MD, PhD, FMedSci, FRSB, FRCP, FRCPEd.

bias

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I want to thank our friend ‘OLD BOB’ for alerting me to Patrick Holford’s comment on a recent trial of vitamin C for COVID-19. Here are three short quotes from Holford:

… Overall, 5 out 26 people (19%) died in the vitamin C group while 10 out of 28 (36%) receiving the placebo died. That means that vitamin C almost halved the number of deaths. Those on vitamin C were 60% more likely to survive.

… Of those most critically ill, 4 people (18%) in the vitamin C group died, compared to 10 (50%) in the placebo group. That’s two-thirds less deaths. Statistically this meant that of those most critically ill who were given vitamin C, they were 80% less likely to die…

… now there is another proven treatment – vitamin C…

And here is the abstract of the actual trial Holford refers to:

Background: No specific medication has been proven effective for the treatment of patients with severe coronavirus disease 2019 (COVID-19). Here, we tested whether high-dose vitamin C infusion was effective for severe COVID-19.

Methods: This randomized, controlled, clinical trial was performed at 3 hospitals in Hubei, China. Patients with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in the ICU were randomly assigned in as 1:1 ratio to either the high-dose intravenous vitamin C (HDIVC) or the placebo. HDIVC group received 12 g of vitamin C/50 ml every 12 hours for 7 days at a rate of 12 ml/hour, and the placebo group received bacteriostatic water for injection in the same way. The primary outcome was invasive mechanical ventilation-free days in 28 days(IMVFD28). Secondary outcomes were 28-day mortality, organ failure, and inflammation progression.

Results: Only fifty-six critical COVID-19 patients were ultimately recruited due to the early control of the outbreak. There was no difference in IMVFD28 between two groups. During the 7-day treatment period, patients in the HDIVC group had a steady rise in the PaO2/FiO2 (day 7: 229 vs. 151 mmHg, 95% CI 33 to 122, P=0.01). Patients with SOFA scores ≥3 in the HDIVC group exhibited a trend of reduction in 28-day mortality (P=0.06) in univariate survival analysis. IL-6 in the HDIVC) group was lower than that in the placebo group (19.42 vs. 158.00; 95% CI -301.72 to -29.79; P=0.04) on day 7.

Conclusion: This pilot trial showed that HDIVC might show a potential signal of benefit for critically ill patients with COVID-19, improving oxygenation even though it failed to improve IMVFD28.

The following points are, I think, worth mentioning:

  • This was, according to its authors, a PILOT study.
  • It was far too small (n=56) to provide reliable results on mortality.
  • The trial authors know that and interpret their findings with sufficient caution.
  • The primary endpoint, the IMVFD28, showed NO significant difference between the groups.
  • The secondary endpoint: HDIVC infusion exhibited a non-significant trend of reduction in 28-day mortality (P=0.06).
  • In more severe patients (SOFA score ≥3), univariate survival analysis and Cox regression showed a similar results (P=0.07, HR, 0.32 [95% CI 0.10-1.06]).

And what does all of this mean? It means that, in this pilot study, vitamin C failed to produce a significant result. Only in a subgroup analysis related to a secondary endpoint was there a slight advantage of vitamin C. This effect is, of course, interesting and needs further investigation (I am sure that is happening as we speak). It could have some clinical significance but, just as likely, it could just be due to chance. There is not way of knowing which is which.

In other words, to hype the findings and to even make statements such as ‘now there is another proven treatment, vitamin C’ is not just exaggerated, it is irresponsible.

This begs the question: why does Mr Holford do it? In case you don’t already know about this man, go on the Internet, and you will quickly find possible answers. Here is an excerpt from his Wiki page which might give you a clue:

Patrick Holford is a British author and entrepreneur who endorses a range of controversial vitamin tablets. As an advocate of alternative nutrition and diet methods, he appears regularly on television and radio in the UK and abroad. He has 36 books in print in 29 languages. His business career promotes a wide variety of alternative medical approaches such as orthomolecular medicine, many of which are considered pseudoscientific by mainstream science and medicine.

Holford’s claims about HIV and autism are not in line with modern medical thought, and have been criticised for putting people in danger and damaging public health.

In 2006 Holford was discovered to be using his PR advisor to delete critical content from his Wikipedia page…

Holford has been the subject of criticism for his promotion of medically dubious techniques and products including hair analysis, his support of the now struck off doctor Andrew Wakefield, and advocating the use of “non-drug alternatives for mental health” for which he has been given an award by the Church of Scientology-backed Citizens Commission on Human Rights.

SAY NO MORE!

Or perhaps not?
Here is the announcement:

Research by a reputable independent research company done for Securivita a German insurance company shows that those receiving homeopathic care were much better off. Over 15,700 patients were involved in the study which also used a comparison group.

The study showed that in a wide range of patients with various pathological problems that if they had homeopathic care they faired dramatically better than those just getting conventional medicine.

Children having homeopathy treatment from birth, were particularly healthier and with less problems. Over the three year study period, the number of children needing antibiotics decreased by 16.7 per cent in the homeopathy group, whereby it increased by 73.9 per cent in the conventional medical comparison group!

The number of hospitalizations in the comparison group increased by 32.6 per cent whereby in the homeopathy treatment group it decreased by 9.8 per cent!

Adults and children treated homoeopathically had dramatic improvements in allergies, dermatitis, asthma, just to name a few.

