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

case-control study

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I was criticised for not referencing this article in a recent post on adverse effects of spinal manipulation. In fact the commentator wrote: Shame on you Prof. Ernst. You get an “E” for effort and I hope you can do better next time. The paper was published in a third-class journal, but I will nevertheless quote the ‘key messages’ from this paper, because they are in many ways remarkable.

  • Adverse events from manual therapy are few, mild, and transient. Common AEs include local tenderness, tiredness, and headache. Other moderate and severe adverse events (AEs) are rare, while serious AEs are very rare.
  • Serious AEs can include spinal cord injuries with severe neurological consequences and cervical artery dissection (CAD), but the rarity of such events makes the provision of epidemiological evidence challenging.
  • Sports-related practice is often time sensitive; thus, the manual therapist needs to be aware of common and rare AEs specifically associated with spinal manipulative therapy (SMT) to fully evaluate the risk-benefit ratio.

The author of this paper is Aleksander Chaibi, PT, DC, PhD who holds several positions in the Norwegian Chiropractors’ Association, and currently holds a position as an expert advisor in the field of biomedical brain research for the Brain Foundation of the Netherlands. I feel that he might benefit from reading some more critical texts on the subject. In fact, I recommend my own 2020 book. Here are a few passages dealing with the safety of SMT:

Relatively minor AEs after SMT are extremely common. Our own systematic review of 2002 found that they occur in approximately half of all patients receiving SMT. A more recent study of 771 Finish patients having chiropractic SMT showed an even higher rate; AEs were reported in 81% of women and 66% of men, and a total of 178 AEs were rated as moderate to severe. Two further studies reported that such AEs occur in 61% and 30% of patients. Local or radiating pain, headache, and tiredness are the most frequent adverse effects…

A 2017 systematic review identified the characteristics of AEs occurring after cervical spinal manipulation or cervical mobilization. A total of 227 cases were found; 66% of them had been treated by chiropractors. Manipulation was reported in 95% of the cases, and neck pain was the most frequent indication for the treatment. Cervical arterial dissection (CAD) was reported in 57%, and 46% had immediate onset symptoms. The authors of this review concluded that there seems to be under-reporting of cases. Further research should focus on a more uniform and complete registration of AEs using standardized terminology…

In 2005, I published a systematic review of ophthalmic AEs after SMT. At the time, there were 14 published case reports. Clinical symptoms and signs included:

  • central retinal artery occlusion,
  • nystagmus,
  • Wallenberg syndrome,
  • ptosis,
  • loss of vision,
  • ophthalmoplegia,
  • diplopia,
  • Horner’s syndrome…

Vascular accidents are the most frequent serious AEs after chiropractic SMT, but they are certainly not the only complications that have been reported. Other AEs include:

  • atlantoaxial dislocation,
  • cauda equina syndrome,
  • cervical radiculopathy,
  • diaphragmatic paralysis,
  • disrupted fracture healing,
  • dural sleeve injury,
  • haematoma,
  • haematothorax,
  • haemorrhagic cysts,
  • muscle abscess,
  • muscle abscess,
  • myelopathy,
  • neurologic compromise,
  • oesophageal rupture
  • pneumothorax,
  • pseudoaneurysm,
  • soft tissue trauma,
  • spinal cord injury,
  • vertebral disc herniation,
  • vertebral fracture…

In 2010, I reviewed all the reports of deaths after chiropractic treatments published in the medical literature. My article covered 26 fatalities but it is important to stress that many more might have remained unpublished. The cause usually was a vascular accident involving the dissection of a vertebral artery (see above). The review also makes the following important points:

  • … numerous deaths have been associated with chiropractic. Usually high-velocity, short-lever thrusts of the upper spine with rotation are implicated. They are believed to cause vertebral arterial dissection in predisposed individuals which, in turn, can lead to a chain of events including stroke and death. Many chiropractors claim that, because arterial dissection can also occur spontaneously, causality between the chiropractic intervention and arterial dissection is not proven. However, when carefully evaluating the known facts, one does arrive at the conclusion that causality is at least likely. Even if it were merely a remote possibility, the precautionary principle in healthcare would mean that neck manipulations should be considered unsafe until proven otherwise. Moreover, there is no good evidence for assuming that neck manipulation is an effective therapy for any medical condition. Thus, the risk-benefit balance for chiropractic neck manipulation fails to be positive.
  • Reliable estimates of the frequency of vascular accidents are prevented by the fact that underreporting is known to be substantial. In a survey of UK neurologists, for instance, under-reporting of serious complications was 100%. Those cases which are published often turn out to be incomplete. Of 40 case reports of serious adverse effects associated with spinal manipulation, nine failed to provide any information about the clinical outcome. Incomplete reporting of outcomes might therefore further increase the true number of fatalities.
  • This review is focussed on deaths after chiropractic, yet neck manipulations are, of course, used by other healthcare professionals as well. The reason for this focus is simple: chiropractors are more frequently associated with serious manipulation-related adverse effects than osteopaths, physiotherapists, doctors or other professionals. Of the 40 cases of serious adverse effects mentioned above, 28 can be traced back to a chiropractor and none to a osteopath. A review of complications after spinal manipulations by any type of healthcare professional included three deaths related to osteopaths, nine to medical practitioners, none to a physiotherapist, one to a naturopath and 17 to chiropractors. This article also summarised a total of 265 vascular accidents of which 142 were linked to chiropractors. Another review of complications after neck manipulations published by 1997 included 177 vascular accidents, 32 of which were fatal. The vast majority of these cases were associated with chiropractic and none with physiotherapy. The most obvious explanation for the dominance of chiropractic is that chiropractors routinely employ high-velocity, short-lever thrusts on the upper spine with a rotational element, while the other healthcare professionals use them much more sparingly.

