Allan S. Jaffe, MD, FACC 2017-04-21 04:20:48
Impact of Optimal Medical Therapy in the Dual Antiplatelet Therapy Study Dr. Jaffe: Dr. Resor, would you start by reminding us of the design of the DAPT study? Dr. Resor: The DAPT Study randomized approximately 11,000 patients who underwent drug-eluting or bare-metal stent placement and then were free of ischemic or bleeding complications for 12 months to an additional 18 months of continued thienopyridine therapy (standard dose clopidogrel and prasugrel) versus placebo. How was OMT defined for this analysis? We defined OMT according to ACC/ American Heart Association Class I indications, such that all patients had an indication for a statin, angiotensin- converting enzyme (ACE) inhibitor or angiotensin-receptor blocker (ARB) or a beta-blocker. Did you look at doses or you just whether the patient was on or off therapy at the time of randomization? We did not have information on medication dosing, so it was just being either on or off those agents at the time of randomization, which was 12 months after the index PCI. If they came off [these drugs] subsequently, did they change group? They stayed in the initial group. What endpoints were you specifically interested in? We were most interested in major adverse cardiac events (MACE), a composite of myocardial infarction (MI) , stroke or death, as well as GUSTO moderate or severe bleeding. What, in general, did you find? The primary results of our study were that the use of OMT had no impact on the treatment benefit and risk of continuing a thienopyridine, such that continued thienopyridine use resulted in consistent reductions in ischemic endpoints and consistent increases in bleeding endpoints in this population. Were the groups the same or were there differences? There were significant differences between the groups. Patients who were on OMT tended to be younger, and they tended to have lower rates of hypertension, chronic kidney disease and prior PCI or MI. We would then expect that they would have lower event rates. That is correct. There were significant differences between the groups. For our comparison of the treatment effect within those two groups, we adjusted our interaction p value for approximately 20 baseline characteristics, procedural characteristics and stent-related factors. Can you give us some sense of the magnitude of these differences? There were some significant differences. There was approximately a ten percent higher rate of hypertension in patients who were not on OMT compared with on OMT. How about the results in terms of MI and MACE? The hazard ratio for the reduction in MI for patients with continued thienopyridine on OMT was about 0. 6, while the hazard ratio in the off-OMT group was about 0.4. While there is some suggestion that the patients off OMT derived a somewhat greater benefit, our interaction analysis showed that the interaction p value did not meet our criteria for significance, suggesting there is a consistent treatment effect between the two groups. Were the absolute rates different between the OMT and no OMT groups? There were significant differences in the rates of all three outcomes between the groups. Was there a cost in terms of bleeding? For the outcome of GUSTO moderate or severe bleeding, the patients off OMT had higher bleeding rates irrespective of the treatment arm. But, when randomized to continued thienopyridine use, there was no difference in the increase in hazard and bleeding between the on- and off-OMT groups. Was there a difference between clopidogrel and prasugrel? Within the primary results of the DAPT Study, there were no differences in ischemic or bleeding outcomes between the two thienopyridines. For this analysis, our results were not different when we adjusted for the particular thienopyridine. Although you didn’t see more detriment, you didn’t see more benefit with prasugrel, which is of interest. We didn’t specifically look to compare outcomes by thienopyridine, but we did not see a difference in event rates in our adjusted and unadjusted analyses. Was there any signal that the various doses of aspirin affected these results? We didn’t specifically look at that in our analysis, but the primary results did not show any significant heterogeneity between the two doses, based on prior reports of the DAPT Study and the supplementary appendix. A patient could be off OMT because of missing either an ACE inhibitor, ARB, beta-blocker or a statin. Did you see any differences in terms of which drug was not present that defined a patient as off OMT? When we looked at the treatment benefit of continued thienopyridine across patients who were on or off a statin, beta-blocker, or ACE inhibitor or ARB we did not see any significant differences. [We observed] no significant heterogeneity between the two groups when looking at the treatment benefit of continued thienopyridine. Were there differences in the absolute rates across the groups? There were differences in relation to being on or off individual components of OMT. It appeared there was a significant difference in outcomes in patients on or off a statin. Similarly, there was a difference for being on or off a beta-blocker, but less so for the use or not of an ACE inhibitor or ARB. However, the comparison of being on or off the components of OMT was not randomized, so we think there is a significant potential for residual confounding. We feel somewhat less strong about drawing conclusions from those comparisons than we do about saying that there’s a consistent treatment benefit across the groups. Certainly reasonable. Where do we go from here? The main conclusion of our paper is that the decision to continue DAPT beyond 12 months should be made irrespective of OMT use. And because the rates were likely somewhat lower in the OMT group regardless of the status of continuing a thienopyridine, you would certainly urge OMT. Absolutely. We would always say your focus should be placed on continuing OMT as much as possible. However, whether or not patients are on OMT should not impact the decision to continue DAPT beyond 12 months. This interview was edited for print from an interview transcript. References Mauri L, Kereiakes DJ, Yeh RW, et al. N Engl J Med 2014;371:2155-66. Resor CD, Nathan A, Kereiakes