ANSWER
Used appropriately, medications can alleviate distressing symptoms that compromise physical and psychological well-being, help prevent the onset of many acute and chronic health illnesses, and improve patient health outcomes. Too often, however, medications are not used appropriately. The Institute of Medicine and other prominent organizations have recognized that medication-related problems plague our healthcare system. 1-3 In the United States, in 2001, an estimated 4.3 million ambulatory visits were for adverse drug events. 4 A cohort study of Medicare enrollees estimated the overall rate of adverse drug events at 50.1 per 1,000 person-years. 5 The study rated more than one-third of the adverse drug events as serious, life-threatening, or fatal; more than 40 percent of these more severe adverse drug events were classified as preventable. Another study found that more than 12 percent of hospitalized patients experienced an adverse drug event within three weeks following hospital discharge. 6
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In addition to problems involving adverse drug events, many patients are not prescribed optimal treatment for chronic conditions such as high blood pressure and hyperlipidemia, increasing their risk of cardiovascular disease and its complications. Moreover, even when optimal therapy is prescribed, a patient’s inability to adhere closely to medication regimens may lead to poor health outcomes. 7

Medication-related problems are especially pronounced among older adults.

5 Individuals 65 years or older constitute 13 percent of the U.S. population, but they consume more than 30 percent of all prescription medications. 5, 8 A 2006 report found that nearly 60 percent of people in this age group were taking five or more drugs, and almost 20 percent were taking ten or more medications, placing nine at increased risk for experiencing adverse drug events. Moreover, these figures reflect a substantial increase in the prevalence of polypharmacy since 1998. 9

Medication therapy management (MTM) services address polypharmacy, preventable adverse drug events, medication adherence, and medication misuse.

10 MTM services are designed to be distinct from medication-dispensing services; in particular, they employ a patient-centric and comprehensive approach rather than an individual product or episodic perspective. 11

MTM is the current term that represents a suite of healthcare services that have evolved out of the philosophy and processes described in the early 1990s as “pharmaceutical care.”

10 Similar to medical care or nursing care, pharmaceutical care is a term that describes professional pharmacy practice, not a discrete intervention. The Medicare Prescription Drug, Improvement, and Modernization Act of 2003 (Public Law 108-173)12 expanded patient access to MTM services and identified the following as goals for MTM services within Medicare Part D: (1) educate and counsel to improve patient understanding of their medications, (2) improve adherence, and (3) detect adverse drug reactions and improper medication use. This law also established the requirements that Medicare Part D Prescription Drug Benefit Plan sponsors have to meet concerning cost, quality, and the requirements for MTM programs sponsored by Part D drug benefit plans. The law established oversight for Part D MTM programs by the Centers for Medicare & Medicaid Services (CMS) and provided a general framework for MTM programs but allowed Part D Plan sponsors flexibility in design, including the patient eligibility criteria for services. The CMS requirements for Part D MTM programs have evolved since their implementation in 2006.

Within a year of the passage of Medicare Part D, 11 national pharmacy organizations established a consensus definition of MTM.

13 “MTM is a distinct service or group of services that optimize therapeutic outcomes for individual patients.” 13, p. 572. This definition further describes MTM as “a broad range of professional activities and responsibilities within the licensed pharmacist’s, or other qualified healthcare provider’s scope of practice.” 13, p. 72. Table 1 lists the types of services that can be considered under the umbrella of the MTM definition.

Table 1. MTM services.
Table 1 \sMTM services.

The pharmacy profession has developed or supported additional efforts to standardize and establish the infrastructure for MTM service delivery. In 2008, a subset of national pharmacy organizations published the second version of core elements for an MTM service model. This model established five core elements for use in practice:
A medication therapy review
A personal medication record
A medication-related action plan
Intervention and referral
Documentation and follow-up
10,15 Also, in 2008, Current Procedural Terminology (CPT®) codes were established to provide a mechanism for reimbursement for services related to medication management. These CPT codes define MTM as “services provided by a pharmacist to optimize the response to medications for the management of treatment-related medication problems or complications.” More recently, the Patient-centered Primary Care Collaborative established its definition of comprehensive medication management to describe MTM in the context of a patient-centered medical home, which includes elements of the CPT definition. 16,17 The evolution from isolated research interventions studying the impact of pharmaceutical care interventions to large-scale, commercial MTM programs or collaborative medication management within primary care represents a journey along a continuum of practice settings, patient populations, and intervention components and features. Over time, the practice and standards for these services have evolved, as have standards for describing and conducting research studies involving these interventions. Thus, establishing the scope of this review was very challenging. A broadly defined range (all clinical pharmacist interventions regardless of setting or patient population) of risks, including studies that may be too different from each other to allow for meaningful comparison and synthesis. A narrowly defined scope (e.g., a focus exclusively on Medicare Part D-defined MTM programs) risks the omission of studies that met the definition of MTM, but that predated the Part D era, were conducted in other countries or used patient eligibility criteria that are less restrictive than Part D. In the next section, we describe background related to population, intervention, comparison, outcomes, timing, and setting (“PICOTS”) that we relied on to establish the scope of this review. Throughout this review, we will use the term MTM to describe the general intervention class. However, when describing individual studies included in this review, we will defer to the terms used by the study author to describe the intervention they were evaluating (e.g., pharmaceutical care, clinical pharmacy services, or MTM) (e.g., pharmaceutical care, clinical pharmacy services, or MTM).