Another review summarised published cases of injuries associated with cervical manipulation in China. A total of 156 cases were found. They included the following problems:

  • syncope (45 cases),
  • mild spinal cord injury or compression (34 cases),
  • nerve root injury (24 cases),
  • ineffective treatment/symptom increased (11 cases),
  • cervical spine fracture (11 cases),
  • dislocation or semi-luxation (6 cases),
  • soft tissue injury (3 cases),
  • serious accident (22 cases) including paralysis, deaths and cerebrovascular accidents.

Manipulation including rotation was involved in 42% of all cases. In total, 5 patients died…

To sum up … chiropractic SMT can cause a wide range of very serious complications which occasionally can even be fatal. As there is no AE reporting system of such events, we nobody can be sure how frequently they occur.

[references from my text can be found in the book]

Despite reported widespread use of dietary supplements by cancer patients, few empirical data with regard to their safety or efficacy exist. Because of concerns that antioxidants could reduce the cytotoxicity of chemotherapy, a prospective study was carried out to evaluate associations between supplement use and breast cancer outcomes.

Patients with breast cancer randomly assigned to an intergroup metronomic trial of cyclophosphamide, doxorubicin, and paclitaxel were queried on their use of supplements at registration and during treatment (n =1,134). Cancer recurrence and survival were indexed at 6 months after enrollment.

There were indications that use of any antioxidant supplement (vitamins A, C, and E; carotenoids; coenzyme Q10) both before and during treatment was associated with an increased hazard of recurrence and, to a lesser extent, death. Relationships with individual antioxidants were weaker perhaps because of small numbers. For non-antioxidants, vitamin B12 use both before and during chemotherapy was significantly associated with poorer disease-free survival and overall survival. Use of iron during chemotherapy was significantly associated with recurrence as was use both before and during treatment. Results were similar for overall survival. Multivitamin use was not associated with survival outcomes.

The authors concluded that associations between survival outcomes and use of antioxidant and other dietary supplements both before and during chemotherapy are consistent with recommendations for caution among patients when considering the use of supplements, other than a multivitamin, during chemotherapy.

These data are interesting but, for a range of reasons, not compelling. There might have been several important confounding factors distorting the findings. Even though clinical and life-style variables were statistically adjusted for in this study, it might still be possible that supplement users and non-users were not comparable in impotant prognostic variables. Simply put, sicker patients might be more likely to use supplements and would then have worse outcomes not because of the supplements but their disease severity.

Moreover, it seems important to note that other research showed the opposite effects. For instance, a study prospectively examined the associations between antioxidant use after breast cancer (BC) diagnosis and BC outcomes in 2264 women. The cohort included women who were diagnosed with early stage, primary BC from 1997 to 2000 who enrolled, on average, 2 years postdiagnosis. Baseline data were collected on antioxidant supplement use since diagnosis and other factors. BC recurrence and mortality were ascertained, and hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated.

Antioxidant supplement use after diagnosis was reported by 81% of women. Among antioxidant users, frequent use of vitamin C and vitamin E was associated with a decreased risk of BC recurrence. Vitamin E use was associated with a decreased risk of all-cause mortality. Conversely, frequent use of combination carotenoids was associated with increased risk of death from BC and all-cause mortality.

The authors concluded that frequent use of vitamin C and vitamin E in the period after BC diagnosis was associated with a decreased likelihood of recurrence, whereas frequent use of combination carotenoids was associated with increased mortality. The effects of antioxidant supplement use after diagnosis likely differ by type of antioxidant.

Yet another study provided limited support for the hypothesis that antioxidant supplements may reduce the risk of breast cancer recurrence or breast cancer-related mortality.

Confused?

Me too!

