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Foxglove, Humble Pie and Other Matters

Musings on why evidence can persuade, but a good story compels

I love digitalis and I wish I could tell you that the feeling is rational or that it has anything to do with its pharmacology.

In the days when the only RAM you could access was the kind you carried in your head, digitalis was easily recalled because of the way it slid off the tongue and because it had a story. As a tyro, I liked the sound of it — dee-gee-tah-lissss. I thought it made me sound intelligent.

The “digital” in digitalis might make you suspect a Silicon Valley connection, but in fact it comes from the Latin digitus, or finger, and that’s because the drug is an extract of the foxglove, a plant with beautiful, elongate flowers you can slide over your finger. You’ve probably seen foxglove (Digitalis purpurea or Digitalis lanata) growing wild, looking from a distance like a garland of delicate thimbles grouped vertically, the mouths pointing down. Folklore (or fox-lore) has it that foxes were taught by fairies to slip these flowers over their paws to soften their tread when they stole into the henhouse. Some people consider foxglove a weed, but I don’t see how something so pretty and a favorite of fairies could have that label.

The current use of digitalis for heart failure began with William Withering, an 18th-century English doctor who fell in love with a botanist who was also his erstwhile patient. She became his wife, and his interest in her and plants proved long-lasting. It helped him recognize that the active ingredient in a dropsy remedy being used by an “old woman from Shropshire” was an extract of foxglove. Dropsy (or swelling of the feet and the body — edema, we would call it now) can be caused by heart failure, or from kidney or liver disease. But in Withering’s days it was all dropsy. An Account of the Foxglove and Some of its Medical Uses: With Practical Remarks on Dropsy and Other Diseases, published in 1785, described Withering’s experience with over 100 patients, showing that in some of them (presumably those with heart failure) it produced a profound diuresis. His study wasn’t “double-blinded” or “placebo-controlled” and the patients weren’t “randomized”; I fear if he were to submit his paper today, it would probably be rejected. Nevertheless his work brought digitalis into mainstream use.

I learned as an intern that there wasn’t much wiggle room between the digitalis dose that worked and the amount that was toxic. I recall a patient telling me that everything looked green. When we withheld the drug, normal color was restored. Still, my sense was that it was a useful drug, when judiciously used. And yet, in the early 1980s, about the time I was finishing my training, digitalis went out of fashion. When I mentioned digitalis, the interns would roll their eyes as if you had suggested cupping or bloodletting. I put away my stories about foxes and henhouses, or love and botany. Then a few years later, digitalis came back in fashion. That’s been the fate of many drugs I’ve known: theophylline, metformin…. New clinical trials giving us new “evidence” cause us to revise our opinions, sometimes happily so.

“Evidence-based medicine” is the buzz word, on every medical tongue it seems, but it’s a term that always leaves me wondering what kind of medicine we were practicing just a few years before EBM came along — witchcraft? Perhaps so. I must say, there is a thrill in picking up the latest medical journal to read the results of a clinical trial that has been in the works for years, enrolling hundreds of patients at many medical centers. Unlike in Withering’s days, clinical trials have become an art — an expensive, complex, logistical feat — but what awaits at the end of the rainbow is the answer, one hopes, to the utility of some drug, or some procedure. The trials tend to have colorful acronyms like BIG-MAC (Beaumont Interventional Group — Mevacor, ACE inhibitor, Colchicine restenosis trial) or WOSCOPS (West of Scotland Coronary Prevention Study); the acronyms get tossed around in debates both in conference rooms and at the bedside in just the way lawyers might cite Brown v. the Board of Education. Incidentally, WOSCOPS was one of the first studies to show that statins, the new class of drugs that reduced cholesterol, did more than that. When given to healthy men who had elevated cholesterols, statins cut the rate of heart attacks and sudden death considerably when compared with the control group, and more than what was expected from the simple lowering of cholesterol; the statins appeared to stabilize the fatty plaques in the coronary arteries and keep them from rupturing. The talk of putting statins in the drinking water wasn’t entirely facetious.

When a new drug that blocked the absorption of cholesterol from the gut came along (ezetimibe) it seemed logical to think that combining this with a statin (simvastatin in this case) would make for a potent pill — a double whammy. The combined pill was sold as Vytorin, and the drug was a blockbuster best seller. Unfortunately, the ENHANCE trial that was just published, much to the distress of the drug company involved, failed to show the combination made a difference in the growth of plaque in the carotid arteries. It doesn’t mean the combo doesn’t work, only that what they measured (fatty deposits in the carotid) didn’t appear different. Since statins work well to begin with, dramatically reducing heart attacks and sudden death, it’s a challenge to show something works better than well, which is why the investigators chose to measure the buildup of plaque in the carotid. Nevertheless, the failure to show a difference caused turmoil as physicians and patients wondered whether they’d been had, and whether the combo had done anything more than add to the coffers of its makers.

