 To investigate how state-authorized pharmacist immunization privileges influence pharmacist intervention effectiveness in delivering pneumococcal and herpes zoster vaccinations and assess the implications these privileges have on vaccination rates.

 Cross-sectional study of Walgreens vaccination records from August 2011 to March 2012.

A random sample of patients having a claim for influenza vaccination in the study period was selected. Vaccination uptake rates for pneumococcal disease and herpes zoster were calculated for previously unvaccinated patients at high risk for these conditions. Rates were examined by state-level pharmacist privileges.

For states authorizing immunization by protocol or prescriptive authority, the 1-year pneumococcal vaccination uptake rate for previously unvaccinated, high-risk persons was 6.6%, compared with 2.5% for states requiring a prescription (

<.0001), and 2.8% for states with no authorization (

<.0001). For herpes zoster, the 1-year vaccination uptake rate was 3.3% for states authorizing per protocol/prescriptive authority, compared with 2.8% (not significant, 

 <.05) for states authorizing by prescription, and 1.0% for states with no authorization (

 <.0001). A 148% increase of pneumococcal vaccination and a 77% increase of herpes zoster vaccination would result if all states granted pharmacists full immunization privileges.

This analysis demonstrates that states that offer pharmacists full immunization privileges have higher vaccination uptake rates than states with restricted or no authorization. Considering the suboptimal vaccination rates of pneumonia and shingles and the public health goals of 2020, states with limited or no immunization authorization for pharmacists should consider expanding pharmacist privileges for these vaccinations.

Community pharmacies can help increase immunization rates in the United States for vaccine-preventable diseases. Specifically, this study demonstrates that:

		Pharmacists can identify people with key risk factors (eg, diabetes, heart disease) for vaccine-preventable diseases, encourage them to receive their Centers for Disease Control and Prevention—recommended vaccinations, and administer the required vaccinations;

		States allowing pharmacists full immunization privileges have significantly higher vaccination uptake rates for pneumococcal disease and herpes zoster than states with restricted or no authorization;

		States with limited or no immunization authorization should be encouraged to expand pharmacist privileges for immunizations.

Community pharmacies are uniquely positioned to increase immunization rates in the United States for vaccine-preventable diseases. A recent survey of public health leaders identified pharmacists as playing a pivotal role in vaccine administration and pandemic planning.

 Evidence in published medical literature suggests that pharmacies have the capacity to influence  previously difficult-to-reach populations.

 Pharmacists may be especially effective in immunizing high-risk, older adults who are more likely to utilize pharmacy services for prescription medication than the general population.

 Pharmacists are also able to leverage their ability to identify people with key risk factors (eg, diabetes, heart disease), encourage them to receive their Centers for Disease Control and Prevention (CDC)-recommended vaccinations, and administer the required vaccine.

A major challenge to pharmacist-provided immunizations is variability in state legislation on the practice. Authority for  pharmacists to administer vaccinations and the scope of that practice is defined by the Board of Pharmacy in each state, including the process by which pharmacists administer vaccines, the type of vaccines permitted, and legal patient age for vaccination. Although the scope of  practice is defined by the board of pharmacy, the actions of each board are subject to legislative regulatory oversight. Consequently, the legislative process produces variability in state statutes governing pharmacy privileges, which has resulted in “considerable differences in how pharmacist-provided immunizations are delivered at the state level.”

The objectives of this study are to (1) investigate how state-authorized pharmacist immunization privileges influence pharmacist intervention effectiveness in delivering pneumococcal and herpes zoster vaccinations and (2) assess the implications these state-authorized pharmacist immunization privileges have on vaccination rates.

This cross-sectional study analyzed vaccination records from the Walgreens pharmacy chain between August 1, 2011, and March 1, 2012. Vaccination records for influenza, pneumococcal disease, and herpes zoster offered by Walgreens during the study period were identified from pharmacy claims and information extracted from the pharmacy computer system for the purposes of the study. Type of vaccination was determined from the US Food and Drug Administration National Drug Code (NDC11).

Risk factors for pneumococcal infection were determined from the Advisory Committee on Immunization Practices (ACIP) of the CDC (

 Risk factors for herpes zoster infection were defined as patients aged 60 years or greater, as identified by the ACIP.

A random sample of 53,000 patients was selected from all patients having a pharmacy claim for influenza vaccination during the study period. For these patients, their Vaccination Administration Record (VAR), a mandatory form which is completed by the patient and the pharmacist upon administration of all vaccinations, was analyzed. The Walgreens VAR form serves as a screening tool to identify relevant high-risk factors for vaccine-preventable diseases, which the pharmacist can then recommend to the patient; it also serves as a patient consent form and administrative record for vaccination. In this study, the VAR was utilized to gather a more complete vaccination history of the patient and to identify relevant high-risk factors. High-risk status for pneumococcal disease, as outlined by the previously mentioned ACIP recommendations, was determined from completed VAR forms. High-risk status for herpes zoster was determined from patient’s age from pharmacy claims. Patients who indicated they previously received a vaccination for pneumococcal disease or herpes zoster were excluded from the  analysis. State-level pharmacist privileges for the administration of pneumococcal and herpes zoster vaccinations were identified from American Pharmacists Association (APhA)

State privileges were classified into 3 levels for pneumococcal and herpes zoster vaccinations: (1) pharmacist authorized to administer vaccinations under a protocol or prescriptive authority; (2) pharmacist authorized to administer vaccinations only with a patient-specific prescription; and (3) pharmacist not authorized to administer vaccinations; however, within this classification, vaccine may be dispensed by pharmacists and administered by onsite nurses. Pharmacy claims for the state of North Dakota, which does not have a Walgreens pharmacy, were excluded from the analysis. We defined vaccination uptake rate as the proportion of previously unvaccinated, high-risk patients who subsequently received vaccination after pharmacist intervention. Rates were determined for pneumococcal disease and herpes zoster, stratified by each of the 3 state privilege categories. There were no known changes in state privileges during the study period. Patients who received a pneumococcal or herpes zoster vaccination in a state with a different pharmacist privilege level than their influenza vaccination were excluded from the analysis. The percentage of patients excluded was 0.02%. All data analysis was performed with SAS 9.2 software (SAS Institute Inc, Cary, North Carolina). Statistical significance was assessed at the α = 0.05 level. This study was approved by Quorum IRB #26510.

Of the 53,000 randomly selected patients who had claims for an influenza vaccination, 46,257 (87.3%) had a complete and legible VAR form and pharmacy records (

). The average age of the sample was 58.5 years and the sample was 42.8% male. Of the total patient population, 30.3% had 1 or more chronic conditions as indicated by their VAR form; these chronic conditions included anemia, asthma, diabetes, heart disease, kidney disease, liver disease, and lung disease. For pneumococcal disease, 30,966 (66.9%) of the patients were found to be at high risk: 22,631 (73.1%) were 65 years or older and 8335 (26.9%) were younger than 65 years and had a high-risk condition for pneumococcal disease. For herpes zoster, 27,190 (58.8%) were high-risk patients.

An assessment of pharmacist immunization authority determined that 41 states allowed pharmacists full authorization to immunize for pneumococcal disease under a protocol or prescriptive authority during the study period of August 2011 through March 2012; 36 states allowed pharmacists full authorization to immunize for herpes zoster under a protocol or prescriptive authority. For pneumococcal disease, 8 states authorized pharmacists to immunize with a patient-specific prescription and 11 states authorized for herpes zoster. Two states did not authorize any immunization privilege for pneumococcal disease and 4 states did not authorize for herpes zoster (Table 2).

