MD, PhD, FMedSci, FSB, FRCP, FRCPEd

Dietary and herbal supplements (DHS) are currently popular. They are being promoted as being natural and therefore safe – an assumption that is clearly wrong: some DHS can contain toxic substances or they might cause interactions with drugs or other DHS.

This study explored whether adverse events were actually associated with such interactions and examined specific characteristics among inpatient DHS users prone to such adverse events. It was designed as a cross-sectional survey of 947 patients hospitalized in 12 departments of a tertiary academic medical centre in Haifa, Israel. It evaluated the rate of DHS use among inpatients, the potential for interactions, and actual adverse events during hospitalization associated with DHS use. It also assessed whether DHS consumption was documented in patients’ medical files. Statistical analysis was used to delineate DHS users at risk for adverse events associated with interactions with conventional drugs or other DHS.

The results show that about half of all patients took DHS. In 17 (3.7%) of the 458 DHS users, an adverse event may have been caused by DHS-drug-DHS interactions. According to the Drug Interaction Probability Scale, 14 interactions “probably” caused the adverse events, and 11 “possibly” caused them. Interactions occurred more frequently in older patients (p = 0.025, 95% CI: 2.26-19.7), patients born outside Israel (p = 0.025, 95% CI: 0.03-0.42), those with ophthalmologic (p = 0.032, 95% CI: 0.02-0.37) or gastrointestinal (p = 0.008, 95% CI: 0.05-0.46) comorbidities, and those using higher numbers of DHS (p < 0.0001, 95% CI: 0.52-2.48) or drugs (p = 0.027, 95% CI: 0.23-3.77).

The authors concluded that approximately one in 55 hospitalizations in this study may have been caused by adverse events associated with DHS-drug-DHS interactions. To minimize the actual occurrence of adverse events, medical staff education regarding DHS should be improved.

This seems to be a good study and it generated interesting findings on an important topic.

Why do I have nevertheless a problem with it?

The answer is simple but not pleasant: very similar results have been published almost simultaneously in more than one journal. The link above is to an article in the BR J CLIN PHARMACOL of October this year. The following text is from the abstract of an article in INTERN EMERG MED also of October this year:

Of 927 patients who agreed to answer the questionnaire, 458 (49.4 %) reported the use of 89 different DHS. Potential DHS-DHS interactions were identified in 12.9 % of DHS users. Three interactions were associated with the actual occurrence of adverse events. Patients at risk of DHS-DHS interactions included females (p = 0.026) and patients with greater numbers of concomitant medications (p < 0.0001) and of consumed DHS (p < 0.0001). In 88.9 % of DHS users, DHS use was not reported in medical files and only 18 % of the DHS involved in interactions were documented. Potential DHS-DHS interactions are common in inpatients, and may lead to hospitalization or worsen existing medical conditions. The causal relationship between potential interactions and actual adverse events requires further study.

END OF QUOTE

And to my surprise, I also found a third article also from the October issue of INTERN EMERG MED reporting on this survey. Here is part of its abstract:

DHS users were determined via a questionnaire. The Natural Medicine database was used to search for potential DHS-drug interactions for identified DHS, and the clinical significance was evaluated using Lexi-interact online interaction analysis. Medical files were assessed for documentation of DHS use. Univariate and multivariate logistic regression analyses were used to characterize potential risk factors for DHS-drug interactions. Of 927 patients consenting to answer the questionnaire, 458 (49 %) reported DHS use. Of these, 215 (47 %) had at least one potential interaction during hospitalization (759 interactions). Of these interactions, 116 (15 %) were potentially clinically significant. Older age [OR = 1.02 (1.01-1.04), p = 0.002], males [OR = 2.11 (1.35-3.29), p = 0.001] and increased number of used DHS [OR = 4.28 (2.28-8.03), p < 0.001] or drugs [OR = 1.95 (1.17-3.26), p = 0.011] were associated with potential interactions in DHS users. Physicians documented only 16.5 % of DHS involved in these interactions in patients’ medical files. In conclusion, a substantial number of inpatients use DHS with potential interactions with concomitant medications. Medical staff should be aware of this, question patients on DHS usage and check for such interactions.