Populations
Adult patients with multiple chronic conditions take many different prescriptions or nonprescription medications, herbal products, or diet supplements (and combinations of these) are the target population for most outpatient-based MTM services.
11 Because older adults are more likely to take multiple medications, MTM services generally target them. However, MTM interventions may also target patients taking a single high-risk medicine (e.g., Coumadin) or may target patients at high risk for an adverse drug event, for example, during a transition in care from a hospital to a home setting. Although some children with complex medication regimens may benefit from MTM, these programs are typically designed and delivered to adults.

As part of Medicare Part D implementation, CMS required that MTM programs target Medicare Part D enrollees, who have multiple chronic diseases, are taking multiple Part D drugs, and are likely to incur annual costs for covered Part D drugs that exceed a predetermined level (“annual cost threshold”). To be eligible for CMS reimbursement, MTM programs originally had to offer services for at least four of seven core chronic diseases: hypertension, chronic heart failure, diabetes, dyslipidemia, respiratory disease (e.g., asthma, chronic obstructive pulmonary disease), bone disease (e.g., osteoporosis, osteoarthritis, rheumatoid arthritis), and mental health diseases. As of January 2013, this criterion specifies that at least five of nine chronic core conditions—Alzheimer’s and end-stage renal disease were the added conditions. Programs may require no more than eight Part D drugs, although they may set the maximum between two and eight. CMS established the annual cost threshold at $4,000 in 2006, lowered it to $3,000 in 2010, and increased it by a yearly percentage beginning in 2012. The cost threshold for 2013 is $3,144. CMS reimburses MTM services for both community-dwelling beneficiaries and beneficiaries in long-term care settings. Although initial Part D MTM programs were designed as “opt-in,” more recently, MTM programs must enroll eligible beneficiaries using an “opt-out” approach.

Healthcare systems, pharmacy benefit management organizations, large self-insured employers, community pharmacies, or individual medical practices may also provide MTM services to beneficiaries who do not have Medicare Part D or do not meet the CMS Part D criteria. For example, the Veterans Health Administration (VHA) includes MTM as one of several clinical activities provided to VHA health beneficiaries by VHA pharmacy services. 18 The VHA does not specify patient eligibility criteria for MTM services. Non-Part D MTM programs and research studies of MTM interventions may define their patient eligibility criteria, which may or may not be similar to current CMS criteria, for example, requiring only one chronic condition to be eligible for services.

Interventions and Comparators
As discussed, several pharmacy organizations have proposed core elements for an MTM service model.
10,11 These features can be summarized as follows:

A comprehensive medication review (CMR) to identify and resolve medication-related problems.
The generation of a personal medication report is a written list of the patient’s prescription and nonprescription drugs, herbal products, and dietary supplements.
A patient-directed medication action developed in collaboration with the patient.
Education, counseling, and resources to enhance patients’ understanding of using the medication and to improve adherence.
Coordination of care, including documenting MTM services, providing that documentation to the patient’s other providers, and referring patients to other providers as needed.
CMS requires each beneficiary enrolled in a Part D MTM program to be offered a minimum level of MTM services. These include:

