Lesion Complexity and Patient Risk: A Balancing Act for DAPT Duration

The longer a patient survives after PCI without incident, the less relevant the complexity of their index lesion becomes to their ischemic event risk over time, according to a new analysis of the DAPT Study. Hence, the decision to extend or shorten the duration of dual antiplatelet therapy (DAPT) may be more dependent on patient factors past 1 year, the researchers say.

Last year, supported by results of from the DAPT Study and PEGASUS TIMI 54, the American College of Cardiology and American Heart Association issued a focused update of their joint guidelines shortening the length of DAPT from 12 to 6 months for the majority of patients, while leaving open the possibility for even shorter or longer treatment depending on ischemic and bleeding risk as well as clinical judgement. Following that, the DAPT Score, which was designed to identify patients who may or may not benefit from extended thienopyridine therapy, was introduced.

Subsequently, however, Gennaro Giustino, MD (Icahn School of Medicine at Mount Sinai, New York), and colleagues published a study in the Journal of the American College of Cardiology in September 2016 that questioned the strategy of using short-term DAPT for patients with especially complex lesions, since lesion complexity was strongly linked to a doubling of MACE over time. In this study, long-term DAPT halved the risk of MACE over time compared with short-term treatment for this complex patient group.

Now, in new research published today in the October 31, 2017, issue of the Journal of the American College of Cardiology, an analysis of patients from the DAPT Study population conducted by Robert Yeh, MD, MSc (Beth Israel Deaconess Medical Center, Boston, MA), and colleagues supports what was shown by Giustino et al, but adds its own twist.

“The consistent findings of our two studies are that it is true that lesion complexity is an early marker of thrombotic and ischemic risk, but it looks as though [when] you get farther away from it, [lesion complexity] sort of becomes less and less of an issue,” Yeh told TCTMD.

Yeh et al’s subanalysis included 25,416 patients who were enrolled in the DAPT Study, including 11,554 subjects who survived event-free for 1 year post-PCI and were randomized to aspirin plus either a thienopyridine or placebo for another 18 months. Lesion complexity was defined as unprotected left main, more than two lesions per vessel, lesion length ≥ 30mm, bifurcation lesion with side branch ≥ 2.5 mm, lesion located on a saphenous vein graft, and thrombus-containing lesion.

Not surprisingly, patients with complex lesions had higher rates of MI or stent thrombosis in the first year after PCI (3.9% vs 2.4%; P < 0.001). But patients from the cohort that was randomized at 1 year had similar rates of MI or stent thrombosis between 12 and 30 months regardless of lesion complexity (complex vs not complex, 3.5% vs 2.9%; P < 0.07). There was also no difference in moderate/severe bleeding in the randomized patients (1.9% vs 1.9%; P = 0.91).

The relative reduction of MI or stent thrombosis linked with prolonged DAPT was similar for those with or without complex index lesions (P = 0.81 for interaction), as was increase in moderate/severe bleeding (P = 0.44 for interaction). The number of complexity factors did not have an impact on the relative treatment effects of continued DAPT with regard to either MI/stent thrombosis or MACCE.

In a separate analysis of subjects by DAPT Score, the researchers found that those with complex lesions and scores of 2 or higher had greater absolute reductions in MI or stent thrombosis with continued thienopyridine treatment versus placebo (3.0% vs 6.1%; P < 0.001) compared with those with lower scores over time (1.7% vs 2.3%; P = 0.42; P = 0.03 for comparing risk differences).

Lastly, in a sensitivity analysis using the definition of lesion complexity employed in the study by Giustino et al, similar results were observed with regard to reductions in MI or stent thrombosis over time, MACCE, and moderate/severe bleeding.

