„Slow Kill” – adulticide protocol in heartworm treatment! Can we use it? When to use it? How to use it?

13549281_10207110414020766_1752592814_oTodor Kalinov DVM

 

veterinary clinic “Vitalis”, Plovdiv, Bulgaria

drkalinov80@gmail.com

 

 

 

Heartworm disease is caused by Dirofilaria immitis. The disease is widely distributed throughout Europe. Species susceptible to infection are dogs, wolves, foxes, coyotes, cats, ferrets, muskrats, sea lions, and humans. The parasite is transmitted by over 70 species of mosquitoes.

Adult heartworms reside in pulmonary arteries and in cases of severe infections in the right ventricle. Mature female parasites produce microfilariae and release them into the circulation. The feeding female mosquitoes ingest these microfilariae, and they undergo two molts, L1 – L2 – L3, over an 8 to 17 dаy period. This process is temperature-dependent (at least 18 C are needed). The L3 are infective and are transmitted by the mosquito to the hosts. In the subcutaneous, adipose, and skeletal muscle tissue L3 molt to L4 for 1 to 12 days and L4 molts to S5 – immature adults, for 2 to 3 months. The Immature adults enter the vascular system, migrating to the heart and lungs, where final maturation and mating occur. Under optimal conditions, completion of the life cyclе takes 184 to 210 days.

The adult worms cause the following through mechanical, immune-induced, and through toxic substances: inflammation and proliferation of the pulmonary arteries, pulmonary thromboembolism, pulmonary hypertension, and right-sided heart failure. Clinical signs of the disease are weight loss, exercise intolerance, lethargy, poor condition, cough, dyspnea, syncope, abdominal distention.1

According to the guidelines of the American Heartworm Society2 treatment of the heartworm infection consists of doxycycline 10 mg/kg BID for 28 days, monthly use of macrocyclic lactones, and melarsomine at days 60, 90 and 91.

In other publication3, the authors suggest administration of melarsomine on day 30 , 60 and 61, to make the protocol shorter, and to better comply with the owner’s financial resources.

 

In certain circumstances, melarsomine dihydrochloride could be contraindicated, unavailable, or not affordable to the owners. In this situation the practicing veterinarian could use the so-called “Slow kill” or “Soft kill” protocol.  It consists of the use of macrocyclic lactones in prophylactic doses with and withоut doxycycline to kill adult heartworms4–6. In most of the studies, the results are not satisfactory. L. Venco et al.6 used ivermectin – 6mcg/kg, monthly and had 100% microfilaricidal efficiency after 7 months, and 71% adulticidal efficiency after 24 months. The authors do not recommend this treatment regime in patient with clinical, radiographic or echocardiographic signs. G. Grandi et al.4 used doxycycline – 10 mg/kg/sid for 30 days and ivermectin-pyrantel – 6mcg/kg-14mg/kg every 15 days. By day 90 one hundred percent of the dogs became negative for microfilariae, and 72.7% became antigen-negative by day 300.

The study of Savadelis et al.7from 2017 had results similar to melarsomine treatment for a relatively short period of time. They used topical moxidectin 2.5%+imidacloprid 10% monthly with combination of doxycycline 10mg/kg/bid for 30 days. All treated dogs became negative for microfilariae at day 21. Ten months after the beginning the adulticidal efficacy was 95.6%. Hence, the conclusion of the authors is that this treatment regimen is a relatively quick, reliable and safe option to treat canine heartworm infection as compared to other treatment regimens involving macrocyclic lactones, when the approved drug melarsomine dihydrochloride is unavailable, contraindicated or declined by an owner unable to afford the more costly treatment or concerned about the potential side effects”.

