An assessment of canine ectoparasiticide administration compliance in the United States based on timing of ectoparasiticide purchases recorded in veterinary hospital transactions.


 Background: This study evaluated the timing of dog owner ectoparasiticide purchases to estimate administration compliance and assess the consequent impact of dose purchase gaps on the proportion of time that dogs are protected over a 12-month period. Methods: Ectoparasiticide purchase transactions over a 12-month period were evaluated for dogs from 626 U.S. veterinary hospitals to determine dose purchase timing and identify consequent gaps between dose administration. Orally administered prescription ectoparasitic medications with active ingredients from the isoxazoline family (afoxolaner, fluralaner, lotilaner, or sarolaner) are included in the analysis. A period was calculated for each of the four isoxazoline-containing medications that represented the duration of protection provided by two doses of ectoparasiticide plus the average gap between these two doses. The maximum percentage of time possible for ectoparasiticide protection for this aggregate period was then calculated for each active. Results: Ectoparasiticide transaction records were analyzed for 506,637 dogs. Of these, 43% of dog owners purchased just one dose over the 12 months. If a dog owner purchased more than one dose, then the timing of these transactions could create a time gap between the completion of ectoparasite protection from the first dose and onset of protection from the subsequent purchase and administration of the second dose. Such gaps were observed in purchases made by 31-65% of dog owners depending on the selected active ingredient and number of doses. The average gap duration between dose purchases was calculated for all possible dose combinations over 12 months of ectoparasite protection. Time gaps between the first and second doses are as follows: for sarolaner (20.3 weeks), afoxolaner (12.9 weeks), fluralaner (12.8 weeks), and lotilaner (8.9 weeks). The proportion of time when protection was provided during the aggregate period between administration of the first and second doses was fluralaner 65%, lotilaner 49%, afoxolaner 40,% and sarolaner 30%. Conclusions: Dog owner ectoparasiticide purchase transactions show that there are time gaps between doses leading to reduced ectoparasite protection. The longer re-administration interval of fluralaner, which results from its extended duration, results in dog owners gaining the greatest proportion of ectoparasite protection time compared with shorter-acting monthly re-treatment medications.

Pet owners are concerned about ectoparasites and vector-borne pathogens with ever-increasing online searching for relevant information [6,21]. Yearly, pet owners purchase 5.2 billion US dollars in ectoparasiticidal products to protect their pets from these pests [22]. Many of these products are highly effective against eas, ticks, and other ectoparasites when administered correctly with re-administration according to the recommended treatment schedule based on their duration of action [23][24][25][26][27][28][29][30][31]. Unfortunately, pet owners often fail to re-administer ectoparasiticides according to the label recommended re-treatment schedule as has been evidenced by their failure to purchase su cient ectoparasiticide doses to adhere to veterinarian recommendations, either continuously throughout the year or seasonally [20,[32][33][34][35]. In a survey of 30,020 dogs in Spain, the number of months of ea and tick protection purchased annually was just 2.9 to 4.3 months depending on the product purchased [32]. In another survey of 231,565 dogs from the U.S., annual monthly purchases of ea and tick products were only 3.3 to 5.7 months of protection [33]. These studies clearly show that dog owners fall short in purchasing the quantities of ea and tick medication necessary to meet veterinarian recommendations for effective ea and tick control [32,33]. However, these studies did not report the timing of dog owner ectoparasiticide purchases or dates of administration. Yet, timely and regular administration of ectoparasiticide medication in a manner consistent with veterinarian recommendations and package insert directions is essential for optimal e cacy and effective ectoparasite control [12,36,37,38]. The timely administration of ectoparasiticides doses is key to successful ectoparasite elimination [8,12,[36][37][38]. Studies have demonstrated that 2-3 months of continual ectoparasiticides treatment is needed to eliminate a ea infestation [25][26][27]31,38]. Delayed doses or missed doses can interrupt the delivery of continuous ectoparasiticidal therapy, allowing the ectoparasite population to rebound in the home environment. To the pet owner, this rebound may appear as a rapid re-infestation and may cause them to question the product e cacy as well as the veterinarian's recommendation.
Gaps in time between the administration of ectoparasiticide doses can result when either the ectoparasiticidal product is purchased in more than one transaction per year or when the pet owner delays administration of subsequent doses beyond the expiration of the period of e cacy of the previous dose. Unfortunately, there is no easy way to accurately assess home medication administration in a large population of pet owners. Transaction analysis does allow an estimation of the best-case administration of medications by assuming that the medication was given on the date of purchase.