Interventions for both beneficiaries and prescribers;
An annual CMR with written summaries in CMS’s standardized format:
The beneficiary’s CMR must include an interactive, person-to-person, or telehealth consultation performed by a pharmacist or other qualified provider (e.g., a nurse or a physician) and may result in a recommended medication action plan.
If a beneficiary is offered the annual CMR and cannot accept the offer to participate, the pharmacist or other qualified provider may perform the CMR with the beneficiary’s prescriber, caregiver, or another authorized individual; and \sQuarterly targeted medication reviews with follow-up interventions when necessary.
CMS expects the CMR to meet the following professional service definition: “a systematic process of collecting patient-specific information, assessing medication therapies to identify medication-related problems, and developing a prioritized list of medication-related problems, and creating a plan to resolve them with the patient, caregiver, and/or prescriber.”
19, p. 6. In addition, CMS expects the CMR to be “an interactive person-to-person or telehealth medication review and consultation conducted in real time between the patient and/or other authorized individual, such as [a] prescriber or caregiver, and the pharmacist or other qualified provider. It is designed to improve patients’ knowledge of their prescriptions, over-the-counter medications, herbal therapies, and dietary supplements; identify and address problems or concerns, and empower patients to self-manage their medications and their health conditions.” 19, p.6 Written summaries of the CMR are to be provided in CMS’s standardized written format, including a beneficiary cover letter, medication action plan, and personal medication list.19

The service-level expectations of a CMR align closely with the definition of MTMs contained in the official health-reporting nomenclature of CPT.

®20,21 The CPT MTM codes define three components that may vary in complexity or time required to complete. These components are (1) assessment of drug-related needs, (2) identification of drug therapy problems, and (3) complexity of care planning and follow-up evaluation. Recently, transitional management CPT codes have been established for use within the first 29 days of patient discharge from an acute care facility. These codes also include elements of medication management, specifically medication reconciliation. MTM CPT codes cannot be used by the same professional in the same time frame as transitional care management codes, suggesting that the medication management activities during transitions of care are a distinct category of MTM services. 22

Disease management, case-management, and self-management interventions overlap with MTM components—for example, the provision of education and counseling to increase medication adherence or coordination of care. Our preliminary literature search yielded many pharmacist-led interventions that were termed as one of these three types of interventions (e.g., a pharmacist-led diabetes disease management intervention) (e.g., pharmacist-led diabetes disease management intervention). We relied on the descriptions in the Robert Wood Johnson Foundation Research Synthesis Report “Care management of patients with complex health care needs” for guidance to make distinctions between MTM and care management, case management, and disease management interventions. 23 We determined that our inclusion and exclusion criteria related to the intervention needed to define specific MTM intervention components, such that we would identify relevant studies whether they were called “MTM” or not. We also considered the topic nominator’s original request: to view different models for assisting patients in managing their medications for chronic disease among patients with multiple conditions. Thus, we synthesized our findings from the preliminary literature search; our exploration of case management, care management, and disease management definitions; and the topic nominator’s original request to determine that our intervention criteria needed to define multiple intervention components related to medication management narrowly, but that these components needed to be applied broadly to patients across their entire medication regimen. As a result, MTM services such as pharmacist-led single-disease management programs or anticoagulation clinics would not be considered for inclusion in our review. By bounding the judgment this way, we end up with a more homogenous set of studies to synthesize.

Outcomes \sMTM is thought to influence a wide variety of outcomes. Two of the most common outcomes measured in MTM studies are drug therapy problems identified and drug therapy problems resolved. Taxonomies to describe drug therapy problems exist, but our preliminary literature search revealed many different approaches to measuring and reporting these outcomes. Other MTM outcomes relate to intermediate health outcomes measured typically by laboratory or other biometric tests for common chronic conditions; these may include hemoglobin A1c, blood pressure, cholesterol (e.g., total, low-density lipoprotein, and high-density lipoprotein cholesterol), and cardiac or pulmonary function (e.g., left ventricular ejection fraction, spirometry) (e.g., left ventricular ejection fraction, spirometry). Finally, still, other MTM services relate to patient-centered outcomes (e.g., morbidity, mortality, adverse drug events, missed days of work or school, patient satisfaction with care, health-related quality of life) (e.g., morbidity, mortality, adverse drug events, missed days of work or school, patient satisfaction with care, health-related quality of life). 24 The impact of MTM on health care utilization, intermediate health outcomes, and patient-centered outcomes may derive from identifying and resolving drug therapy problems, including improved medication adherence, fewer drug-related adverse events, and more efficient coordination of care.