DJ, et al. Circulation 2016;134:989-98. Left Atrial Appendage Occlusion in Patients Ineligible for OAC In this ACCEL interview, Ori Ben-Yehuda, MD, FACC, is interviewed by former JACC Editor-in-Chief Anthony DeMaria, MD, MACC, on the topic of left atrial appendage occlusion (LAAO) in patients not eligible for oral anticoagulation (OAC). Dr. DeMaria: Please give us the background of your study. Dr. Ben-Yehuda: There are very few data on patients who may have contraindications for OAC or at least their physicians are worried enough that they donft place them on OAC for stroke prophylaxis in the setting of atrial fibrillation (AFib). We know the increasing incidence of Afib due to the aging of the population and comorbid conditions is a problem. We wanted to obtain data on the number of such patients and their outcomes. Do they bleed more? Do they have more stroke? What happened if there were not on OAC? Intuitively I would have thought we knew what happens to people with Afib who have contraindications to OAC, but as you say those data have not been clear. They havenft been clear because studies that assessed OAC and their efficacy have excluded such patients. We believed also that their incidence is not very high, but theyfre out there. This is where big data comes in, by providing databases that collect information on millions of patients. We partnered with an entity called Marketplace, now owned by IBM, that collects insurance claims data on millions of patients. They have 40 million employersponsored insurance records, and Medicare supplemental claims data for another 3.4 million. They have information on inpatient and outpatient visits with diagnoses and pharmacy claims, which is very important. We know whether patients were on OAC or whether they filled a prescription. Tell us about the database and the patient demographics. We looked at a time period between 2010 and 2012 and included patients who had at least one diagnosis code for Afib that was not within 30 days of CABG. We then looked at possible contraindication events, including the most severe (intracranial hemorrhage, intraocular hemorrhage, gastrointestinal hemorrhage), and conditions that would be contraindications that are rarer but recorded in the database, such as untreated (type B) aortic dissection. We identified 43,000 patients who had these contraindications in the setting of Afib who were not prescribed either OAC or low-molecular-weight heparin. What did you observe? There was a correlation between the underlying CHADS2 score and CHA2DS2-VASc score and risk of stroke, which increased with increasing scores. We also found these patients, not unexpectedly, had a high bleeding risk even though they're not on OAC . About 20 percent had another bleeding episode. I think that's very important because it justifies their physician's decision not to place them on OAC. Also, we found a very high risk of ischemic stroke during follow-up in patients with a history of intracranial hemorrhage. Independent of the CHADS2 score, but this was limited by the smaller sample size. In the 20 percent of patients not on OAC who had bleeding, if they had been on an OAC and had bleeding, would it have been attributed to the OAC? Is it possible If everyone had been on OAC that only about 20 percent would have had bleeds and perhaps they're the same 20 percent that had bleeding off OAC? In other words, is that finding interesting in terms of whether this group of patients should be given a trial of OAC? It's a very interesting question. Intuitively, in general, you would think that if a patient has bleeding and then goes on an OAC that the bleeding would be more severe. I think it would be very hard to study this in a controlled manner, as an institutional review board would have a hard time signing on to giving patients who are already at risk a medicine that would increase their risk. In a large database, we can at least match patients who have similar conditions to those in our study on OAC to see the outcomes. However, beyond the risk scores, physicians have an additional intuitive ability. As we try to develop frailty scores, for example, we see these are not as good as the physician's assessment. You look at the overall patient and you know whether or not they're frail. I think that physicians know their patients, and therefll still be a selection bias, even if we match them on different characteristics. What did you conclude from your observations? Bleeding was common and ischemic events were fairly prevalent too. There is an overall a correlation between the CHADS2 and CHA2DS2- VASc scores for both ischemic events, for which they were designed to detect risk, and bleeding events. This puts physicians and patients in a quandary. The more you need these medications, the more you're at risk for side effects (bleeding) of these medications. We definitely showed that [patients who are ineligible and therefore not treated with OAC] is not a rare phenomenon. They tend to have relatively high CHADS2 scores. The vast majority of our patients had a CHADS2 score >1 and a CHA2DS2-VASc score >4. Thus, this is an important group of patients for whom we need to find a solution This sets the stage for innovative new therapies that are now approved, such as LAAO to eliminate not the entire risk but at least reduce it to a significant degree and help protect these patients. These patients were evaluated prior to the availability of occlusion devices. How many would qualify today? This is a high-risk group and would qualify. The studies for LAAO and other databases had wider inclusion criteria. An ongoing debate is who really needs these devices. Their cost and availability is an issue, but I think these data support the notion that there is a group of patients in whom the risk is sufficient to warrant consideration of these devices. Is there a CHADS2 score that helps to define who should have an occlusion device? A CHADS2 score of .2 identified patients who were at significant risk. As with our decision to implement OAC, this study suggests that in the absence of the ability to give OAC, the patient should be considered for a closure device. This interview was edited for print from an interview transcript.
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