Stent thrombosis relationship to discontinuation of antiplatelet therapy


 * Associate Editors-In-Chief: Smita Kohli, M.D.; Varun Kumar, M.B.B.S.; Lakshmi Gopalakrishnan, M.B.B.S.

Incidence Of Premature Discontinuation Of Antiplatelet Therapy
In a prospective study analyzing 1622 patients who received at least one DES, 14.4% discontinued at least 1 antiplatelet drug, predominantly clopidogrel with an incidence of 11.8% for at least five consecutive days during the first year post-implantation.

Predictors Of Premature Discontinuation Of Antiplatelet Therapy in A Broad Population of Patients
According to a prospective study analyzing 1622 patients, the following were identified as the reason for discontinuation of one or both antiplatelet therapy:

Bleeding Events or Invasive Procedures

 * Nearly 50% patients had interventions or minor bleeding that did not require discontinuation.
 * In patients who discontinued due to bleeding events/invasive procedures, predictors included renal impairment, prior major hemorrhage, or peripheral artery disease

Medical Decisions
32% of patients were either undergoing procedures in a private hospital or did not receive information as to who made the medical decision.

Patient decision
18% patients stopped antiplatelet therapy on their own accord or were on psychotropic drugs.

Predictors Identified in the PREMIER Registry Of Acute MI Patients
According to the PREMIER registry of MI patients, predictors of premature thienopyridine discontinuation included:
 * Older age,
 * Lower level of education,
 * Avoidance of healthcare because of cost,
 * Unmarried marital status,
 * Anemia,
 * Preexisting cardiovascular disease,
 * Absence of discharge instructions about the medication, and
 * Lack of referral to a cardiac rehabilitation program.

Complications Associated With Premature Discontinuation Of Antiplatelet Therapy
In patients with DES  , the most important risk factor for late stent thrombosis (> 30 days to 1 year) was premature cessation (less than 6 months) of antiplatelet therapy.

Supportive trial data:
 * In a prospective observational cohort study of 3021 patients followed for 18 months, thienopyridine discontinuation during the first six months was the major determinant of stent thrombosis (hazard ratio 13.7). There is currently insufficient information regarding the benefit of continuing thienopyridine beyond 6 months.


 * From a total cohort of 2974 consecutive patients treated with DES, 38 patients presented with angiographic evidence of stent thrombosis.
 * Acute ST occurred in 5 patients, subacute ST in 25 patients and late ST in 8 patients.
 * Individuals who discontinued clopidogrel were more likely to sustain late stent thrombosis (36.8% versus 10.7% in those without stent thrombosis). The mean duration between cessation of clopidogrel and stent thrombosis was 153 days.


 * Drug-eluting stents significantly reduce restenosis, but require 3 to 6 months of thienopyridine therapy to prevent stent thrombosis. The rate and consequences of prematurely discontinuing thienopyridine therapy were also evaluated in the PREMIER registry of MI patients.
 * Almost 14% MI patients treated with DES discontinued thienopyridine therapy at 30 days.
 * Those who discontinued medication were more likely to die during the next 11 months (7.5% versus 0.7%).

Summary: The above studies suggest that dual antiplatelet therapy with thienopyridine plus aspirin for at least six months, reduces the likelihood of stent thrombosis during the first year after DES placement.

However, there is currently insufficient information available regarding the optimal duration of thienopyridine therapy. thienopyridine therapy.

Complications Associated With The Late Discontinuation Of Antiplatelet Therapy
Stent thrombosis (ST) has been documented in patients who have received dual antiplatelet therapy for 1 year or more and then had their thienopyridine or both their thienopyridine and aspirin discontinued.

Supportive Trial Data

 * In a study of 2,006 patients with DES, late stent thrombosis developed in 8 cases.
 * 3 cases were related to complete cessation of antiplatelet therapy,
 * 2 cases occurred while patients were on aspirin therapy within one month of cessation of clopidogrel, and
 * 3 cases occurred at a time when patients were apparently clinically stable on aspirin monotherapy.

Discontinuation of Aspirin Therapy
There are several studies which indicate that even if aspirin therapy if used alone there is partial protection against late stent thrombosis.


 * In a study of 1,236 patients hospitalized for acute coronary syndrome, 20% of stent thrombosis developed after discontinuation of aspirin with mean delay between aspirin withdrawal and the acute coronary event being 10 +/- 1.9 days. This suggests that aspirin withdrawal in coronary patients may represent a real risk for the occurrence of a new coronary event.


 * In an observational study in Japan, 2 year outcomes were assessed in 10,778 patients undergoing sirolimus-eluting stent implantation. It was concluded that discontinuation of both thienopyridine and aspirin, but not discontinuation of thienopyridine therapy only, was associated with an increased risk of stent thrombosis.

Summary: The above studies suggest aspirin should be continued indefinitely in patients with coronary artery disease.

