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Dual antiplatelet therapy (DAPT) is recommended after acute coronary syndrome.
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DAPT for 12 months prevents recurrent ischemia but may increase bleeding risk.
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Continued DAPT beyond 12 months is beneficial when bleeding risk is low.
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P2Y12 inhibitor monotherapy may be considered to reduce bleeding risk.
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Nurse practitioners can help maximize benefits and minimize risks of DAPT.
Abstract
Long-term dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 inhibitor (clopidogrel, prasugrel, or ticagrelor) is recommended after acute coronary syndrome (ACS) to reduce the risk of secondary ischemic events. DAPT is recommended for at least 12 months after ACS, with prolonged DAPT suggested in patients with low bleeding risk. Nurse practitioners have an important role in managing patients after ACS, acting as patient advocates and collaborating with the cardiology provider to ensure adherence to DAPT. This review describes current recommendations for DAPT in patients with ACS and the nurse practitioners role in maximizing benefits of antiplatelet therapy.
American Association of Nurse Practitioners (AANP) members may receive 1.0 continuing education contact hour, including 0 of pharmacology credit, approved by AANP, by reading this article and completing the online posttest and evaluation at aanp.inreachce.com.
Introduction
Dual antiplatelet therapy (DAPT), defined as low-dose aspirin and a P2Y12 inhibitor (clopidogrel, prasugrel, or ticagrelor), is recommended by the American College of Cardiology (ACC)/American Heart Association (AHA) for secondary prevention of ischemic events following an acute coronary syndrome (ACS).
2014 AHA/ACC guideline for the management of patients with non-ST-elevation acute coronary syndromes: a report of the American College of Cardiology/American Heart Association task force on practice guidelines.
2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association task force on practice guidelines.
AHA/ACCF secondary prevention and risk reduction therapy for patients with coronary and other atherosclerotic vascular disease: 2011 update: a guideline from the American Heart Association and American College of Cardiology Foundation.
ACC/AHA guidance strongly recommends continuing DAPT for ≥12 months after ACS (Class I), and suggests continuing DAPT beyond 12 months in patients at low bleeding risk who tolerate DAPT without bleeding complications (Class IIb).
Therefore, US guidelines highlight implementation of secondary prevention strategies, including DAPT, to reduce the risk of subsequent ischemic events after ACS.
2014 AHA/ACC guideline for the management of patients with non-ST-elevation acute coronary syndromes: a report of the American College of Cardiology/American Heart Association task force on practice guidelines.
AHA/ACCF secondary prevention and risk reduction therapy for patients with coronary and other atherosclerotic vascular disease: 2011 update: a guideline from the American Heart Association and American College of Cardiology Foundation.
Nurse practitioners (NPs) have a critical role in the multidisciplinary care of post-ACS patients, including DAPT management. The aim of this review is to support primary care NPs in the outpatient setting, who must determine the length of DAPT as part of a long-term post-ACS care strategy. Current guideline recommendations regarding the choice of P2Y12 inhibitor and duration of DAPT in patients with ACS are reviewed herein.
Pathophysiology of ACS
ACS encompasses 2 clinical presentations: ST-segment elevation myocardial infarction (STEMI) ACS and non–ST-segment elevation (NSTE)-ACS. STEMI is characterized by persistent ST-segment elevation on electrocardiogram and increases in cardiac biomarkers.
2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association task force on practice guidelines.
Myocardial ischemia without persistent ST-segment elevation indicates NSTE-ACS, which includes NSTE myocardial infarction (NSTEMI; cardiac biomarkers elevated) and unstable angina (UA; cardiac biomarkers not elevated).
2014 AHA/ACC guideline for the management of patients with non-ST-elevation acute coronary syndromes: a report of the American College of Cardiology/American Heart Association task force on practice guidelines.
Platelets play a major role in the pathophysiology of ACS. Both STEMI and NSTE-ACS are caused by the formation of a platelet-rich thrombus in a coronary artery, triggered by rupture of an inflamed atherosclerotic plaque. Rupture exposes the thrombogenic plaque contents to circulating platelets, causing platelet activation and aggregation.
Platelet activation stimulates the release of secondary mediators, including thromboxane A2, which binds to the thromboxane receptor, and adenosine diphosphate (ADP), which binds to P2Y1 and P2Y12 receptors.
