N=1, evidence-based medicine in real patients

Mr. C is a 76-year-old with locally advanced rectal cancer and severe COPD. Two weeks before potentially curative surgery for his cancer, he's admitted with an MI. His course is complicated by cardiogenic shock requiring intubation. Cardiac catheterization revealed total occlusion of the right coronary and left circumflex arteries, and a 90 percent proximal left anterior descending artery lesion. No acute coronary intervention is performed. He recovers, and is transferred out to a general medicine team. I met Mr. C when he was transferred out of the ICU to my general medicine team. As a newly-minted second-year resident, I had the primary responsibility for helping his family make the difficult decisions related to his future care. His children were in his room with him, and when I walked in and introduced myself, one of his sons looked at me and said, "So, where do we go from here?" Good question. Where do we go from here? I knew (or could look up) the relevant evidence. But every answer came with a new question, and none of those questions had easy answers. In patients with three-vessel coronary artery disease, coronary artery bypass grafting is superior to percutaneous intervention (1). But with his severe COPD, it took Mr. C nearly a week to come off the ventilator – and the pulmonology team was so concerned that he would go into respiratory failure off the ventilator that they’d discussed the issue with his family, who had agreed that he should not be reintubated if that occurred. How could he ever survive a major cardiothoracic surgery? In patients undergoing percutaneous intervention with stenting, dual antiplatelet therapy reduces mortality compared with aspirin alone (2). But when Mr. C was treated with aspirin and clopidogrel, he had a major bleed from his rectal cancer. If we could not treat him with clopidogrel, was it even safe to attempt percutaneous intervention? Mr. C's cardiac issues were severe, but his rectal cancer was also a ticking time bomb. Mortality is considerably higher in patients undergoing major surgery soon after a myocardial infarction (3). But the longer Mr. C waited, the more likely it was that his curable rectal cancer would turn metastatic. Did it make sense to wait on surgery? And if so, how long? And then there was the question of how his cardiac and oncologic issues interacted. In patients with coronary disease undergoing high-risk surgery, revascularization with percutaneous intervention does not improve perioperative mortality (4). But does that really apply to a patient with a recently completed myocardial infarction (5), and with a heart receiving all of its blood flow through 10 percent of the lumen of a single coronary artery? I was left with a conundrum: Mr. C needed surgery to cure his cancer, but he couldn't have that surgery because of his coronary disease, and part of the reason we couldn't help his coronary disease was the risk of bleeding from his cancer. And that's not even taking into account his pulmonary issues, which were significant. To buy myself some time, I told Mr. C's son that I would talk to the surgeons, talk to the cardiologists, and look further into the medical literature, and that we'd talk about Mr. C's options later in the week. For two days, I poured over the medical literature, trying to answer every question. As I suspected, the literature was not much help; the cardiologists and the surgeons could offer only opinions based on their own anecdotal experience. Despite a medical education filled with lectures about evidence-based medicine and encouragement to look up primary data related to the care of my patients, I knew that our evidence base was far from perfect. But never before had its imperfections been thrown into such sharp relief. I had always assumed that one day medicine would have all the answers, or at least most of them. Given enough time, all the important puzzles would be solved. But then along comes a patient like Mr. C, who, by virtue of his complexity and uniqueness, makes that concept seem far-fetched. When it comes to patients like Mr. C, evidence-based medicine can only be a guide, not a course of action. Instead, the physician has to turn into a scientist and think back to the first principles of pathology and physiology. For me, that’s what makes clinical medicine fun, but also impossibly challenging. Because in the lab, you can try two (or three, or a dozen) different approaches to a problem, and learn from each experiment. But when your sample size is just one unique patient, irreplaceable to his family and loved ones, there is often no chance to try a different approach. The experiment cannot be replicated. Ultimately, Mr. C’s case was not as complicated as it seemed. The surgeons deemed him too high-risk for surgery, and the interventionalists deemed him too high-risk for intervention. As I explained this to Mr. C and his family, they looked appreciative. “Well,” his son said, “at least we have a plan.” And in the end, that plan was evidence-based, but only to a point. The evidence indicated that surgery was dangerous, but it said nothing about how dangerous it would be not to operate. Even in cases where our evidence is robust, applying that evidence to inform the care of any flesh-and-blood patient requires a leap of faith – that your patient is similar to those in the trial, that your patient will respond to the treatment, that the results from a big experiment will hold for the n=1 in front of you. Alexander Fanaroff, MD Duke University Medical Center PGY-1, Medicine

1. ^back Serruys PW, et al. Percutaneous Coronary Intervention versus Coronary-Artery Bypass Grafting for Severe Coronary Artery Disease. N Engl J Med 2009; 360:961-972. Pubmed
2. ^back Leon MB, et al. A Clinical Trial Comparing Three Antithrombotic-Drug Regimens after Coronary-Artery Stenting. N Engl J Med 1998; 339:1665-1671 Pubmed
3. ^back Livhits M, et al. Risk of surgery following recent myocardial infarction. Ann Surg 2011;253:857-6. Pubmed
4. ^back McFalls EO, et al. Coronary-Artery Revascularization before Elective Major Vascular Surgery. N Engl J Med 2004; 351:2795-2804 Pubmed
5. ^back Livhits M, et al. Coronary revascularization after myocardial infarction can reduce risks of noncardiac surgery. J Am Coll Surg 2011;212:1018-26 Pubmed