Editorial Note: Ten years ago I was at a meeting in Ottawa Canada looking at the issue of adverse events on treatment and how to manage these. The attendees were mostly left leaning activists. But Terence Young, then recognizably a conservative and later a conservative Member of the Canadian Parliament was also there. He was the only person speaking from direct experience of losing a loved one to a treatment related event. There was no Left or Right when it came to listening to his story. What happened to him and what happens to anyone who is the victim of a treatment related event should not be happening in a civilized healthcare system, private or socialized.
A father takes on his daughter’s killer
Fourteen years ago in Oakville Ontario, Terence Young’s fifteen year old daughter Vanessa who had been taking cisapride – Prepulsid – for almost no reason at all, dropped dead in front of him. Her heart had suddenly stopped.
Causing hearts to suddenly stop was a recognized side effect of Prepulsid in lots of countries other than Canada, as Terence found out afterwards. Had the warnings that were on Prepulsid in the USA been on the Canadian packet, there was much less chance Vanessa’s doctor would have prescribed it for such a minor problem or if prescribed much less chance she would have taken it. The story is told in Death by Prescription, described as “a father takes on his daughter’s killer”.
This year Vanessa’s Bill – making adverse event reporting mandatory – is working its way through the Canadian Parliament. A huge step forward. But Vanessa’s death opens a perspective on adverse event reporting that this Bill if passed might not remedy.
The Q-T iceberg
Vanessa died because of the effects of Prepulsid on the rhythm of her heart, specifically on what is called the Q-T interval when these things are mapped on an electrocardiogram (ECG or EKG). The effects of drugs on this aspect of cardiac functioning have recently led more drugs to be withdrawn or not approved than any other adverse event.
RxISK has just published an article that outlines the history of these treatment induced sudden cardiac deaths. The story began fifty years ago in Canada with an antipsychotic called Mellaril. It takes roughly twenty years for the major hazards of drugs to be warned about but the company responsible for Mellaril, Sandoz, took forty years to put warnings on the drug. It’s likely that tens of thousands of older people across the Western world during these forty years died prematurely because they were on this drug as a hypnotic or seemingly gentle anxiolytic.
By the time warnings went on Mellaril, Prepulsid had been withdrawn in many countries and it was becoming clear that Q-T interval changes are an iceberg. Mellaril and Prepulsid are its tip. The body of the iceberg is out of sight. There are a huge number of drugs that affect Q-T intervals on the market without any warnings. Many readers of this blog are likely to be on one.
Whose drugs did you say are causing problems…
The companies get away without warnings if the effect of their drug on Q-T intervals is not as dramatic as that of Prepulsid. The effects of Clozapine and Citalopram (Celexa, Lexapro, Cipramil, Cipralex) for instance are all pretty marked but not quite as bad as Mellaril when used in lower or conventional doses. Push the dose up and you can drop dead on many antidepressants or antipsychotics currently on the market without warnings that this could happen or awareness of the problems by the doctors who prescribe them.
But the real problems come when someone combines almost any antidepressant with almost any antipsychotic, or either of these drug groups with many antibiotics in common use or heart drugs like amiodarone or diuretics like furosemide. There is a good chance that both drugs will have effects on Q-T intervals and their combined effects will head into the Prepulsid range.
There have been a rash of stories of children being treated for ADHD dropping dead. The stimulants and other drugs like atomoxetine used for ADHD all cause Q-T changes.
The biggest story of all may be in the US military where there have been a rash of deaths of young men, often found dead in their beds. This has led to worries that many are committing suicide. While there does seem to be a high confirmed suicide rate, many of these deaths are unexplained, leading some to think the suicide rate is even worse.
Again and again however the accounts of the deaths show little signs of suicide and are marked by combinations of drugs that combined can definitely stop hearts.
The reverse dodo verdict
In Alice in Wonderland, Alice and others get soaked and to get them dry the Dodo proposes a Caucus race. Basically everyone ran till they were dry. At the end all wanted the Dodo to tell them who had won. The Dodo replied that “Everyone has won, and all must get Prizes”.
The idea was adapted by those supporters of psychotherapy who figured that whatever else psychotherapy did having someone wise to consult was a good thing and in so far as all forms of psychotherapy potentially offered this, all had won and should be reimbursed
In this case what we have is a Reverse Dodo Verdict. Many drugs and certainly all companies have drugs that cause problems and know they cause problems but none will get penalized because none causes such a problem in its own right that companies are at risk of legal actions even in the United States.
How to avoid extinction
Vanessa’s and Jeannie’s problems will be helped by Terence Young’s Bill, but for most people keen to avoid becoming extinct, the ultimate answer lies in something like having a smartphone App that reads QT intervals and lets you know whether a drug you are on has pushed you closer to the QT danger zone.
RxISK has been chasing possible partners to help with this. There are many groups producing cardiac rhythm Apps. These come for free. The way companies make money is to offer expert interpretation for a fee. But reading QT intervals isn’t a matter of interpretation – so it should be possible to do it for free. But weirdly reading QT intervals is just not something that machines can do all reliably. It should be possible to print them off and measure them. Or there may be other things about the cardiac rhythm that could be automatically measured more reliably to pick up danger signs.
Saving your life or your children’s or parent’s life is a pretty good incentive to get people involved – once involved there may be scope for companies to make money out of selling expert interpretations on the rhythm strips people will end up with. So there is a potential win win here – you can only make money out of people who stay alive. The mystery is no-one seems to see the chance to save a lot of lives here.
In the meantime, the best bet is for anyone taking a drug, or more to the point going on a second drug to check on RxISK for the profile of this drug in terms of QT interval changes, Sudden Cardiac Death, torsade de pointes – and cardiac changes generally.
Will getting people to check the cardiac profile of their drugs make the entire population hypochondriacal? Nope.
What it will do is to remind everyone what medicine is about – its a mysterious art that involves collaboration between doctors and patients to use poisons in risky situations to achieve good things. If the situation isn’t really risky to begin with, you shouldn’t be on the poison. If you are already on one poison, adding another ups the risks substantially and makes it ever more important that your doctor has as many people as possible helping her keep you safe – that she has you really involved.
The iceberg’s tip
Prepulsid, Mellaril, Celexa-Lexapro and Clozapine are the tip of an iceberg that includes a very large proportion of the drugs in common use.
But there is another iceberg of which sudden cardiac death is the tip. Almost all these drugs that lead to cardiac rhythm abnormalities lead to dependence and withdrawal also. Many people struggling with difficulties in coming off antidepressants, mood-stabilizers and antipsychotics have for instance in the case of the antidepressants tried every manipulation of the serotonin system they can think of but nothing helps.
The answer may lie in the fact that dependence and withdrawal stem from effects all these drugs have on something else such as sodium, potassium or calcium channels that leads to rhythm disturbances. One reason to suspect this is because the withdrawal from benzodiazepines, antidepressants, and antipsychotics shows so much overlap that all of these drugs look like they should be working on something in common. The in-common thing is their effect on rhythms – not just cardiac but also nervous.
It may be that one of the better bets to help withdrawal are drugs like the calcium channel blockers – verapamil for instance – used to stabilize rhythm disturbances. This can certainly help some people and even some cases of tardive dyskinesia for instance.
Just as the Cheshire Cat could disappear leaving just its grin behind, it might be that there are drugs out there that alleviate withdrawal without us spotting what’s going on. We need your help to spot the Grin.