Wednesday, August 20, 2014

Highly Sensitive Troponins – False Positive Bonanza

The “highly sensitive” troponin has received a great deal of publicity, hyped ad nauseum, see: “Simple test could help rule out heart attacks in the ER.”

But, as sensitivity increases – invariably, specificity decreases.  However, that is not the fault of the test – it is a failure of clinicians to ask the correct question of the test.  When asking “does this patient have an acute myocardial infarction?”(most commonly Type 1 MI in the ED), our training and education has been outpaced by assay technology – the test no longer provides a dichotomous “yes” or “no”.

This publication provides a lovely window into precisely the added value of the hsTnI compared with conventional TnI, both assays by Abbott Laboratories.  In this study, the authors simultaneously drew research samples of blood any time a cTnI was ordered.  The sample was frozen, and then analyzed at least 1 month following presentation.  Authors performed hospital records review, telephone follow-up, and vital records search to evaluate adverse events in patients with hsTnI or cTnI elevation.

Overall, they enrolled 808 patients, 40 of which received an adjucated diagnosis of “acute coronary syndrome” – 26 with AMI and 14 with unstable angina.  61 patients had acute heart failure, 7 had volume overload, 7 had pulmonary emboli, and 41 had other non-ACS cardiac diagnoses.

All told, there were 105 elevated cTnI samples – and 164 elevated hsTnI samples.  This means, essentially – in the acute setting, asking our question of interest – there were 50% greater false positives associated with hsTnI.  No patients would have been reclassified as nSTEMI based on the hsTnI result.  The authors sum this up nicely in their discussion:
“The preponderance of novel elevations (roughly 10% in this study) will be observed mainly in subjects with non-ACS conditions.”
The authors go on to note the value in detecting these novel or detectable troponin levels – essentially, non-ACS, subclinical disease – with a much poorer long-term prognosis.  This is almost certainly the case, although it will require further investigation to reliably demonstrate cost-effective management strategies based on these results.

“Troponin Elevations Only Detected With a High-sensitivity Assay: Clinical Correlations and Prognostic Significance”
http://www.ncbi.nlm.nih.gov/pubmed/25112512

Monday, August 18, 2014

Should the 48-hour Cardioversion Window Be Revised?

It has become generally accepted practice to treat new-onset atrial fibrillation and atrial flutter with electrical cardioversion in the acute setting – provided the known onset of atrial fibrillation is less than 48 hours.  Beyond that, caution tends to be advised – whether through use of transesophageal echocardiography to rule out left atrial thrombus, or through pre- and post-procedural anticoagulation.

However, this data from a research letter in JAMA suggests – possibly we ought to be even more cautious regarding time-of-onset.

This is a re-analysis of FinCV, a 7 year trial registry of cardioversion for atrial fibrillation from Finland.  The study cohort is comprised of 2,481 patients undergoing 5,116 electrical cardioversions, all without peri-procedural anticoagulation for symptom onset <48 hours.  Outcomes were gathered from vital records review, evaluating for cerebrovascular thrombotic complications within 30 days.

Of these patients undergoing cardioversion, there were 38 definite thrombotic complications.  30 of these 38 occurred in patients whose symptom onset was >12 hours.  There were few apparent pro-thrombotic differences between groups, and thus, the authors very reasonably conclude – we should be cautious regarding cardioversion after 12 hours.  Other predisposing factors in their multivariate analysis include female sex, heart failure, and diabetes – but increasing length of time showed the strongest association.

The 12-48 hour window in this study still only represented a 1.1% risk for 30-day thromboembolism, compared to the ~2% risk after 48 hours.  However, it still exceeds the ~0.3% risk of thromboembolism with peri-procedural anticoagulation.  There are other risks associated with anticoagulation, but it is reasonable to suggest the management strategy is no longer as clear-cut around 48 hours.

