Dual Antiplatelet Therapy (DAPT): Just How Long Is Enough?

The appropriate duration of dual antiplatelet therapy (DAPT) for patients following placement of a drug-eluting stent (DES) remains controversial.¹ Many clinicians have pushed for prolonged DAPT — beyond 12 months — on the assumption that extended therapy reduces recurrent cardiovascular (CV) events.  However, the benefits and harms of extended DAPT therapy are unclear and many health systems won’t authorize it.  Does the Dual Antiplatelet Therapy (DAPT) study provide sufficient evidence to change the standard of care?

Currently, DAPT is recommended for six to 12 months after DES placement.^2,3  Drug-eluting stents reduce the need for repeat revascularization compared to bare metal stents (BMS).²  While DES reduce the risk of early stent thrombosis, patients are at a higher risk of delayed thrombotic events due to delayed endothelial cell regrowth.  The DAPT study was designed — at the request of the Food and Drug Administration (FDA) — to determine whether prolonged DAPT reduces CV events.  It was the first study adequately powered to answer this question and funded by eight stent and pharmaceutical manufacturers.⁴

The DAPT study was an international, multicenter, randomized and placebo-controlled trial evaluating the benefits and risks DAPT continued beyond 1 year following the placement of a coronary stent (DES or BMS).⁴  The primary analysis only included patients who received a DES. Enrolled patients were at least 18 years of age and a candidate for DAPT for at least 30 months.  Major exclusion criteria included life expectancy less than 3 years, dual DES and BMS, long-term warfarin therapy, planned surgery requiring therapy cessation for more than 14 days, and poor medication adherence (defined as less than 80% or greater than 120% of doses during the initial 12 months of treatment).  All patients received DAPT for 12 months and were excluded if the subject had a CV event (MI, stroke, death, repeat revascularization, stent thrombosis) or major bleeding event on DAPT.  Baseline characteristics were similar in both groups.

At 12 months, patients were randomized at a 1:1 ratio to continued thienopyridine therapy (n=5020) or placebo (n=4940) for an additional 18 months.  Of note, the clopidogrel:prasugrel utilization ratio was 2:1 in the two groups.⁴  All patients continued aspirin  (75 – 162 mg) therapy. The mean age of study participants was 61.5 years and most were white (91%) males (75%).  The co-primary efficacy end points for the study were definite/probable stent thrombosis and major adverse cardiovascular and cerebrovascular events (MACCE).  The primary safety end point was the incidence of moderate or severe bleeding.⁴

Continued DAPT demonstrated statistically significant reductions in the co-primary efficacy end points (See Table 1).⁴ While continue DAPT appears to have a positive impact on myocardial infarction, it did not have a positive impact on stroke.  Researchers on the DAPT study also reported the impact of continued thienopyridine therapy in patients treated with BMS.  Unlike the observed benefits in patients with DES stents, there were no statistically significant differences in stent thrombosis, MACCE, or moderate/severe bleeding events in those who received a BMS.⁵

Table 1. DAPT Efficacy Endpoints⁴

Table 2. DAPT Study Primary Safety Endpoints⁴

The incidence of major bleeding — as determined by either the GUSTO (Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Arteries) or BARC (Bleeding Academic Research Consortium) Criteria —  was significantly higher in patients who continued DAPT (See Table 2).  Patients who continued DAPT were more likely to experience moderate GUSTO (1.7% vs 1.0%, 95% CI: 0.2-1,2, p= 0.004), and BARC type 2 (3.1% vs 1.5%, 95% CI: 0.9-2.1, p < 0.001) and BARC type 3 (2.6% vs 1.5%, 95% CI: 0.6-1.7, p < 0.001) bleeding.  More severe forms of major bleeding were not statistically different but numerically greater in the DAPT group.⁴

An increased risk of noncardiovascular death with continued DAPT use (0.62% vs. 0.28%; p=0.02) was an unexpected finding in the DAPT study.  The DAPT group had more patients with a history of cancer (22 more patients) prior to enrollment.  When these patients were excluded in the post-hoc analysis, there were no significant differences in mortality (all cause or noncardiovascular death).⁴  The higher incidence of pre-existing cancer in the DAPT group may explanation these results.

The results of DAPT are in contrast to the ARCTIC-Interruption study which also assessed DAPT therapy beyond 1 year.⁶  The occurrence of the primary end point in the ARTIC-Interruption study was essentially the same in both treatment groups (4%), showing no apparent benefit.  But patients randomized to DAPT were more likely to experience major or minor bleeding based on the STEEPLE criteria. While the bleeding criteria used in the DAPT and ARTIC-Interruption studies are not equivalent, increased bleeding risk is a consistent theme with prolonged DAPT use.

A recent meta-analysis of 10 studies found that shorter DAPT (6 months) decreased all-cause mortality, while prolonged (> 1 year) DAPT increased noncardiovascular mortality that was not balanced by a reduction in cardiac mortality.²   DES-LATE evaluated aspirin-alone versus clopidogrel plus aspirin for 24 months following 12 months of DAPT.  Exclusion criteria was similar to the DAPT study; however, an additional 24 months of DAPT did not reduce the primary end point (composite of death from cardiovascular causes, MI, or stroke)  (HR: 0.94, 95% CI: 0.66-1.35, p= 0.75).⁷

Similarly, ITALIC demonstrated non-inferiority (but not superiority) of 6- vs. 24- month DAPT for the primary endpoint (death from any cause, MI, stroke, target vessel revascularization, or major bleeding) (HR: 1.072, 95% CI: 0.517 – 2.221, p= 0.85).⁸  Like the DAPT study, ITALIC excluded high risk patients (e.g. patients who had a end point event during the first 6 months of DAPT).

One potential limitation of the DAPT study is the exclusion of high-risk patients.⁴  Patients who experienced a end point event during the first 12 months of therapy were excluded from the trial.  This raises the question of whether patients at higher risk for major CV events would have derived greater benefit from prolonged DAPT and thus improving the benefit:risk ratio.  However, the PRODIGY study — which examined the use of DAPT for 6 vs. 24-months in patients with either a DES or BMS — randomized subjects after 30 days of therapy and thus included high-risk patients in the analysis.⁹ Unlike the DAPT study results, prolonged DAPT was not superior in the PRODIGY study for the primary end point (all cause mortality, myocardial infarction, or cerebrovascular accident) (HR: 0.98, 95% CI: 0.74 – 1.29, p= 0.91).  Further, there was a statistically significant increase in bleeding based on the BARC criteria (HR: 0.38, 95% CI: 0.21 – 0.69, p= 0.0016).

The DAPT study supports the continued use of DAPT in patients who receive a drug-eluting stent and who are event-free during the first year.  Prolonged (30 months) DAPT reduced the incidence of stent thrombosis (NNT= 100) and major adverse cardiovascular and cerebrovascular events (NNT= 63) but increased the risk of moderate (NNH=143) and severe (NNH= 500) bleeding.⁴ Admittedly, the results of the DAPT study conflict with previous evidence regarding prolonged DAPT; however, this is the largest, most robust study conducted to date.  I believe prolonged DAPT should be offered to patients at low bleeding risk – patients younger than 65 years of age who have been screened for colon cancer. Those who elect to continue DAPT should be warned to refrain from taking NSAIDs and herbal products that impact platelet function or increase the risk of bleeding, such as ginko biloba, garlic, cranberry extract, and dong quai.  Should the DAPT study shift the standard of care from 12 months to 30 months in patients who receive a DES?  Does the increased risk of bleeding essentially offset the benefits? To whom would you recommend continued DAPT? In whom would you avoid it?

See the companion commentary regading the PEGASUS Study.