Experience versus Evidence [1]. Opioid Therapy for Rheumatoid Arthritis Pain.

5 12 2011

ResearchBlogging.orgRheumatoid arthritis (RA) is a chronic auto-immune disease, which causes inflammation of the joints that eventually leads to progressive joint destruction and deformity. Patients have swollen, stiff and painful joints.  The main aim of treatment is to reduce swelling  and inflammation, to alleviate pain and stiffness and to maintain normal joint function. While there is no cure, it is important to properly manage pain.

The mainstays of therapy in RA are disease-modifying anti-rheumatic drugs (DMARDs) and non-steroidal anti-inflammatory drugs (NSAIDs). These drugs primarily target inflammation. However, since inflammation is not the only factor that causes pain in RA, patients may not be (fully) responsive to treatment with these medications.
Opioids are another class of pain-relieving substance (analgesics). They are frequently used in RA, but their role in chronic cancer pain, including RA, is not firmly established.

A recent Cochrane Systematic Review [1] assessed the beneficial and harmful effects of opioids in RA.

Eleven studies (672 participants) were included in the review.

Four studies only assessed the efficacy of  single doses of different analgesics, often given on consecutive days. In each study opioids reduced pain (a bit) more than placebo. There were no differences in effectiveness between the opioids.

Seven studies between 1-6 weeks in duration assessed 6 different oral opioids either alone or combined with non-opioid analgesics.
The only strong opioid investigated was controlled-release morphine sulphate, in a single study with 20 participants.
Six studies compared an opioid (often combined with an non-opioid analgesic) to placebo. Opioids were slightly better than placebo in improving patient reported global impression of clinical change (PGIC)  (3 studies, 324 participants: relative risk (RR) 1.44, 95% CI 1.03 to 2.03), but did not lower the  number of withdrawals due to inadequate analgesia in 4 studies.
Notably none of the 11 studies reported the primary and probably more clinical relevant outcome “proportion of participants reporting ≥ 30% pain relief”.

On the other hand adverse events (most commonly nausea, vomiting, dizziness and constipation) were more frequent in patients receiving opioids compared to placebo (4 studies, 371 participants: odds ratio 3.90, 95% CI 2.31 to 6.56). Withdrawal due to adverse events was  non-significantly higher in the opioid-treated group.

Comparing opioids to other analgesics instead of placebos seems more relevant. Among the 11 studies, only 1 study compared an opioid (codeine with paracetamol) to an NSAID (diclofenac). This study found no difference in efficacy or safety between the two treatments.

The 11 included studies were very heterogeneous (i.e. different opioid studied, with or without concurrent use of non-opioid analgesics, different outcomes measured) and the risk of bias was generally high. Furthermore, most studies were published before 2000 (less optimal treatment of RA).

The authors therefore conclude:

In light of this, the quantitative findings of this review must be interpreted with great caution. At best, there is weak evidence in favour of the efficacy of opioids for the treatment of pain in patients with RA but, as no study was longer than six weeks in duration, no reliable conclusions can be drawn regarding the efficacy or safety of opioids in the longer term.

This was the evidence, now the opinion.

I found this Cochrane Review via an EvidenceUpdates email alert from the BMJ Group and McMaster PLUS.

EvidenceUpdate alerts are meant to “provide you with access to current best evidence from research, tailored to your own health care interests, to support evidence-based clinical decisions. (…) All citations are pre-rated for quality by research staff, then rated for clinical relevance and interest by at least 3 members of a worldwide panel of practicing physicians”

I usually don’t care about the rating, because it is mostly 5-6 on a scale of 7. This was also true for the current SR.

There is a more detailed rating available (when clicking the link, free registration required). Usually, the newsworthiness of SR’s scores relatively low. (because it summarizes ‘old’ studies?). Personally I would think that the relevance and newsworthiness would be higher for the special interest group, pain.

But the comment of the first of the 3 clinical raters was most revealing:

He/she comments:

As a Palliative care physician and general internist, I have had excellent results using low potency opiates for RA and OA pain. The palliative care literature is significantly more supportive of this approach vs. the Cochrane review.

Thus personal experience wins from evidence?* How did this palliative care physician assess effectiveness? Just give a single dose of an opiate? How did he rate the effectiveness of the opioids? Did he/she compare it to placebo or NSAID (did he compare it at all?), did he/she measure adverse effects?

And what is “The palliative care literature”  the commenter is referring to? Apparently not this Cochrane Review. Apparently not the 11 controlled trials included in the Cochrane review. Apparently not the several other Cochrane reviews on use of opioids for non-chronic cancer pain, and not the guidelines, syntheses and synopsis I found via the TRIP-database. All conclude that using opioids to treat non-cancer chronic pain is supported by very limited evidence, that adverse effects are common and that long-term use may lead to opioid addiction.

