Potent Antithrombotic Therapy Cuts Spontaneous MI After PCI for ACS

More research is needed in a post-COMPLETE population to answer the question of 6 vs 12 months of DAPT, says Eric Bates.

Potent Antithrombotic Therapy Cuts Spontaneous MI After PCI for ACS

Longer-term dual antiplatelet therapy (DAPT) can improve cardiovascular outcomes following acute coronary syndromes, predominantly by reducing de novo atherothrombotic ischemic events, a new analysis of stented patients from the TRITON-TIMI 38 finds.

For ACS patients, much of the research looking at DAPT duration has focused on preventing periprocedural and stent-related complications. On top of this, current guidelines recommend between 6 months and 1 year of DAPT even though several studies have suggested that a shorter treatment duration might be acceptable and cause less bleeding, so long as newer-generation stents are used.

“There's a lot of understandable confusion about dual antiplatelet therapy after stenting, and I think it's important based on our data to remember that the patient who has had an acute coronary syndrome is at very high risk of recurrent atherothrombotic events independent of the stent,” lead author Benjamin M. Scirica, MD (Brigham and Women’s Hospital, Boston, MA), told TCTMD. “Thus, the duration of dual antiplatelet therapy in general and [use of] more-potent dual antiplatelet therapy really should be based on the overall atherothrombotic risk of the patient and not the stent or the procedure.”

Prasugrel Reduces Events

For the study, published in the March 17, 2020, issue of the Journal of the American College of Cardiology, Scirica and colleagues followed 12,844 patients with ACS from the TRITON-TIMI 38 study who had received at least one stent for a median of 14.5 months. They categorized MI and cardiovascular death events as one of the following:

  • Procedural (related to revascularization)
  • Due to definite or probable stent thrombosis
  • Spontaneous (unrelated to stent thrombosis or the procedure)

Unsurprisingly, most of the 846 events occurring within 30 days were procedural (69.0%), with the remainder classified as stent thrombosis-related (14.9%) or spontaneous (16.1%). However, after 30 days, spontaneous events made up the majority (81.8%), with only 4.7% categorized as procedural and 13.5% stent thrombosis-related.

Use of prasugrel compared with clopidogrel reduced the rate of overall MI or cardiovascular death (8.9% vs 11.1%; HR 0.79; 95% CI 0.71-0.89) as well as events specifically deemed stent thrombosis-related (1.0% vs 2.1%; HR 0.47; 95% CI 0.35-0.65) and spontaneous (3.9% vs 4.8%; HR 0.80; 95% CI 0.67-0.95), with a trend seen for procedural events (4.4% vs 5.1%; HR 0.87; 95% CI 0.74-1.02). The effect of prasugrel was consistent for STEMI and NSTEMI across all three event types.

It's important based on our data to remember that the patient who has had an acute coronary syndrome is at very high risk of recurrent atherothrombotic events independent of the stent. Benjamin M. Scirica

Non-CABG TIMI major bleeding episodes were most often spontaneous (60.2%) followed by procedure- (31.3%) and trauma-related (8.4%). Prasugrel increased the risk of spontaneous bleeds (1.6% vs 1.1%; HR 1.46; 95% CI 1.06-2.03) but had no effect on procedure-related non-CABG major bleeding (0.7% vs 0.6%; HR 1.11; 95% CI 0.71-1.73).

Ischemic vs Bleeding Risk

For Scirica, the way the proportion of spontaneous events grew throughout the study period was most surprising. At the end of the trial, “you're treating as much the other arteries of the heart as the stent,” he said. “With the more-potent antiplatelet agent, we saw consistent reductions in spontaneous MI that we saw in procedural MI and stent-related events so that the take home that I really see is that dual antiplatelet therapy in general, and more potent dual antiplatelet therapy specifically, not only protects against early stent thrombosis and periprocedural events but [also] has an important role in reducing the risk of new MIs from other atherosclerotic plaques in the remainder of the arterial bed.”

In an accompanying editorial, Stefanie Schüpke, MD (German Heart Center of Munich, Germany) and Klaus Tiroch, MD (Bodensee Heart Center, Konstanz, Germany), write that a consistent finding seen here as well as in other trials looking at “intensified and/or prolonged antiplatelet therapy is the significant increase in bleeding, which is a strong and independent predictor of mortality. Therefore, any potential reduction in ischemic events has to be balanced against a heightened bleeding risk.”

Scirica noted the importance of being able to personalize therapy by using tools like clinical risk scores or genetic testing, although the jury is still out on the concrete benefits of the latter. “All of these do need to be tested prospectively, but I think the feeling that there is one solution for the entire population is too simplified and there will have to be simplification based on not only the risk of thrombosis but also the risk of bleeding,” he said.