These are just a few examples of the remarkable benefits of homeopathic treatment outlined in the study by by the Leipzig Health Forum , an independent analytical institute specializing in health services conducted for Securvita Krankenkasse Insurer.

“We don’t need fewer, but more homeopathic doctors who will continue on this successful path,” says Götz Hachtmann , director of the health insurance company Securvita.

The study is in German and can be found here.

____________________________

Blessed are those who don’t read German (at least in this instance)!

As I am not amongst the blessed, I ought to tell you a bit about the ‘massive’ study. The OHR, the ‘OFFICIAL HOMEOPATHIC RESOURCE’ (btw what makes the OHR ‘official’?) claims that the study can be found here. The OHR is evidently not well enough resourced for translating the German text into English; if they were, they would know that the link goes not to a ‘study’ but to some kind of a glossy marketing brochure about the ‘study’ (there is no actual published scientific paper on the ‘study’). It provides hardly any relevant information; all we learn is that 15 700 individuals who regularly consulted homeopathic physicians were compared over a three year period to an equally sized control group who did not consult homeopathic doctors… And that’s essentially it! No further relevant details are offered.

By contrast, quite a bit of information is offered about the findings, for instance:

  • In the homeopathy group, the hospitalisation rate of depressive patients dropped by 10%, while it increased in controls by 33%.
  • The days off work dropped by 17% vs an increase in controls of 17%.
  • The use of antibiotics decreased by 17% vs an increase of 74%.

And how do they explain these differences?

Yes, you guessed it:

they are due to homeopathy!

One does not need to have a perfumer’s nose to smell a few badly decomposing rats here, for example:

  1. We do not learn how many variables were tested in this ‘study’. Therefore, it is likely that the ‘results’ provided are the positive ones, while the not so positive potential effects of homeopathy remained unmentioned. Perhaps the death rate was higher in the homeopathy group? Perhaps they suffered more heart attacks? Perhaps they had a lower quality of life? Perhaps they caused more costs? Perhaps they committed more suicides? etc. etc.
  2. Even more obvious is the stench of selection bias. The individuals in the homeopathy group were clearly different from the controls to start with. They might have been more health conscious. They clearly were more cautious about antibiotics. They might have been of better general health. They might have been younger. They could have contained more women. They might have been more afraid of going into a hospital. They might have been keener to attend work. In fact, the only variable in which the two groups were comparable is sample size.

Even if we eventually we see this ‘study’ published in a peer-reviewed journal with full methodological details etc., it will not allow even the smartest spin-doctor to establish cause and effect. Its findings would not be more conclusive than those of previously discussed attempts to produce positive evidence for homeopathy. The ‘positive’ findings could have been the result of hundreds of causes, none of which are related to homeopathy.

In a nutshell: this new German ‘study’ is a textbook example for arguing in favour of conducting proper research rather that rampant pseudo-research.

But I must not always be so negative!!!

So, let me try to point out the positive sides of this ‘study’:

The ‘massive independent study’ is a true masterpiece of advertising and marketing for both Securivita and homeopathy.

Well done guys!

I am proud of you!

  • That’s exactly the stuff needed for successfully misleading the public.
  • That’s precisely the info required to increase your cash flow.
  • That’s helpful ‘research’ for convincing politicians.
  • That’s definitely the type of baloney to impresses the Ullmanns of this world.
  • That’s even the sort of ‘science’ which the ‘OFFICIAL HOMEOPATHIC RESOURCE’ cannot recognise for what it truly is:

invalid junk.

This recent review claimed to evaluate the evidence on the use of human and veterinary homeopathy, evidence level 1a studies were considered. Focusing on the external evidence on the use of homeopathy in infections, some evidence level 1a, 1b, 2c studies, and a case report, are described in more detail.

In conclusion, evidence for the effectiveness of human and veterinary homeopathy in general, and in particular, of homeopathic treatment for infections, is available. Especially, individualized homeopathy demonstrates effects at all quality levels according to Cochrane criteria, even in the methodologically high-quality studies. As in most areas of veterinary medicine and medicine, further good/excellent studies are necessary. In compliance with the principles of homeopathy, further methodologically high-quality trials focusing on the homeopathic treatment of infections are the next logical step. The selection of the simile (individually fitting homeopathic medicinal product) by appropriately trained homeopathic doctors/veterinarians is essential for the effectiveness of homeopathy. Implementation of studies at university facilities is a prerequisite for quality assurance. Consequently, further integration of homeopathy at universities is a necessary requirement for the patients’ best interests.

Who wrote this bizarre paper?

The authors who state to have no conflicts of interest are P Weiermayer 1M Frass 2T Peinbauer 3L Ellinger 4

  • 1Tierärztin, Tierarztpraxis Dr. Weiermayer, Diplom der Europ. Akademie für Veterinärhomöopathie (EAVH), Fachtierärztin für Homöopathie, Sprecherin der Sektion Forschung der Wissensch. Gesellsch. für Homöopathie (WissHom), Präsidentin ÖGVH, Wien, Österreich.
  • 2Facharzt für Innere Medizin und Internistische Intensivmedizin, em. Professor für Innere Medizin der Medizinischen Universität Wien, Diplom der Österreichischen Ärztekammer (ÖÄK) für Homöopathie sowie für Begleitende Krebsbehandlung, Wien, Österreich.
  • 3Arzt für Allgemeinmedizin, ÖÄK-Diplom für Homöopathie, Universitätslektor für Allgemeinmedizin und Modulbeauftragter für Komplementärmedizin, Medizinische Fakultät, Johannes Kepler Universität Linz, Österreich.
  • 4Tierärztin, Centaurea, Apeldoorn, Holland.

