DR. BERGER: No, it did not.
DR. FERDINAND: So recognizing that the guidelines are pretty much silent on that higher dose of clopidogrel, do you think that because there is the potential for benefit it’s reasonable, recognizing that the guidelines don’t explicitly note the twice a day clopidogrel?
DR. FOODY: This is not guideline-based. There are studies of small subgroups of patients. In higher risk patients undergoing PCI not on a prasugrel or ticagrelor strategy, a higher dose clopidogrel strategy may be beneficial. However, to emphasize, this is not supported by the guidelines.
DR. FERDINAND: So now the plot thickens. We go to a patient who has a drug-eluting stent with a STEMI. We’re beyond one year with clopidogrel, prasugrel, or ticagrelor. The guidelines now have dropped it down to a IIb and a level of evidence C, so it’s almost expert opinion, meaning you could do it if you want, but we don’t really know. Should we go beyond one year with dual antiplatelet therapy after a drug-eluting stent?
DR. LAVIE: I personally think that we would need a trial to answer this question. There is some evidence from the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial showing that patients with prior thrombo embolic disease still had between a 15% and 20% benefit from continued clopidogrel.7 We have all seen patients who have gone off their antiplatelet therapy past a year and soon afterward had an ACS.
Since the guidelines say we have to go one year with dual anti platelet therapy, it is not wrong to stop dual antiplatelet therapy at one year and then just continue aspirin alone. However, in the patient who has very severe disease, who has had multiple procedures or, for example, the patient who had the “widow maker” disease of proximal left anterior descending artery (LAD) or who had sudden death with their ACS, those would all be situations where I would be more favorable to continuing dual antiplatelet therapy indefinitely.
Now, when I do so, I would personally prescribe clopidogrel for my long-term dual antiplatelet therapy. At least there are some long-term studies with clopidogrel, whereas there are no long-term studies with prasugrel or ticagrelor.
DR. FERDINAND: Didn’t the Clopidogrel Versus Aspirin in Patients at Risk of Ischaemic Events (CAPRIE) trial use a subset of people who stayed on it indefinitely who have peripheral vascular disease and diffuse vascular disease and they still had benefit?
DR. BERGER: CAPRIE was a very, very important trial. It compared clopidogrel monotherapy vs aspirin monotherapy and it showed a small but significant 9% reduction in the risk of cardiovascular events with clopidogrel.8 As you point out, it was driven mostly by a 24% reduction in patients with peripheral artery disease.8 That was using monotherapy, so that was not two drugs.
DR. FERDINAND: That doesn’t mean it’s without question.
DR. BERGER: Right. Nonetheless, I agree with Dr. Lavie. I think that there are some data, although it is a subgroup analysis of a negative trial, but there are some data that patients with established cardiovascular disease, that aspirin and clopidogrel may be better than aspirin alone. I think that we are really entering an area where there is a scarcity of data. There are a lot of ongoing important clinical trials in this area that will shed a lot of light on what to do with some of these patients, but I think we have to also remember the bleeding. I think that bleeding is not a benign event. Patients who bleed do very bad in the short- and long-term. I think we really need large clinical trials which are ongoing to sort of help us figure out who should be on two drugs vs one following a year after an ACS.
DR. FERDINAND: Dr. Foody, let’s get your take on long-term dual antiplatelet therapy after STEMI with a drug-eluting stent or if you want to just make a general comment about long-term dual antiplatelet care.
DR. FOODY: Keith, the way I approach this is on an individual patient basis. I think we have suggestions from trials that there are certain groups of individuals, those with significant burden of atherosclerotic peripheral vascular disease who may benefit, but the studies are really lacking in post PCI patients long-term. I think the guidelines are relatively silent on this. I think, again, this goes back to a discussion about risk—risk of subsequent events relative to bleeding risk. Like most things, this is an individual decision on a case-by-case basis.
DR. FERDINAND: So we’re in a real grey area here.
DR. FOODY: Right.
DR. FERDINAND: When we discussed the NSTEMI I mentioned that we always discuss what should be done, but I also like to look at harm because it’s sometimes underdiscussed and it becomes a blind spot for a clinician because no one has brought it up. When I looked at the new guidelines specifically as they relate to patients with STEMI in prior stroke or TIA they give a Class III harm with direct notation evidence level B for prasugrel. Why is that? Does anyone have any take on that?