“Time to Cardioversion for Acute Atrial Fibrillation and Thromboembolic Complications”
http://www.ncbi.nlm.nih.gov/pubmed/25117135

Friday, August 15, 2014

The BATiC Score for Pediatric Trauma – Promising, But Not Prime-Time

Excluding significant intra-abdominal trauma on the basis of clinical evaluation is a lost art in the realm of zero-miss.  Nowhere is this more important than in a pediatric population, considering the small, but real, potential from harms due to exposure to ionizing radiation from CT.

This is the Blunt Abdominal Trauma in Children (BATiC) score, derived in 2009 by a Swiss group.  This rule promotes use of clinical exam, ultrasonographic findings, and laboratory results to determine need for CT.  In this study, authors from the Netherlands retrospectively applied the rule to 216 pediatric trauma patients presenting in a four-year span between 2006 and 2010.  All told, this cohort contained 18 patients for whom intra-abdominal injury were identified, and a BATiC score cut-off of 6 would have a sensitivity of 100% and specificity of 87%, with an AUC of 0.98.  So, this all sounds splendid.

But, only 34 of these patients even received a CT scan as part of their evaluation – and, with the standard outcome definition being injuries diagnosed on CT or as part of hospitalization, there is potential for a fair number of missed diagnoses.  A reasonable case may be made whether any missed injuries were clinically significant, given lack of observed morbidity, but it would be difficult to have confidence based on such as small sample.  Furthermore, just as a simple cultural issue, trauma surgeons in the U.S. tend to feel any injury is clinically significant.

Then, 18.5% of observations used to validate this rule were missing from the retrospective data collection and required imputation.  The extent of this missing data further degrades the reliability of the observed diagnostic characteristics.  No confidence intervals are presented along with their results – but, rest assured, they are quite wide.  Ultimately, this decision-instrument may indeed be valid – but requires specific prospective evaluation.

As an interesting Costs of Care side note, the additional charge for a such a trauma encounter including a CT scan in the Netherlands?  A mere 148 euros.

“External validation of the Blunt Abdominal Trauma in Children (BATiC) score: Ruling out significant abdominal injury in children”
http://www.ncbi.nlm.nih.gov/pubmed/24747461

Wednesday, August 13, 2014

Nitric Oxide Supplies No Miracles in Sepsis

An interesting context to end-organ dysfunction in sepsis stems from microcirculatory dysfunction, secondary to endothelial activation and vascular disruption as part of the inflammatory cascade.  Even though abnormal vasoconstriction in sepsis may be pharmacologically ameliorated, microcirculatory perfusion remains impaired.

This interesting trial attempted to modulate microcirculation through the use of inhaled nitric oxide.  Authors enrolled patients whose macrocirculation had been optimized, using objective targets consistent with contemporary care in septic shock, and randomized them to inhaled nitric oxide or sham.  Using a custom device for 40 ppm nitric oxide inhalation – for which authors all deny COI – an enrollment of 138 patients was planned.

However, after 49 patients, the trial was stopped due to futility.  The device was a success – as measured by circulating nitrite levels.  Unfortunately, from a microcirculation perfusion endpoint, there was no difference.  Likewise, there were no obvious differences or trends in secondary clinical outcomes.  There were, at least no obvious harms related to therapy.

Next steps in evaluation of this therapy – if any – are as of yet unclear.

“Randomized Controlled Trial of Inhaled Nitric Oxide for the Treatment of Microcirculatory Dysfunction in Patients With Sepsis”
http://www.ncbi.nlm.nih.gov/pubmed/25080051

Monday, August 11, 2014

Just Another Advertisement for tPA

As with last week's coverage of the updated Cochrane Systematic Review for tPA in acute ischemic stroke, the key question is: what’s new?

The first pooled meta-analysis, published in The Lancet in 2004, included NINDS, ECASS I, ECASS II, and ATLANTIS.  It was subsequently updated in 2010 to add ECASS III and EPITHET.  Now, these authors have decided to add IST-3.