DAPT comprises 2 antiplatelet agents with different mechanisms of action: aspirin and a P2Y12 inhibitor (clopidogrel, prasugrel, or ticagrelor). Aspirin irreversibly and selectively inhibits the platelet enzymes cyclooxygenase 1 (COX-1; involved in platelet production of thromboxanes) and COX-2 (affects upregulation of prostaglandins with vasodilator and antiaggregation activity).
Low-dose aspirin more selectively inhibits COX-1, disrupting thromboxane A2 production and reducing platelet activation and aggregation, whereas higher doses of aspirin result in COX-2 inhibition as well, leading to a reduction in prostaglandin E and prostacyclin production.
The P2Y12 inhibitors clopidogrel and prasugrel are thienopyridine prodrugs that require enzymatic conversion to their active metabolites, which irreversibly bind to P2Y12 receptors, thereby inhibiting the platelet activation-aggregation cascade triggered by ADP.
Unlike thienopyridines, ticagrelor is a cyclopentyl-triazolopyrimidine with distinct pharmacokinetic and pharmacodynamic properties. Ticagrelor is active upon administration, has a rapid onset of action, and reversibly and noncompetitively binds to the P2Y12 receptor, thereby providing continued inhibition, even of new platelets.
starting in the acute setting. Table 1 summarizes the recommended agents and doses of antiplatelet therapy for maintenance therapy, depending on the type of ACS and the chosen management approach.
2014 AHA/ACC guideline for the management of patients with non-ST-elevation acute coronary syndromes: a report of the American College of Cardiology/American Heart Association task force on practice guidelines.
2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association task force on practice guidelines.
2014 AHA/ACC guideline for the management of patients with non-ST-elevation acute coronary syndromes: a report of the American College of Cardiology/American Heart Association task force on practice guidelines.
2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association task force on practice guidelines.
2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association task force on practice guidelines.
2014 AHA/ACC guideline for the management of patients with non-ST-elevation acute coronary syndromes: a report of the American College of Cardiology/American Heart Association task force on practice guidelines.
Any (Class I) For maintenance therapy, ticagrelor preferred over clopidogrel (Class IIa) and prasugrel preferred over clopidogrel in patients without high risk of bleeding or history of stroke/TIA (Class IIa)
Clopidogrel (Class I)
Ticagrelor or clopidogrel (Class I) Ticagrelor preferred over clopidogrel (Class IIa) including for maintenance therapy
Any (Class I) Ticagrelor preferred over clopidogrel (Class IIa)
An ischemia-guided strategy based on noninvasive assessment and response to initial medical treatments.
including for maintenance therapy Prasugrel preferred over clopidogrel in patients without high risk of bleeding or history of stroke/TIA (Class IIa) including for maintenance therapy
Several studies have evaluated the efficacy of DAPT over the first 12 months after ACS (Supplementary Table 1). In the CURE study, the first seminal study to demonstrate the benefit of DAPT during the 12 months after NSTE-ACS, clopidogrel plus aspirin for 12 months post-ACS reduced the relative risk (RR) of major adverse CV events (MACE; ie, CV death, nonfatal myocardial infarction [MI], or nonfatal stroke) by 20% versus aspirin plus placebo, although the RR of major bleeding was increased.
In the seminal TRITON-TIMI 38 study, patients presenting with ACS (UA, NSTEMI, or STEMI) who were scheduled to undergo percutaneous coronary intervention (PCI) had a 19% RR reduction of MACE at 12 months with prasugrel- versus clopidogrel-based DAPT, primarily due to a reduced risk of nonfatal MI.
Major non–coronary artery bypass graft (CABG)-related bleeding was higher with prasugrel; therefore, it is important to note that prasugrel should only be considered in patients without an increased risk of bleeding complications, for example age <75 and weight >60 kg.
Prasugrel is only indicated for patients with ACS going on to PCI and is contraindicated in patients with a history of transient ischemic attack (TIA) or stroke.
In the PLATO trial, the RR of MACE was reduced by 16% with ticagrelor and aspirin as compared with clopidogrel and aspirin in patients with ACS (UA, NSTEMI, or STEMI), with or without intended revascularization.
