 (Published 28 December 2011) Also re-posted in Dr. Richard Lehman’s British Medical Journal weekly review of medical journals.
(3) Psychology Today, “Get Your Doctor To Treat You Right”, January 7 2012. Dr. Alice Dreger is a Professor of Clinical Medical Humanities and Bioethics at Northwestern University’s Feinberg School of Medicine in Chicago. Dr. Aron Sousa is Senior Associate Dean for Academic Affairs at Michigan State University’s College of Human Medicine.