DAPT: Long-Term Poststenting Dual Antiplatelet Therapy a Risk/Benefit Balancing Act

November 16, 2014

CHICAGO, IL — Four new trials comparing different durations of dual antiplatelet therapy following placement of a drug-eluting stent that appear to have shown different results have highlighted the difficulty of trying to formulate one recommendation for how long such therapy should be given.

The four trials were all presented at the first late-breaking clinical-trial session of the American Heart Association (AHA) 2014 Scientific Sessions on November 16.

Untangling all the data, most experts polled by heartwire seemed to agree that there was no "one-size-fits-all" recommendation for duration of therapy, and the issue needs to be addressed as two separate questions—how to protect patients from simple stent thrombosis, and the more generalized secondary prevention of native coronary disease.

For the first scenario of stent thrombosis, the data suggest that 6 months of treatment appear to be safe if there are bleeding concerns, especially in low-risk patients who have received a contemporary stent. In patients at higher ischemic risk, however, long-term treatment—maybe for life—may be beneficial.

The largest of the studies presented today, with almost 10 000 patients—the Dual Antiplatelet Therapy (DAPT) study[1]—is the only one truly powered to be able to show a definite result; it was designed in conjunction with the US Food and Drug Administration (FDA) to answer the question of the optimal duration of dual antiplatelet treatment after stent placement once and for all. It compared 12 months vs 30 months of thienopyridine therapy (clopidogrel or prasugrel [Effient, Lilly/Daiichi-Sankyo]) added onto aspirin, with patients at high ischemic or bleeding risk excluded.

Dr Laura Mauri

The DAPT results showed that longer-term treatment with dual therapy reduced the risk of stent thrombosis and MI (both related and unrelated to stent thrombosis), with an associated increase in moderate bleeding. Of particular interest, it was found that ischemic-event rates increased markedly in the 3-month period after discontinuing thienopyridine treatment regardless of when that occurred, leading to suggestions that treatment should maybe continue longer, even for life.

Presenting the data, principal investigator Dr Laura Mauri (Brigham and Women's Hospital, Boston, Massachusetts) concluded: "Continued thienopyridine therapy is beneficial in patients who have tolerated 1 year of dual antiplatelet therapy after drug-eluting-stent placement. These results should be applied excluding patients with a history of major bleeding."

One particular subgroup of the DAPT trial—patients who received the Taxus Liberté (Boston Scientific) stent (all of whom used prasugrel as the thienopyridine)—was presented as a separate study (the Taxus Liberté Post Approval Study [TL-PAS], published online November 16 in Circulation[2]). This group appeared to show a greater reduction in ischemic events with longer-duration dual antiplatelet therapy and a more marked increase in events in stopping therapy.

On the unveiling of DAPT here at the sessions, the FDA issued a statement in response to a signal of increased all-cause mortality risk observed with extended thienopyridine treatment (p=0.05)[3]. The agency said it's still evaluating the trial's results, and until it announced its conclusions and recommendations, it "believes the benefits of clopidogrel (Plavix) and prasugrel (Effient) therapy continue to outweigh their potential risks when used for approved uses."

Clinicians, it said, "should not change the way they prescribe these drugs at this time. Patients should not stop taking these drugs because doing so may result in an increased risk of heart attacks, blood clots, strokes, and other major cardiovascular problems."

Shorter Treatment Safe in European Studies

The other two studies presented—both from Europe—focused on shorter durations of antiplatelet therapy, which is more the standard of care in Europe. Both ISAR-SAFE and ITALIC found no differences in ischemic events or bleeding risk between 6 months of treatment and longer durations. Both these trials were stopped early because of recruitment issues and low event rates, but both presenters still concluded that 6 months of treatment were noninferior to longer periods and a realistic option, especially in patients a low risk of future events.

