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DAPT: Longer-duration therapy decreased stent thrombosis and MACCE, increased bleeding
CHICAGO — After drug-eluting stent implantation, 30 months of dual antiplatelet therapy compared with 12 months of therapy was associated with reductions in stent thrombosis and MACCE, but increased the risk for bleeding, according to results from the DAPT trial presented at the American Heart Association Scientific Sessions.
According to results presented by Laura Mauri, MD, MSc, rates of stent thrombosis from 12 to 30 months, a co-primary efficacy endpoint of the trial, were significantly reduced among patients who received the 30-month vs. 12-month DAPT regimen (0.4% vs. 1.4%; HR=0.29; 95% CI, 0.17-0.48; P<.001), as were rates of MACCE (4.3% vs. 5.9%; HR=0.71; 0.59-0.85; P<.001), the other co-primary efficacy endpoint, during that same period.
Laura Mauri
Likewise, rates of MI were also lower among patients who received the extended duration of DAPT (2.1% vs. 4.1%; HR=0.47; P<.001).
However, the rate of GUSTO moderate or severe bleeding, the primary safety endpoint, was significantly increased in the 30-month DAPT group (2.5% vs. 1.6%; P=.001).
Furthermore, the rate of all-cause mortality was numerically higher with 30 months of DAPT (2% vs. 1.5%; HR=1.36; 95% CI, 1-1.85; P=.052), which was driven by an increased rate of non-CV mortality in that group (1% vs. 0.5%; P=.002). This latter finding was unexpected, and “might have reflected a chance imbalance in subjects that were enrolled,” Mauri said during a press conference.
The researchers also performed a meta-analysis of 69,000 patients in randomized trials and found no difference in mortality or non-CV mortality.
"In this analysis, we found no signal for all-cause or non-CV mortality, so we are reassured that there is unlikely to be a true difference in mortality associated with prolonged thienopyridine treatment,” Robert W. Yeh, MD, MBA, DAPT trial investigator who led the analysis, told Cardiology Today.
Mauri added that in the 3 months following discontinuation of thienopyridine treatment, there was an increased risk for stent thrombosis and MI in both groups.
“Continued therapy markedly reduced both stent-related and other ischemic events beyond the stent-treated region in patients who have tolerated the first year of DAPT after [implantation with] drug-eluting coronary stents,” Mauri, physician at Brigham and Women’s Hospital and associate professor of medicine at Harvard Medical School, said.
Interpreting the results
Going forward, Yeh said it is important to remember that all patients in this trial had undergoing a full year of treatment with DAPT without sustaining a major event. He added that for those patients who are able to receive a full year of treatment, clinicians and patients need to weigh the balance between the risk for MI and stent thrombosis vs. the risk for bleeding.
“Our standpoint is that MI and stent thrombosis, which can be really catastrophic events, are more impactful than bleeding events,” Yeh, from Massachusetts General Hospital Institute for Heart, Vascular and Stroke Care, said. “In the DAPT study, the vast majority of the bleeding events were not fatal and did not lead to severe drops in BP.”
For patients who have done well on DAPT and those who have not experienced significant bleeding events and do not have to undergo a major surgical procedure, the results would suggest they are best kept on continued thienopyridine therapy, according to Yeh.
“On the other hand, there probably are some patients for whom the risk-benefit balance would be in favor of stopping it, and those would be patients at very high risk for bleeding events,” he said.
FDA comments
In a press release issued by the FDA during the AHA Scientific Sessions, the agency stated that it believes the benefits of clopidogrel and prasugrel (Effient, Eli Lilly/Daiichi Sankyo) therapy continue to outweigh the potential risks when used for approved uses.
“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,” according to the FDA release. “Health care professionals should not change the way they prescribe these drugs at this time.”
The FDA added that it has not yet reviewed the DAPT trial results, and will communicate its final conclusions and recommendations once the evaluation is complete.
