The Cholesterol Hypothesis on the Beam: Dalcetrapib, PCSK9 inhibitors, and "off-target" effects of statins

The last month has witnessed the publication of three lines of research that could tip the balance of the evidence for the cholesterol hypothesis depending how things play out.  Followers of this blog know that I have a healthy degree of skepticism for the cholesterol hypothesis which was emboldened by studies of torcetrapib (blogged here and here) and anacetrapib that have come to light along with the failures of vytorin (ezetimibe; blogged here and here and here) and the addition of niacin to statins to improve cardiovascular outcomes in parallel with improvements in cholesterol numbers.

I think it's finally time to bury the CETP inhibitors. The November 29th NEJM (published online on November 5th) reports the results of the dal-OUTCOMES trial of dalcetrapib in patients with a recent acute coronary syndrome. Almost 16,000 patients were enrolled in this study of high risk patients, providing the study with ample power to detect meaningful improvements in cardiovascular outcomes - but alas, none were detected. The target is HDL, so the LDL hypothesis is not debunked by these data, but I think it is challenged nonetheless.

The enemy of good evidence is better evidence: Aspirin, colorectal cancer, and knowing when enough is enough

An epidemiological study of the impact of aspirin (ASA) on outcomes from colorectal carcinoma (CRCA) in JAMA has made quite a splash which has extended to the lay press (see Chan et al: http://jama.ama-assn.org/cgi/content/short/302/6/649?home ; and http://www.nytimes.com/2009/08/12/health/research/12aspirin.html ). I read this study, which normally would not have been of interest to me, because I knew that it was an epidemiological study and suspected that numerous methodological flaws would limit the conclusions that one could draw from it. And I admit that I was surprised that it has all the trappings of a methodologically superb study, complete in almost every way, including reporting of the Wald test for the assumption of proportional hazards, reporting of assessment for collinearity and overfitting of the model etc. It's all there, everything that one could want.


I should start by stating that there is biological plausibility of the hypothesis that ASA might influence the course of these cancers which express COX-2. I am no expert in this area, so I will take it as granted that the basic science evidence is sound enough to inflate the pre-test probability of an effect of ASA to a non-negligible level. Moreover, as pointed out by the authors, other smaller epidemiological investigations have suggested that ASA might improve outcomes from CRCA. The authors of the current investigation found a [marginally] statistically significant reduced hazards of death of approximately 0.3 in patients who took ASA after a diagnosis of CRCA, but not before.

Without delving into the details (knowing that one might find the devil there), I found the conclusions the authors made interesting, namely that additional investigations and randomized controlled trials will be needed before we can recommend ASA to patients diagnosed with CRCA. This caught me as a bit odd, depending upon what our goals are. If our goal is to further study the mechanisms of this disease in pursuit of the truth of the EFFICACY of ASA (see previous blog entry on vertebroplasty for the distinctions between efficacy and effectiveness research), then fine, we need a randomized controlled trial to eliminate all the potential confounding that is inherent in the current study, most notably the possibility that patients who took ASA are different from those who didn't in some important way that also influences outcome. But I'm prepared to accept that there is ample evidence that ASA benefits this condition and that if I had CRCA, the risks of not taking ASA far exceed the risks of taking it, and I would shun participation in any study in which I might be randomized to placebo. This may sound heretical, but allow me to explain my thinking.

I do worry that something that "makes sense" biologically and which is bolstered by epidemiological data might prove to be spurious, as happened in the decades-long saga of Premarin-prevention which came to a close with the Women's Health Initiative (WHI) study. But there are important differences here. Premarin had known side effects (clotting, increased risk of breast cancer) and it was being used long-term for the PREVENTION of remote diseases that would afflict women in the [distant] future. ASA has a proven safety profile spanning over a century, and patients with CRCA have a near-term risk of DEATH from it. So, even though both premarin and ASA might be used on the basis of fallible epidemiological data, there are important differences that we must consider. (I am also reminded of the ongoing debates and study of NAC for prevention of contrast nephropathy, which I think has gone on for far too long. There is ample evidence that it might help, and no evidence of adverse effects or excessive cost. When is enough enough?)

