DAPT Study Supports Safety and Effectiveness of Extended Therapy After Stent Implantation

November 16, 2014—The Harvard Clinical Research Institute (HCRI) announced the results of the DAPT study, a major international study that investigated the duration of dual-antiplatelet therapy (DAPT) after coronary stent implantation. Laura Mauri, MD, presented these results in a late-breaking clinical trial session at the American Heart Association (AHA) Scientific Sessions 2014 in Chicago, Illinois.

Dr. Mauri, et al published the results online simultaneously in The New England Journal of Medicine. Dr. Mauri serves as Principal Investigator of the DAPT study and is an interventional cardiologist at the Brigham and Women’s Hospital, Associate Professor of Medicine at Harvard Medical School, and Chief Scientific Advisor for HCRI.

According to HCRI, the DAPT study assessed the benefits of 12 versus 30 months of DAPT for preventing stent thrombosis and major adverse cardiovascular and cerebrovascular events (MACCE; composite of death, heart attack, or stroke) in patients undergoing percutaneous coronary intervention with drug-eluting stent (DES) placement for the treatment of coronary artery lesions. 

The study found that the continuation of DAPT beyond 1 year resulted in significant benefits compared with aspirin alone, including reducing the rare but serious problem of stent thrombosis and preventing heart attack in other vessels. Although longer-term DAPT expectedly increased bleeding, severe and/or fatal bleeding was uncommon, and the difference between study groups was not statistically significant, reported the investigators. 

As noted in the announcement, the background of the study was that although clotting inside the stent or in other blood vessels may occur after 1 year, the benefit of continuing treatment was unknown. The DAPT study was performed as a public-private partnership in response to a request from the US Food and Drug Administration (FDA) to the manufacturers of FDA-approved coronary stents to examine this important public health question in a broadly inclusive and well-powered study. 

The HCRI press release outlined the DAPT study protocol, noting that the American College of Cardiology and the AHA currently recommend at least 12 months of DAPT for patients undergoing percutaneous coronary intervention after placement of a DES. The DAPT study was a prospective, randomized, double-blind trial that evaluated patients treated with a DES or BMS at 452 centers in 11 countries. A total of 25,682 patients were enrolled into the study by HCRI and from four participating stent manufacturer-sponsored studies that each followed the DAPT study protocol. 

The primary analysis involved the 12- to 30-month treatment period for the DES-treated cohort, which was composed of 22,866 DES patients who received 12 months of open-label thienopyridine/antiplatelet treatment in addition to aspirin. After 12 months, a total of 9,961 patients who were free from all MACCE or major bleeding events and were compliant with thienopyridine treatment were randomized 1:1 to either placebo (n = 4,941) or ongoing DAPT (n = 5,020) for an additional 18 months, followed by 3 months of observational follow-up. Both arms continued aspirin therapy. The choice of stent type (from FDA-approved devices) and thienopyridine drug (clopidogrel or prasugrel) was at the discretion of the patient and physician. 

The coprimary effectiveness endpoints were stent thrombosis (defined as definite/probable by the Academic Research Consortium) and MACCE (composite of mortality, myocardial infarction, or stroke) during the primary analysis period. 

The investigators found that compared with patients treated with DAPT for 12 months, patients randomized to 30 months of treatment had a significantly lower cumulative incidence of stent thrombosis (0.4% vs 1.4%; hazard ratio [HR], 0.29; P < .001) and of MACCE (4.3% vs 5.9%; HR, 0.71; P < .001), which was driven by a reduction in myocardial infarction (2.1% vs 4.1%; HR, 0.47; P < .001). Nonstent thrombosis-related myocardial infarction comprised 55% of the treatment benefit (1.8% vs 2.9%; HR, 0.59; P < .001). The incidence of stroke was similar between the two treatment arms (0.8% vs 0.9%; P = .32).
 
Regarding safety, the DAPT study investigators found that the incidence of moderate or severe bleeding by GUSTO (Global Utilization of Streptokinase and TPA for Occluded Arteries) classification was the primary safety endpoint and was significantly higher in patients who received 30 months of DAPT (2.5% vs 1.6%; HR, 1.61; P = .001) and did not meet the prespecified definition of noninferiority. Cases of severe or fatal bleeding or intracranial hemorrhage were rare and did not differ significantly between the two arms. 

An increased risk of stent- and nonstent-related myocardial infarction was detected in the 3-month period following discontinuation of active therapy in both treatment arms. During the primary analysis period, cardiac mortality (0.9% vs 1%; P = .98) and vascular mortality (0.1% vs 0.1%; P = .98) were similar across the two arms, and all-cause mortality was 2% versus 1.5% (HR, 1.36; P = .05). 

In the press release, Dr. Mauri commented, “The benefits of continuing DAPT for 30 months were quite remarkable. The relative risk of a stent-related blood clot was reduced by 71%, compared with taking only aspirin after 1 year. The DAPT study was the first and only study that was adequately powered to detect this benefit. Furthermore, the relative risk of heart attack was reduced by 53% by preventing these stent-related events, as well as by preventing events in vessels beyond the stented lesion.” 