The combined vaccination uptake rate for high-risk patients across all states for pneumococcal disease was 5.5%, and 2.8% for herpes zoster. For states authorizing immunization by protocol or prescriptive authority, the pneumococcal vaccination uptake rate was 6.6%, compared with 2.5% for states requiring a prescription (

 <.0001). For herpes zoster, the rate was 3.3% for states authorizing per protocol or prescriptive authority, compared with 2.8% (not significant, 

 <.05) for states authorizing with a prescription, and 1.0% for states with no authorization (

We conducted an opportunity analysis to estimate the rates of pneumococcal disease and herpes zoster vaccinations among influenza vaccination patients if states with restricted authority were granted full immunization privileges (Table 3). Based on the results of this study, an additional 38,071 pneumococcal vaccinations (a 148% increase) could be administered if states with limited immunization privileges were granted full vaccination privileges. An additional 15,401 herpes zoster vaccinations (a 77% increase) could also be administered if full authorization were granted.

In this study, the aggregate vaccination uptake rate for pneumococcal vaccine was 5.5%; when analyzing those states with full privilege, the rate was 6.6%. An earlier study conducted by Taitel et al10 showed a similar periodic uptake rate of 4.9% among patients who were at high risk for pneumococcal disease. These rates compare favorably with the benchmark uptake rate of 2.9% cited in the study, which is a rate typical of traditional care delivery at physicians’ offices.

Similarly, the aggregate vaccination uptake rate for herpes zoster was 2.8% and the rate for states having full privileges was 3.3%. These rates provide evidence of the unique value of the pharmacist in improving pneumococcal vaccination uptake and in meeting one of the objectives of the Healthy People 2020 campaign, which is to increase rates for vaccinepreventable diseases for those at high risk.

 It is important to note that reported rates in this study are vaccination uptake rates for previously unvaccinated persons who present for influenza vaccination and are not overall adult vaccination coverage rates in the United States.

If all states would adopt legislation to authorize pharmacists to administer vaccinations under a protocol or prescriptive authority, a dramatic increase in vaccinations administered to high-risk patients for pneumococcal disease and herpes zoster

would likely occur. In a study conducted by Steyer et al,

 individuals 65 years and older who lived in states where pharmacists could provide vaccines had significantly higher (

 <.01) influenza vaccine rates than individuals of this age group who resided in states where pharmacists are not authorized to provide vaccines.

This study also demonstrates the pharmacist’s ability to recommend and administer other immunizations for  vaccine preventable diseases in addition to influenza. The Walgreens vaccine administration record facilitates this process by giving pharmacists the ability to prescreen, identify, and administer appropriate vaccinations to their patients. This demonstrates the value that pharmacists can provide to the healthcare system. Further, payers who cover vaccinations in states with full immunization privileges could realize savings, as vaccination administration costs are less expensive in a pharmacy setting.

 Finally, if states adopted legislation to expand pharmacist immunization privileges for other vaccine-preventable diseases, they would realize a subsequent increase in vaccination uptake.

A limitation of the current study was its observational design and the reliance on pharmacy claims for estimation of uptake rates. As with any non-randomized study, causality cannot be confirmed. However, the current study was an enhancement

to the previous study conducted by Taitel et al

 in that it utilized VAR forms in addition to pharmacy claims to more accurately identify high-risk status and estimate vaccination rates. Based on patient indication per the VAR form, the study was able to focus on those at high risk and in need of pneumococcal and herpes zoster vaccinations.

Another limitation to the study is that not all of the risk factors for pneumococcal disease, as specified by the ACIP, could be identified from the VAR forms. The VAR form does not capture certain risk factors for pneumococcal disease, such as being a resident of nursing homes or long-term care facilities. Furthermore, the VAR form relies upon patient self-reporting to collect information on vaccination history and high-risk conditions. Lastly, patients who receive an influenza vaccination at the study pharmacy may have subsequently received a pneumococcal or herpes zoster vaccination at another retail pharmacy chain or physician’s office. Generally, the influence of these limitations would cause an underestimation of vaccination rates. Thus, these results are a conservative estimate of the potential impact of pharmacy-based immunizations.

States that offer pharmacists full immunization privileges have significantly higher vaccination uptake rates for pneumococcal disease and herpes zoster than states with restricted or no authorization. Extrapolation of these results could result in a 148% increase in uptake for pneumococcal vaccine and a 77% increase in uptake for herpes zoster vaccine. Considering the suboptimal vaccination rates of pneumonia, shingles, and other conditions and the public health goals of 2020, states with limited or no immunization authorization for pharmacists should consider expanding pharmacist privileges.

From Walgreen Co (MST, LEF, AEC, ESC), Deerfield, IL.

Financial support for this study was provided entirely by Walgreen Co. This study was approved by Quorum IRB #26510.

 All authors report employment with Walgreen Co.

 Concept and design (MST, LEF, AEC, ESC); acquisition of data (LEF, AEC); analysis and interpretation of data (MST, LEF, AEC); drafting of the manuscript (MST, LEF, AEC, ESC); critical revision of the manuscript for important intellectual content (MST, LEF, AEC, ESC); statistical analysis (MST, LEF, AEC); obtaining funding (MST, LEF, AEC, ESC); and supervision (MST).

Michael S. Taitel, PhD, Walgreen Co, 1415 Lake Cook Rd, MS #L444, Deerfield, IL 60015. E-mail: michael.taitel@walgreens.com.1. Rambhia KJ, Watson M, Sell TK, Waldhorn R, Toner E. Mass vaccination for the 2009 H1N1 pandemic: approaches, challenges, and recommendations. Biosecur Bioterror. 2010;8(4):321-330.

2. Crawford ND, Blaney S, Amesty S, et al. Individual- and neighborhood-level characteristics associated with support of in-pharmacy vaccination among ESAP-registered pharmacies: pharmacists’ role in reducing racial/ethnic disparities in influenza vaccinations in New York City. J Urban Health. 2011;88(1):176-185.

3. CDC. Adult vaccination coverage—United States, 2010. MMWR. 2012; 61(4):66-72.

4. Uscher-Pines L, Maurer J, Kellerman A, Harris KM. Healthy young and middle age adults: what will it take to vaccinate them for influenza? Vaccine. 2010;28(46):7420-7422.

5. Westrick SC. Pharmacy characteristics, vaccination service characteristics, and service expansion: an analysis of sustainers and new adopters. J Am Pharm Assoc. 2010;50(1):52-61.

6. Francis MAH. Vaccination services through community pharmacy: a literature review. Public Health Wales; August 17, 2010.

7. American Pharmacists Association and Academy of Managed Care Pharmacy. Pharmacist-provided immunization compensation and recognition: white paper summarizing APhA/AMCP stakeholder meeting. J Am Pharm Assoc. 2011;51(6):704-712.

8. Prevention of pneumococcal disease: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR. 1997;46(RR-8):1-24.

9. Harpaz R, Ortega-Sanchez IR, Seward JF. Prevention of herpes zoster: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR. 2008;57(RR-5):1-30; quiz CE32-34.

10. Taitel M, Cohen E, Duncan I, Pegus C. Pharmacists as providers: targeting pneumococcal vaccinations to high risk populations [published online August 22, 2011]. Vaccine.

Articles

WEB EXCLUSIVE

States offering pharmacists full immunization privileges have significantly higher vaccination uptake rates for pneumococcal disease and herpes zoster than states with restricted or no authorization.

Improving Pneumococcal and Herpes Zoster Vaccination Uptake: Expanding Pharmacist Privileges

 To assess whether the addition of a peer testimonial to an informational mailing increases conversion rates from brand name prescription medications to lower-cost therapeutic equivalents, and whether the testimonial’s efficacy increases when information is added about an affiliation the quoted individual shares with the recipient.

 A total of 5498 union members were randomly assigned to receive 1 of 3 different informational letters: 1 without a testimonial (No Testimonial Group), 1 with a testimonial from a person whose shared union affiliation with the recipient was not disclosed (Unaffiliated Testimonial Group), and 1 with a testimonial from a person whose shared union affiliation with the recipient was disclosed (Affiliated Testimonial Group).

