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Thursday, July 31, 2014

Trifexis Safety Concerns: Poor Reporting And Media Hype

Anyone want to take bets on how long it takes for someone to make a disparaging or hateful comment on today's blog post?  Or how quickly someone accuses me of being stupid, uninformed, or a shill for Elanco?  I'm expecting it because I know that there are some people who are pretty heated about this topic.  Well, so am I, so prepare for my rant.

Last November WSB TV in Atlanta, Georgia "broke" a story about possible dog deaths related to the owners having given them Trifexis, a common and popular oral preventative for fleas, heartworms, and several intestinal parasites.  Living in the metro area near Atlanta and carrying Trifexis, I was of course interested in the story and even a little concerned.  Then I watched it and had to shake my head in amazement at the hack job that was done.  I have always liked WSB and watch them in the morning when I'm getting ready for work.  But the reporter, Jim Strickland, did such a horrible job of presenting the facts that I can no longer fully trust their news department and when I see his reports I wonder what he's leaving out.

Here's a link to the original story, including a video of the broadcast segment.  I encourage you to watch it, as I'll be discussing specifics about it.

It seems pretty damning, right?  But let's analyze how the story was presented.  You get a mention that a University of Georgia pathologist concluded that the hearts of these puppies were inflamed, consistent with a bacterial infection and that there were no signs consistent with a drug toxicity.  Okay, seems like the toxicity has been ruled out.  Nope!  Just a little after that we see a huge "31 DEATHS" fill the screen, even though these were not confirmed to be related to Trifexis.  Which part do you think people will remember?  Does anyone really think that the reporter was trying to present a fair and balanced representation of the facts?

A couple of weeks later a follow-up story was broadcast.  This one proudly proclaimed "Owners blame 700 dog deaths on Trifexis"!  And during the lead-in to the story Strickland says "Since the pill was launched on the market on average every 36 hours a pet owner reports that Trifexis killed a dog."  Shortly after that you see a big yellow "700 DEATHS" fill the screen.  The story goes on and a couple of times the reporter mentions that these are reports made by owners and not confirmed deaths.  He admits that there is no proof of the connection.  Hmmmm....How different would people have taken the story if they mentioned 700 deaths reported but then flashed a big yellow "NO PROOF" on the screen?  Manipulation, folks.  And many people bought into it.

There was also a whooooole lot that was left out and that is pertinent to interpreting the case.
  • Trifexis is made of spinosad and milbemycin oxime, neither of which are new compounds.
  • Milbemycin is the same antiparasitic used in Interceptor and Sentinel.  It has been on the market since the 1990s and has been used consistently since then with no significant adverse effects reported, especially deaths.
  • Spinosad is the same compound used in Comfortis.  It has been on the market and used extensively since 2006.  The only significant side-effect reported is vomiting.
  • Trifexis has been on the market since 2011 and tens of millions of doses have been sold in 15,000 veterinary clinics across the US.  The only thing "new" about Trifexis is that it is the first time that two already existing chemicals were combined into one product.
  • There is extensive testing before any pharmaceutical makes it to market.  While this certainly does not eliminate all possible reactions or problems, it rules out many of the common ones.
  • The reporter never looked into whether or not any of these dogs had any underlying health conditions or were on other medications.  Some investigation!  He never even seemed to consider the possibility of other causes of death or illness.  I'm sure he never bothered to look at the medical records of these dogs to see whether or not the people's thoughts were supported by science and diagnostics.  Investigative reporter my lily white toches!!!  It's obvious that Strickland was more interested in emotions than facts.
Stop and think about this for a moment.  If either spinosad or milbemycin was a dangerous chemical, why are there no reported deaths with the products prior to this news report?  And why are we not getting reports about deaths with Interceptor, Sentinel, or Comfortis?  I think that knowing the history behind the chemicals puts good perspective on how not dangerous they really are.

