Heartworm-positive dog requires tailored treatment

Since melarsomine dihydrochloride (Immiticide®, Merial Ltd., Duluth, Ga.) became available for administration by veterinarians in the USA in 1995, it has gradually replaced thiacetarsamide, which is no longer available, and is now widely used as a heartworm (Dirofilaria immitis) adulticide. Both drugs are arsenicals and known to possess a relatively low safety margin, but they kill adult heartworms, and after many years of use still remain the only drugs approved for this purpose by the U.S. Food and Drug Administration. Melarsomine is superior to thiacetarsamide in its (1) greater efficacy against adult heartworms and immatures; (2) increased safety, with no hepatic or renal toxicity, the option to use dimercaprol as an antidote in case of inadvertent overdosing, and reduced severity of injection site reactions; (3) convenience of administration, with two to three IM injections rather than four IV injections; and (4) increased shelf life due to its availability as an unreconstituted, lyophilized drug.

Treating adult heartworms

For adulticide therapy with melarsomine, the veterinarian has the option of the standard two-dose regimen or the alternative three-dose protocol. For both options, melarsomine is administered via deep intramuscular injection in the epaxial lumbar muscles. Mild swelling and some soreness, usually lasting for only a few days but may linger for 30 days, may occur at the injection site in up to 30 percent of the patients. Rarely, a firm nodule may persist indefinitely. Strict adherence to the manufacturer's instructions and classifying the stage of disease before treatment will minimize local reactions and reduce the risk of pulmonary thromboembolism due to dead worms and existing arterial disease. Also, for clinically ill dogs, an attempt should be made to stabilize the patient's clinical signs with supportive therapy before proceeding with adulticidal treatment. Exercise restriction during the first- (standard) or second- (alternative) month period following treatment is also essential for minimizing cardiovascular complications.

Table 1.

The standard protocol of two injections, separated by a 24-hour interval, is recommended for dogs at low risk of thromboembolic complications. This regimen kills more than 90 percent of the adult worms and 4-month-old immatures. For dogs at greater risk, a gradual two-stage elimination of worms may be accomplished by using the alternative treatment protocol. This protocol includes a single initial dose, which kills about 50 percent of the worms (90 percent of the males and 20 percent of the females), followed one to two months later by the standard two-dose regimen, with an overall efficacy of about 99 percent. By initially killing fewer worms and completing the treatment in two stages, the cumulative impact of worm fragments on severely diseased pulmonary arteries and lungs can be reduced. More veterinarians are now using this alternative protocol, regardless of the stage of disease, due to the increased safety and efficacy.

Surgical care

Prompt surgical removal of worms from the right atrium and orifice of the tricuspid valve of dogs with caval syndrome is necessary for survival of the patient, and sometimes veterinarians choose the option to remove worms from the pulmonary artery and lobar branches of other dogs from high risk areas, after confirmation by sonographic techniques that adult heartworms are in accessible locations. Within a few weeks following recovery from surgery, adulticide treatment is generally recommended to remove any remaining worms.

Emboli in a caudal lobar artery of a dog, following arsenical adulticide treatment.

Diagnostic follow-up

A negative heartworm antigen test four to six months after adulticide therapy is indicative of elimination of adult heartworms, and this is more frequently achieved with the higher-efficacy alternate regimen than with the standard protocol. Retreatment of a dog that is antigen-positive at this time is generally acceptable. However, the health risk of a few residual heartworms should be assessed on an individual case basis, with consideration of the general health of the patient, age in relation to life expectancy, and performance expectations for the patient, before committing to retreatment. As implied later in this article, continuous monthly prophylactic dosing with IVM should generally eliminate the few heartworms remaining after adulticide treatment or surgery.