The conversion rate for the No Testimonial Group was 12.2%, which is higher than the Unaffiliated Testimonial Group rate of 11.3% and the Affiliated Testimonial Group rate of 11.7%. The differences between the groups are not statistically significant.

 Short peer testimonials do not increase the impact of a mailed communication on conversion rates to lower-cost, therapeutically equivalent medications, even when the testimonial is presented as coming from a more socially proximate peer.

We found that adding a short peer testimonial to a mailed letter about the benefits of generic drugs did not increase the likelihood of the recipient converting to a lower-cost therapeutic alternative.

		Even when the testimonial was from a close peer, there was no increase in conversion rates.

		Testimonials did not decrease the number of days to conversion.

		Organizations do not need to spend the time and effort to solicit short testimonials from peers of their health communication recipients.

Healthcare organizations often try to change individuals’ health behaviors by using printed communications.

 We hypothesized  that adding a peer testimonial to an informational letter would significantly increase the letter’s efficacy, and that the testimonial’s effectiveness would be increasing in the perceived social closeness of the peer to the recipient. Testimonials may work because individuals imitate their peers,

 and studies show that the influence of a peer is increasing in the peer’s social proximity.

We conducted a randomized controlled trial to assess whether adding a peer testimonial to a mailing increases conversions from brand name prescription medications to lower-cost equivalents. In coordination with a pharmacy benefit manager (PBM), 5498 union members were randomly assigned to receive 1 of 3 informational letters. Members were selected for the study if they had, in the 6 months prior to May 2011, filled a brand name prescription that had a cheaper therapeutic equivalent.

Members in the No Testimonial Group received a letter listing cheaper therapeutic equivalents available for the recipient’s brand name prescription medication and the associated cost savings to the recipient from switching to each of these alternatives. Members in the Unaffiliated Testimonial Group received a letter identical to the No Testimonial letter except for the addition of the following testimonial from a member of their union: “Switching to a lower-cost generic medication puts money back in my pocket every month.” Beneath the testimonial appeared the quoted member’s first name, last initial, city, and state. Members in the Affiliated Testimonial Group received a letter identical to the Unaffiliated Testimonial letter except for the addition of the quoted member’s union affiliation below the testimonial.

The letters were sent on May 1, 2011. The PBM measured the targeted members’ prescription drug claims for 6 months after the mailing.

The conversion rate to lower-cost alternatives for the No Testimonial Group was 12.2%, which is higher than the Unaffiliated  Testimonial Group rate of 11.3% and the Affiliated Testimonial Group rate of  11.7%. The differences in the conversion rate between the control and the treatment groups are not statistically significant, and adding demographic controls does not change the significance or the rank order of the groups’ conversion rates (

The differences between the control and the treatment groups in the percent of employees who converted to a cheaper alternative and never reconverted to the brand name are also not statistically significant, and including demographic controlsdoes not change their significance (Table 1, columns 4-6).

In conclusion, we found that adding a short peer testimonial to a letter about the benefits of generic drugs did not increase the likelihood of the recipient converting to a lower-cost therapeutic alternative, even when the testimonial was marked as coming from a member of the recipient’s union. These results suggest that organizations need not expend the considerable effort required to solicit short testimonials from peers of their health communication recipients.

 From National Bureau of Economic Research (JB), Graduate School of Business, Stanford University, Stanford, CA; National Bureau of Economic Research (JJC), Yale School of Management, Yale University, New Haven, CT; National Bureau of Economic Research (DL), Harvard University, Cambridge, MA; National Bureau of Economic Research (BCM), John F. Kennedy School of Government, Harvard University, Cambridge, MA; National Bureau of Economic Research (GR), Cambridge, MA.

 We acknowledge individual and collective financial support from National Institutes of Health grants P30-AG-034532, R01-AG-021650, and P01-AG-005842.

 Drs Beshears, Choi, Laibson, and Madrian and Ms Reynolds report that they have received grants from Humana. Dr Laibson reports that he has also received consultancies from Express Scripts.

 Concept and design (JB, JJC, DL, BCM); acquisition of data (JB, DL, GR); analysis and interpretation of data (JJC, DL, BCM); drafting of the manuscript (JJC, BCM, GR); critical revision of the manuscript for important intellectual content (JJC, BCM, GR); obtaining funding (JB, DL, BCM); administrative, technical, or logistic support (GR); and supervision (JB, JJC, DL, BCM).

Gwendolyn Reynolds, MTS, National Bureau of Economic Research, 1050 Massachusetts Ave,  ambridge, MA 02138.E-mail: Reynolds@nber.org.1. Sedjo RL, Cox E. The influence of targeted education on medication persistence and generic substitution among consumer-directed health care enrollees. Health Serv Res. 2009;44:2079-2092.

2. Duflo E, Saez E. Participation and investment decisions in a retirement plan: the influence of colleagues’ choices. J Pub Econ. 2002; 85:121-148.

3. Sacerdote B. Peer effects with random assignment: results for Dartmouth roommates. Q J Econ. 2001;116:681-704.

4. Christakis NA, Fowler JH. The spread of obesity in a large social network over 32 years. N Engl J Med. 2007;357:370-379.

5. Hoxby C. Peer effects in the classroom: learning from gender and race variation. NBER Working Paper 7867;2000.

6. Soetevent AR, Kooreman P. A discrete-choice model with social interactions: with an application to high school teen behavior. Journal of Applied Econometrics. 2007;22:599-624.

We conducted a randomized controlled trial to assess whether adding a peer testimonial to a mailing increases conversion rates from brand name prescription medications to lower-cost equivalents.

Testimonials Do Not Convert Patients From Brand to Generic Medication

To evaluate our outpatient parenteral antimicrobial therapy (OPAT) program to determine its impact on infection management in a facility notable for high patient comorbidity and a large catchment area that includes most of Southern California.

 We reviewed all episodes of patients receiving OPAT from our institution from 2006 through 2009 for patient utilization characteristics and assessment of complications.

 A total of 333 patients received 393 courses of OPAT for a mean of 21.1 days. Diabetes mellitus (53.5%), psychiatric disease (39%), and chronic kidney disease (31%) were common; more than half the patients lived more than 20 miles from our medical center. Osteomyelitis (39.7%) and bacteremia (19.3%) accounted for the majority of OPAT indications. Staphylococcus aureus (36.4%) was the most frequent infecting organism, and vancomycin (37.4%) was the most frequently prescribed medication. Complications including hospital readmission, adverse drug reactions, or line-related complications were noted in 96 of 393 (24.4%) episodes, but most were minor, reversible, or not directly related to the OPAT given. Serious line-related complications that required hospital readmission were noted in only 6 (1.5%) episodes. OPAT was completed as planned in 313 (79.6%) episodes; end-stage renal disease was associated with OPAT noncompletion in multivariable analysis (odds ratio = 2.20, 

= .047). We estimated that OPAT saved our medical center $4 million per year.

 Despite our patients’ high level of comorbidity and our facility’s large catchment area, we were able to deliver OPAT successfully and safely with significant cost savings.

Outpatient parenteral antimicrobial therapy (OPAT) improves patient convenience and ecreases hospital stay for patients requiring long-term parenteral antimicrobials.

		OPAT can be delivered safely in populations with significant comorbidity and in facilities that serve large catchment areas.

		Involvement of a pharmacist trained in infectious diseases was important for our program’s success.

 outpatient parenteral antimicrobial therapy (OPAT) has become integral in decreasing duration of hospitalization and reducing healthcare costs. Outpatient parenteral antimicrobial therapy facilitates hospital discharge for  patients  who would otherwise require ongoing hospitalization for the sole purpose of receiving intravenous antibiotics. Prolonged hospital stays have been associated with an increased risk of nosocomial infections,

 including hospital-acquired pneumonia, catheter-related bloodstream infections (CR-BSIs), and Clostridium difficile—associated diarrhea. One study estimated that an average hospital stay is associated with a 17.6% chance of infection and that each additional day of stay increases this risk by 1.6%.