What is needed, it seems, is a systematic review of all these contradicting studies. A 2009 review is available of the associations between antioxidant supplement use during breast cancer treatment and patient outcomes.

Inclusion criteria were: two or more subjects; clinical trial or observational study design; use of antioxidant supplements (vitamin C, vitamin E, antioxidant combinations, multivitamins, glutamine, glutathione, melatonin, or soy isoflavones) during chemotherapy, radiation therapy, and/or hormonal therapy for breast cancer as exposures; treatment toxicities, tumor response, recurrence, or survival as outcomes.

A total of 22 articles met the criteria. Their findings did not support any conclusions regarding the effects of individual antioxidant supplements during conventional breast cancer treatment on toxicities, tumor response, recurrence, or survival. A few studies suggested that antioxidant supplements might decrease side effects associated with treatment, including vitamin E for hot flashes due to hormonal therapy and glutamine for oral mucositis during chemotherapy. Underpowered trials suggest that melatonin may enhance tumor response during treatment.

The authors concluded that the evidence is currently insufficient to inform clinician and patient guidelines on the use of antioxidant supplements during breast cancer treatment. Thus, well designed clinical trials and observational studies are needed to determine the short- and long-term effects of such agents.

Still confused?

Me too!

Antioxidants seem to have evolved as parts of elaborate networks in which each substance plays slightly different roles. This means that each antioxidant has a different spectrum of actions. And this means that it is probably not very constructive to lump them all together and excect to see uniform effects. What we would need to create more clarity is a series of RCTs on single antioxidants. But who is going to fund them? We might be waiting a long time for more clarity. Meanwhile, consuming a healthy and well-balanced diet might be the best advice for cancer patients and everyone else.

This study assessed the patterns of dietary supplement usage among cancer survivors in the United States in a population-based setting. National Health and Nutrition Examination Survey (NHANES) datasets (1999-2016) were accessed, and adult respondents (≥ 20 years old) with a known status of cancer diagnosis and a known status of dietary supplements intake were included. Multivariable logistic regression analysis was then used to assess factors associated with dietary supplements intake. Moreover, and to evaluate the impact of dietary supplements on overall survival among respondents with cancer, multivariable Cox regression analysis was conducted.

A total of 49,387 respondents were included in the current analysis, including a total of 4,575 respondents with cancer. Among respondents with cancer, 3,024 (66.1%) respondents reported the use of dietary supplements; while 1,551 (33.9%) did not report the use of dietary supplements. Using multivariable logistic regression analysis, factors associated with the use of dietary supplements included:

  • older age (OR: 1.028; 95% CI: 1.027-1.030);
  • white race (OR for black race vs. white race: 0.67; 95% CI: 0.63-0.72);
  • female gender (OR for males vs. females: 0.56; 95% CI: 0.53-0.59),
  • higher income (OR: 1.13; 95% CI: 1.11-1.14),
  • higher educational level (0.59; 95% CI: 0.56-0.63),
  • better self-reported health (OR: 1.36; 95% CI: 1.17-1.58),
  • health insurance (OR: 1.35; 95% CI: 1.27-1.44),
  • history of cancer (OR: 1.20; 95% CI: 1.10-1.31).

Using multivariable Cox regression analysis and within the subgroup of respondents with a history of cancer, the use of dietary supplements was not found to be associated with a difference in overall survival (HR: 1.13; 95% CI: 0.98-1.30).

The authors concluded that dietary supplement use has increased in the past two decades among individuals with cancer in the United States, and this increase seems to be driven mainly by an increase in the use of vitamins. The use of dietary supplements was not associated with any improvement in overall survival for respondents with cancer in the current study cohort.

Many cancer patients, when they first get diagnosed, are tested for vitamin D levels and found to be low or borderline. Consequently, they get a prescription for supplements. Other than this, there is rarely an indication to take any vitamins or other dietary supplements. Yet, cancer patients take them because they think these ‘natural’ preparations can do no harm (and because the industry can be persuasive [there is big money at stake] and the odd breed of ‘integrated’ oncologists might even recommend them). Sadly, this assumption is not correct. The biggest danger, in my view, is the possibility of supplements to interact with one of the many drugs that cancer patients need to take. So, in a way, it is reassuring that, on average, there is no detrimental effect on overall survival.

The paper will probably also reignite the perennial discussion about the effects of vitamin C on the natural history of cancer. My understanding is that there is none (and this verdict seems to be supported by the findings reported here). But I am, of course, aware that this is a ‘hot potato’ and that some readers will think differently. To them I say: please show me the evidence.

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.

