Hydroxychloroquine Cardiotoxicity: A Rare But Potentially Deadly Adverse Effect

The antimalarial drug hydroxychloroquine (HCQ) has been promoted by President Trump as a game-changing treatment for coronavirus infection. Of the drug, Trump declared “What do you have to lose? Take it! Try it if you’d like.”

As with any drug treatment one should consider the risks and the benefits of HCQ before “trying.” For expert virologists and infectious disease doctors, HCQ has not been proven to be beneficial in the treatment of coronavirus infection despite a glimmer of hope from early, small, poorly controlled trials from China and France.

The Chinese and French papers which reported on the use of HCQ with or without azithromycin in patients with coronavirus did not clearly show a clinical benefit. The most recent information suggests no benefits and potential harms to HCQ use.

With benefit unproven, we must be particularly cognizant of the adverse effects of any proposed or experimental treatment, and both HCQ and azithromycin (AZ) have well documented potentially lethal cardiac adverse effects.

I wrote about the risk of QT prolongation and sudden death with azithromycin here

A patient of mine with known left bundle branch block and cardiomyopathy recently contacted me because he had been prescribed HCQ for a rheumatologic disease. To determine if he should take this drug I reviewed the literature on HCQ cardiotoxicity.

Hydroxychloroquine Cardiotoxicity

HCQ is primarily utilized now for the treatment of rheumatologic disorders, most commonly systemic lupus erythematosus ( SLE.)

A recent review of  HCQ use in SLE concluded

HCQ may reduce the risk of flares, allow the reduction of the dosage of steroids, reduce organ damage, and prevent the thrombotic effects of anti-phospholipid antibodies. The drug is generally safe and may be prescribed to pregnant women. However, some cautions are needed to prevent retinopathy, a rare but serious complication of the prolonged use of HCQ

The Johns Hopkins Lupus Center section devoted to “Treating Lupus with Anti-Malarial Drugs” mentions a dozen side effects but does not mention cardiotoxicity.

However, the scientific literature contains numerous case reports of patients with SLE who developed either severe heart failure or conduction abnormalities (sometimes both) with strong evidence that HCQ was responsible.

Joyce, et al, (Hydroxychloroquine cardiotoxicity presenting as a rapidly evolving biventricular cardiomyopathy: key diagnostic features and literature reviewdescribed a case of HCQ cardiotoxicity in 2013 and reviewed the literature on the topic. They emphasized typical findings on cardiac biopsy and concluded:

“although rare, hydroxychloroquine cardiotoxicity can be fatal, particularly if irreversible histopathological changes have occurred prior to drug discontinuation. Given this, regular screening with 12-lead electrocardiography and transthoracic echocardiography to detect conduction system disease and/or biventricular morphological or functional changes should be considered in hydroxychloroquine-treated patients”

The most recent review of HCQ was published in 2018 and identified 127 patients from case reports or case series with cardiac complications from HCQ or chloroquine.

Two-thirds of these patients were female and the majority were treated with chloroquine (58%.)

Patients had been on drug treatment from 3 days to 35 years (median 7 years.)

The median cumulative dose was 1.235 grams for HCQ.

Conduction disorders were the most common adverse cardiac effect noted with 85% of patients

Other non-specific adverse cardiac events included ventricular hypertrophy (22%), hypokinesia (9.4%), heart failure (26.8%), pulmonary arterial hypertension (3.9%), and valvular dysfunction (7.1%).

For 78 patients reported to have been withdrawn from treatment, some recovered normal heart function (44.9%), while for others progression was unfavorable, resulting in irreversible damage (12.9%) or death (30.8%)

To summarize:

  1. HCQ and chloroquine have associated and well-documented, albeit rare cases of potentially lethal cardiotoxicity.
  2. The benefit of these drugs in the treatment of coronavirus infection is currently unproven.
  3. Data from high-quality randomized trials of HCQ treatment in patients with coronavirus is needed before we can assess whether the drug benefits outweigh its risk in COVID-19 patients.

Much has been written in the cardiology literature recently about QT prolongation with HCQ and ECG monitoring and I will publish a separate post on that topic shortly.