Another study estimates that, when it occurs, nosocomial infection further multiplies length of stay  by a  factor of 2.87.

 Furthermore, increased lengths of hospitalization have been associated with deconditioning

 and have been shown to predict poor functional outcomes in the elderly.

 While few prospective studies evaluating outcomes of OPAT versus continued inpatient therapy have been performed, retrospective data have demonstrated comparable rates of treatment success.

The purpose of this study is to review our program’s utilization data to determine rates of OPAT completion and related complications in a population with a substantial rate of background comorbidities.

The Department of Veterans Affairs Greater Los Angeles Healthcare System (VAGLA) OPAT program was established in 2003. Our OPAT team consists of an infectious diseases faculty attending physician, an infectious diseases fellow, an infectious diseases pharmacist, and a home health coordinator. The majority of patients in our cohort were initially hospitalized at VAGLA for their illness and subsequently identified by their healthcare providers as potential candidates for OPAT. A small percentage of OPAT patients were referred from clinics or initially hospitalized at outside facilities. The final decision to administer OPAT, as well as antibiotic selection and duration, was made only after consultation with the OPAT team, who reviewed all OPAT requests for appropriate selection and duration of antimicrobial therapy, typically in consultation with the infectious diseases consulting service for OPAT candidate inpatients at VAGLA. The Department of Veterans Affairs Greater Los Angeles Healthcare System arranges fee-basis services with home infusion pharmacies and nursing agencies for the delivery of antimicrobials and nursing services over a broad catchment area extending as far north as Bakersfield, as far west as San Luis Obispo, as far south as Orange County, and as far east as the San Gabriel Valley. The decision about whether the antimicrobial is to be self-administered by the patient or administered by a healthcare professional is made after a collective evaluation by home healthcare professionals and the OPAT team; both types of patients were included in the analysis.

All patients who received OPAT through our program between January 1, 2006, and December 31, 2009, were identified. Patient data from this period were collected from the VA Computerized Patient Record System. Extracted data included patient  diagnosis and demographics (including medication copay status, with “exempt” status serving as a surrogate marker for limited financial means, based on a yearly income of approximately $12,000-$25,000 according to the patient’s number of dependents), medical comorbidities, zip code where patient received OPAT, antibiotics received, duration of treatment,  microbiology, and information pertaining to complications and readmissions. We excluded patients who were discharged to community nursing homes, primarily because detailed records from these facilities were not available through the VA Computerized Patient Record System.

Complications during OPAT were recorded, including all-cause readmission, any line-related complaint, any adverse drug event consisting of a laboratory result or subjective complaint attributable to an administered antibiotic, or death. Acute kidney injury was defined as an increase in glomerular filtration rate of more than 50% above the recorded value at time of hospital discharge (if hospitalized) or at initiation of OPAT (if outpatient). Leukopenia was defined as an absolute white blood cell count of less than 4000/μL. The decision to continue, switch, or terminate therapy following an adverse drug event was made on an individualized basis by the infectious diseases and OPAT team. We defined a line-related complication as any adverse event pertaining to intravenous access, ranging from self-limited insertion site irritation to readmission for line-related sepsis. We further stratified these complications by assigning a severity grade ranging from 1 (least severe) to 3 (most severe).  Complications that were self-limited and ultimately had no impact on duration and route of therapy were assigned a severity grade of 1. Complications that resulted in a truncated duration of intravenous therapy or change in route of administration were assigned a severity grade of 2. Complications that required hospitalization due to CR-BSI or exit site infections were assigned a severity grade of 3. We specifically chose to differentiate patients with a severity grade of 3 from patients readmitted due to a line-related complication, as several patients were briefly admitted solely for peripherally inserted central catheter (PICC) placement after a mechanical complication (eg, PICC line displaced). Using our grading system, these patients would receive a severity grade of 1 despite being readmitted due to a line-related complication.

We defined treatment completion as a patient who received a course of outpatient intravenous antibiotics for the duration prescribed at the onset of therapy. Patients who required a switch to an alternative intravenous agent (eg, due to an adverse drug event) but who still completed the prescribed course length were also counted as completions. Patients who required a switch to oral medications or had intravenous therapy stopped early due to OPAT complication, or who were admitted for any reason during their OPAT course, were counted as incomplete treatments. Logistic regression analysis of OPAT noncompletion was performed with Stata release 10 (StataCorp LP, College Station, Texas).

An informal cost analysis was conducted by subtracting outpatient costs related to OPAT from the projected costs of continued hospitalization. The cost of OPAT was determined by adding per diem nursing visit charges, cost of antibiotics (provided by contracted pharmacy), and per diem pharmacy charges. The projected inpatient cost was calculated by adding the total inpatient antimicrobial cost (VA price) and cost of continued hospitalization (average daily bed cost multiplied by total hospital days). The projected length of hospitalization was obtained by assuming that patients would have remained hospitalized for the duration of IV therapy.

From 2006 to 2009, 393 OPAT courses were received by 333 individual patients (

). Average age was 62 years, and mean duration of outpatient treatment was 21.1 days (range, 0-88 days; interquartile ratio, 9-30 days). A total of 37 (9.4%) OPAT courses were referred from an outside facility and 41 (10.4%) OPAT courses were referred from an outpatient clinic within our system, 22 of which were from the infectious diseases clinic. Initial and/or ongoing infectious diseases consultation was obtained in 274 (69.7%) OPAT courses. Medical comorbidities were frequent in our population, particularly diabetes mellitus (53.5%), psychiatric disease (39.0%), congestive heart failure (38.7%), coronary artery disease (31.5%), and chronic kidney disease with estimated glomerular filtration rate of less than 60 mL/min (30.9%). A total of 27 (8.1%) patients had end-stage renal disease (ESRD), defined as an estimated glomerular filtration rate of less than 15 mL/min and/or receipt of hemodialysis at the time of OPAT initiation. Most (253/333, 76%) patients had limited financial means (as determined from exemption from VA copay), and 205 (62%) lived more than 20 miles away from our facility.

Principal diagnoses were made by the physicians initiating the OPAT consult, with additional assistance from infectious diseases and the OPAT team. The most common indication for OPAT was osteomyelitis of the foot (113/393, 28.8%), which most commonly occurred in diabetic patients (

). The second-leading diagnosis was bacteremia, which included both primary and secondary bacteremia (76/393, 19.3%) Other common indications included nonfoot osteomyelitis (43/393, 10.9%) and soft tissue infections (40/393,  10.2%).

The most commonly isolated pathogen was Staphylococcus aureus (143/393, 36.4%), of which 80 of 143 (56%) were methicillin-resistant S aureus. Other frequently isolated microorganisms included Streptococcus species (50/393, 12.7%) and Pseudomonas aeruginosa (38/393, 9.7%). In 92 of 393 courses (23.4%), treatment was given empirically in the absence of an isolated pathogen or relevant culture.

The most commonly prescribed antibiotics were vancomycin (147/393, 37.4%), ceftriaxone (109/393, 27.7%), and ertapenem (79/393, 20.1%). In 50 of 393 (12.7%) OPAT courses, patients were treated with 2 intravenous agents simultaneously.

Complications related to OPAT were noted in 96 of 393 (24.4%) episodes (

). The major categories of complincations were hospital readmission, adverse drug events, an PICC-related complications.