I am actually a huge fan of individual-patient meta-analyses.  Depending on the data availability, the similarity of trial protocols, and other issues associated with heterogeneity, this is the gold-standard for aggregating data and increasing power.  Individual-patient analyses also allow for more reliable exploration of subgroup effects not otherwise possible through regular meta-analyses or systematic reviews.

But, at the crux of it, a meta-analysis is only as good as the included trials – and this is a topic much debated over the last twenty years.  Entertainingly, the 2014 publication includes this bland statement:
Role of the funding source 
The funders had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding author had full access to all the data and responsibility for the decision to submit for publication.

Yes, the funding source had nothing to do with the study design, excepting all the folks receiving speaker fees and honoraria – and the fact the original idea and refinements to the approach were contributed by one of the authors who is an employee Boehringer Ingelheim:
KRL has received speaker fees from and has served on the data monitoring committee of trials for Boehringer Ingelheim; his department has received research grant support from Genentech.  GA has received research grant support from Lundbeck, fees for consultancy and advisory board membership from Lundbeck, Covidien, Codman, and Genentech, fees for acting as an expert witness, and owns stock in iSchemaView. EB is employed by Boehringer Ingelheim. SD has received honoraria from Boehringer Ingelheim, EVER Pharma, and Sanofi and has received fees for consultancy and advisory board membership from Boehringer Ingelheim and Sanofi. GD has received research grant support from the NHMRC (Australia) and honoraria from Pfizer and Bristol-Myers Squibb. JG has received fees for consultancy and advisory board membership from Lundbeck. RvK has received speaker fees and honoraria from Penumbra and Lundbeck. RIL has received honoraria from Boehringer Ingelheim. JMO has received speaker fees from Boehringer Ingelheim. MP has received travel support from Boehringer Ingelheim. BT has received honoraria from Pfizer.  DT has received speaker fees and fees for consultancy and advisory board membership from Boehringer Ingelheim and Bayer.  JW has received research grant support from the UK Medical Research Council and from Boehringer Ingelheim to the University of Edinburgh for a research scanner bought more than 10 years ago. WW has received research grant support from the UK Medical Research Council. PS has received honoraria for lectures which were paid to the department from Boehringer Ingelheim. KT has received research grant support from the Ministry of Health, Labour, and Welfare of Japan, and speaker fees from Mitsubishi Tanabe Pharma.  WH has received research grant support from Boehringer Ingelheim, and speaker fees and fees for consultancy and advisory board membership from Boehringer Ingelheim.
The same level of COI was present in previous versions – including employees of the sponsor as authors – but, interestingly, at least the 2004 version explicitly acknowledges a critical issue:
Role of the funding source 
For the ATLANTIS trials, Genentech provided full support for the study and Genentech employees participated to some extent in study design, data collection, data analysis, and data interpretation, writing of the report, and in the decision to submit the manuscript for publication. For the ECASS trials, Boehringer Ingelheim provided full support. Employees of Boehringer Ingelheim participated in study design, in data collection, data analysis, data interpretation, writing of the report, and in the decision to submit the report for publication.
Nothing has changed.  If you trusted the data then, you trust the data now – and vice-versa.

So, what is new?  If anything, what’s new is worse than preceded it.  The authors have nearly doubled the cohort for analysis – by the inclusion of a decade-long trial crippled by the bias introduced by an open-label, mostly unblinded design.  Despite the massive resources invested in conducting it, unfortunately, IST-3 is too flawed for inclusion – due to the unfortunate likelihood any small positive signals regarding tPA are certain to be exaggerated.  And, simply put, that’s where the astute reader ought to stop reading this publication.  There’s no point in trying to interpret their results, to fuss over the heterogeneity between trials, missing baseline characteristics for their many subgroup analysis, or whether the trials stopped early for harm or futility – ATLANTIS – are properly acknowledged.  The authors also omit several planned secondary analyses described in their statistical protocol – although, considering the garbage-in/garbage-out nature of this work, it's of debatable importance.

