We’re all crazy now

PRO-logue. It’s telling that an identical German study to PRO-HEART was shutdown early. Comments by psychiatrist Andreas Ströhle and Nina Rieckmann from their Institute of Public Health : “Dr Angermann and colleagues reported that escitalopram did not reduce all-cause death or hospitalization… It is not clear why the authors expected that it would, as it does not reduce mild to moderate levels of depression… Rather, it adds to the mounting evidence that questions the risk-benefit ratio of prescribing antidepressants to patients with less than severe depression.”

Once upon a time, psychs drew a distinction between depression originating from within (endogenous) or that which arose due to circumstances (reactive). The former was treated by meds, but the market for anti-depressants has grown as the two-type concept has fallen out of favour. Pills manipulating neurotransmitter levels are a simple solution with scrip from your GP, one that doesn’t require psych expertise. The American Psychiatric Association aren’t blameless, since the criteria for mental illnesses is loosened with every release of the DSM. That manual has also expanded in order to inform practitioners of the complexity of the complex. But they have lost control in this non-infectious pandemic. Prof Peter Gotzsche is fanatical in advocating that prescriptions of such meds be reduced 50-fold, but for a less emotive perspective I suggest you follow psychiatrist Professor David Healy, or read his ‘Pharmageddon’.

Followon book to 'Deadly Medicines and Organised Crime'

Followon book to ‘Deadly Medicines and Organised Crime’

Earlier posts have complained at the fabricated conclusion that chronic pain is  manifestation of a mental illness. It was a researcher’s invented report that then conveniently led into a publicly funded trial for anti-depressants in osteoarthritis. It’s to the Royal Aust & NZ College of Psychiatry’s credit that their submission  against Medicine Aust code-of-misconduct application to regulatory authority ACCC was the only one to address perversion of research by industry. If they’re to be believed, academics are corrupted. And if Gotzsche is right, you can’t trust Patient Organisations for … “having done absolutely nothing to stop the blatant abuse of patients in industry-sponsored trials“, citing Dr Ben Goldacre’s book ‘Bad Pharma’ of 2012. It’s worse than that, as you’ll find out.

Heart Foundation Vic CEO Jennifer Johns has earlier come in for ridicule over statins, echoing her disgraced NSW President’s associations with the refined sugar industry. An Austin hospital cardiologist, in 2010 she funded her colleague David Hare and Baker IDI’s Prof Krum to trial  Lexapro as treatment for the depression that their heart failure patients are presumed to suffer, PRO-HEART. Also in this year the manufacturer’s promotion of such off-label usage cost them $USD313m in fines, with civil actions continuing. Such as 03-10395-NMG for wrongful dismissal of sales rep and whistleblower Chris Gobble, who complained to supervisors of “illegal kickbacks (i.e. paying doctors for no other reason than to induce them to prescribe Celexa and Lexapro)”. The marketing budget disclosed in the Confidential plan provided to the US Senate was $35m on speakers fees, and $36m on lunches. In one year. In one country.

The drug is also associated with hyponatremia, ie it worsens heart failure risk. None of the team answered this concern, but they were defended by the Heart Foundation’s Deidre Cope: “In regard to its Research Program, the Heart Foundation follows the NHMRC guidelines around disclosure of interest. The research funded by the Heart Foundation undergoes a rigorous peer review process involving assessment by independent, external reviewers. All funding decisions are scrutinised by an external committee to ensure that all aspects of the peer review process are consistent, transparent and ethical.” Affirming that they’re just as utterly corrupt as the NHMRC, as evidenced by Cicuttini and Wluka’s impunity.

