With mounting evidence that prolonged dual antiplatelet therapy (DAT) offers no advantage, but certainly increases risk, the Goldilocks question is: when is DAT duration "just right?"

Roxana Mehran, MD, professor of medicine and director of interventional cardiovascular research and clinical trials at Mount Sinai School of Medicine, New York, admits "This is a daily question: When can I stop DAT safely after I've put in a stent?" A growing body of data suggests the answer may be much sooner than commonly practiced after percutaneous coronary intervention (PCI.)"

It's been 10 years since FDA approval of the first drug-eluting stents (DES): sirolimus-eluting in 2003 and paclitaxel-eluting in 2004. Original recommendations for patients receiving first-generation DES advised 3 to 6 months of DAT with aspirin and a thienopyridine.

After a warning of late risk in 2004 and alarming evidence in 2006, it appeared that the reduction in restenosis associated with DES was achieved at the cost of late—and potentially fatal—stent thrombosis. Current guidelines support prolonged administration (at least 12 months) of DAT for patients undergoing DES implantation, although earlier discontinuation "is reasonable" if risk from bleeding outweighs anticipated benefit. Yet with evidence suggesting that drug-eluting stent use is associated with a late increased risk of catastrophic stent thrombosis at a rate significantly higher than with bare-metal stents, it was speculated that DES use may require protracted and possibly indefinite clopidogrel therapy.

Eisenstein et al. were among those reporting support for extended therapy.¹ They conducted an observational study in 4,666 patients with follow-up at 6, 12, and 24 months after stenting. In patients treated with bare-metal stents (BMS), continued use of clopidogrel did not influence death or MI rates between 6 and 24 months. Conversely, in DES patients, extended use of clopidogrel at 6, 12, and 24 months was associated with reduced death or death/MI rates at every time intervals.

What about even longer use? At the recent 2014 CRT meeting, investigators from Thomas Jefferson University Hospital reported on "very, very late" stent thrombosis occurring more than 5 years after DES placement. They found seven patients in their center with definite late stent thrombosis from 5.6-7.1 years after DES placement. None of the patients were taking clopidogrel and only two were taking aspirin at the time of their very, very late stent thrombosis. The interval between clopidogrel discontinuation and stent thrombosis ranged from days to months to years. The authors concluded, "There appears to be no definable 'safe' time when antiplatelet therapy may be discontinued without potential stent thrombosis."

OPTIMIZE-ing the Data

Conversely, FAST MI found that use of DAT at 1 year was not a predictor of 5-year mortality and PRODIGY suggests that 24 months of DAT is no better than 6 months. Indeed, in patients with stable coronary artery disease or low-risk acute coronary syndrome (ACS) treated with zotarolimus-eluting stents, the OPTIMIZE study showed that 3 months of DAT was noninferior to 12 months of therapy for a composite of all-cause death, myocardial infarction (MI), stroke, or major bleeding and without significantly increasing the risk of stent thrombosis (TABLE 1).

Fausto Feres, MD, Instituto Dante Pazzanese de Cardiologia, Sao Paulo, Brazil, was first author of OPTIMIZE and said "Our prospective randomized trial showed that second-generation DES might not always require 12-month DAT to reduce the risk of adverse thrombotic events and this outcome may be specially relevant for patients who are at high risk of bleeding complications following PCI such as the elderly and those with a history of hemorrhage in whom we might have to stop DAT early."²

When OPTIMIZE was presented at TCT.13, Gilles Montalescot, MD, PhD, PitiéSalpétrière Hospital, Paris, France—who was not involved in the study—said, "It is difficult to follow the guidelines that say we should give 1 year of dual antiplatelet treatment and only 1 year. [In OPTIMIZE] there was clearly no benefit from the prolongation of dual antiplatelet therapy whereas safety in terms of major and minor bleeding was significantly impacted." William O'Neill, MD. Henry Ford Hospital, Detroit, Michigan, told Dr. Feres, "I'm a very strong proponent of less as far as dual antiplatelets are concerned as I think we often harm people with this approach. So I congratulate you on starting this process—it took a lot of courage as it's very tough to convince people to go against prevailing wisdom."

Other evidence has come from a prospective, observational cohort study of 56,440 patients with new-onset ST-elevation MI (STEMI) or non-ST-elevation MI (NSTEMI) who were prescribed DAT (aspirin plus clopidogrel).³ Participants were all registered in SWEDEHEART, an online cardiac registry covering all hospitals in Sweden. It is unique because it allows long-term follow-up and immediate feedback from online reports.

