MD, PhD, FMedSci, FSB, FRCP, FRCPEd

case-control study

WHAT DOCTORS DON’T TELL YOU (WDDTY) is probably the most vile publication I know. It systematically misleads its readers by alarming news about this or that conventional treatment, while relentlessly promoting pseudoscientific non-sense. This article , entitled “MMR can cause skin problems and ulcers if your immune system is compromised” is a good example (one of a multitude):

The MMR vaccine can cause serious adverse reactions, researchers have admitted this week. The rubella (German measles) component of the jab increases the risk of infection from the rubella virus itself, and can cause serious skin inflammation and ulcers in anyone whose immune system is compromised.

The risk is highest among people with primary immunodeficiency diseases (PIDD), chronic genetic disorders that cause the immune system to malfunction.

Although the risk for people with compromised immune systems has been known, and is even included in the package inserts supplied with the vaccine, it was theoretical, say researchers from the Children’s Hospital of Philadelphia, who say they have uncovered “genuine evidence of harm.”

The researchers analysed the health profile of 14 people—four adults and 10 children—who suffered some form of a PIDD. Seven of them still had the rubella virus in their tissues, suggesting that their immune systems were too weak to get rid of the virus in the vaccine. The virus can damage skin cells and cause ulcers, and makes the person more susceptible to the actual rubella virus, the researchers say.

People with a poor immune system already have compromised T-cells—which are responsible for clearing viral infections—and the MMR makes the problem worse.

END OF QUOTE

And what is wrong with this article?

The answer is quite a lot:

  1. The research seems to be about a very specific and rare condition, yet WDDTY seem to want to draw much more general conclusions.
  2. The research itself is not described in a way that it would be possible to evaluate.
  3. The sample size of what seems to have been a case-control study was tiny.
  4. The study is not properly cited for the reader to verify and check; for all we know, it might not even exist.
  5. I was not able to find the publication on Medline, based on the information given.

Collectively, these points render the article not just useless, in my view, but make it a prime example of unethical, unhelpful and irresponsible scaremongering.

 

Use of complementary and alternative medicine (CAM) is common among cancer patients, not least because all sorts of claims are being made for CAM. One of these claims is that it prolongs survival.  But does it improve survival? This new study from the US was aimed at finding out; specifically, the authors wanted to determine whether CAM use impacts on the prognosis of breast cancer patients.

Health Eating, Activity, and Lifestyle (HEAL) Study participants (n = 707) were diagnosed with stage I-IIIA breast cancer. Participants completed a 30-month post-diagnosis interview including questions on CAM use (natural products such as dietary and botanical supplements, alternative health practices, and alternative medical systems), weight, physical activity, and comorbidities.

Outcomes were breast cancer-specific and total mortality, which were ascertained from the Surveillance Epidemiology and End Results registries in Western Washington, Los Angeles County, and New Mexico. Cox proportional hazards regression models were fit to data to estimate hazard ratios (HR) and 95 % confidence intervals (CI) for mortality. Models were adjusted for potential confounding by socio-demographic, health, and cancer-related factors.

Among the 707 participants, 70 breast cancer-specific deaths and 149 total deaths were reported. 60.2 % of participants reported CAM use post-diagnosis. The most common CAM were natural products (51 %) including plant-based estrogenic supplements (42 %). Manipulative and body-based practices and alternative medical systems were used by 27 and 13 % of participants, respectively. No associations were observed between CAM use and breast cancer-specific (HR 1.04, 95 % CI 0.61-1.76) or total mortality (HR 0.91, 95 % CI 0.63-1.29).

The authors concluded that CAM use was not associated with breast cancer-specific mortality or total mortality. Randomized controlled trials may be needed to definitively test whether there is harm or benefit from the types of CAM assessed in HEAL in relation to mortality outcomes in breast cancer survivors.

These findings tie in with the results of several other studies, some of which even seem to show that cancer patients who use CAM die sooner than those who don’t. I have previously pointed out that this could have several reasons, for instance:

1) Some patients might use ineffective alternative therapies instead of effective cancer treatments thus shortening their life and reducing their quality of life.

2) Other patients might employ alternative treatments which cause direct harm; for this, there are numerous options; for instance, if they self-medicate St John’s Wort, they would decrease the effectiveness of many mainstream medications, including some cancer drugs.

3) Patients who elect to use alternative medicine as an adjunct to their conventional cancer treatment might, on average, be more sick than those who stay clear of alternative medicine.

