Aspirin for cardioprotection and strategies to improve patient adherence.

C L I N I C A L F O C U S : C A R D I O VA S C U L A R E V E N T S , U RO L O G Y F O R T H E P R I M A RY C A R E D O C T O R

Aspirin for Cardioprotection and Strategies to Improve Patient Adherence

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DOI: 10.3810/pgm.2014.01.2721

Danielle Duffy, MD 1 Erik Kelly, BA 2 Amanda Trang, MD 3 David Whellan, MD, MHS 4 Geoffrey Mills, MD, PhD 5 Assistant Professor, Division of Cardiology, Jefferson Medical College; 2 Medical Student, Jefferson Medical College, Thomas Jefferson University; 3 Medical Resident, Division of Internal Medicine, Thomas Jefferson University Hospital; 4James C. Wilson Associate Professor of Medicine, Assistant Dean of Clinical Research, Director, Jefferson Coordinating Center for Clinical Research, Jefferson Medical College; 5Assistant Residency Program Director, Assistant Professor, Department of Family and Community Medicine and Department of Physiology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA 1

Correspondence: Danielle Duffy, MD, Assistant Professor, 925 Chestnut Street, Mezzanine, Philadelphia, PA 19107. Tel: 215-955-3607 Fax: 215-503-5650 E-mail: [email protected]

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Abstract: Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in North America. Aspirin therapy has proven clinical effectiveness in the prevention and treatment of CVD and is one of the most widely used drugs nationwide. However, despite the medication’s popularity and utility, adherence to a proper aspirin regimen is suboptimal, resulting in adverse health outcomes and increased health care costs. Our review outlines current knowledge on aspirin therapy adherence, causes of nonadherence, and strategies available to increase adherence to aspirin and medications in general. We demonstrate that, indeed, aspirin adherence rates are suboptimal, ranging from 72% to 92%, and that a combination of patient- and medication-related factors contribute to nonadherence. A multidimensional approach involving patient education and medication innovations to reduce aspirin side effects is imperative to improving rates of aspirin therapy adherence. Keywords: aspirin; cardiovascular disease (CVD); adherence; gastrointestinal; safety

Introduction

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in North America1 and in developing countries around the world.2 More than 1 in 3 Americans will develop CVD in their lifetime, and the presence of multiple CVD comorbidities is common.1 Preventive care and lifestyle modifications are proven interventions that reduce the incidence of both primary and recurrent CVD events.3,4 Aspirin, originally utilized for its antipyretic and analgesic properties, is predominantly used today as an antithrombotic agent to treat or prevent cardiovascular events. The medication, at a dose ranging from 75 mg to 325 mg, is protective in multiple clinical scenarios for patients at increased risk of cardiac, vascular, and thrombotic events, and current guidelines reflect this understanding (Table 1). The Antithrombotic Trialists’ Collaboration analysis of aspirin compared with placebo in secondary prevention demonstrated a significant reduction in the combined endpoint of nonfatal myocardial infarction (MI), nonfatal stroke and vascular death (6.8% vs 8.2% per year; P , 0.0001), as well as total stroke (2.08% vs 2.54% per year; P = 0.002), and coronary events (4.3% vs 5.3%; P , 0.0001), with an absolute increase in major bleeding on order of magnitude, smaller than these benefits5; however, it is well documented, particularly in the setting of primary prevention, that the benefits of aspirin therapy are offset by potential risks of major bleeding.5,6 The established clinical effectiveness of aspirin makes it one of the most widely used drugs in the United States. Approximately 36% of the US adult population and 83% of patients with CVD take aspirin daily, mostly for primary and secondary cardio vascular prevention.7,8 Despite the proven effectiveness and widespread therapeutic use of aspirin, it is well known that patient adherence to a proper aspirin regimen is low.9

© Postgraduate Medicine, Volume 126, Issue 1, January 2014, ISSN – 0032-5481, e-ISSN – 1941-9260 ResearchSHARE®: www.research-share.com • Permissions: [email protected] • Reprints: [email protected] Warning: No duplication rights exist for this journal. Only JTE Multimedia, LLC holds rights to this publication. Please contact the publisher directly with any queries.