I just think we have become too beholden to certain mantras (like RCTs being the end-all-be-all or mortality being the only acceptable outcome measure), and we don't look at different situations with an independently critical eye. This is not low tidal volume ventilation where the critical care community needs unassailable evidence of efficacy to be convinced to administer it to patients who will have little say in the tidal volume their doctor uses to ventilate them. These are cognizant patients with cancer, this is a widely available over-the-counter drug, and this is a disease which makes people feel desperate, desperate enough to enroll in trials of experimental and toxic therapies. The minor side effects of ASA are the LEAST of their worries, especially considering that most of the patients in the cohort examined in this trial were using ASA for analgesia! If they are generally not concerned about side effects when it is used for arthritis, how can we justify withholding or not recommending it for patients with CANCER whose LIVES may be saved by it?

I were a patient with CRCA, I would take ASA (in fact I already take ASA!) and I would scoff at attempts to enroll me into a trial where I might receive placebo. The purists in pursuit of efficacy and mechanisms and the perfect trial be damned. I would much rather have a gastrointestinal hemorrhage than an early death from CRCA. That's just me. Others may appraise the risks and values of the various outcomes differently. And if they want to enroll in a trial, more power to them, so long as the investigators have adequately and accurately informed them of the existing data and the risks of both ASA and placebo, in the specific context of their specific disease and given the epidemiological data. Otherwise, their enrollment is probably ethically precarious, especially if they would go home and take an ASA for a more benign condition without another thought about it.

The PSA Screening Quagmire - If Ignorance is Bliss then 'Tis Folly to be Wise?

The March 26th NEJM was a veritable treasure trove of interesting evidence so I can't stop after praising NICE-SUGAR and railing on intensive insulin therapy. If 6000 patients (40,000 screened) seemed like a commendable and daunting study to conduct, consider that the PLCO Project Team randomized over 76,000 US men to screening versus control (http://content.nejm.org/cgi/reprint/360/13/1310.pdf) and the ERSPC Investigators randomized over 162,000 European men in a "real-time meta-analysis" of sorts (wherein multiple simultaneous studies were conducted with similar but different enrollment requirements and combined; see: http://content.nejm.org/cgi/reprint/360/13/1320.pdf.)   This is, as the editorialist points out a "Hurculean effort" and that is fitting and poignant - because ongoing PSA screening efforts in current clinical practice represent a Hurculean effort to reduce morbidity and mortality of this disease and this reinforces the importance of the research question - are we wasting our time? Are we doing more harm than good?

The lay press was quick to start trumpeting the downfall of PSA screening with headlines such as "Prostate Test Found to Save Few Lives" . But for all their might, both of these studies give me, a longtime critic of cancer screening efforts, a good bit of pause. (Pulmonologists may be prone to "sour grapes" as a result of the failures of screening for lung cancer.)

Before I summarize briefly the studies and point out some interesting aspects of each, allow me to indulge in a few asides. First, I direct you to this interesting article in Medical Decision Making "Cure Me Even if it Kills Me". This wonderful study in judgment and decision making shows how difficult it is for patients to live with the knowledge that there is a cancer, however small growing in them. They want it out. And they want it out even if they are demonstrably worse off with it cut out or x-rayed out or whatever. It turns out that patients have a value for "getting rid of it" that probably arises from the emotional costs of living knowing there's a cancer in you. I highly recommend that anyone interested in cancer screening or treatment read this article.

This article invokes in me an unforgettable patient from my residency whom we screened in compliance with VA mandates at the time. Sure enough, this patient with heart disease had a mildly elevated PSA and sure enough he had a cancer on biopsy. And we discussed treatments in concert with our Urology colleagues. While he had many options, this patient agonized and brooded and could not live with the thought of a cancer in him He proceeded with radical prostatectomy, the most drastic of his options. And I will never forget that look of crestfallen resignation every time I saw him after that surgery because he thereafter came to clinic in diapers, having been rendered incontinent and impotent by that surgery. He was more full of self-flagellating regret than any other patient I have seen in my career. This poor man and his experience certainly jaded me at a young age and made me highly attuned to the pitfalls of PSA screening.

Against this backdrop where cancer is the most feared diagnosis in medicine, we feel an urge towards action to screen and prevent, even when there is a marginal net benefit of cancer screening, and even when other greater opportunities for improving health exist. I need not go into the literature about [ir]rational risk appraisal other than to say that our overly-exuberant fear of cancer (relative to other concerns) almost certainly leads to unrealistic hopes for screening and prevention. Hence the great interest in and attention to these two studies.

