Compressed 2-dose melarsomine protocol is safe and effective in shelter dogs with heartworm, JAVMA trial finds

A shortened heartworm treatment using 2 injections of melarsomine was safe and effective in shelter dogs with subclinical to moderate disease, according to a randomized clinical trial published in the Journal of the American Veterinary Medical Association.¹ All 168 dogs in the study survived treatment. None required intensive management or hospitalization for complications.

Researchers from Toronto Humane Society, the University of Florida Shelter Medicine Program, Lucky Dog Animal Rescue, and EveryPet compared compressed 2-dose and 3-dose melarsomine protocols. Each protocol was paired with the adjunctive therapies now standard in heartworm treatment: sustained-release moxidectin, doxycycline, and prednisone.¹ The study authors described the trial as the largest randomized controlled clinical trial in the heartworm literature. PetSmart Charities funded the research.¹

The American Heartworm Society (AHS) has recommended a 3-dose melarsomine protocol for all dogs, regardless of clinical status, since 2005.¹ According to the study authors, the AHS recommendation followed early research in which melarsomine was the sole therapeutic agent. In the early studies, the 3-dose protocol was more effective than the 2-dose protocol. It also carried lower risks of complications and death in more severe cases. Since then, a macrocyclic lactone heartworm preventive, a 28-day course of doxycycline, and prednisone have become standard components of treatment guidelines. Aside from a recent retrospective study by the same research group, no studies had compared 2-dose and 3-dose melarsomine, according to the authors.¹

How the trial worked

The trial ran from April 2024 to December 2025 at the Lucky Dog Animal Rescue campus in Florence, South Carolina.¹ Dogs at least 12 months old with Class 1 or Class 2 heartworm disease were randomly assigned to a treatment group. Of 170 dogs enrolled, 168 remained in the study after 2 exclusions: 85 in the 2-dose group and 83 in the 3-dose group. Dogs with more severe heartworm disease were not enrolled. Lucky Dog Animal Rescue noted that the 2-dose protocol's safety in dogs with more severe disease is unknown.² Study personnel were not masked to treatment groups. To limit bias in clinical observations, the researchers engaged a postdoctoral researcher as the primary study staff member, used clearly defined observation categories, and relied on objective measures (antigen tests and survival) for key outcomes.¹

All dogs received sustained-release moxidectin on day 1 and once-daily doxycycline on days 1 through 28.¹ The 2-dose group received melarsomine on days 14 and 15. The 3-dose group received melarsomine on days 14, 44, and 45. Prednisone began the day before melarsomine. Every dog received butorphanol before melarsomine injections. Both timelines start melarsomine well ahead of the AHS protocol, which waits until day 60.¹ Neither group received the standard AHS protocol, so the study does not show whether clinical signs or complications would have differed under the AHS protocol.¹

Exercise restriction consisted of two 5- to 10-minute leash walks daily, or 10 minutes in a yard with no other dogs nearby. The restriction lasted 4 weeks after melarsomine, adding up to about 1 month for the 2-dose group and 2 months for the 3-dose group.^1,2 Once exercise restriction ended, the dogs became available for adoption. Adopters agreed to bring their dogs in for antigen testing 6 months after the last melarsomine injection.^1,2 If the 6-month test was positive or missed, testing was performed at 9 months.¹ Treatment success was defined as a negative final antigen test.

Results

A total of 165 dogs completed follow-up testing.¹ In the 2-dose group, 95.3% of dogs tested antigen negative, compared with 98.8% in the 3-dose group. The difference was not statistically significant.

One question remains open. The trial was designed as a noninferiority study to determine whether the 2-dose protocol's efficacy was no more than 4% lower than the 3-dose protocol's. The noninferiority analysis was inconclusive, meaning the study's main hypothesis could not be proven.¹ According to the authors, the high efficacy in both groups limited the study's precision in detecting small differences. A conclusive result at the 4% margin would require thousands of dogs, which the authors considered unlikely to be feasible in any future study. The authors added that larger studies or a meta-analysis might detect slightly lower efficacy for 2-dose protocols, a possibility to be weighed against the benefits of a shorter, less expensive protocol.¹

Complications were rare in both groups.¹ Seven dogs needed additional diagnostics, with or without treatment, for respiratory concerns after melarsomine: 2 in the 2-dose group and 5 in the 3-dose group. No dog developed a severe cough. The incidence of moderate cough, increased respiratory effort, and weakness did not differ significantly between the groups. No dogs were suspected of having pulmonary thromboembolism. Cough was common both before and after melarsomine. The authors wrote that active daily monitoring, the inclusion of mild and short-lived cough, and the baseline presence of canine infectious respiratory disease complex most likely contributed to the high overall prevalence of cough.¹

Gastrointestinal signs after melarsomine were significantly more common in the 3-dose group (48.2%) than in the 2-dose group (31.8%).¹ Significantly more dogs in the 3-dose group also showed low energy after melarsomine. In most affected dogs, low energy was recorded for only 1 day.¹

Considerations for shelters and practice

Compared with the AHS protocol, the compressed 2-dose protocol offers 33% lower melarsomine costs, 61% fewer days of exercise restriction, 84% fewer days from intake to the last treatment day, 63% fewer days on prednisone, and an estimated 60% lower cost of care, according to the authors.¹ The authors also noted that many of the benefits of 2-dose melarsomine apply to owned animals.

Several secondary findings may also be useful in practice:

• Activity level: Dogs recorded as very active or active did not have a significantly different risk of cough than less active dogs. The authors wrote that the findings indicate dogs with Class 1 and Class 2 disease can be safely treated while kenneled.¹
• Moxidectin without pretreatment: Current guidelines recommend pretreating microfilaremic dogs with an antihistamine and glucocorticoid before administering preventives. About 60% of study dogs had circulating microfilariae at intake, yet no systemic reactions followed sustained-release moxidectin injections. The authors suggested routine administration without pretreatment, followed by monitoring and treatment of any adverse reactions, may be a more resource-effective approach.¹
• Injection comfort: With prednisone started a day ahead and butorphanol given before injections, approximately two-thirds of dogs showed no reaction (flinching, vocalizing, or trying to bite) at the time of melarsomine injection.¹
• Follow-up testing timing: At 6 months, 13.0% of tested dogs in the 2-dose group and 6.4% in the 3-dose group were still antigen positive. According to the authors, positive 6-month results should be repeated at 9 months, or testing can be delayed until 9 months as the AHS recommends, to avoid prematurely declaring treatment failure.¹
• Doxycycline dosing: Once-daily doxycycline produced good results. The authors wrote that there appears to be no compelling reason to use twice-daily dosing.¹

The authors concluded that the compressed 2-dose protocol has the potential to expand access to heartworm treatment by offering a practical, cost-effective alternative for dogs without access to the traditional 3-dose protocol.¹

References

1. Jacobson LS, Dyer JL, Van Vlake A, DiGangi BA, Horowitz MA, Levy JK. Comparing compressed 2-dose and 3-dose melarsomine protocols in the era of adjunctive therapy: a randomized clinical trial of 168 dogs with heartworm disease. J Am Vet Med Assoc. Published online September 2, 2026. doi:10.2460/javma.26.06.0518
2. Lucky Dog Animal Rescue heartworm study. Lucky Dog Animal Rescue. Accessed October 28, 2026. https://www.luckydoganimalrescue.org/south-carolina-rescue-campus/about-campus/lucky-dog-animal-rescue-heartworm-study