Luck that Looks Like Logic? Statins (Rosuvastatin), the Cholesterol Hypothesis, and Causal Pathways

The Cholesterol Hypothesis (CH), namely that the association between elevated cholesterol (LDL) and cardiovascular disease and events is a CAUSAL one, and thus that intervening to lower cholesterol prevents these diseases has seduced mainstream medicine for decades. However, much if not most of the evidence for the causality of cholesterol in atherogenesis and its reversal by lowering cholesterol derives from studies of "Statins" or HMG-CoA-reductase inhibitors; indeed the evidence that lowering LDL cholesterol (or raising HDL) through other pathways has salutary effects on cardiovascular outcomes is scant at best as has been chronicled on this blog (see posts on torcetrapib and ezetimibe/Vytorin). Not myself immune to the beguiling allure of the CH, I admit that I take Niacin, in spite of normal HDL levels and scant to no trustworthy evidence that, in addition to raising HDL and lowering LDL, it will have any primary (or secondary or tertiary) preventative effects for me.

In yesterday's NEJM, Glynn et al report the results of analysis of data on a secondary endpoint from the JUPITER trial of Rosuvastatin. (http://content.nejm.org/cgi/content/abstract/360/18/1851 .) The primary aim of the trial was to determine if Rosuvastatin was effective for primary prevention of cardiovascular events in people with normal cholesterol levels and elevated CRP levels. The secondary endpoint described in the article was the occurrence of venothromboembolism during the study period. Because I see no obvious evidence of foul play, and because this study was simply impeccably designed, conducted, and reported, I'm going to hereafter ignore the fact that it was industry sponsored, and that there is probably some motive of "off-label promotion by proxy" (http://medicalevidence.blogspot.com/2008/06/off-label-promotion-by-proxy-how-nejm.html .) here...

Lo and behold: Rosuvastatin lowered venothromboembolism rates. The difficulties posed by ascertainment of this outcome notwithstanding, this trial has convincing evidence of a statistically significant reduction in DVT and PE event rates (which were very low - ~0.2%/100 persons/year) during the four year period of study. And this does not make a whole lot of sense from the standpoint of the CH. There's something more going on. Like an anti-inflammatory property of Statins. Which is very interesting and noteworthy and worthwhile in its own right. But I'm more interested in what kind of light this sheds on the validity of the CH.

Because of my interest in the fraility of the normalization hypothesis/heuristic (the notion that you just measure something and then raise or lower it to the normal range and make things ALL better) I am obviously a reserved skeptic of the Cholesterol Hypothesis, which was bolstered by if not altogether reared by data from trials of statins. And these new data, combined with emerging evidence that statins may have salutary effects on lung inflammation in ARDS and COPD, among perhaps others, make me wonder - was it just pure LUCK rather than a triumph of LOGIC that the first widely tested and marketed drug for cholesterol happened to both reduce cardiovascular endpoints AND lower cholesterol, even though not necessarily as part of the same causal pathway? Is it just "true, true, and unrelated?" Are they the anti-inflammatory properties or some other piece of the complex biochemical effects of these drugs on the body that leads to their clinical benefits? Other examples come to mind: Is blood pressure lowering just an epiphenomenon of another primary ACE-inhibitor effect on heart failure? Because these effects appear to be superficially and intuitively related does not mean that they are an obvious causal pathway.

What if things had happened another way. What if Statins had eluded discovery for another 20-30 years. What if study of the cholesterol hypothesis meanwhile proceeded through evaluation of Cholestyramine, Cholestipol, Niacin, and other drugs, and what if it had been "disconfirmed" by failure of these agents to reduce cardiovascular outcomes? These hypotheticals will be answerable only after more study of Statins and other drugs as well as their mechanisms. The data presented by the Harvard group as well as their other work with CRP are but one leg of a long journey toward elucidation of the biological mechanisms of atherogenesis, coagulation, and downstream clinical events.

