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Monday, November 29, 2010

Why so much fuss about Anacetrapib?

I'm a bit puzzled by all the excitement about Merck's new drug, Anacetrapib (MK-0859) that's said to lower risk for cardiovascular disease by lowering bad cholesterol. Earlier this week at the annual meeting of the American Heart Association, researchers presented promising findings on the drug, including results from the phase III DEFINE (Determining the Efficacy and Tolerability of CETP Inhibition with Anacetrapib) trial. The list of disclosures for that abstract is long and fairly shocking. On Wednesday, the results were published online in the NEJM.

The new drug interests me, as an oncologist, because it's an enzyme inhibitor – in some ways like many new and in-the-pipeline cancer treatments. Anacetrapib raises high-density lipoprotein (HDL, a.k.a. "good cholesterol") and lowers low-density lipoprotein (LDL, a.k.a. "bad cholesterol") by interfering with a cholesterol enzyme transfer protein (CETP). The experimental medication is a pill that, based on earlier safety studies, is taken at 100 mg by mouth, once daily. So it's convenient enough.

In some respects, the results of this randomized, placebo-controlled large trial are knock-your-socks-off impressive: patients on the drug had, an average, a more-than doubling of their serum HDL levels, from 41 to 101 mg per deciliter (cho­les­terol units: mil­ligrams per deciliter). At the same time, the HDL shift was just 40 to 46 for patients assigned to the placebo (control). Conversely, LDL levels went down dramatically in patients taking Anacetrapib, from 81 to 45 mg per deciliter on average, and the corresponding drop seen among the control patients was only 82 to 77. These numbers are really terrific, and the results highly significant from a statistical perspective. The study lasted for 76 weeks, i.e. well over a year, and the drug was very-well tolerated according to all published reports.

What's wrong here? Well, it's that we don't know for sure how this new drug affects heart disease and other vascular conditions. In this study, the plasma cholesterol levels were monitored as surrogate markers for risk of atherosclerotic events, but these laboratory parameters are not the same thing as direct measures of disease. It is uncertain if this drug has any impact on mortality, or even on heart attacks, strokes or other clinical endpoints.

In my opinion, we need a lot more information about this new drug before we prescribe it to thousands or millions of people who have hyperlipidemia. Fortunately, as pointed out by Dr. Harlan Krumholz, writing for Forbes, Merck is "doing the right thing" by testing the drug in additional studies now, with clinical endpoints in mind. Still, his enthusiasm for what amount to very favorable blood testing seems extreme in light of the previous experience to which he refers with Pfizer's torcetrapib, a drug of the same class that turned out to have significant side effects, and Merck's previous marketing of Zetia.

According to the New York Times, John Boris, an analyst at Citigroup, wrote in a note to investors on Wednesday that the drug could potentially have sales of more than $1 billion a year. Dr. Steven Nissen, a sometimes cautious leader in the field, found the results encouraging, according to widely-cited comments such as those appearing in the Dow Jones Newswires.

In a few years, we'll see what Merck finds out with the ongoing trials, and if the drug really helps reduce heart attacks and deaths in people with hyperlipidemia.

Meanwhile, for those who are skeptical about cholesterol-lowering drugs and their side effects, as I am for people who have only modestly elevated lipid levels, you might consider the old-fashioned approach of dietary modification. The NIH offers tips for therapeutic lifestyle changes that can help reduce hyperlipidemia in many patients.

This post originally appeared at Medical Lessons, written by Elaine Schattner, ACP Member, a nonpracticing hematologist and oncologist who teaches at Weill Cornell Medical College, where she is a Clinical Associate Professor of Medicine. She shares her ideas on education, ethics in medicine, health care news and culture. Her views on medicine are informed by her past experiences in caring for patients, as a researcher in cancer immunology and as a patient who's had breast cancer.

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6 Comments:

OpenID marilynmann said...