“Greater, faster, and more uniform platelet inhibition has been suggested to explain the superior outcome of the potent P2Y12 inhibitors over clopidogrel,” the editorialists add. “In this regard, platelet function or genotype-based strategies may be useful to identify those patients who would benefit most from potent P2Y12 inhibitors compared with patients who have an adequate response to clopidogrel and could benefit from de-escalation in terms of bleeding reduction without an increase in ischemic events.”

Schüpke and Tiroch add that the soon-to-be-released results of the TAILOR-PCI trial as well as a number of ongoing meta-analyses “will shed more light on the value of this approach for guiding the choice of antiplatelet therapies in patients undergoing PCI, including the potential of this approach to prevent late spontaneous events.”

Post-COMPLETE Analysis Needed

Commenting for TCTMD, Eric Bates, MD (University of Michigan, Ann Arbor), said this analysis is “a nice study that supports the findings we saw in the COMPLETE trial, where treating nonculprit lesions might've altered prognosis, and does support . . . the concept that nonculprit lesions potentially are prognostically important and can cause acute coronary syndromes.”

All of this backs current guideline recommendations for 12 months of DAPT, he added. However, Bates would have liked to have seen the study address the question of whether or not to shorten DAPT duration to 6 months.

“The clinical question is: do we stay at 12 months or can we drop the dual antiplatelet therapy duration down to 6 months in the ACS patients?” he said. “They were more inclined to make the argument that they've made before that longer duration dual antiplatelet therapy and higher intensity platelet inhibition is better. . . . What I would challenge the authors to do is go back and look at their data and look at the 6-12 month time period and give us absolute counts of how many ischemic events there were and how many bleeding events there were, so that we can try to get more information on assessing this risk balance.”

Bates said he would also like to see absolute event rates for bleeding. “Bleeding events should be minor and major and they should by TIMI, GUSTO, and by BARC criteria,” he suggested. “They only made a short reference to TIMI major bleeding, but that's an incomplete assessment of the risk I think by current criteria.”

Lastly, because the data from TRITON-TIMI 38 are now more than a decade old, Bates said that while Scirica and colleagues have published that nicely emphasizes the potential risk carried by nonculprit lesions, “hopefully it'll stimulate a more-focused and more-current evaluation of that risk. . . . What we really need to do is take a look at these patients post-COMPLETE trial, where more-complete revascularization is being performed with newest-generation stents and high-dose statins with better risk factor control, and then reevaluate the benefit of treating with 6 months versus 12 months of DAPT in ACS patients.”

  • The TRITON-TIMI 38 trial was sponsored by Daiichi-Sankyo and Eli Lilly. All authors are members of the TIMI Study Group, which has received institutional research grant support through Brigham and Women’s Hospital from Abbott, Amgen, Aralez, AstraZeneca, Bayer HealthCare Pharmaceuticals, Inc., BRAHMS, Daiichi-Sankyo, Eisai, GlaxoSmithKline, Intarcia, Janssen, MedImmune, Merck, Novartis, Pfizer, Poxel, Quark Pharmaceuticals, Roche, Takeda, The Medicines Company, and Zora Biosciences.
  • Scirica reports receiving consultant fees/honoraria from AbbVie, Allergan, Covance, Eisai, Elsevier Practice Update Cardiology, Esperion, Lexicon, Medtronic, Novo Nordisk, Sanofi, AstraZeneca Pharmaceuticals, Biogen Idec, Boehringer Ingelheim Pharmaceuticals, Inc., Dr. Reddy’s Laboratories Inc., Forest Laboratories, GE Healthcare, GlaxoSmithKline, Health@Scale, Lexicon, Merck & Co., Inc., and St. Jude Medical; receiving institutional research grants from AstraZeneca, Daiichi-Sankyo, Eisai, Merck, Pfizer, and Poxel; and holding equity in Health@Scale.
  • Schüpke reports receiving research support for the ISAR-REACT 5 trial from the German Center for Cardiovascular Research (DZKH); receiving consulting fees from Bayer Vital; and receiving the Else Kröner-Memorial Stipendium from the Else Kröner-Fresenius-Stiftung.
  • Tiroch reports receiving speaker fees from Amgen, Abbott, AstraZeneca, Bayer Vital, Berlin Chemie, Bristol-Myers Squibb/Pfizer, Daiichi-Sankyo, Novartis, Lilly, and Sanofi; and receiving consulting fees from Daiichi-Sankyo, Medtronic, and Novartis.
  • Bates reports no relevant conflicts of interest.