Patients were divided into groups based on DAT duration and clopidogrel tablets dispensed at any pharmacy within Sweden:

• 3 months; 84-100 tablets (n = 13,671)
• >3 months; >100 tablets (n = 15,009)
• 6 months; 168-200 tablets (n = 6,948)
• >6 months; >200 tablets (n = 6,640)

For the combined primary endpoint, defined as all-cause death, stroke, or re-infarction, only patients with an uneventful first 3-month period (no death, stroke, re-infarction, bleeding, ST, or revascularization) were included. The incidence of the primary endpoint was 16% lower in the >3-months DAT group compared with the 3-month DAT group, while the primary endpoint was 25% lower with >6-months versus 6-month DAT (TABLE 2).

Bleeding was much more common in the >3-months treatment group (adjusted HR = 1.56; 95% CI 1.18-2.07; p = 0.0018), but the absolute number of events was small (316 vs. 180 reported bleeds). Bleeds were mostly gastrointestinal (76.1%) but 12.9% were intracranial bleeds.

While pill counting remains an imperfect way of estimating treatment duration, particularly since patients who filled their prescriptions only once may have been a less compliant group overall, the results in this contemporary, large real-life ACS population support DAT for >3 months.

New Stents: Less Thrombogenic?

One reason shorter-term DAT may be feasible today is evidence that newer-generation stents featuring durable polymers, biodegradable polymers, or abluminal coating might be less thrombogenic than previous such stents. Newer DES designs also typically feature smaller struts or cobalt chromium alloys, plus there are better implantation techniques available today than available when DES were first approved.

In a recent meta-analysis of randomized studies, cobalt-chromium everolimus-eluting stents produced the lowest rate of stent thrombosis within 2 years of implantation.⁴ Indeed, use of these stents was associated with a stent thrombosis rate lower than that seen with BMS. If confirmed in future randomized trials, this would signify a paradigm shift.

A number of studies have now suggested significantly improved safety and efficacy with second-generation stents, including three in just the last 3 months in JACC Cardiovascular Interventions.^5-7 In a registry of more than 18,000 unselected patients undergoing coronary stenting, researchers found a significant excess risk of ST at 3 years for first-generation DES versus BMS placement. On the other hand, second-generation DES were associated with a similar risk of ST versus BMS.

Given the new generation of stents—and knowing that prolonged DAT is associated with a constant risk of bleeding while the risk of ST diminishes over time—Adnan Kastrati, MD, noted at the 2011 ESC meeting (where the PRODIGY results were presented), "Although we are still awaiting the results of larger trials, the PRODIGY trial represents one more victory against the greatest enemy of DES: the wrongly assumed need for endless dual antiplatelet therapy."

At ESC.13, Jurrien M. Ten Berg, MD, said, "After uncomplicated DES stenting, 6 months of dual antiplatelet therapy is probably enough."

DAT Keeps Going and Going and...

Just how long are patients today staying on DAT? The PARIS (patterns of non-adherence to anti-platelet regimens in stented patients) registry is a prospective observational study of patients undergoing PCI with stent implantation in 15 clinical sites in the United States and Europe.⁵ The mean duration of sustained DAT in patients without cessation was 686 days. The FAST-MI 2005 Registry data extend the results of the PARIS study with an identical rate of DAT use at 2 years (47%).

At ESC 2013, François Schiele, MD, PhD, of the Université de Franche Comté (Besançon, France) reported the landmark 5-year analysis from FAST-MI, which included 3,319 patients who were discharged after acute MI. Of these patients, 9% received no antiplatelet therapy, 17% were on single antiplatelet therapy, and 73% on DAT. At 2 years, fully 43% of patients were still on dual therapy and nearly one-third remained on DAT at 3 years (31%) and 4 years (29%). The percentage of patients receiving no antiplatelet therapy was never higher than 14% (at 3 years) and averaged about 8%.

Dr. Schiele noted it was good to see such high use of DAT at 1 year but it was surprising to see the high use at 2 years and "quite unexpected" to see relatively high use at 3 and 4 years.

The predictors of prolonged dual antiplatelet therapy:

• At 1 year, DAT use was lower in the elderly (>75 years of age) and in patients on chronic oral anticoagulation (OAC).
• At 2 years, DAT was more likely to be used in males, diabetics, individuals with previous MI, no OAC, and PCI with DES.
• Use of DAT attenuated over time in the elderly, individuals with a GRACE score >140, and in patients with renal failure.

According to Dr. Montalescot, "The majority of patients get more than 1 year and they often get more than 2 years. So we need to re-inform physicians about the duration of antiplatelet therapy."

(Let's make it clear, the current guidelines state: After PCI, aspirin should be continued indefinitely. The same for UA/NSTEMI: aspirin should be "continued indefinitely in patients who tolerate it." In both cases, that's a Class I Level A recommendation, so little debate there.)