The last decade of prospective research – ECASS III and IST-3 – has done nothing but degrade the quality of evidence describing tPA in acute ischemic stroke.  If there is, indeed, anyone left on the fence regarding the pro/con tPA debate, this effort ought move the needle zero to none.  Very early treatment with tPA probably benefits a properly selected subset of patients with acute ischemic stroke.  The rest – whether increasing age, high-or-low NIHSS, specific stroke syndromes, or time-dependent factors – have much smaller, if any, chance of benefit exceeding chance of harm.  Until we have unbiased evidence, we’ll never truly know how to best select patients for this therapy – and neurologists will continue to lament low treatment rates, while Emergency Physicians continue to reject pro-tPA clinical policies.  Only new, independent data has a chance to substantially change our approach to acute ischemic stroke.

“Effect of treatment delay, age, and stroke severity on the effects of intravenous thrombolysis with alteplase for acute ischaemic stroke: a meta-analysis of individual patient data from randomised trials”
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(14)60584-5/abstract

Friday, August 8, 2014

Get to the Choppa! Or ... Maybe Not?

Helicopter transport is entrenched in our systematic management of trauma.  It is glamorized on television, and retrospective National Trauma Data Bank studies seem to suggest survival improvement – and those with head injury seem to benefit most.

But, these NTDB studies encompass heterogenous populations and are challenged in creating truly equivalent control groups.  This study, on the other hand, is a single-center experience, allowing greater consistency across divided cohorts.  In a novel approach, these authors collected all HEMS trauma transfer requests to their facility across their 30-county catchement area – and specifically looked at occasions when weather precluded HEMS.  This therefore created two cohorts of patients eligible for HEMS, with a subset that was transported by ALS due to chance events.  The paramedic crews manning the HEMS and ALS transfers were staffed by the same company, and therefore had roughly equivalent training.

This created a cohort of 2,190 HEMS transports and 223 ground transports.  Across ISS, GCS, initial transfusion requirements, and vital signs, the two groups had generally minor differences.  However, there was some potentially important variability of initial operative intervention upon arrival at the Level 1 trauma center – 27.4% of HEMS underwent craniotomy, compared with 15.4% of ALS transfers.  Based on multivariable logistic regression, type of transport did not enter into a best fit model of survival – and, thus, there was no difference (9.0% vs 8.1% mortality) between HEMS or ALS transport of trauma patients, despite the additional hour added from call time to arrival at the Level 1 trauma center.

Unfortunately, there are potentially critical flaws in their methods for patient selection.  They report 3,901 patients had a request for trauma transfer – but the number of patients transferred by HEMS or ALS only sums to 2,398.  An additional 49 were transported by BLS.  Then, another 208 died while awaiting transfer.  How many of these 208 died during weather delays awaiting ALS?  Are those deaths, in some fashion, related to the paucity of craniotomies performed on ALS transports?  And, what of the other 965 patients?

I tend to agree with their conclusion – HEMS is expensive and far over-utilized for patients who receive no particular benefit from the time savings.  However, I’m not sure this analysis includes all the data needed to be reliable evidence.

“When birds can’t fly: An analysis of interfacility ground transport using advanced life support when helicopter emergency medical service is unavailable”
http://www.ncbi.nlm.nih.gov/pubmed/25058262

Wednesday, August 6, 2014

Bizarrely Alarmist Pediatric URI Study

In our new Gawker and Buzzfeed-fueled, short-attention span reality, attention-grabbing headlines are essential.  So, let me come up with the modern headline for news coverage of this latest article, published in Pediatrics:  “Is your child's next cold a killer?”