This analysis was aimed at assessing the associations of acupuncture use with mortality, readmission and reoperation rates in hip fracture patients using a longitudinal population-based database. A retrospective matched cohort study was conducted using data for the years 1996-2012 from Taiwan’s National Health Insurance Research Database. Hip fracture patients were divided into:

  • an acupuncture group consisting of 292 subjects who received at least 6 acupuncture treatments within 183 days of hip fracture,
  • and a propensity score matched “no acupuncture” group of 876 subjects who did not receive any acupuncture treatment and who functioned as controls.

The two groups were compared using survival analysis and competing risk analysis.

Compared to non-treated subjects, subjects treated with acupuncture had

  • a lower risk of overall death (hazard ratio (HR): 0.41, 95% confidence interval (CI): 0.24-0.73, p = 0.002),
  • a lower risk of readmission due to medical complications (subdistribution HR (sHR): 0.64, 95% CI: 0.44-0.93, p = 0.019)
  • and a lower risk of reoperation due to surgical complications (sHR: 0.62, 95% CI: 0.40-0.96, p = 0.034).

The authors concluded that postoperative acupuncture in hip fracture patients is associated with significantly lower mortality, readmission and reoperation rates compared with those of matched controls.

That’s a clear and neat finding; the question is, what does it mean?

Here are a few possibilities for consideration:

  1. As a result of having at least 6 acupuncture sessions, patients had lower rates of mortality, readmission and reoperation.
  2. As a result of having lower rates of mortality, readmission and reoperation, patients used acupuncture.
  3. As a result of some other factor, patients had both lower rates of mortality, readmission and reoperation and at least 6 sessions of acupuncture.

Which of the three possibilities is the most likely?

  1. Some enthusiasts might think that acupuncture makes you live longer. But does anyone truly believe it reduces the likelihood of needing a reoperation? Seriously? Well, I don’t see even a hint of a mechanism by which acupuncture might achieve this. Therefore, I would categorise this possibility as highly unlikely.
  2. It stands to reason that patients who are alive and well use more acupuncture than those who are dead or in need of surgery. So, this possibility is not entirely inconceivable.
  3. It seems very likely that people who are more health conscious might use acupuncture and live longer, need less readmissions or surgery. No doubt, this possibility is by far the best explanation of the findings of this retrospective matched cohort study.

If that is so, does this paper tell us anything useful at all?

Not really (that’s why it was published in an acupuncture journal which few people would read)

On second thought, perhaps it does tell us something valuable: retrospective matched cohort studies are hopeless when it comes to establishing cause and effect!

Glucosamine is currently one of the most popular of all dietary supplements. It is marketed as a treatment for arthritis, and there is some evidence that it is moderately helpful for this indication. But evidence had been accumulating to suggest that glucosamine might have other effects as well. The latest analysis evaluated the associations of regular glucosamine use with all-cause and cause-specific mortality in a large prospective cohort.

This population-based prospective cohort study included 495 077 women and men from the UK Biobank study. Participants were recruited from 2006 to 2010 and were followed up through 2018. The investigators evaluated all-cause mortality and mortality due to cardiovascular disease (CVD), cancer, respiratory and digestive disease. Hazard ratios (HRs) and 95% CIs for all-cause and cause-specific mortality were calculated using Cox proportional hazards models with adjustment for potential confounding variables.

At baseline, 19.1% of the participants reported regular use of glucosamine supplements. During a median follow-up of 8.9 years (IQR 8.3-9.7 years), 19 882 all-cause deaths were recorded, including 3802 CVD deaths, 8090 cancer deaths, 3380 respiratory disease deaths and 1061 digestive disease deaths. In multivariable adjusted analyses, the HRs associated with glucosamine use were 0.85 (95% CI 0.82 to 0.89) for all-cause mortality, 0.82 (95% CI 0.74 to 0.90) for CVD mortality, 0.94 (95% CI 0.88 to 0.99) for cancer mortality, 0.73 (95% CI 0.66 to 0.81) for respiratory mortality and 0.74 (95% CI 0.62 to 0.90) for digestive mortality. The inverse associations of glucosamine use with all-cause mortality seemed to be somewhat stronger among current than non-current smokers (p for interaction=0.00080).

The authors concluded that regular glucosamine supplementation was associated with lower mortality due to all causes, cancer, CVD, respiratory and digestive diseases.

Previous epidemiological investigations indicated that glucosamine use might play a role in prevention of cancer, cardiovascular disease and other diseases. This suggests that the finding is more than the result of a large ‘fishing expedition’ to which epidemiological studies are sadly prone. It we are indeed dealing with a true phenomenon, we should ask by what mechanism these remarkable outcomes might be achieved. It is well documented that glucosamine has powerful anti-inflammatory effects. Therefore it is conceivable that such anti-inflammatory mechanisms are the cause for the observed outcomes.