An American in PARIS

It's not just that so many patients continue on DAT well beyond guideline recommendations, but during this time of prolonged therapy the odds of patients or their physicians stopping therapy is high. Usually, DAT cessation is classified using a binary on-or-off approach that ignores the clinical reasons and underlying context in which antiplatelet treatment is discontinued. Such a distinction might be clinically relevant because the effect of DAT cessation on cardiac risk might be attributable to withdrawal of antiplatelet treatment itself and patient-related risks and circumstances that led to DAT discontinuation.

We mentioned PARIS above; in this registry, modes of DAT cessation analyzed were:

• Discontinuation, defined as recommended, physician-directed withdrawal of antiplatelet treatment for patients thought to no longer need DAT.
• Interruption, defined as temporary cessation of antiplatelet treatment due to surgical necessity with reinstitution of DAT within 14 days.
• Disruption, which included cessation of antiplatelet treatment due to bleeding or non-compliance.

DAT cessation was further classified by duration of therapy as either brief (1-5 days), temporary (6-30 days), or permanent (>30 days). All adverse events and episodes of DAT cessation were independently adjudicated.

Over 2 years, the overall incidence of any DAT cessation was 57.3%, with the most common mode of DAT cessation in PARIS being physician-guided discontinuation with an incidence of 40.8%, whereas the corresponding rate of brief interruption was 10.5% and for disruption 14.4%. The corresponding overall 2 year MACE rate was 11.5%, most of which (74%) occurred while patients were taking DAT.

Outcome did vary by manner of discontinuation: disruptions due to bleeding or noncompliance were associated with a substantially increased risk of MACE, although this association largely attenuated after 30 days (TABLE 3). Compared with those remaining on DAT, patients who had temporary DAT interruption lasting up to 14 days did not have an increased rate of thrombotic events, and physician-guided discontinuation was associated with a substantially lower MACE risk.

Dr. Mehran, first author of the PARIS study, said the investigators got as granular as possible in terms of analyzing the specific reason or reasons DAT was stopped. "And we found very interestingly that physicians, when they discontinued DAT, it's totally fine - whether they decide at 3 months, they decide at 6 months or 12 months. So, the art of medicine is working, which is good news."

What's needed, she said, is a prospective large randomized study comparing 3 months versus 12 months of DAT, because, at the moment, a large percentage of patients receive DAT for up to 2 years or longer. Until then, further examination of registries such as PARIS can identify clinical factors that may lead to inappropriate DAT cessation and highlight patients at increased risk for adverse events.

Dr. Mehran told CSWN during an interview at CRT.14, "Obligatory DAT for prolonged periods of time should not be acceptable to us as a therapy for our patients who are in their sixties, because you can't be on dual antiplatelet therapy without interruption for a long period of time." Interruption is going to happen, she said, adding, "The good news from PARIS is that under the guidance of the physician, it works to interrupt if you need to."

Existing Paradigms Challenged

Because three-quarters of the adverse events in PARIS occurred while patients were taking DAT, the overall contribution of DAT cessation on cardiac risk was small, which challenges the existing paradigms for extending antiplatelet treatment in otherwise stable patients after PCI.

What about those many studies that came to different conclusions when evaluating the effect of DAT cessation on subsequent cardiovascular risk? The PARIS team noted that most of those other studies included selected cohorts and were limited by absence of standardized definitions for DAT cessation that did not incorporate the underlying context in which antiplatelet therapy was withdrawn. By contrast, PARIS enrolled a large multinational sample in an all-comer design that is more akin to real-world PCI practice patterns.

How does Dr. Mehran apply the lessons from PARIS in her own practice? "I follow the guidelines," she stressed, "but in certain patients who are at high risk for bleeding, I don't ration the use of DES anymore. In part that's because of the safety data with the second-generation DES as well as the low rate of ischemic events after 3 months." Plus, she added, most of the events are occurring on, rather than off, DAT.

In reporting results of the RESET trial, yet another study suggesting an abbreviated (in this case, 3-month) DAT regimen is noninferior to 12 months of standard therapy, investigators said the implication is that 3 months of DAT could be useful for selected patients:

• those at risk for bleeding complications
• those at risk of poor compliance with medication, especially in the elderly population
• those with a high probability of unexpected non-cardiac surgery or invasive procedures
• those with a low risk of stent thrombosis

A new analysis in JACC adds one group who may benefit from long-term administration of aspirin plus clopidogrel: patients treated for in-stent restenosis.⁹

As Dr. Mehran put it, "What's important is to really look at the patient's risk profile. We have to be doctors after all, and when we do practice medicine we do a really good job, and we showed that in PARIS. So, I look at every patient, look at their ischemic risk, their bleeding risk – and 3 months of DAT is a must, I believe after DES. After that, I evaluate them; if they're having issues with even minor but clinically important bleeding, like nosebleeds or bleeding that's really terrible for them and hurting their daily life, and I feel that the ischemic risk is small, I will stop. And I won't feel bad about it. But if they're doing really well and they're tolerating the dual antiplatelet therapy, I don't think there's anything wrong with continuing it. This is not in the ACS population, where I do believe 12 months is obligatory."

