Profile on Harlan Krumholz
I just want to highlight this profile on my friend Harlan Krumholz in Yale Alumni Magazine. Harlan is a Yale cardiologist who is a leader in the field of outcomes research — figuring out what works in the real world and applying those lessons to improve outcomes for patients. In the process, he has not been afraid to take on powerful interests, as he did by testifying in the Vioxx trials (described in Snigdha Prakash’s new book All the Justice Money Can Buy) and publishing articles on how the Vioxx debacle happened and what we can learn from it (see here, here, here and here).
I first contacted Harlan after reading about his presentation on the ENHANCE trial at the March 2008 American College of Cardiology meeting. The ENHANCE trial was designed to test whether ezetimibe, a drug that lowers LDL, added any benefit to a statin in slowing the progression of atherosclerosis, as measured by carotid intima-media thickness. My daughter, who has heterozygous familial hypercholesterolemia, had been on ezetimibe at one point, so I was particularly interested in the trial. Unfortunately, ezetimibe added no benefit at all and Harlan, representing a panel of cardiologists, was not afraid to state that it is not enough to know a drug’s effect on laboratory markers such as LDL. Rather, we need to know whether a drug improves clinical outcomes, such as heart attacks, strokes and death. As Harlan put it,
There are 3 possibilities with this drug. Eventually—one day, when outcomes studies are finally done—we may recognize that it is an effective medication for reducing cardiovascular risk. The ENHANCE study makes that less likely, but it is not impossible.
It could be that ezetimibe is simply an expensive placebo, and its principal harm is that it drains precious resources from our health care system and possibly leads people to use fewer of the drugs that have been shown to be beneficial. The ENHANCE study suggests that this may be true.
Third, it could be harmful. We do not know enough about the clinical risks of this drug. It is well tolerated and there are no obvious safety problems, but we cannot say if there is an increased risk of acute myocardial infarction or death or another important health problem.
* * * * *
This study heralds the need for clinical research to guide us in decisions for our patients; ideally, this work must be done early in the drug’s development. It is not right that we are this far down the line with this drug and we have so much uncertainty about its balance of risks and benefits. We must understand the effect of new drugs on people and that relying on a drug’s effect on a set of laboratory tests may not tell the whole story. We have learned this lesson before. It appears that we must learn it again.
Addendum: Just published in Circulation: Cardiovascular Quality and Outcomes, this editor’s perspective by Harlan Krumholz entitled “Patient-Centered Medicine: The Next Phase in Health Care.” Here’s an excerpt:
What matters most to patients are outcomes: Did I recover? Is my quality of life better? Patients want to know what has been accomplished by the tests and treatments they have undergone and what has been achieved by the time and resources that have been expended. It is time for us to fully embrace patient-centered medicine, which is ultimately outcomes oriented, with a focus on what patients experience and, among the range of medically reasonable options, gives precedence to what patients prefer.
Posted on July 16, 2011, in cardiology and tagged drug safety, ezetimibe, Harlan Krumholz, rofecoxib, Snigdha Prakash, Vioxx. Bookmark the permalink. 3 Comments.
Hi Marilyn –
First off, sorry to hear about your daughter, it is a condition I hope some of the more tailored therapies are able to overcome. I know in speaking with Dr. Robert Hegele (Robarts Institute), there are a number of ways he is looking at therapy, both drug and genetic.
Just a couple of points:
– the reason some of the big name “cardiologists” or “specialists” get involved is not as pure as one might think. I believe there is a massive ego component that is satisfied for the likes of Krumholz or Nissen…by constantly having their names in the spotlight. With that much time spent doing interviews, how are they able to maintain regular everyday practices? (or do they 😉 )
– I believe there was legitimate concern with both Vioxx and Avandia (especially Advandia)
– Kruholz’s commentary listed above for Ezetimibe is utterly rediculous. The purpose of his commentary was to be the mouthpiece of negativity for theheart.org, etc.
– the ENHANCE trial was a silly trial, which never should have been done, especially AFTER the ASAP (IMTs – 0.90mm) trial. The patient’s IMTs were far too thin (0.69mm) and because the patients were FH, the finalized LDL levels were still high enough that plaque was building.
– there is now M&M data for ezetimibe, go read the SHARP trial (I believe Krumholz and Nissen both had placed retracted statements on the utility of Ezetimibe)
– background on why Ezetimibe was used in this patient group can read up on by checking out the UK-HARP I UK HARP II trials (even with simvastatin at the reduced dose of 20 mg)
– the editorial for SHARP does make note that patients need to be treated more upstream and if the ending LDL figure can be obtained with just a statin, minus the upper dose side effects…then great!
– the entire data set known to the world show the lower the better, disease can be slowed (<80) and likely regressed (<61), so a high risk target of 70 seems appropriate (the Europeans have recently made it a hard target)
– reducing risk in the future should be about looking further into the more detailed numbers – apoB, non-HDL-C, HDL sub fractions, etc.
Fortunately my daughter’s LDL is under control with 20 mg. atorvastatin.
I disagree that ENHANCE was a silly trial. At the time ENHANCE was done, ezetimibe’s effect on LDL was known, but its effect on atherosclerosis was unknown. It was a perfectly reasonable question to test in a clinical trial. Moreover, I am not a fan of the “thin IMT” theory. First, there was no benefit in the subgroup of patients who had not previously been on statins. Second, the idea that these FH patients, with very high LDL even while on statins, had already benefited to the maximum extent possible, and therefore could not benefit from additional LDL-lowering, is not plausible and, in any case, is unproven.
I disagree with your interpretation of the SHARP trial. In SHARP, one arm was on simvastatin/ezetimibe and the other was on placebo. Although there was a benefit in the simva/eze arm, we have no way of knowing how much of the benefit, if any, was due to ezetimibe.
I’m not sure I’m following you when you say Drs. Krumholz and Nissen “had placed retracted statements on the utility of ezetimibe.” If you are saying that they have changed their opinions about ezetimibe based on SHARP, I happen to know that’s not true.
My father had elevated cholesterol and triglyceride levels all of his life, with triglycerides frequently being in excess of 2500, and his cholesterol levels in excess of 1500, and every physician that examined him said that he was an “aberration”.
He died in 2003, at the age of 103+, and was healthy and medication free until 10 days prior to his death. My mother lived to be 86, and died as the directed result of an accident.
My levels of both are medication controlled, but I wonder if I will approach their longevity. I am now 75+, and feel great, and constantly wonder whether I should stop all my medications.
So much for “accepted” medical standards.