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Tuesday, June 21, 2016

Is there a pill to make you live longer? The HOPE-3 trial and the hype that will surely follow

Today in the New England Journal of Medicine an article has appeared reporting the results of the Heart Outcomes Prevention Evaluation-3 (HOPE-3)trial. Exciting simplifications are sure to follow in the news. If you would like to stop reading now, the answer to the question posed in the title is probably no.

The question:
For many years researchers have discussed the possibility of a creating a pill that might contain several kinds of medication that would reduce people's risk of dying of cardiovascular disease. It is an attractive thought. Since cardiovascular disease is the major cause of death globally, reducing that risk has the potential to vastly reduce death and disability. Originally we thought that a suitable “polypill” might contain something to lower the blood pressure, something to lower cholesterol and something to reduce the risk of blood clots. Many studies have looked at the mortality benefits of various blood pressure pills, cholesterol lowering strategies and anti-clotting drugs and we have found that some of them help some people to some extent and some cause some people problems. Drat. So complex.

The history:
The original HOPE trial looked at a blood pressure pill (ramipril) which was added to whatever other medication a group of people at high risk of cardiovascular disease were taking. It lowered the risk of heart attack, stroke and death significantly enough that the study was stopped early and drugs in the ramipril class (ACE inhibitors) were aggressively prescribed, especially for patients with diabetes, probably to good effect.

The HOPE-2 trial looked at using vitamins to reduce homocysteine levels, which appeared to be a significant risk factor for heart attack and stroke. The studied doses of vitamin B6, B12 and folate did not reduce any of the outcomes they looked at. HOPE-2 was dashed.

In 2007 HOPE-3 began, looking at a combination of blood pressure medication and cholesterol medication, specifically to reduce death from heart attack or stroke, new heart failure, cardiac arrest or non-fatal heart attack or angina. The study was performed in academic medical centers all over the world, including the U.S., Europe, China and India, South Africa and Southeast Asia. Over 14,000 patients were enrolled, limited to men 55 and over and women 65 and over with intermediate cardiovascular risk (calculated at about 1% per year). Women 60-65 years of age were eligible if they had one of several specific risk factors, including glucose intolerance, smoking and high waist to hip ratios. These were people who had never had heart problems or strokes.

Drug company involvement:
Astra Zeneca helped fund this study along with the Canadian Institutes of Health Research. The cholesterol and blood pressure medication used in the study was on patent and sold by Astra Zeneca. The cholesterol pill was rosuvastatin (Crestor) and the blood pressure medication was candesartan/hydrochlorothiazide (Atacand/HCT). There were many drugs to choose from in the categories of effective blood pressure reducers and statin cholesterol medication, some of which would have been cheap and generic. The drugs they did choose are now generic but not yet cheap. I suspect Astra Zeneca hoped the study would have ended in time for them to reap financial benefits as their particular drug proved miraculously effective, or that the combination of the drugs could be made into a new formulation that would extend their market share.

So what happened? Getting to the point.
First there was a run-in phase. The 14,000+ patients were given the study drugs and about 2000 of them dropped out because they didn't tolerate them or didn't want to participate anymore. 12,000 patients were left. Of these about 3000 took placebo pills, 3000 took the blood pressure pills only, 3000 took the cholesterol pill only and 3000 took both blood pressure and cholesterol medication. After about 5.5 years, the patients taking blood pressure medication did not have a significantly lower risk of death, heart attack or stroke or the other cardiovascular outcomes. The patients taking cholesterol medication did have a reduced risk of death and cardiovascular outcomes. Taking both blood pressure medication and cholesterol medication was no better than just taking the cholesterol medication.

How big was the effect and how much does this cost?
The article quotes a hazard ratio of 0.71 for patients taking the combination medication, meaning that the medicated patient has 7 tenths the risk of a bad outcome of the unmedicated patient. The raw numbers are way more interesting. After about five and a half years of taking the combination of drugs or placebo, 163 patients in the active drug group had died and 178 of the placebo group had died, a difference of 15. At the present cost of these drugs, about $280 per month, it would cost about $3.7 million per life saved, which is pretty steep. Just taking the cholesterol medication, which is really the only one that had a positive effect, would cost about $2.6 million per life saved. If there were drugs on a $4 a month plan that did the same thing we might get down to a very reasonable cost of $53,000, assuming no other associated costs like doctor visits or lab testing (which is not a fair assumption.) Death is not the only thing we care about, of course, but other differences, such as numbers of hospitalizations, were not much more impressive when I reviewed the supplemental data.

How about side effects?
To begin with, 2,000 of 14,000 patients did not like or tolerate the study drugs, so some of them probably had intolerable side effects. During the study, however, there weren't many important side effects except a bit more dizziness in the patients on blood pressure medication, which apparently didn't do them much good anyway. There was some muscle pain, but patients on placebo also had that. The dose of the cholesterol pill was very low, which might have explained the pretty awesome side effect profile. Also the patients most bothered by side effects probably dropped out in the run-in period. By the end of the study only about 70% of patients were still taking the prescribed drugs, so there may have been intolerance that was not reported. There was no excess of development of diabetes, perhaps because of the very low statin dose. Good studies have shown more development of diabetes in statin users, but doses are often significantly higher.

Other interesting findings from the supplemental data:
I was very pleased that the NEJM published a well written summary of data that didn't get discussed in the article. There were some really weird things that showed up.
1. South Asians and to some extent Chinese subjects did not have near as much benefit from the study drugs as did subjects of European descent.
2. Stroke risk was actually higher for patients with borderline high blood pressure when they were treated with the blood pressure lowering drugs, though reduced for patients with higher and lower blood pressures.
3. Patients with the highest cholesterol levels (LDL greater than 141, mean of 166) did not benefit from treatment with cholesterol lowering drugs. That's really strange and counterintuitive.

Bottom line?
We have not discovered a pill yet that will make everyone live longer. Taking a statin drug which lowers cholesterol (who knows if that's the important effect) may lower your risk of cardiovascular disease or death, but you need to take it a long time to make a small difference and we aren't sure which one is most effective. Most people who take statin drugs (Lipitor, Crestor/rosuvastatin etc.) for primary prevention (meaning they haven't had heart attacks or strokes) will not benefit from them. Low doses of Crestor/rosuvastatin usually have a low risk of side effects. Treating normal or slightly high blood pressure with low dose candesartan/HCTZ doesn't reduce the risk of heart attacks, strokes or cardiovascular death. Navigating the pros and cons of all of these pills and potions is neither obvious nor simple and is best done with a doctor who you know and trust.

Janice Boughton, MD, ACP Member, practiced in the Seattle area for four years and in rural Idaho for 17 years before deciding to take a few years off to see more places, learn more about medicine and increase her knowledge base and perspective by practicing hospital and primary care medicine as a locum tenens physician. She lives in Idaho when not traveling. Disturbed by various aspects of the practice of medicine that make no sense and concerned about the cost of providing health care to every American, she blogs at Why is American Health Care So Expensive?, where this post originally appeared.

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Blog log

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 Iowa City, IA, 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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