Therefore, I totally agree with the conclusions of the present paper: Randomized controlled trials may be needed to definitively test whether there is harm or benefit…

A new nationally representative study from the US analysed ∼9000 children from the Child Complementary and Alternative Medicine File of the 2012 National Health Interview Survey. Adjusting for health services use factors, it examined influenza vaccination odds by ever using major CAM domains: (1) alternative medical systems (AMS; eg, acupuncture); (2) biologically-based therapies, excluding multivitamins/multiminerals (eg, herbal supplements); (3) multivitamins/multiminerals; (4) manipulative and body-based therapies (MBBT; eg, chiropractic manipulation); and (5) mind–body therapies (eg, yoga).

Influenza vaccination uptake was lower among children ever (versus never) using AMS (33% vs 43%; P = .008) or MBBT (35% vs 43%; P = .002) but higher by using multivitamins/multiminerals (45% vs 39%; P < .001). In multivariate analyses, multivitamin/multimineral use lost significance, but children ever (versus never) using any AMS or MBBT had lower uptake (respective odds ratios: 0.61 [95% confidence interval: 0.44–0.85]; and 0.74 [0.58–0.94]).

The authors concluded that children who have ever used certain CAM domains that may require contact with vaccine-hesitant CAM practitioners are vulnerable to lower annual uptake of influenza vaccination. Opportunity exists for US public health, policy, and medical professionals to improve child health by better engaging parents of children using particular domains of CAM and CAM practitioners advising them.

The fact that chiropractors, homeopaths and naturopaths tend to advise against immunisations is fairly well-documented. Unfortunately, this does not just happen in the US but it seems to be a global problem. The results presented here reflect this phenomenon very clearly. I have always categorised it as an indirect risk of alternative medicine and often stated that EVEN IF ALTERNATIVE THERAPIES WERE TOTALLY DEVOID OF RISKS, THE ALTERNATIVE PRACTITIONERS ARE NOT.

TODAY IS ‘WORLD HOMEOPATHY DAY!!!

Let’s celebrate it by looking at the latest ‘cutting edge’ research on the world’s most commercially successful homeopathic remedy, Oscillococcinum®, a preparation of duck organs that are so highly diluted that not one molecule per universe is present in the end-product. It is therefore surprising to read that this new investigation finds it to be effective.

According to its authors, the goal of this controlled observational study was “to investigate the role of the homeopathic medicine in preventing respiratory tract infections (RTIs)”. The ‘study’ was not actually a study but a retrospective analysis of patients’ medical records. It examined 459 patients who were referred to a respiratory diseases specialist in Italy. Subjects who had taken any form of flu vaccine or any other type of vaccine (immuno-stimulants, bacterial lysates, or similar) were excluded from the study.  248 patients were treated with the homeopathic medicine, while 211 were, according to one statement by the authors, not treated. The latter group was deemed to be the control group. All patients were followed-up for at least 1 year, and up to a maximum of 10 years.

A significant reduction in the frequency of onset of RTIs was found in both the homeopathic medicine and untreated groups. The reduction in the mean number of RTI episodes during the period of observation vs. the year before inclusion in the study was significantly greater in the homeopathic-treated group than in untreated patients (-4.76 ± 1.45 vs. -3.36 ± 1.30; p = 0.001). The beneficial effect of the homeopathic medicine was not significantly related to gender, age, smoking habits or concomitant respiratory diseases when compared to the effect observed in untreated patients. The number of infections during the follow-up period is plotted in the graph.

40248_2016_49_Fig1_HTML

The authors concluded that these results suggest that homeopathic medicine may have a positive effect in preventing RTIs. However, randomized studies are needed before any firm conclusion can be reached.

This could well be the worst study of homeopathy, an area where there is no shortage of poor research, that I have seen for a long time. Here are some of its most obvious problems:

  • The aim was to investigate the role of homeopathic medicine – why then do the authors draw conclusions about its effectiveness?
  • The ‘control group’ was not ‘not treated’ as the authors claim, but these patients were prescribed the homeopathic remedy and did not comply. They were neither untreated – most would have self-medicated something else) nor a proper control group. This is what the authors state about it: “The physician initially instructed all 459 patients to take 1 dose of homeopathic medicine…A total of 211 patients were found to be non-compliant (i.e., they did not take the homeopathic medicine as recommended by the medical doctor), and these formed the control group.”
  • Why were vaccinated patients excluded? This would skew the sample towards anti-vaxers who tend to be homeopathy-fans.
  • A follow-up between 1 and 10 years? Are they serious? The authors tell us that “a total of 21 (4.6 %) patients ended the follow-up before 2012…” Did all the others die of homeopathic over-dose?
  • Before the start of the ‘study’, patients had more than 5 infections per year. This is way beyond the normal average of 1-2.
  • The authors inform us that “the primary outcome measure for assessing the effectiveness of the preventive treatment with homeopathic medicine was the reduction in the average number of RTI episodes per year versus the year before inclusion in the study.” This begs the question as to how the primary endpoint was assessed. The answer is by asking the patients or phoning them. This method is wide open to recall-bias and therefore not suited as a primary outcome measure.