Aspirin Adherence in Cardiovascular Prevention

Table 1. Summary of Guidelines for Aspirin Use in Patients With CVD CVD State Primary Prevention MI/CVD

Stroke Secondary Prevention CAD


Acute STEMI Unstable Angina/Non-STEMI Stroke Atrial Fibrillation PAD, Carotid and Vertebral Artery Disease CABG Surgery PCI Bioprosthetic Valve Implantation Kawasaki Disease

Guideline USPSTF 20096 2011 AHA Guidelines for Women74 ACCF 201275 AHA/ASA 201176 USPSTF 20096 AHA/ACCF 20114 ACCF 201275 ACCF/AHA 20134,77 ACCF 201275 ACCF/AHA 201278 AHA/ASA 201179 ACCF 201280 ACCF/AHA 20134,81 ASA/ACCF/AHA/AANN/AANS/ ACR 20114,82 ACCF/AHA 20134,77 ACCF/AHA 20134,77 ACCF 201275 ACCF 201283 AHA 200484

Abbreviations: AANN, American Association of Neuroscience Nurses; AANS, American Association of Neurological Surgeons; ACCF, American College of Cardiology Foundation; AHA, American Heart Association; ASA, American Society of Anesthesiologists; CABG, coronary artery bypass graft; CAD, coronary artery disease; CVD, cardiovascular disease; MI, myocardial infarction; PAD, peripheral artery disease; PCO, percutaneous coronary intervention; STEMI, ST-elevation myocardial infarction; USPSTF, US Preventive Services Task Force.

Consequences of poor adherence may include increased risk of major cardiovascular events, resulting in substantial morbidity and mortality. A meta-analysis of 50 279 patients at risk for coronary artery disease revealed that aspirin nonadherence or withdrawal was associated with a 3-fold higher risk of major adverse cardiac events (odds ratio [OR] 3.14, 95% CI 1.75–5.61; P = 0.0001).10 Equally troubling, the reasons for poor patient adherence with aspirin therapy and the extent of the problem have not been well characterized. Furthermore, potential solutions to increase patient adherence, and the effectiveness of such strategies, have not been fully elucidated. We performed a literature search of both the PubMed and Cochrane Library databases from January 1990 through November 2013 to assess patient adherence to aspirin therapy, identify specific predictors and causes of nonadherence, and detail strategies available to combat aspirin nonadherence. A secondary aim was to analyze medication adherence solutions in general, in order to provide context to the specific discussion on aspirin therapy. Search terms included: aspirin adherence, aspirin compliance, aspirin side effects, medication adherence.

Medication Adherence

Patients fail to adhere to medical therapy for many reasons, including cost, attitudes towards medication use, perceived benefits versus risks of treatment, and adverse effects of medication. 11,12 Nonadherence is associated with poor patient clinical outcomes, disease progression, and increased health care costs. It is estimated that the cost of US hospital admissions due to poor medical adherence is approximately $100 billion per year.11 Furthermore, reduced adherence is predicted to increase as the population ages.11 With regard to the rate of aspirin nonadherence, figures differ greatly based on factors such as the population studied and the indication for aspirin use. As primary and secondary prevention of CVD is the most common indication for aspirin use today, our discussion of adherence is focused on these indications. The methods used to assess adherence vary as greatly as the rates themselves. Indirect methods, such as pill counts and pharmacy records, are easier to use but often overestimate patient adherence, as they do not guarantee patient ingestion.13 Direct methods, including blood and urine analysis, or direct observation of medication ingestion, may be more accurate but are often difficult to implement and more costly.13 The benefits and shortcomings of each method are important for providers to understand both when interpreting medication adherence literature and when deciding on potential methods to treat patients under their care.