In summary, the PLCO study showed no reduction in prostate-cancer-related mortality from DRE (digital rectal examination) and PSA screening. Absence of evidence is not evidence, however, and a few points about this study deserve to be made:

~Because of high (and increasing) screening rates in the control group, this was essentially a study of the "dose" of screening. The dose in the control group was ~45 and that in the screening group was ~85%. So the question that the study asked was not really "does screening work" but rather "does doubling the dose of screening work". Had there been a favorable trend in this study, I would have been tempted to double the effect size of the screening to infer the true effect, reasoning that if increasing screening from 40% to 80% reduces prostate cancer mortality by x%, then increasing screening from 0% to 80% would reduce it by 2x%. Alas this was not the case with this study which was underpowered.

~I am very wary of studies that have cause-specific mortality as an endpoint. There's just too much room for adjudication bias, as the editorialist points out. Moreover, if you reduce prostate cancer mortality but overall mortality is unchanged, what do I, as a potential patient care? Great, you saved me from prostate cancer and I died at about the same time I would have but from an MI or a CVA instead? We have to be careful about whether our goals are good ones - the goal should not be to "fight cancer" but rather to "improve overall health". The latter, I admit, is a much less enticing and invigorating banner. We like to feel like we're fighting. (Admittedly, overall mortality appears to not differ in this study, but I'm at a loss as to what's really being reported in Table 4.) The DSMB for the ESRCP trial argue here that cancer specific mortality is most appropriate for screening trials because of dilution by other causes of mortality, and because screening for a specific cancer can only be expected to reduce mortality for that cancer. From an efficacy standpoint, I agree, but from an effectiveness standpoint, this position causes me to squint and tilt my head askance.

~It is so very interesting that this study was stopped not for futility, nor for harm, nor for efficacy, but because it was deemed necessary for the data to be released because of the [potential] impact on public health. And what has been the impact of those data? Utter confusion. That increasing screening from 40% to 80% does not improve prostate specific mortality does not say to me that we should reduce screening to 0%. In fact I don't know what to do, nor what to make of these data. Especially in the context of the next study.

In the ERSPC trial, investigators found a 20% reduction in prostate cancer deaths with screening with PSA alone in Europe. The same caveats regarding adjudication of this outcome notwithstanding, there are some very curious aspects of this trial that merit attention:

~This trial was, as I stated above, a "real-time meta-analysis" with many slightly different studies combined for analysis. I don't know what this does to internal or external validity because this is such an unfamiliar approach to me, but I'll be pondering it for a while I'm sure.

~I am concerned that I don't fully understand the way that interim analyses were performed in this trial, what the early stopping rules were, and whether a one-sided or two-sided alpha was used. Reference 6 states that it was one-sided but the index article says 2. Someone will have to help me out with the O'Brien-Fleming alpha spending function and let me know if 1% spending at each analysis is par for the course.

~As noted by the editorialist, we are not told what the "contamination rate" of screening in the control group is. If it is high, we might use my method described above to infer the actual impact of screening.

~Look at the survival curves that diverge and then appear to converge again at a low hazard rate. Is it any wonder that there is no impact on overall mortality?


So where does this all leave us? We have a population of physicians and patients that yearn for effective screening and believe in it, so much so that it is hard to conduct an uncontaminated study of screening. We have a US study that is stopped prematurely in order to inform public health, but which is inadequate to inform it. We have a European study which shows a benefit near the a priori expected benefit, but which has a bizarre design and is missing important data that we would like to consider before accepting the results. We have no hint of a benefit on overall mortality. We have lukewarm conclusions from both groups, and want desperately to know what the associated morbidities in each group are. We are spending vast amounts of resources and incurring an enormous emotional toll on men who live in fear after a positive PSA test, many of whom pay dearly ("a pound of flesh") to exorcise that fear. And we have a public over-reaction to the results of these studies which merely increase our quandary.

If ignorance is bliss, then truly 'tis folly to be wise. Perhaps this saying applies equally to individual patients, and the investigation of PSA screening in these large-scale trials. For my own part, this is one aspect of my health that I shall leave to fate and destiny, while I focus on more directly remediable aspects of preventive health, ones where the prevention is pleasurable (running and enjoying a Mediterranean diet) rather than painful (prostatectomy).