The more you know, the more uncertain you are.
– by Alan Cassels –
In the 2008 book “Agnotology: The Making and Unmaking of Ignorance”, historians Robert Procter and Londa Schiebinger describe the concept of Agnotology which means the “study of intentionally induced ignorance or doubt, particularly the publication of intentionally inaccurate or misleading scientific data.”
My world is riven with doubt because so much of the published pharmaceutical research has enormous potential for bias. Questions regarding which drug should be prescribed, for whom, and for how long are never easily answered. It is fair to say our collective ignorance around the harms related to drugs has become a monumental stain on the credibility of modern medicine. When I hear a researcher say he “knows” something for sure about drug safety, the only thing I “know” for sure is he’s misleading all of us.
Over the last decade or so I have followed intense debates over the harm associated with a widely-used heartburn drug, where two lines of debate follow competing visions of what truth is. The reason this debate is so important is that there are lives at stake. A lot of them. Proton Pump Inhibitors (PPIs) are primarily prescribed to treat symptoms of heartburn or gastroesophageal reflux disease (GERD), reflux esophagitis and peptic ulcer disease (PUD). These drugs include the following (brand names in brackets):
pantoprazole (Pantoloc®, Tecta™)
rabeprazole (Pariet®) and
While these drugs can be very effective at treating short term bouts of heartburn, for the tens of millions around the world who take them for years on end, we can’t say for sure if they are shortening their lives. While some researchers (including myself) might view these drugs as poster children for the rampant use of potentially dangerous drugs, others don’t have such worries.
About a third of Canadians over 65 use PPIs, and nearly a quarter of them use them chronically (consuming a minimum of 180 days worth in a year). Many of those taking PPIs, are taking them beyond the 90 days that are recommended as a maximum. In BC, almost 50,000 seniors have been taking the drugs for five years or more, and extrapolated across the country that would mean, at a minimum, half a million seniors across Canada are long-term users. This could be a disaster right in front of our eyes. Or not.
A two sided debate
Some researchers maintain that long-term use of PPIs could be contributing to the early death of many, many people. Others say that there is little to worry about and that most of the research showing PPI-related deaths is unreliable. Who is right?
There is one fact upon which people on both sides agree: if you need to take a PPI, you should take it for the shortest period of time at the lowest possible dose. Go low and go slow, is a principle that applies to most every pill you swallow. However, despite this agreement, collectively we have to recognize that there is a lot of ignorance and doubt surrounding the long-term use of PPIs. Which brings me to Agnotology and the kind of “culturally induced ignorance or doubt” which is likely leading to misleading science, biased conclusions and ignorant, potentially fatal use of these drugs.
Many readers of Common Ground are well-versed in the various controversies where powerful interests (think oil companies and climate change or tobacco companies and the safety of tobacco) mount terribly effective campaigns based on ignorance. After all, if you don’t know for sure that cigarettes kill people or whether C02 emissions are warming the planet, then how can you act properly? The PR companies defending the tobacco industry famously described their activities as “doubt is our product.” You could say the same about climate change deniers. By planting seeds of doubt about the dangers of cigarettes, they effectively forced decades of delay before governments began to regulate and restrict what was clearly a murderous product.
I see the same thing all the time in the drug world. Those companies who stand to win or lose billions are heavily invested in the production of doubt. If you can skillfully build a case for doubt around long-term drug safety, you can keep markets buoyant and lucrative. Whether or not physicians believe PPIs can kill comes down to what they consider as “true”.
Randomized Controlled Trials vs. Observational studies: which ones are closer to the truth?
The list of alleged adverse effects of PPIs has continued to grow over the last 20 years, including C-difficile (a sometimes deadly infection), pneumonia, fractures, as well as chronic kidney disease, cancer of the stomach and cardiovascular disease. These adverse effects have only really been found in longer-term observational studies which follow groups of patients over many years, and monitor PPI patients against similar groups of patients who don’t take PPIs, or who take other heartburn drugs. Observational studies have used large groups of PPI users from health insurance databases, where statistical methods can tease out whether PPI users are at greater harm than non-users.
Many people discount observational studies, saying they are full of confounding factors and hence can’t be trusted. Maybe there are more smokers, more overweight people, more people with genuine stomach diseases among the PPI users, and that’s why they have higher rates of illness. If the PPI patients were sicker to start with, then a higher death rate might be due to underlying disease, and not the PPI.
PPIs are approved for sale around the world based on results from short-term randomized controlled trials (RCTs). RCTs are considered the most reliable proof of effectiveness and safety of drugs. During such trials, some patients are randomly assigned the drug and others get a placebo or a control treatment. Then the patients are followed for a period of time, and any effects – both beneficial and harmful – are measured. However, trials used to approve PPIs may be less than 12 weeks long and are basically too short to uncover potential serious harms related to long term use. RCTs of PPIs don’t show the same rate of adverse effects compared to observational studies, because those harms, if real, are related to long term use.
So here’s the conundrum: If you rely only on RCTs as being “the truth” you’d say PPIs are mostly perfectly safe. But if you only believed the long-term observational studies, you’d say the PPIs are probably deadly.
So what do you believe?
I have had a front row seat on this controversy, reading many of the studies done on PPIs and then watching what guideline writers, physicians and other pundits say about them. Here’s the big difference. The defenders of PPIs who don’t think they are deadly have one thing mostly in common: they have ties to drug companies that make them. And they have a way of putting a smiley face on questions of safety. Just recently a three-year RCT run by researchers at McMaster University claimed to show that PPIs have few of the major harms found in observational studies. They claimed their RCT showed definitive proof of safety. Case closed.
Not so fast say others, pointing to what is a recent game-changer of a study. The largest observational study ever done on PPIs was published in the BMJ medical journal in March of 2019. Known as the Xie trial, it followed more than 300,000 US veterans for ten years, looking to see what kind of effects were seen in PPI users.
The results rocked the world.
The PPI patients were matched to other patients who were taking other classes of heartburn drugs. The researchers were extremely careful in this study, ruling out confounders like the types of diseases patients may have been suffering. The researchers found increased deaths by cardiovascular disease, chronic kidney disease and gastrointestinal cancer. All of these causes of death are corroborated by other observational studies, as well as studies in Canada and the US that analyzed reports made to national adverse event reporting systems.
How big were the differences?
The main finding of the Xie study is that the longer patients take a PPI, the more risk of harm they face. Obviously risks increase depending on how sick a person already is, how old they are and the amount of PPI they have swallowed over the years. The study found 45 excess deaths per 1000 patients in 10 years of follow-up in this group of predominately older male adults. If this is true for seniors in Canada taking a PPI over five years or so, (maybe half a million patients) this could mean more than 20,000 excess deaths in Canada due to long term PPI use.
So again, who do you believe?
Let’s be clear about one thing that any researcher needs to do: follow the money. The multibillion dollar PPI industry has had an overly dominant impact on health effects messaging ever since these drugs were first approved in the early 1990s. At one point, Canadians were swallowing over a billion dollars a year worth of PPIs. Today, it’s about $230 million per year due to generic versions being sold at much cheaper costs. Hence, there was a ton of money to shape our ignorance around the safety of these products.
The world’s major drug companies have had a very important role in determining what we know – and especially what we don’t know – about the safety of PPIs. This troubles me greatly. Why? Because if powerful companies wish to spread ignorance, and intentionally spread doubt, there are very few of us around to stop them.
Alan Cassels has studied pharmaceutical policies for 25 years and he lives in Victoria.
Image: stylised esomeprazole molecule