END OF QUOTE

What is the difference between the three articles? The first one in INTERN EMERG MED authored by Levy I, Attias S, Ben Arye E, Goldstein L, Schiff E evaluated “potential DHS-DHS interactions among inpatients”. The second one in INTERN EMERG MED also authored by Levy I, Attias S, Ben Arye E, Goldstein L, Schiff E evaluated “potentially dangerous interactions of DHS with prescribed medications among inpatients”. Finally the one in BR J CLIN PHARMACOL also authored by Levy I, Attias S, Ben-Arye E, Goldstein L, Schiff E  assessed in addition the interactions between DHS and prescription drugs.

Dual publications are usually considered to be a violation of research ethics. Publication of different aspects of one single data-set in multiple articles is called ‘salami-slicing’ and is often considered to be poor form.

My question to you, the reader of this post, is: What type of scientific misconduct do we have here?

4 Responses to Interactions caused by dietary supplements (+ a case of scientific misconduct?)

  • As the authors failed to declare an interest in the ‘other two publications’, failed to cross-reference and are seeking to mislead readers (what other reason could there be?), the type of misconduct identified is ‘false reporting’.

    Wikipedia offers a Danish definition of SM: “Intention or gross negligence leading to fabrication of the scientific message or a false credit or emphasis given to a scientist.”

    If authors are capable of falsely giving credit, seeking emphasis on themselves and fabricating the message (by salami), to what extent can any of their results be trusted?

    Will the editors of all three publications issue clear statements as to what their opinions are?

  • I’ve seen plenty of examples of salami-slicing of datasets. It’s understandable, but not forgivable, in an era when academic institutions measure the performance of their staff by the number of papers they publish. But this case is a particularly egregious example of the practice. The second paper (Br. J. Clin. Pharmacol.) cross references the first one (Intern. Emerg. Med.) in its reference list, but it doesn’t mention it anywhere in the text!

    Not for the first time, you have picked up on something that (anecdotally) confirms my suspicion: editors of biomedical journals often take handsome remuneration for doing effectively nothing, and referees are too busy to pay proper attention to detail. At least the authors have avoided outright double publication. That’s the most that can be said in their favour.

    • I recall a time when journal publishers would refuse publication if the same data had previously been or was planned to be published elsewhere. As for the reliability of journal editors, I lost hope many years ago. In the 1990s, the excuse used to be that when it came to the subject of medicinal plants, dietary supplements, complementary medicine, and the like, there were very few editors available with sufficient expertise to handle the work. Today, with the exception of a handful of journals, I don’t see much improvement. When I see egregious errors of syntax, formatting, and spelling, I know the editors have pocketed the cash and not done their job.

      • Editors still get worked up over duplicate publication: it remains a major sin of science. But this is not duplicate publication. The authors did a quite extensive study then divided the results into three parts: DHS-drug interactions, DHS-DSH interactions and overall DHS interactions with drugs or other DHS. Of course, this ‘salami slicing’ of study outcomes (I can’t think of a better term than the one Edzard used)) results in some duplication. Table 1 in the two Intern. Emerg. Med. papers, describing the basic characteristics (sex, age, etc.) of the DHS users is almost identical.

        Don’t even start me on errors of syntax, formatting, spelling and grammar. Only the top journal editors actually edit papers nowadays. The rest just bung in the work as written, amended for scientific problems in response to referees’ comments but not for poor literacy.

        By the way, I have heard a modern science publication philosophy that a good paper should make one point only, or address just one issue. That’s a sure recipe for ‘salami slicing’! Compare that principle with papers published around a century ago. The contrast is very striking. Authors didn’t at all feel the pressure to rush into print and their publications often explore a topic in great detail. More than 100 years ago, of course, specialist journals were in their infancy and people sometimes waited years before writing up their results in books (Darwin springs to mind as an obvious example).

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