This already explains quite a lot, I think.

The paper itself is in German, so I will try to make some sense of part of it for you.

In their ‘methods section’, the authors explain that they evaluated meta-analyses and systematic reviews (SRs) of homeopathy for various conditions. Furthermore, they considered the ‘1st and 2nd’ NHMRC reports. Specifically for the question whether homeopathy is the answer to antibiotic resistance, the authors also considered RCTs, observational studies, heath service research and even case-studies. The authors then elaborate at length on the assumptions of homeopathy, on legal issues and on the nature of evidence-based medicine all of which I disregard for the moment (suffice to say that this material has been often and better reviewed before).

When finally discussing the evidence on homeopathy for human conditions, the authors state that, up until 2014, six comprehensive SRs had been published. In their opinion, these are the following 6 papers:

  1. Kleijnen, J., Knipschild, P., Ter Riet, G. (1991): Clinical trials
    of homeopathy. BMJ 302(6772): 316-23.
  2. Linde, K., Clausius, N., Ramirez, G., Melchart, D., Eitel, F.,
    Hedges, L.V., Jonas, W.B. (1997): Are the clinical effects of
    homeopathy placebo effects? A meta-analysis of placebo-controlled trials. Lancet 350(9081): 834–843.
  3. Linde, K., Scholz, M., Ramirez, G., Clausius, N., Melchart,
    D., Jonas, W.B. (1999): Impact of study quality on outcome
    in placebo-controlled trials of homeopathy. J Clin Epidemiol 52(7): 631–636.
  4. Cucherat, M., Haugh, M.C., Gooch, M., Boissel, J.P. (2000): Evidence of clinical efficacy of homeopathy. A meta-analysis of clinical trials. HMRAG. Homeopathic Medicines Research Advisory Group. Eur J Clin Pharmacol 56(1): 27–33.
  5. Mathie, R.T., Lloyd, S.M., Legg, L.A., Clausen, J., Moss, S.,Davidson, J.R.T., Ford, I. (2014a): Randomised placebocontrolled trials of individualised homeopathic treatment: systematic review and meta-analysis. Syst Rev 3: 142.
  6. Shang, A., Huwiler-Müntener, K., Nartey, L., Jüni, P., Dörig, S., Sterne, J.A.C., Pewsner, D., Egger, M. (2005): Are the clinical effects of homeopathy placebo effects? Comparative study of placebo-controlled trials of homeopathy and allopathy. Lancet 366(9487): 726–32.

(As it happens, I have reviewed these papers here and come to very different conclusions)

Without bothering about a critical assessment of these papers, the authors report that all arrived at a positive conclusion, except the last one. They then claim that the ‘1st’ NHMRC report was partly positive but was initially suppressed by the Australian government. Instead it was replaced with the 2nd NHMRC report which was designed to arrive at a wholly negative conclusion. Likewise, the ‘EASAC Statement’ neglected some of the available positive evidence. These facts, the authors believe, discredits all of these negative reports.

The authors then discuss the various reviews by Mathie et al and point out that, in their view, these papers are superior to all other documents as they arrive at very clearly positive conclusions.

Next the authors focus on the field of veterinary homeopathy, while admitting weaker and weaker evidence, inclusing case-reports. This is also where I lost the will to live and gave up my detailed criticism of the text; the task is too tedious and simply not worth it, I felt.

In summary, here are few points relating to the human evidence:

The authors seem to have no intention of conducting an objective, systematic review. Such a project is essentially based on two principles. Firstly, it needs to include all eligible evidence according to pre-defined criteria. Secondly, it must include a critical evaluation of the admitted evidence. This review fails on both of these principles.

There are virtually dozens of systematic reviews which the authors decided to ignore. Here are just six of them:

  1. … homoeopathy as a whole may be considered as a placebo treatment.
  2. We tested whether p-curve accurately rejects the evidential value of significant results obtained in placebo-controlled clinical trials of homeopathic ultramolecular dilutions. Our results suggest that p-curve can accurately detect when sets of statistically significant results lack evidential value.
  3. We found no evidence to support the efficacy of homeopathic medicinal products
  4. … no firm conclusions regarding the effectiveness and safety of homeopathy for the treatment of IBS can be drawn.
  5. Due to both qualitative and quantitative inadequacies, proofs supporting individualized homeopathy remained inconclusive.
  6. … the use of homeopathy currently cannot claim to have sufficient prognostic validity where efficacy is concerned.

Why do they do it? A reasonable reply to this question might be, because their findings did not fit the preconceived ideas of the authors. This omission alone makes the article little more than a poorly conceived marketing brochure.

Even more important is the second omission. The paper  lacks any kind of critical evaluation of the included evidence. On the contrary, the authors praise the evidence that generated what they think was a positive result (even in cases where the actual result was not all that positive; for instance: A meta-analysis of all extractable data leads to rejection of our null hypothesis, but analysis of a small sub-group of reliable evidence does not support that rejection. Reliable evidence is lacking in condition-specific meta-analyses, precluding relevant conclusions) and bash all negative findings. This goes as far as perpetuating untruth about the two NHMRC reports: what they call the 1st report was a draft that had been rejected because it was deemed to be of sub-standard quality. What is here called the ‘2nd’ report is thus the only valid document ever published. Similarly, the authors pretend that the Mathie reviews were all clearly positive and fail to mention even the most obvious problems with these articles, such as the facts that Mathie was paid by a homeopathy-lobby group or that even he included important caveats in his conclusions.