Speaking of perspective, let's delve into how the Food and Drug Administration handles reporting.  If a client contacts them and says "Product X killed my dog!", they have to put down that Product X is a potential cause of the death.  The "700 deaths" reported are simply the owner claiming that it happened and is prior to any investigation of the facts and other details of the cases.  I'm not knocking the clients as they likely legitimately feel that Product X was the cause.  But when someone like one of the clients in the Trifexis story are convinced that the product killed her dog, then an independent pathologist reports heart disease unrelated to toxicity, which one is a fact and which is an opinion?  And even if the conclusion is that the dog's death was unrelated to Product X, the FDA report will still list it as a "possible" death.  The big yellow "700 DEATHS" is owner-reported and isn't necessarily connected to the truth at all.  And there is no way to remove cases that are confirmed to be unrelated.  So even cases confirmed to be unrelated stay in these preliminary reports.  People don't seem to understand that a report of death doesn't mean that it's confirmed.

In the time that I've been in and around veterinary medicine I've seen similar hype that turned out to be simply hot air.  When I first started practicing in the late 1990s Rimadyl (carprofen) had recently come onto the market as a pain medication for dogs.  It was great and helped a lot of pets, especially with chronic arthritis.  But then all of the message boards (remember, we're pre-Facebook and pre-Twitter here) started blowing up over "Rimadyl killed my dog!"  There were "thousands" of dogs who had died from it, or at least that's what the internet was claiming.  The manufacturer and FDA investigated and found that there was no connection.  In fact, some of the details were pretty ridiculous once you looked into them.  I remember one dog died from lymphoma, yet it had been originally reported with Rimadyl being a possible cause of death.  Some of the deaths happened months after being given Rimadyl.  This is why the "700 deaths" above really doesn't mean anything without more details.  What happened to Rimadyl?  Well, almost 20 years later it is now the single most common pain medication used for dogs in veterinary medicine.  It is trusted and used by tens of thousands of vets in millions of dogs world-wide and we haven't seen wide-spread problems since that initial set of reports (and those were not really "wide-spread problems").

Back in the early 2000s a heartworm preventative called ProHeart6 came onto the US market.  It's an injection that lasts for six months, keeping people from having to remember a pill every month and possibly missing doses.  After a couple of years of use there was an internet blow-up about dogs dying from ProHeart6 injections.  This spread like wildfire as people talked about it via email and forums.  It reached the FDA as people wanted it pulled from the market because of its extreme danger.  Around 2006 the manufacturer volutarily pulled it from the market to conduct further research on safety.  The worked with a well-know epidemiology specialist and compared reaction rates of all heartworm preventatives in the US market.  The study (peer-reviewed and published) showed that reaction rates were statistically the same across all types of heartworm prevention.  There was no difference in illnesses or death regardless of whether the pet took Heartgard, Interceptor, or ProHeart6.  In 2008 it was brought back on the US market with significant restrictions, which were then mostly lifted in 2010.  Over the last six years it has been very closely tracked and monitored, and there haven't been the wide-spread deaths that people seemed to claim.  You know what else?  During all of this investigation it was available outside of the US at a much higher dose that gave a full 12 months of protection, all without the reports of deaths that were seen in the US.

Okay, so the Trifexis report was last November, why bring it up now?  Because apparently WSB and Jim Strickland believe that there is still a story there, and on July 30th broadcast an update.  What was the new, breaking information that caused them to visit it?  There wasn't any.  Seriously.  There really wasn't anything new.  There apparently have been more reports to the FDA of adverse reactions, but once again these are concerns that clients had, and not illnesses or deaths directly related to Trifexis.  So far, every case has shown other causes related to the illnesses or deaths. Thankfully, he was more obvious about stating that these cases were not proven to be related to Trifexis.  But if they weren't proven, where is the story?  What is it other than speculation and emotions?