Settings \sMTM services can be delivered in a variety of settings. These include inpatient facilities, ambulatory care settings (e.g., outpatient clinics, physician practices), retail pharmacies in the community, and long-term care settings such as assisted living or skilled nursing facilities. In addition, telephone-based MTM services may be provided to community-dwelling adults by professional staff (often pharmacists) employed by pharmacy benefits management companies or other commercial healthcare companies with centralized call centers. The setting in which MTM is delivered depends on the type of provider providing the service and the goals and scope of the MTM program. Because MTM refers to a wide variety of services, a review of such interventions needs to be bounded to ensure that the interventions synthesized in the review are reasonably comparable. For example, studies focused on MTM services provided during and shortly after an acute hospital stay may not be similar to MTM services provided to outpatients because the goals of therapy and the understanding of the patient’s status are very different. Based on our preliminary literature search, we found that most inpatient studies focused either on single-medication reconciliation interventions during or at discharge or on integrated clinical pharmacy management in acute settings. We also considered the topic nominator’s proposed research questions, which focused on MTM provided to outpatients.

Timing
Because MTM is used to define a broad range of services. MTM services can be provided as one-time interventions or longitudinally during multiple episodes of care, depending on the specific type of MTM service and care setting. For example, medication reconciliation or immunization is a type of MTM service that is typically done during a single episode of care. The pharmacy profession’s consensus definition for MTM includes monitoring and evaluating a patient’s response to therapy, and the MTM Core Service Model has followup as a component. Similarly, CPT codes for MTM services include an element involving care planning and follow-up complexity. Requirements for Medicare Part D MTM programs include a follow-up component at least quarterly following an initial comprehensive medication review. Thus, we determined that we needed to establish inclusion criteria to distinguish interventions designed to support longitudinal medication management as opposed to studies of one-time interventions.

Contextual Factors
Our preliminary literature search identified pharmacists as the typical interventionist for MTM services. CMS guidelines require that MTM be delivered by a pharmacist or other qualified healthcare provider. Professional pharmacy organizations have been actively involved in proposing delivery models, standards, and recommendations for MTM services. Pharmacist training varies considerably. Before the 1990s, individuals could become registered pharmacists with a bachelor of science (B.S.) degree that required a minimum of 5 years of study. Current regulations require that individuals have a doctor of pharmacy (Pharm.D.) degree, which requires a minimum of 6 years of research and provides more clinical training than B.S. programs. In addition, many Pharm.D. graduates pursue advanced training through residency, fellowship, and certificate programs. Some of these programs focus on areas such as MTM. The influence that interventionist type (e.g., physician, nurse pharmacist), education, and MTM-specific training have on MTM effectiveness is unknown.

Numerous factors other than clinical specialty may affect the quality of MTM services. Mode, frequency, and interval of delivery may influence MTM success, as may specific MTM components and the fidelity of their implementation. One key factor is how well an MTM provider understands the patient-specific goals of medication therapy. Integrating MTM services with usual care may help ensure that the goals of MTM are achieved. Integration of services and regular maintenance refers to the ability of the MTM provider to bidirectionally communicate with patients and multiple prescribers and the ease of MTM interventionist access to patients’ medical records.

Healthcare reimbursement systems may also influence the delivery of MTM services. Not all private insurers cover MTM services. The degree to which MTM component services differ for Medicare beneficiaries compared to non-Medicare beneficiaries is unknown.

Finally, specific patient populations may have difficulty accessing or participating in MTM services. Examples include:
Individuals who are homebound.
Individuals who have physical or cognitive disabilities.
Patients without health insurance.
Patients living in rural areas.

Go to: \sScope and Key Questions
Scope of the Review
MTM is a complex intervention, which could have different components depending on the goals and scope of the MTM program. This review seeks to catalog outpatient-based MTM interventions, assess the overall effectiveness of outpatient-based MTM in comparison with usual care, examine the factors under which outpatient-based MTM is effective and optimally delivered, consider what types of patients are likely to benefit from outpatient-based MTM services, and assess what types of patients may be at risk of harms from such programs. This review does not address the following:
MTM services are provided within inpatient settings or shortly after hospital discharge
Disease management services provided by pharmacists
Interventions designed as a single episode of contact
The rationale for limiting the scope to exclude some types of MTM interventions is to ensure that included studies are reasonably comparable concerning the intended goals and purpose of the MTM intervention.

Relevance of Research Question to Clinical Decisionmaking or Policymaking
The Key Questions (KQs) we address are highly relevant to clinical decision-making and MTM services policies. Identifying demonstrably effective models and components of MTM services will help patients and their healthcare providers achieve important intermediate and long-term health-related outcomes. Our findings will help providers of MTM services, particularly pharmacists and pharmacy benefit managers, understand what works well in which settings and with which patients; the results will potentially improve the efficiency of delivery and thus improve the value of MTM services. Lastly, a better understanding of the comparative effectiveness of MTM services will assist CMS with future revisions or enhancements to the policies governing coverage for MTM services.
QUESTION
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