This was largely driven by a significant reduction in CV death and MI; however, there was no difference in the risk of stroke between the 2 treatment groups. More than 50% of the overall benefit of ticagrelor occurred between 30 and 360 days.
Specifically, the guidelines recommend ticagrelor over clopidogrel as maintenance therapy in patients with STEMI or NSTE-ACS after PCI and in patients with NSTE-ACS receiving medical management alone (Class IIa), and prasugrel over clopidogrel in patients with STEMI or NSTE-ACS after PCI (Class IIa) who do not have high bleeding risk or history of stroke or TIA (Table 1).
In the real-world setting, ACS patients often have comorbidities (eg, diabetes, chronic kidney disease, or peripheral vascular disease) or a history of previous ACS or complex multivessel disease, which increases the risk of recurrent MACE. In these patients, the benefit of continuing DAPT beyond 12 months often outweighs the bleeding risk.
A decision-analytic model showed that, compared with 12 months of DAPT after PCI, prolonging DAPT to 30 months would only have to prevent 2 MACE or stent thrombosis events per 1,000 patients for the benefit to outweigh the bleeding risk.
Balancing the risks of bleeding and stent thrombosis: a decision analytic model to compare durations of dual antiplatelet therapy after drug-eluting stents.
According to ACC/AHA guidelines, the decision on how long to continue DAPT after ACS should consider the individual patient’s risk-to-benefit profile and preferences.
Several studies provide insight into the risks and benefits of continuing DAPT beyond 12 months (Supplementary Table 1). CHARISMA, an early study of DAPT, analyzed a subgroup of patients with a history of prior MI, ischemic stroke, or symptomatic peripheral artery disease.
The risk of cardiovascular death, MI, or stroke was significantly lower with clopidogrel plus aspirin versus placebo plus aspirin, with no increase in the risk of severe bleeding, over a median of 27.6 months.
Likewise, in the DAPT study, DAPT (aspirin plus either clopidogrel or prasugrel) during months 12 to 30 post-ACS reduced the risk of major adverse CV and cerebrovascular events by 29% versus aspirin alone, primarily in patients with a history of MI, and the overall risk of severe bleeding was not increased.
In the PEGASUS-TIMI 54 study, ticagrelor-based DAPT reduced the risk of CV death, MI, or stroke by 15% versus aspirin plus placebo at 36 months in high-risk patients with a recent history of STEMI/NSTEMI, although bleeding risk was increased. An additional analysis demonstrated that treating 1,000 patients with ticagrelor 60 mg twice daily plus aspirin for 3 years would prevent 18 primary outcome events (CV death, MI, or stroke) and cause 9 major bleeds, with no increase in intracranial hemorrhage or fatal bleeding events.
The net benefit of DAPT use beyond 12 months is not uniform across all patients, and assessing the risk/benefit for an individual patient is not always straightforward. Many patients with ACS have clinical factors that increase both thrombotic risk and bleeding risk, complicating decisions about the choice of P2Y12 inhibitor and duration of DAPT. The bleeding risk on DAPT is directly proportional to the potency and duration of DAPT. In a recent analysis of the PEGASUS trial, spontaneous bleeding requiring hospitalization and the presence of anemia were independent predictors of bleeding; the presence of either was associated with a threefold increased rate of major or minor bleeding with ticagrelor 60 mg and aspirin. There was a reduction in mortality and a favorable net clinical benefit with ticagrelor 60 mg in patients without these bleeding risk factors but no net benefit in those with them.
ACC/AHA guidelines recommend a shorter DAPT duration for patients with low thrombotic risk/high bleeding risk, whereas longer DAPT duration is recommended for patients with high thrombotic risk/low bleeding risk.
Decisions on the optimal duration of DAPT should be based on the individual patient’s risk/benefit, with regular assessment of risk factors for thrombosis and bleeding during clinic visits.
Thrombotic and bleeding risk can be estimated using risk scores, including the Academic Research Consortium (ARC), PRECISE-DAPT, and DAPT scores. The ARC initiative on assessment of bleeding risk has defined major and minor criteria for high bleeding risk based on 20 clinical variables (Table 2).