Rates of Adherence to Aspirin

The reported rates of patient aspirin adherence for cardiovascular protection range from 72% to 92% in the current literature9,14–21 (Table 2). Larger studies thus far have focused on adherence to the 4 major classes of medications for secondary prevention of coronary disease: aspirin, β-blockers, angiotensin-converting-enzyme (ACE) inhibitors, and statins. Data from several studies revealed that patient aspirin adherence rates for secondary prevention were comparable with patient adherence rates for other cardiovascular medications.14,22 Interestingly, data from other studies indicated that the rate of patient adherence to aspirin therapy was higher than adherence to other cardiovascular medications,9,15–17 possibly due to aspirin being well known, inexpensive, and easy to dose. The study showing the lowest rate of adherence at 72% was performed in a subset of patients reporting gastrointestinal (GI) side effects from the medication.21 The Global Registry of Acute Coronary Events (GRACE) study reported the highest patient adherence rate at 92%, which was possibly due to a younger average age of patients (mean, 65 years), assessment of patient compliance via telephone, initiation

© Postgraduate Medicine, Volume 126, Issue 1, January 2014, ISSN – 0032-5481, e-ISSN – 1941-9260 19 ResearchSHARE®: www.research-share.com • Permissions: [email protected] • Reprints: [email protected] Warning: No duplication rights exist for this journal. Only JTE Multimedia, LLC holds rights to this publication. Please contact the publisher directly with any queries.

Duffy et al


Table 2. Adherence Rates to Aspirin Therapy Study

Aspirin Indication

Study Summary

Adherence Rate to Aspirin, %

Simpson, 200314

Secondary prevention

74

Eagle, 200415


Sud, 200585


Ho, 200616


Newby, 200617


Wald, 200786


Bi, 200919


Kronish, 201320


Kumbhani, 201318


Moberg, 201121

Primary and secondary prevention

Silagy, 199487

Primary prevention

Waeber, 199988

Primary prevention

N = 14 057; patients aged . 65 years; from Quebec database, who survived hospital admission for acute MI. Evaluated compliance to 4 CV meds (ASA, BB, ACEI, lipid-lowering therapy), defined by having filled a prescription within 1 year N = 13 830; patients aged .18 years in GRACE, after hospital discharge for MI/unstable angina. Evaluation of compliance to 4 CV meds (ASA, BB, ACEI, statin) at 6 months, per patient report N = 208, patients diagnosed with ACS. Evaluated adherence to 4 CV meds (ASA, BB, ACEI, lipid lowering agents) at 10 months post discharge, per patient report via telephone interview N = 2498; patients aged . 18 years with acute MI registered in PREMIER study. Evaluation of compliance to 4 CV meds (ASA, BB, ACEI, statin) at 1 month post discharge, per patient report N = 31 750, with documented CAD in Duke Databank. Evaluated compliance to 4 CV meds (ASA, BB, statin, ACEI), from 1995 to 2002, per patient self-report N = 206, with coronary disease who underwent PCI. Evaluated adherence after 2 years, per patient report N = 2901; Chinese patients diagnosed with ACS. Evaluated adherence to 4 CV meds (ASA, BB, ACEI, statin) at 1 year post discharge, per patient report N = 169; patients diagnosed with both depression and ACS. Evaluated adherence to aspirin recorded by electronic pill cap at 3 months post discharge for ACS N = 37 154, patients with established atherothrombotic disease enrolled in REACH registry. Evaluated adherence to 3 CV meds (antiplatelet, lipid-lowering, antihypertensive agents), per patient report at baseline and at 1 year N = 1007; patients prescribed aspirin for primary or secondary prevention, who also experienced GI side effects. Evaluated adherence to aspirin per patient report to mailed questionnaires N = 400; patients aged . 70 years, enrolled in Australian RCT of low-dose aspirin therapy vs placebo. Assessed compliance by pill count and platelet function tests during 12-month period N = 236; patients with hypertension. Evaluated compliance during 1 year via electronic pill cap

92

87.4

82

83

82 87

78

85

72

87

78.3

Abbreviations: ACEI, angiotensin-converting-enzyme inhibitor; ACS, acute coronary syndrome; ASA, aspirin; BB, β-blocker; CAD, coronary artery disease; CV, cardiovascular; GI, gastrointestinal; GRACE, Global Registry of Acute Coronary Events; MI, myocardial infarction; PCI, percutaneous coronary intervention; RCT, randomized controlled trial; REACH, Reduction of Atherothrombosis for Continued Health.