The other half of the $820,000 raised by door-knockers and tin-shakers that PRO-HEART is costing was from Beyond Blue. No responses to approaches were provided at all. It’s too early to allege misconduct – the trial is running three years behind schedule, and a staffer thought late 2017 would see a report released. But it already stinks like something’s died. [Sep 2017 update: 2018 perhaps? BB CEO Georgie Harman states that she’s happy with the study progress – seven years after the first patient was enrolled in the 6month study]

There’s often a trite closing disclaimer in articles that if you suffer from depression, there’s phone support available at these numbers…… who’ll suggest medical advice. I’m more of the opinion that you think carefully, so have linked further material on happiness or absence thereof at http://themindfulgap.com.au/2016/02/05/the-blue-bird-and-the-black-dog/

 

 

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Framework or Façade?

Introduction. A decade ago the outlook for a diagnosis of HIV positive had turned, due to anti-retro viral drugs. Well-meaning folk were concerned that the therapy elevated cardiovascular risk, so a large multi-centre trial was initiated to record death rates if the drug were titrated to a minimal dosage.  The endpoint of interest was rarely achieved, since backing off therapy let the AIDS virus go viral. The job of burying the bodies was given to the biostatisticians.

Studies have found that 37% of statistics are made up on the spot….[Reliable source]
To explore manipulation of medical research, here’s a hypothetical. Investigators studying obesity and fitness in schoolchildren ensure that prior to athletic tests, carbohydrate loading is provided per specifications from endurance sports nutritionists. The broadly aged kids are given portions appropriate to their size, and field times adjusted for calorific energy levels. Remarkably, BMI had very little effect on athletic results. Heartened by this interventional study, the makers of V-Bomb (corn syrup based energy drinks) sponsor an observational report: Making An Impact – Zoom & Effort (or MAIZE) study. Parents supervised the event, where prior to the test V-Bomb was dropped off with family groups for optional consumption. This was a short run and block of a padded bag, measuring the force of collision. The greatest impacts were delivered by the largest consumers of the energy drink, and an outstanding effort by Georgie ‘Porgie’ P&P (participant privacy protected) saw him approached by the football coach for a fullbacker position.
ppt
I hope a laugh was scored at overriding commercial interest in a fictional scenario, but seriously wonder at the trust placed in our medications. We don’t believe that influence is applied to drug trials, since we haven’t been fully informed of the extent of sponsorship. Past editor of the British Medical Journal Richard Smith’s article ‘Is the pharmaceutical industry like the mafia?’ argues “… that drug companies are doing what is expected of them in maximising financial returns for shareholders, but doctors and academics are supposed to have a higher calling.”

Inspecting the integrity issues arising from ‘CD4+ Count–Guided Interruption of Antiretroviral Treatment’ in the New England Jnl of Med, Nov 2006 raises questions about ‘supposed to’. This example of misconduct is unclouded by any allegations of pharma interference – the medicos created a smokescreen all by themselves. Testing whether episodic use of antiretroviral drugs (ART) against HIV was safer in long term than continuous usage, the strategy’s disastrous results showed the opposite to a benefit  and the trial was stopped. But not because participants in Strategic Management of ART (SmART) were dying. It was stopped only once the hypothesis was proven false – the hazard ratio fell on the ‘bad luck old chap’ side of the line pictured here. The doctors kept waiting for cardiovascular results, but uncooperative participants kept snuffing it for another reason – AIDS. The end of the abstract’s results paragraph plays down the magnitude of the 2.6-fold worse risk, in that after adjusting for CD4+ and HIV counts the hazard confidence interval now nudged the 1.0 (no statistically significant risk) level. Sorry? The effect of the treatment strategy, after adjusting for the effects of the treatment (ART maintains CD4+ counts and inhibits virus growth) is supportive of the null hypothesis … this introduces another acronym, WTF!!! The second to fourth confidence range pictured in each of the three outcomes are these ‘fixed’ figures, shown alongside the true unadjusted (conveniently using a log scale, where the fourfold risk of “fatal or nonfatal opportunistic disease” just appears as a doubling). Another study finding: the more spin applied to the figures, the better they look. Thousands of lives were shortened, but after adjusting for the fact that everybody dies anyway no harm was done.

