Stent Safety: Balancing Risks Associated with DAPT
February is American Heart Month. Follow events and discussions at #HeartMonth.
Medication safety can sometimes be a tightrope walk of balancing various risks against potential benefits. Finding that equilibrium can be particularly challenging in cardiovascular medicine. After placement of a coronary stent, the care team has to perform a careful balancing act between the risk of an ischemic event, bleeding, and stent thrombosis using dual antiplatelet therapy (DAPT). That requires keeping up with changing guidelines and technology in cardiovascular care.
Even when clinicians find the appropriate therapeutic balance, patient adherence or financial constraints can topple the plan.
The American College of Cardiology Foundation and The American Heart Association Task Force on Practice Guidelines (ACCF/AHA) are constantly monitoring new study results, medications, and devices that merit modifications to existing clinical practice guidelines. Guidelines should reflect up-to-date knowledge, technology, current recommendations, and treatment options, so that optimum medical care can be provided.
There is no set time limit for updates. When the committees see one or a few potential changes to one or more sections of the guidelines, they may release a focused update, depending on the critical nature of the information. This acts as an amendment to the original. When there are impactful studies and advancements in care strategies and technology, then the guidelines get completely rewritten. This happens approximately every 3 to 10 years.
After percutaneous coronary intervention (PCI) and placement of a coronary stent, patients are at risk for developing in-stent restenosis due to neointimal hyperplasia or stent thrombosis due to activation of platelets.
Dual antiplatelet therapy (DAPT) must be continued for the recommended duration to reduce the risk of stent thrombosis and other major adverse cardiac events. DAPT consists of:
- Daily low dose aspirin (81 mg) taken while on DAPT and then indefinitely
- P2Y12 inhibitor:
This decrease in risk of ischemic events comes with an increased risk of bleeding, which most commonly presents as minor bleeding up to gastrointestinal bleed. On rare occasion, intracranial hemorrhage can occur.
Due to the tightrope walk of balancing the ischemic risk against the bleeding risk, anything affecting systemic drug concentrations may adversely affect one of those dangerous possibilities. Choosing the appropriate P2Y12 inhibitor can help reduce the safety risks.
- Prasugrel is contraindicated in patients with previous stroke or TIA and is not recommended for use in patients over 75 years of age due to the risk of intracranial hemorrhage.
- Clopidogrel is a prodrug that is activated via CYP2C19 and, to a lesser extent, CYP3A4 and CYP2C9. Genetic polymorphisms in those cytochromes, especially with CYP2C19, can affect the bioavailability, and ultimately, the effectiveness of clopidogrel.
- Drug interactions with other medications (e.g., anticoagulants) in patients who require triple antithrombotic therapy may also increase the risk of bleeding.
The DAPT Score was developed to assist clinicians in making these treatment decisions. It is a calculation that predicts combined ischemic and bleeding risk for individual patients to help the determine most appropriate type and duration of therapy, for example, continued thienopyridine therapy in addition to daily aspirin extending longer than a year after coronary stent treatment. The Score was developed from randomized trial data, which compared patients who were on continued DAPT therapy with those on a placebo. Patients involved in the study had to meet certain health history criteria, including never having sustained a heart attack and a track record of adherence with medications during the first year.
Compared with traditional bare metal stents (BMS), newer drug-eluting stents (DES) decrease the risk of in-stent restenosis and the need for target vessel revascularization. This development revolutionized the treatment of ischemic heart disease. While first-generation DES were successful, safety concerns still existed, and second-generation DES were developed, leading to less inflammatory response and lower rates of adverse cardiac events (e.g., stent thrombosis).
DES slowly release an antiproliferative drug (e.g., sirolimus, which is no longer available in the U.S.; everolimus; zotarolimus) that slows down the vascular endothelialization of the stent itself, leaving the stent exposed within the coronary artery for a longer period of time. This is desirable because it decreases the frequency of in-stent restenosis.
However, this delayed healing requires a longer duration of DAPT to prevent stent thrombosis. The greatest risk for DES thrombosis is early discontinuation of DAPT.
