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Clinician's Forum: Expert Views from a Roundtable on Heartworm Prevention

Clinician's Forum: Expert Views from a Roundtable on Heartworm Prevention

Chris Adolph, DVM, MS, DACVM-Parasit

Byron L. Blagburn, MS, PhD

Dwight D. Bowman, PhD

Lynn Buzhardt, DVM

Peter H. Eeg, DVM

Susan Little, DVM, PhD, DACVM-Parasit

Tom L. McTier, PhD

Andrew R. Moorhead, DVM, MS, PhD, DACVM-Parasit

Cassan N. Pulaski, DVM, MPH, PhD(c)

Christopher J. Rehm, Sr., DVM

Parasitology

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Clinician's Forum: Expert Views from a Roundtable on Heartworm Prevention

Sponsored by an educational grant from Zoetis

Participants

  • Chris Adolph, DVM, MS, DACVM-Parasit, Zoetis, Tulsa, OK
  • Byron L. Blagburn, MS, PhD, Auburn University, Auburn, AL
  • Dwight D. Bowman, PhD, Cornell University, Ithaca, NY
  • Lynn Buzhardt, DVM, The Animal Center, Inc., Zachary, LA
  • Peter H. Eeg, DVM, Poolesville Veterinary Clinic, Poolesville, MD
  • Susan Little, DVM, PhD, DACVM-Parasit, Oklahoma State University, Stillwater, OK
  • Tom L. McTier, PhD, Zoetis, Kalamazoo, MI
  • Andrew R. Moorhead, DVM, MS, PhD, DACVM-Parasit, University of Georgia, Athens, GA
  • Cassan N. Pulaski, DVM, MPH, PhD(c) , Louisiana State University, Baton Rouge, LA
  • Christopher J. Rehm, Sr., DVM, Rehm Animal Clinic, P.C., Mobile, AL
  • Kathy Gloyd, DVM, Moderator, President, Elevate DVM

Heartworm Prevention and Treatment: Clinical Recommendations in the Age of Resistance

Key Points

  • All dogs should receive year-round heartworm preventives.
  • All dogs should be screened for heartworm infection yearly with an antigen and a microfilariae test.
  • Resistance to macrocyclic lactones has been shown to occur throughout the southeastern US.
  • Despite resistance, macrocyclic lactones remain the mainstay of preventive treatment and are highly effective when used as prescribed.
  • When prescribing a heartworm preventive, one should consider the ability of pet owners to comply with prescribed regimens and successfully administer medications.

Heartworm is an important parasite to prevent in dogs because of its life-threatening consequences. Yet, despite the broad availability and use of effective heartworm preventives and generally high awareness of the disease among dog owners, its incidence is increasing. Heartworm infection has now been diagnosed in dogs in all 50 states,1 and according to the American Heartworm Society (AHS) 2016 Incidence Survey, the average number of positive cases per veterinary clinic rose by 21.7% over 2013 numbers.1

Macrocyclic lactones (MLs) are the only class of drugs approved for the prevention of canine heartworm disease, and veterinarians have been prescribing them for decades. An increase in lack of efficacy of MLs was first reported in 2004,2,3 mainly in the Mississippi River Valley, with research confirming the existence of isolates of Dirofilaria immitis that are resistant to MLs presented in 2013.4,5 Since then, additional resistant strains have been identified, with some strains outside the lower Delta region.6-8 Recent survey work sponsored by AHS has further confirmed these findings through genetic analysis of microfilariae from field cases of dogs suspected of harboring ML-resistant D. immitis.9 Figure 1 is a composite showing 14 different individually identified isolates/strains resulting from the work of the above investigators.  

Location of confirmed or suspected ML-resistant heartworm isolates/strains. Each dot indicated an individual isolate. Map courtesy of Dr. Tom McTier.
Location of confirmed or suspected ML-resistant heartworm isolates/strains. Each dot indicated an individual isolate. Map courtesy of Dr. Tom McTier.

Figure 1 Location of confirmed or suspected ML-resistant heartworm isolates/strains. Each dot indicated an individual isolate. Map courtesy of Dr. Tom McTier.

Figure 1 Location of confirmed or suspected ML-resistant heartworm isolates/strains. Each dot indicated an individual isolate. Map courtesy of Dr. Tom McTier.