The most common complication was readmission, which occurred in 49 of 393 (12.5%) episodes. Of these 49 admissions, 13 (26.5%) were deemed to be unrelated to either OPAT or the underlying infectious process. Excluding these unrelated hospitalizations, our overall hospital readmission rate was 36 out of 393 (9.2%). Of the 36 potentially relevant readmissions, 9 were due to PICC-related complications and 8 were due to adverse drug events. Readmission due to “failure to improve” while receiving OPAT occurred in 15 cases. Four patients were rehospitalized at outside facilities; in these cases, records were not sufficiently detailed to reliably determine the cause for hospitalization. One of these 4 patients subsequently expired during this hospitalization; the cause of death was unclear due to paucity of records.

Overall, 40 of 393 (10.2%) courses were notable for an adverse drug event, resulting in shortening of OPAT (including switches to oral antimicrobial therapy) in 29 of those 40 (72.5%) courses. The most commonly encountered events were acute kidney injury (11/40, 27.5%), pruritus/rash (10/40, 25%), and leukopenia (7/40, 17.5%).Vancomycin accounted for 40% of all adverse drug events recorded during the study period, followed by ertapenem (20%) and ceftriaxone (17.5%). However, when expressed as a percentage of total courses administered, an adverse drug event was recorded in 16 of 146 (11%) courses of vancomycin, 7 of  79 (8.9%) courses of ertapenem, and 8 of 109 (7.3%) courses of ceftriaxone. The most common adverse drug event due to vancomycin was acute kidney injury (8/16), followed by leukopenia (4/16). In 5 of the cases of acute kidney injury, a clinical decision was made to discontinue vancomycin. The overall rate of acute kidney injury in patients receiving vancomycin  was 5.5% (8/146). In all cases, acute kidney injury in patients receiving vancomycin was reversible and did not result in any permanent sequelae.

Line-Related Complications. Our overall line-related complication rate was 6.4% (25/393) over the 4-year study period. The majority were related to PICC (22 of 25 cases), with the 3 remaining complications due to peripheral intravenous line placement. The most commonly reported line-related complications were mechanical in nature (occlusion/accidental  displacement) and accounted for 9 of 25 events. Of these 25 events, 6 were self-limited local reactions (erythema, tenderness),  and therapy was not interrupted in any of these cases. Six bloodstream infections attributed to line-related complications were  diagnosed.

Of the 25 line-related complications, 13 were deemed grade 1, 6 were grade 2, and 6 were grade 3. Therefore, our  rates of minor, moderate, and major line-related complications were, respectively, 3.3%, 1.5%, and 1.5%. In all 6 cases of moderate  line-related complications, venous access was discontinued prior to the scheduled end date after evaluation by the infectious diseases or OPAT service, and transition to oral therapy was deemed to be appropriate.

Of our 6 major line-related complications, an organism was isolated from the bloodstream in 5 cases: vancomycinresistant Enterococcus facecium, 

. In the sixth case, CR-BSI was diagnosed based on high clinical suspicion despite no bloodstream isolate (possibly due to prior administration of antibiotics). In 2 cases, it was not clear whether bacteremia stemmed from a PICC line or hemodialysis catheter. Because CR-BSI due to PICC line could not be ruled out in either instance, these episodes were designated as major line-related complications. All 6 patients had their PICC and/or hemodialysis catheters removed, and all but 1 had their intravenous antimicrobials discontinued. All in all, rates of PICC complications decreased from 2006 to 2009 (8.4% to 4.5%), though the c2 test for trend was not significant.

Of 393 courses of OPAT, 313 were completed, giving an overall completion rate of 79.6%. Of the 80 patients with incomplete treatments, 49 were readmitted, and 1 patient was admitted to an outside facility and died of unknown causes before completing OPAT treatment as described above. In all cases of incomplete treatment due to readmission, the patient received appropriate intravenous antibiotics while hospitalized and the need for further antimicrobial therapy was assessed by the OPAT team at time of discharge. Of the remaining 30 noncompletions of OPAT, 20 were changed early to oral antibiotics, 8 had antibiotics discontinued altogether, and 2 were changed to a different OPAT regimen (Table 3). To determine whether any factors were associated with noncompletion of OPAT, we performed bivariate logistic regression using most of the demographic data from Table 1 and the clinical diagnosis and antibiotic data from Table 2. Those factors that approached or met statistical significance included bacteremia (odds ratio [OR] = 1.82; 

 = .040), concomitant congestive heart failure (OR = 1.64; 

 = .051), and concomitant ESRD (OR = 2.59; P = .015). When these 3 variables were combined in a multivariable model, only ESRDremained significantly associated with OPAT noncompletion (OR = 2.20; 

The total cost of OPAT was $2,178,569 ($450,934 for antibiotics provided by contracted pharmacy plus $832,200 in per diem pharmacy charges plus $895,435 in per diem nursing charges). Projected inpatient cost savings were calculated by adding what our OPAT antibiotics would have cost if they had been given in an inpatient setting (we calculated this figure to be $234,637; VA prices are generally lower than contract pharmacy prices) to the estimated cost of continued hospitalization (average daily bed cost multiplied by total hospital days). Creating estimations regarding hospital days saved can be problematic, as patients who remain hospitalized (as opposed to receiving OPAT) may theoretically transition to oral therapy at some point and/or be discharged home. However, we can infer that patients are enrolled into OPAT specifically because an infectious diseases specialist has determined that the patient requires intravenous antibiotics for the duration of their treatment. We made the crude assumption that each day of outpatient therapy represented 1 saved day of hospitalization; using that metric, OPAT was responsible for a reduction of 8322 days in additional hospitalization over 4 years. Our hospital administrators estimate that a day of inpatient hospitalization costs $2198. Thus, a total of $18,526,393 (8322 days —$2198 per day + $234,637 in drug costs) in hospitalization costs were potentially averted. As such, overall estimated cost savings with OPAT were $16,347,824 ($4,086,956 per year, $41,598 per OPAT episode).

In this retrospective study, we demonstrate that OPAT can be delivered effectively and safely for a cohort of patients with a high acuity of illness, advanced age, and multiple baseline comorbidities. Our completion rate of ~80% is lower than that reported in other data sets, which is likely a result of the high number of all-cause hospital readmissions. All readmitted patients were evaluated by the OPAT service upon discharge, and there was significant heterogeneity in treatment course postdischarge (eg, continuation of OPAT, transition to oral therapy) depending on length of hospital stay or change in clinical status. Therefore, we considered all patients who were readmitted (regardless of cause) to have incomplete treatment. A significant number of patients were admitted because of “failure to improve” on OPAT; however, given the significant baseline comorbidities of our patient population, it is possible that many of these cases represent the natural progression of a disease state and not  treatment failure per se.

Any analysis of an OPAT program must include the 2 most common complications of extended intravenous antimicrobial therapy: line-related complications and adverse drug events. In a cohort of 2059 OPAT episodes over a 13-year period, Matthews and colleagues9 reported (for self-administered and healthcare professional—administered OPAT, respectively) overall complication rates of 24% and 23%, readmission rates of 10.5% and 12.6%, vascular device complication rates of 1% and 0.5%, and drug adverse-event rates of 12%. Our 4-year experience was similar to these findings, other than a higher frequency of line complications. However, our rates of line-related complications did decrease annually from 2006 to 2009. We believe that this decrease was partially due to several OPAT protocol changes implemented in 2007: (1) a telephone follow-up was performed on the day following discharge to ensure proper implementation of OPAT by pharmacy and nursing agencies; (2) weekly phone calls were made to the patient with the express purpose of troubleshooting and to ensure compliance with lab monitoring; and (3) increased allowances were made for nursing visits for PICC dressing changes. Of note, only 1 episode of line-related venous thrombosis (brachial vein thrombus) was diagnosed in our study. The reported incidence of catheterrelated thrombotic complications has varied, depending on the patient population studied, catheter location, and diagnostic  modalities utilized. In a retrospective analysis of 2063 patients who received a PICC for intravenous antibiotics, the incidence of venous thrombosis was 2.5% with a mean time to diagnosis of 18.7 days. Deep venous thromboses slightly outnumbered superficial thromboses (55.8% vs 44.2%), and pulmonary embolism was diagnosed in 2 patients.

