Pfeffer, 58, received his bachelor’s degree in 1969 from Rockford College in Illinois, and then went to the University of Oklahoma, where he earned his doctorate in physiology and biophysics in 1972 and his medical degree in 1976. He then spent the next four years completing his medical training at Peter Bent Brigham Hospital (one of three Boston institutions later combined into the current Brigham and Women’s Hospital) and Harvard Medical School. In 1980 he joined the faculty of the Medical School, where he is now a professor of medicine.

   You started your career studying hypertension in rats and are now deeply immersed in the world of human clinical trials. How did you make this transition?

You are right in that I did my Ph.D. on hemodynamic effects of hypertension in spontaneously hypertensive rats. That was in Oklahoma under the wonderful mentorship of Edward Frohlich. I worked on these studies with my late wife, Janice, who was also a graduate student of Professor Frohlich. Our animal studies led me to attempt to relate our findings to clinical hypertension. Fortunately, Frohlich was also a clinical investigator and he directed me towards medical school. During med school I kept my roots in research working with Janice and Professor Frohlich. Janice and I came to Boston, I as a medical intern and she as a postdoctoral fellow under Professor Eugene Braunwald. I sincerely believe that Braunwald is the most prominent, and deservingly so, cardiovascular scientist of 20th century. He was the chair of medicine at what was then Peter Bent Brigham Hospital, which was and is one of the premier places to train. Braunwald’s work is fundamental to our understanding of cardiac function and the pathophysiology of coronary artery disease, and he conducted the landmark animal studies that first demonstrated that heart muscle can be salvaged during a heart attack. Braunwald is equally recognized as a leader of international clinical trials. He originated the TIMI Group—TIMI stands for Thrombolysis in Myocardial Infarction—and most of my prominently cited studies were conducted in collaboration with this remarkable scientist and leader.

We moved to Boston with our rats and shifted our focus from hypertension to myocardial infarction. Janice soon discovered that after a heart attack, the structure of the left ventricle slowly undergoes progressive enlargement with a progressive deterioration in function. She also observed that these changes could be attenuated by an angiotensin-converting enzyme (ACE) inhibitor. At that time, in the early 1980s, this was a new potential use of an ACE inhibitor. By this time, I had finished a clinical training in cardiology and was able, with colleagues, to conduct a study in 59 patients, which indicated that Janice’s finding in animals could apply to patients recovering from a myocardial infarction. This study showed that survivors of a heart attack can feel well afterward, but still undergo ventricular enlargement, and that the ACE inhibitor captopril could attenuate these adverse changes in cardiac structure and function. That then led to my first real exposure to an international clinical trial, which was SAVE. SAVE was published in 1992, and I have been in clinical trials ever since. I love doing them. Among other things, I just enjoy the interaction and the camaraderie; getting together as a team to focus on a question and solve the problems that are inevitable within the conduct of a trial.

   What was the SAVE trial?

SAVE stands for Survival and Ventricular Enlargement, and what we did was enroll patients with recent myocardial infarction and some degree of left-ventricular dysfunction and then test the idea that long-term therapy with the ACE inhibitor captopril would result in an improved clinical outcome, which it did.

   How did you move from there into also studying statins, an area that now constitutes a large share of your citations?

Highly Cited Papers by Marc A. Pfeffer et al., Published Since 1995 (Ranked by total citations) Rank Paper Citations 1 F.M. Sacks, et al., "The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels," New Engl. J. Med., 335(14): 1001-9, 1996. 3,308 2 P.M. Ridker, et al., "Long-term effects of pravastatin on plasma concentration of C-reactive protein," Circulation, 100(3): 230-5, 1999. 611 3 K. Lindpaintner, et al., "A prospective evalution of an angiotensin-converting-enzyme gene polymorphism and the risk of ischemic heart disease," New Engl. J. Med., 332(11): 706-11, 1995. 588 4 P.M. Ridker, et al., "Inflammation, pravastatin, and the risk of coronary events after myocardial infarction in patients with average cholesterol levels," Circulation, 98(9): 839-44, 1998. 540 5 C.P. Cannon, et al., "Intensive versus moderate lipid lowering with statins after acute coronary syndromes," New Engl. J. Med., 350(15): 1495-1504, 2004. 407 SOURCE: Thomson Scientific Web of Science

Simple—opportunity knocked! The Squibb medical scientists involved in SAVE were also developing pravastatin and wanted to determine whether it could reduce cardiovascular events in people with known coronary disease. We (Frank Sacks, Braunwald, and I) expanded the U.S. and Canadian investigators we had assembled for the SAVE trial, and we were off and running with what was then my second major international trial. We knew that the 4S, which stands for the Scandinavian Simvastatin Survival Study, had just started to determine whether that statin could improve survival in patients with high cholesterol.

   How were the two trials different?

Eugene Braunwald’s philosophy was that you should never do a "me too" trial. If you are going to put in the all-out effort required for a study, focus on a question that has the potential to impact patient care. The Cholesterol and Recurrent Events (CARE) trial shifted the focus from elevated cholesterol to patients with coronary artery disease with what was considered at the time to be "average" baseline cholesterol. CARE extended the impressive benefits shown with a statin in 4S to a larger population.

Good clinical trials generate much more information than just the benefit/risk ratio for the study medication. Paul Ridker, a colleague at the Brigham and Women’s Hospital, effectively used the CARE study for one of the early key components of the C-reactive protein, or CRP, story that he was unfolding. Paul hypothesized that CRP, a measure of inflammation, would be reduced by statins. Well, we were smart enough, in designing CARE, to save and store plasma for future questions. Paul used the randomized cohort in CARE to demonstrate that statins lower CRP.

   Considering that randomized controlled trials constitute such a critical aspect of modern medicine, what would you say is the most important lesson you’ve taken away from your experience?

That a randomized controlled trial starts with the patient. Good trials offer patients the best of today’s medicine and then ask the question, "Can we do better?" You need a committed team around you that lives and breathes the belief that quality trials advance medical care and improve our understanding of disease processes. One of the things we do in a trial is physician education. When we have a collaborative meeting, and we have them frequently, we don’t just focus on trial issues. We discuss the field—did you know this, did you know that? So when we look to put a team together, we make sure we have a broad base of experts.

   After all this time, what’s your take on the mechanisms by which statins reduce heart-disease risk?

Thanks to a collaborative group, we now have information on 90,000 patients enrolled in trials of statins. It’s more apparent than it was with any single trial that the effects of statins are related to the degree of LDL lowering. There is harmony between the more basic mechanistic investigations that LDL-lowering results in less inflammation and plaque stabilization with the clinical trials demonstrating reduced cardiovascular deaths, myocardial infarctions, and strokes.

   Since you’re a clinician as well as a researcher, tell us who you prescribe statins for and who you don’t.

Statins are remarkable. So who gets a statin? Anybody who is at risk. Selective use in primary prevention and across the board in secondary prevention. The beauty of statins is that they are very well tolerated. For the most part, people taking a statin do not experience "side effects." But this is where the practice of medicine cannot be done over the telephone. Everyone needs an individual cardiovascular risk assessment. If somebody is smoking, for instance, the most important intervention for that person is to stop. We still have to practice medicine one patient at a time.

   Your papers from the CHARM study are among the hottest in medicine over the last year. What was that study about and what did you learn?