Alternative Treatment for Heartworm Disease Does Not Replace Gold Standard

In February 2021, a Clinician’s Brief newsletter included a review with the headline, “Alternative Treatment for Heartworm Disease,” that discussed a 2020 article by Savadelis et al¹ and summarized the clinical findings associated with a 2017 article by Savadelis et al.² Andrew Moorhead was the primary investigator for both studies, which involved the only published necropsy-based experiment to-date using topical moxidectin and oral doxycycline.

It was not intended that the regimen performed in these studies should supplant the recommended American Heartworm Society (AHS) melarsomine-based protocol. Although there was a 95.9% efficacy rate, there was still a single worm remaining in 3 out of 8 dogs, even after 10 doses of topical moxidectin were administered. A single worm can cause local and diffuse pulmonary arterial damage via inflammation, antigen-antibody complexes, and thromboembolism.

The relative ease of the colloquially named moxi–doxy protocol may be an attractive alternative as compared with the AHS protocol, but the alternative protocol is a salvage procedure that can be used when melarsomine administration is contraindicated or impossible. Although it could be assumed from the newsletter headline that the moxi–doxy protocol is equivalent to the AHS protocol, the newsletter stated that melarsomine-based treatments are still the gold standard. However, that critical point could be overlooked by those reading quickly. Melarsomine-based treatments are preferable and approved, and slow-kill (ie, nonarsenical) protocols are salvage procedures that should be portrayed as such.

AHS Does Not Recommend Nonarsenical Adulticide Therapy

The AHS-recommended protocol described in the current guidelines³ advocates initiation of a macrocyclic lactone (monthly) and doxycycline (10 mg/kg PO every 12 hours for 28 days) at the time of diagnosis and melarsomine (2.5 mg/kg IM deep in the epaxial muscles) on days 60, 90, and 91 (ie, split-dose or 3-dose protocol). 

Melarsomine is proven to be efficient at killing adult heartworms.⁴ In a study, 98% of 55 dogs with naturally occurring heartworm infection had no antigens detected 5 months after receiving a 3-dose protocol of melarsomine.⁴ The second and third melarsomine doses were administered 50 to 70 days after the first dose. Doxycycline was not used. 

If the 3-dose protocol is not possible, 2 melarsomine injections (2.5 mg/kg IM 24 hours apart), ideally after doxycycline (10 mg/kg PO every 12 hours) has been administered for 28 days, is considered the next best option. Melarsomine without doxycycline in this 2-dose protocol has been shown to clear only 90.7% of worms in 6 dogs with transplanted adult heartworms⁵; one worm was still present in 3 of 6 dogs.⁵ A benefit, however, is that adulticide therapy can be initiated soon after diagnosis, increasing the likelihood the patient will receive the entire treatment protocol.  

Exacerbation of pulmonary parenchymal and arterial damage is an inevitable consequence of worm death due to treatment with melarsomine or macrocyclic lactones or natural worm death. Worm death is faster with melarsomine as compared with a nonarsenical protocol. Faster worm kill likely reduces ongoing damage to pulmonary arteries and therefore reduces cumulative pathology.

Rigid exercise restriction is recommended during arsenical and nonarsenical treatments, is important in reducing heartworm-related thromboembolic complications, and should be enforced for 6 to 8 weeks after the final melarsomine injection. Although the duration of exercise restriction during nonarsenical protocols is not known, it may be safest to continue restricting exercise until heartworm antigens are no longer detected.   

Nonarsenical protocols require strict compliance by pet owners (some who may have failed to achieve this goal previously). 

Chronic administration of macrocyclic lactones in dogs with heartworm infection may contribute to development of drug resistance in Dirofilaria immitis.^6,7 A goal of all adulticidal protocols should be to clear microfilariae and/or prevent microfilariae from producing viable infection, as this can prevent development of macrocyclic lactone resistance. Although there are macrocyclic lactone-resistant heartworms, the biology of resistance is complex and may have multiple contributing factors.

What Is Known Regarding Nonarsenical Adulticide Therapy?