How do we prove or disprove the hypothesis that glucosamine reduces the mortality of a range of diseases? A reasonable starting point would be to consult the good old Hill criteria of causality:

(1) The strength of association is small to moderate – certainly not strong

(2) The consistency of the findings is quite remarkable; that is unless dozens of epidemiological studies that failed to yield and association were never published.

(3) The specificity of the association with diseases linked to inflammation is also impressive (with the caveat above).

(4) Temporality seems also not a problem, as far as I can see.

(5) Biological gradient needs further testing, I think.

(6) Plausibility is not a problem, since there is a possible mechanism that could explain the findings.

(7) The same applies to coherence.

(8) Experiment is needed, but it is far from easy to conduct clinical trials where mortality is an endpoint.

(9) Analogy is realised through the well-established concept of (cardiovascular) risk factors.

What does all this actually mean?

It means, I think, that glucosamine could well have clinical effects that go far beyond easing the pain of arthritis. However, we cannot be sure. Once again, it boils down to the need of robust clinical trial data. The subject certainly seems important enough to consider this option.

 

When tested rigorously, the evidence for so-called alternatives medicine (SCAM) is usually weak or even negative. This fact has prompted many SCAM enthusiasts to become utterly disenchanted with rigorous tests such as the randomised clinical trial (RCT). They seem to think that, if the RCT fails to generate the findings we want, let’s use different methodologies instead. In other words, they are in favour of observational studies which often yield positive results.

This line of thinking is prevalent in all forms of SCAM, but probably nowhere more so that in the realm of homeopathy. Homeopaths see that rigorous RCTs tend not to confirm their belief and, to avoid cognitive dissonance, they focus on observational studies which are much more likely to confirm their belief.

In this context, it is worth mentioning a recent article where well-known homeopathy enthusiasts have addressed the issue of observational studies. Here is their abstract:

Background: Randomized placebo-controlled trials are considered to be the gold standard in clinical research and have the highest importance in the hierarchical system of evidence-based medicine. However, from the viewpoint of decision makers, due to lower external validity, practical results of efficacy research are often not in line with the huge investments made over decades.

Method: We conducted a narrative review. With a special focus on homeopathy, we give an overview on cohort, comparative cohort, case-control and cross-sectional study designs and explain guidelines and tools that help to improve the quality of observational studies, such as the STROBE Statement, RECORD, GRACE and ENCePP Guide.

Results: Within the conventional medical research field, two types of arguments have been employed in favor of observational studies. First, observational studies allow for a more generalizable and robust estimation of effects in clinical practice, and if cohorts are large enough, there is no over-estimation of effect sizes, as is often feared. We argue that observational research is needed to balance the current over-emphasis on internal validity at the expense of external validity. Thus, observational research can be considered an important research tool to describe “real-world” care settings and can assist with the design and inform the results of randomised controlled trails.

Conclusions: We present recommendations for designing, conducting and reporting observational studies in homeopathy and provide recommendations to complement the STROBE Statement for homeopathic observational studies.

In their paper, the authors state this:

It is important to realize three areas where observational research can be valuable. For one, as already mentioned, it can be valuable as a preparatory type of research for designing good randomized studies. Second, it can be valuable as a stand-alone type of research, where pragmatic or ethical reasons stand against conducting a randomized study. Additionally, it can be valuable as the only adequate method where choices are involved: for instance, in any type of lifestyle research or where patients have very strong preferences, such as in homeopathy and other CAM. This might also lead to a diversification of research efforts and a broader, more realistic, picture of the effects of therapeutic interventions.

My comments to this are as follows:

  1. Observational research can be valuable as a preparatory type of research for designing good randomized studies. This purpose is better fulfilled by pilot studies (which are often abused in SCAM).
  2. Observational research can be valuable as a stand-alone type of research, where pragmatic or ethical reasons stand against conducting a randomized study. Such situations rarely arise in the realm of SCAM.
  3. Observational research can be valuable as the only adequate method where choices are involved: for instance, in any type of lifestyle research or where patients have very strong preferences, such as in homeopathy and other CAM. I fail to see that this is true.
  4. Observational research leads to a diversification of research efforts and a broader, more realistic, picture of the effects of therapeutic interventions. The main aim of research into the effectiveness of SCAM should be, in my view, to determine whether the treatment per se works or not. Observational studies are likely to obscure the truth on this issue.

Don’t get me wrong, I am not saying that observational studies are useless; quite to the contrary, they can provide very important information. But what I am trying to express is this:

  • We should not allow double standards in medical research. The standards and issues of observational research as they exist in conventional medicine must also apply to SCAM.
  • Observational studies cannot easily determine cause and effect between the therapy and the outcome.
  • Observational studies cannot be a substitute for RCTs.
  • Depending on their exact design, observational studies measure the outcome caused by a whole range of factors, including the therapy per se, the placebo-effect, the natural history of the disease, the regression towards the mean.
  • Observational studies are particularly useful in effectiveness research, AFTER the efficacy of a therapy has been established by RCTs.
  • If RCT fail to show that a therapy is effective and observational studies seem to indicate that they work, the therapy in question is probably a placebo.
  • SCAM-enthusiasts’ preference for observational studies is transparently due to motivated reasoning.