As to the focus of the review, the question whether homeopathy might be a solution to antibiotic resistance, the authors found virtually no compelling evidence from trials directly comparing antibiotics with homeopathy. This seems to bother the authors little – they conclude that “the data demonstrate the potential of a significant reduction of antibiotic usage through homeopathic treatments”. They seem to have reached this conclusion by turning a blind eye to all the evidence that does not fit their preconceived idea.

As the paper is published in German and in a journal which hardly anyone will ever read, one could easily argue that none of all this does really matter because it is merely a storm in a very small tea cup. Perhaps that’s true. But this paper nevertheless might attain some significance because it is already being heavily promoted by the homeopathy lobby. And no doubt, it will thus be cited in the English literature which, in turn, will be read by people who do not read German, unable to check the original and are thus likely to believe the nonsense promoted by Frass and friends.

For this reason, I want to conclude by making it quite clear that

this ‘review’ is a dilettante attempt to white-wash the evidence on homeopathy and mislead the public.

 

Researchers from the Department of Physiotherapy, Guru Jambheshwar University of Science and Technology, Hisar, Haryana, India, and the Mother Teresa Saket College of Physiotherapy, Saket, Panchkula, Haryana, India, have just published a systematic review which is remarkable in several ways. Let me therefore present to you the abstract unaltered:

Background: Spinal pain or misalignment is a very common disorder affecting a significant number of populations resulting in substantial disability and economic burden. Various manual therapeutic techniques such as spinal manipulations and mobilizations can be used to treat and manage pain and movement dysfunctions such as spinal mal-alignments and associated complications. These manual therapeutic techniques can affect the cardiovascular parameters.

Objective: The objective of this systematic review and meta-analysis is to assess the effect of spinal manipulation and mobilization on cardiovascular parameters.

Methods: We conducted a systematic review and meta-analysis to assess the effects of spinal mobilization and manipulation on cardiovascular responses. Mean changes in Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) and Heart Rate (HR) were primary outcome measures. RevMan 5.3 software was used for the meta-analyses. Quality of the included studies was assessed by PEDro Rating scale. Risk of bias was assessed by Cochrane collaboration tool of risk of bias.

Results: Results of meta-analysis showed that there was statistically significant decrease in SBP ( MD=-4.56 , 95% CI=-9.20 , 0.08; p≤0.05 ) with moderate heterogeneity ( I2=75% , p<0.0002 ) in experimental group as compared to control group. There was statistically non-significant decrease in DBP ( MD=-1.96 , 95% CI=-4.60 , 0.69; p=0.15 ) with high heterogeneity ( I2=91% , p<0.00001 ), Change HR was statistically non-significant ( MD=-0.24 , 95% CI=-3.59 , 3.11; p=0.89 ) with moderate heterogeneity ( I2=60% , p=0.01 ). Exclusion of short duration studies in sensitivity analysis revealed a statistically significant change in DBP ( MD=-0.94 , 95% CCI=-1.85 , -0.03 ; p=0.04 ). However, the result was statistically non-significant for HR after sensitivity analysis.

Conclusion: Spinal manipulations and mobilizations may result in significant decrease of systolic as well as diastolic Blood Pressure.

After reading the full paper, I was uncertain whether to laugh or to cry. Then I decided for the former option.

Any paper that starts with the statement ‘spinal pain or misalignment is a very common disorder affecting a significant number of populations resulting in substantial disability and economic burden‘ can only be a hoax! In case you are uncertain about the reason of my amusement: spinal pain is not the same as spinal misalignment, and spinal misalignment (in the sense it is used here) is the figment of the imagination of a 18 carat charlatan called DD Palmer.

The rest of the article offers more superb hilarity: the authors write, for instance, that spinal malalignments (such as scoliosis) are mainly caused by body’s abnormal posture, asymmetries in bone growth and abnormalities of neuromuscular system. Scoliosis is an abnormal lateral curvature of the spine, not a spinal malalignment and certainly not one that can be treated with spinal manipulation.

Then the authors state that spinal pain and malalignment mainly occur due to structure deterioration, altered biomechanics and abnormal posture. Workplace physical and psychosocial factors, emotional problems, smoking, poor job satisfaction, awkward posture and poor work environment can be the possible risk factors for spinal pain and malalignment. This leads to various musculoskeletal, psychosomatic, cardiovascular and respiratory dysfunctions which affect the functional capacity of the patient as well as quality of life. Oh really?

So, the findings of the authors’ meta-analysis do suggest a tiny effect on blood pressure.

Compared to what?

In the paper, the review authors repeatedly try to make us believe it is compared to placebo. However, this is not true; mostly it was compared to no treatment.

Was the hypotensive effect verified in hypertensive patients?

No, it was measured mostly in healthy volunteers.

Is the effect clinically relevant?

No, I don’t think so!

Is it comparable to or better than the one achievable with established treatments for hypertension?

No! In fact it is much smaller.

Does that bother the authors?

No, on the contrary, they state that in this meta-analysis, spinal manipulation and mobilization resulted in statistically significant reduction in SBP. Therefore, it can be used as an adjuvant therapy for the management of hypertension.