Putting the data together, Dr Giles Montalescot (Pitié-Salpêtrière University Hospital, Paris, France) said the issue should be regarded as two separate questions—short-term treatment after stenting to prevent stent thrombosis, and long-term treatment of patients with native coronary heart disease.

Noting that much of the benefit shown in the DAPT trial came from a reduction in ischemic events unrelated to stent thrombosis, Montalescot suggested that what was being seen was a general secondary-prevention effect, supporting observations from previous studies—such as CREDO and TRILOGY ACS—that dual antiplatelet therapy may be appropriate long term in patients with coronary artery disease.

Dr Giles Montalescot

He suggested that the European studies were addressing the other question of simply preventing stent-thrombosis–related events in patients having a stent but at otherwise low coronary risk. He said the ISAR-SAFE and ITALIC results, combined with previous similar studies, show that "we can safely stop dual therapy at 6 months if the patient has risk factors for bleeding."

He also pointed out that the European studies included more third-generation stents than in DAPT and showed a very low event rate.

Montalescot concluded: "There is no common rule for duration of dual antiplatelet therapy. It has to be individualized. With more than 35 000 patients now having been randomized in clinical trials, we can see that it is not possible to come up with a magic number of 6, 12, 24, or 30 months."

He suggested the four new trials presented today show that "if the patient has had a new-generation stent and you want to stop early at 6 months you probably can. But if you have multiple ischemic factors or if you have the Taxus stent in the left main—you would want to continue for a long time, maybe forever."

Many other experts seemed to agree with this stance. Dr Valentin Fuster (Mount Sinai Hospital, New York, and Centro Nacional de Investigaciones Cardiovasculares [CNIC], Maid, Spain) commented to heartwire : "The message is simple. If the patient has a tendency to bleed, stop at 6 months. If there are no comorbidities that might increase bleeding risk, continue for benefits on the native disease."

Dr Robert Harrington (Stanford University, CA), chair of the AHA scientific sessions, added: "My take-home from all this is that if you have a reason for stopping short term, 6 months is reasonable, particularly if the patient has not had an ACS. But if the patient is at high ischemic risk, more prolonged therapy is beneficial."

DAPT in Detail

In an interview with heartwire , Mauri emphasized the ischemic benefit seen in the DAPT trial with prolonged therapy. "DAPT shows a clear benefit in reducing the risk of ischemic events with longer duration of dual antiplatelet therapy—a 71% reduction in stent thrombosis and a 53% reduction in MI."

DAPT: Major Efficacy Results

Outcome Continued thienopyridine, n=5020 (%) Placebo, n=4941 (%) HR (95% CI) P
Stent thrombosis* 0.4 1.4 0.29 (0.17–0.48) <0.001
Major ischemic events (death/MI/stroke)* 4.3 `5.9 0.71 (0.59–0.85) <0.001
Death 2.0 1.5 1.36 (1.00–1.85) 0.05
MI 2.1 4.1 0.47 (0.37–0.61) <0.001
Stroke 0.8 0.9 0.80 (0.51–1.25) 0.32

*Co–primary end points

Extended dual antiplatelet therapy was associated with an increase in bleeding events, but Mauri noted that severe and/or fatal bleeding was uncommon and not significantly different between study arms. Mauri said: "Yes, there was an increased bleeding risk, but only one in 1000 of those bleeds were fatal. So the benefit of longer therapy clearly outweighs the risk in this population. But you have to remember that the patents at highest risk of ischemic events were not randomized, as they would already have been given longer-duration treatment, and those with a high risk of bleeding were also excluded, as you wouldn't think of continuing in this group."

"But we still had a broad patient population with hardly any other exclusions. We used four different drug-eluting stents and two different antiplatelet drugs, and even though this was not the highest-risk population, we still saw a reduction in ischemic events across the board. We might have expected a lower relative reduction in the lower-risk patients, but actually it was same."