When I first saw this press-release, I thought it was a hoax. After all, it came from a most dubious homeopathic source. Then I read it again and was no longer sure.

What do you think?

Here it is in full:

Santa Clara, Cuba, April 3,2020 (Prensa Latina) The homeopathic medicine Prevengho-VIR began to be administered as a measure to confront the Covid-19 in this province of central Cuba.

Dr. Mirtha Rosa Hernandez, head of the Department of the Elderly in Villa Clara, reported that the supply of the preparation began in the Grandparents’ Homes and Elderly Homes of the territory, which has 184,000 people over 60 years old, 23.9 percent of the local universe. The medicine is administered by doctors and nurses of the basic working group where the Grandparents’ Homes and Nursing Homes are located in the 13 municipalities of this province.

This homeopathic medicine comes in a 10-milliliter bottle, and the daily dosage is 5 drops, thrice a day; while on the tenth day a reactivation of the initial dose is performed. It is aimed at preventing the respiratory diseases in this risk group, in addition to other medical conditions, such as dengue.

In the upcoming days it will be extended to the Maternal Homes. It is administered by the doctors and the nurses from the basic work group of the senior homes.

She said, that besides avoiding the new coronavirus the formula is also aimed at preventing respiratory diseases in this risk group, in addition to others such as dengue fever.

This medicine can also be administered to children under 10 years old, pregnant women, nursing mothers, and patients with liver disorders.

Combination Medicine
Anas berberiae 200
Baptisia tinctora 200
Bascilinum 30
Pyrogenum 200
Eupetorium perf 200
Influezinum 200
Arsenicum Album 200

As I said, I was not sure whether this was for real. Is it possible that even officials are so stupid, brainwashed or gullible to go for homeopathy in such a serious situation?

In an attempt to find out, I did a little search and quickly found that the story has been reported by multiple media. This, for instance, is what the Miami Herald reported:

As scientists around the world speed up clinical trials to find a cure or vaccine for the coronavirus, the Cuban government will begin distributing a homeopathic remedy to the elderly and other vulnerable people to “prevent” the spread of the disease, a top health official said.

Dr. Francisco Durán, national director of Epidemiology at the Ministry of Public Health, said in a press conference on Sunday that “sublingual drops” of the compound PrevengHo-Vir “prevent different diseases such as influenza, the common cold, dengue, and emerging viral infections such as this one.”

On Monday, Durán tried to correct his statements and said that the product “does not prevent contagion” but rather “increases resistance, the body’s defenses against a certain virus.”

Several state media outlets reported that PrevengHo-Vir is already being used in various Cuban provinces to treat the elderly and other groups vulnerable to the coronavirus. There is no internet record of PrevengHo-Vir, other than press reports about the announcement of its distribution in Cuba.

So, it’s not a hoax!

In this case, let me try to predict what will happen next:

  • When the pandemic is over, the Cubans will publish mortality rates achieved with their homeopathic prevention [A].
  • They will compare them to data from a cohort that did not receive the homeopathic treatment [B].
  • Neither of the data-sets will be transparent and nobody will be able to check its reliability.
  • The comparison will yield a significant difference in favour of homeopathy.
  • The Cubans will use this to market their remedy.
  • The world of homeopathy will use it as a proof that homeopathy is effective (it wouldn’t be the first time).

Nothing wrong with that, some will say. Others who understand research methodology will, however, point out that these data are less than convincing.

In such case/control studies, one large group of patients [A] is compared to another group [B]. Group A has been treated homeopathically, while group B received no homeopathy. Any difference in outcome between A and B might be due to a range of circumstances that are unrelated to the homeopathic treatment, for instance:

  • group A might have been less ill than group B,
  • group A might have been better nourished,
  • group A might have benefited from better hygiene,
  • group A might have received better care,
  • group B might have received treatments that made the situation not better but worse,
  • the researchers might have prettified the data to make group A look better.

Such concerns are not totally unfounded; after all, Cuba seems to have a long history of making irresponsible claims for their homeopathic products.

During my almost 30 years of research into so-called alternative medicine (SCAM), I have published many papers which must have been severe disappointments to those who advocate SCAM or earn their living through it. Many SCAM proponents thus reacted with open hostility. Others tried to find flaws in those articles which they found most upsetting with a view of discrediting my work. The 2012 article entitled ‘A Replication of the Study ‘Adverse Effects of Spinal Manipulation: A Systematic Review‘ by the Australian chiropractor, Peter Tuchin, seems to be an example of the latter phenomenon (used recently by Jens Behnke in an attempt to defame me).

