DAPT Durations: Keeping Up with the Times

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We have 3-6-12-30 … No, we’re not talking about random lottery picks here, but rather the well-deliberated number of months of dual antiplatelet therapy (DAPT) for patients treated with drug-eluting stents. A growing evidence base is helping cardiologists make decisions with reasonable confidence about the optimal duration of DAPT for certain patient populations. 

When to end

Drug-eluting stents address the problem of restenosis that was associated with bare-metal stents in patients who underwent PCI, but they bring their own baggage in the form of stent thrombosis. The combination of a P2Y12-receptor inhibitor and aspirin reduces the risk of stent thrombosis and recurrent ischemic events, at the cost of potential increased bleeding. Guidelines in the U.S. recommend at least 12 months of DAPT after placement of drug-eluting stents and European recommendations call for six months of DAPT after stent implantation.

 - DAPT Graph 1Many physicians wonder if widening or narrowing those windows might benefit some patients. Not every patient tolerates DAPT, while others may not be compliant and yet others will require a respite for planned surgeries or other reasons. Interventional cardiologists must weigh the risk of thrombosis against the risk of bleeding, both infrequent but potentially devastating. And the relatively low number of adverse events on either side of the equation make it difficult to conduct sufficiently powered clinical trials to answer questions about duration and outcomes.

“Event rates were so low,” says Anil Pandit, MD, a cardiologist at HaysMed’s DeBakey Heart Institute in Hays, Kan. As a fellow at the Mayo Clinic in Scottsdale, Ariz., he and colleagues reviewed the efficacy and safety of six months or less or 12 months or more of DAPT in a meta-analysis of four randomized trials that included 8,163 patients with acute coronary syndrome (Catheter Cardiovasc Interv online April 18, 2014). There was no difference in the rates of all-cause mortality, cardiac death, MI and cerebrovascular accidents between the groups. Stent thrombosis rates were similar, at 0.75 percent with the shorter duration and 0.58 percent for the longer duration. Major bleeding was higher with longer duration DAPT but it was still less than 1 percent. 

“Even in our group at Mayo, some would say when rates are so low, what is the harm in prolonging dual antiplatelet therapy for 12 months or even after 12 months? When rates are so low anyway it might not make any clinical sense to us,” he observes.

Adding clarity on DAPT

The individual trials assessed by Pandit and colleagues had several limitations. They under-represented women; they had different endpoints and studied different durations; they included stable and unstable patients; they used only clopidogrel (Plavix, Bristol-Myers Squibb/Sanofi-Aventis) as the P2Y12-receptor inhibitor; and they were all open-label and stent-specific. Despite those drawbacks, they were among the more robust DAPT trials. Other studies have been plagued by slow enrollment, with some terminating early.

Also, some DAPT studies are too small to draw definitive conclusions, says Robert W. Yeh, MD, an interventional cardiologist at Massachusetts General Hospital in Boston and an investigator in the Dual Antiplatelet Therapy (DAPT) study. DAPT, conducted at the request of the FDA, used an unusual design to avoid the pitfalls in previous trials. The international, randomized, placebo-controlled study compared 12 and 30 months of DAPT after placement of one of four different drug-eluting stents.

 - DAPT Graph 2

Stent thrombosis (ST) outcomes at one year in first- (A) and second-generation drug-eluting stents (DES) (B). ATD = Antiplatelet therapy discontinuation. Source: The American Journal of Cardiology

“As a practicing interventional cardiologist, I know that the primary reason we continue DAPT for many of these patients is to avoid stent thrombosis and also myocardial infarctions in the nonstented region,” he says. “The DAPT study is the only study that was sufficiently powered to answer the question we were interested in.”

The DAPT trial allowed a combination of either clopidogrel or prasugrel (Effient, Daiichi Sankyo), plus aspirin in patients enrolled through either the Harvard Clinical Research Institute or postmarketing surveillance studies (N Engl J Med online Nov. 16, 2014). Before randomization, patients had to be adherent to their therapy and have had no major adverse cardiovascular or cerebrovascular events, repeat revascularization, or moderate or severe bleeding for 12 months. That left 9,961 patients randomized to receive aspirin and thienopyridine therapy or aspirin and placebo for 18 months. At that point, patients took aspirin only and were observed for an additional three months.

The primary efficacy endpoints were the cumulative incidence of definite or probable stent thrombosis and of major adverse cardiovascular or cerebrovascular events in the randomization study period. They found that extending DAPT compared with placebo reduced the risk of stent thrombosis, major adverse cardiovascular or cerebrovascular events and MI significantly; but it carried a higher risk of moderate or severe bleeding, at 2.5 percent vs. 1.6 percent with placebo.

“Those patients at elevated ischemic risk and perhaps less of a bleeding risk would benefit from continued dual antiplatelet therapy,” Yeh says, based on DAPT’s results, while patients with an elevated bleeding risk might benefit less.

In addition, they found that both groups had an elevated risk of stent thrombosis and MI in the first three months after discontinuing DAPT. “Some of those events were stent thrombosis but usually more were myocardial infarction in the nonstented vessel,” he says.

Dealing with discontinuation

In real-world practice, cardiologists sometimes manage patients who must discontinue DAPT before completing the full term of recommended treatment. In an analysis of patients treated at MedStar Washington Hospital Center in Washington, D.C., researchers calculated that 8.1 percent of patients implanted with first-generation drug-eluting stents and 6.2 percent of patients with second-generation stents discontinued clopidogrel treatment within a year (Am J Cardiol 2014;113:1968-1976).