Here's something else frustrating about these news reports....there is more information on the TV station's website that isn't mentioned in the broadcasts.  So to get more details you have to be willing to go to their site and click on links other than the video.  For example, here is part of a statement from the FDA that you can find on the WSB site:

FDA is aware of adverse event reports in connection with Trifexis and continues to closely monitor them. It is very important to realize that reports of adverse events do not necessarily mean that the product caused the event. Other factors, such as existing disease, exposure to chemicals or contaminants, foods, or other medications may have triggered or contributed to the cause of the event.

I also bet you don't remember Strickland saying anything like the following in his reports: 

For any given ADE report, there is no certainty that the reported drug caused the adverse event. The adverse event may have been related to an underlying disease, using other drugs at the same time, or other non-drug related causes.  And, this listing does not include information about underlying diseases, other drugs used at the same time, other non-drug related causes, or the final outcome of the reaction.

Yet that statement is on the WSB website from last November, specifically attributed to him.  Knowing other underlying conditions and treatments is extremely important in fully evaluating adverse events like the ones currently in question.  I think it's worthwhile to point out a few of those cases so that the average person can see just how much is left out of these stories and how biased the media is in presenting the case.
  • The case that started these reports was related to three Viszla puppies who died after receiving Trifexis.  All three puppies had necropsies preformed by an independent pathologist and reviewed by another pathologist.  In all three puppies there were no signs related to the Trifexis and all three had changes in the heart consistent with a bacterial infection.  Elanco has provided a copy of this report to vets, which I've read, and it is very clear that the pathologists who were not paid by Elanco concluded that the deaths were unrelated to Trifexis.  How much of that made it into the news reports?
  • A Scottish terrier was reported to have had a reaction after a single dose of Trifexis in 2013, having vomiting, lethargy, and ataxia lasting a few minutes, but the recovered.  Okay, that sounds like a problem, right?  And this may be the same dog in the most recent broadcast story, though Elanco's case report doesn't list the client's name.  That same dog had been reported to have vomiting and lethargy after Comfortis in 2012 (remember, same flea ingredient).  The dog also had been diagnosed with cerebellar atrophy in 2004-2005, though that wasn't initially disclosed by the client.  In 2010 there was an elevation in one of the liver values.  Prior to taking Trifexis the dog had other health problems, including hypothyroidism, and was on various homeopathic nutritional supplements.  A liver biopsy after the Trifexis dose showed long-term cirrhosis of the liver.  You see on the news report "my dog took Trifexis, did poorly, and died."  You don't get the full story of the multiple factors and problems involved.  You aren't told that the dog had previous history of liver and neurological problems.  With all of these underlying issues there were multiple potential causes of the dog's illness.  It may also have reacted poorly to the Trifexis due to pre-existing liver problems.  Did these already existing problems make it on the news report?  Only a brief mention, which isn't as impactful as the owner getting emotional.
  • Watch the bulldog case on the same video.  The dog suffered seizures "after her third Trifexis dose".  And her other dogs continued to take it without any problems.  But the woman breaks down crying over this tragic death.  When you read the full report of the case you see that the dog had Trifexis for over six months, with a seizure starting in October 2013.  The vet she saw at that time concluded that the seizures happened unrelated to the Trifexis.  Seizures continued off and on for a month, but seemed to resolve from November until January 2014.  They became worse and by March the dog was euthanized due to seizures being uncontrolled.  The timing and likelihood of underlying problems weren't reported on the news.
The news reports the upset, crying owners, which pulls at the hearstrings.  I completely understand that these owners honestly believe that Trifexis was responsible for their dogs' death and illness.  Their grief is real and in their minds they know the answer.  I'm not belittling their feelings and genuinely wish this hadn't happened to them.  But when you get past emotions and look at ALL of the details objectively, a different picture comes to mind of other health problems.

Could Trifexis be a problem?  Possibly.  I'm open to that possibility, especially if further objective investigation leans in that direction.  But so far I've seen nothing that convinces me that this is a general problem of the medication's safety.  I still consider it safe for the majority of dogs and continue to recommend it to my clients.  If information comes out that confirms deaths and other serious adverse reactions, I'm willing to change my opinion.

