On 2015 Feb 09, David Keller commented:

Dr. Lee,

Your arguments against prescribing ezetimibe at this time are very persuasive, especially with regard to the cost of preventing cardiovascular events with this drug, even if the recent reports of such efficacy are eventually verified. This kind of perspective from a cardiovascular scientist is most beneficial to general internists like me.

Your comments regarding rosiglitazone form a sort of inverse analogy to ezetimibe; if physicians who prescribed rosiglitazone are not to be condemned for "guessing wrong" in advance of the data proving that drug was harmful, then physicians who prescribed ezetimibe should not be congratulated for "guessing right" if this drug is proven to be beneficial. Good point.

However, I chose never to prescribe rosiglitazone, even before its harmful outcomes were known. My decision was not due to luck or clairvoyance, but to the simple fact that rosiglitazone raises LDL cholesterol, and a very similar alternative drug (pioglitazone) exists which lowers LDL cholesterol instead. Knowing that every point of LDL increase in a diabetic is correlated with increased cardiovascular risk, I thought it would be folly to choose an agent which worsened LDL, even if it was only a surrogate marker.

So, all of these examples get back to the question of the strength of LDL-lowering as a surrogate marker for reduction of cardiovascular events. The example of rosiglitazone versus pioglitazone seems to strengthen LDL as a valid surrogate marker for events. It appears that the new data for ezetimibe will also do so, if it confirms that this weak LDL-lowering drug also weakly improves cardiovascular event rates. Of course, ezetimibe still may not be worth its cost, as you point out, and that appears to be the bottom line, at least until ezetimibe is available as a cheap generic medication.

On 2015 Feb 03, Todd Lee commented:

Dr. Keller,

You do make a very interesting point about hindsight.

It is a fact that billions of dollars have been spent in North America on a drug that, to date, does not have any high quality published evidence of efficacy in terms of clinical endpoints. This drug was thus used on the basis of theoretical arguments and a belief that lower LDL means lower events. The findings of IMPROVE-IT may suggest that some patients that have received this drug all of this time did derive benefit. However, based on the effect size in the trial and the patients enrolled, this may be the minority -- and at a considerable health care cost for each benefit.

I'm really not sure what to infer about physicians who believed in the drug all this time. Are they to be commended for being correct?

I'm not certain that money could not have been used for greater benefit with another intervention -- that is a question for health care economists; however, at $1,000,000 per event prevented (earlier post) it seems likely there may have been a more cost effective option.

Let me contrast that with another example as I believe the case for ezetimibe and LDL is analogous to what people believed about hemoglobin A1c and the complications of diabetes. ROSIGLITAZONE was an extremely popular drug in 2006 -- to the tune of US prescriptions exceeding 2 billion dollars. This was because people inferred that lower A1c meant improved outcomes. Later, after the landmark paper showed that ROSIGLITAZONE might have been associated with increased cardiovascular risks, the sales plummeted to less than 15 million dollars in 2012. Thousands of lawsuits were settled and billion dollar fines were paid (for ROSIGLITAZONE and issues around other drugs) by the manufacturer. Furthermore, that drug was withdrawn from numerous European markets.

I'm not sure what to infer about all of the physicians who believed in that drug. Are they all to be condemned? The answer is no. Physicians do the best they can for their patients within the limits of current medical knowledge. They had no a priori way of knowing that this intervention may actually harm patients more than help them.

That said, it is not an accident that both agents were billion dollar winners for their prospective companies and that they were heavily marketed.

Our group incidentally received a marketing pamphlet on ezetimibe in the mail today extolling the IMPROVE-IT trial. The jist of it: the lipid hypothesis is reaffirmed and ezetimibe has been proven effective in patients at risk of coronary artery disease. Does it matter that the paper hasn't been peer reviewed or put in the context of all of the negative papers before it? Not at all. That wouldn't be very good marketing.

On 2015 Jan 24, David Keller commented:

Thank you, Dr. Lee, for that thorough, informative and excellent reply to my comment. For many years, I avoided prescribing ezetimibe (either alone or with a statin) due to the lack of data documenting improved outcomes. Prior to IMPROVE-IT, I would not have questioned the need for your study, and I would have been curious to learn why other clinicians were prescribing ezetimibe despite its interesting ability to improve lipids but not outcomes. Other non-statins which improve lipids - such as niacin, fibrates and bile acid sequestrants - had been able to demonstrate improved cardiovascular outcomes, at least in certain populations or under certain circumstances. The reports of improved outcomes from IMPROVE-IT seemed to reaffirm the importance of lowering LDL and to remove the major obstacle which had prevented me from adding ezetimibe when patients failed to achieve their LDL goal on a tolerable dose of statin. Based on the reservations you have expressed regarding IMPROVE-IT, I will hold back from prescribing it until the questions you raised are answered.

For the sake of discussion, assume that cardiovascular outcome benefits of ezetimibe are eventually proved to your satisfaction. How, then, would that affect the utility of your investigation of why physicians were prescribing a drug which lacked outcome data, if their patients were thereby benefiting from lower event rates? These physicians may have prescribed ezetimibe based on their anecdotal experience with the drug, their knowledge of lipid physiology and pharmacology, or other factors, making them guilty of nothing more than being ahead of the randomized trial data, correctly predicting the outcome benefits of ezetimibe, and benefiting their patients with better outcomes sooner than more conservative physicians like me. Should we be trying to "correct" that kind of "mistake"?

