Therapy of Canine Heartworm Disease

By | 2013-06-11

Melarsomine

In most cases of HWD, it is imperative to rid the patient of the offending parasite. Thiacetarsemide, for decades the only drug approved for this purpose, is no longer available. It has been replaced by melarsomine (Immiticide), an organoarsenic superior in safety and efficacy to thiacetarsemide. With two doses (2.5 mg/kg intramuscularly every 24 hours), the efficacy is over 96%. Melarsomine has a mean retention time five times longer than thiacetarsemide, and its metabolites are free in the plasma (on which heartworms feed). In a study of 382 dogs with heartworm infection receiving melarsomine, none required cessation of therapy due to hepatorenal toxicity (as compared with 15% to 30% with thiacetarsemide), and no case of severe postadulticidal thromboembolization was observed.

Despite the enhanced safety of this product, adverse reactions are still noted. In fact, successful pharmacologic adulticidal therapy, by definition, dictates thromboembolic events. The clinician can diminish the severity of this complication by restricting exercise after melarsomine administration. Perhaps the drug’s biggest asset is the possibility of flexible dosing (“split-dose” — three injections over 1 month or longer), allowing the potential for a safer 50% initial worm kill, followed by subsequent injections to approach 100% efficacy. Studies have shown that patients treated with the split-dose regimen have a higher seroconversion to a negative antigen status than patients treated with either caparsolate or the standard melarsomine dosing regimen.

Manufacturer’s Recommendations for the Use ofMelarsomine Dihydrochloride, Based on Patient Status

Class1

Heartworm Infection (Asymptomatic, Nitric Oxide Radiocraphic Lesions)

Class 2

Symptomatic Heartworm Disease (Mild To Moderate Signs)

Class 3

Symptomatic Heartworm Disease (Severe Signs)

Class 4

Caval Syndrome

Two doses melorsomine 24 hours apart (2.5 mg/kg IM) Two doses melarsomine 24 hours apart (2.5 mg/kg IM) One dose melarsomine (2.5 mg/kg IM), followed in approximately 1 month with 2 injections 24 hours apart Melarsomine not indicated for acute care

A split-dose protocol can be used in severely afflicted individuals or in those in which pulmonary thromboembolism is anticipated (Table Manufacturer’s Recommendations for the Use ofMelarsomine Dihydrochloride, Based on Patient Status). This method allows for destruction of only one half the worms initially (one intramuscular injection of 2.5 mg/kg), thereby lessening the chance for embolic complications. This single dose is followed by a two-dose regimen in 1 to 3 months, if clinical conditions permit. Although the manufacturer recommends this protocol for severely affected dogs, the author uses it for all cases unless financial constraint or underlying concern for arsenic toxicity exists (e.g., pre-existent severe renal or hepatic disease). Disadvantages to the split-dose method include additional expense, increased total arsenic dose, and the need for 2 months’ exercise restriction.

In 55 dogs with severe heartworm disease that were treated in this manner, 96% had a good or very good outcome with more than 98% negative for antigenemia 90 days post-therapy. Of the 55 severely affected dogs, 31% had “mild or moderate PTE,” but no fatalities resulted. The most common sign was fever, cough, and anorexia 5 to 7 days post-treatment. This was associated with mild perivascular caudal lobar pulmonary radiographic densities and subsided spontaneously or after corticosteroid therapy.

Microfilaricidal and Preventative Therapy in Heartworm-Positive Dogs

At the time of diagnosis (usually by a positive heartworm antigen test) a minimum data base is completed. This includes a microfilaria test, chemistry panel, complete blood count (CBC), urinalysis, and thoracic radiographic evaluation. If liver disease is suspected from clinical and laboratory findings, serum bile acid evaluation may be useful in evaluating liver function. At this time, monthly macrolide preventative is prescribed. This approach, which differs from the recommendations of the American Heartworm Society, is used to prevent further infection, to eliminate micro-filariae (chronic therapy renders the dog of no further risk to infect itself or other dogs and cats), and to destroy developing L4 (not yet susceptible to adulticidal therapy). In microfi-laremic dogs, the first macrolide dose is administered in the hospital or at home, with observation, so an adverse reaction might be recognized and treated promptly.