The perception is that resistance is only a problem in the Mississippi Delta, but resistant strains can be found anywhere there are infected dogs. —Dr. Susan Little

Infection with heartworm, whether due to ML-sensitive or ML-resistant strains, is now a nationwide concern with very simple risk factors. Heartworm disease can exist anywhere there are dogs, mosquitoes, and the potential for introducing infected dogs. At present, while ML resistance appears to be primarily concentrated in the Delta region, it is not understood how rapidly or how far it will spread. Today it is not unusual for dogs to travel with their families, and dogs are often transported to be rehomed following natural disasters from areas with high incidence of infection where resistant strains have been identified to areas where heartworm has been less frequently diagnosed. These factors, and others, create a situation where any dog is at risk—one that all clinicians need to be aware of and adjust their clinical practice to address. The AHS has issued a Heartworm Resistance statement acknowledging the confirmation of ML resistance with key points to discuss with pet owners.10 

In the last 5 years, I have changed my approach to heartworm prevention because every dog in my clinic is at risk today. My clients don’t know where the dog that lives next door traveled this year or if it was adopted from the Southeast US. —Dr. Peter Eeg

This article summarizes a recent roundtable discussion among practicing veterinarians and veterinary parasitologists on how clinicians can best address these issues and actions they can take to provide the best protection for their patients.

D. immitis isolates with confirmed resistance to MLs have been found as far north as Illinois and as far east as Alabama, with the majority of these isolates concentrated in the Mississippi Delta. —Dr. Tom McTier

Best Practices for Heartworm Prevention

The two main tenets of best clinical practice for preventing heartworm disease the roundtable experts identified are:

  • Testing all dogs for heartworm antigen and microfilariae at least once a year, and
  • Administration of an FDA-approved heartworm preventive medication, year-round, at the appropriate dose using a protocol designed for maximum compliance in the individual patient.

Year-Round Protection for Every Dog

Research has shown that a single heartworm-positive dog substantially increases the risk of infection for other healthy dogs in that neighborhood.11 In an area where a large percentage of dogs are on prevention, an owner may be able to get away with no prevention or missed doses for a while because few of the mosquitoes in that area will be carrying heartworm. That should not deter us from emphasizing the importance of year-round prevention for all dogs. —Dr. Peter Eeg

Veterinarians are strongly encouraged to adhere to the recommendations of the AHS12 and the Companion Animal Parasite Council (CAPC).13 Both groups recommend year-round protection, with no lapses, with an FDA-approved ML as well as limiting contact with mosquitoes. These drugs affect microfilariae, third and fourth-stage larvae, and in some instances of continuous use, adult heartworms.7 Currently marketed preventives include:

  • Oral, administered monthly by pet owner
    • Ivermectin
    • Milbemycin oxime
  • Topical, administered monthly by pet owner
    • Moxidectin
    • Selamectin
  • Injectable, administered every 6 months by veterinarian
    • Moxidectin

For information on specific products, many of which are combined with other agents to provide broad-spectrum efficacy against multiple parasites, consult the AHS and CAPC websites.12,13

Annual Testing: Looking for Heartworm Infection Means Looking for Microfilariae as well as Antigen

If you are not testing for heartworm, you won’t find it and you will think you don’t have it. We have to be testing for both antigen and microfilariae routinely. Until a client has a heartworm-positive dog, a lot of them really don’t understand the devastation the disease causes. It’s our job to educate them—it is what our clients expect from us. —Dr. Chris Rehm

Annual testing is another essential component of heartworm prevention. Both AHS and CAPC recommend that all dogs, including those on heartworm prevention, be tested annually using both antigen (Ag) and microfilariae (Mf) tests starting at 6 months of age. In some high-incidence areas, testing dogs twice each year may be indicated, particularly in dogs with high exposure to mosquitoes.

Both Ag and Mf testing is recommended because surveys have shown that some infected dogs can be Ag-positive and Mf-negative while others are Mf-positive and Ag-negative. —Dr. Susan Little

Best Practice—Perform Both Antigen and Microfilariae Testing at Least Once a Year

Antigen Tests

  • Antigen tests detect antigen from the adult female heartworm.
  • Several good options are available for in-house testing, or samples can be sent out to a lab.
  • False-negative results can occur when infections are light, female worms are still immature, only male worms are present, test instructions have not been followed correctly, or Ag is blocked due to immune complexes.
  • Heat pretreatment of serum samples breaks down Ag-antibody complexes that can cause false-negative results,14-18 but this approach is not recommended for routine use on all samples tested in clinical practice. 