Were the studies using spinal manipulation as an adjuvant therapy?

No, mostly not.

Is the effect lasting long enough to be relevant for the management of hypertension?

No.

I better stop here because already my whole body hurts from laughing so much. Please, do read the full text, if you are in need of some comic relief.

And, I almost forgot: many thanks to the Indian researchers for this hilarious hoax!

Or did you perhaps mean all that seriously?

Patients with advanced non-small cell lung cancer (NSCLC) have limited treatment options. Alongside conventional anticancer treatment, additive homeopathy might help to alleviate side effects of conventional therapy. The aim of this study was to investigate whether additive homeopathy might influence quality of life (QoL) and survival in NSCLC patients.

In this prospective, randomized, placebo-controlled, double-blind, three-arm, multi-centre, phase III study, the researchers evaluated the possible effects of additive homeopathic treatment compared to placebo in patients with stage IV NSCLC, with respect to QoL in the two randomized groups and survival time in all three groups. Treated patients visited the university teaching hospital every 9 weeks: 150 patients with stage IV NSCLC were included in the study.

  1. 51 patients received individualized homeopathic remedies plus conventional treatments,
  2. 47 received placebo plus conventional treatments,
  3. 52 control patients without any homeopathic treatment were treated with conventional therapies and observed for survival only.

For groups 1 and 2, the study was double-blind. The constituents of the different homeopathic remedies were mainly of plant, mineral, or animal origin. The remedies were manufactured by stepwise dilution and succussion, thereby preparing stable GMP grade formulations.

QoL as well as functional and symptom scales showed significant improvement in the homeopathy group when compared with placebo after 9 and 18 weeks of homeopathic treatment (p < .001). Median survival time was significantly longer in the homeopathy group (435 days) versus placebo (257 days; p = .010) as well as versus control (228 days; p < .001). Survival rate in the homeopathy group differed significantly from placebo (p = .020) and from control (p < .001).

The authors concluded that QoL improved significantly in the homeopathy group compared with placebo. In addition, survival was significantly longer in the homeopathy group versus placebo and control. A higher QoL might have contributed to the prolonged survival. The study suggests that homeopathy positively influences not only QoL but also survival. Further studies including other tumour entities are warranted.

First of all, let me thank my friend Dana Ullman for alerting me to this new and interesting study. I have read what seems to be the full paper several times and have to admit that it puzzles me (and perhaps this version is just some type of pre-publication paper). Firstly, there seems to be no methods section (the abstract is followed by several tables and a discussion), and I am left guessing much of the details. Secondly, the paper raises several questions in my mind:

  1. What is the purpose of group 3? The authors call it a control group and state it allows assessing the real homeopathic effect on the homeopathic cohort as the real effect will be the natural historical effect minus the placebo effect and the homeopathic effect. Does that make sense?
  2. Was the study under-powered? From my reading of the text, the answer seems to be yes.
  3. What is the full list of conventional treatments the patients received, and did they differ between the 3 groups?
  4. If I understand it correctly, the study patients did not receive immuno-oncological therapy. Does that fact not render the study unethical?
  5. What homeopathic potencies were prescribed in group 1? The paper says: The constituents of the different homeopathic remedies were mainly of plant, mineral, or animal origin. This is unlikely, as most homeopathic remedies contain nothing.
  6. The authors seem to have used individualised homeopathy according to Hahnemann’s instructions. Did Hahnemann not strictly forbid combining his approach with other types of treatment?
  7. How well respected is THE ONCLOLOGIST, the journal that published the paper?
  8. Was the article peer-reviewed? If so, by whom?
  9. Was the placebo indistinguishable from the verum?
  10. Was the success of patient-blinding checked?
  11. Have similar findings regarding survival been reported previously? The authors call this finding ‘unexpected’; I find it more than that; it is baffling.
  12. Should we accept such surprising findings, or would it be more prudent to wait until independent replications are available?
  13. The first author of this trial is Prof Frass who has featured on this blog several times before (see for instance here, here, here, here and here). Frass has published several studies of homeopathy and invariably manages to produce positive results. Am I the only one to find this odd?

I would be most grateful, if the readers of this blog could assist me in finding answers to some of the above questions.

A 2020 article that I just came across concluded with this rather remarkable statement:

High-dose enzyme therapy is a natural cancer protocol that has been highly successful in treating this much-feared disease.

Since we can find a plethora of similar claims on social media and elsewhere, it is high time, I think, to dedicate a post to this alleged cancer cure.

Enzyme therapy involves the administration of proteolytic enzymes by mouth. Proteolytic enzymes are large molecules that are nevertheless said to be absorbed in the gut before they are dispersed into different compartments of the body where they can be detected in various concentrations. Proteolytic enzymes (serine endopeptidases such as trypsin or chymotrypsin and cysteine endo-proteinases such as bromelain and papain or combinations of those enzymes) have long been available for diverse medical indications, including cancer. They are claimed to exert anticancer activities by restoring the reduced cytotoxic activity of patients’ sera.