Skeptically Yours,

-ACP

20 thoughts on “Hydroxychloroquine Cardiotoxicity: A Rare But Potentially Deadly Adverse Effect”

  1. Costa Rica, where I live, has been prescribing HCQ (notably, without Azithromycin) whenever it isn’t contraindicated.

    They’re doing it early, sometimes before the definitive diagnosis is returned.

    They have the lowest fatality rate in the world.

    That enviable position could be the result of many factors.

    But they seem to rather be anecdotally alive than peer-reviewed dead.

    (I note that, although 3 days is the shortest duration, 7 years is the median for those who developed heart problems.

    They’re prescribing it for less than 10 days here).

  2. Several years ago I was prescribed hydroxychloroquine for osteoarthritis. After taking the drug for a little over a month I had a bought of a-fib and ended up in the hospital. The arthritis doctor said she had never had such a thing. After seeing my eye doctor, a native of India, familiar with drug because of use for malaria, he advised stay away from it because of the QT interval prolongation. Although I do have a history of PVC’s I had never before and never since had an incident of a-fib.

    1. I had not seen the Tisdale Risk Score before. Thanks for bringing that to my attention. I carry something like it in my brain but its nice to have a semiquantative approach to QT prolongation risks.
      That is also a very well done article.
      Looking at the factors/points highlights how patients who are critically ill may move into a high risk category from a low risk due to their illness and its complications. For example, many fo these patients have NSTEMIs-2 points, with heart failure-3 which is treated with diuretics-1 points and lowers the potassium-2 points. That’s 8 points additional and could easily take you from <6 poinds or low risk to >11 and high.
      Then a secondary bacterial infection causes sepsis-3 points which is treated with a QT prolonging antibiotic-3 points, adding another 6 points.

  3. I heard of some healthcare workers talking about taking it prophylactically at low doses. But this was back in March before the studies came out. I wonder if the dose makes a difference?

    1. The dose will make a difference. Just this afternoon JAMA published a randomized trial of high and low dose chloroquine in Covid-19 patients. Trial stopped earlly because the higher dosage patients were dying more frequently than the lower dosage patients.

  4. Always enjoy reading your posts whether I agree or disagree. I reviewed the Abstract. I think it should be pointed out

    > only 39% in the studies were treated with hydroxychloroquine. I believe that is the RX of choice of physicians that disagree with your opinion.

    > You point out the median is 7 yrs; however, but fail to mention the current practice (I believe) is to treat COVID with hydroxy for 5 days.

    > Study limitations :The risk of cardiac complications attributed to chloroquine/hydroxychloroquine was not quantified because of the lack of randomized controlled trials and observational studies investigating the association.

    1. Richard,
      All excellent points!
      I do indicate that “the majority were treated with chloroquine (58%)” in the post. I wrote the bulk of this a couple of weeks ago and acquired the full article since. My initial plan was to provide lots more details but ultimately decided they would not change the overall point of the piece.

      Definitely, the cases tended to be patients who had been on the drug for a while.

      And most certainly, it is impossible to know the risk without knowing the denominator. I would also add for these case reports it is not always clear that HCQ caused the cardiac abnormality.

      1. Here is something that is relevant re Chang’s JACC article on this subject: ” If I did the math correctly, 1 of 90 cases in Chang’s group had notable QTc prolongation, but no arrhythmia other than “rapid ventricular response.” This suggests the safety (!) of UNMONITORED use of HCQ + azith + likely Zn, rather than danger. There has been a tremendous over-reaction by cardiology & EPS people to this combination Rx. That Rx has proven SAFE, if not quite effective in moderate CoV-19 infections and is WIDELY and carefully used. My original internet blog thoughts regarding the Heart Rhythm Society recommendations were: “Seldom have I seen such a misguided and slanted “scientific” piece. Literally, while Rome (the USA and world) is burning (CoV2-19 pandemic NOW!!)these politically motivated authors,who deserve much greater castigation, want a double blind, placebo controlled cross-over study. Yes, pay attention to the likely much more troublesome serum potassium and magnesium levels, but that is “elementary, my dear Watson.” Quoting General Decker played by Rod Steiger in the hilarious movie “Mars Attacks”: “Idiots!” HRS, MD, FACC

      2. I was perplexed that your post seemed out of date but that you wrote most of it a couple weeks ago explains that. Latest I’ve been reading is HCQ is not recommended for CV19, not even by the president.