At times clinical trials of a particular drug can come to completely different conclusions, and then they are often published side by side in the same journal — a situation that can be hopelessly confusing. The differing conclusions might be explained by a host of reasons: Sicker patients were enrolled in one study, or stricter criteria to define the disease were used in the other and so on. But these fine points are not always explained or are willfully ignored when the popular press gets hold of this information. Indeed when there are wild and wildly publicized swings for and then against a drug (Vytorin, estrogen, Vioxx, Vitamin E) it generates confusion and distrust. At a time when patients perceive health care in this country as being fractured, expensive and hugely profitable for drug companies and doctors, an unexpected clinical trial result fuels the discontent.

Perhaps that points out the greatest challenge in medicine: clinical trials are well and good, and evidence-based medicine is the way to go, but the fact is we as consumers don’t really go by evidence.

Take the ACCORD (Action to Control Cardiovascular Risk in Diabetes) trial, a large study begun in 2001 but stopped this year by a safety board before it was complete. It’s been known for years that diabetics have a very high risk of heart and blood vessel disease, and this study was designed to see if very tight control of the blood sugar in diabetics might help prevent these complications. The study was stopped because tight regulation of blood sugar seemed to actually increase mortality. The minute the news hit the press, I heard from a number of friends and patients. “Gotcha!” they seemed to be saying; “All that badgering you did about keeping my blood sugar down — you were dead wrong! What else has medicine got wrong?” But that wasn’t the lesson I took away. ACCORD aimed for and reached a hemoglobin A1c level (a crude measure of the average blood sugars) of less than 6. That’s a number I rarely see in my diabetic patients; I’d be thrilled to see a number close to 7, and even that’s a struggle. ACCORD showed that trying to get blood sugars too low might backfire. But meanwhile, there’s been plenty of evidence from prior trials that lowering the HbA1c to 7 helps delay complications of diabetes, preserve vision, save limbs. That part got buried in the press reports; it wasn’t news, or not the kind anyone wanted to hear about.

Perhaps that points out the greatest challenge in medicine: clinical trials are well and good, and evidence-based medicine is the way to go, but the fact is we as consumers don’t really go by evidence. What makes us human is our willingness to pin our hopes on things we believe might work, or that we think should work. An unstudied remedy, particularly if it’s labeled “natural” or comes from the rain forests of the Amazon, has a special charm, and I’ll confess that a few of these find their way into my medicine cabinet. A loophole in our laws allows potent drugs and potentially toxic substances to escape all scrutiny from the FDA as long as they don’t make claims to treat or cure disease. You can put nail clippings into a pill and make any claims you want as long as you don’t say you are curing or treating a disease: You can say you are going to “promote” prostate health, or “enhance” libido, for example. It’s an industry with powerful lobbyists that keep it free from government scrutiny. If you dispense hope in a pill, the evidence is good that we will buy it and swallow it — hook, line and sinker.

In the clinic with an individual patient, my sense is that it isn’t about the evidence and it isn’t about this organ or that — at least it isn’t for me. As William Carlos Williams, physician and poet laureate, said, “The abstract, categorical mind can be wonderful — the glory of the intellect at work, coming to its great big (and big deal!) conclusions. But we’ve got to keep a close check on all that — the head running away with itself.” What we face in the clinic, to paraphrase Williams, is not a liver, or a spleen or a high cholesterol or a blood sugar. What we face is someone just like us, someone faced with a problem who is handling it in a way that is a function of who they are, where they were raised, and contingent on their beliefs and aspirations. Trotting out the “evidence” and the “shoulds” and the “musts” does no good if it turns the patient off so one never sees them again.

Before evidence-based medicine, we need basic self-evident medicine, which is to say a physician-patient relationship based on trust, one that allows a dialogue, a discussion of the knowledge that is out there, the ever-changing knowledge and how that translates into the regimen of care. I’m not always successful in getting my patients to take what I think they should take, or stop taking what I think isn’t helping them; sometimes, what I thought was good for them turns out not to be so, and I have to eat humble pie. Humble pie is good for physicians; the anecdotal evidence strongly supports this. There is a famous remark by a physician of a bygone era, Francis Peabody, who said to medical students in 1925: “The secret of the care of the patient is caring for the patient.” The proof? The evidence? Well … you’ll have to take my word for that.

Abraham Verghese, MD, is a professor of medicine at Stanford.






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