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Time to Step It Up

The protocols used to protect dogs from heartworm may have lost some effectiveness; here’s what you can do to protect your dog now.

News item by Mary Straus, published in the Whole Dog Journal, July 2011. Note this article has been updated to correct some information regarding the MP3 strain of heartworms.

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As we reported in WDJ in March 2011 (Are Heartworms Developing Resistance to Preventatives?), there is now ample evidence that some strains of heartworms have developed resistance to all of the market’s best-known preventives. In addition, there is evidence to suggest that one of the most popular heartworm preventives, Heartgard, has an efficacy rate of less than 100 percent. The U.S. Food and Drug Administration’s Center for Veterinary Medicine has sent at least one warning letter to Merial, the maker of Heartgard, asking the company to stop claiming 100 percent effectiveness for heartworm prevention. Given these developments, what should responsible dog owners do differently to better protect their dogs?

The answer depends a bit on where you live and what you’ve already been doing to prevent heartworm infection.

Resistant Strains

Reports of dogs developing heartworm disease despite being given preventatives year-round were dismissed for years as being due to “owner non-compliance,” but the outcry finally became too loud to ignore.

In August 2010, representatives of the American Heartworm Society (AHS), the Companion Animal Parasite Council (CAPC), and experts in the field of nematode resistance met in Atlanta for a “heartworm roundtable.” A joint statement released afterward announced, “This meeting was convened to discuss the implications of reports of lack of efficacy of macrocyclic lactones [preventive medications] against Dirofilaria immitis, the canine heartworm. Participants
concluded that while we do not have a comprehensive picture of the scope or severity of the problem, we agree that there is a problem. There is evidence in some heartworm populations for genetic variations that are associated with decreased in vitro susceptibility to the macrocyclic lactones.”

Translation: investigators have verified that some strains of heartworms show resistance to heartworm preventives in the lab.

Further, the statement offered a hint that resistant strains are not yet present everywhere heartworms are found. "Most credible reports of lack of efficacy (LOE) that are not attributable to compliance failure are geographically limited at this time.” The statement did not identify the region, but investigations have centered on the Mississippi Valley from Missouri to Louisiana.

Useful information has since emerged from a small study conducted by researchers at Auburn University’s College of Veterinary Medicine in Alabama. Four commercial heartworm preventive medications (Heartgard Plus, Interceptor, Revolution, and Advantage Multi) were tested on the MP3 resistant strain of heartworm. Forty dogs were infected with heartworm larvae. Thirty days later, the dogs were treated with one of the four preventives.

Update

The MP3 heartworm strain was isolated from a dog in Georgia in 2006 and kept in the laboratory for study, but has apparently not been found outside the lab since. More recently, studies have identified additional heartworm isolates with “reduced susceptibility” (the term researchers prefer to “resistance”) in the lab to heartworm preventives. These strains were taken from dogs in the Mississippi Valley region who developed heartworm infections despite being on monthly preventives. Unpublished laboratory studies show that none of the existing heartworm preventive medications, including Advantage Multi, were 100 percent effective against these isolates.

In addition, further unpublished results from the MP3 study showed that all four of the heartworm preventives tested (Heartgard, Interceptor, Revolution, and Advantage Multi) were 100 percent effective against this strain after three consecutive monthly doses were given. Based on this information, giving heartworm preventatives year-round rather than discontinuing during colder months could be more effective against resistant strains of heartworm.

Four months after treatment, an average of 2.3 adult heartworms were found in seven of eight dogs in each of the first three groups; only Advantage Multi was found to be 100 percent effective. There was no significant difference in efficacy against the MP3 strain between Heartgard Plus, Interceptor, and Revolution. Based on the number of adult worms found in the untreated control group, the efficacy rate for the other three products was determined to average 95.5 percent.

Say what? How can the efficacy rate be more than 95 percent, when 7 of 8 treated dogs (87.5 percent) were heartworm-positive? One might guess that “95 percent effective” means that 95 percent of dogs remained heartworm-free, but it actually means the treated dogs had 95 percent fewer adult worms than untreated dogs – a whole different can of worms!

Best preventive?

Does this mean we should all switch to Advantage Multi, the only heartworm preventive found in this study to be effective against the MP3 strain of heartworms? Well, the answer is not that simple.

The active ingredient in Advantage Multi is moxidectin (Advantage Multi also contains imidacloprid, the flea-killing ingredient in Advantage and K9 Advantix).