Here is the abstract of the Tuchin paper:

Objective: To assess the significance of adverse events after spinal manipulation therapy (SMT) by replicating and critically reviewing a paper commonly cited when reviewing adverse events of SMT as reported by Ernst (J Roy Soc Med 100:330-338, 2007).

Method: Replication of a 2007 Ernst paper to compare the details recorded in this paper to the original source material. Specific items that were assessed included the time lapse between treatment and the adverse event, and the recording of other significant risk factors such as diabetes, hyperhomocysteinemia, use of oral contraceptive pill, any history of hypertension, atherosclerosis and migraine.

Results: The review of the 32 papers discussed by Ernst found numerous errors or inconsistencies from the original case reports and case series. These errors included alteration of the age or sex of the patient, and omission or misrepresentation of the long term response of the patient to the adverse event. Other errors included incorrectly assigning spinal manipulation therapy (SMT) as chiropractic treatment when it had been reported in the original paper as delivered by a non-chiropractic provider (e.g. Physician).The original case reports often omitted to record the time lapse between treatment and the adverse event, and other significant clinical or risk factors. The country of origin of the original paper was also overlooked, which is significant as chiropractic is not legislated in many countries. In 21 of the cases reported by Ernst to be chiropractic treatment, 11 were from countries where chiropractic is not legislated.

Conclusion: The number of errors or omissions in the 2007 Ernst paper, reduce the validity of the study and the reported conclusions. The omissions of potential risk factors and the timeline between the adverse event and SMT could be significant confounding factors. Greater care is also needed to distinguish between chiropractors and other health practitioners when reviewing the application of SMT and related adverse effects.

The author of this ‘replication study’ claims to have identified several errors in my 2007 review of adverse effects of spinal manipulation. Here is the abstract of my article:

Objective: To identify adverse effects of spinal manipulation.

Design: Systematic review of papers published since 2001.

Setting: Six electronic databases.

Main outcome measures: Reports of adverse effects published between January 2001 and June 2006. There were no restrictions according to language of publication or research design of the reports.

Results: The searches identified 32 case reports, four case series, two prospective series, three case-control studies and three surveys. In case reports or case series, more than 200 patients were suspected to have been seriously harmed. The most common serious adverse effects were due to vertebral artery dissections. The two prospective reports suggested that relatively mild adverse effects occur in 30% to 61% of all patients. The case-control studies suggested a causal relationship between spinal manipulation and the adverse effect. The survey data indicated that even serious adverse effects are rarely reported in the medical literature.

Conclusions: Spinal manipulation, particularly when performed on the upper spine, is frequently associated with mild to moderate adverse effects. It can also result in serious complications such as vertebral artery dissection followed by stroke. Currently, the incidence of such events is not known. In the interest of patient safety we should reconsider our policy towards the routine use of spinal manipulation.

In my view, there are several things that are strange here:

  1. Tuchin published his paper 5 years after mine.
  2. He did not publish it in the same journal as my original, but in an obscure chiro journal that hardly any non-chiropractor would ever read.
  3. Tuchin never contacted me and never alerted me to his publication.
  4. The journal that Tuchin chose was not Medline-listed in 2012; consequently, I never got to know about the Tuchin article in a timely fashion. (Therefore, I did never respond to it.)
  5. A ‘replication study’ is a study that repeats the methodology of a previous study.
  6. Tuchin’s paper is therefore NOT a replication study. Firstly, mine was a review and not a study. Secondly, and crucially, Tuchin never repeated my methodology but used an entirely different one.

But arguably, these points are trivial. They should not distract from the fact that I might have made mistakes. So, let’s look at the substance of Tuchin’s claim, namely that I made errors or omissions in my review.

As to ‘omissions’, one could argue that a review such as mine will always have to omit some details in order to generate a concise summary. The only way to not omit any details is to re-publish all the primary papers in one large volume. Yet, this can hardly be the purpose of a systematic review.

As to the ‘errors’, it seems that the ages and sex of three patients were wrong (I have not checked this against the primary publications but, for the moment, I believe Tuchin). This is, of course, lamentable and – even though I have no idea whether the errors happened at the data extraction phase, during the typing, the revising, or the publishing of the paper – it is entirely my responsibility. I also seem to have mistaken a non-chiropractor for a chiropractor. This too is regrettable but, as the review was about spinal manipulation and not about chiropractic, the error is perhaps not so grave.