Seriously, as covered by Medscape (subscription required):
“As many as 1 in 3 children seeking treatment in the emergency department for influenza-like illnesses (ILI) at the peak of influenza season are at high risk of suffering severe complications, such as pneumonia.”
But, that’s hardly the case.  The study upon which they report is an observational cohort of ILI presenting to a tertiary children’s hospital.  To be eligible for inclusion, children needed to have ILI, defined as fever + cough/sore throat, and have “moderate to severe” symptoms.  However, their definition of “moderate to severe” is not based on any specific clinical criteria – it’s based off the surrogate of whether a clinician judged venipuncture and viral testing necessary.

So, 125,940 children were screened during the study period, and this cohort comprises the, presumably, sickest 241 of those.  Of those 241, over half had one of a predefined list of high-risk conditions: asthma, neurologic/neuromuscular disease, respiratory disease, heart disease, or immunosuppression.  And, yes, about 40% of each cohort developed a complication – most frequently pneumonia.  But, it should not be concluded there are killer viruses everywhere – rather, the sickest ILI, particularly those children who presumably appeared ill despite lacking underlying chronic illness, are the tiny cohort at higher risk of subsequent complication.

The authors also try to single out H1N1 influenza as an independent risk factor for subsequent complications.  11/29 patients with H1N1 influenza developed pneumonia, compared with 1/20 patients without, leading to their conclusion H1N1 confers particular risk.  However, 22/29 of patients diagnosed with H1N1 carried high-risk comorbidities, compared with only 10/20 in the non-H1N1 influenza cohort.  Yes, H1N1 probably increases risk of respiratory complications, but these data may not reliably support their conclusion.

“Severe Complications in Influenza-like Illnesses”
http://pediatrics.aappublications.org/content/early/2014/07/29/peds.2014-0505.abstract

Tuesday, August 5, 2014

A Moratorium on Steroids for TBI

A guest post by Rory Spiegel (@EMNerd_) who blogs on nihilism and the art of doing nothing at emnerd.com.

In 2004 the CRASH trial examining the efficacy of steroids for acute traumatic brain injury (TBI) was published in The Lancet.  This massive trial included over 10,000 patients was stopped prematurely because of an increased mortality in the patients who received corticosteroids. This should have definitively closed the book on such a therapy.  Despite this damning evidence, it appears all one has to do to make this question relevant again is to devise a disease-oriented endpoint with plausible clinical relevance and test it using a sample size too small to differentiate these harms from the surrounding noise of statistical chance.

Authors of the recently published Corti-TC trial did just this. Asehnoune et al examined the effect of the combination of hydrocortisone and fludrocortisone for the prevention of hopsital-acquired pneumonia (HAP) in patients with severe TBI. This is not the authors first foray into the efficacy of steroids for TBI. Their original trial was published in JAMA in 2011 and examined the effects of hydrocortisone to prevent HAP in patients having experienced poly-trauma. In this initial trial, about half the 149 patients randomized to either hydrocortisone or placebo suffered a severe TBI. The authors found that 35.6% of the patients in the active treatment arm developed HAP compared to 51.3% in the placebo group. This difference was seen exclusively in the subgroup of patients with TBI.  Thus the authors set out to validate these findings by solely examining patients suffering from acute TBI. As a harbinger of things to come, the authors justified the 3% increase in mortality as statistical chance, since it failed to reach statistical significance due to the small sample size.

In what essentially is a validation cohort the Corti-TC  trial was devised. Patients were randomized to either a 10 day course of both hydrocortisone and fludrocortisone or equivalent placebos. Cortisol levels were drawn before treatment was initiated, and in those found to be adrenally competent treatment was stopped. Once again the authors’ primary endpoint was the 28-day incidence of HAP as defined by a new infiltrate on chest x-ray with at least two of the following criteria; a temperature >38°C, leucocytosis >12 000 cells per mL, leucopenia <4000 cells per mL, or purulent pulmonary secretions.