Idraparinux, the van Gogh investigators, and clinical trials pointillism: connecting the dots shows that Idraparinux increases the risk of death

It eludes me why the NEJM continues to publish specious, industry-sponsored, negative, non-inferiority trials. Perhaps they do it for my entertainment. And this past week, entertained I was indeed.

Idraparinux is yet another drug looking for an indication. Keep looking, Sanofi. Your pipeline problems will not be solved by this one.

First, let me dismiss the second article out of hand: it is not fair to test idraparinux against placebo (for the love of Joseph!) for the secondary prevention of VTE after a recent epidode! (http://content.nejm.org/cgi/content/short/357/11/1105).

It is old news that one can reduce the recurrence of VTE after a recent episode by either using low intensity warfarin (http://content.nejm.org/cgi/content/abstract/348/15/1425) or by extending the duration of warfarin anticoagulation (http://content.nejm.org/cgi/content/abstract/345/3/165). Therefore, the second van Gogh study does not merit further consideration, especially given the higher rate of bleeding in this study.


Now for the first study and its omissions and distortions. It is important to bear in mind that the only outcome that cannot be associated with ascertainment bias (assuming a high follow-up rate) is mortality, AND that the ascertainment of DVT and PE are fraught with numerous difficulties and potential biases.

The Omission: Failure to report in the abstract that Idraparinux use was associated with an increased risk of death in these studies, which was significant in the PE study, and which trended strongly in the DVT study. The authors attempt to explain this away by suggesting that the increased death rate was due to cancer, but of course we are not told how causes of death were ascertained (a notoriously difficult and messy task), and cancer is associated with DVT/PE which is among the final common pathways of death from cancer. This alone, this minor factoid that Idraparinux was associated with an increased risk of death should doom this drug and should be the main headline related to these studies.

Appropriate headline: "Idraparinux increases the risk of death in patients with PE and possibly DVT."

If we combine the deaths in the DVT and PE studies, we see that the 6-month death rates are 3.4% in the placebo group and 4.5% in the idraparinux group, with an overall (chi-square) p-value of 0.035 - significant!

This is especially worrisome from a generalizability perspective - if this drug were approved and the distinction between DVT and PE is blurred in clinical practice as it often is, we would have no way of being confident that we're using it in a DVT patient rather than a PE patient. Who wants such a messy drug?

The Obfuscations and Distortions: Where to begin? First of all, no justification of an Odds Ratio of 2.0 as a delta for non-inferiority is given. Is twice the odds of recurrent DVT/PE insignificant? It is not. This Odds Ratio is too high. Shame.

To give credit where it is due, the investigation at least used a one sided 0.025 alpha for the non-inferiority comparison.

Second, regarding the DVT study, many if not the majority of patients with DVT also have PE, even if it is subclinical. Given that ascertainment of events (other than death) in this study relied on symptoms and was poorly described, that patients with DVT were not routinely tested for PE in the absence of symptoms, and that the risk of death was increased with idraparinux in the PE study, one is led to an obvious hypothesis: that the trend towary an increased risk of death in the DVT study patients who received idraparinux was due to unrecognized PE in some of these patients. The first part of the conclusion in the abstract "in patients with DVT, once weekly SQ idraparinux for 3 or 6 months had an efficacy similar to that of heparin and vitamin K antagonists" obfuscates and conceals this worrisome possibility. Many patients with DVT probably also had undiagnosed PE and might have been more likely to die given the drug's failure to prevent recurrences in the PE study. The increased risk of death in the DVT study might have been simply muted and diluted by the lower frequency of PE in the patients in the DVT study.

Then there is the annoying the inability to reverse the effects of this drug with a very long half-life.

Scientific objectivity and patient safety mandate that this drug not receive further consideration for clinical use. Persistence with the study of this drug will most likely represent "sunk cost bias" on the part of the manufacturer. It's time to cut bait and save patients in the process.