Be that as it may, these errors are unquestionably not good, and I can only apologise for them. If Tuchin had dealt with them in the usual way – by publishing in a timely fashion a ‘letter to the editor’ of the JRSM – I could have easily corrected them for everyone to see.

But I think there is a more important point to be made here:

Tuchin concludes his paper stating that it is unwise to make conclusions regarding causality from any case study or multiple case studies. The number of errors or omissions in the 2007 Ernst paper significantly limit any reported conclusions. I believe that both sentences are unjustified. The safety of any intervention in routine use has to be examined on the basis of published case studies. This is particularly true for chiropractic where no post-marketing surveillance similar to that for drugs exists.

The conclusions based on such evidence can, of course, never be firm, but they provide valuable signals that can prompt more rigorous investigations in the interest of patient safety. In view of such considerations, my own conclusions in my 2007 paper were, I think, correct and are NOT invalidated by my relatively trivial mistakes: spinal manipulation, particularly when performed on the upper spine, has repeatedly been associated with serious adverse events. Currently the incidence of such events is unknown. Adherence to informed consent, which currently seems less than rigorous, should therefore be mandatory to all therapists using this treatment. Considering that spinal manipulation is used mostly for self-limiting conditions and that its effectiveness is not well established, we should adopt a cautious attitude towards using it in routine health care. 

And my conclusions in the abstract have now, I believe, become established wisdom. They are thus even less in jeopardy through my calamitous lapsus or Tuchin’s ‘replication study’: Spinal manipulation, particularly when performed on the upper spine, is frequently associated with mild to moderate adverse effects. It can also result in serious complications such as vertebral artery dissection followed by stroke. Currently, the incidence of such events is not known. In the interest of patient safety we should reconsider our policy towards the routine use of spinal manipulation. 

 

 

A team of chiropractic researchers conducted a review of the safety of spinal manipulative therapy (SMT) in children under 10 years. They aimed to:

1) describe adverse events;

2) report the incidence of adverse events;

3) determine whether SMT increases the risk of adverse events compared to other interventions.

They searched MEDLINE, CINAHL, and Index to Chiropractic Literature from January 1, 1990 to August 1, 2019. Eligible studies were case reports/series, cohort studies and randomized controlled trials. Studies of high and acceptable methodological quality were included.

Most adverse events are mild (e.g., increased crying, soreness). One case report describes a severe adverse event (rib fracture in a 21-day-old) and another an indirect harm in a 4-month-old. The incidence of mild adverse events ranges from 0.3% (95% CI: 0.06, 1.82) to 22.22% (95% CI: 6.32, 54.74). Whether SMT increases the risk of adverse events in children is unknown.

The authors concluded that the risk of moderate and severe adverse events is unknown in children treated with SMT. It is unclear whether SMT increases the risk of adverse events in children < 10 years.

Thanks to their ingenious methodology, the authors managed to miss 11 of the 13 studies included in the review by Vohra et al which reported 9 serious adverse events and 20 cases of delayed diagnosis associated with SMT. Another review reported 15 serious adverse events and 775 mild to moderate adverse events following manual therapy. As far as I can see, the authors of the new review make just one reasonable point:

We recommend the implementation of a population-based active surveillance program to measure the incidence of severe and serious adverse events following SMT treatment in this population.

In the absence of such a surveillance system, any incidence figures are not just guess-work but also a depiction of the tip of a much bigger iceberg. So, why do the authors of this review not make this point clearly and powerfully? Why does the review read mostly like an attempt to white-wash a thorny subject? Why do they not provide a breakdown of the adverse events according to profession? The answer to these questions can be found at the very end of the paper:

This study was supported by the College of Chiropractors of British Columbia to Ontario Tech University. The College of Chiropractors of British Columbia was not involved in the design, conduct or interpretation of the research that informed the research. This research was undertaken, in part, thanks to funding from the Canada Research Chairs program to Pierre Côté who holds the Canada Research Chair in Disability Prevention and Rehabilitation at Ontario Tech University, and from the Canadian Chiropractic Research Foundation to Carol Cancelliere who holds a Research Chair in Knowledge Translation in the Faculty of Health Sciences at Ontario Tech University.

This study was supported by the College of Chiropractors of British Columbia to Ontario Tech University. The College of Chiropractors of British Columbia was not involved in the design, conduct or interpretation of the research that informed the research. This research was undertaken, in part, thanks to funding from the Canada Research Chairs program to Pierre Côté who holds the Canada Research Chair in Disability Prevention and Rehabilitation at Ontario Tech University, and funding from the Canadian Chiropractic Research Foundation to Carol Cancelliere who holds a Research Chair in Knowledge Translation in the Faculty of Health Sciences at Ontario Tech University.

I have often felt that chiropractic is similar to a cult. An investigation by cult members into the dealings of a cult is not the most productive of concepts, I guess.

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