Trial background
For the DAPT trial, Mauri and colleagues randomly assigned 9,961 patients who had undergone PCI with a DES to receive either thienopyridine treatment or placebo from 12 to 30 months. In the first 12 months, all patients received treatment with a thienopyridine — either clopidogrel or prasugrel — and aspirin. Operators chose stent and thienopyridine type from those that were FDA approved at the time of enrollment. Baseline characteristics were similar between groups, with the exception of rate of hypertension (thienopyridine, 75.8% vs. placebo, 74%; P=.03). – by Brian Ellis
For more information:
Mauri L. LBCT.01: Risk and Benefit of Dual Antiplatelet Therapy. Presented at: American Heart Association Scientific Sessions; Nov. 15-19, 2014; Chicago.
Mauri L. N Engl J Med. 2014;doi:10.1056/nejmoa1409312.
Disclosure: Mauri reports receiving grants and/or personal fees from Abbott, Biotronik, Boston Scientific, Cordis, Eli Lilly/Daiichi Sankyo, Medtronic, ReCor, Sanofi Aventis/Bristol-Myers Squibb and St. Jude Medical. Yeh reports personal fees from Abbott Vascular, Boston Scientific, Gilead Sciences and Harvard Clinical Research Institute outside this study.
Perspective
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This is not one question. There are two different questions which have been asked in the four studies presented [at AHA 2014]. I would like to make the point that looking at shorter duration of DAPT is not the same as looking at longer duration of DAPT.
If we accept the fact that platelets play a role, looking at the shorter duration of treatment is expected to benefit on safety and on major bleeding, with the same protection against major events such as MI and stent thrombosis. None of the studies [presented at AHA 2014 during the late-breaking clinical trial session] were able to show significant reduction of major bleeding.
When we look at the longer duration of treatment, it is a different issue. We are looking already at similar prevention with double antiplatelet therapy. None of the studies here were adequately powered to look at that situation, but the DAPT study is adequately powered to look at events. In this case, we expect to see the safety issue with the continuation of double treatment, but we expect also to see a benefit on the ischemic side.
In total, we had 20,000 patients included in previous studies, and today we have 15,000-plus patients from the three studies presented [ISAR-SAFE, ITALIC, DAPT]. ISAR-SAFE compared 6 months to 12 months of double treatment in patients receiving a DES, with an analysis of the primary endpoint after the interruption of the treatment. ITALIC was a comparison between 6 months and 24 months of double treatment, with an evaluation of the clinical endpoints on-treatment. But actually the studies have more similarities than differences. If you look carefully at the primary endpoint in both studies, there was a net clinical benefit, with wide margins for noninferiority of 20% or more. There was a long enrollment period for both studies; they both started in 2008. There were very low event rates; 1.5% for the primary endpoint in both studies. We had premature study interruption. The study treatment was not followed in 14% of participants enrolled and randomized in the two studies. And we had patients lost to follow-up. What does it mean? It means that these studies are very difficult to conduct. It means also that no study in itself is conclusive.
But these two studies are aligned with the five previous studies. So remember, what we want to see is the same protection against ischemic events, MI and stent thrombosis, with the shorter duration of DAPT. The individual studies were not able to show that, but all together, if you pool their results, there is no difference between the shorter duration of treatment and the longer duration of treatment in 15,000-plus patients. But remember, the goal is to prevent bleeding with the shorter duration of treatment. None of the studies were able to show that for major bleeding. But when we pool the data, we now have a significant reduction of major bleeding in a meta-analysis. So actually, the hypothesis has been fulfilled with all the studies together, even if the individual studies were unable to complete it.
It is a different issue now if we look at the longer duration of DAPT. We are talking of secondary prevention. We are talking of relying on treatment to prevent ischemic events, knowing that we should see in this type of study an excess of bleeding complications. So this DAPT study was powered for events, was powered for stent thrombosis for the first time, was powered for major bleeding, and had the potential also to look at another endpoint, which was mortality. It is a double blind study. We have both clopidogrel and prasugrel, which is good. We have also a 3-month follow-up period after interruption, which is also important. And we have all types of stents, which is good also.
The results are in line with what we know with stronger and longer duration of antiplatelet therapy when we use two or three drugs. The results of DAPT are aligned with three other important studies looking at complicated patients with previous comorbidities. So this study is actually in line with what we know from other previous studies in the field of coronary disease.