Editor’s Note: Two trials are wrapping up that will shed some light on this question of prolonged DAT. The estimated primary completion date for the trial known as DAPT (yes, it stands for the Dual Antiplatelet Therapy study) is May 2014. The investigators are looking at 12 months of thienopyridine therapy – clopidogrel or prasugrel – in addition to aspirin therapy then, continuing aspirin plus randomization to placebo or continued active therapy for 18 additional months (30 months total). A second trial is called PEGASUS (ticagrelor on a background of aspirin therapy – and with an official trial title that goes on forever) is due to wrap in November 2014. In PEGASUS the follow-up is for at least 12 months and may extend to 44 months.

Laura Mauri, MD, of Brigham and Women’s Hospital and Harvard University, talks with CSWN at ACC.14 most about these trials and what they could mean for DAPT.

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References

1. Eisenstein EL, Anstrom KJ, Kong DF, et al. JAMA 2007;297:159-68.
2. Feres F, Costa RA, Abizaid A, et al. JAMA 2013;310:2510-22.
3. Varenhorst C, Jensevik K, Jernberg T, et al. Eur Heart J 2013; Oct 11. [Epub ahead of print]
4. Palmerini T, Biondi-Zoccai G, Della Riva D, et al. Lancet 2012;379:1393-402.
5. Tada T, Byrne RA, Simunovic I, et al. JACC Cardiovasc Interv 2013;6:1267-74.
6. Sabaté M, Räber L, Heg D, et al. J Am Coll Cardiol Intv 2014;7:55-63.
7. Valgimigli M, Tebaldi M, Borghesi M, et al. J Am Coll Cardiol Intv 2014;7:20-28.
8. Mehran R, Baber U, Steg PG, et al. Lancet 2013;382:1714-22.
9. Campo G, Tebaldi M, Vranckx P, et al. J Am Coll Cardiol 2014;63:506-12.

TABLE 1. OPTIMIZE: Results
	E-ZES + 3 month DAT (n = 1,059)	Standard therapy (12 mos DAT; n = 1,058)	Difference (95% CI)	p Value
Primary endpoint*	4.7%	4.7%	0.0% (-2.5 to 2.5)	0.84 (<0.01 for noninferiority)
Any death, MI, or stent thrombosis	0.8%	1.3%	-0.5% (NA)	0.48
Stent thrombosis, n	2 (0.2%)	3 (0.3%)	-0.1% (-0.5 – 0.3)	0.65
<1 month	2	0
1 - 3 months	0	0
3 - 12 months	0	3

*Composite of death from cardiovascular cause, MI, stent thrombosis, TVR, or bleeding at 1 year.
E-ZES = Endeavor zotarolimus-eluting stent; DAT = dual antiplatelet therapy; TVR = target vessel revascularization.

 

TABLE 2. SWEDEHEART: Combined Primary Endpoint*
Dual Antiplatelet Therapy Duration (months)	Hazard Ratio† (95% CI)	p Value	Events/1000 Person Years
3	0.84 (0.75;0.95)	0.042	65.2
>3			45.3
6	0.75 (0.59;0.95)	0.01550	29.2
<6			20.4

* All-cause death, stroke, or re-infarction
† Adjusted

 

TABLE 3. PARIS: 2-year Incidence of Cardiac Events Categorized by Patient DAT Status Prior to the Clinical Event
	On-DAT	Discontinuation	Interruption	Disruption	Total
MACE	413 (74%)	52 (9%)	26 (5%)	67 (12%)	558
Spontaneous MI	116 (64%)	18 (10%)	7 (4%)	39 (22%)	180
Definite or probable ST	57 (80%)	3 (4%)	1 (1%)	10 (14%)	71
Clinically indicated TLR	274 (77%)	31 (9%)	20 (6%)	31 (9%)	356
Cardiac death	100 (68%)	15 (10%)	7 (5%)	26 (18%)	148

MACE = major adverse cardiovascular event; DAT = dual antiplatelet therapy; ST = stent thrombosis; TLR = target lesion revascularization

Keywords: Incidence, Registries, Thrombosis, Drug-Eluting Stents, Research Personnel, Ticlopidine, Sirolimus, United States, Stents, Percutaneous Coronary Intervention, Paris, ACC Publications, CardioSource WorldNews

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