of medications at time of hospital d ischarge, and a lack of appropriate follow-up.15 Most other large studies reported adherence rates of 82% to 87%.14,16–19 Numerous studies have sought to examine patterns and timing of patient medication adherence. Newby et al17 found that aspirin adherence rates increased annually from 59% in 1995, to 83% in 2002, which is encouraging. However, consistent use of and adherence to cardiovascular medications is poor overall, although in 1study, consistent use of aspirin was higher than any other medication class analyzed.17 Kumbhani et al18 observed that patient adherence rates were similar at 20

different time points, noting that compliance did not differ at baseline and 1 year later. The authors went on to suggest that adherence rates will not improve without active intervention. A study by Ho and colleagues16 showed that the most significant drop in medication adherence occurred between hospital discharge and 1 month post-discharge, while compliance rates at 6 and 12 months remained stable. Studies on aspirin use for secondary prevention are widely available, however, literature examining aspirin adherence for primary prevention is greatly lacking. One study by Moberg et al,21 surprisingly found that patients taking low-dose aspirin for




secondary prevention were less adherent than patients taking it for primary prevention (68% vs 75%). A meta-analysis of 376 162 patients, assessing adherence to aspirin, antihypertensives, and cholesterol-lowering medications found a statistically significant difference in general adherence for primary prevention compared with secondary prevention (50% vs 66%; P = 0.012)22; however, the meta-analysis did not include any studies on aspirin adherence for primary prevention, again demonstrating the absence of literature on this subject. One potential factor that could affect the accuracy of reported patient adherence rates is that in the majority of studies, compliance was assessed by patient report—via interview, mailed survey, or telephone. Self-report measures have poor sensitivity in detecting noncompliance due to patient memory recall issues and the potential for distortion of facts. The method may overestimate adherence compared with electronic measures, but results are moderately correlated.23 Nevertheless, given the clear-cut benefits of aspirin therapy, especially for secondary prevention, there is room to improve current rates of patient adherence.

General Reasons for Medication Nonadherence

To address nonadherence to aspirin therapy, it is important to review nonadherence to medications in general (Table 3). As the studies discussed have shown, rates of patient nonadherence to aspirin are similar to those for other medications and it is likely that reasons for discontinuation can be broadly applied. Many factors affecting adherence concern the patient, such as forgetfulness, lack of knowledge about the disease or medication, or fear of adverse effects. Characteristics that have been associated with poor adherence include older age, lower level of education, ethnicity, unmarried status, and depression.11,15–18

Factors under the control of the physician that can adversely affect compliance include poor therapeutic relationship with the patient, inadequate patient counseling, inability to assess for nonadherence, and lack of follow-up. The health care system can also be a barrier by limiting access to medications with a strict formulary or high drug costs.11 Characteristics of the medication itself can also affect adherence. It has been shown that more frequent dosing leads to worsened compliance. In a study by Claxton et al,24 compliance was 79% with once-daily dosing but decreased to 51% with 4-times-daily dosing (P , 0.001). Side effects are also a common cause of medication discontinuation. In a study by Moberg et al,21 examining patients using aspirin for cardiovascular protection, many patients complained of GI symptoms and stopped their aspirin as a result.

General Strategies to Improve Adherence

Methods to improve medication adherence can be approached in a patient-centric, physician-centric, or medication-centric fashion (Table 4). Patient-focused strategies involve educating the patient regarding the disease process, medication regimen, and the benefits and potential side effects of therapy. It has been shown that patients who believe they are at low risk are less likely to be adherent to their medications.25 The Heart Health Counts program, a patient-education program to facilitate statin adherence, featured mailed educational packets to patient participants, and program results showed improvement in patient prescription refills.26 Informational handouts provided on discharge or at outpatient visits may be beneficial as a physical reference to review. Other possible interventions include patient reminder systems via alarms, text message, mail, or phone calls. A recent trial sent text-message reminders to lower-income patients with poorly controlled diabetes; resulting data showed a significant improvement in

Table 3. Risk Factors for Medication Nonadherence11,23,89 Patient

Provider

Medication

Disease

• Poor mental health

• Inadequate therapeutic relationship with patient • Inability to assess barriers to adherence • Poor quality of instructions regarding medications • Longer time between follow-up

• Complex treatment/multiple medications • Side effects • Frequent dosing • High cost