Patient vs Lesion Complexity

The results are “reassuring” in that after implantation of the new-generation drug-coated stents once “you get far enough away from the index procedure, we need to really stop thinking about the lesion and start thinking much more about the patient risk factors,” Yeh said. “We sort of confirmed that in our analysis by looking at how the DAPT Score, for example, continued to stratify treatment benefit versus treatment harm among both complex lesion anatomy patients versus noncomplex patients.”

Specifically, a patient with a complex bifurcation lesion treated during the index procedure, but with a low DAPT score at a certain time point postprocedure wouldn’t need to continue DAPT, because “the harms probably would exceed the benefits,” he explained. “On the other hand, you could have a very simple lesion at index procedure, but if you have a high DAPT score even if you have a simple lesion, you still would [benefit] more greatly by extending the duration of dual antiplatelet therapy.”

These data should be encouraging for physicians who might not be aware of the initial lesion complexity of their patients, Yeh added.

In an email, Giustino told TCTMD that this new analysis “is a robust and well-performed study that consolidates the impact of angiographic complexity on ischemic risk after PCI.” It is “not discordant, but rather is complementary” to his own study, he said.

The single most important finding from the current study, according to Giustino, is that “angiographic factors to risk-stratify for more intense or prolonged antiplatelet therapy may be more important in the earlier periods (< 1 year), while patient-related risk factors may be more relevant beyond 1 year,” he said. “However, we should not forget that in the DAPT [Study], all patients experiencing events in the first year were not randomized—so this is a selected patient population.” This limitation is important given that patients with complex index lesions are at greater risk of recurrent events or repeat revascularization, which often leads to another extension of DAPT, Giustino noted.

Also, “the fact that the DAPT [Study] randomized only event-free patients at 1 year limits the external validity of the current findings to a real-world complex PCI population, in which recurrent events within the first year are frequent,” he said.

Finding the ‘Sweet Spot’

In an editorial accompanying the study, Antonio Colombo, MD, and Francesco Giannini, MD (IRCCS San Raffaele Scientific Institute, Milan, Italy), write that there is “a valuable need to define the ‘sweet spot’ for a specific patient where we optimize the benefits of DAPT with minimal associated risks.”

They make the case that, especially over time, patient characteristics are much more important than index lesion complexity, as evidenced by the findings of this subanalysis. “Lesion complexity may not affect the benefits of DAPT duration because of a need to protect the entire coronary tree as opposed to the stented/treated segments,” Colombo and Giannini write. “This need is better expressed by patient-related factors, whereas lesion complexity remains an indirect marker of disease burden.”

However, they argue that “the power of lesion complexity to be a marker for disease burden depends upon the definition of a complex lesion.”

Of note, Giustino et al’s paper used a different definition than that used by Yeh and colleagues.

On this point, Yeh conceded that “there’s no one right definition for complex lesion anatomy that everybody would agree on,” but said the results of the sensitivity analysis here should reassure physicians that the study findings aren’t totally beholden to the definition used.

No Longer a ‘Black vs White Decision’

Enduring questions relate to ongoing studies looking to shorten DAPT treatment even further, including the XIENCE Short DAPT study, Yeh said. “There are CE Marks in Europe for very, very short durations of dual antiplatelet therapy, and I think our study might suggest that for a high-risk coronary lesion, that's just probably not what you'd want to be doing,” he noted.

While many of these studies exclude patients with exceptionally high-risk coronary lesions, “I can imagine people pushing the envelope and starting to use very short durations of dual antiplatelet therapy,” Yeh continued. “We don’t have data to support in a randomized fashion [that] is it safe to do that, so I'm really looking forward to what these data look like.”

Giustino, for his part, pointed to the nuances of DAPT use. “We have reached a point now where I believe we should not debate anymore if DAPT should be longer or shorter like a black versus white decision,” he observed. “Conversely, tailoring antithrombotic intensity and duration should be dynamic (ie, repeated over time for a single patient) and [take into account] the individual risk/benefit ratio for ischemia and bleeding. We should keep working in refining our ability in predict and tailor risk to apply more precise and individualized care.”