Corticosteroids with or without antihistamines (dexamethasone at 0.25 mg/kg intravenously and Benadryl at 2 mg/kg intramuscularly or 1 mg/kg of prednisolone orally 1 hour before +/- 6 hours after administration of the first dose of preventative) may be administered to reduce the potential for adverse reaction in highly microfilaremic patients. It is important to emphasize that adverse reactions are unusual with macrolides at preventative doses.

Depending on the time of year, up to 2 to 3 months might be allowed to lapse before adulticidal therapy is administered. Although monthly macrolide administration prevents further infection, this delay allows larval maturation to adulthood, ensuring that the only stage of the life cycle present is the adult, which is vulnerable to melarsomine therapy. This is more important if the diagnosis is made during or at the end of a mosquito exposure season. If the diagnosis is made in the spring or late winter, when infective larvae have matured, adulticidal therapy may be immediately administered.

Procedure

The first injection of Melarsomine is administered by deep intramuscular injection (2.5 mg/kg) in the lumbar musculature (as described in the package insert) and the injection site recorded. Before injection, the needle is changed and care is taken to inject deep into the muscle and nowhere else. Patients are typically, but not necessarily, hospitalized for the day. The need for exercise restriction for 1 month is emphasized, and sedation is provided if necessary. Owners are also advised as to adverse reactions (fever, local inflammation, lassitude, inappetence, cough, dyspnea, collapse), to call if they have concerns, and to return for a second series of two injections in approximately 1 month.

If serious systemic reaction results, the second stage of the adulticidal treatment is delayed or, occasionally, even canceled. Typically, however, even with severe reactions, the entire treatment protocol is completed within 2 to 3 months. After a minimum of 1 month, the melarsomine injection procedure is repeated, again with a record of the injection site. If significant local reaction was noted after the first injection, subsequent injections are accompanied by dexamethasone or oral nonsteroidal anti-inflammatory drugs (NSAIDs) to minimize pain at the injection site. The next day (approximately 24 hours after the first injection) the process is repeated with melarsomine injection into the opposite lumbar area. Client instructions are similar to those previously given, with reemphasis of the need for 1 months’ strict restriction of exercise. Antigen testing is repeated 6 months after the second series of injections, with a positive test result indicating incomplete adulticidal efficacy. It is emphasized that despite the proven efficacy of melarsomine, not all worms are killed in every patient. The worm burden is typically markedly reduced, but if as few as one to three adult female worms remain, positive antigen tests are likely. Whether to repeat adulticidal therapy, under these circumstances is decided on a case-by-case basis with input from the owners.

Macrolides

It is now known that certain macrolides have adulticidal properties. Ivermectin, when administered monthly for 31 consecutive months, has nearly 100% adulticidal efficacy in young HWIs. Selamectin, when administered continuously for 18 months, killed approximately 40% of transplanted worms. Milbemycin and sustained release moxidectin appear to have minimal adulticidal efficacy. Although there may be a role for this therapeutic strategy in cases in which financial constraints or concurrent medical problems prohibit melarsomine therapy, the current recommendations are that macrolides not be adapted as the primary adulticidal approach (see discussion of controversies, following).

Exercise Restriction

Cage rest is an important aspect of the management of heartworm disease after adulticidal therapy, after PTE, or during therapy of heart failure. This can often be best, or only, accomplished in the veterinary clinic. If financial constraints preclude this, crating or housing in the bathroom or garage at home, tranquilization, or both, with only gende leash walks are useful alternatives. Nevertheless, some owners do not or cannot restrict exercise, resulting in or worsening thromboembolic complications.

Surgical Therapy

Sasaki, Kitagawa, and Ishihara have described a method of mechanical worm removal using a flexible alligator forceps. This method was 90% effective in 36 dogs with mild and severe HWD. Only two of the severely affected dogs (n = 9) died of heart and renal failure over 90 days postoperatively. These data suggest that, in skilled hands, the technique is safe. Subsequent studies by Morini and colleagues demonstrated superior results as compared with melarsomine, producing less postadulticidal thromboembolization and CS. It is important to note that the majority of dogs treated surgically required subsequent melarsomine administration for adequate worm destruction. Advantages to this technique include its diminished potential arsenic toxicity (subsequent adulticidal therapy would be administered to an asymptomatic dog) and relative freedom from thromboembolic complication. Disadvantages include the need for general anesthesia, a degree of operator skill, fluoroscopy, and subsequent arsenic administration. Nevertheless, it remains a potential alternative for the management of high-risk patients.