• Mild severity or disability caused by disease • Asymptomatic

• Forgetfulness • Poor understanding of disease or medication • Lack of support system • Lower socioeconomic status and level of education • Older age


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Table 4. General Strategies to Improve Adherence Patient

Provider

Medication

• Education/counseling • Informational brochures • Reminders • Family support

• Identify poor adherence • Education: medication indications and national guidelines • Physician tracking/incentives • Patient-provider relationship • Multidisciplinary team

• Minimize side effects • Improve dose schedule • Fixed-dose combination pills

patient medication adherence.27 Pillbox use may also serve as a reminder for patients and as a way to organize multiple medications. Recruiting support from the patient’s family, friends, and community is also important. In addition to patient education, physician education must be an ongoing effort. Physicians need to remain aware of current indications for the medications they prescribe. Data from the National Ambulatory Medical Care Survey, 2007–2008, showed that physicians prescribed aspirin at only 46.9% of outpatient visits for patients with ischemic vascular disease, and only at 17.1% of visits for patients at risk for ischemic vascular disease.28 Moreover, the correct dosing of indicated medications is suboptimal. One study of patients followed after hospital discharge for acute MI found that only 1 in 3 patients were discharged on goal doses of cardiac medications, and up-titration during follow-up occurred in approximately 25% of patients.29 Adherence to evidence-based therapies recommended in national guidelines remains suboptimal and there is much improvement needed. Several large-scale initiatives aimed at improving adherence to management guidelines in patients admitted to the hospital with acute MI have been developed, including the Guidelines Applied in Practice (GAP) pilot30 from the American College of Cardiology, and the Get With The Guidelines (GWTG) project31 from the American Heart Association. The programs involve guideline-oriented tools integrated into every step, from initial presentation through hospitalization, discharge planning, and long-term follow-up. The GAP project demonstrated increases in aspirin administration on patient admission (81% vs 87%; P = 0.02), and on discharge (84% vs 92%; P = 0.002).30 Thirty-three GAP hospitals in Michigan found that the intervention resulted in reduced patient mortality at 30 days (10.4% vs 13.6%; P , 0.02) and at 1 year (33.2% vs 38.3%; P , 0.02).32 The ongoing Million Hearts initiative, aimed at preventing 1 million heart attacks and strokes by 2017, also includes a focus on aspirin use for at-risk patients. The initiative also contains physician tracking and incentive programs, such as the CMS Pay for Performance, CMS Premier Hospital Quality Incentive Demonstration, and the Physician Quality 22

Reporting Service, all of which encourage physicians to prescribe indicated medications. Additionally, physicians must learn to identify patient risk factors for medication nonadherence, such as missed appointments, psychological problems, poor insight, or lack of access to care or medication. Recognizing at-risk patients enables the physician to prophylactically address issues or concentrate their efforts accordingly. Physicians should ask their patients about medication-taking behaviors in a nonjudgmental way. A trusting patient-physician relationship is key to improving adherence and providers should be flexible in tailoring medication regimens to patient preferences when possible. Providers should always follow-up with the patient after a medication has been initiated to ensure ongoing compliance and address any issues that may arise, such as side effects. Another important health care-focused strategy is to involve a multidisciplinary team, including the physician, pharmacist, nurse, behavior specialist, social worker, and home health aide. All team members play an important role in medication counseling and adherence. A recent study showed that the presence of a pharmacist on a cardiology unit increased patient use of β-blockers, aspirin, and statins for secondary prevention of coronary disease.33 In the outpatient setting, the Pharmacist Assessment of Adherence, Risk and Treatment in Cardiovascular Disease (PAART CVD) Pilot Project enlisted 12 community pharmacists to counsel 70 patients at high risk for CVD; findings supported positive outcomes, with a 25% proportional risk reduction in overall CVD risk.34 Additionally, nursing staff and physician assistants have been shown to improve adherence to evidence-based practices in the management of patients with heart failure.35 Medication-focused strategies to improve patient adherence involve minimizing side effects and streamlining the dosing regimen. As mentioned, once-daily dosing is associated with the highest rates of adherence.24 Fixed-dose combination pills are a possible solution to this issue by combining several medications into 1 “polypill.” Many antihypertensive and human immunodeficiency virus medications are often