Defining high bleeding risk in patients undergoing percutaneous coronary intervention: a consensus document from the Academic Research Consortium for High Bleeding Risk.
Patients with at least 1 major or 2 minor criteria are at high risk of bleeding. The PRECISE-DAPT score uses 5 factors (age, creatinine clearance, hemoglobin, white blood cell count, and prior bleeding) to predict out-of-hospital major and minor bleeding events in patients on DAPT.
Derivation and validation of the predicting bleeding complications in patients undergoing stent implantation and subsequent dual antiplatelet therapy (PRECISE-DAPT) score: a pooled analysis of individual-patient datasets from clinical trials.
A PRECISE-DAPT score of 25 defines DAPT duration in patients with ACS undergoing PCI: 12 months of DAPT when the score is <25 and 6 months when the score is ≥25.
Derivation and validation of the predicting bleeding complications in patients undergoing stent implantation and subsequent dual antiplatelet therapy (PRECISE-DAPT) score: a pooled analysis of individual-patient datasets from clinical trials.
The DAPT score was derived from DAPT trial data and can be used in patients with a history of ACS and PCI to determine which patients could benefit from continuing DAPT beyond 12 months based on their bleeding versus thrombotic risk (Figure 1).
Development and validation of a prediction rule for benefit and harm of dual antiplatelet therapy beyond 1 year after percutaneous coronary intervention.
Derivation and validation of the predicting bleeding complications in patients undergoing stent implantation and subsequent dual antiplatelet therapy (PRECISE-DAPT) score: a pooled analysis of individual-patient datasets from clinical trials.
the DAPT score does not require tests for kidney function or hemoglobin. The DAPT score ranges from −2 to 10. Patients with a DAPT score >2 receiving thienopyridine treatment for >12 months had reductions in MI/stent thrombosis compared with those with placebo (2.7% vs 6.0%, P < 0.001, for any prior MI and 2.6% vs 5.2%, P = 0.002, for no prior MI), and comparable bleeding rates. In patients with DAPT scores <2 (irrespective of prior MI), ongoing thienopyridine use was associated with significantly increased bleeding but no differences in ischemia.
Development and validation of a prediction rule for benefit and harm of dual antiplatelet therapy beyond 1 year after percutaneous coronary intervention.
Defining high bleeding risk in patients undergoing percutaneous coronary intervention: a consensus document from the Academic Research Consortium for High Bleeding Risk.
Reprinted with permission from Urban P, Mehran R, Colleran R, et al. Defining high bleeding risk in patients undergoing percutaneous coronary intervention: a consensus document from the Academic Research Consortium for High Bleeding Risk. Circulation 2019;140:240-261.
a Excluding vascular protection doses.
b Active malignancy diagnosis within 12 months and/or ongoing requirement for treatment (including surgery, chemotherapy, or radiotherapy).
c National Institutes of Health Stroke Scale score ≥5.
2017 ESC focused update on dual antiplatelet therapy in coronary artery disease developed in collaboration with EACTS: the task force for dual antiplatelet therapy in coronary artery disease of the European Society of Cardiology (ESC) and of the European Association for Cardio-Thoracic Surgery (EACTS).
Treatment that mitigates bleeding risk without compromising thrombotic risk reduction would maximize the net clinical benefit of antiplatelet therapy after ACS. For some patients, switching from prasugrel or ticagrelor to clopidogrel as the P2Y12 inhibitor component of DAPT may provide sufficient ischemic benefit with lower risk of bleeding beyond 12 months.
The TWILIGHT and TICO studies evaluated whether deescalation to ticagrelor monotherapy after 3 months of ticagrelor and aspirin would reduce bleeding without compromising ischemic benefit compared with continuing ticagrelor-based DAPT in patients after PCI.
Effect of ticagrelor monotherapy vs ticagrelor with aspirin on major bleeding and cardiovascular events in patients with acute coronary syndrome: the TICO randomized clinical trial.
In patients undergoing elective or urgent PCI (TWILIGHT), ticagrelor monotherapy reduced the risk of bleeding by 44% over 12 months versus ticagrelor plus aspirin (P < 0.001), with no increase in the risk of ischemic events
and similar results in prespecified high-risk subgroups (patients with NSTE-ACS, diabetes, and complex coronary anatomy). The TICO study in patients with ACS who had undergone PCI reported a 34% reduction in the risk of a net adverse clinical event (composite of major bleeding and major adverse cardiac or cerebrovascular events) at 12 months with ticagrelor monotherapy versus ticagrelor-based DAPT (P = 0.01).