Corti-TC demonstrated a similar difference in rates of HAP in patients given steroids vs those who received the placebo. Specifically 45% of the patients in the steroid group compared to 53% in the control group developed HAP over the first 28-days.  Although this difference did not reach statistical significance due to a lower than anticipated overall incidence of HAP, a relevant divergence between the active and control groups is evident. This difference remained consistent whether or not patients were found to have adrenal deficiency, indicating that cortisol levels do not predict a subset of patients who will benefit from steroids. Of concern is the 2% absolute increase in mortality of patients treated with steroids. This difference was observed primarily in the subset of patients later found to be adrenally intact. The authors once again justify this increased mortality by its failure to reach statistical significance (p-value of 0.32). That this exact trend was demonstrated in their original study goes unmentioned.  In fact, the same magnitude of harm caused the authors of the CRASH trial to halt their study prematurely. Given the collective consistency with which this mortality detriment has been demonstrated across trials it should not be written off as fluctuations of random chance. Interpreting this literature in its totality, it becomes obvious that these recent examinations of steroids in head trauma are vastly underpowered to detect the true harms involved with the utilization of such an intervention.

In the discussion section of both their trials, the authors question why their patients fared better than those in the CRASH cohort. They hypothesize that the overall higher acuity of their patients may be responsible for this difference in outcomes. The authors recommend further studies be performed to elucidate this uncertainty. I would argue that their cohorts fared no better than the CRASH patients. In fact, the absolute increase in mortality was identical to that of the CRASH trial. It is only because these authors defined success with a disease oriented outcome of little clinical significance(HAP), that their cohorts appear to fare better than the far more robustly powered CRASH cohort. At this point it seems clear steroids in acute TBI are harmful. Further studies to clarify the magnitude of benefit of irrelevant outcomes seem unwarranted.

"Hydrocortisone and fludrocortisone for prevention of hospital-acquired pneumonia in patients with severe traumatic brain injury (Corti-TC): a double-blind, multicentre phase 3, randomised placebo-controlled trial"
http://www.thelancet.com/journals/lanres/article/PIIS2213-2600(14)70144-4/fulltext




Monday, August 4, 2014

The tPA Cochrane Review Takes Us For Fools

It’s been 5 years since the last Cochrane Review synthesizing the evidence regarding tPA in acute ischemic stroke.  Clearly, given such a time span, in an area of active clinical controversy, a great deal of new, important, randomized evidence has been generated!

Or, sadly, the only new evidence available to inform practice is IST-3 – a study failing to demonstrate benefit, despite its pro-tPA flaws and biases.  So, it ought not be a very exciting update, considering the 2009 version included 26 trials, and the 2014 update now includes only 27 trials.  Their summary conclusion, with only additional evidence of regression to the mean, ought remain essentially the same, or even less optimistic, right?

Of course not:
2009:
Overall, thrombolytic therapy appears to result in a significant net reduction in the proportion of patients dead or dependent in activities of daily living. This overall benefit was apparent despite an increase both in deaths (evident at seven to 10 days and at final follow up) and in symptomatic intracranial haemorrhages. Further trials are needed to identify which patients are most likely to benefit from treatment and the environment in which thrombolysis may best be given in routine practice.
2014:
Thrombolytic therapy given up to six hours after stroke reduces the proportion of dead or dependent people. Those treated within the first three hours derive substantially more benefit than with later treatment. This overall benefit was apparent despite an increase in symptomatic intracranial haemorrhage, deaths at seven to 10 days, and deaths at final follow-up (except for trials testing rt-PA, which had no effect on death at final follow-up). Further trials are needed to identify the latest time window, whether people with mild stroke benefit from thrombolysis, to find ways of reducing symptomatic intracranial haemorrhage and deaths, and to identify the environment in which thrombolysis may best be given in routine practice. 
They added a neutral trial comprising 43% of the tPA subjects to the existing analysis, and now it can be decisively promoted “up to six hours”?  How is this conceivable?

