Meta-analyses Shed Light on the Impact of DAPT Duration

Coinciding with the American College of Cardiology (ACC)/i2 Scientific Session, data from 2 new meta-analyses addressing the ideal duration of dual antiplatelet therapy (DAPT) were released this week.

One meta-analysis, published online March 14, 2015, ahead of print in the Lancet, found that while DAPT beyond 1 year after DES implantation lowers the risks of MI and stent thrombosis, it is also associated with a higher likelihood of mortality. The other, published in the March 24, 2015, issue of the Journal of the American College of Cardiology, suggests that 6 months of DAPT is as effective as 12 months at preventing MACE and also reduces bleeding.

Recently reported data from the DAPT Study, which randomized nearly 10,000 patients receiving DES to regimens of 12 or 30 months, showed a trend toward greater all-cause mortality—driven by noncardiovascular death due to bleeding, trauma, and cancer—but the results were inconclusive.

“However, if real, an increased risk of mortality of even about 0.5% with extended DAPT (as was present in the DAPT trial) would equate to tens of thousands of deaths in the millions of patients treated with drug-eluting stents every year worldwide,” researchers note in the Lancet paper.

Mortality Rises With DAPT Beyond 1 Year

For the Lancet study, Gregg W. Stone, MD, of Columbia University Medical Center (New York, NY), and colleagues identified 10 randomized trials of DAPT duration involving 31,666 patients and categorized each trial by whether its DAPT was:

• Shorter or longer
• Given for ≤ 6 months, 1 year, or > 1 year

Included studies were: ARCTIC-Interruption, DAPT, DES-LATE, EXCELLENT, ISAR-SAFE, ITALIC, OPTIMIZE, PRODIGY, RESET, and SECURITY.

By frequentist analysis, shorter DAPT imparted lower all-cause mortality than did longer DAPT, a difference driven by noncardiac mortality (table 1). There was no significant heterogeneity for mortality across trials.

Shorter DAPT also carried a lower risk of major bleeding (HR 0.58; 95% CI 0.47-0.72) but increased the likelihood of MI (HR 1.51; 95% CI 1.28-1.77) and definite/probable stent thrombosis (HR 2.04; 95% CI 1.48-2.80). Stroke rates were similar irrespective of DAPT duration.

Bayesian analyses indicated that all-cause and noncardiac mortality were lower for patients receiving DAPT for ≤ 6 months or for 1 year compared with > 1 year. The shorter durations were associated with more MI and definite/probable stent thrombosis but less major bleeding. Between the ≤ 6-month and 1-year groups, mortality, MI, and stent thrombosis risks were similar, but shorter therapy still translated into reduced major bleeding.

“The mechanistic underpinnings of the greater risk of noncardiac mortality with extended DAPT remain unclear,” the researchers say, suggesting that it may be related to major bleeding after PCI. “Additionally, a greater propensity to bleed on DAPT might increase mortality in patients who have trauma or in whom cancer develops.”

In an email interview, Dr. Stone described all-cause mortality as “the ultimate arbiter of patient outcomes, and as regards prolonged DAPT, the benefits just don’t make up for the risks. The balance against prolonged DAPT is particularly evident with contemporary DES, which are safer than the first generation.”

However, he cautioned, this does not exclude the possibility of longer DAPT duration for some patients. “Those in whom the ischemic risk is particularly high and the bleeding risk is low may benefit from longer DAPT,” Dr. Stone advised. “Thus, 6 months might be reasonable for most patients with stable coronary artery disease undergoing PCI, whereas 1 year is still a reasonable standard after PCI in ACS. Some patients may benefit from 3 months, 2 years, or even life-long DAPT depending on their particular risk-benefit profile.

“The decision must be individualized for each patient—remembering, however, primum non nocere and that for the average patient, prolonged DAPT appears to be more harmful than beneficial,” he concluded.

According to the paper, additional research may help tease out the “demographic, laboratory-based, and genetic variables… that might remove the guesswork from this equation.”