Some of the patients in DAPT received a paclitaxel-eluting stent, and the results are very impressive in this study. We know that this stent is actually an additional risk factor for the patient. We know that stent thrombosis was reduced from 2.9% to 0.8% with prasugrel. And prasugrel was used off-label for more than 12 months in stable patients. This is new education as well. Prasugrel prevented MI, related or not to stent thrombosis, which shows that you can have secondary prevention in these types of patients, on double treatment with antiplatelet agents. And the rebound effect at the interruption of prasugrel is important to support long-term treatment with double antiplatelet therapy.
This is the global picture for DAPT. For every 1,000 patients with continued DAPT up to 30 months, you will have 20 fewer MIs, nine fewer stent thromboses, and 10 more bleedings. And possibly, five more deaths, if this is not play of chance.
You have seen the meta-analysis by Dr. Mauri looking at 17,000 patients treated with double treatment vs. single treatment and showing no significant difference for death when double treatment is given to a large volume of patients. Here, we are looking at three studies looking at a similar population of patients: patients undergoing stenting with a DES and being tested for long treatment vs. 1-year treatment with DAPT. The mortality rates in these three studies are very comparable. Identical with 12 months of treatment. When we look at prolonged treatment, the same signal has been observed in the large DES-LATE study. And when pooling all these data in a meta-analysis of the three studies, we find a trend for mortality which is not significant, but superimposable to what has been seen in the DAPT study with almost the same P value of .054.
So what is the interpretation about mortality? First, we have reassuring factors. This is a small signal and we have a small number of events. We also have a late appearance of this signal after 24 months, when the exposure to risk is the same from the beginning. All these factors suggest the play of chance. There is an asymmetrical split for cancer-related deaths, which does not make much sense. Again, possibly the play of chance. There is no signal of death in the cohort of patients receiving paclitaxel-eluting stents, there is no signal of death in the group of patients receiving a bare-metal stent, and no significant signal in the meta-analysis that has been presented.
There are also disturbing factors. There is an asymmetrical split on bleeding related to non-CV death where we see a difference, and this is 21 vs. five patients leading to death. There is a relation between major bleeding and death, which is well-documented in the literature, so this finding makes sense. And we have seen a similar trend on death in a small meta-analysis of similar DES studies.
So in conclusion, what do we have? To the question of a shorter treatment in patients receiving a DES, probably we can accept that 6 months treatment is indeed safer than 12 months treatment of double antiplatelet therapy. And in patients with high bleeding rates, it would make sense to stop the treatment at 6 months and avoid more bleeding complications. And these patients are well-identified: those with prior bleeding complications, the patients needing surgery, the patients who need oral anticoagulation for atrial fibrillation, for example. In the other patients, we may want to continue treatment up to 12 months, and eventually longer than 12 months, according to the ischemic risk. That may be for 30 months or even longer in some very high-risk patients.
So what are the conclusions for today? First, interruption of DAPT 6 months after DES implantation is possible, including in ACS patients, according to the data we have seen. Patients studied beyond 1 year were at low risk for ischemic events and bleeding events. There is an ischemic benefit with DAPT continuation beyond 1 year, and this benefit is not questionable. There is more bleeding, also, with continuation of double treatment. There is a hazard within 3 months of discontinuation of double antiplatelet therapy, even 30 months later. The magnitude of benefit may be greater with prasugrel than clopidogrel, although this finding may be confounded. It’s difficult, probably, to identify the patients who may benefit more from continuation, and we need more analyses of the DAPT study for this question.
My impression is that we cannot define a common rule for the duration of antiplatelet therapy, but only individualize decisions, which makes the practice of medicine sometimes so challenging.
Perspective
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This is a study that has provided objective evidence that prolonged DAPT in people receiving drug-eluting stents was effective at reducing both adverse CV events and stent thrombosis. At the same time, there was an increased bleeding risk in those individuals. Doctors need to have a discussion with their patients who have received a DES that they may benefit overall from long-term DAPT with a reduction in the risk for stent thrombus and MI. The discussion, however, also has to include the bleeding risk associated with DAPT, particularly if the patient fits into a category with established increased bleeding risk — including the very elderly, someone who has bled previously, or someone on an anticoagulation agent for another reason such as atrial fibrillation. In that case, the physician should be circumspect about recommending prolonged DAPT.