So, in the most literal sense, technically, the authors' statement is not untrue.  Analyses 1.12 and 1.13 aggregate all patients treated in trials between 0-6 hours, looking at mRS 0-2 and 0-1 at the end of follow up.  Indeed, for mRS 0-2, the OR favors thrombolysis at 1.17 (1.06 to 1.29), and for mRS 0-1, the OR favors thrombolysis at 1.29 (1.16 to 1.43).  Therefore, the authors are not falsely advertising tPA as beneficial for reducing death and dependency out to six hours – as long as you wear your pro-tPA blinders.

These authors, with multiple professional and financial conflicts-of-interest, simply choose to focus on inappropriate chunking of data for a theoretically time-dependent condition, rather than acknowledge their own analyses performed providing evidence to the contrary.  Analysis 1.21, in which they split out the patients treated into 0-3 and 3-6 hour cohorts, clearly demonstrates there is no basis upon which to claim benefit beyond 3 hours.  The OR for favorable outcome with thrombolysis in the 0-3 hour window is 1.53 (1.26 to 1.86), but the OR for 3-6 hours is 1.07 (0.96 to 1.20).  Then, the authors also neglect to mention Analysis 1.26, showing deaths are neutral between 0-3 hours, with an OR of 0.91 (0.73 to 1.13), but increased by thrombolysis in the 3-6 window, with an OR of 1.16 (1.00 to 1.35).

So, tPA after 3 hours: no functional outcome benefit and increased deaths – yet the authors are extolling the benefits of tPA to 6 hours?  There is no reasonable justification for such distorted reporting of their own analyses.  Simply unacceptable – and grossly misleading for the vast population of clinicians who do not or cannot access the full text, and only read the abstract.

Let's be perfectly clear – I am not anti-tPA.  I am, however, opposed to the unfettered expansion of tPA as guideline-mandatory treatment to a larger eligible cohort – as is increasingly prevalent across contemporary literature, and fueled by manufactured-sponsored COI.  Acute ischemic stroke is a heterogenous disease, with varying underlying etiology and diverse cerebrovascular substrate.  It is clear there are subsets of patients for whom the likelihood of harm from tPA exceeds the benefit, and we ought to be using precision medicine to narrow the treatment population, not expand it.

Thanks to Rory Speigel (@EMNerd_) for alerting me to this publication.

“Thrombolysis for acute ischaemic stroke (Review)”
http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD000213.pub3/abstract

Friday, August 1, 2014

Nocebo Effects, the Dark Side of Placebo

We easily appreciate the placebo effect – the simple expectation of a treatment’s success positively affects its efficacy.  To prove a new treatment’s utility, then, we compare it against a placebo – a sham with the same expectation of success – to reveal a true magnitude of benefit (or harm).

However, much less appreciated is the flip side: nocebo effects.  I.e., if  patient expects to have adverse effects from a treatment, they are more likely to do so.  This has implications for clinical trials, of course, but also for discontinuation of therapy in general practice.  For example, consider those lovely pharmaceutical commercials, showing happy couples skydiving, in bathtubs, or otherwise living faux healthy lives – while simultaneously providing the droning voice-over detailing a litany of dire, disabling side effects.  Each mention of adverse outcome increases the likelihood a patient will perceive or experience it, and thereby potentially harm patients through decreased adherence to otherwise beneficial treatment.

Nocebo - Darren Cullen (2012)
These authors review the causes and implications of nocebo effects, and have several recommendations regarding effective strategies to minimize nocebo effects.  My favorite, by far:
“Refer to web-based and other information systems that provide evidence-based information, instead of unproven, anxiety-increasing comments.”
Ah, yes – you mean, basically, the entire Internet: insane, uninformed, anecdotal.  Good luck with that.

“Avoiding Nocebo Effects to Optimize Treatment Outcome”
http://www.ncbi.nlm.nih.gov/pubmed/25003609