Dr. Schattner,

I am puzzled how you came to the conclusion that Dr. Krumholz had an extreme amount of enthusiasm for anacetrapib. In his blog post on the Forbes website that you reference, he clearly states that showing an effect on laboratory values -- HDL and LDL, in this case -- is not enough. I quote:

"The torcetrapib experience has had a great influence in this class of drugs ... and perhaps is changing the perspective for a range of drugs that are intended to lower risk. Various recent studies have shown that what happens to patients is not always what we expect from changes in risk factors.

Merck is setting a good example by evaluating the drug in steps, carefully assessing its effect on patients, and not proceeding toward approval before testing the effect of the drug on patient outcomes in a large study. The question is not what the drug does to the lab tests -- but what does it do to the risk of patients. The change in the lab test makes us hopeful -- but cannot tell us what will happen to patients."

Nowhere in Dr. Krumholz's post do I see an extreme or inappropriate amount of enthusiasm for anacetrapib. In fact, it appears to me that the two of you are in agreement on the need to have evidence that the drug reduces the risk of cardiovascular endpoints and death before FDA approval.

Best,
Marilyn Mann

November 29, 2010 at 9:40 PM  
Anonymous Elaine Schattner, M.D. said...

Hi Marilyn,
The tone of the article, as a whole, is notably upbeat from the start:

"It would be great to have a new drug that had a wonderful effect..."

The second paragraph rich with optimistic words: "...At the (AHA) meeting Merck and other investigators are presenting the results of a very promising drug that may reduce heart risk above and beyond what is possible with drugs like Lipitor..." The piece goes on like this, such that any stated caution gets lost in all the positivity.

Even the article's title - that "Merck Does the Right Thing," and which it's possible the author didn't choose, leads the reader to think this is about something good, which it may or may not be.

November 30, 2010 at 10:10 AM  
OpenID marilynmann said...

Dr. Schattner,

I do not believe your characterization is a fair reading of Dr. Krumholz's post. I suggest your readers read Dr. Krumholz's post and decide for themselves.

The title refers to the fact that Merck is planning to conduct a large phase III trial with clinical endpoints. Isn't that what you would like them to do? Isn't that in fact the main point of your post?

November 30, 2010 at 11:46 AM  
Anonymous Harlan Krumholz said...

The positivity was about the promise of the drug, acknowledging its potential - and the applause for Merck was because they are going to pursue a large scale outcomes trial now rather than try to get approval based on the change in the lipid profile. I am an advocate for the need for studies to assess the effect of interventions on outcomes whenever possible. Marilyn has accurately characterized my position.

November 30, 2010 at 12:19 PM  
Anonymous Elaine Schattner, M.D. said...

I agree with Dr. Krumholz that a phase III trial of this drug and more studies with clinical endpoints are warranted.

November 30, 2010 at 4:08 PM  
Anonymous Harlan Krumholz said...

My positivity was about the promise of the drug. My applause for Merck was for their decision to pursue an adequately-powered outcomes trial before seeking approval. I am a strong advocate for the use of outcomes trials to evaluate the effect of new drugs on patients whenever possible. Improvements in lipid profiles are not a guarantee that patients will benefit. I tried to make that clear in my contribution to Forbes. Ms. Mann does characterize my position in the blog accurately. I encourage anyone who is interested to read the blog. http://blogs.forbes.com/sciencebiz/2010/11/17/merck-does-the-right-thing/

December 1, 2010 at 8:18 AM  

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Members of the American College of Physicians contribute posts from their own sites to ACP Internistand ACP Hospitalist. Contributors include:

Albert Fuchs, MD
Albert Fuchs, MD, FACP, graduated from the University of California, Los Angeles School of Medicine, where he also did his internal medicine training. Certified by the American Board of Internal Medicine, Dr. Fuchs spent three years as a full-time faculty member at UCLA School of Medicine before opening his private practice in Beverly Hills in 2000.

And Thus, It Begins
Amanda Xi, ACP Medical Student Member, is a first-year medical student at the OUWB School of Medicine, charter class of 2015, in Rochester, Mich., from which she which chronicles her journey through medical training from day 1 of medical school.