My favourite alternative explanation for the reported findings – and there are many that have nothing to do with homeopathy – goes like this: some patients did not comply because their condition did not respond to homeopathy. These were the ones who were, on average, more severely ill. They needed something better than a homeopathic placebo and they therefore became the ‘control group’. As the differed systematically from the verum group, it would be most extraordinary, if they did not show different findings during follow-up.

So, is there nothing interesting here at all?

Not really…hold on, here is something: “The corresponding author thanks the Scientific Department of Laboratories Boiron S.r.l. (Milan, Italy) for funding the independent statistical analysis made at the Department of Medical and Surgical Sciences of the Alma Mater Studiorum-University of Bologna (Bologna, Italy).”

BOIRON SEEMS TO DECIDE ON FUNDING AFTER HOMEOPATHICALLY DILUTING SCIENTIFIC RIGOR AND COMMON SENSE.

On this blog, I have repeatedly tried to alert consumers and patients to the risks of herbal medicine. The risks include:

A new paper throws more light on the latter issue which has been not well-studies so far.

The objective of this study was to investigate the relationship between the use of medicinal plants and medication adherence in elderly people. The authors conducted an observational, cross-sectional study of elderly residents in Cuité-PB, Northeastern Brazil, through a household survey. A stratified proportional and systematic random sample of 240 elders was interviewed in their homes and the use of pharmaceutical medicines and of medicinal plants was assessed by direct examination. The association of medication adherence with socio-demographic, clinical, medication and use of medicinal plants was analysed with multiple logistic regression.

The results showed that medication non-adherence increases with use of herbal medicines (adjusted odds ratio 2.022, 95% CI 1.059–3.862, p = 0.03), as well as with the number of different medicinal plants used (adjusted odds ratio 1.937, 95% CI 1.265–2.965, p = 0.002).

The authors concluded that this study provides first-hand evidence that the use of herbal medicines is associated with poor medication adherence. Given the high frequency of the use of herbal medicines, further research into the mechanisms of this association is justified.

This conclusion is well-put, I think. If these findings are confirmed in other populations, we are confronted with a somewhat paradoxical situation: combining herbal and synthetic medicines can reduce adherence to the synthetic drugs and, in cases where adherence is not affected, it could increase the risk of herb/drug interactions.

Anthroposophic medicine is based on Rudolf Steiner’s mystical ideas. It is popular in Germany and is slowly also spreading to other countries.  Anthroposophic drugs are prepared according to ancient notions of alchemy and are fly in the face of modern pharmacology. Anthroposophic doctors treat all sorts of diseases, and their treatments  include anthroposophic medications, and a range of other modalities.

A recent paper reported a secondary analysis from an observational study of 529 children with respiratory or ear infections (RTI/OM) <18 years from Europe and the USA. Their caregivers had chosen to consult physicians offering either anthroposophic (A-) or conventional (C-) treatment for RTI/OM.

During the 28-day follow-up antibiotics were prescribed to 5.5% of A-patients and 25.6% of C-patients (P < 0.001); the unadjusted odds ratio for non-prescription in A- versus C-patients was 6.58 (95%-CI 3.45-12.56); after adjustment for demographics and morbidity it was 6.33 (3.17-12.64). Antibiotic prescription rates in recent observational studies with similar patients in similar settings, ranged from 31.0% to 84.1%. Compared to C-patients, A-patients also had much lower use of analgesics, somewhat quicker symptom resolution, and higher caregiver satisfaction. Adverse drug reactions were infrequent (2.3% in both groups) and not serious.

What can we conclude from these data?

Not a lot, I fear!

The authors of the study are a little more optimistic than I; they conclude that this analysis from a prospective observational study under routine primary care conditions showed a very low use of antibiotics and analgesics/antipyretics in children treated for RTI/OM by physicians offering AM therapy, compared to current practice in conventional therapy settings (antibiotics prescribed to 5% versus 26% of A- and C-patients, respectively, during days 0–28; antipyretics prescribed to 3% versus 26%). The AM treatment entailed no safety problem and was not associated with delayed short-term recovery. These differences could not explained by differences in demographics or baseline morbidity. The low antibiotic use is consistent with findings from other studies of paediatric RTI/OM in AM settings.

They are clearly careful to avoid causal inferences; but are they implying them? I would like to know what you think.