On 2015 Jan 24, Todd Lee commented:

As stated in our paper, we need the data from IMPROVE-IT to better inform us on the use of ezetimibe. However, rather than relying on a conference presentation and press releases we will also need to await the peer-reviewed and sponsor-independent analysis of the IMPROVE-IT trial to judge the quality of the results and evaluate their impact on general practice. Given interim analysis was performed (and the study was subsequently re-sized) any multiple comparisons performed will require expert statistical review.

Furthermore, given no other positive studies exist, it may be prudent to perform an independent individual patient data analysis of all similar studies to better refine or confirm the estimate of effect prior to making any final conclusions from one trial.

The net conclusion of this study, if the presented data is taken at face value, is a number needed to treat (NNT) of 50 over 7 years for the composite outcome. Overall mortality was not reduced. At generic Canadian prices it would cost approximately $58,765 to prevent 1 event over 7 years (Ontario formulary price as of January 2015). However, at US brand name prices of approximately $8.50 per day (Lexicomp 2015) the cost of preventing one composite outcome would be more than $1,000,000.

It is also important to note that IMPROVE-IT was a secondary prevention study (acute event within 10 days) and not primary prevention. In primary prevention, the NNT is likely much higher and the corresponding costs per event prevented would increase proportionately and likely be substantial even at generic prices. In our cohort 6/17 (35%) were receiving ezetimibe for primary prevention.

Whether the drug lowers event rates in the absence of a statin remains unproven and cannot be inferred from this study. Nonetheless, it will be interesting to see the effects on monotherapy uptake given the publicity around this study and also when IMPROVE-IT is ultimately published.

The impact of this study on the uptake of other drugs approved on the basis of LDL as a surrogate marker is also not to be underestimated. The issue of treating to specific LDL targets is currently being debated amongst experts after recent changes to the guidelines. It would be somewhat naive to think that there isn't a substantial market pressure behind bringing back targets to be measured and obtained through additional medications.

On 2015 Jan 23, David Keller commented:

Recent evidence of ezetimibe outcome benefits undermines the premise of this study

The underlying premise of this study of ezetimibe prescribing patterns is that there is “a lack of evidence supporting its efficacy” in reducing adverse cardiovascular outcomes, despite its demonstrated efficacy in improving lipids and other surrogate endpoints (1).

In the recently reported “IMPROVE-IT” study, patients taking ezetimibe plus simvastatin experienced significantly fewer major cardiovascular events (as measured by a composite of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, rehospitalization for unstable angina or coronary revascularization occurring at least 30 days after randomization) than patients treated with simvastatin alone (2).

Now that there is evidence that ezetimibe improves cardiovascular outcomes, the question of why clinicians prescribed it inappropriately in the past seems moot. Perhaps their clinical experiences using ezetimibe convinced them that evidence of beneficial outcomes would emerge over time. If ezetimibe was improving outcomes all along, then studies based on the premise that it should not have been used seem less relevant.

References:

1: McDonald EG, Saleh RR, Lee TC. Ezetimibe use remains common amongst medical inpatients. Am J Med. 2014 Oct 19. pii: S0002-9343(14)00917-6. doi: 10.1016/j.amjmed.2014.10.016. [Epub ahead of print] PubMed PMID: 25448168.

2: Kohno T. Report of the American Heart Association (AHA) Scientific Sessions 2014, Chicago. Circ J. 2014 Dec 15. [Epub ahead of print] PubMed PMID: 25502168.

On 2015 Jan 23, David Keller commented:

Recent evidence of ezetimibe outcome benefits undermines the premise of this study

The underlying premise of this study of ezetimibe prescribing patterns is that there is “a lack of evidence supporting its efficacy” in reducing adverse cardiovascular outcomes, despite its demonstrated efficacy in improving lipids and other surrogate endpoints (1).

In the recently reported “IMPROVE-IT” study, patients taking ezetimibe plus simvastatin experienced significantly fewer major cardiovascular events (as measured by a composite of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, rehospitalization for unstable angina or coronary revascularization occurring at least 30 days after randomization) than patients treated with simvastatin alone (2).

Now that there is evidence that ezetimibe improves cardiovascular outcomes, the question of why clinicians prescribed it inappropriately in the past seems moot. Perhaps their clinical experiences using ezetimibe convinced them that evidence of beneficial outcomes would emerge over time. If ezetimibe was improving outcomes all along, then studies based on the premise that it should not have been used seem less relevant.

References:

1: McDonald EG, Saleh RR, Lee TC. Ezetimibe use remains common amongst medical inpatients. Am J Med. 2014 Oct 19. pii: S0002-9343(14)00917-6. doi: 10.1016/j.amjmed.2014.10.016. [Epub ahead of print] PubMed PMID: 25448168.

2: Kohno T. Report of the American Heart Association (AHA) Scientific Sessions 2014, Chicago. Circ J. 2014 Dec 15. [Epub ahead of print] PubMed PMID: 25502168.