Is MIRACL a miracle or not?

November 17, 2000

New Orleans, LA - Atorvastatin (Lipitor® - Pfizer) has reduced the combined risk of subsequent clinical events when given to patients immediately after an acute coronary event in the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) study, reported here today at the AHA. However, the risk reduction only just reached statistical significance and many clinicians feel that another study will be needed to confirm these results. Also, there are questions about the study population in MIRACL, given the findings of another study presented here today.

Previous trials with other statins have established the benefit of lipid-lowering therapy in patients with stable coronary heart disease over periods of years. However, these studies excluded patients who had recent acute coronary events, because they are at high risk of having a subsequent event. MIRACL is the first study to show that the clinical benefit of aggressive lipid lowering can be achieved within the critical weeks following an acute coronary event.

MIRACL demonstrated that intensive treatment with atorvastatin, begun immediately after an acute coronary event, produces beneficial effects that are apparent within several weeks.

Principal investigator Dr Gregory Schwartz (Denver Veterans Administration Medical Affairs Center, Denver, CO) said the results prove that treatment with a statin in unstable angina patients should be started in hospital, regardless of baseline cholesterol levels, "because those in hospital are most amenable to treatment and we will lose the opportunity to treat patients if they leave hospital."

"MIRACL demonstrated that intensive treatment with atorvastatin, begun immediately after an acute coronary event, produces beneficial effects that are apparent within several weeks. This provides evidence that the addition of intensive lipid-lowering therapy to the standard of care may help improve the outcomes of these patients," Schwartz commented.

Promising, but benefit in those with normal LDL levels not proven

Professor Lars Wallentin (Uppsala University Hospital, Uppsala, Sweden) said: "I think the MIRACL results are very promising concerning early treatment with statins. The treatment was only randomized for 4 months, and you should not expect too much because the patients had a fairy low event rate and still there was a positive signal that they did better - they had less ischemia and less readmissions and everything went in the right direction."

Dr Robert Califf (Duke Clinical Research Institute, Durham, NC) told heart wire : "The really positive thing about MIRACL is that if you have a high LDL cholesterol we now know it's safe to give a statin acutely. But I disagree with the conclusion that this is a definitive enough trial to routinely treat people with normal LDL cholesterol."

Wallentin agrees: "These were patients with lower cholesterol levels than previously treated and we haven't seen any breakdown with the different lipid levels so far. We have to wait for that. The results very much support that we should start statin treatment early in patients with lipid levels which would indicate long-term treatment, we should not wait 3-6 months. But the issue of whether we should treat patients with normal cholesterol levels is still open."

Class effect or not?

Schwartz said the results of MIRACL could not be extrapolated to other statin drugs: "We looked at one dose of one agent and it would be speculative to say that another dose of atorvastatin or another statin would produce the same effects."

But another investigator, Dr Anders Olsson, told heartwire : "I don't think this is a particular atorvastatin effect, you can probably obtain it with any statin. I think it is an LDL-lowering effect." Wallentin agreed, commenting to heartwire : "I would guess it is a class effect, yes."

Should A to Z be stopped?

Olsson added that, because the MIRACL results were "of borderline significance," it would be good to have an extra study to confirm the findings. The A to Z study - Aggrastat ® (tirofiban) to Zocor ® (simvastatin), being conducted by Merck - is a similar study to MIRACL. But it should not be stopped prematurely on the basis of the MIRACL results "because more evidence should be gathered before guidelines on how to treat these patients are changed," Olsson said.

Both Califf and Wallentin agreed. Califf said: "I would not stop it. This really emphasizes the need for the A to Z trial." Wallentin said: "Would I stop the A to Z trial? Absolutely not. Definitely not. It's crucial that we have additional data from more trials, especially concerning patients with levels below what is today considered an indication for treatment."

Califf added: "The critical issue to me is when you start saying treat patients with an LDL cholesterol of <125, you're now talking about everyone in the world with coronary disease and that's a huge economic issue for the world and you need more than a p value of 0.048, with no effect on death or MI, before you accept that."

There are also questions about the study population in MIRACL, given the findings of another study presented here today - TACTICS-TIMI 18 - that showed that all unstable angina patients should ideally have a revascularization procedure. However MIRACL excluded patients who were due to have an early intervention, therefore, some feel that the patients in the MIRACL may not in future be representative of the real clinical population. The A to Z study differs from MIRACL in that patients undergoing interventions are included.

MIRACL results

The primary endpoint was the time to occurrence of one of the following: nonfatal acute MI (AMI), cardiac arrest with resuscitation or recurrent symptomatic myocardial ischemia requiring emergency rehospitalization. Patients on atorvastatin (14.8%) had a primary endpoint event compared with placebo patients (17.4), a 16% reduction, which was only just significant (p=0.048). The study was originally powered to detect a 25% difference between atorvastatin and placebo in the primary endpoint.

This 16% reduction was primarily due to a favorable effect of atorvastatin on recurrent symptomatic myocardial ischemia, which was reduced by 26% (p=0.02). "The number of events were not as high as we had anticipated," Olsson told heartwire, "However, we were reassured by the fact that all the endpoints were pointed in the same direction."

LDL levels fell by 40% in those treated with atorvastatin to an average of 70 mg/dL, while levels in the placebo group increased slightly. There was also an unexpected 50% reduction in stroke in those treated with atorvastatin (p=0.045), a finding Schwartz called "surprising."

Atorvastatin was well tolerated in the study, with only a slight increase in reversible elevation of liver function tests in the active treatment group compared with placebo. Reassuringly, there were no documented cases of myositis with atorvastatin.

MIRACL is miraculous, according to the media

New York, NY - Comments elicited by the media on November 15, 2000 about the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) study mostly highlighted the positive results of immediate statin therapy. "Patients who are in the hospital in the setting of an acute event are most amiable to accept statin treatments recommended by their physicians," says Dr Gregory Schwartz in a CBS Health Watch report. "Once discharged, many patients do not get accepted therapies, even in accordance with published guidelines. If we don't start in the hospital, we may lose the chance in many patients. We feel strongly that the study supports the immediate use of lipid lowering agents. The Associated Press quoted Dr Robert O Bonow (Chief of Cardiology, Northwestern University, Chicago, IL): "Their approach was to start therapy and ask questions later. That might be the right approach. Their data were compelling." In the CBS Health Watch report, Bonow says the study "raises the issue of whether we shouldn't be treating patients with statins in the hospital the way we now have guidelines to start aspirin and beta blockers and, in many patients, ACE inhibitors within in the hospital setting within the first day or so after a myocardial infarction." Bonow adds: "When you have a patient in the hospital with a myocardial infarction, it's a captive audience who tend to take medicines for the rest of their lives more readily than if you tried doing this on an outpatient basis. One of the thoughts is that if you are going to start a statin anyway, why wait 4-6 weeks to re-measure the cholesterol when you may be able to start that statin early on." MSNBC quotes Dr Russell V Luepker (University of Minnesota, Minneapolis, MN), who agrees: "These results are striking and have wide applicability. Most people aren't treated with early, aggressive use of statins, and it looks like many people would benefit." Luepker told MSNBC "it was likely" that new recommendations by the guidelines committee would consider urging earlier, more aggressive treatment with statins. No one knows, he says, whether the short-term benefits of atorvastatin are due to its cholesterol-lowering effect or to other unknown mechanisms.

- Mark L Fuerst

[Dr Califf is a member of the editorial board of]





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