She added, “The study is a result of unprecedented collaboration amongst industry, government, and academia, and valuable contributions from the investigators and patients.” 

Dr. Mauri concluded, “The benefits with extended treatment were present across all stent and drug types included in the study. Additionally, the results were consistent regardless of patient characteristics, such as whether the stent was placed during a heart attack or whether the procedure was technically simple or complex.” 

On November 18 at the AHA meeting, the DAPT study’s Coprincipal Investigator Dean J. Kereiakes, MD, will present findings from a secondary analysis of patients who were treated with bare-metal stents (BMS). Dr. Kereiakes is Medical Director of The Christ Hospital Heart and Vascular Center and The Carl and Edyth Lindner Center for Research and Education at The Christ Hospital in Cincinnati, Ohio.

In the secondary analysis comparing the rates of stent thrombosis and MACCE for DES- versus BMS-treated patients, those patients with DES had significantly lower rates of stent thrombosis and noninferior major adverse cardiac event rates compared with BMS through 33 months of follow-up. The treatment benefit effect (reduced stent thrombosis events) of 30 months of DAPT (vs 12 months) in BMS-treated patients was consistent with that observed in the DES-treated patients, but further study is required to discern if BMS-treated patients derive equal benefit. 

In the BMS group, bleeding events with extended therapy followed a similar trend as that seen in the primary analysis of DES patients, wherein bleeding rates were higher but bleeding was rarely severe or fatal.

In the secondary analysis that included the final follow-up time point of 33 months, all-cause mortality was 2.3% in the 30-month arm versus 1.8% in the 12-month arm (HR, 1.36; P = .04). The higher mortality in the 30-month arm was driven by a higher rate of noncardiovascular death. The observed difference in noncardiovascular mortality was not entirely accounted for by differences in bleeding. 

Although there was no difference between the study arms in new cancer occurrences reported over the course of the study, there were 22 more patients with cancer at baseline in the continued treatment arm, and cancer-related deaths were 31 versus 14 (P = .02). A blinded review of cancer-related deaths identified an imbalance in the longer-term treatment arm (eight patients versus one patient in the placebo arm with the diagnosis of the cancer that led to death detected before enrollment in patients that were subsequently randomized). When these patients were excluded in a post hoc sensitivity analysis, the differences in mortality between the two study arms were no longer significant.

Dr. Kereiakes stated, “We believe that the overall benefits of continuing DAPT to at least 30 months after treatment with DES outweigh the bleeding risks in patients without a history of major bleeding, and these results may warrant a shift in clinical practice. Our observations from a secondary analysis suggest that continued DAPT beyond 1 year may be beneficial in patients treated with BMS, but further study is required to discern if these patients derive equal benefit.” 

The findings from the additional secondary analysis of extending therapy to 33 months prompted an in-depth, blinded adjudication of noncardiovascular causes of death and an independent meta-analysis of previous randomized trials. The meta-analysis was published by Sammy Elmariah MD, et al in The Lancet and will be released concurrently with the late-breaking clinical trial session at AHA. 

The meta-analysis, which was led by Robert Yeh, MD, concluded that an extended duration of DAPT was not associated with a difference in the risk of all-cause, cardiovascular, or noncardiovascular death compared with aspirin alone or a short of duration DAPT. Dr. Yeh serves as an investigator of the DAPT study and is an interventional cardiologist at Massachusetts General Hospital, Assistant Professor of Medicine at Harvard Medical School, and Medical Director of Trial Design for HCRI. 

Regarding the findings of the secondary analysis, Dr. Mauri commented, “While we don’t discount the observations regarding noncardiovascular mortality, the findings of our additional analyses and adjudication were reassuring. The blinded adjudication revealed that among patients whose death was related to cancer, more patients with known cancer before enrollment were randomized into the 30-month study group rather than into the placebo group. Taken together with the fact that a meta-analysis of over 60,000 patients enrolled in previous large randomized studies comparing longer-term thienopyridine treatment to placebo showed no difference in mortality, it is possible that the mortality finding was related to a chance imbalance between the groups studied in the trial.” 

The DAPT study was conducted by HCRI through a public-private collaboration involving HCRI, four major stent manufacturers, the manufacturers of thienopyridine/antiplatelet medications, and the FDA. HCRI, which was responsible for the scientific and operational management of the DAPT study and the independent analysis of the resulting data, received funding support from each of the drug and device manufacturers and the FDA, as well as a grant from the US Department of Health and Human Services. 

The devices and their manufacturers are: Xience V (Abbott Vascular), Taxus, Promus (Boston Scientific Corporation), Cypher (Cordis Corporation), and Endeavor 
(Medtronic, Inc.). The medications and manufacturers are: Plavix (clopidogrel bisulfate, Bristol-Myers Squibb Company/Sanofi Pharmaceuticals Partnership) and Effient/Efient (prasugrel, Eli Lilly and Company and Daiichi Sankyo Company, Limited). 

The stent manufacturer-sponsored studies contributing to the DAPT study are: Boston Scientific’s TAXUS Liberté Post Approval study, Abbott Vascular’s XIENCE V USA DAPT cohort, Medtronic’s EDUCATE study, and Cordis’s CYPRESS trial.