The first-generation DES (sirolumus- and paclitaxel-eluting stents) had higher rates of stent thrombosis as compared with the second-generation stents (zotarolimus- and everolimus-eluting stents), which feature more biocompatible stent platforms (e.g., cobalt-chrome). Second-generation stents have almost completely replaced the use of first-generations stents due to overall better clinical outcomes.
Bare metal stents
The composition of bare metal stents does not include an antiproliferative drug, so they endothelialize more rapidly. This translates to less platelet activation and, therefore, a shorter duration of DAPT is needed. BMS do, however, have a higher incidence of in-stent restenosis compared with DES, which eventually require revascularization. The 2011 Percutaneous Coronary Intervention guideline from the ACCF/AHA and the Society for Cardiovascular Angiography and Interventions (SCAI) recommends that BMS should be used in patients with a high bleeding risk, inability to adhere to 12 full months of DAPT (but can at least adhere to 30 days of DAPT), or who anticipate an invasive or surgical procedure within the next 12 months.
According to the most recent dual antiplatelet therapy guidelines put forth by the ACC/AHA, the recommendation is 12 months of DAPT for patients with an acute or recent acute coronary syndrome (ACS) who receive either stent type. For patients with stable ischemic heart disease, the minimum duration of DAPT is much less: 1 month for BMS and 6 months for DES. When elective surgery is needed, DAPT can be interrupted after 30 days with a BMS. A DES requires a minimum of 3-6 months of DAPT before interrupting therapy, although this depends on the risk of not getting the surgery before the 6-month mark. In any case, aspirin should be continued throughout, if possible, and DAPT should be reinstituted as soon as possible after surgery, assuming that continued therapy is necessary based on guideline recommendations.
The Patient Factor
Another often overlooked factor that affects systemic drug concentrations more than any other issue is how often the patient actually takes the medication. It is imperative that patients understand the importance of taking DAPT medications each and every day for the full duration of the therapy.
Medication cost has a great impact on patient adherence.
Low-dose aspirin is very affordable at a few dollars for a large-count bottle. Currently, the only P2Y12 inhibitor available as a generic is clopidogrel. Both prasugrel and ticagrelor offer discount savings cards for commercially insured patients and patient assistance programs for those who qualify, but otherwise, those drugs can cost several hundred dollars — sometimes up to $500 — for a 30-day supply. Multiply that cost by 12, and it becomes clear how financial concerns can impact a patient's DAPT adherence.
In some cases, patients who are in the hospital can be evaluated by the pharmacist (usually a cardiology specialist) before they receive their drug-eluting stent to determine if acquiring medications or adherence may be an issue. If it is determined that the patient may not be adherent due to various reasons, alternatively, a BMS may be recommended so that the patient does not require such a long duration of DAPT.
What’s Next for Stents?
In October 2015, the FDA approved the SYNERGY stent which is the first bioresorbable polymer DES. After the polymer containing the antiproliferative drug is resorbed, bioresorbable polymer stents leave behind a bare metal stent which is, theoretically, less prone to stent thrombosis compared with a durable polymer DES.
Subsequently, the Absorb GT1 Bioresorbable Vascular Scaffold (BVS) stent was approved in July 2016. This DES fully dissolves over the course of about 3 years. Once the artery is fully healed and functioning properly, the stent is no longer necessary. Since this stent dissolves, it allows the vessel to respond in the normal fashion.
Theoretically, bioresorbable stents have a lower risk of late (occurring >30 days after implantation) or very late stent thrombosis (occurring >1 year after implantation). However, this remains to be seen when compared to the newer second-generation DES.
There are several advantages and disadvantages of these new stent platforms, and the full value of these stents has yet to be determined.
William Alvarez, Jr., PharmD, BCPS, is one of the clinical managers within the Core Pharmacology division of Wolters Kluwer Clinical Drug Information, specializing in cardiovascular medicine and critical care. He is an active contributor and oversees a clinical team responsible for the development of drug information for Wolters Kluwer solutions. Prior to his role at Wolters Kluwer, Dr. Alvarez served close to 10 years at The Johns Hopkins Hospital as its cardiovascular clinical specialist.
David Boyce is a PharmD student at Northeast Ohio Medical University and is expected to graduate in the spring of 2017.
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