In an editorial accompanying the Lancet paper, Nick Curzen, BM, PhD, of the University Hospital Southampton NHS Foundation Trust (Southampton, England), says the meta-analysis “will, and indeed should, call into question a universal shift towards a policy of 30 months of DAPT after drug-eluting stent implantation, despite the scientific rigor of the DAPT trial. After all, who would swap a lower risk of stent thrombosis for an increased risk of bleeding or death?”

What with the mixed bag of evidence available from existing trials—with diverse patient populations and various DAPT regimens used—clinicians are in a difficult position, he notes. “It is surely time to revisit a personalized approach to DAPT,” Dr. Curzen agrees. “The notion that this heterogeneous group of patients given drug-eluting stents can be treated with a one-size-fits-all antiplatelet strategy is looking increasingly facile.”

Six Months as Good as or Better Than 1 Year

The JACC study, also led by Dr. Stone but involving a slightly different set of coauthors, homed in on a shorter time horizon, using patient-level data to assess 1-year outcomes of 8,180 patients in 4 randomized trials according to DAPT durations of 3, 6, and 12 months.

At 1 year, patients who had taken DAPT for ≤ 6 months had a similar risk of MACE (cardiac death, MI, or definite/probable stent thrombosis) compared with those receiving the drugs for 1 year (HR 1.11; 95% CI-0.86-1.43) but a lower risk of bleeding (HR 0.66; 95% CI 0.46-0.94).

The researchers also conducted a landmark analysis in the “as treated” cohort, excluding patients with clinical events occurring before the landmark time point, those with premature discontinuation of DAPT, and those in whom DAPT was prolonged at least 1 month beyond their assigned duration. Results for the period between DAPT interruption and 1-year follow-up were consistent with those of the main analysis.

In addition, there were no differences in 1-year MACE between DAPT durations of 3 months vs 1 year, 6 months vs 1 year, or 3 months vs 6 months. However, 6-month DAPT was associated with less major bleeding compared with 1-year DAPT (OR 0.38; 95% CI 0.14-0.95).

Need for Antiplatelet Protection May Evolve Over Time

In an accompanying JACC editorial, Roxana Mehran, MD, Gennaro Giustino, MD, and Usman Baber, MD, all of Mount Sinai Hospital (New York, NY), agree that the goals of DAPT vary over time.

“Early after PCI, the salient question centers on the minimum duration of DAPT required to prevent largely local (ie, stent-related) complications,” they write. “After this initial period, however, identifying those patients who might benefit most from DAPT extension to prevent increasingly systemic events becomes the key.”

While 3 to 6 months of DAPT meets the early need, decisions in the latter period must be based on each patient’s risk profile, the editorialists say.

Even after multiple randomized trials involving more than 30,000 patients on the topic, the best DAPT regimen is not apparent, they conclude. “As more evidence accrues, the answer to this complex question will not be a ‘one-size-fits-all’ approach. We return to our ‘gut’ feeling and the art of medicine to make important decisions regarding this critical issue.”

Note: Dr. Stone and several coauthors of the meta-analyses are faculty members of the Cardiovascular Research Foundation, which owns and operates TCTMD.

Sources:
1. Palmerini T, Benedetto U, Bacchi-Reggiani L, et al. Mortality in patients treated with extended duration dual antiplatelet therapy after drug-eluting stent implantation: a pairwise and Bayesian network meta-analysis of randomised trials. Lancet. 2015;Epub ahead of print.
2. Curzen N. Prolonged antiplatelet therapy after drug-eluting stents [comment]. Lancet. 2015;Epub ahead of print.
3. Pamlerini T, Sangiorgi D, Valgimigli M, et al. Short- versus long-term dual antiplatelet therapy after drug-eluting stent implantation: an individual patient data pairwise and network meta-analysis. J Am Coll Cardiol. 2015;65:1092-1102.
4. Mehran R, Giustino G, Baber U. DAPT duration after DES: what is the “mandatory” duration [editorial]? J Am Coll Cardiol. 2015;65:1103-1106.

Related Stories:

• Long-Term DAPT with Ticagrelor Reduces Ischemic Risk, Ups Bleeding in MI Patients
• Despite New Findings, Optimal DAPT Duration Still Up in the Air
• DAPT Study Shows Benefit of Long-Term Treatment After DES Implantation