Overwhelming evidence supports the use of beta-blockers in patients after a myocardial infarction (MI), but not all patients can benefit from this simple yet life-saving treatment. A subset of 5% to 10% of patients have been unable to take beta-blockers after an acute MI because of symptomatic bradycardia or heart block. There is compelling evidence, however, that the benefits of beta-blockers may not only be due to slowing of the heart rate but also due to decreased risk of ventricular arrhythmias, particularly potentially fatal arrhythmias, in patients who have had an MI.
Jeffrey J. Goldberger, FACP, a cardiologist and electrophysiologist at Northwestern University in Chicago, is the principal investigator of the multicenter PACE-MI (PACEmaker and beta-blocker therapy after Myocardial Infarction) trial, which will study beta-blocker use after pacemaker implantation in patients with absolute contraindications to beta-blocker therapy. The trial will randomly assign 1,124 patients in 60 to 70 centers to a control group (standard post-MI therapy without the use of beta-blockers) or a treatment group (beta-blocker therapy after pacemaker insertion plus standard post-MI therapy).
The target population includes patients who have had an acute MI within 90 days and have either documented symptomatic bradycardia while taking beta-blockers or any of these rhythm contraindications: resting heart rate of 55 beats per minute or less while awake, pauses of more than two seconds while awake, a PR interval of at least 260 milliseconds, or type 1 (Wenckebach) second-degree atrioventricular block. The primary end point for this groundbreaking trial is the composite of overall mortality and nonfatal MI.
Dr. Goldberger recently spoke with ACP Hospitalist about why the PACE-MI trial is important and how it could impact clinical practice.
Jeffrey J. Goldberger, FACP
Q: This is the first trial of its type. Is this a project you have wanted to pursue for a long time?
A: We first started working on this in 1999. In the ‘90s, as people were noticing a lot of people being undertreated or not being treated with beta-blockers, there was a lot of focused attention on that. The logical question was, “How can we get more people on beta-blockers?” I'm sure there were many reasons why people were not treated or undertreated. [Contraindications to beta-blocker treatment that could be ameliorated with pacemaker placement] popped up as one potential source of untreated patients.
If you are an accountant and you look at what the potential benefits of beta-blockers are versus the risks of the pacemaker, the ledger sheet is far in favor of the combination of pacemaker and beta-blockers, if that's what you need to do to get the patient treated. The only caveat is there are no data showing the efficacy of beta-blockers in this population, because they have always been excluded from trials. There is huge potential.
Q: What are some ways that this research could change clinical practice?
A: If the trial is positive and we show that this combination is beneficial, then we could extend beta-blocker therapy to this patient group. Based on the hypothesized mortality benefits we have, this equals 34 lives saved per 1,000 treated. That falls right into a range that's been shown for thrombolytic therapy.
Another area that you might extend this into is underdosing of beta-blockers. Is there a group of patients who are getting very small doses of beta-blockers, not the ones shown to be beneficial in clinical trials, who could perhaps benefit from getting higher doses, even if it means facilitating that with bradycardia pacing? This trial won't answer that specific question but we may get some information about low doses of beta-blockers. Our trial's observational arm includes patients who have the same eligibility requirements as for the randomized arm but whose physicians have decided that beta-blockers are relatively contraindicated rather than absolutely contraindicated. They will be started on low-dose beta-blockers and get titrated up as tolerated. My guess is that they will be on submaximal doses, so we might be able to see if there is an effect of dose.
We also have a registry where we are collecting discharge doses of beta-blockers. We are finding that between discharge and three weeks, 25% of patients are taking less than 50 mg of metoprolol per day.
Q: How could the results of the PACE-MI trial change Medicare reimbursement?
A: Right now, Medicare excludes coverage for pacemaker implantation in patients with asymptomatic bradycardia. We asked Medicare to change their criteria, and they said there are not enough data to support this. If the trial is positive, this could change Medicare coverage policy.
Q: What were the challenges in organizing this trial?
A: Initially we approached the National Institutes of Health. NIH thought it was interesting, but there were funding issues related to coverage for the pacemakers. It took a number of years to coordinate with NIH and CMS to work out the coverage for the pacemakers. Ultimately, Medicare made a small change in their coverage policy that allows the implant procedures to be covered under the clinical trials policy. Industry donated the actual devices. The whole set of negotiations was challenging and time-consuming, but everyone worked cooperatively to facilitate evaluating this question in the setting of a clinical trial.
Q: Given that many patients in the PACE-MI trial have historically been excluded from trials, patient inclusion and exclusion is an important issue. The EDICT white paper released this spring spelled out many ways for trialists to reach people, such as minorities and elderly patients who are often excluded from trials. What are you doing to expand your recruitment efforts?
A: We obviously would like to reach a wide spectrum of patients. We have targeted 50% women and 25% minorities in the trial, as mandated by NIH. To try to achieve that, we have a lot of geographic diversity. We have a lot of educational materials available, and we have translated them into Spanish and other languages. Our goal is to start enrollment, and then we can evaluate whether we are achieving the mandated targets. In this age group, men equal women, so [achieving gender parity] should not be a barrier. Right now, it's hard enough to get anybody involved, so I can't say we have had any particular problem.
Q: How can hospitalists get involved in this trial?
A: Hospitalists are taking care of a lot of patients following an MI, when they come out of the coronary care unit. That's the ideal time to start to evaluate somebody for the trial. Clearly if the patient meets the eligibility criteria, the physician would have the option of deciding whether they would go into the observational arm or the randomized arm. [Hospitalists] would be able to identify those patients.
Q: If the trial shows that pacemakers improve mortality, how many additional pacemakers per year might be implanted in the U.S.?
A: It's important to point out that if this trial is positive, then it's the combination of pacemakers and beta-blockers that's improving mortality. Our estimates initially are based on the 1 million people who have MIs each year in the U.S. Of that group, 5% to 10% meet the eligibility criteria, and some of those patients are not going to be able to enroll due to other mitigating diseases. So it may be at an upper limit of 50,000 [additional pacemakers per year].
Q: Where can physicians find out more information about this trial?
A: The Web site is PACE-MI.org.
Q: How can doctors recruit patients?
A: These patients are rare. Any individual cardiologist will only see a handful every year. The key is vigilance. When you identify one, you have to make a push to enroll that one. One referral can make or break the trial if we can get the support of the medical community.