23 co-authors signed off on this article and NEJM editors have also been remiss, but worse is to come. The planned six-year trial was abandoned after four years due to the sixth meeting of the data safety monitoring board (DSMB) finally deciding that the strategy worsened, rather than improved outcomes. Look up Chart A of Figure 2 in the report to see that this was apparent after just a few months. A statistical power prediction of a result this bad gives the answer that only 35 unfortunate events would suffice to call it quits. A total of 2720 HIV-positive men and women were allocated to the risky treatment group, and left underdosed whilst the disease progressed. Furthermore there’s a page listing 712  SmART medicos who agreed to the study protocol, which minimizes the number of looks the independent DSMB takes at progress results (according to an O’Brien Fleming spend function*). But if a DSMB adheres to International Conference on Harmonisation guideline E9 by not discussing the interim analyses with SmART then those spend rules become void. The DSMB can investigate every event, confidentially. And when death is a primary outcome, why did it take four years instead of four months to call ‘whoops’? 2720-35/712= an average of 3.8 lives harmed per doctor. Hippocratic oath, WTF!

My next posts will move onto the half-hearted disclosure of conflict-of-interest problems, then will explore fabricated conclusions thereafter … standby.

* A biostatistical way of saying that it spoils the surprise for the researchers upon study conclusion.

Fibromyalgia appears destined to remain the elephant in the room if this month’s Rheumatology edition of Australian Family Physician is anything to go by – not a mention of it. So what do healthcare specialists offer? In 2006 Drs Littlejohn and Guymer published, through their work as Monash Director of Rheumatology and trainee respectively “Fibromyalgia Syndrome: Which Antidepressant Drug Should We Choose”. Linking their Medical Centre with the University seems a worthy approach so as to redress physician misconceptions  – indeed, shortly thereafter the Journal of Clinical Rheumatology published a survey of Southeast Asian rheumatologists. 87% of them believed fibromyalgia incorporated aspects of psychological illness and only 40% of those associated with an institution reported inclusion of FM in their undergraduate training.

Dr Littlejohn then contributed to the 2009 yearlong study on effectiveness of duloxetine/Cymbalta led by Eli-Lilly employee Amy Chappell, which was discredited by exclusion on quality grounds from the independent Cochrane musculoskeletal group’s systematic review of studies on SNRIs . Their supposedly * impartial conclusion drawing upon another five, unbiased assessments was that 10% more people reported significantly reduced pain with duloxetine than those duped by a placebo, however another 9% discontinued treatment due to side-effects. Withdrawal in itself is harmful, the US FDA has published a safety advisory for Cymbalta Discontinuance Syndrome. Agreements posted in 32,000 blogs are somewhat alarming! Any benefits obtained are ‘figure-atively’ outweighed by weightgain reducing propensity to exercise, consensus being that moderate exercise is beneficial for fibro.

2009 was a bad year for pharma. Eli-Lilly pleaded guilty to illegal marketing of anti-psychotic drug Zalprexa for off-label use, and was fined $1.4bn. A recent out-of-court settlement was made with the family of a boy who suicided whilst on Cymbalta, whose claim being that another suicide during drug trials should have prompted warnings.  And Pfizer paid a record $2.3bn for fraudulent marketing of painkillers, including Lyrica. Nonetheless these two medications remain highly profitable with an estimated $18bn in sales in 2012…. which trivialises the settlement for $43m with US attorneys generals that year for once again marketing Lyrica other than for an approved purpose. With such monetary power, when federal NHMRC funding was approved for only 17% of applications for 2014 is it any wonder that Littlejohn and Guymer are reliant on consultancy fees paid by  Eli-Lilly and Pfizer declared (inconsistently*) under their conflicts of interest? “The medical profession—in the US, Europe, and beyond—remains heavily reliant on industry funded continual medical education, and many doctors have accepted substantial hospitality and consultancy fees. Very few have been prosecuted. Disclosure remains patchy and inconsistent. Yet it is their decisions that ultimately determine if medicines are reaching patients for whom they are not suitable. If drug companies need to change their attitude, so do prescribers“. Andrew Jack, Financial Times correspondent writing in the BMJ July 2012.