 We have no explanation for our unusually low rates of venous thrombosis complications. The potentially subclinical nature of venous thrombosis is, of course, recognized. Nevertheless, a low rate of venous thromboses portends favorably for avoiding the potentially life-threatening complication of pulmonary embolism.

Our overall rate of adverse drug events was 10.2%, which is similar to what has been previously reported in the literature.

 Although more patients had adverse events with vancomycin than with other commonly used agents in our study, vancomycin’s overall ratio of adverse events to courses received was similar to that of the other agents. In a multicenter series from  1997 through 1999 following 1053 episodes of outpatient vancomycin administration, adverse events were reported in 11.3% of patients, with rash being the most common (3% of all episodes). A “renal toxic reaction” was encountered in 1.5% of all courses.

 While the total number of adverse drug events due to vancomycin approximates that reported in previous studies, our 

of vancomycin-associated acute kidney injury was higher (5.5%). We postulate that our higher rate of    vancomycin-related acute kidney injury may be related to our protocol of aiming for high goal vancomycin troughs (15-20 mg/L) for the treatment of invasive S aureus infection, an approach advocated by recent guidelines issued by the Infectious Diseases Society of America, the American Society of Health-System Pharmacists, and the Society of Infectious Diseases Pharmacists.

 The relationship between elevated vancomycin troughs and nephrotoxicity admittedly remains a subject of debate, as many studies are limited by concomitant nephrotoxic agents, varying definitions of nephrotoxicity, and an inability to determine whether an elevated trough leads to nephrotoxicity or vice versa.

It is unclear why ESRD was associated with OPAT noncompletion in our study, but this association likely speaks to the complexity of illness of this particular patient population and potential issues related to hemodialysis access that should prompt further study. Also, a majority of our ESRD population receives hemodialysis outside of our system, so coordination of care may have been an issue as well.

Our OPAT experience may differ from others for a variety of reasons. Most notably, the advanced age and high background rate of comorbidites of the average VA patient may not reflect the general population encountered by other OPAT programs. In fact, it is conceivable that patients with similar profiles might routinely be transferred to a skilled nursing  facility to complete their  antibiotic therapy. Cox and colleagues14 previously demonstrated in a series of 205 patients that OPAT could be  self-administered to older adults with a rate of efficacy and safety similar to that of the comparator arm of younger patients. Our data support this option as a means to complete intravenous antibiotic therapy without institutionalization in a short-term healthcare facility. In addition, our data demonstrate the ability to deliver OPAT over a wide catchment area, as nearly 65% of our patients who received OPAT lived more than 20 miles from our facility. Our patients also benefit from an integrated healthcare system with longitudinal follow-up from initial point of care; this design increases adherence and may reduce rates of OPAT-related complications. Furthermore, our OPAT program enjoys the benefit of a full-time infectious diseases pharmacist who has primary responsibility for coordinating services between home health nursing, laboratory services, pharmacy, and multiple physicians (inpatient, prescribing, and outpatient primary care). The value of a centralized coordinator who can tie together the issues of infectious diseases and pharmacology cannot be overstated.

 From Department of Medicine, Huntington Hospital (AL), Pasadena, CA; Infectious Diseases Section (TT, JF, DOB, CJG), VA Greater Los Angeles Healthcare System, Los Angeles, CA; Pharmacy Service (TT), VA Greater Los Angeles Healthcare System, Los Angeles, CA; Kaiser Permanente Northwest (HMN), Portland, OR; David Geffen School of Medicine at the University of California (JF, DOB, CJG), Los Angeles, CA.

The authors (AL, TT, HMN, JF, DOB, CJG) report no relationship or financial interest with any entity that would pose a conflict of interest with the subject matter of this article.

Concept and design (TT, JF, DOB, CJG); acquisition of data (TT, HMN, JF, DOB, CJG); analysis and interpretation of data (AL, TT, JF, CJG); drafting of the manuscript (AL, TT, DOB, CJG); critical revision of the manuscript for important intellectual content (AL, TT, JF, DOB, CJG); statistical analysis (TT, CJG); provision of study materials or patients (CJG); administrative, technical, or logistic support (TT, JF); and supervision (TT, JF, DOB, CJG).

 Christopher J. Graber, MD, MPH, Infectious Diseases Section, VA Greater Los Angeles Healthcare System, 11301 Wilshire Blvd, 111-F, Los Angeles, CA 90073. E-mail: christopher.graber@va.gov. 1. Rucker RW, Harrison GM. Outpatient intravenous medicatios in the management of cystic fibrosis. Pediatrics. 1974;54(3):358-360.

2. Delgado-Rodríguez M, Bueno-Cavanillas A, López-Gigosos R, et al. Hospital stay length as an effect modifier of other risk factors for nosocomial infection. Eur J Epidemiol. 1990;6(1):34-39.

Outpatient parenteral antimicrobial therapy was successfully delivered in our facility despite significant comorbidity and geographic limitations.

Outpatient Parenteral Antimicrobial Therapy at Large Veterans Administration Medical Center

 To investigate adherence, persistence, and switching in patients initiating dabigatran.

 Descriptive analysis using pharmacy claims databases.

 Patients with a claim for dabigatran and who were continuously enrolled in pharmacy benefits for 180 days prior to and 180 days following the initiation of dabigatran were identified and stratified by whether there was a history of warfarin treatment prior to dabigatran initiation. Medication adherence was calculated as the proportion of days covered (PDC). Persistence to treatment at 180 days was measured. Among patients who discontinued dabigatran, time to initiating warfarin was determined.

 In the overall population, 39.9% of 17,691 patients were nonpersistent to dabigatran. The PDC for the warfarin-naïve cohort was 0.674 (standard deviation [SD] 0.364), and 0.712 (SD 0.354) for the warfarin-experienced cohort. For patients persistent to dabigatran, the PDCs for warfarin-naïve and warfarin-experienced cohorts were 0.935 (SD 0.075) and 0.937 (SD 0.074), respectively. In patients discontinuing dabigatran, 16.1% of warfarin-naïve and 41.1% of warfarinexperienced patients initiated warfarin. Among patients discontinuing dabigatran, the mean time to discontinuation in warfarin-naïve and warfarinexperienced cohorts, respectively, was 59.8 (SD 36.2) and 59.6 (SD 36.2) days. The mean time to initiating warfarin in  warfarin-naïve and warfarin experienced cohorts, respectively, was 62.5 (SD 47.2) and 60.5 (SD 43.0) days.

 Two in 5 patients discontinued dabigatran therapy within 6 months, and the majority of these patients were not anticoagulated with warfarin upon discontinuation. These findings highlight potential gaps in the care of patients treated with dabigatran in routine practice.

Dabigatran has been shown in trials to reduce the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation. However, patterns of dabigatran use inroutine practice remain unknown. The objective of the study is to investigate adherence, persistence, and switching to warfarin upon dabigatran discontinuation, in patients initiating dabigatran therapy.

		Findings may highlight gaps in the care of patients treated with dabigatran.

		Due to the dependence on adherence and persistence to dabigatran for prevention of stroke and thromboembolic events, there may be a need for healthcare professionals to provide additional patient support with this medication.

Dabigatran, an oral direct thrombin inhibitor, was approved by the US Food and Drug Administration (FDA) in October 2010 to reduce the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation. It was the first oral anticoagulant to be introduced in the over 50 years since warfarin was approved. Dabigatran does not share warfarin’s potential limitations of having a variable response, extensive food and drug interactions, lab monitoring requirements, and narrow therapeutic index  concerns. However, dabigatran is dosed twice daily rather than once daily for warfarin, and is likely to have an increased  prescription cost burden to patients and payers.