The aim of this study was to use a large transaction database to evaluate dog owner ectoparasiticide purchase timing and estimate adherence with veterinary recommendations for ea and tick protection given to dogs. The study examined the total number of doses and months of protection purchased in a 12-month period, as well as the timing of those purchases, which would allow an estimate of the proportion of time that owners provide ectoparasiticide protection. Ectoparasiticide purchases and time gaps between these purchases can provide insight into these parameters. A secondary aim was to compare the impact of ectoparasiticide purchase gaps when a longer 12-week duration ectoparasiticide (Bravecto, Merck Animal Health, Madison, NJ, USA) is prescribed compared with monthly duration ectoparasiticides.

Methods
Dog owner ectoparasiticide transaction records from U.S. veterinary hospitals were analyzed to determine purchase intervals and calculate time gaps between dose purchases. Time gaps between ectoparasiticide dose purchases were used to calculated timely medication administration. A purchase gap was declared when the second or subsequent dose of medication was purchased at a time after completion of the recommended duration of e cacy of the rst dose, as described in the package insert (PI). The duration of e cacy was considered to be 4.3 weeks for products intended to be re-dosed monthly and 12 weeks for uralaner. Dog owners were assumed to have administered medication on the date of purchase, therefore, the calculated gap represents the smallest potential time gap between administered doses.
A measurable time gap can be detected when pet owners purchase medication in two or more transactions per year. The gap could not be measured between administered doses when the dog owner either purchased multiple doses at the same time or purchased one or more subsequent doses before the conclusion of the period of e cacy of the previous dose. The data were analyzed to calculate the proportion of dog owners who purchased a single dose per year and the proportion who purchased multiple (>1) doses per year, with a detectable time gap between doses.
Transaction data for ectoparasiticide purchases made for individual dogs from 626 veterinary hospitals throughout the U.S. were examined retrospectively from January 1, 2017 through December 31, 2019. Data records were masked to conceal the identity of both the veterinary hospital and the dog owner by using unique numeric identi ers for the dog that allowed each record to be associated with an individual animal. Dog demographic data, including age and body weight, were also collected and summarized. Purchases of four different prescription isoxazoline ectoparasiticide medications were included, afoxolaner (NEXGARD® Chewables, Boehringer Ingelheim Animal Health USA, Duluth GA), uralaner (BRAVECTO® Chew, Merck Animal Health, Madison NJ,USA), lotilaner (CREDELIO® Chewable Tablets, Elanco, Green eld, IN) and sarolaner (SIMPARICA® Chewables, Zoetis, Kalamazoo, MI).
To permit comparative analysis, client transactions were limited to those who stayed with the same brand over the 12month period. Each transaction record included the date, product -including presentation -and the quantity purchased.
Presentations could include single packs, single doses, multi-packs, and/or multiple doses for each product. Transaction records included were for ectoparasite medication sales made by the hospital to the client in the name of a single patient.
The study period for each client was de ned as the 12 months following their initial purchase of an ectoparasiticide. Dogs were included if purchase records were available for the 12 months following the initial purchase, regardless of whether more product was purchased or not. Any doses returned to the hospital for credit were excluded. The retreatment interval for each ectoparasiticide was used to calculate the gaps based on 12-week dosing for uralaner and monthly (4.3 weeks) dosing for the 3 other medications. Monthly products could have a maximum of 12 purchases and uralaner could have a maximum of 5 purchases for administration within a single 12-month period. The label for uralaner also speci es an 8-week dosing interval for protection against Amblyomma americanum which requires a maximum of 7 purchases for 12 months of protection.
Each transaction could include the purchase of one or more doses for each product. Because of the purchase gap, each pair of transactions potentially resulted in variable durations of ectoparasiticide protection. Following completion of the protection period of the rst dose, there was the possibility of a period of time before the dog owner purchased the next dose. Gaps in protection were calculated based on the purchase dates for each product dose. For a purchase of a single dose, the purchase date was also the "administration" date for that dose with a protection end date calculated based on the product label recommended re-administration interval. For a single purchase of multiple doses, the administration date of the rst dose was the purchase date and the administration dates for remaining doses were set based on the recommended re-administration interval with the assumption that doses were administered consecutively when due. For dog owners with multiple purchase records per year, potentially with a variable number of doses at each purchase, the same assumptions were applied to each purchase record. This analysis assumes that each dose was administered to the dog on the date of purchase and at the correct consecutive interval(s) when multiple doses were purchased. This assumption provides an optimal estimate of timely re-administration of ectoparasiticide doses. If a dog owner deferred giving either the rst or subsequent dose(s) then the gap could have been larger than calculated in this analysis.