The rates of definite and probable stent thrombosis were 3.8 percent and 2.5 percent in patients treated with first-generation sirolimus-eluting stents (Cypher, Cordis) or paclitaxel-eluting stents (Taxus, Boston Scientific) who discontinued DAPT before three months and between three and 12 months, respectively. None of the patients implanted with second-generation everolimus-eluting stents (Xience V, Abbott Vascular or Promus, Boston Scientific) had stent thrombosis events. But both first- and second-generation stent groups had higher rates of death and major adverse cardiac events compared with patients who continued DAPT for a year.

Ron Waksman, MD, the senior investigator in the study and associate director of the cardiology division at MedStar Heart Institute, says he follows guideline recommendations of 12 months of DAPT after PCIs with drug-eluting stents. But when circumstances require another strategy, physicians try to determine what is appropriate for that individual patient.

“There is the patient level and the stent level,” Waksman says. “On the stent level, I am more comfortable with the new generation [stent] that does not require very long duration. On the patient level, they may need longer duration to protect themselves from other events. If you have a patient who has a high risk for heart attack, he may benefit from longer duration irrespective of stent.  But if you have a stable patient who is not at high risk, then when you look at the stent level it may not require the 12 months of duration.”

Getting granular

Pandit and Yeh agree, saying that optimal duration is nuanced. “So much of practice has to be individualized to the patient,” Yeh notes. Given insights from DAPT, for instance, he would talk with the patient to assess his or her bleeding risk. “For those patients who typically do well on dual antiplatelet therapy, the benefit of continuing that treatment certainly outweighs the risk,” he says. He likely would recommend discontinuation for those with bleeding complications or upcoming surgeries “but I would be sure to counsel them about the slightly elevated risk that they incur by doing so.”

Applying existing evidence to factors such as disease severity, the number of stents implanted and lesion characteristics can inform the course of action with DAPT, Pandit proposes. He reviews the patient’s history, asks a series of questions and uses that knowledge to determine DAPT duration.

He envisions an app that one day could help in the decision-making process and provide a more patient-centered approach to care. “We should come up with a multivariate risk model where we enter a patient’s data like age, number of stents, lesion severity and then it gives us six months or 12 months.” Nonetheless, Pandit adds, many unanswered questions about earlier durations and patient subpopulations remain.

“If you follow the guidelines, for all drug-eluting stents it is 12 months,” he says. “I think the pendulum has slightly shifted toward shorter duration, but still there are lots of gray areas and nuances that we need to be aware of. We need to look at the patient in front of us and factor in differences.”

Many cutoffs, many results

Here are key results from other recent clinical trials that evaluated dual antiplatelet therapy (DAPT).

TAXUS Liberté Post Approval Study
This study compared outcomes from 12- and 30-month DAPT treatment in patients implanted with TAXUS Liberté paclitaxel-eluting coronary stents (Boston Scientific). A total of 3,904 patients received open-label prasugrel plus aspirin for 12 months after stenting. Those with no ischemic or bleeding events (2,191 patients) stayed on aspirin therapy and were randomized to receive either prasugrel or placebo for an additional 18 months.

The two groups had similar rates for death and stroke but MI rates were lower for those with prolonged DAPT (1.9 percent vs. 7.1 percent). Stent thrombosis was also lower (0.2 percent vs. 2.9 percent). In both the 12-month and 30-month groups, MI rates increased within 90 days of discontinuation of prasugrel.

Is There A LIfe for DES after Discontinuation of Clopidogrel
The multicenter trial compared aspirin alone vs. clopidogrel-plus-aspirin therapy at six months vs. 24 months after placement of a drug eluting stent (Xience V, Abbott Vascular) in 2,031 patients who were not resistant to aspirin. It ran into difficulties with recruitment and was discontinued early.

The researchers found no significant difference in the composite of death, MI, urgent target revascularization, stroke and major bleeding or in stent thrombosis and bleeding complications. They reported that six-month DAPT was noninferior to 24-month DAPT in good aspirin responders and in the subgroup of unstable patients.

OPTIMIZE: Optimized Duration of Clopidogrel Therapy Following Treatment With the Zotarolimus-Eluting Stent in Real-World Clinical Practice
OPTIMIZE compared three vs. 12 months of DAPT in patients with stable or low-risk coronary artery disease who underwent PCI with a zotarolimus-eluting stent (Endeavor, Medtronic). The open-label, multicenter study enrolled 3,119 patients in 33 sites in Brazil.

The primary end point was a composite of all-cause death, MI, stroke, or major bleeding. The primary endpoint occurred in 6 percent of patients in the three-month group and 5.8 percent of the 12-month group. The rate of stent thrombosis at one year was 0.3 percent and 0.1 percent, respectively.

SECURITY: Second Generation Drug-Eluting Stent Implantation Followed by Six- Versus Twelve-Month Dual Antiplatelet Therapy
The trial compared six and 12 months of DAPT in 1,399 patients with stable or unstable angina and silent ischemia who underwent PCI with at least one second-generation drug-eluting stent. The primary endpoint was a composite of cardiac death, MI, stroke, definite or probable stent thrombosis or bleeding at 12 months.

The rate of the primary endpoint was 4.5 percent with six months and 3.7 percent with 12 months of DAPT, with similar low rates of stent thrombosis at 12 months and between 12 and 24 months.

ISAR-SAFE: Safety and Efficacy of Six Months Dual Antiplatelet Therapy after Drug-eluting Stenting
The randomized, double-blind trial compared six and 12 months of treatment of aspirin and clopidogrel in patients with drug-eluting stents. It was terminated early because of slow recruitment and low event rates. The researchers found no difference between the groups but the study was underpowered to draw any strong conclusions.