 

Few subjects lead to such heated debate as the risk of stroke after chiropractic manipulations (if you think this is an exaggeration, look at the comment sections of previous posts on this subject). Almost invariably, one comes to the conclusion that more evidence would be helpful for arriving at firmer conclusions. Before this background, this new publication by researchers (mostly chiropractors) from the US ‘Dartmouth Institute for Health Policy & Clinical Practice’ is noteworthy.

The purpose of this study was to quantify the risk of stroke after chiropractic spinal manipulation, as compared to evaluation by a primary care physician, for Medicare beneficiaries aged 66 to 99 years with neck pain.

The researchers conducted a retrospective cohort analysis of a 100% sample of annualized Medicare claims data on 1 157 475 beneficiaries aged 66 to 99 years with an office visit to either a chiropractor or to a primary care physician for neck pain. They compared hazard of vertebrobasilar stroke and any stroke at 7 and 30 days after office visit using a Cox proportional hazards model. We used direct adjusted survival curves to estimate cumulative probability of stroke up to 30 days for the 2 cohorts.

The findings indicate that the proportion of subjects with a stroke of any type in the chiropractic cohort was 1.2 per 1000 at 7 days and 5.1 per 1000 at 30 days. In the primary care cohort, the proportion of subjects with a stroke of any type was 1.4 per 1000 at 7 days and 2.8 per 1000 at 30 days. In the chiropractic cohort, the adjusted risk of stroke was significantly lower at 7 days as compared to the primary care cohort (hazard ratio, 0.39; 95% confidence interval, 0.33-0.45), but at 30 days, a slight elevation in risk was observed for the chiropractic cohort (hazard ratio, 1.10; 95% confidence interval, 1.01-1.19).

The authors conclude that, among Medicare B beneficiaries aged 66 to 99 years with neck pain, incidence of vertebrobasilar stroke was extremely low. Small differences in risk between patients who saw a chiropractor and those who saw a primary care physician are probably not clinically significant.

I do, of course, applaud any new evidence on this rather ‘hot’ topic – but is it just me, or are the above conclusions a bit odd? Five strokes per 1000 patients is definitely not “extremely low” in my book; and furthermore I do wonder whether all experts would agree that a doubling of risk at 30 days in the chiropractic cohort is “probably not clinically significant” – particularly, if we consider that chiropractic spinal manipulation has so very little proven benefit.

My message to (chiropractic) researchers is simple: PLEASE REMEMBER THAT SCIENCE IS NOT A TOOL FOR CONFIRMING BUT FOR TESTING HYPOTHESES.

The very first article on a subject related to alternative medicine with a 2015 date that I came across is a case-report. I am afraid it will not delight our chiropractic friends who tend to deny that their main therapy can cause serious problems.

In this paper, US doctors tell the story of a young woman who developed headache, vomiting, diplopia, dizziness, and ataxia following a neck manipulation by her chiropractor. A computed tomography scan of the head was ordered and it revealed an infarct in the inferior half of the left cerebellar hemisphere and compression of the fourth ventricle causing moderately severe, acute obstructive hydrocephalus. Magnetic resonance angiography showed severe narrowing and low flow in the intracranial segment of the left distal vertebral artery. The patient was treated with mannitol and a ventriculostomy. Following these interventions, she made an excellent functional recovery.

The authors of the case-report draw the following conclusions: This report illustrates the potential hazards associated with neck trauma, including chiropractic manipulation. The vertebral arteries are at risk for aneurysm formation and/or dissection, which can cause acute stroke.

I can already hear the counter-arguments: this is not evidence, it’s an anecdote; the evidence from the Cassidy study shows there is no such risk!

Indeed the Cassidy study concluded that vertebral artery accident (VBA) stroke is a very rare event in the population. The increased risks of VBA stroke associated with chiropractic and primary care physician visits is likely due to patients with headache and neck pain from VBA dissection seeking care before their stroke. We found no evidence of excess risk of VBA stroke associated chiropractic care compared to primary care. That, of course, was what chiropractors longed to hear (and it is the main basis for their denial of risk) – so much so that Cassidy et al published the same results a second time (most experts feel that this is a violation of publication ethics).

But repeating arguments does not make them more true. What we should not forget is that the Cassidy study was but one of several case-control studies investigating this subject. And the totality of all such studies does not deny an association between neck manipulation and stroke.