Auscultation
Ira S. Nash, MD, FACP, is the senior vice president and executive director of the North Shore-LIJ Medical Group, and a professor of Cardiology and Population Health at Hofstra North Shore-LIJ School of Medicine. He is Board Certified in Internal Medicine and Cardiovascular Diseases and was in the private practice of cardiology before joining the full-time faculty of Massachusetts General Hospital.

Zackary Berger
Zackary Berger, MD, ACP Member, is a primary care doctor and general internist in the Division of General Internal Medicine at Johns Hopkins. His research interests include doctor-patient communication, bioethics, and systematic reviews.

Controversies in Hospital Infection Prevention
Run by three ACP Fellows, this blog ponders vexing issues in infection prevention and control, inside and outside the hospital. Daniel J Diekema, MD, FACP, practices infectious diseases, clinical microbiology, and hospital epidemiology in Iowa City, Iowa, splitting time between seeing patients with infectious diseases, diagnosing infections in the microbiology laboratory, and trying to prevent infections in the hospital. Michael B. Edmond, MD, FACP, is a hospital epidemiologist in Richmond, Va., with a focus on understanding why infections occur in the hospital and ways to prevent these infections, and sees patients in the inpatient and outpatient settings. Eli N. Perencevich, MD, ACP Member, is an infectious disease physician and epidemiologist in Iowa City, Iowa, who studies methods to halt the spread of resistant bacteria in our hospitals (including novel ways to get everyone to wash their hands).

db's Medical Rants
Robert M. Centor, MD, FACP, contributes short essays contemplating medicine and the health care system.

Suneel Dhand, MD, ACP Member
Suneel Dhand, MD, ACP Member, is a practicing physician in Massachusetts. He has published numerous articles in clinical medicine, covering a wide range of specialty areas including; pulmonology, cardiology, endocrinology, hematology, and infectious disease. He has also authored chapters in the prestigious "5-Minute Clinical Consult" medical textbook. His other clinical interests include quality improvement, hospital safety, hospital utilization, and the use of technology in health care.

DrDialogue
Juliet K. Mavromatis, MD, FACP, provides a conversation about health topics for patients and health professionals.

Dr. Mintz' Blog
Matthew Mintz, MD, FACP, has practiced internal medicine for more than a decade and is an Associate Professor of Medicine at an academic medical center on the East Coast. His time is split between teaching medical students and residents, and caring for patients.

Everything Health
Toni Brayer, MD, FACP, blogs about the rapid changes in science, medicine, health and healing in the 21st century.

FutureDocs
Vineet Arora, MD, FACP, is Associate Program Director for the Internal Medicine Residency and Assistant Dean of Scholarship & Discovery at the Pritzker School of Medicine for the University of Chicago. Her education and research focus is on resident duty hours, patient handoffs, medical professionalism, and quality of hospital care. She is also an academic hospitalist.

Glass Hospital
John H. Schumann, MD, FACP, provides transparency on the workings of medical practice and the complexities of hospital care, illuminates the emotional and cognitive aspects of caregiving and decision-making from the perspective of an active primary care physician, and offers behind-the-scenes portraits of hospital sanctums and the people who inhabit them.

Gut Check
Ryan Madanick, MD, ACP Member, is a gastroenterologist at the University of North Carolina School of Medicine, and the Program Director for the GI & Hepatology Fellowship Program. He specializes in diseases of the esophagus, with a strong interest in the diagnosis and treatment of patients who have difficult-to-manage esophageal problems such as refractory GERD, heartburn, and chest pain.

I'm dok
Mike Aref, MD, PhD, FACP, is an academic hospitalist with an interest in basic and clinical science and education, with interests in noninvasive monitoring and diagnostic testing using novel bedside imaging modalities, diagnostic reasoning, medical informatics, new medical education modalities, pre-code/code management, palliative care, patient-physician communication, quality improvement, and quantitative biomedical imaging.