Microfilariae Tests 

Microfilariae may be identified microscopically by several methods:

  • The modified Knott procedure, a concentration technique, is the preferred screening test with the most accurate results.
  • Examination of a wet mount of fresh blood or blood treated with an anticoagulant is a quick and easy option, although less sensitive than the Knott test.
  • Examining the buffy coat(liquid-cell interface) in a micro-hematocrit tube, looking for movement, is another method.
  • Concentration using a stained or unstained Millipore filter(now available from Amazon) is an additional option.
  • D. immitis Mf must be differentiated from those of Acanthocheilonema (formerly Dipetalonema) reconditum and, rarely in the US, from other Dirofilaria spp found in fresh blood samples.

Managing the Microfilaremic Dog

Understanding the life cycle of the heartworm (Figure 2) is key to understanding heartworm treatment protocols. Melarsomine dihydrochloride, the only drug approved by the FDA for heartworm treatment, eliminates adult heartworms but does not kill larval stages. Therefore, after melarsomine (adulticide) treatment, dogs should be continued on ML preventives to kill these immature stages.12,13 Topical moxidectin is the only drug with a label claim for the removal of circulating Mf in heartworm-positive dogs; other MLs have been used off label to clear Mf. No adverse events were seen in the studies conducted to secure FDA label approval of topical moxidectin for clearing Mf. If reactions are a concern in dogs with high numbers of circulating Mf, pretreatment with antihistamines and glucocorticosteroids can help minimize risk.12

Persistent circulating microfilariae must be eliminated because they serve as a means of presenting mosquitoes with a population of Mf that have been preselected for resistance by surviving the killing of the susceptible Mf with MLs. —Dr. Dwight Bowman

The heartworm life cycle. Reprinted with permission from the American Heartworm Society.
The heartworm life cycle. Reprinted with permission from the American Heartworm Society.

Figure 2 The heartworm life cycle. Reprinted with permission from the American Heartworm Society.

Figure 2 The heartworm life cycle. Reprinted with permission from the American Heartworm Society.

Microfilariae can persist in infected dogs for more than a year after adults have been cleared,12 even in the presence of very high levels of some MLs. In addition, a heartworm-positive dog may harbor heartworms ranging from <1 month to as long as 7 years. The wide range in maturity of heartworms in an infected dog can make it difficult to eliminate all stages of the parasite. A clinician may think a dog has been successfully treated only to find continued infection with adult heartworms or with Mf when retesting 6 or 12 months later. This needs to be a consideration when choosing a treatment protocol. Eliminating Mf at the beginning of treatment, initiating a 30-day course of doxycycline (to eliminate Wolbachia, a gram-negative bacteria found within the heartworm), providing continuous ML prevention (monthly or sustained-release moxidectin injectable), followed by a three-dose melarsomine protocol gives the highest probability of achieving heartworm-free status in the affected dog.12 Delaying the start of adulticide treatment can allow additional pathology to develop in the patient. 

Heartworm Resistance: The Threat to Our Patients Is Here to Stay

The perception that resistance is only a problem in some areas of the South may stem in part from the fact that we are not screening to the same degree in other regions. —Dr. Susan Little

Some veterinarians I talk to underestimate the threat in their local area. That may be due, in part, to the fact that they are not specifically looking for resistant strains when they have a heartworm-positive dog; they are more likely to presume it is due to a lack of compliance. —Dr. Tom McTier

Reported cases of loss of efficacy (LOE) of heartworm preventives were first published in the US in 2005,2 with a heavy concentration in the Mississippi River Valley and Southeast region, and have persisted since then. Many of these cases were attributed to lack of full compliance with preventive regimens.3 However, ML resistance has been confirmed in cases with well-documented compliance with preventives.4,5 Whole genome analysis has been performed on isolates with documented LOE to identify genetic markers that correlate with evidence of resistance.15

There’s no question that resistance is real; we have the scientific data to support that.5 Multiple isolates have been identified—such as JYD-34 originally isolated from a dog in Illinois,6 Yazoo-2013 from a dog in Mississippi, and Metairie-2014 isolated from a dog in Louisiana. Yet some veterinarians I talk to underestimate the threat in their local area. That may be due, in part, to the fact that they are not specifically looking for resistant strains when they have a heartworm-positive dog; they are more likely to presume it is due to a lack of compliance. —Dr. Tom McTier

A complete review of the causes of ML resistance in heartworms is beyond the scope of this article, but contributing factors could include improper use of MLs (eg, using “slow kill” protocols, poor compliance leaving gaps in protection, not looking for Mf), as well as the parasite’s natural adaptation to the drugs over time. Macrocyclic lactones remain the only effective FDA-approved class of drug currently available to prevent heartworm disease. Preserving efficacy of MLs is of paramount importance in veterinary medicine.