Enzyme therapy has been subjected to experimental investigations and to a few studies in cancer patients. A systematic review claimed that, for plasmacytoma patients, systemic enzyme therapy was shown to increase the response rates, the duration of remissions, and the overall survival times.[1]

This statement is based on just one study. Here is its abstract[2]:

Purpose: To evaluate the impact of an additive therapy with an oral enzyme (OE) preparation given for more than 6 months additionally to standard combination chemotherapy (vincristine/melphalan/cyclophosphamide/prednisone (VMCP)- or methylprednisolone/ vincristine/CCNU/cyclophosphamide/melphalan (MOCCA)-regimen) in the primary treatment of patients with multiple myeloma stages I-III.

Methods: A cohort of 265 patients with multiple myeloma stages I-III was consecutively treated at our institution in two parallel groups (control group (n = 99): chemotherapy +/-OE for less than 6 months; OE-group (n = 166): chemotherapy + OE for more than 6 months). The median follow-up time in the stages I, II, and III for the OE-group was 61, 37, and 46.5 months, respectively; for the control group the respective values were 33, 51.5, and 31.5 months. The primary endpoint of the study was disease-specific survival. Secondary endpoints were response to therapy, duration of first response and side effects. The chosen method for evaluation was the technique of a retrolective cohort analysis with a concurrent control group. Survival analysis was performed by the Kaplan-Meier method and multivariate analysis was done with the Cox proportional hazards model.

Results: Significantly higher overall response rates and longer duration of remissions were observed in the OE-group. Primary responders showed a longer mean survival time than non-responders. Additive therapy with OE given for more than 6 months decreased the hazard of death for patients at all stages of disease by approximately 60%. Observation time was not long enough to estimate the median survival for patients at stages I and II; for stage III patients it was 47 months in the control group versus 83 months for the patients treated with OE (P = 0.0014) which means a 3-year gain of survival time. Significant prognostic factors for survival, in the Cox regression analysis, were stage of disease and therapy with OE. The OE-therapy was generally well tolerated (3.6% of patients with mild to moderate gastrointestinal symptoms).

Conclusion: OEs represent a promising new additive therapy in multiple myeloma which will be further evaluated in a randomized phase III trial in the USA.

My searches located no prospective clinical trials supporting the notion that enzyme therapy is an effective cancer cure for any type of human cancer. So, what about the bold statement quoted above? In my view, it is a dangerous and highly irresponsible claim that endangers the lives of many vulnerable cancer patients desperately looking for alternative cancer cures.

REFERENCES

[1] Beuth J. Proteolytic enzyme therapy in evidence-based complementary oncology: fact or fiction? Integr Cancer Ther. 2008 Dec;7(4):311-6. doi: 10.1177/1534735408327251. PMID: 19116226.

[2] Sakalová A, Bock PR, Dedík L, Hanisch J, Schiess W, Gazová S, Chabronová I, Holomanova D, Mistrík M, Hrubisko M. Retrolective cohort study of an additive therapy with an oral enzyme preparation in patients with multiple myeloma. Cancer Chemother Pharmacol. 2001 Jul;47 Suppl:S38-44. doi: 10.1007/s002800170008. PMID: 11561871.

Recently, I had a notable comment on one of my posts:

“these treatments are not the best we can offer to LBP-patients.”
Have to agree with you. As a stand alone treatment the research is underwhelming. When used as part of a suite of therapies they have some utility. All therapeutic approaches when studied in isolation are underwhelming (including exercise and rehab). Research needs to reflect how chiro’s/physio’s/osteo’s practice.

The post was about a new RCT suggesting that neither spinal manipulation nor spinal mobilization is effective treatments for chronic low back pain. And the comment came, of course, from an ardent defender of chiropractic. As I have heard this type of argument so often – from virtually all types of providers of so-called alternative medicine (SCAM) – it is perhaps worth considering it in more detail.

What does it mean?

It means that those SCAM-providers who believe in the argument think that, in order for their SCAM to work, it needs to be accompanied by some other therapy. To me, this assumption has always raised doubts.

  • My fake 5£ note is worth nothing, unless you add a real fiver to it.
  • This mine sweeper will work fine, as long as you use another one in parallel.
  • This drink is very strong, but you need a double vodka in order to feel it.

Yes, of course, I am exaggerating. So, let’s use a few more sensible examples from the realm of healthcare:

  • This new medication is effective only if you combine it with the standard drug for this disease.
  • Ultrasound therapy reduces shoulder pain, as long as you also take a pain-killer.
  • This slimming aid works wonders, if you stop eating while you take it.
  • Chiropractic manipulations work wonders, but you need to combine them with exercise therapy.
  • Crystal healing is very effective, as long as you don’t discontinue your conventional treatments.

A + B is only more than B, if A amounts to more than zero.

If A is zero, A + B = B.

If A is negative, A + B is less than B.

Of course, the argument could also mean that treatment A needs the addition of treatment B, because there is a synergism between the two. Synergism is the interaction of treatments such that the total effect is greater than the sum of the individual effects. It is a phenomenon that occurs with certain medications; it can be studied and must be proven before we can accept it as relevant. Has synergism been studied for any of the SCAMs? No, not as far as I am aware. This means, in SCAM, it is unproven. Until it is proven, we thus should not claim it.

So, what does it mean when SCAM-providers say AS A STAND-ALONE THERAPY MY SCAM IS NO GOOD; IT NEEDS ANOTHER TREATMENT TO WORK?

Call me a cynic, but I think it is an admission that the SCAM in question is ineffective (or perhaps even detrimental).

In my last post, I reported that there are no rigorous studies of homeopathy for diabetes. This was only partly true: there are no such trials to test homeopathy’s effects on the disease itself, but I did find a study of homeopathy for diabetic complications.