Could an individual dog have a sensitivity to the ingredients in Trifexis and have serious health concerns?  Absolutely.  In fact, that may be what has happened in some cases.  However, unexpected or rare reactions are unpredictable and don't indicate a pervasive problem with the product.  We can never tell when a pet is going to have an unexpected reaction.  But the same thing happens in people.  I think most people consider aspirin to be safe, and never think to look at the warnings on the label.  Well, I did, and here are some of the possible side effects listed
Body as a Whole: Fever, hypothermia, thirst.
Cardiovascular: Dysrhythmias, hypotension, tachycardia.
Central Nervous System: Agitation, cerebral edema, coma, confusion, dizziness, headache, subdural or intracranial hemorrhage, lethargy, seizures.
Fluid and Electrolyte: Dehydration, hyperkalemia, metabolic acidosis, respiratory alkalosis.
Gastrointestinal: Dyspepsia, GI bleeding, ulceration and perforation, nausea, vomiting, transient elevations of hepatic enzymes, hepatitis, Reye's Syndrome, pancreatitis.
Hematologic: Prolongation of the prothrombin time, disseminated intravascular coagulation, coagulopathy, thrombocytopenia.
Hypersensitivity: Acute anaphylaxis, angioedema, asthma, bronchospasm, laryngeal edema, urticaria.
Musculoskeletal: Rhabdomyolysis.
Metabolism: Hypoglycemia (in children), hyperglycemia.
Reproductive: Prolonged pregnancy and labor, stillbirths, lower birth weight infants, antepartum and postpartum bleeding.
Respiratory: Hyperpnea, pulmonary edema, tachypnea.
Special Senses: Hearing loss, tinnitus. Patients with high frequency hearing loss may have difficulty perceiving tinnitus. In these patients, tinnitus cannot be used as a clinical indicator of salicylism.
Urogenital: Interstitial nephritis, papillary necrosis, proteinuria, renal insufficiency and failure.
Holy, freakin' heck!  If you take an aspirin it might kill you!!!!

EVERY medication carries potential side effects, some of them potentially serious.  There are no medicines on the market, even natural supplements, that have a completely 0 risk of adverse effects.  It simply doesn't happen!  Seriously, the next time you buy any over-the-counter medication, take a look at the product labeling and worry about the problems you might have.  Could Trifexis have caused some side-effects?  Yes.  But there is no evidence that it is a "dangerous" medication.

If anyone doesn't believe in media manipulation of facts, they need to seriously analyze these stories by Jim Strickland and WSB.  This is pure and simple one-sided fear-mongering and manipulation of emotions.  This is not real reporting, as a true investigation would easily bring up the facts that I've written here.  But that would not make good ratings, and that's all this story is about.  It's designed to make people watch because they fear for their pets.  It's not presenting all of the facts.

Now I know that there are plenty of web sites and reports from people who are convinced that Product X is deadly and should be removed from the market.  I've visited many of them in relation to Trifexis, Rimadyl, and ProHeart6.  I know that there is a good likelihood of someone making a comment, screaming at me for my ignorance, willingness to ignore "facts", and being a "Big Pharma sheep".  In fact, I'm expecting it.  But let's get beyond emotions and look at facts.  Let's look at the full details on cases, not just the emotional people that make it on the news, or the 10 second snippet from pet owner.  And let's put everything in the same font and style, rather than filling the screen with "935 DEATHS". 

With both Rimadyl and ProHeart6 there was a hue and cry about dogs getting sick and dying left and right.  When it was fully investigated it was learned that there was no basis to wide-spread problems and subsequent use over years and years proved the fears to be unfounded.  I fully expect the same thing to happen with Trifexis.

The question I then frequently get is "What do you use with your own dogs?"  I use ProHeart6 for heartworms and Comfortis for fleas.  If ProHeart6 wasn't available, I would use Trifexis.  Yes, even after all of these recent reports.