Informatics Professor
William Hersh, MD, FACP, Professor and Chair, Department of Medical Informatics & Clinical Epidemiology, Oregon Health & Science University, posts his thoughts on various topics related to biomedical and health informatics.

David Katz, MD
David L. Katz, MD, MPH, FACP, is an internationally renowned authority on nutrition, weight management, and the prevention of chronic disease, and an internationally recognized leader in integrative medicine and patient-centered care.

Just Oncology
Richard Just, MD, ACP Member, has 36 years in clinical practice of hematology and medical oncology. His blog is a joint publication with Gregg Masters, MPH.

KevinMD
Kevin Pho, MD, ACP Member, offers one of the Web's definitive sites for influential health commentary.

MD Whistleblower
Michael Kirsch, MD, FACP, addresses the joys and challenges of medical practice, including controversies in the doctor-patient relationship, medical ethics and measuring medical quality. When he's not writing, he's performing colonoscopies.

Medical Lessons
Elaine Schattner, MD, FACP, shares her ideas on education, ethics in medicine, health care news and culture. Her views on medicine are informed by her past experiences in caring for patients, as a researcher in cancer immunology, and as a patient who's had breast cancer.

Mired in MedEd
Alexander M. Djuricich, MD, FACP, is the Associate Dean for Continuing Medical Education (CME), and a Program Director in Medicine-Pediatrics at the Indiana University School of Medicine in Indianapolis, where he blogs about medical education.

More Musings
Rob Lamberts, MD, ACP Member, a med-peds and general practice internist, returns with "volume 2" of his personal musings about medicine, life, armadillos and Sasquatch at More Musings (of a Distractible Kind).

Prescriptions
David M. Sack, MD, FACP, practices general gastroenterology at a small community hospital in Connecticut. His blog is a series of musings on medicine, medical care, the health care system and medical ethics, in no particular order.

Reflections of a Grady Doctor
Kimberly Manning, MD, FACP, reflects on the personal side of being a doctor in a community hospital in Atlanta.

The Blog of Paul Sufka
Paul Sufka, MD, ACP Member, is a board certified rheumatologist in St. Paul, Minn. He was a chief resident in internal medicine with the University of Minnesota and then completed his fellowship training in rheumatology in June 2011 at the University of Minnesota Department of Rheumatology. His interests include the use of technology in medicine.

Technology in (Medical) Education
Neil Mehta, MBBS, MS, FACP, is interested in use of technology in education, social media and networking, practice management and evidence-based medicine tools, personal information and knowledge management.

Peter A. Lipson, MD
Peter A. Lipson, MD, ACP Member, is a practicing internist and teaching physician in Southeast Michigan. The blog, which has been around in various forms since 2007, offers musings on the intersection of science, medicine, and culture.

Why is American Health Care So Expensive?
Janice Boughton, MD, FACP, practiced internal medicine for 20 years before adopting a career in hospital and primary care medicine as a locum tenens physician. She lives in Idaho when not traveling.

World's Best Site
Daniel Ginsberg, MD, FACP, is an internal medicine physician who has avidly applied computers to medicine since 1986, when he first wrote medically oriented computer programs. He is in practice in Tacoma, Washington.

Other blogs of note:

American Journal of Medicine
Also known as the Green Journal, the American Journal of Medicine publishes original clinical articles of interest to physicians in internal medicine and its subspecialities, both in academia and community-based practice.

Clinical Correlations
A collaborative medical blog started by Neil Shapiro, MD, ACP Member, associate program director at New York University Medical Center's internal medicine residency program. Faculty, residents and students contribute case studies, mystery quizzes, news, commentary and more.

Interact MD
Michael Benjamin, MD, ACP member, doesn't accept industry money so he can create an independent, clinician-reviewed space on the Internet for physicians to report and comment on the medical news of the day.

PLoS Blog
The Public Library of Science's open access materials include a blog.

White Coat Rants
One of the most popular anonymous blogs written by an emergency room physician.

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