DR. LAVIE: Yes, Dr. Berger discussed that, Keith, when we were discussing the NSTEMI data, that in the patients who had previous TIA or stroke, in the TRITON trial they did considerably worse with the very high risk of fatal bleeding/hemorrhagic stroke if they received prasugrel, which led to prasugrel being contraindicated for TIA or stroke. This was not the case with ticagrelor in the PLATO trial, as these patients with prior TIA or stroke did better with ticagrelor than clopidogrel, with no more harm, similar to the benefit/harm noted in patients who did not have a previous TIA or stroke.
DR. FERDINAND: Okay. There is an excellent algorithm for reperfusion therapy with STEMI. We now know that there are still a lot of patients who will be seen at a local community hospital where direct PCI is not available. They suggest that if your door in/door out time is less than 30 minutes you still should transfer them to a primary PCI hospital. Drs. Berger, Foody, and Lavie, all of you are in major metropolitan areas. For a STEMI, do you see that there will be any reason for a small community hospital to hold on to that patient once they have diagnosed an ST-segment myocardial infarction?
DR. FOODY: Keith, I think it’s difficult for us to imagine sitting in academic centers, but in fact, I think the last count was that 90% of hospitals in the United States do not have 24/7 PCI capable catheterization labs.9 So it’s surprising, as much as we talk about an invasive strategy, that there really are a very significant proportion of Americans who present to hospitals without traffic 90 minutes away from a center. Clearly, these are the recommendations. We would rather, certainly, if there were an approach that could get individuals to a catheterization lab within that timeframe, that’s great, but even in a place like New York, where Dr. Berger is, traffic and other issues, transfers, may make that exceedingly difficult.
DR. FERDINAND: So in that particular case the algorithm clearly says to administer fibrinolytic therapy within 30 minutes if it’s expected that you will not be able to get to a device within 120 minutes. Drs. Berger and Lavie, what do you think about that? What Dr. Foody seems to be saying is that although we’ve discussed at length the need for PCI in these patients and what medicines should be used, that especially in widespread geographic areas and even sometimes within an urban center it may not be realistic to get that person to a device within less than 120 minutes and at that time fibrinolytic agents can be used with a Class I level of evidence B. You think the guidelines are reasonable at that point?
DR. LAVIE: I would think so Keith. We have a pretty sophisticated helicopter system with the referral hospitals in the region, but even then sometimes the helicopter may be out transporting another patient and sometimes the weather prevents the helicopter from flying. So there are definitely still needs for patients in the community hospitals to receive fibrinolytic therapy.
DR. FERDINAND: Dr. Berger?
DR. BERGER: I completely agree. I also think we have to remember that if you can administer fibrinolytic therapy very quickly the data are very good. It’s just that once you sort of miss that very short window then clearly a PCI strategy is significantly better.
DR. FERDINAND: Very good. As we talked about with unstable angina and the NSTEMI, while it’s important to talk about which drug and whether the person should get direct PCI or be transferred to an academic center or a major medical center for direct PCI, the thing that really plays a major component in how these patients live and die is medication adherence and timely follow-up by their healthcare team.
As I have practiced cardiology for many years, I’ve been more and more impressed that, while which medication and which device remains important, diet, physical activity, and compliance for secondary prevention is probably more important as a public health intervention and it’s a challenge that we should never forget that we do a procedure, write a prescription, or send an electronic prescription to a local pharmacy and think that our job is completed.
My take home message is we should continue to try to look at the guidelines and the updated guidelines for direction but we can’t forget that we’re treating the patient and we’re not just treating the lesion.
DR. FOODY: Keith, from my perspective in thinking about the STEMI patients, I think the most important thing is that time is of the essence, that there need to be systematic approaches in whatever hospital system one might exist, with respect to giving early therapy, whether it be fibrinolytic or PCI-based strategy in conjunction with dual antiplatelets. The key is that that’s done in a systematic way that ensures that patients get evidence-based care.
DR. FERDINAND: Dr. Berger?