Increase in Total Mortality

An unexpected finding in DAPT was that all-cause mortality was numerically higher for the continued thienopyridine group, driven by an increase in noncardiovascular deaths. Mauri said this finding "primarily reflected a chance imbalance in subjects with known cancer prior to enrollment."

To address this further, the investigators conducted a meta-analysis of 14 studies in a total of 69 644 patients randomized to shorter- or longer-term dual antiplatelet therapy.

Published online in the Lancet to correspond with the DAPT presentation[4], the meta-analysis found that compared with aspirin alone or short-duration dual antiplatelet therapy (<6 months), continued treatment was not associated with a difference in all-cause mortality (HR 1.05, 95% CI 0.96–1.19; P=0.33). Similarly, cardiovascular (HR 1.01, 95% CI 0.93–1.12; P=0.81) and noncardiovascular mortality (HR 1.04, 95% CI, 0.90–1.26; P=0.66) were no different with extended-duration vs short-duration dual antiplatelet therapy or aspirin alone.

To heartwire , Mauri commented: "We were concerned about noncardiovascular mortality in DAPT, and that is why we did the meta-analysis. We wanted to better understand the cancer data. The meta-analysis suggests that the noncardiovascular deaths in DAPT were outliers. Most were not related to the mechanism of action of antiplatelet therapy. Very few of the cancer deaths were linked to bleeding."

Noting that there was an increase in bleeding-related trauma deaths in DAPT, she said, "It has to be expected that if patients have a major trauma and they are on more potent antiplatelet therapy then they do have a higher risk of fatal bleeding, but such traumas are rare. I wouldn't recommend a patient who had an increased risk of such trauma through their occupation to take dual antiplatelet therapy long term."

DAPT: Bleeding results

Outcome Continued thienopyridine, n=4710 (%) Placebo, n=4649 (%) Difference P
Moderate or severe GUSTO bleeding 2.5 1.6 1.0 (0.4–1.5) 0.001
Severe bleeding 0.8 0.6 0.2 (-0.1 to 0.6) 0.15
Moderate bleeding 1.7 1.0 0.7 (0.2–1.2) 0.004

 

When to Stop Treatment: The $64 000 Question

As events were increased when treatment was stopped even after 30 months, the question arises as to how long dual therapy should be continued for. Mauri said she couldn't answer that question from the DAPT data, but she added: "Continuing dual therapy for longer than 30 months is certainly something to think about." She said the ongoing risks and benefits would have to be considered carefully in each individual patient. "I myself tend to follow what clinical trials have shown, and you have to be very careful in extrapolating data, as the benefit may decline but it might be worth continuing for longer than 30 months in certain patients."

Another DAPT investigator, Dr Dan Simon (Case Medical Center, Cleveland, Ohio), said he would likely continue dual therapy indefinitely in many patients after these results. "When to stop is the $64 000 question," he told heartwire . "But since the event curves were diverging until the dual therapy was stopped, when there was a noticeable increase in events, this justifies to me continuing long term—maybe forever—if patients have an acceptable risk/benefit ratio." He added: "I'm sure lots of substudies will be done to see whether any groups can be identified that are likely to benefit most. But I fully expect that my phone will be ringing off the hook from Monday onward with patients who have stopped dual therapy and now want to restart."

The DAPT trial was published online in the New England Journal of Medicine to coincide with its presentation at the AHA meeting. In an accompanying editorial[5], Drs Antonio Colombo and Alaide Chieffo (San Raffaele Scientific Institute, Milan) acknowledge that the ischemic benefits of prolonged treatment are clear but point out that "the increased bleeding and total mortality leaves us with uncertainty regarding the incremental benefit." They reach a conclusion similar to the DAPT investigators, that the optimal duration of dual antiplatelet therapy must be individualized for each patient, balancing ischemic benefits and bleeding risks.

ISAR-SAFE

The ISAR-SAFE trial randomized patients to 6 months or 12 months of clopidogrel after drug-eluting-stent implantation. The trial managed to recruit only 4000 of its planned 6000 participants, and this, along with a low event rate, led to it being stopped early.