It comes from India and seems to be based on proper preliminary ground-work:

A prospective multi-centric clinical observational study was published in 2013 in the journal ‘HOMEOPATHY’. It was carried out from October 2005 to September 2009 by Central Council for Research in Homeopathy (CCRH) at its five institutes/units. Its authors were Chaturbhuja Nayak 1Praveen OberaiRoja VaranasiHafeezullah BaigRaveender ChG R C ReddyPratima DeviBhubaneshwari SVikram SinghV P SinghHari SinghShashi Shekhar Shitanshu. Patients suffering from diabetes mellitus (DM) and presenting with symptoms of diabetic polyneuropathy (DPN) were screened, investigated and were enrolled in the study after fulfilling the inclusion and exclusion criteria. Patients were evaluated by the diabetic distal symmetric polyneuropathy symptom score (DDSPSS) developed by the Council. A total of 15 homeopathic medicines were identified after repertorizing the nosological symptoms and signs of the disease. The appropriate constitutional medicine was selected and prescribed in 30, 200 and 1 M potency on an individualized basis. Patients were followed up regularly for 12 months.

Of 336 patients (167 males and 169 females) enrolled in the study, 247 patients (123 males and 124 females) were analysed. All patients who attended at least three follow-up appointments and baseline curve conduction studies were included in the analysis.). A statistically significant improvement in DDSPSS total score (p = 0.0001) was found at 12 months from baseline. Most objective measures did not show significant improvement. Lycopodium clavatum (n = 132), Phosphorus (n = 27) and Sulphur (n = 26) were the medicines most frequently prescribed. Adverse event of hypoglycaemia was observed in one patient only.

The authors concluded that this study suggests homeopathic medicines may be effective in managing the symptoms of DPN patients. Further studies should be controlled and include the quality of life (QOL) assessment.

As good as their word, they then conducted a more rigorous trial which was published this year:

This study (authored in 2020 by Pritha Mehra 1Bindu Sharma 2Hafeezulla Baig 3Ch Raveendar 4R V R Prasad 5M Prakash Rao 6Kolli Raju 7J S Arya 8Raj K Manchanda 9Daisy Katarmal 10Arvind Kumar 11 and published in ‘EXPLORE’, an even worse journal than ‘HOMEOPATHY’, in my view) assessed the efficacy of individualized homoeopathic medicines in management of diabetic distal symmetric polyneuropathy (DDSP). It was designed as a multi-centric double-blind, placebo controlled, randomised clinical trial and conducted by the Central Council for Research in Homoeopathy at 6 centres with a sample size of 84. Based on earlier observational studies and repertorial anamnesis of DDSP symptoms 15 homoeopathic medicines were shortlisted and validated scales were used for evaluating the outcomes post-intervention.

The primary outcome measure was change in Neuropathy Total Symptom Score-6 (NTSS-6) from baseline to 12 months. Secondary outcomes included changes in peripheral nerve conduction study (NCS), World Health Organization Quality of Life BREF (WHOQOL-BREF) and Diabetic Neuropathy Examination (DNE) Score at 12 months.

The data of 68 enrolled cases was considered for data analysis. Statistically significant difference (p<0.014) was found in NTSS-6 post intervention in the Verum group. Positive trend was noted for Verum group as per the graph plotted for DNE score and assessment done for NCS. No significant difference was found between the groups for WHOQOL-Bref. Out of 15 pre-identified homoeopathic medicines 11 medicines were prescribed in potencies in ascending order from 6C to 1M.

The authors concluded that further studies must be taken up with larger sample size and defined parameters for NCS to assess the effectiveness of homoeopathy.

This looks to me as though the trial failed to produce a positive result on inter-group comparisons. The abstract is unfortunately not very clear, and I have no access to the full text (in case someone has, please send it to me). Judging from the abstract, the study has several important flaws. For instance, it was small and we don’t know why only 68 of 84 patients were considered for analysis. Normally, an intention to treat analysis would be needed for analysis of all 84 patients.

________________________________

So, does homeopathy have anything to offer to patients with diabetes?

As far as I can see, the answer is NO!

I’d be happy to change my mind, provided someone shows me convincing evidence.

Prof. Shailendra Ramchandra Vishampayan is the 1st author of the paper we discussed yesterday. He was kind enough to repeatedly join us in the comments section, and I was therefore keen to learn more about him. On his website, he says about himself that he is a renowned academician and famous homeopath, enriched with decades of ideal experiences and quality services. He is registered medical practitioner (M.D), performs all the duties of registered medical practitioner following the law of land in India. Globally he is considered as homeopath and known as “Dr.V”. He is a registered member of Society of Homeopaths (overseas).

Dr. V, is a practicing homeopath with clinical experience of over 20 years. In course of his years of practice he had successfully helped more than 250 happy families globally, with various kinds of cases like thyroid, immune compromised, epilepsy, endocrine disorders, paediatric, gynaecological disorders addictions, psychiatric disorder, children with special needs, pets and plants.

He is famous for his path breaking concept and novel idea of creating an organization called ‘Folk Homeopathy ‘, which is dedicated to professional enrichment of homeopathic practitioners helping them to improve their clinical acumen with spot on prescription.

His practical approach in solving cases has earned him accolades and fame throughout the globe.

Dr. V is the author of ‘Kinder Garten Materia Medica’ a reference book for beginners widely used by homeopathic students in India. It is a book with unique combination of pictorial and pneumonic.