I used this protocol numeral times with very good results. Most of the dogs were with class 4 heartworm disease and caval syndrome. Probably the most severe case was a 10-year-old Bulgarian shepherd dog. At presentation, the dog was cachectic, could not walk, did not eat for several days, and had ascites. Blood work revealed slight leukocytosis, neutrophilia, and thrombocytopenia, slightly increase in ALAT, ASAT, BUN, decrease in albumin, and the test for HW antigens was positive. Echocardiographic examination revealed severely dilated right atrium and right ventricle, with heartworms in the tricuspid valve region(video 1).

photo2

photo 2

The left atrium and ventricle were collapsed due to severe pulmonary hypertension. Of course, in this situation surgical extraction of the worms is the first choise8, but this option was declined by the owners. So we started treatment with doxycycline 10 mg/kg/sid, moxidectin+imidacloprid topically, and sildenafil 1mg/kg/bid. Several days after the start of the treatment the dog was in better condition, and on the echocardiographic examination we found that the left ventricle is relatively dilated, compared with the previous exam, the number of worms in the tricuspid valve region was subjectively lower. However, on m-mode, the systolic motions of Interventricular septum and left ventricular free wall was weak(photo 2). Therefore we suggested that the dog has subclinical dilated cardiomyopathy, which contributed to the development of the caval syndrome. We added pimobendane – 0.25mg/kg/bid and benazepril – 0.5 mg/kg/bid and prednisolone – 0.5mg/kg/sid to the therapy for thromboembolism prophylactic. On the next control examination, the dog was feeling better, there were no heartworms in the right atrium and ventricle and in the pulmonary artery(photo 3,4).

photo4

photo 4

photo3

photo 3

photo 5

photo 5

After a month from the diagnosis we stopped the doxycycline and continued with other pimobendane, benazepril, topical moxidectin+imidacloprid, sildenafil, and prednisolone – 0.5 mg/kg/48h. After two more months we gradually stopped the prednisolone. Six months after diagnosis the antigen test for heartworms was negative. The dog still had severe pulmonary hypertension, exercise intolerance and coughed occasionally. We continued treatment with pimobendane, benazepril and sildenafil and monthly moxidectin+imidacloprid for heartworms prophylactic. The dog lived for two more years and died from noncardiogenic reasons. I have similar results with two other large-breed dogs, also with caval syndrome, with complete resolution of clinical signs and withdrawal of all drugs, only continuing with moxidectin+imidacloprid for heartworm prophylactic. A small-bred dog developed severe pulmonary hypertension and tricuspid valve granuloma after the third month probably due to damages of the tricuspid valve from heartworms(photo 5), and untreatable right-side heart failure. Soon after the dog was euthanized.

The “slow kill” protocol is arguably more suitable for large and giant breed dogs, where the surgical extraction is more challenging, and the treatment with melarsomine is more expensive. In caval syndrome, the worms could be moved back in the pulmonary artery with a combination of pimobendane and sildenafil. Sildenafil is a phosphodiesterase 5 inhibitor, and pimobendane is a phosphodiesterase 3 inhibitor. The combination leads to more profound reduction in pulmonary artery pressure. The pimobendane has positive inotropic effect, hence the combination of improved myocardial function and lower pulmonary artery pressure helps in movement of the heartworms from right heart in pulmonary artery9(photo 6, 7 – before and after administration of pimobendane and sildenafil).

photo 6

photo 6

photo 7

photo 7

In small and medium dog breeds the surgical extraction, when possible, is the best choice, however, do not exclude the use of macrocyclic lactones and melarsomine.

In conclusion, when we treat a dog with dirofilariosis, we should first rely on the American heartworm society guidelines2. When we decide to use the Slow kill protocol, the macrocyclic lactone of choice is topical moxidectin. It has a unique pharmacokinetic, establishing a peak several days after application, long half-life about 28 days, and steady-state levels after four monthly applications, ensuring constant and high exposure of the parasites to the drug10,11. Of course doxycycline is also mandatory for adulticide therapy. Last but not least, we always have to think of the patient, we have to treat the patient rather than the disease, and to ensure good quality of life to them.