Adherence is defined as the extent to which a patient follows directions for a prescribed medication, whereas persistence is defined as the act of continuing the treatment for the prescribed duration.

In the setting of prescription claims analyses, drug adherence and persistence could be markers of drug efficacy and tolerability, and therapy switches may indicate unsatisfactory treatment response and/or unacceptable adverse effects.

Understanding patient adherence and persistence to anticoagulation therapy in routine practice is important, since nonadherence and nonpersistence to anticoagulation therapy could potentially result in subtherapeutic responses and increased riskof thromboembolic events. Although warfarin has a long  istory as a standard of care in anticoagulation, warfarin nonadherence continues to be a substantial problem that has been linked to risk of ischemic stroke. In a prospective cohort study of adults initiating warfarin in anticoagulation clinics, patients exhibited nonadherence on 21% of the measured patient-days.

 Another study demonstrated a correlation between warfarin nonadherence and the risk for ischemic stroke.

 In a recent retrospective medical claims analysis of 14,149 Medicare patients with a diagnosis of non-valvular atrial fibrillation, adherence to warfarinwas measured using proportion of days covered (PDC).  the risk for ischemic stroke was significantly lower in those with better adherence to warfarin, with a PDC 

80%, compared with those with a lower adherence to warfarin, with a PDC <0% (adjusted odds ratio, 0.59; 95% confidence interval, 0.48-0.72;

There have been few findings regarding the use of dabigatran outside clinical trials. One study, which used medical and pharmacy claims, assessed demographic and clinical characteristics, prescriber specialty, and persistence to dabigatran therapy over a 4-month period.

 Results showed that 17% of all patients (n = 1143) were nonpersistent over a 4-month follow-up period, and 71% of these patients had a history of warfarin use in the 6 months prior. However, these results may be limited because of the short identification period of 2 months immediately following FDA approval. In a New Zealand study of inpatients starting dabigatran, the authors found that over a follow-up period of 1 to 7 months, 24% of all patients discontinued, with a median treatment duration of 140.5 days.

 Approximately 10% of the overall population discontinued due to the side effects of dabigatran (eg, gastrointestinal side effects, bleeding, major adverse cardiovascular events). An additional 8% of patients stopped dabigatran due to planned discontinuation of therapy after electrical cardioversion, adverse media coverage, or medication adherence issues. Results of this study may be limited by a smaller study size of 70 patients. Therefore, there is a need to study dabigatran in a larger population over a longer time period to further explore the real-world use of dabigatran. The objective of our study is to investigate adherence and persistence to dabigatran therapy, and switching to warfarin upon dabigatran discontinuation, in patients initiating dabigatran therapy.

This was a descriptive, retrospective, observational analysis using administrative pharmacy claims from a large pharmacy benefits manager (PBM). The study was conducted using prescription claims from Medicare Part D Prescription Drug Plan (PDP), Medicare Advantage Prescription Drug (MAPD), commercial, and Medicaid plan patients. Patients were identified by a first fill (index fill) of dabigatran during the identification period of October 29, 2010, through June 30, 2011. The pre-index period was defined as 180 days prior to the index date, and the post-index period was defined as 180 days after the index date. The inclusion criteria were that patients had at least 1 fill of dabigatran during the identification period, and that they were continuously eligible for pharmacy benefits during the pre-index and postindex periods.

Patients were stratified by presence of a warfarin claim (“warfarin-experienced”) or absence of a warfarin claim (“warfarin-naïve”) in the pre-index period to analyze the cohorts separately. It was hypothesized that there could potentially be differences in behavior between the 2 cohorts, based on previous use of anticoagulants.

The study measures included a description of various demographic characteristics (ie, age, gender, plan type, and geographical region) and clinical characteristics (ie, frequency of chronic heart failure [CHF], diabetes mellitus [DM], hypertension [HTN], coronary heart disease [CHD], and dyslipidemia, Chronic Disease Score [CDS],

 and number of concomitant medications, measured by the number of prescriptions with days supply on the index date). The presence of concomitant diseases was detected by proxy of specific medication classes in the pre-index period (details can be found in the 

The primary outcomes measures included persistence, as defined by continuous use of dabigatran with no days supply gap of 30 days or more during the post-index period, and adherence, as described by the PDC calculated as the number of calendar days that patients had a supply of dabigatran during the post-index period divided by 180 days. In patients nonpersistent to dabigatran therapy, time to discontinuation (number of days from the index date to the last day of supply prior to a gap in therapy of 30 days or greater), incidence of switching to warfarin (number of patients who had a claim for warfarin in the post-index period), and time to switch to warfarin (number of days from the index date to the first fill of warfarin in the post-index period) were measured.

All statistical tests were performed using SAS version 9.2. Means were tested for variance and compared by independent t tests, and proportions were compared using the

 test. All comparisons were 2-sided and performed at a 0.05 level of significance.

There were 7322 patients identified for the warfarin-naïve cohort, and 10,369 patients identified for the warfarin-experienced cohort (

). The average age of the study population was 76 years, and the majority of patients were enrolled in a PDP plan (77.2% for the warfarin-naïve cohort and 80.6% for the warfarin-experienced cohort, 

 <.001). Chronic concomitant conditions included hypertension (88.9% and 92.6% of the warfarin-naïve and warfarin-experienced cohorts, respectively,  

 <.001), CHD (69.8% and 71.9% of the warfarin-naïve and warfarin-experienced cohorts, respectively, 

 = .002), and dyslipidemia (58.2% and 63.0% of the warfarin-naïve and warfarin-experienced cohorts, respectively, 

 <.001). Warfarin-naïve patients had a mean of 6.4 total prescriptions (including dabigatran), and warfarin-experienced patients had a mean of 7.5 total prescriptions (including dabigatran) with days supply on the index date (

<.001). The mean Chronic Disease Scores were 4.2 and 6.4 (

 <.001) for tively. While other statistically significant differences were observed for characteristics between the cohorts, a number of the statistically significant differences may be driven by the large population size and may not be of clinical significance.

The number of patients persistent to dabigatran therapy was 4137 (56.5%) in the warfarin-naïve cohort and 6492 (62.6%) in the warfarin-experienced cohort (

). Of all 17,691 patients, 7062 (39.9%) were nonpersistent to dabigatran therapy over the 6-month period. Adherence was determined using PDC for the overall population and also for patients persistent to dabigatran therapy. The mean PDC for patients persistent to dabigatran therapy was 0.935 (standard deviation [SD] 0.075) for the warfarin-naïve cohort and 0.937 (SD 0.074) for the warfarin-experienced cohort (

 = .28). In the overall population, the mean PDC was 0.674 (SD 0.364) for the warfarin-naïve cohort and 0.712 (SD 0.354) for the warfarin-experienced cohort (

Among patients discontinuing dabigatran therapy, the mean time to discontinuation in warfarin-naïve and warfarinexperienced cohorts, respectively, was 59.8 (SD 36.2) days the warfarin-naïve and warfarin-experienced cohorts, respectively, was 59.8 (SD 36.2) days and 59.6 (SD 36.2) days (

= .83), with approximately 50% of patients discontinuing after the first 30-day fill of dabigatran. The mean time to initiating warfarin in warfarin-naïve and warfarin-experienced cohorts, respectively, was 62.5 (SD 47.2) and 60.5 (SD 43.0) days (

). The number of patients nonpersistent to dabigatran therapy who switched to warfarin was 513 (16.1%) in the warfarin-naïve cohort and 1595 (41.1%) in the warfarinexperienced cohort (

 <.001). The Kaplan-Meier curves for the time to discontinuation and time to switch to warfarin are shown in Figures 1 and 2.