The total doses purchased were determined for each dog for the entire 12-month period and the gaps between dose administrations were calculated based on purchase dates. These possibilities were used to prepare a matrix that captured all possible dose-gap combinations. For example, uralaner users could have up to 5-7 doses administered within 12 months and therefore all possible gaps include "Dose 1-2", "Dose 2 -3", "Dose 3--4" and "Dose 4 -5".
Monthly products users could have up to 12 doses administered and all possible dose gaps could include "Dose 1 -2", "Dose 2 -3", and so on up to "Dose 11 -12". The dose gaps for each possible interval were combined across all of the annual purchased doses for each active ingredient and then used to calculate the average gap in weeks for each dose interval.
A "doses plus gap" period was created for each 2-dose period and de ned as the time duration encompassing the ectoparasite protection interval for the two doses plus the average gap between these doses. The percentage of time when ectoparasite protection was available could then be calculated for each "doses plus gap" using the recommended redosing interval for each product (8 or 12 weeks for uralaner and 4.3 weeks for the other actives). Dogs would be considered to be unprotected against ectoparasites during the gap portion.
Finally, statistical summaries were created for the age and weight of patients within the products being compared. Mean, range, and standard error of the mean for age and weight of patient dogs were calculated within the products being compared. Means were compared across groups using a t-test with a signi cance set at P < 0.05.

Results
Ectoparasiticide transaction records for four prescription ea and tick products were obtained from veterinary hospitals from across the United States (Table 1). More than half of dog owners obtained only 1-3 months of ea and tick protection, with less than 1/3 of owners obtaining 4-6 months of protection and less than 20% obtaining 7-12 months of protection (Tables 3 and 4). This ectoparasiticide purchasing record is inconsistent with veterinarian recommendations for nearly year-round ea and tick protection [1, 2,4,9,19,20]. Nearly half (43%) of all dog owners obtained just one dose of ectoparasiticide in the 12-month period regardless of ea/tick medication purchased. Similarly, close to half (42%) of dog owners who obtained more than one dose allowed time gaps between their purchase transactions of ea and tick medication ( Table 4). The proportion of transactions that created a protection gap tended to decrease with increasing numbers of doses purchased because the average length of these gaps tended to decrease. However, for dog owners who obtained more than 6 doses of the monthly administered products, the proportion of transactions with gaps increased between doses 6 and 7 ( Table 4). The longest average purchase gap duration was calculated for dog owners obtaining sarolaner (3.6 to 20.3 weeks) with shorter gaps for uralaner (3.3 to 12.8 weeks), afoxolaner (2.1 to 12.9 weeks) and lotilaner (1.6 to 8.9 weeks) (see Table 5). For dog owners obtaining uralaner, the protection proportion calculated for the "doses plus gap" period gradually increased with subsequent doses indicating a greater duration of administered protection and was: 65% for the period between doses 1 and 2; 74% for the period 2-3; 83% for period 3 -4; and, 88% for period 4 -5 ( Table 5). The protection proportion of each 2 dose plus gap period for the monthly administered products was smaller than for uralaner at the dose intervals for the rst 6 doses ( Table 5). The protection proportion for all the monthly medications generally increased and the gap size decreased from dose periods 1 to 12 with the exception of dose 6-7 which demonstrated one of the longest gaps between purchases (Table 5).  The impact of purchase gaps on the percentage of time that ectoparasite protection was available is shown for owners who purchased 1-3 months and 1-6 months of ea and tick medication in a year, the most common amount of protection purchased ( Table 3). The uralaner dosing interval is 12 weeks, therefore 1 and 2 doses (2.8 months and 5.6 months) of uralaner were compared to 3 and 6 doses of the monthly duration products afoxolaner, sarolaner, and lotilaner. Because uralaner is approved in the United States for an 8-week dosing interval when necessary for the control of Amblyomma americanum, 2 and 4 doses of uralaner were also compared to 3 and 6 doses of the monthly duration products. The total duration of the 3-month and 6-month "doses plus gap" period for each product are shown (Figures 1 a-b) and for each of these periods, the percentage of time when ectoparasiticide protection could be available was determined and compared.