Early studies comparing ivermectin, selamectin, and milbemycin suggested ivermectin had a relatively better adulticidal effect,⁸ and, until recently, ivermectin has been most-studied and was the original slow-kill macrocyclic lactone, taking >2 years to clear infections as a monotherapy. Interest has grown in topical moxidectin/imidacloprid as an adulticide due to its favorable pharmacokinetic profile (ie, relatively rapid development of peak blood levels, long half-life of 28 days). 

A nonarsenical protocol other than slow-kill should only be considered if the majority of dogs are antigen-free by ≤9 months. Regardless of protocol, doxycycline should be administered, as it reduces the lung damage produced by dead and dying worms.⁹ This is likely because the combination of a slowly adulticidal macrocyclic lactone and bacteriostatic doxycycline leads to reduction in Wolbachia spp numbers and worm mass, resulting in less antigen extrusion at the time of worm death. The macrocyclic lactone/doxycycline studies summarized in Table involved a small number of dogs, and larger prospective studies are needed.

STUDIES IN WHICH A MACROCYCLIC LACTONE WITH DOXYCYCLINE WAS USED AS ADULTICIDAL THERAPY

Doxycycline (20 mg/kg every 24 hours for 30 days)

Moxidectin/imidacloprid (preventive dose, monthly for 9 months, starting 1 month postimplantation)

| 95.9% efficacy<sup†sup> at 10 months (5 of 8 dogs had no worms vs control group, which had an average 10.6 worms) | | Bendas et al, 2017 (n = 22)¹⁰ | Naturally infected (Brazil) |

Doxycycline (20 mg/kg every 24 hours for 30 days; repeated every 6 months)

Moxidectin/imidacloprid (preventive dose, monthly)

| 100% efficacy at 18 months (no antigens detected on 2 consecutive heat-treated samples) | | Genchi et al, 2019 (n = 14)¹¹ | Naturally infected (Italy) |

Doxycycline (20 mg/kg every 24 hours for 28 days)

Moxidectin/imidacloprid (preventive dose, monthly)

| 93% efficacy at 9 months (no antigen detected) | | Ames et al, 2020 (n = 22)¹² | Naturally infected (Michigan) |

Doxycycline (mean dose, 14.6 mg/kg every 24 hours for 15 days)

Moxidectin/imidacloprid (preventive dose, twice monthly for 3 months, then monthly)*

| 86% efficacy at 12 months, 95% efficacy at 16 months (no antigens detected) | |     Grandi et al, 2010 (n = 11)¹³ | Naturally infected (Italy) |

Doxycycline (10 mg/kg every 24 hours for 30 days)

Ivermectin (preventive dose, twice monthly for 6 months)

| 73% efficacy at 10 months (no antigens detected) | | Bazzocchi et al, 2008 (n = 5)¹⁴ | Implanted adult worms: n = 16; 9 female, 7 male (experimental) |

Doxycycline (10 mg/kg every 24 hours every 2 to 6 weeks for 20 weeks)

Ivermectin (preventive dose, weekly for 36 weeks, starting 6 weeks) postimplantation

| 78% reduction in worm burden at necropsy at 9 months |

*Twice-monthly administration is unlikely to increase worm exposure to the drug because of the long half-life of topical moxidectin.

<sup†sup>Percent efficacy is the percentage of worms cleared at necropsy.

Conclusion

The AHS protocol (split-dose melarsomine, macrocyclic lactone, and doxycycline) is the best approach to heartworm adulticide therapy. Current data suggest almost 100% efficacy 6 months postmelarsomine treatment (9 months from protocol start). Two injections of melarsomine 24 hours apart (with initiation of macrocyclic lactone and, ideally, doxycycline) is currently considered the next best option. Macrocyclic lactone/doxycycline protocols can be used when melarsomine is unavailable or otherwise not an option (see When Can a Nonarsenical Approach Be Used?). These protocols have not been directly compared. The moxidectin/doxycycline protocols may result in clearance of adult heartworms earlier than ivermectin/doxycycline protocols.

AHS = American Heartworm Society