Effect of ticagrelor monotherapy vs ticagrelor with aspirin on major bleeding and cardiovascular events in patients with acute coronary syndrome: the TICO randomized clinical trial.
Decisions about de-escalating by switching from ticagrelor or prasugrel to clopidogrel or from DAPT to P2Y12 inhibitor monotherapy should be made using a multidisciplinary approach involving the patient’s primary care provider and interventional cardiologist.
Role of NPs
NPs have an important role in helping patients to adjust to the lifestyle changes and medication regimens that comprise their “new normal” after ACS. NPs can liaise between the patient and cardiologist and facilitate risk assessment by obtaining an accurate patient history and up-to-date clinical information, especially about concomitant medications and comorbidities, and ensure completion of relevant tests (Table 3).
Table 3Roles/Activities of Nurse Practitioners in Relation to DAPT and Other Long-Term Preventive Care
Ensure patient records are up to date with respect to comorbidities and concomitant medications, especially those that could affect bleeding risk (eg, PPIs, NSAIDs, corticosteroids)
Order tests for information relevant to DAPT continuation decisions (eg, kidney function, CBC for platelet and hemoglobin levels, liver function as needed)
Assess adherence and identify barrier(s) (eg, affordability)
Regularly ask about bleeding events, including nuisance bleeding—take all bleeding seriously as a potential trigger for nonadherence or sign of other comorbidities (eg, cancer)
Liaise between cardiology and primary care
Provide advice about appropriate discontinuation of DAPT in relation to surgical procedures (major or minor)
Assess patient for signs of depression; this can affect adherence
Engage family members as needed to maintain lifestyle changes and medication adherence
Be a source of reliable health information/education
Reinforce/encourage lifestyle changes
Recommend nonpharmacologic interventions/techniques to support overall needs, including referral for counseling/psychological support, dietary advice, and exercise therapy as needed
NP involvement in patient care can have a positive impact on adherence to DAPT. Adherence is essential because the risk of ischemic events increases when patients stop DAPT because of nonadherence but not when DAPT is deescalated in select patients or discontinued under the direction of a cardiologist.
Patterns and impact of dual antiplatelet cessation on cardiovascular risk after percutaneous coronary intervention in patients with acute coronary syndromes.
NPs can monitor patients’ medication-taking practices, assess the risk of nonadherence, and engage patients and family members in medication-taking routines. Although bleeding is the primary safety concern, dyspnea has also been reported and can lead to nonadherence and should therefore be monitored as well.
Long-term tolerability of ticagrelor for the secondary prevention of major adverse cardiovascular events: a secondary analysis of the PEGASUS-TIMI 54 trial.
If treatment affordability is affecting adherence, the NP can investigate tools to reduce out-of-pocket expenses. Patients who cannot afford the recommended P2Y12 inhibitor should be switched to a less expensive P2Y12 inhibitor in preference to aspirin monotherapy in an effort to maintain adherence to guideline recommendations.
At all patient encounters, NPs should query patients about bleeding. About one-third of patients on DAPT experience “nuisance” bleeding, such as easy bruising or bleeding from mild injury (eg, during shaving or from gums while brushing teeth).
All spontaneous bleeding events during DAPT should be investigated because they may not be related to antiplatelet therapy. A study of post-ACS patients on DAPT showed that 1 in 13 cases of bleeding was related to underlying cancer.
Gastrointestinal prophylaxis is recommended in patients at high risk of gastrointestinal bleeding (ie, those with a history of gastrointestinal bleeding, advanced age, or concomitant use of anticoagulants, nonsteroidal anti-inflammatory drugs, or corticosteroids).
Temporary DAPT interruption is sometimes necessary, such as with noncardiac surgery. Nonurgent or screening procedures should be delayed, if possible, until after the initial 12 months of DAPT. When surgery cannot be deferred, only patients at high thrombotic risk should continue DAPT perioperatively (Supplementary Table 2)
after preoperative risk assessment by a cardiologist. In others, P2Y12 inhibitor therapy should be discontinued 3−7 days before surgery (Figure 2) and resumed 1‒4 days later.