The percentage of ectoparasite protection available during use of the rst 12 weeks or 3 months of the product purchased was 100% for uralaner with the 12-week dosing interval (12 weeks or 2.8 months) and 56% with the uralaner 8-week dosing interval, 36% for afoxolaner, 26% for sarolaner and 46% for lotilaner (Fig 1a). The percentage of ectoparasite protection available when dog owners purchased up to 6 months of medication was 65% for uralaner with the 12-week dosing interval and 55% with the uralaner 8-week dosing interval, 36% for afoxolaner, 25% for sarolaner and 46% for lotilaner (Fig 1b).

Discussion
Timely and regular administration of ectoparasiticide medication in a manner consistent with veterinarian recommendations and package insert directions is essential for optimal effectiveness and effective ectoparasite control [12,[36][37][38]. Prior studies have shown that dog owners fall short in purchasing the quantities of ea and tick medication necessary to meet veterinarian recommendations for effective ea and tick control [32,33]. The present study of ectoparasiticide purchase records for 506,637 dogs con rms these previous ndings with 43% of dog owners purchasing just 1 single dose of ectoparasiticide medication in a 12-month period, and 54-70% of dog owners purchasing just 1-3 months of the ectoparasiticide protection. The present study also shows that of dog owners purchasing more than one dose of ectoparasiticide, 42.4% delayed purchases of subsequent doses beyond the e cacy duration of the prior dose noted in the manufacturer's product insert making timely redosing impossible Gaps in timely ectoparasiticide purchases represent times when dogs may not be protected against eas and ticks. In addition, if an established ectoparasite population was not eliminated by prior treatment, then a purchase gap interrupts the treatment and may allow that parasite population to recover. Also, treatment gaps lead to an increased risk for prolonged ectoparasite infestation and potential exposure to vector-borne pathogens [36,38].
For this study, medication administration was assumed to have occurred on the day of purchase. The owners may have delayed the dose administration for days, weeks, or longer following purchase, but the actual day of administration was not veri ed in this study involving a large dog owner population. Therefore, the timing of medication administration presented here represents the best possible amount of time between the delivery of consecutive doses. However, studies in both human and veterinary medicine have shown that timely administration frequently fails to occur even when all necessary doses are dispensed at once [35,[39][40][41][42][43][44]. Therefore, it is possible that the actual time to administration was longer than reported here, and delays in administration may have occurred even when multiple doses of medication were purchased at one time.
Considering the realities of dog owner ectoparasiticide purchases, the present study examined the value of the longer duration uralaner medication compared to monthly administered ea and tick medications. The bene ts come from the length of time that a single uralaner dose protects against ectoparasites as well as the reduced number of doses that need to be given to provide protection for a given period of time. The facts that owners allow gaps to occur in their ea and tick medication purchases and that there is a need for more frequent redosing intervals for monthly administered products result in smaller proportions of time when dogs receive ectoparasite protection than is seen with longer duration medication. More frequent gaps in dosing for monthly products can reduce their e cacy in accomplishing the goal of ectoparasite elimination and consistent ectoparasite control.
When dog owners purchase more than one month of ea and tick medication, they often purchase either 3 months or 6 months of protection. If the dog owners' goal is to provide continuous protection for these 3 or 6 months, then their dog can get 12 weeks of continuous protection with one dose of uralaner or with multiple one month intervals using shorter duration ectoparasiticides. The shorter duration products require repeated on-time dosing to achieve the same continuous protection as one dose of uralaner. The gap analysis demonstrates that dog owners buying monthly products usually do not achieve the goal of on-time dosing with inter-dose intervals that range from 9.9 to 12.9 weeks for afoxolaner, 16.4 to 20.3 weeks for sarolaner, and 6.5 to 8.9 weeks for lotilaner. The proportion of time when ectoparasite protection is provided with the purchase of up to 3 months of product are: 100% for uralaner (2.8 months or 12 weeks), 36% (3 months) for afoxolaner, 26% (3 months) for sarolaner and 46% (3 months) for lotilaner (Fig 1a). If a shorter 8-week dosing interval is used for the calculation with uralaner, then the percentage of time when ectoparasite protection is available is 56%.