It is very important that as a profession we use macrocyclic lactones appropriately and at the right doses if they are going to retain their efficacy to prevent canine heartworm disease. —Dr. Dwight Bowman

Definitive diagnosis of suspected drug-resistant heartworm cases is not possible in the clinic due to the lack of point-of-care clinical tests or validated laboratory tests for detecting resistance in heartworms. Currently, the only means available to prove resistance is to perform a controlled efficacy study in a laboratory,4,5 a time-consuming and expensive process that is not practical in clinical practice. The microfilariae suppression test (MFST), which measures Mf levels both before and after a microfilaricidal dose of ML, was first proposed by Geary and colleagues as a means for detecting resistance.20 An algorithm utilizing the MFST to help clinicians evaluate cases of suspected resistance to MLs was recently reported.21 Suspect blood samples can be sent to Dr. Cassan Pulaski at Louisiana State University for further laboratory analysis. Samples then undergo screening by the team at McGill University to confirm the presence of genes believed to be related to drug resistance.

Best Practice: Minimizing Heartworm Transmission by Relocated Dogs

I see a lot of rescue dogs coming up from the South in my practice in Maryland. We immediately take a blood sample and test for microfilariae because they are very often heartworm positive. The rescue groups usually are only using an antigen test. If positive for Mf, we follow the AHS protocol and monitor them as closely as we can. —Dr. Peter Eeg

Transporting and relocating dogs is an increasingly common practice—for example, during emergencies, such as hurricanes, when homeless dogs from heartworm-endemic areas in the southern US are transported to other areas to be rehomed. The AHS and Association of Shelter Veterinarians (ASV) have developed a protocol to minimize the risk of heartworm transmission in these cases,19 which stipulates both Ag and Mf testing before transport. Some shelters and rescue groups may only do Ag testing, especially in a crisis situation. Clinicians treating these dogs upon arrival should first test for Mf, as Ag-negative, Mf-positive dogs are more common than previously thought.

It is important to obtain as much history as possible on relocated dogs regarding drugs used in past heartworm prevention and treatment. For example, some dogs may have received incomplete heartworm treatment, or been treated with levamisole to clear Mf that were not cleared with MLs.

Five Steps Clinicians Can Take to Manage the Risk of Resistance Today and Looking Forward

1

Consistently Test and Use the Correct Methods

As discussed earlier, all dogs should be tested annually for heartworm using both an Ag test and a Mf test.

Early detection and early treatment lead to better outcomes. People have gotten the message with other chronic diseases; we need them to get the message with heartworm. Dogs should be re-tested every year because we know that some dogs become infected despite the fact that they were given a preventive. —Dr. Susan Little

2

Use the Right Preventive Product for Each Patient and Owner

Factors in selection of a heartworm preventive include compliance (see below), cost, convenience, and safety. Not all preventives have equal efficacy; some, like moxidectin in a sustained-release injectable formulation (ProHeart® 6, Zoetis) or in a high dose topical formulation, may be effective immediately while some other monthly products require three successive doses before they are fully effective, depending on the specific strain to which the dogs are exposed. Evaluate the prescribing information for each product, available online from the manufacturer, before making your selection.

There is no cookie cutter parasite control protocol for all clients. Veterinarians should talk to each client about their lifestyle and their pet’s lifestyle before choosing a medication. —Dr. Lynn Buzhardt 

3

Select Preventives for Your Practice—and Your Patients—That Increase Compliance

Compliance has long been a problem in heartworm prevention, with no reliable way to confirm whether preventives purchased are actually administered at home by the owner. The consensus among practicing veterinarians in this roundtable was that use of injectable moxidectin increases compliance because it puts control back in the veterinary clinic, rather than having to rely on the pet owner remembering to treat the dog on time, all the time. The product provides 6 months of protection in a single dose and can only by be administered by veterinarians and veterinary staff certified to do so.