2017 ESC focused update on dual antiplatelet therapy in coronary artery disease developed in collaboration with EACTS: the task force for dual antiplatelet therapy in coronary artery disease of the European Society of Cardiology (ESC) and of the European Association for Cardio-Thoracic Surgery (EACTS).
Figure 2Recommendations for the perioperative management of dual antiplatelet therapy (DAPT) in patients undergoing surgery and considerations for stopping DAPT (thrombotic and hemorrhagic risk).
2017 ESC focused update on dual antiplatelet therapy in coronary artery disease developed in collaboration with EACTS: the task force for dual antiplatelet therapy in coronary artery disease of the European Society of Cardiology (ESC) and of the European Association for Cardio-Thoracic Surgery (EACTS).
DAPT with low-dose aspirin plus P2Y12 inhibitor (clopidogrel, prasugrel, or ticagrelor) is recommended for secondary prevention of thrombotic events after ACS, but the duration of DAPT varies depending on the patient’s bleeding risk. NPs play a vital role in improving clinical outcomes after ACS, maintaining a global perspective of the patient’s care, including DAPT. As well as helping to manage comorbidities and medications, NPs are privy to individual patient challenges, including cost issues and adherence challenges. Therefore, it is crucial that NPs understand treatment strategies after ACS to ensure patients obtain the maximal benefit from DAPT while remaining at the lowest bleeding risk.
2014 AHA/ACC guideline for the management of patients with non-ST-elevation acute coronary syndromes: a report of the American College of Cardiology/American Heart Association task force on practice guidelines.
2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association task force on practice guidelines.
AHA/ACCF secondary prevention and risk reduction therapy for patients with coronary and other atherosclerotic vascular disease: 2011 update: a guideline from the American Heart Association and American College of Cardiology Foundation.
Balancing the risks of bleeding and stent thrombosis: a decision analytic model to compare durations of dual antiplatelet therapy after drug-eluting stents.
Defining high bleeding risk in patients undergoing percutaneous coronary intervention: a consensus document from the Academic Research Consortium for High Bleeding Risk.
Derivation and validation of the predicting bleeding complications in patients undergoing stent implantation and subsequent dual antiplatelet therapy (PRECISE-DAPT) score: a pooled analysis of individual-patient datasets from clinical trials.
Development and validation of a prediction rule for benefit and harm of dual antiplatelet therapy beyond 1 year after percutaneous coronary intervention.
Effect of ticagrelor monotherapy vs ticagrelor with aspirin on major bleeding and cardiovascular events in patients with acute coronary syndrome: the TICO randomized clinical trial.
Patterns and impact of dual antiplatelet cessation on cardiovascular risk after percutaneous coronary intervention in patients with acute coronary syndromes.
Long-term tolerability of ticagrelor for the secondary prevention of major adverse cardiovascular events: a secondary analysis of the PEGASUS-TIMI 54 trial.
2017 ESC focused update on dual antiplatelet therapy in coronary artery disease developed in collaboration with EACTS: the task force for dual antiplatelet therapy in coronary artery disease of the European Society of Cardiology (ESC) and of the European Association for Cardio-Thoracic Surgery (EACTS).
Suzanne O’Keefe, DNP, CRNP, is an adult nurse practitioner at the University of Maryland Upper Chesapeake Health, in Bel Air, Maryland. Dr. O’Keefe can be reached at [email protected]
Shannon K. Idzik, DNP, ANP-BC, FAANP, FAAN, is the associate dean for the Doctor of Nursing Practice Program at the School of Nursing, University of Maryland, in Baltimore, MD.
Article info
Publication history
Published online: August 15, 2022
Footnotes
Medical writing support was provided by Catherine Rees, Alma Orts-Sebastian, PhD, and Sarah Greig, PhD, in Science Communications, Springer Healthcare, in accordance with Good Publication Practice and funded by AstraZeneca. Otherwise, the authors have no conflicts of interest to declare and, in compliance with national ethical guidelines, they have no other relationships with business or industry that would pose a conflict of interest.
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