DR. BERGER: I would say that I think this is an area where there are a lot of data. We have a lot of very effective therapies and once again, I would agree with what you just said, which is that I think that there are so many different therapies and devices that are effective in this patient population and I think we just need to spend a little more time making sure that our patients take whichever therapy they are on. I think that we need to do a better job basically telling our patients why they are taking their therapy. They need to understand how important it is. I think that patients need to know that their health and their future really lie in their hands and that they can effectively have a very significant impact on their outcomes if they take their medicine and follow a really good healthy lifestyle.
DR. FERDINAND: Very good. Dr. Lavie, you have the last word. I’m going to ask for an addendum. Each of you can think about this. We didn’t say anything about women. Is the evidence good for women? You can make the addendum to the NSTEMI or STEMI. Is there some nuance we should say about women? Dr. Lavie?
DR. LAVIE: I think obviously we should emphasize evidence-based therapy and we need to get patients on beta blockers. I personally think the evidence supports carvedilol. We should get patients on ACE inhibitors, especially if they have left ventricular systolic dysfunction or significant hypertension. Most diabetic patients should also receive an ACE inhibitor or angiotensin receptor blocker, and I think the evidence mostly supports the ACE inhibitor, ramipril. We not only have to get patients on statins but we need high, intense doses of statins (e.g. atorvastatin 80 mg/day). Obviously, we discussed mostly today dual antiplatelet therapy, and I think that in that regard maintenance therapy with 81 mg baby aspirin and with the more potent dual antiplatelet drug, particularly ticagrelor, in combination with baby aspirin appears to be preferable for the reduction of cardiovascular death.
The one thing we did not discuss in either the NSTEMI or the STEMI discussion today is that patients need to be routinely referred to and strongly encouraged to attend formal cardiac rehabilitation programs following acute coronary events.
DR. FERDINAND: I know this is an important consideration for which you have a high degree of interest and experience.
DR. LAVIE: That is evidence-based therapy proven to prolong survival, and there are national efforts being made by the AHA, the American College of Cardiology, and by other organizations to not only assure that patients are referred to cardiac rehabilitation programs but that we have a much greater number of patients actually attending and completing these programs.
DR. FERDINAND: So the utilization of cardiac rehabilitation is as of as much importance as the acute interventions in terms of the long-term outcomes and is often overlooked, unfortunately.
DR. LAVIE: Yes.
DR. FERDINAND: Anything specific on women? Dr. Foody?
DR. FOODY: Across a wide range of patients, including women and African-Americans and various racial and ethnic groups, these evidence-based strategies apply across all of them, but we know that they are inefficiently and incompletely applied. That’s really where our challenge is, again, to ensure that we provide evidence-based therapy for all those who are likely to benefit.
For patients presenting with either STEMI or UA/NSTEMI, while the current ACCF/AHA guidelines recommend universal strategies that apply to both males and females, there are gender-specific considerations that must be taken into account with respect to female patients. At symptomatic presentation, female patients are often older, have comorbidities such as diabetes mellitus and hypertension and may present anginal-equivalent or atypical symptoms. As a result, STEMI is often underdiagnosed and the treatment is delayed. Analysis of the Get With the Guidelines-Coronary Artery Disease (GWTG-CAD) Registry results revealed that, in patients presenting with STEMI, in-hospital mortality was significantly higher in both younger (≤ 45 years) and older (> 45 years) women compared to age-matched males (≤ 45 years cohort, 3.23% vs 1.17%; P = 0.03 and > 45 years cohort, 8.56% vs 5.34%; P < 0.0001).10 Gender differences in response to treatment strategies should also be noted. The Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes with Early Implementation of the ACC/AHA Guidelines (CRUSADE) trial reported a higher risk of bleeding with antiplatelet therapy in females, risk which persisted even when adjusted for a number of confounding factors including age, weight, and blood pressure.11
DR. FERDINAND: This conversation has been very interesting for me—particularly as a follow up to our previous expert roundtable discussion on unstable angina and NSTEMI. I look forward to reading both of these and sharing with our colleagues. Of course, we have done our best to clearly delineate where we have given personal opinion outside of guidelines. I don’t think that there’s any conflict there as a result.
Thank you, Drs. Berger, Foody, and Lavie, for all of your remarks. I think our colleagues will find it interesting and informative. That closes our roundtable.