Gaps in ea and tick protection seen when dog owners purchase 6 months of annual treatment are shown in Figure 1b. The size of the gaps usually shrinks when dog owners buy more months of protection. This shrinkage may simply be secondary to the effect of purchasing more doses within a dwindling period of possible unprotected time. Owners who purchased two doses of uralaner obtained 24 weeks of protection with a 12.8-week gap between doses, resulting in their dog being protected from eas and ticks for 65% of the "doses plus gaps" interval. The monthly product purchases were spread out by gaps of various sizes that ranged from 4 to 20 weeks between doses and provides protection from eas and ticks for 36% of the "doses plus gaps" interval for afoxolaner, 25% for sarolaner and 46% for lotilaner. Even if a shorter 8-week dosing interval is used for the calculation with uralaner, the percentage of the "doses plus gaps" time when ectoparasite protection is available is 55%.
For each of the ea and tick medications dosed monthly, the longest "doses plus gap" interval was between the 6 th and 7 th dose ( Table 5). Manufacturers often package monthly ea and tick medications into packages of 3 or 6 doses. The size of the gap following the 6 th dose may be secondary to a delayed repeat purchase following an initial purchase of a single card with 6 doses.
This difference in number and duration of purchase gaps and the resultant percent of time when dogs are protected against ectoparasites has practical implications. Interruptions in ectoparasiticide protection that arise from either gaps in dose purchase timing or other delays in administration can result in a perceived lack of effectiveness if the duration of continuous use is insu cient to eliminate established infestations on the animal, in the home, or in the face of continued parasite exposure. Previous studies have shown that multiple, consecutive doses of afoxolaner, sarolaner, or lotilaner were required to eliminate an established ea infestation, with evidence of the infestation continuing following a single dose [23,[26][27][28]. A treatment gap between doses of a monthly ectoparasiticide may allow the infesting ectoparasite population to rebound if the population is not eliminated. The longer duration medication, uralaner, provides ectoparasiticide protection for a duration that provides complete resolution of ea infestation without re-dosing [26].
Studies on patient and pet owner adherence to prescribed treatment regimens in both human and veterinary medicine have shown that simpler, less frequent dosing regimens improve compliance across a variety of therapeutic classes [39][40][41][42][43][44][45][46][47][48][49]. The present study similarly demonstrates the bene t of less frequent dosing with a longer duration ectoparasiticide. Dog owners who purchased ectoparasiticides with time gaps between doses, but chose the longer duration product, provided more consecutive weeks of medication, reduced treatment interruptions, and increased the overall percentage of time when ectoparasite protection is available during each "doses plus gap" period than dog owners who purchased a monthly treatment. Such increases in the overall duration of ectoparasite protection with fewer interruptions provided by the longer duration uralaner medication should improve ectoparasite control, decrease exposure to VBP and provide greater pet owner satisfaction with efforts to remove ectoparasites.
In the United States, dog owners purchase isoxazoline ectoparasiticides with a prescription from a veterinarian. We have seen that veterinarians may recommend up to 12 months of protection for eas and ticks. The dog owner has the option to purchase one or multiple doses in one or more transactions. Veterinarians expect that dog owners use the doses they purchase and that they apply the next dose when a previous dose has completed its label recommended protection interval. More information is still needed to establish actual owner behavior in administering ea and tick medications at home; however, it is clear that there are delays in ectoparasiticide administration based on veterinary hospital transaction records. There is a real bene t to the pet owner and the dog when a longer-acting ectoparasiticide is prescribed and this relates directly to the additional week/months of coverage per administered dose with a need for fewer dose administrations throughout the year.

Conclusion
This study demonstrated that dog owners fail to adhere to veterinarian recommendations for ectoparasiticide protection by purchasing fewer doses of ectoparasiticide than recommended and allowing time gaps between their dose purchases that make adherence to recommended re-administration intervals impossible. Dog owners prescribed a longer duration medication, uralaner, obtained more consecutive weeks of ectoparasite protection with a larger overall percentage of time when their dogs are protected from ectoparasites compared with monthly re-administration medications. Saini SD, Schoenfeld P, Kaulback K, Dubinsky MC. Effect of medication dosing frequency on adherence in chronic diseases. Am J Manag Care. 2009;15 6:e22-33.

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Stanford RH, Averell C, Parker ED, Blauer-Peterson C, Reinsch TK, Buikema AR. Assessment of Adherence and Asthma Medication Ratio for a Once-Daily and Twice-Daily Inhaled Corticosteroid/Long-Acting β-Agonist for Asthma. J Allergy Clin Immunol Pract. 2019;7 5:1488-96.e7. Figure 1 Impact of ectoparasiticide purchase gaps on the percent of time protected. a. Impact of purchase gap when up to 3 months of ectoparasite protection is purchased with gaps. a b. Impact of purchase gaps when up to 6 months of