Guideline Critics Shift Attacks From Beta Blockers To Statins

With the release today of updated European and US guidelines the ongoing controversy regarding beta-blockers appears to be resolved. But that doesn’t necessarily mean there will be an outbreak of guideline peace and harmony. The critics who helped ignite the controversy over beta blockers now say new statin recommendations contained in the guidelines are based on deeply flawed evidence.

The previous incarnation of the European guideline on perioperative evaluation and treatment of people undergoing noncardiac surgery was the subject of intense criticism due to the scandal discrediting Don Poldermans, a Dutch researcher widely published in the field. To address the current uncertainty US and European medical societies earlier today released updated versions of these guidelines.

“Given the recent publication of several large-scale trials, including POISE-II, and new risk calculators, as well as the controversy regarding the use of beta blockers related to the DECREASE trials, the writing committee felt it was necessary to reevaluate all of the data on cardiovascular care for the patient undergoing noncardiac surgery,” said US Writing Committee Chair Lee Fleisher, in a press release.

Regarding beta-blockers the US and European guidelines now do not recommend routine use in patients who undergo non-cardiac surgery, though people who are already taking beta-blockers should continue taking them. (Previously the European guideline but not the US guideline did support routine use of beta-blockers.) Both guidelines state that beta blocker therapy may be initiated prior to surgery in carefully selected higher risk patients.

Statin Recommendation Comes Under Fire

Both the new European and US guidelines say that preoperative initiation of statin therapy may be considered in patients undergoing vascular surgery and that people already taking statins should continue taking them. Now some of the same critics who attacked the reliability of the beta blocker guideline say that this recommendation is not supported by the evidence.

The new recommendation is based on several observational studies and one randomized controlled trial. (Two other randomized trials were not considered because they were performed by Poldermans’ group and have been discredited.) The  critics, UK cardiologists and researchers Darrel Francis and Graham Cole, say that the one  trial by Durazzo et al has fatal flaws that make it completely unreliable. (Durazzo, it may be worth noting, had been a frequent co-author of Polderman’s and had been a co-author of several of the controversial or retracted studies.)

In an analysis published earlier this year, Cole, Francis, and co-authors wrote that the Durazzo study

…was a double-blind randomised trial of 100 patients undergoing vascular surgery, with a 45-day course of atorvastatin or placebo. It sought reduced perioperative events in the atorvastatin arm, which indeed was what was found: 8% versus 26% (p = 0.031) at 6 months [22].

This study has serious failings, which make it an unsound basis for recommending therapy. First, its sample size calculation is stated to have been based on a 22% event rate at 6 months in a previous paper [23]. In reality, the source article states that the rate was 12% at 6 months. Such a transcription error would cause a study to be approximately 4-fold undersized.

Second, the authors indicate that they designed their study to detect a relative risk reduction of 95%. This study design is not credible as no therapy has ever been so effective in preventing myocardial infarction. If the true effect size was, for example, half of this, this overestimate would have contributed a further ~ 4-fold undersizing of the study.

Third, the survival data published cannot be correct. The paper reports that of the 50 patients in each arm, none were lost to follow-up. Therefore, every patient surviving to each displayed time point should be exactly 2%. With this in mind, in the Kaplan–Meier graphs, almost all the numerical values in the survival follow-up figure contradict the graphical values shown.

Finally, for 50-patient groups with no loss to follow-up, event-free survival rates must again be multiples of 2%. They are quoted as 91.4% and 73.5%, values that are not possible.

Francis and Cole sent the following comment about the new guidelines:

We are very sad that over 100 world authorities were forced to sign the European guideline without all having had time to read the papers on which their recommendations were based, and without being able to openly voice dissent.

Their awful predicament is easiest to see for a therapeutic idea whose road has been very “bumpy” indeed: the perioperative course of statins. The outcome data of the key trial by Durazzo et al has for over 6 months been publically known to be impossible. This is buttressed by Don Poldermans’ now notorious DECREASE III and IV trials, whose own university’s investigation revealed extensive fictionalisation, and by meta-analyses whose events arose mostly or entirely amongst these extraordinary pieces of science.

There are important lessons to learn. First, guidelines must in future have the right to say that all the major trials have now been discredited, so there is no longer a recommendation. If we fail to recognise this, we have truly failed our patients.

Second, never again should we pretend that all the experts have agreed on recommendations. It was always unlikely, and in this case clearly ridiculous.

In an interview, Fleisher, the chair of the US guideline, defended the committee’s recommendation of statins. He said that the committee was aware of the limitations of the Durazzo study and that the recommendation was based on the totality of the evidence, including the observational studies. He agreed that there was a significant need for more high quality studies.

Guideline Critics Shift Attacks From Beta Blockers To Statins