Early Statin Therapy in ACS: What's the Level of Evidence?

Sunday, October 4, 2009

by Lisa Nainggolan


September 29, 2009 (Los Angeles and San Francisco, California) — A group of California cardiologists is questioning the strength of the evidence informing current US guidelines recommending the use of high-dose statin therapy early in the course of acute coronary syndrome (ACS) [1].

In a viewpoint and commentary article in the October 6, 2009 issue of the Journal of the American College of Cardiology, Dr Ryan P Morrissey (Cedars Sinai Medical Center, Los Angeles, CA) and colleagues say the current evidence is insufficient to support the class IA recommendation that is given to this indication by the ACC/AHA joint task force, a recommendation that has recently been elevated to a performance measure.

Senior author of the paper, Dr Sanjay Kaul (Cedars Sinai Medical Center), told heartwire that giving early intensive statin therapy in ACS before hospital discharge and regardless of the baseline level of LDL has been formally endorsed as a treatment guideline, "but there's never been any high-quality randomized evidence informing that recommendation." And therein lies the rub, he says, because since this advice is already given the highest recommendation, "there's no motivation for any one individual, sponsor, or professional body to pursue that kind of research, so that's a disservice."

But in a counterpoint article in the same issue [2], Drs David D Waters (San Francisco General Hospital, CA) and Ivy Ku (UCSF) argue that guidelines "prove their utility when their implementation improves outcomes across a broad population at risk, such as in this instance." Commenting on the paper by Morrissey et al, they say: "We disagree with their conclusions and with their interpretation of the facts."

Waters told heartwire : "Statins are the biggest pharmacologic advance we've ever had in cardiology to treat coronary disease. After an acute coronary event, the risk of another event, another MI, hospitalization for unstable angina, or cardiac death is highest in the first six months, and these drugs have been shown in two trials--MIRACL and PROVE-IT--to reduce events at that time." Waters says Morrissey et al are "nitpicking. It's hard to say much about their paper without sounding uncharitable."

Strengths and Limitations to the Evidence

The basic thrust of the argument by the Cedars Sinai doctors is that the current evidence from randomized trials--while indicating that early initiation of high-dose statin therapy in ACS does reduce recurrent ischemia and may reduce revascularization--does not indicate benefit in terms of hard clinical outcomes such as death or MI and may be associated with increased liver and muscle-related adverse outcomes.

"Our message should not be that patients should not be treated with statins," Kaul stressed to heartwire . "Our message is that statins are useful and effective drugs, but you have to recognize that there are strengths and limitations to the evidence."

Kaul says that "from a practical perspective, the evidence is sufficient for clinical practice," but "there are many things we do in clinical practice that are not well-informed by high-quality evidence. . . . That does not necessarily invalidate them. But strictly speaking, from a technical perspective, the evidence does not support a class IA recommendation for this indication. Even though we tend to conflate the two, 'general agreement' should not have the same currency as 'evidence.' Guidelines should dictate the 'standard of care,' not be driven by them."

As substance for his argument, he points out that the European guidelines on this "are somewhat more faithful to the evidence. They say to start early, within one to four days of ACS admission, but this is given a class IB rather than a class IA recommendation, and they put their target treatment level at <100 mg/dL. For the more aggressive treatment target of 70 mg/dL, they have a class IIA, level B recommendation," he notes, adding, "This is more in line with the evidence than the American guidelines. So here we have two professional societies looking at the same evidence and coming up with different recommendations--it's open to interpretation and it becomes more of an opinion."

Kaul also objects to the fact that the recommendations to begin high-dose statin therapy early in the course of ACS have been elevated to a performance measure "using the same evidence. Now our performance is going to be judged on this, and that has broad implications."

Statins Early in ACS a "No-Brainer"

For his part, Waters says, "it's very hard to get a clinical trial to show benefit now because there's so much standard treatment that's beneficial. These two trials [MIRACL and PROVE-IT] clearly show you can reduce end points like stroke, heart attack, hospitalization for recurrent angina, and coronary revascularization with statins.

"It's kind of a no-brainer. The guidelines pretty much universally have recommended that patients with ACS take these drugs, and I think it's made a big difference."

As to the discordance between the US and European guidelines, Waters says: "It's true, there is a slight discordance. But anywhere you get two august bodies of experts on different sides of the ocean trying to turn the results of trials into recommendations for treatment, it's a little tricky."

He adds: "We have more trials with statins in cardiology than we do with any other drug class. We've got randomized, double-blind, placebo-controlled trials in well over 100 000 patients, and we haven't yet found a level below which lowering your LDL threshold doesn't provide additional benefit. If you lower LDL, you get benefits; some say it's from effects other than LDL lowering, and that may be true."

Kaul Would Take a Statin for ACS, But Personal Choice and Policy Don't Mix

Asked by heartwire whether he would personally take a statin early in the course of ACS were he unfortunate enough to suffer such an event, Kaul said: "Yes, I would definitely start with a moderate-dose statin and be content with an on-treatment LDL level of 75 or 80 mg/dL." However, he notes there is "nothing magical about an LDL threshold of 70" and says that starting on a modest dose would "enable me to avoid the side effects, thereby minimizing the potential for nonadherence and maximizing the likelihood of benefit."

But Kaul stresses that his above response in no way invalidates what he and his colleagues are trying to say in their paper. "We need to separate personal belief or clinical judgment from policy statements that have broad implications. Guidelines work best when they are based on empirical facts, not cogent hypotheses; when they inform our clinical judgment, not replace it. Guidelines that are not informed by high-quality, strong evidence have the potential to misinform future research and lead to suboptimal clinical practice.

"I want to emphasize that the goal of our paper is to make people more aware of the quality of the evidence that informs the guidelines, and hopefully the [National Cholesterol Education Program Adult Treatment Panel] NCEP ATP IV recommendations coming out in the near future will be more cognizant of the strengths and weaknesses of the data and will implement their recommendations accordingly," he concludes.

Waters has received honoraria for lectures from Pfizer and consulting fees from AstraZeneca, Merck/Schering-Plough and Pfizer. Kaul reports no conflicts of interest; coauthor Dr George A Diamond (Cedars Sinai Medical Center) serves on the speaker's panel of Schering-Plough and Merck.


  1. Morrissey RP, Diamond GA, Kaul S et al. Statins in acute coronary syndromes. Do the guidelines match the evidence? J Am Coll Cardiol 2009; 54:1425-1433.
  2. Waters DD and Ku I. Early statin therapy in acute coronary syndromes. The successful cycle of evidence, guidelines and implementation. J Am Coll Cardiol 2009; 54:1434-1437.


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