Moxidectin is the same ingredient used in ProHeart 6, an injectable heartworm preventive that reportedly caused problems for many dogs when it was first introduced. Due to the large number of adverse events reported, including many deaths, it was withdrawn from the market in 2004; it was reintroduced in 2008 with new warnings on the label. Unlike ProHeart 6, a sustained-release injectable product used every six months, Advantage Multi is applied topically once a month. There’s a strong probability that the worst dangers of ProHeart 6 were related to the injectable, sustained-release method of application. If there is an adverse reaction to moxidectin, it’s unlikely to be as intense or as long-lasting from a topical application as from an injected form, which continues to be released into the body for six months.

While every product has some adverse side effects, I have not heard any horror stories associated with Advantage Multi since it was introduced in the U.S. in 2007. Note that moxidectin remains in the system much longer than ivermectin (Heartgard), selamectin (Revolution), or milbemycin (Interceptor), so adverse effects can occur up to three weeks after application.

Dr. Byron Blagburn, one of the vets who participated in the Auburn University study, has hypothesized that moxidectin’s persistence in the body might account for its increased effectiveness against the MP3 strain of heartworms.

What about the other preventives? The study above found no significant differences in effectiveness between Heartgard, Interceptor, and Revolution against the MP3 strain of heartworms; their efficacy rate ranged from 95.4 to 95.6 percent.

These findings correspond with anecdotal evidence observed by practitioners in the area where heartworm resistance has been reported. Dr. Everett Mobley of Kennett Veterinary Clinic in Kennett, Missouri, is one of the veterinarians who drew attention to increasing failures of heartworm preventives that led to this discovery. He found reports of failure coming from the Mississippi River valley, starting about 100 miles south of St. Louis, and getting worse as one goes south. “I saw roughly equal rates of lack of efficacy whether the dog was on Revolution, Heartgard, Interceptor, or Sentinel (the four preventives I was using at that time),” comments Dr. Mobley.

He emphasizes that “I’m a simple general practitioner, detailing only my own clinical experiences and the impressions of those I have spoken with personally. I am by no means a specialist in parasitology or in pharmacology. My opinions are based on my experience with my cases.”

While he has not yet seen any failures with clients using Advantage Multi, he feels that the study referenced above is inconclusive due to its small size. Dr. Mobley says he has also seen a decrease in the number of heartworm-positive dogs taking other medications from 2009 to the present. He says, “while the big switchers to Advantage Multi feel that they see no product failures at all, our non-switchers have also seen a reduced failure rate in the last two years.”

This could be due to cooler and drier weather, at least in 2009. The American Heartworm Society’s (AHS) triennial survey for 2010 showed that “the pattern of heartworm incidence overall was similar to that of previous years.” While heartworm was found in all 50 states, the incidence map does show a decrease from the previous survey done in 2007, when the fallout from Hurricanes Katrina and Rita had far-reaching effects on mosquito vectors and heartworm transmission. The wet winter we’ve just had may well have a similar effect.

It might make sense for pet owners who live in the Mississippi valley to use Advantage Multi, as long as their dogs have no problems with it. For the rest of us, presumably not yet threatened by resistant strains of heartworm, other products may be acceptable.

Other alternatives

Interceptor, another heartworm preventive, may have one advantage over other products: its dosage of active ingredient (milbemycin oxime) is five times the minimum amount that has been determined to prevent heartworms; the higher dose is used to control intestinal parasites as well.

Because the level of medication is higher than was needed in the initial approvals for 100 percent efficacy, it’s possible that Interceptor may continue to be more effective against non-resistant strains of heartworms. Sentinel, which combines Interceptor with Program (lufenuron, a product that prevents fleas from reproducing), is another option with the same dosage of milbemycin oxime.

Revolution, a topical heartworm preventive whose active ingredient, selamectin, is also effective against fleas, ear mites, sarcoptic mange, and one type of tick, offers another alternative. You might use Revolution if you want to take advantage of any of these other properties, or if you prefer a topical treatment but do not want to use Advantage Multi.

Heartgard

Heartgard, like Interceptor and Revolution, demonstrated an efficacy rate of only about 95 percent in the Auburn University study on the MP3 strain of heartworms. But there is evidence – some of it in active legal dispute – to suggest that Heartgard may exhibit only about 95 percent efficacy against all heartworms, not just the drug-resistant type.