used in combination form. The recent Use of a Multidose Pill in Reducing Cardiovascular Events (UMPIRE) trial37 examined 2004 patients with established CVD or who were at risk for CVD and randomized them to 1 of 2 combination pills (aspirin, statin, ACE inhibitor, and either a β-blocker or thiazide diuretic), or usual care. The investigators found that use of a combination pill resulted in significantly improved medication adherence at 15 months (RR 1.33; P , 0.001), with evidence of larger benefits in patients with lower adherence at baseline (RR 3.35; P , 0.001).36 Additional advantages of a combination pill include patient convenience and cost saving.37 Disadvantages include reduced flexibility in dosing and possible increased risk of side effects.

Reasons for Aspirin Nonadherence

The published data presented in our review show that poor adherence is common among patients taking aspirin for primary and secondary prevention of CVD. In addition to the reasons for nonadherence to medications in general, the often asymptomatic nature of the disease state being treated with aspirin may also be a contributing factor. Multiple studies have identified patient characteristics associated with poor compliance to low-dose aspirin therapy for cardioprotection (Table 5), including depression, female sex, single marital status, and lower level of education.9,16,17,38,39 Other factors, such as cigarette smoking, obesity, and lack of exercise are associated not only with nonadherence to aspirin, but are independently associated with CVD, making these populations particularly susceptible to poor cardiovascular outcomes.17,40 With regard to medication-related factors for nonadherence, aspirin side effects and over-the-counter (OTC) availability of aspirin must be considered. The primary mechanism of action of aspirin, the irreversible inhibition of

cyclooxygenase-1 (COX-1), leads to decreased prostaglandin production, which impairs mucus and bicarbonate synthesis in gastric and duodenal epithelium, increasing susceptibility to luminal irritants.41 The mechanism is responsible for upper GI symptoms associated with aspirin use, including nausea, vomiting, dyspepsia, and bleeding.42 Overall patient bleeding risk on aspirin therapy, regardless of severity or location, is approximately doubled compared with placebo.8 The standard dose, 325 mg/day, is associated with a significantly higher risk of GI bleeding than is 75 mg; however, even the low dose carries twice the risk of GI bleeding compared with no aspirin.43 In the Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial, 17.59% of patients taking aspirin complained of nausea, vomiting, or dyspepsia; 2.66% had GI hemorrhage; and 0.53% experienced intracranial hemorrhage.44 Another analysis found patients taking aspirin to be 1.79 times (95% CI, 1.1–2.9) more likely to experience GI symptoms than those not taking aspirin.45 Risk factors for upper GI events include a history of peptic ulcers or bleeding ulcers,46–50 concomitant use of nonsteroidal anti-inflammatory drugs (NSAIDs) with aspirin,47,49,51–54 and infection with Helicobacter pylori.48,55,56 Older age (especially over 70 years), history of dyspepsia, higher aspirin dose, and the presence of severe comorbidities are other risk factors for increased incidence of patient bleeding.57 Symptoms are well-recognized, use-limiting side effects. Whether it is knowledge of, or experience with these side effects, several studies have shown that in patients who were poorly compliant with aspirin therapy, up to half cited adverse effects as the reason for their noncompliance.58–63 In a multicenter observation study, having . 3 episodes of upper GI symptoms was associated with increased risk of aspirin discontinuation compared with no episodes of upper GI symptoms (HR, 2.60; 95% CI, 1.00–6.80).64 Data from

Table 5. Predictors of Poor Patient Compliance to Aspirin Therapy Predictors of Low-Dose Aspirin Non-Compliance

Predictors of Low-Dose Aspirin Discontinuation

Depression Diabetes mellitus Symptomatic angina pectoris Cigarette smoking Overweight Female sex Failure to exercise regularly High pill burden and polypharmacy Treatment by a non-cardiologist

Female sex History of cigarette smoking Single marital status Lower level of education Less severe neurologic impairment among patients with ischemic stroke or transient ischemic attack

“Discontinuation” was defined as complete cessation of treatment, either by decision of the patient or physician. “Non-compliance” was defined as failure of a patient to fully comply with a low-dose aspirin treatment regimen, for any reason. Reproduced from Herlitz J, Toth PP, Naesdal J. Low-dose aspirin therapy for cardiovascular prevention: quantification and consequences of poor compliance or discontinuation. Am J Cardiovasc Drugs. 2010;10(2):125–141.7 © Postgraduate Medicine, Volume 126, Issue 1, January 2014, ISSN – 0032-5481, e-ISSN – 1941-9260 23 ResearchSHARE®: www.research-share.com • Permissions: [email protected] • Reprints: [email protected] Warning: No duplication rights exist for this journal. Only JTE Multimedia, LLC holds rights to this publication. Please contact the publisher directly with any queries.