Patients with a history of warfarin use prior to initiating dabigatran therapy had a greater burden of comorbidity than those without prior warfarin use, as demonstrated by a greater prevalence of CHF, DM, HTN, CHD, dyslipidemia, a higher CDS score, and a greater total number of medications compared with warfarin-naïve patients. Other statistically significant differences between the cohorts were likely driven by the large size of the study population. Examples of variables with small, but statistically significant, differences include mean age (76.0 years in warfarin-naïve versus 76.7 years in warfarin-experienced patients, P <.001), patients with concomitant diabetes mellitus (21.2% in warfarin-naïve vs 22.5% in warfarin-experienced  patients, P = .03), and the percentage of patients with PDP coverage (77.2% in warfarin-naïve vs 80.6% in warfarin-experienced patients, P <.001). Among patients persistent to dabigatran therapy, both cohorts demonstrated good adherence with mean PDC values of 0.935 (warfarin-naïve) and 0.937 (warfarin-experienced). The suboptimal adherence of the overall cohort (including both patients persistent and nonpersistent to dabigatran therapy) appears to be attributed to nonpersistence. In the overall study cohort, 40% of patients were nonpersistent to dabigatran therapy (ie, discontinued dabigatran therapy). In patients nonpersistent to dabigatran therapy, the mean trial of dabigatran (ie, time to discontinuation) was a length of 60 days.

Among patients who were nonpersistent to dabigatran therapy, approximately 50% of patients discontinued by 30 days and approximately 80% had discontinued by 90 days. The observed decline in persistence at these points likely reflects discontinuation after only the first fill (either a 30- or 90-day supply). Of patients switching to warfarin, the mean time to switch was also approximately 60 days. In patients nonpersistent to dabigatran therapy, the majority did not switch to warfarin in either cohort. This suggests that most patients may discontinue dabigatran without being switched to warfarin, despite the need for patients with atrial fibrillation to be persistent to chronic anticoagulation therapy. It is possible that patients may have discontinued dabigatran therapy at their own discretion without informing their healthcare providers. If this is the case, then patients taking dabigatran still may require closer monitoring, in spite of the lack of need for laboratory monitoring with  dabigatran therapy. It may be necessary for healthcare professionals and managed care organizations to provide additional support and counseling for patients on dabigatran therapy.

The results of this study should be interpreted with caution, as it was not possible to verify reasons for dabigatran  discontinuation. Potential reasons may include adverse event occurrence (eg, a bleeding episode or dyspepsia as was observed in the RE-LY trial

), a switch to aspirin or rivaroxaban, or use of dabigatran for an off-label indication with a shorter duration of treatment. In terms of adverse events, in the RE-LY trial,8 reasons for discontinuation that were reported included gastrointestinal bleeding, gastrointestinal symptoms, a serious adverse event, an outcome event, and patient’s decision. (For reference, in the RE-LY trial,

gastrointestinal bleeding was cited as the reason for discontinuation in 1.3% of patients taking dabigatran 150 mg vs 0.9% of patients who were taking warfarin [P value not reported]. Gastrointestinal side effects led to discontinuation in 2.1% of patients taking 150 mg dabigatran vs 0.6% of patients who were taking warfarin [

value not reported].) Rivaroxaban was initially approved in the United States on July 1, 2011, for the prevention of deep vein thrombosis (DVT) in patients undergoing knee or hip replacement surgery. According to the time frame of this study (with the latest possible day of the post-index period as December 31, 2011), some patients could have switched from dabigatran to rivaroxaban, accounting for some of the nonpersistence. However, this is less likely, as a very low incidence of switching from dabigatran to rivaroxaban was observed in a prescription claims study examining switch rates among oral anticoagulants (warfarin, dabigatran, and rivaroxaban).

The study found that only 0.02% of switchers changed from dabigatran to rivaroxaban, while 87.3% of switchers changed from warfarin to dabigatran. Lastly, it is possible that some discontinuation occurred appropriately and may be accounted for by patients who were treated with dabigatran, off label, for a fi nite duration (eg, DVT prophylaxis in patient undergoing knee or hip replacement surgery). However, it is less  likely that this accounts for the majority of discontinuations observed in this study, for several reasons. First, dabigatran required Prior Authorization (PA) approval for benefit coverage in this population. A review of PA cases among Part D patients during a 4-month period found that less than 1% had off-label indications for finite duration of dabigatran therapy, and the majority of indications were for atrial fi brillation,requiring chronic dabigatran therapy. Secondly, the findings of an observational study reported that during the identification period of our study (October 29, 2010, through June 30, 2011), the majority of patients in the United States were using dabigatran for the atrial fi brillation indication.

 The research utilized the IMS Health National Disease and Therapeutic Index, a nationally representative audit of office-based providers, to quantify patterns of oral anticoagulant use for the prevention of thromboembolism. The authors found that dabigatran has been rapidly adopted into ambulatory practice in the United States, primarily for the treatment of atrial fi brillation, but increasingly is being used for off-label indications. They found that the proportion of US patients who used dabigatran for the indication of atrial fi brillation was 92% in the last quarter of 2010 and 63% in the last quarter of 2011. Thus, we believe that the majority of discontinuations observed in our study are due to true nonpersistence, rather than appropriate discontinuations for off-label indications. A follow-up study, with pharmacy and medical claims, could offer explanations for nonpersistence (eg, capturing a medical claim with the 

diagnosis code for hemorrhage of gastrointestinal tract may indicate that a patient discontinued because of a gastrointestinal bleed).

Limitations of this prescription claims database study include lack of information regarding diagnoses and medical claims. Comorbidities were inferred from pharmacy claims, by assuming that taking certain medications indicates the presence of a particular disease state. (Validation of the proxy measures was done by reviewing published studies and referencing an internal process performing similar identifications of disease states through pharmacy claims.) Secondly, measures of adherence and persistence were based on claims data, which assumes that the patient is taking the medication rather than stockpiling it. It is not possible in a claims analysis to determine whether patients discontinued at their own discretion or upon the direction of their healthcare provider, nor is it possible to determine reasons behind discontinuations of therapy. Having this information could aid in the design of potential specific interventions to increase adherence and persistence to therapy. Lastly, claims data do not capture plan exclusion OTC utilization or other patient out-of-pocket purchases, which could contribute to a more comprehensive understanding of patient practices.

Two in 5 patients discontinued dabigatran therapy within 6 months in this observational, retrospective analysis using administrative pharmacy claims from a large PBM. The majority of patients discontinuing dabigatran therapy were not anticoagulated with warfarin during the post-index period. These findings highlight potential gaps in the care of patients treated with dabigatran therapy in routine practice. Patients should be educated to report intolerance, adverse events, or cost burden to their healthcare provider, instead of discontinuing therapy on their own. Due to the dependence on good adherence and persistence to dabigatran therapy for prevention of stroke and thromboembolic events, there may be a need for healthcare professionals and managed care organizations to provide additional patient support and counseling on this medication. Further research is needed to explain the reasons for nonpersistence to dabigatran therapy.

From OptumRx (KT, SCE, JY, ASMH, BKS, HCL), Irvine, CA.

 The authors (KT, SCE, JY, ASMH, BKS, HCL) report no relationship or financial interest with any entity that would pose a conflict of interest with the subject matter of this article.

Concept and design (KT, SCE, BKS, HCL); acquisition of data (KT, JY); analysis and interpretation of data (KT, SCE, JY, ASMH, BKS); drafting of the manuscript (KT, SCE, ASMH); critical revision of the manuscript for important intellectual content (KT, SCE, ASMH); statistical analysis (KT, JY); provision of study materials or patients (KT); administrative, technical, or logistic support (ASMH, BKS, HCL); and supervision (SCE, BKS, HCL).

We present a descriptive analysis utilizing pharmacy claims from a managed care population to quantify adherence, persistence, and switching patterns for patients initiating dabigatran.

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