The fact that the owner must bring the dog back for a second visit in 5 to 7 months for the next 6-month dose benefits the patient by ensuring year-round protection and brings peace of mind to the owner who doesn’t have to remember to give a monthly dose. A further benefit is that moxidectin has demonstrated efficacy against a resistant heartworm isolate.22

The one to pick is the product the client is able to consistently give and that covers the parasites that they’re worried about. —Dr. Andy Moorhead

We all have clients we assume are perfect in their compliance—only to find out they aren’t! —Dr. Chris Adolph

If we solve the compliance issue, we solve 98% of our heartworm infection problems. —Dr. Byron Blagburn

Injectable moxidectin brings clients in more frequently, at least twice a year. I also think it protects the pet better overall, and takes away the compliance issue. I have seen no adverse reactions of any import. —Dr. Peter Eeg

In parasite discussions with clients, we prioritize heartworms because they are the parasite most likely to kill the dog. Broad-spectrum preventives are great if the owner gives them consistently, but we want to make sure the dog gets 6 months of heartworm medication and the injection will guarantee that. If clients see a flea or tick, they’ll remember to give medication, but there’s no visible reminder with heartworm. —Dr. Lynn Buzhardt

Moxidectin, the molecule itself, is the most potent ML preventive against Dirofilaria immitis. In the original studies of the oral formulation (available outside the US), moxidectin was 100% effective in preventing heartworm disease, providing complete efficacy at lower doses and for longer durations than other oral MLs.23 This should be a factor in making optimal decisions about parasite control. —Dr. Tom McTier

4

Communication—EVERYONE in the Practice Must Send the Same Simple Message

A clear and consistent message about heartworm prevention and screening is crucial. Resources are available to help educate pet owners about the importance of heartworm prevention, including clinic scripts for better communication about heartworm, on the AHS website. It is critical that the entire staff is on board. Below are some helpful tips from the panel to help improve client communications in your clinic.

Compliance is always going to be one of our biggest challenges, but we can improve it with good communication. We send an email, or sometimes a snail mail or a text, to remind our clients when their pets are due for parasite prevention and testing. We then follow up with a phone call or two if needed. The way we get them back is by making sure that we lead off our parasite discussion with heartworms. —Dr. Cassan Pulaski

Keeping everyone in the practice on the same page, with the same talking points, is really important. Have three different people repeat one simple concise message and clients are more likely to retain the important parts when they leave. —Dr. Lynn Buzhardt

Instead of going into the exam room and asking the client what they are using for flea and heartworm prevention, ask when is the last time they gave heartworm and flea prevention, and then ask what they gave. That changes their answers and can open the all-important compliance discussion. —Dr. Cassan Pulaski

5

Provide Protocols to Cover All Parasite Needs

Many of the ML preventives feature broad-spectrum coverage against a variety of other internal and external parasites, such as hookworms, roundworms, whipworms, and mange mites. Detailed information is available for each product at the CAPC website in the Quick Product Reference Guide.13 Depending on the ML you choose, you’ll need to put together a plan for protection from other parasites that are concerns for an individual patient.

For example, injectable moxidectin protects against hookworms (Ancylostoma caninum, Uncinaria stenocephala) in addition to the L3 and L4 stages of D. immitis. If roundworms (Toxocara canis, Toxascaris leonina) are an issue, you’ll need to add pyrantel pamoate. If whipworms (Trichuris vulpis) are a problem, fenbendazole can be added to the regimen.

If we prioritize heartworm as the most life-threatening parasite for the dog, we want to improve compliance for that particular parasite first. Then we can structure our protocol for control of other harmful parasites from that starting point. —Dr. Lynn Buzhardt

One thing we consider is potential for zoonotic disease transmission. When we choose a parasiticide protocol in Louisiana, it has to include roundworm and hookworm prevention to protect not only the pet but also the pet’s family. —Dr. Lynn Buzhardt

Best Practice: The New Clincal Standard Set Out By The Experts

Year-round heartworm protection should be the standard for all dogs.

  • Heartworm is now found in all 50 states, so all dogs are at risk.
  • Use the right preventive product for each patient and their owner.
  • Choose a product that is likely to increase compliance to enhance prevention.
  • Despite resistance, MLs are still highly effective when used properly.
  • Make a plan for protection from other parasites to supplement the heartworm preventive selected for each patient.

Perform annual screening tests.

  • Conduct both an Ag test and a Mf test.
  • Test twice a year in endemic areas where risk is high.

Follow AHS and CAPC recommended protocols to treat heartworm infection.

  • Monitor for and treat persistent circulating Mf.
  • Send suspect blood samples for further laboratory analysis.

The consensus among practicing veterinarians in this roundtable was that use of injectable moxidectin increases compliance because it puts control back in the veterinary clinic, rather than having to rely on the pet owner remembering to treat the dog on time, all the time.

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References

For global readers, a calculator to convert laboratory values, dosages, and other measurements to SI units can be found here.

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