Much more important is the fact that a re-analysis of the Cassidy data found that prior studies grossly misclassified cases of cervical dissection and mistakenly dismissed a causal association with manipulation. The authors of this new paper found a classification error of cases by Cassidy et al and they re-analysed the Cassidy data, which reported no association between spinal manipulation and cervical artery dissection (odds ratio [OR] 5 1.12, 95% CI .77-1.63). These re-calculated results reveal an odds ratio of 2.15 (95% CI.98-4.69). For patients less than 45 years of age, the OR was 6.91 (95% CI 2.59-13.74). The authors of the re-analysis conclude as follows: If our estimates of case misclassification are applicable outside the VA population, ORs for the association between SMT exposure and CAD are likely to be higher than those reported using the Rothwell/Cassidy strategy, particularly among younger populations. Future epidemiologic studies of this association should prioritize the accurate classification of cases and SMT exposure.
I think they are correct; but my conclusion of all this would be more pragmatic and much simpler: UNTIL WE HAVE CONVINCING EVIDENCE TO THE CONTRARY, WE HAVE TO ASSUME THAT CHIROPRACTIC NECK MANIPULATION CAN CAUSE A STROKE.

How many times have we heard from practitioners of alternative medicine, particularly chiropractors, that their patients are more severely ill than those of conventional clinicians. The claim is usually that they have tried all that conventional medicine can offer and eventually, as a last resort, they turn to the alternatives.

But is this true? If so, it would explain why these patients do no better or even worse than those treated conventionally.

Here is a new article that goes some way in addressing these issues.

For this study, Danish chiropractors and general practitioners recruited adult patients seeking care for low back pain (LBP). Extensive baseline questionnaires were obtained and descriptive analyses were performed to define the differences between the two populations.

Questionnaires were returned from 934 patients in chiropractic practice and 319 patients from general practice. Four out of five patients had previous episodes, one-fourth were on sick leave, and the LBP considerably limited daily activities. The general practice patients were slightly older and less educated, more often female, and generally worse on all disease-related parameters than chiropractic patients. All the disease specific parameters showed a statistically significant difference between general and chiropractic practice. Patients in general practice were generally more severely affected. They had higher pain intensity (mainly for leg pain), longer pain duration, more previous episodes, more sick leave, more activity limitation on the disability scale, slightly higher level of depression, slightly more fear-avoidance beliefs, and a poorer self-reported general health. All these differences were statistically significant.

The authors concluded that LBP in primary care was recurrent, causing sick leave and activity limitations. There were clear differences between the chiropractic and general practice populations in this study.

I know, I know: these findings are from Denmark and therefore they cannot be generalised to other countries. However, the authors point out that similar findings have been reported from the US. Furthermore the observations relate to chiropractors and must not be applied to other alternative practitioners. Nevertheless they do show that, in this specific scenario, patients opting for the alternative are not more but less severely ill.

The next time an alternative practitioner claims ‘my patients have worse outcomes because they are sicker’, I will insist on seeing the evidence before I believe it.

For this blog, I am constantly on the lookout for ‘positive news’ about alternative medicine. Admittedly, I rarely find any.

All the more delighted I was when I found this new study aimed to analyse the association between dietary long-chain n-3 polyunsaturated fatty acids (PUFAs) and incidence of rheumatoid arthritis (RA) in middle-aged and older women.

Data on diet were collected in 1987 and 1997 via a self-administered food-frequency questionnaire (FFQ). The risk of RA associated with dietary long-chain n-3 PUFAs and fish intake was estimated using Cox proportional hazard regression models, adjusted for age, cigarette smoking, alcohol intake, use of aspirin and energy intake.

The results show that, among 32 232 women born 1914–1948, 205 RA cases were identified during a mean follow-up of 7.5 years. An intake of dietary long-chain n-3 PUFAs (FFQ1997) of more than 0.21 g/day (lowest quintile) was associated with a 35% decreased risk of developing RA compared with a lower intake. Long-term intake consistently higher than 0.21 g/day (according to both FFQ1987 and FFQ1997) was associated with a 52% decreased risk. Consistent long-term consumption (FFQ1987 and FFQ1997) of fish ≥1 serving per week compared with<1 was associated with a 29% decrease in risk.

The authors concluded that this prospective study of women supports the hypothesis that dietary intake of long-chain n-3 PUFAs may play a role in aetiology of RA.

These are interesting findings which originate from a good investigation and which are interpreted with the necessary caution. As all epidemiological data, this study is open to a number of confounding factors, and it is therefore impossible to make firm causal inferences. The results thus do not led themselves to clinical recommendation, but they are an indication that more definitive research is warranted, all the more so since we have plausible mechanisms to explain the observed findings.

A most encouraging development for alternative medicine, one could conclude. But is this really true? Most experts would be surprised, I think, to find that PUFA-consumption should fall under the umbrella of alternative medicine. Remember: What do we call alternative medicine that works? It is called MEDICINE!

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