Optimal Duration of Dual Antiplatelet Therapy
Supportive trial data:
 * A study that combined two randomized trials- REAL-LATE and ZEST-LATE analyzed 2701 patients who had received DES and had been free of major adverse cardiac or cerebrovascular events and major bleeding for a period of at least 12 months to receive clopidogrel plus aspirin or aspirin alone. The primary end point was a composite of MI or death from cardiac causes and the median duration of follow up of 19.2 months.
 * The cumulative risk of the primary outcome at 2 years showed no significant difference between dual antiplatelet therapy and aspirin monotherapy (1.8% versus 1.2% respectively).
 * Between the two groups there were no significant difference in the individual risks of MI, stroke, stent thrombosis, need for repeat revascularization, major bleeding, and death from any cause.
 * The trial also did not study the impact of cilostazol use during the first year after DES placement.


 * The role for prolonged dual antiplatelet therapy (DAT) comes from observational studies and meta-analyses of randomized trials that evaluated the rates of stent thrombosis, MI or death after discontinuation of clopidogrel in patients who received DES or BMS.


 * Some studies benefit associated with continuation of dual antiplatelet therapy (DAT) for longer than 12 months, although the strongest evidence is for the maintenance of therapy during the first six months..


 * An ongoing trial DAPT study is a double blind randomized controlled trial intended to determine the appropriate duration for dual antiplatelet therapy (DAPT) as well as the safety and effectiveness of DAPT to protect patients from stent thrombosis and major adverse cardiovascular and cerebrovascular events following the implantation of DES.

Failure of therapy
Premature discontinuation of dual antiplatelet therapy (DAT)is a risk factor for stent thrombosis (ST), however it is important to note that administration of dual antiplatelet therapy does not prevent the occurrence of ST and many patients are on DAT at the time of the event.

Supportive trial data: An observational study in Japan analyzed 10,778 patients undergoing sirolimus-eluting stent placement.


 * Incidences of definite stent thrombosis were 0.34% at 30 days, 0.54% at 1 year, and 0.77% at 2 years.


 * Patients who discontinued both thienopyridine and aspirin had a significantly higher rate of ST than those who continued both (1.76% vs 0.1% at an interval of 31 to 180 days; 0.72% vs 0.07% at an interval of 181 to 365 days; 2.1% vs 0.14% at an interval of 366 to 548 days).

Summary:

Discontinuation of both thienopyridine and aspirin, but not discontinuation of thienopyridine therapy only, was associated with an increased risk of stent thrombosis.

There was no apparent clinical benefit observed with thienopyridine use beyond 6 months after sirolimus-eluting stent implantation.

Preventing Premature Discontinuation Of Antiplatelet Therapy
Dual antiplatelet therapy which includes thienopyridine and aspirin has become the mainstay treatment strategy for prevention of stent thrombosis. As mentioned above, premature discontinuation of antiplatelet therapy markedly increases the risk of stent thrombosis, which may have catastrophic consequences. The key modifiable contributors to premature discontinuation of antiplatelet therapy are:


 * Inadequate patient education and understanding about importance of compliance of antiplatelet therapy
 * Drug costs
 * Physician/dentists' instructions to patients to discontinue therapy before procedures

Combined recommendations from AHA, ACC, SCAI, ACS, ADA and ACP are as follows:

1. Before implantation of a stent, the physician should discuss the need for dual antiplatelet therapy. In patients not expected to comply with 12 months of thienopyridine therapy, whether for economic or other reasons, strong consideration should be given to avoiding a DES.

2. In patients who are undergoing preparation for percutaneous coronary intervention and are likely to require invasive or surgical procedures within the next 12 months, consideration should be given to implantation of a bare metal stent or performance of balloon angioplasty with provisional stent implantation instead of the routine use of a DES.

3. A greater effort by healthcare professionals must be made before patient discharge to ensure patients are properly and thoroughly educated about the reasons they are prescribed thienopyridines and the significant risks associated with prematurely discontinuing such therapy.

4. Patients should be specifically instructed before hospital discharge to contact their treating cardiologist before stopping any antiplatelet therapy, even if instructed to stop such therapy by another healthcare provider.

5. Healthcare providers who perform invasive or surgical procedures and are concerned about periprocedural and postprocedural bleeding must be made aware of the potentially catastrophic risks of premature discontinuation of thienopyridine therapy. Such professionals who perform these procedures should contact the patient’s cardiologist if issues regarding the patient’s antiplatelet therapy are unclear, to discuss optimal patient management strategy.

6. Elective procedures for which there is significant risk of perioperative or postoperative bleeding should be deferred until patients have completed an appropriate course of thienopyridine therapy (12 months after DES implantation if they are not at high risk of bleeding and a minimum of 1 month for bare-metal stent implantation).

7. For patients treated with DES who are to undergo subsequent procedures that mandate discontinuation of thienopyridine therapy, aspirin should be continued if at all possible and the thienopyridine restarted as soon as possible after the procedure because of concerns about late-stent thrombosis.

8. The healthcare industry, insurers, the US Congress, and the pharmaceutical industry should ensure that issues such as drug cost do not cause patients to prematurely discontinue thienopyridine therapy and to thus incur catastrophic cardiovascular complications.