In a letter sent in 2006 by the Food & Drug Administration (FDA) to Merial, the maker of Heartgard, the FDA warns, “In a letter dated August 24, 2005, we requested that you stop claiming 100% effectiveness for heartworm prevention. As you know, this request was based on the post-approval adverse drug event (ADE) reports we have received for lack of effectiveness for heartworm prevention. In a letter dated September 30, 2005, you agreed to immediately discontinue promotion and advertising 100% effectiveness for your heartworm prevention products.”

The allegation that Heartgard has only a 95 percent efficacy rate was leveled at Merial recently from another source – a “whistleblower” lawsuit filed by a former Merial employee.

Kari Blaho-Owens, PhD, global head of pharmacovigilance for Merial from 2006 to July 2010, alleged in documents filed in late May of this year that she “discovered that Merial had been aware of serious lack of efficacy adverse events reported regarding ‘Heartgard Plus’ since as early as 2002.” She believes that Merial terminated her employment because she refused to stop her investigation of the loss of efficacy of Heartgard and its related products. Dr. Blaho-Owens also asserts that she found a statistical analysis done by another Merial employee showing that Heartgard Plus was 95 percent effective. (That analysis would apply to all heartworms, not just resistant strains.)

Merial denies the allegations. (See Allegations From a Former Merial Insider below.)

Even if the allegations of a 95 percent efficacy rate were true, there are a couple of good reasons to continue to use Merial’s Heartgard, in our opinion. The first is the fact that Heartgard’s active ingredient (ivermectin) has some effect against adult heartworms – ones that developed while the dog was unprotected by any preventive or ones that developed despite the use of preventive.

One study we reviewed showed that Heartgard had nearly 100 percent efficacy in killing young adult heartworms when administered continuously for 31 months, and more than 50 percent efficacy after 18 months. Other recent studies on the use of a combination of pulsed doxycycline and weekly ivermectin resulted in a reduction of over 78 percent of adult worms after 36 weeks (for more information, see Important New Information Regarding Heartworm Treatment and Doxycycline).

According to studies we’ve reviewed, selamectin (Revolution) has a lesser effect on adult heartworms, while neither milbemycin (Interceptor) nor moxidectin (Advantage Multi) have been found to have a significant effect against them.

If your dog is infected with heartworms, it makes sense to use Heartgard prior to and during treatment with Immiticide, as it weakens the adult worms. It also makes sense to continue to use Heartgard for one year following treatment, to kill any heartworms that might mature from older larvae that neither Immiticide nor heartworm preventives can kill.

Iverhart and Tri-Heart Plus are generic equivalents to Heartgard that are manufactured by different companies. Efficacy and safety should be identical to Heartgard. Just be sure to purchase these products from reliable sites, preferably those that carry the Veterinary-Verified Internet Pharmacy Practice Sites seal of approval (Vet-VIPPS) and offer guarantees against product failures, such as 1-800-PetMeds, PetCareRx, and Drs. Foster & Smith (see “When Buying Veterinary Drugs Online, Look for Accredited Sites,” June 2011).

Use more, or more often?

If you want to continue to use Heartgard for heartworm prevention, it also may be reasonable to use a higher dosage. The studies done for the initial approval of Heartgard showed that lower doses were less effective at eliminating heartworms than the dosage that was ultimately chosen for the label recommendation, which was the lowest dose found to be 100 percent effective. Increasing that dosage may well increase Heartgard’s effectiveness in preventing heartworm infection from non-resistant strains.

Is an increased dose safe? For most dogs, the answer is yes. Ivermectin is used to treat dogs with demodectic mange (demodex) using a dosage that is 50 times the amount used to prevent heartworms, and this dosage is given daily for weeks or even months. These very high doses of ivermectin are not safe when combined with products such as Comfortis or Trifexis (also called Vethical AcuGuard and ComboGuard) that contain spinosad, a newer flea-control product that increases the risk of neurological side effects from ivermectin. Dogs infected with heartworms may suffer an anaphylactic reaction from the death of too many microfilariae at once when given very high doses of ivermectin as well.

Doubling the dosage of Heartgard should be safe for most dogs. Keep in mind that dogs at the low end of the weight range for each Heartgard product are already getting twice the dosage compared to dogs at the high end of the range; smaller dogs weighing 12 pounds or less get even more.

Higher dosages are not safe for dogs with the MDR1 mutation that makes them more susceptible to ivermectin and other drugs. There is an inexpensive genetic test available to find out if your dog has this gene. Most affected dogs are from herding breeds, primarily Australian Shepherds (including Minis) and Collies, but it’s also common in Long-Haired Whippets and Silken Windhounds. Mixed-breed dogs can also be affected. See Dogs with a Drug Problem and Multidrug Sensitivity in Dogs for more information.