Results showed no difference between the two treatment groups in the primary composite end point of death/MI/stent thrombosis/stroke/TIMI major bleeds or in ischemic events or major bleeding separately.

Presenting the data, Dr Stefanie Schulz-Schüpke (Deutsches Herzzentrum, München, Germany) concluded that 6 months dual antiplatelet therapy was noninferior to 12 months. But she added that the results must be considered in view of its premature termination and lower-than-expected event rates.

 

ISAR-SAFE: Outcomes at 1 Year

Outcome 6 mo clopidogrel, n=1997 (%) 12 mo clopidogrel, n=2003 (%) HR (95% CI) P
Primary end point (death/MI/stent thrombosis/stroke/TIMI major bleed) 1.5 1.6 0.91 (0.55–1.50) 0.70
Death 0.4 0.6 0.66 (0.27–1.63) 0.37
MI 0.7 0.7 0.93 (0.44–1.97) 0.85
Stent thrombosis 0.3 0.2 1.25 (0.33–4.65) 0.74
Stroke 0.4 0.3 1.40 (0.44–4.41) 0.57
TIMI major bleeding 0.2 0.3 0.80 (0.21–2.98) 0.74

 

ITALIC

Dr Matine Gilard

The ITALIC trial, presented by Dr Martine Gilard (University of Brest, France), randomized patients undergoing implantation of the Xience V (Abbott Laboratories) drug-eluting stent to receive 6- or 24-month dual antiplatelet therapy. The trial was prematurely terminated due to problems with recruitment but managed to enroll 2031 patients. Of these, 131 were found to resistant aspirin and moved from the main analysis.

There was a much lower rate of events (1.5% compared with the 3% expected) in the trial. One-quarter of the patients (24.2%) allocated to the short-duration arm did not respect the 6-month treatment duration. However, only 83 (8.9%) of these continued treatment longer, whereas the vast majority stopped early.

Results showed there was no significant difference between the two groups regarding the primary end point—a composite of death, MI, urgent target vessel revascularization, stroke, and major bleeding at 12 months poststenting, even in high-risk (ACS) patients.

ITALIC: Outcomes at 1 Year

Outcome 24-mo dual antiplatelet therapy 6-mo dual antiplatelet therapy HR (95% CI) P
Primary end point (death/MI/stroke/TVR/major bleed) 1.5 1.6 1.07 (0.52–2.22) 0.85
Major bleed 0.3 0 NA NA

Gilard concluded that noninferiority was demonstrated for 6- month vs 24-month DAPT, with an absolute risk difference of 0.11% (95% CI: -1.04 to 1.26; P for noninferiority=0.0002).

The ITALIC study was published to coincide with its presentation in the Journal of the American College of Cardiology[6].

The DAPT trial was funded by eight stent and pharmaceutical companies: Abbott Vascular, Boston Scientific, Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership, Cordis, Daiichi Sankyo, Eli Lilly, and Medtronic Vascular. Mauri reports institutional research grants from Abbott, Boston Scientific, Cordis, Medtronic, Eli Lilly/Daiichi Sankyo, and Sanofi/Bristol-Myers Squibb and personal fees from Medtronic, Recor, St Jude Medical, and Biotronik. Disclosures for the coauthors are available here. Colombo and Chieffo have reported they have no relevant financial relationships. The TL-PAS trial was funded by Boston Scientific. Disclosures for the authors are listed in the article. The ITALIC trial was sponsored by Abbott Vascular Devices. Gilard and coauthors report they have no relevant financial relationships. ISAR-SAFE was supported by Abbott Vascular. Schulz-Schüpke reports no relevant financial relationships. Montalescot reports receiving research grants from and serving on the speakers’ bureau or advisory board of multiple pharmaceutical and device companies.

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