Safety and efficacy

Although postmarketing pharmacovigilance studies indicate that the adverse reactions and mortality values reported from the clinical use of Immiticide are much less than what is predicted and stated on the package insert, mortality following adulticide treatment with this product is not a rare event. Following treatment with an arsenical, essentially all the adult worms die over a one- to two-month period. Spreading the death of adult worms over a period of several months or longer should greatly reduce the risk of severe thromboembolism and death of the canine patient. Thus, alternative measures for the elimination of adult heartworms with reduced adverse reactions and mortality is greatly needed.

During the past two decades, my laboratory has been actively engaged in evaluating the effectiveness of monthly administration at prophylactic dosages of macrocyclic lactone (ML) preventive drugs, particularly ivermectin (IVM, with and without pyrantel pamoate) and milbemycin oxime (MBO), against late larval stages (precardiac), immatures (early cardiac), young adults, and adult heartworms (Table 1, p. 17). The results of these studies indicate that IVM has potent safety-net (reach-back or retroactive activity against immatures) and adulticidal activity. The slow killing effects of IVM are related to the age of the heartworms at initiation of monthly dosing. The earlier treatment is started, the more stunted the developing worms are (Ž 20 percent), the greater the reduction in worm mass (Ž 20 percent) of older worms, and the shorter the survival time of the worms. For example, when continuous monthly dosing with IVM is started four months after infection, approximately 70 percent of the worms are dead after six months of treatment and six additional months are required for 95 percent efficacy. Moreover, 16 monthly doses of IVM against 8-month-old adult heartworms kills over half of the worms, with all surviving worms moribund, and an additional year of dosing results in 95 percent efficacy against worms of similar age. Microfilaremia and antigenemia levels are influenced similarly by the age at which monthly dosing is started. The earlier treatment is started, the fewer the number of dogs that become microfilaria- or antigen-positive, the lower the blood levels of microfilariae and antigen, and the sooner these test values become negative.

In contrast, MBO is only moderately effective (41 percent) against 4-month-old immatures and completely ineffective against adult heartworms, under similar dosing schedules. Limited studies with selamectin and injectable, sustained-release moxidectin suggest that they have potent safety-net activity and that their activity against adult worms is somewhat less than that of IVM.

Suggested Reading

Although prolonged monthly administration of prophylactic doses of IVM clearly kills adult heartworms, the use of this method as an alternative adulticidal therapy at this time should be done only with caution and adequate monitoring (at least once every six months) of the infection and disease status of the patient. Although dead adult heartworms induce more acute clinical disease (which sometimes includes death) than do live adult heartworms, it is generally accepted that the presence of live worms during this protracted monthly treatment will continue to cause disease, the severity of which depends on the health status of the dog at the time of treatment, the worm burden, and the level of activity of the patient. It is yet to be determined whether or not monthly treatment with IVM would allow irreversible, unacceptable pathologic changes to occur during this time. For many patients, pathologic changes should be minimal and acceptable, compared with the serious consequences frequently resulting from arsenical therapy. Our observation that no heartworm-positive dogs on monthly IVM have died, while at least two nontreated control dogs have died, strongly suggests that less active dogs (e.g., "lap dogs," "couch potatoes") are at virtually no risk to severe thromboembolism and death. On the other hand, we must assume that heartworm-positive working dogs would be more at risk from this monthly dosing with IVM than less active dogs, but this is yet to be determined.

Historically, clearance of circulating microfilariae three to six weeks after adulticide therapy was the next step in treating the heartworm-positive dog. No drugs are currently approved by the FDA in this country as microfilaricides, however, the MLs are safe and effective drugs for this purpose. More recently, the use of ML preventives, with their broad life-cycle filaricidal activity, has led to the incorporation of microfilaricidal treatment into the routine prevention program in most practices. All of the MLs are effective at the prescribed prophylactic dosages. MBO is the most potent microfilaricide at its label dosage and produces the most rapid clearance of rate, but close observation of treated dogs with moderate to high microfilarial counts for systemic adverse effects is advised for 8 to 12 hours following treatment with such a product. Injectable moxidectin, topically applied selamectin, and orally administered IVM preventives gradually eliminate the microfilariae in most dogs within six months.