Note that dogs with the MDR1 gene are also affected by selamectin, milbemycin, and moxidectin, the active ingredients in Revolution, Interceptor, and Advantage Multi, respectively, though heartworm-preventive dosages are considered safe.

One problem with increasing the dose of Heartgard is that most people use Heartgard Plus, which also includes pyrantel pamoate, used to kill roundworms, hookworms, and tapeworms. In fact, it’s become difficult to find plain Heartgard. Just as with ivermectin, dosage of pyrantel pamoate is twice as high for dogs at the low end of the product’s weight range compared to those at the high end. This is not a problem, as the recommended dosage range for pyrantel pamoate is 5 to 10 mg per kg, exactly the amounts used in Heartgard Plus. Increasing dosage further, however, can lead to increased side effects, primarily vomiting, particularly problematic if your dog vomits up his heartworm medication..

If your dog is at the high end of the weight range for the Heartgard product you’ve been using, it should be safe to move to the next level product. For example, if your dog weighs 45 pounds and you’ve been giving Heartgard Green for dogs weighing 26 to 50 pounds, it may be better to switch to Heartgard Brown, for dogs weighing 51 to 100 pounds. If your dog is at the low end of the weight range (say, 30 pounds), you’re already giving a higher amount of ivermectin and so Heartgard may already be more effective.

Another option might be to give heartworm preventives twice a month rather than monthly, particularly if you live in an area with a high incidence of heartworm disease. There is a window of opportunity in which heartworm larvae are susceptible to the treatments used against them. Once the larvae reach a certain age, preventives will no longer affect them. By giving the preventives twice as often, more larvae may be killed. You could use the same product each time, or alternate between two different products when using this approach.

Keep in mind that none of these changes are likely to be completely effective against resistant strains of heartworms. Dr. Mobley, whose practice is in the Mississippi valley, says that he has seen or heard of heartworm infections occurring despite using higher doses of ivermectin, in one case an extremely high dose. “I have tried changing preventives, giving two different preventives per month (every two weeks), increasing doses, and still had some failures.” After seeing the increase in heartworm preventive failures in 2006, he began giving his own dog Heartgard on the first of the month and Revolution on the 15th, and she became infected with heartworms anyway.

Final thoughts

It’s important that people continue to give their dogs heartworm preventives, even if they are not 100 percent effective. A small number of heartworms cause far less damage than a heavier infection would. All of the preventives destroy most heartworm larvae before they can mature into adults and thus continue to offer significant protection.

Dr. Mobley points out that “Merial (and the other manufacturers) have been super great to honor their guarantee and pay for the treatment of these dogs. While they initially felt veterinarians were overreacting, they took steps to hold meetings and get feedback on the situation.” He also says, “These dogs do not have heartworm disease, per se. They test positive, meaning that they do have some small number of heartworms, but they are not sick. Thus, I (and others) feel that most of the heartworm exposure has been handled by the preventives, even when we have these ‘lack of efficacy’ cases.”

While WDJ has made recommendations in the past that it can be safe and effective to give a dog heartworm preventives less frequently than every 30 days (e.g., every 40 days) or to use slightly lower dosages than the label recommendations, this newer evidence about the decreasing effectiveness of heartworm preventives made us rethink our position.

We strongly advise against giving heartworm preventives less often than monthly, or giving lower than recommended dosages. While this may have worked in the past, based on the original efficacy studies, it seems clear that it’s not working now.

It’s best to give heartworm preventives year-round as well, not only for better protection against infection, but also to ensure that the manufacturer will pay for treatment should your dog become infected with heartworms. Note that manufacturers will only guarantee products purchased from veterinarians and given year-round according to label instructions. We also recommend annual testing for dogs, especially for those who live in heartworm-endemic areas, even if you give preventives all year round.

You can reduce the risk of heartworm infection by keeping dogs indoors, particularly during peak mosquito times at dawn, dusk, and early evening, and at night; installing screens on windows and doors; reducing outside lights and using yellow bulbs where possible; and eliminating mosquito breeding sites, such as by draining any standing water, changing the water in birdbaths and wading pools at least once a week, and stocking ponds with mosquito fish. None of these measures, including keeping dogs indoors at all times, is 100 percent effective or replaces the need for heartworm preventive medications.

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If you have any questions or comments, you can contact me, but I have less time to answer questions than I used to, and it may be several days to a week before I can respond. My name is Mary Straus and you can email me at either or

   


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