Duffy et al

these studies illustrate that aspirin side effects are associated with poor medication adherence. Rates of aspirin adherence may differ depending on whether the medication is obtained by prescription or purchased OTC. In general, OTC medications are widely available and often self-prescribed, suggesting that patients view them as safer than prescription medications. Over-thecounter medicines also provide savings to patients due to lower cost compared with prescription drugs.65 On the other hand, patients often take prescription drug instructions more seriously than OTC instructions and, consequently, may display increased compliance with prescription drugs.65 However, studies have shown that patients often associate more frequent and negative side effects with prescription drugs compared with OTC drugs, which may decrease adherence.65 Unfortunately, there is no evidence in the literature specific to aspirin adherence patterns based on route of acquisition. Furthermore, no studies have investigated whether patient adherence is improved when aspirin is obtained by prescription compared with OTC purchase. Finally, while the medication-related factors are likely the largest contributor to aspirin nonadherence, the often asymptomatic nature of the disease state being treated with aspirin may also play a role. Cardiovascular disease, unlike many other disease states treated with medication, is largely asymptomatic until an acute, life-threatening event is induced, such as MI or stroke. Therefore, without the stimulus of overt and immediate improvement in symptoms or quality of life, many patients may believe they do not need to adhere to an aspirin regimen.66

Strategies for Improving Aspirin Adherence

Understanding the populations at risk for aspirin nonadherence and the potential barriers to proper aspirin use allow for

identification of strategies to combat the problem (Table 6). It is not surprising that increased aspirin adherence improves health outcomes and reduces healthcare costs.67 One study found that consistent use of aspirin resulted in significantly lower adjusted mortality compared with patients not consistently taking aspirin (HR 0.58; 95% CI 0.54–0.62).17 Although many well-described strategies for improving medication adherence in general have been discussed and can be applied to aspirin therapy, there are specific opportunities to intervene on aspirin nonadherence. Identification of risk factors associated with low aspirin adherence (Table 5) allow for the use of targeted strategies for these patients. A study by Quilici et al68 showed that motivational mobile phone messages from care providers to patients improved self-reported aspirin adherence (OR 0.37; 95% CI, 0.15–0.90; P = 0.02). Therefore, use of mobile reminders, particularly with at-risk populations, may be a useful strategy to increase aspirin adherence rates. Studies have shown that it is not simply how interventions are delivered, but also by whom they are delivered that matters in patient compliance to aspirin therapy. In a study of . 10 000 patients followed for 6 months after an MI or unstable angina, those cared for by a cardiologist compared with patients seen by a nonspecialist had higher rates of aspirin adherence (OR 1.45; 95% CI, 1.19–1.75; P , 0.001),15 possibly suggesting that, particularly for patients who see both a primary care physician and a cardiologist, that specialists should be responsible for educating and managing aspirin therapy. Multiple strategies have been implemented with the goal of reducing the use-limiting GI side effects of aspirin. One strategy utilized different formulations of aspirin to attempt to reduce GI irritation. Enteric-coated aspirin contains an outer layer that dissolves in the more alkaline pH of the small intestine, opposed to the high acidity of the stomach.69

Table 6. Potential Interventions and Remedies Specific to Aspirin Therapy Nonadherence Intervention