Evidence update: Two books elaborate these concerns from a practitioner’s perspective. Dr Ben Goldacre’s ‘Bad Pharma’ and leader of the Nordic Cochrane Centre, Prof Peter Gøtzsche’s ‘Deadly Medicines and Organised Crime: How Big Pharma Has Corrupted Healthcare’. Peter’s alarmist chapter title: ‘Very few patients benefit from the drugs they take’  explains that “… apart from such scientific misconduct, insufficient blinding can also make us believe that ineffective drugs are effective.” In damning the exalted gold-standard comparison – the randomised control trial, he warns of assessor bias if they’re aware to whom they gave placebo. To give weight to this claim that doctors lie, his colleague Asbjørn Hróbjartsson is cited … the effect was exaggerated by 36% when evaluated by nonblinded observers. Wow, this Cochrane review ‘Observer bias in randomised clinical trials with binary outcomes: systematic review of trials with both blinded and non-blinded outcome assessors.’ needs a read. Ooops, the title omits the keyword ‘subjective’, and 71% of the studies were surgery or the like. cochraneFigure 1 meta-analysis shows that two weighty transmyocardial laser revascularisation outcome reports by Oesterle et al and Burkhoff et al dragged the conclusion from one of no significant difference to a non-blinded bias Odds Ratio of 0.64! So, if you ask F.I.G.J.A.M. whether they THINK the patient’s angina has improved recently, there’s a leaning towards affirmation if they’re aware that surgery has been done? Cardiologists genuinely believing that their interventions are beneficial can hardly be extrapolated to mandating that all trials must be blinded in order to avoid falsification of data, but that’s what’s happened. Peter’s Mentalaz speaking tour claimed that all anti-depressants were ineffective – arguing that severe side-effects results in unblinding. And the effect size was typically <36%, whereby he proves all benefit of the med resulted from bias! And these are the watchdogs? When Cochrane’s doctors stretch the truth about the 36% shift in truth by other research doctors, they’re all damned.
 infinityCochrane pioneers Gotzsche and Chalmers are much alike in their evidence fudging. The Handbook warns  that sneaky research doctors will try to break the blind and fudge the facts. The last para of ‘Rationale for concern about bias’ cites a study by Schultz, Altman, and Sir Iain Chalmers et al in Feb 1995 JAMA. Just one review, covering studies particular to pregnancy & childbirth actually contradicts their own argument: “Trials with inadequate sequence generation yielded estimates of treatment effects that were similar to those derived from trials with adequate sequence generation, after adjusting for the other three methodological dimensions”. But on pg410 a subgroup analysis limited to those trials reporting adequate allocate concealment only managed to find a statistically insignificant p=0.07 (ie close, but no cigar) exaggeration in effect size as a result of poor sequence generation.

This cracks me up. That’s a negative outcome elsewhere than the Cochrane Collaboration, and it relied upon data dredging to obtain a semi-significant conclusion. But it underpins one of their criteria for downgrade of all studies – sanctimonious dogma used thereafter in box-ticking exercises, which actually detracts from quality analysis of evidence trustworthiness. This recalls the classical Ouroboros, the snake eating itself – as a symbol of perpetuation.
*Aust Family Physician Oct 2013: “Competing interests: None”

<Jan 2016 update: an Austrian survey found 89% of GPs would refer fibromyalgia to a rheumatologist, but only 12% of those wanted to treat the patient. With great neuro research nearby by Uçeyler, Sommer & Hauser you’d hope for more than just a handpass: http://journals.plos.org/plosone/article?id=10.1371%2Fjournal.pone.0146149 >