He is a Professor (PG) at D.Y.Patil Homeopathy Medical College (Pune). He has a teaching experience of over 16 years in teaching UG and PG. He has drawn large number of followers through webinars which is accessible throughout the globe. He has given more than 50 international seminar ,workshops and webinars in countries like USA, Ireland, Malaysia, with presentations on Homeopathic approach to female hormonal imbalance cases at OMICS Conference of Alternative Medicine, presentation on Psychiatric cases at Asian Homeopathic League. And various presentation at University of Cyberjaya, Malaysia, California Homeopathic Medical society, San Diego and also at Corte Madera, 98th FOH Congress, Liverpool and Kinvara Co Galway, Ireland.

And on the same site, we also learn that ‘Dr V’ is particularly adept at treating diabetes:

India is now considered as the diabetes capital of the world. Approximately 8.7 percent of Indians between the age of 20 to 70 years are diabetic. This translates to approximately 62.5 million diabetics living in India, according to estimates by the World Health Organisation (W.H.O.) The economic burden of managing this disease is also substantial since this is a combination of cost of treatment and loss of productivity in such a high number of diabetics. Diabetes can affect multiple organ systems resulting in a wide range of serious issues in patients. Many of these complications in a diabetic do not have any specific treatment with conventional medicines. However, an indication of the popularity of homeopathy amongst diabetics is that the doctors at our clinic treat approximately two hundred cases of diabetes or diabetes related issues every day. We have, in fact, developed specific diabetes management protocols for patients based on the experience of thousands of cases we have seen over four decades.

This is interesting, I thought, and conducted a few Medline searches to see whether there is any evidence to show that homeopathy is an effective therapy for diabetes. I am afraid, I found no papers of ‘Dr V’ to suggest such an effect. But what I did find was certainly fascinating.

Last year, Italian diabetologists published an review entitled ‘Alternative treatment or alternative to treatment? A systematic review of randomized trials on homeopathic preparations for diabetes and obesity‘. Here is what they reported:

The searches failed to retrieve any trial comparing homeopathic remedies with placebo or any active drug for the treatment of either diabetes or obesity.

These authors commented that

… if homeopathy is used as an alternative to available and effective treatments, the consequences can be catastrophic, particularly in some conditions such as insulin-requiring diabetes. In conclusion, there is no scientific evidence on efficacy and no demonstration of safety of homeopathy in diabetes and obesity…

I agree with my Italian colleagues and I have previously expressed this view bluntly; I even entitled one of my posts ‘This is how homeopathy could kill millions‘.

‘Dr V’ will probably point out that he is a fully qualified doctor and uses homeopathy merely as an adjunct to conventional anti-diabetic treatments; thus he kills nobody.

I certainly hope this is so! But, even in this case, I must still ask: WHERE IS THE EVIDENCE THAT HOMEOPATHY IS AN EFFECTIVE ADJUNCT TO CONVENTIONAL MEDICINE?

I have to thank one of our regular commentators for inspiring me to write this post. He recently contributed this insight about homeopathic provings:

If you didn’t experience anything from a proving you didn’t perform it properly.

It is an argument that, in different forms and shapes, I have heard very often. Essentially it holds that, if an investigation or a test fails to produce the desired result, the methodology must have been faulty. Donald Trump is, I fear, about to use it in the upcoming US election: if he is voted out, he will claim that there was too much fraud going on. Therefore, he cannot accept the result as valid. Thus it is his democratic duty to remain in post, he is likely to claim.

In medicine, the argument has been popular since millennia. In our book TRICK OR TREATMENT?, we recount the story of blood letting. Based on the doctrine of the 4 humours, it was believed for centuries to be a panacea. If someone died after losing litres of blood to the believers in the doctrine, the assumption was not that he had been bled to death, but that he had sadly not received enough of the ‘cure all’. Eventually, some bright chap had the novel idea of running a rigorous test of blood-letting, and it turned out that the patients who had received the treatment had a worse chance of survival than those who had escaped it. Aaaahhh !!!, shouted the blood-letters, this shows that the concept of the scientific test is flawed.

Checking the methodological rigour of clinical studies (or homeopathic provings) can be a tricky and tedious business. It requires proper learning and experience – qualities that SCAM fanatics rarely possess. Amongst other things, one needs to know about:

  • trial design,
  • statistics,
  • sources of bias,
  • confounding,
  • and the many tricks people use to hide flaws in published studies.

This is not easy and it takes time – lots of time – to acquire the necessary skills. Having discussed such issues with enthusiasts of so-called alternative medicine (SCAM) for decades, I realise that it would be unrealistic to expect of them to spend all this time learning all these complicated things (they have to make a living, you know!). I therefore propose an entirely new and much simpler method of differentiating between valid and invalid research of SCAM. It rests on merely 2 golden rules:

  1. Any research methodology is valid, if it produces the desired result.
  2. Any research methodology is invalid, if it fails to produce the desired result.

In analogy to these two rules, one can easily extrapolate further. For instance, one can state that:

  • any person who generates or promotes the desired result is honest;
  • any person who contradicts the desired result is corrupt (bought by ‘Big Pharma’).

I am sure my readers all see the beauty of this revolutionary, new system: it’s easy to learn, practical to apply, it avoids controversy and it takes full account of the previously much-neglected needs of the SCAM fraternity.

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