        1. Holly,
          The post is still very relevant because many hospitals and individual doctors are utilizing HCQ routinely for patients with documented or suspected Covid-19.
          This despite most authorities recommending against it.

  5. I’m not surprised that the French and Chinese studies came up short. Watch:
    https://www.youtube.com/watch?v=U7F1cnWup9M
    for a creditable analysis of the mechanism by which HCQ works due to being a zinc ionophore. If there is little intracellular zinc there is impaired innate immunity. Hence many clinicians pair HCQ with zinc.

    As a long time AFibber, I recognize the rhythm risk but based on my personal analysis I’d agree with the previous comment…I’d “rather be anecdotally alive than peer-reviewed dead.”

  6. HCQ is not the only Zn ionophore, the plant-derived ‘Quercetin’ is another, as is an ingredient in green tea (extract).
    However, not as likely to be “$upported” as they aren’t a factory-manufactured / patented product.
    While you decide about QT intervals, eat oysters & pumkin seeds, (Zn slows viral replication inside the cell…) washed down with green tea !
    Anecdotal is merely ‘data not yet formally published’, and yes, A- alive is cheaper and preferable for arguing the case
    – Later!

  7. Holly,
    No doctors I know would be so irresponsible as to prescribe a drug that they don’t think offers this patient the best chance in this situation. Let’s trust their intuition, practice results, and personal research. Essentially everything in the media is biased by either the desire to make a political opponent look bad (Trump, for example) or by the perceived need to prevent “everybody from doing it” (wearing N95 masks, for example).

  8. There appears to be a correlation between Vit. D and seriousness of symptoms, the more D – the better your outcomes.
    This may be part of the story for us in Australia and our relatively low ICU – incarceration and deaths.

    (it’s the end of our summer here,- and we see the Sun for 9+ months of the year, enough to burn…)

    Confined spaces such as air-conditioned trains / coaches is being fingered as excessively dangerous environments, as compared to being in a highly ventilated space.

    So get outdoors in the sun, and let the wind blow through your hair !

  9. Interesting article. I live in Scotland, am 55 and was prescribed HCQ two years ago for rheumatoid arthritis. I had a sub-total thyrodectomy when I was 20 and have required thyroid replacement for 30+ years and things have been very stable, however since menopause my levels have shown my medication to be too high on three different occasions and the dose has been lowered each time. The latest episode of this was the week before Christmas and my thyroxine was dropped to 100 micro grams per day. On top of everything else, around October last year I developed a strange heart rhythm which has caused me great anxiety. In February 2020 my GP did an ECG and found I had borderline long QT (I did not have this when I had surgery for a carpal tunnel release four years ago.) I was referred to a cardiologist but in the meantime I stopped taking my prescribed HCQ as well as 20mg amitryptyline for nerve pain because I read that both could cause QT prolongation. Covid-19 meant my cardiology appointment was cancelled, but I have just had a Holter monitoring by a cardiac physiologist which showed I had ‘an extra beat’ or benign PVCs. Much to my relief there’s no evidence of the borderline long QT. I’ve been told by my GP not to worry about the PVCs despite the fact they happen a lot and waken me during the night (that’s easier said than done!) I already take 50mgs per day of propranalol and Amlodipine for hypertension. I found this site last week and was so relieved to learn that there are others who have symptoms from PVCs as I’d never even heard of this, and your articles and Qs & As are full of information and so helpful. With all the bad press HCQ is receiving right now, is it possible that it could have caused my PVCs? I’ve been off the medication for 14 weeks, but it hasn’t made any difference and unfortunately my arthritis is very active now. Many thanks in advance for your consideration – I am very grateful.

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