Efficacy

Study

Care given by cardiologist

Patients cared for by a cardiologist vs a nonspecialist had higher rates of aspirin adherence (OR, 1.45; 95% CI, 1.19–1.75; P , 0.001) Improved self-reported aspirin adherence (OR, 0.37, 95% CI, 0.15–0.90; P = 0.02) Adjusted risk of aspirin discontinuation was 15% less among continuous PPI users than among PPI nonusers (HR, 0.85; 95% CI, 0.78–0.92) Continuous PPI use associated with lower risk of aspirin interruption compared with intermediate PPI use Use of combination pill, consisting of aspirin, statin, ACE inhibitor, and β-blocker or thiazide, in patients with established CVD or at risk for CVD resulted in significantly improved medication adherence at 15 months compared with no combination pill (RR 1.33; P , 0.001)

Eagle, 200415

Mobile phone message reminders PPI use with aspirin therapy

Cardiovascular “polypill”

Quilici, 201368 Merino, 201372 Hedberg, 201373

Thom, 201236

Abbreviations: ACE, angiotensin-converting-enzyme; CI, confidence interval; CVD, cardiovascular disease; HR, hazard risk; OR, odds ratio; PPI, proton pump inhibitor.

24




lternatively, buffered aspirin formulations include an A antacid to neutralize the acidity of the stomach.69 Unfortunately, despite theoretic benefits of these strategies, studies have found that neither formulation actually reduces GI side effects of aspirin in patients.69 Another strategy aimed at addressing the barrier of aspirin side effects is acid-suppression co-therapy to prevent or treat upper GI symptoms and complications. Several studies have demonstrated that addition of a proton pump inhibitor (PPI) to daily aspirin therapy prevents and treats gastroduodenal ulcers and other upper GI side effects associated with aspirin use.46,70,71 Importantly, the prevention and treatment of these side effects improves adherence rates to aspirin therapy. One study reported the adjusted risk of aspirin discontinuation to be 15% less among continuous PPI users than among PPI nonusers (HR 0.85; 95% CI, 0.78–0.92).72 Furthermore, continuous use of a PPI, opposed to intermittent use, has been associated with better protection from aspirin-induced GI ulcers and bleeding.73 Currently, there are no commercially available combination pills, however, concomitant use of a PPI and aspirin has the potential to decrease use-limiting side effects and therefore improve patient adherence. As discussed, creation of a cardiovascular prevention “polypill” that incorporates aspirin has been shown to increase medication adherence.36 Although not commercially available, this strategy has the potential to also increase aspirin adherence by dramatically simplifying the dosing regimen. As our review indicates, there is no simple “one-size-fitsall” strategy to improve patient adherence to aspirin therapy. Future research could focus on method of prescription (ie, written prescription versus recommendation for OTC purchase), formulations designed to improve tolerability, and strategies to harness technologic advances to educate and remind patients and providers of the importance of aspirin therapy for the prevention and treatment of CVD.

Conclusion

Aspirin therapy has established clinical effectiveness in the prevention and treatment of patients with CVD and is one of the most widely used drugs nationwide; however, patient adherence to aspirin therapy is suboptimal, resulting in poor health outcomes and increased health care costs. The reasons behind nonadherence are many and complex; however, the characterization of barriers has resulted in the implementation of strategies that have improved aspirin adherence. The future of improved aspirin adherence likely involves targeted educational strategies for at-risk patients by qualified health

care providers, decreasing use-limiting side effects, and identification of the best means to distribute aspirin to the public. It is only with continued investment in these strategies and investigation into further causes of aspirin nonadherence that substantial improvement can be made in the rates of patient aspirin therapy adherence for primary and secondary prevention of CVD.

Acknowledgments

Pozen, Inc (Chapel Hill, NC) provided funding for coordination and editorial support of a review on the general topic of aspirin adherence. Content and direction were the sole discretion of the authors without review by Pozen employees. Scientific editorial support was provided by Courtney Zeni, PhD (QSci Communications, King of Prussia, PA).

Conflict of Interest Statement

Danielle Duffy, MD, has received honoraria for educational activities from Genzyme. She has received research grants from Amgen, Forest Laboratories, and Roche/Genentech. David Whellan, MD, has been a consultant for Pozen, Novartis, Medtronic, and Viamet. He has received grants funded by Medtronic, McNeil Pharmaceuticals, Forest Laboratories, and the National Heart, Lung, and Blood Institute. Erik Kelly, BA, Amanda Trang, MD, and Geoffrey Mills, MD, disclose no conflicts of interest.

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