I’m sorry to note that although the alerting service is great as an alert, such personal ratings are not very helpful for interpreting and *true* rating of the evidence.

I would rather prefer a truly objective, structured critical appraisal like this one on a similar topic by DARE (“Opioids for chronic noncancer pain: a meta-analysis of effectiveness and side effects”)  and/or an objective piece that puts the new data into clinical perspective.

*Just to be clear, the own expertise and opinions of experts are also important in decision making. Rightly, Sackett [2] emphasized that good doctors use both individual clinical expertise and the best available external evidence. However, that doesn’t mean that one personal opinion and/or preference replaces all the existing evidence.

References 

  1. Whittle SL, Richards BL, Husni E, & Buchbinder R (2011). Opioid therapy for treating rheumatoid arthritis pain. Cochrane database of systematic reviews (Online), 11 PMID: 22071805
  2. Sackett DL, Rosenberg WM, Gray JA, Haynes RB, & Richardson WS (1996). Evidence based medicine: what it is and what it isn’t. BMJ (Clinical research ed.), 312 (7023), 71-2 PMID: 8555924
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How will we ever keep up with 75 Trials and 11 Systematic Reviews a Day?

6 10 2010

ResearchBlogging.orgAn interesting paper was published in PLOS Medicine [1]. As an information specialist and working part time for the Cochrane Collaboration* (see below), this topic is close to my heart.

The paper, published in PLOS Medicine is written by Hilda Bastian and two of my favorite EBM devotees ànd critics, Paul Glasziou and Iain Chalmers.

Their article gives an good overview of the rise in number of trials, systematic reviews (SR’s) of interventions and of medical papers in general. The paper (under the head: Policy Forum) raises some important issues, but the message is not as sharp and clear as usual.

Take the title for instance.

Seventy-Five Trials and Eleven Systematic Reviews a Day:
How Will We Ever Keep Up?

What do you consider its most important message?

  1. That doctors suffer from an information overload that is only going to get worse, as I did and probably also in part @kevinclauson who tweeted about it to medical librarians
  2. that the solution to this information overload consists of Cochrane systematic reviews (because they aggregate the evidence from individual trials) as @doctorblogs twittered
  3. that it is just about “too many systematic reviews (SR’s) ?”, the title of the PLOS-press release (so the other way around),
  4. That it is about too much of everything and the not always good quality SR’s: @kevinclauson and @pfanderson discussed that they both use the same ” #Cochrane Disaster” (see Kevin’s Blog) in their  teaching.
  5. that Archie Cochrane’s* dream is unachievable and ought perhaps be replaced by something less Utopian (comment by Richard Smith, former editor of the BMJ: 1, 3, 4, 5 together plus a new aspect: SR’s should not only  include randomized controlled trials (RCT’s)

The paper reads easily, but matters of importance are often only touched upon.  Even after reading it twice, I wondered: a lot is being said, but what is really their main point and what are their answers/suggestions?

But lets look at their arguments and pieces of evidence. (Black is from their paper, blue my remarks)

The landscape

I often start my presentations “searching for evidence” by showing the Figure to the right, which is from an older PLOS-article. It illustrates the information overload. Sometimes I also show another slide, with (5-10 year older data), saying that there are 55 trials a day, 1400 new records added per day to MEDLINE and 5000 biomedical articles a day. I also add that specialists have to read 17-22 articles a day to keep up to date with the literature. GP’s even have to read more, because they are generalists. So those 75 trials and the subsequent information overload is not really a shock to me.

Indeed the authors start with saying that “Keeping up with information in health care has never been easy.” The authors give an interesting overview of the driving forces for the increase in trials and the initiation of SR’s and critical appraisals to synthesize the evidence from all individual trials to overcome the information overload (SR’s and other forms of aggregate evidence decrease the number needed to read).

In box 1 they give an overview of the earliest systematic reviews. These SR’s often had a great impact on medical practice (see for instance an earlier discussion on the role of the Crash trial and of the first Cochrane review).
They also touch upon the institution of the Cochrane Collaboration.  The Cochrane collaboration is named after Archie Cochrane who “reproached the medical profession for not having managed to organise a “critical summary, by speciality or subspecialty, adapted periodically, of all relevant randomised controlled trials” He inspired the establishment of the international Oxford Database of Perinatal Trials and he encouraged the use of systematic reviews of randomized controlled trials (RCT’s).

A timeline with some of the key events are shown in Figure 1.

Where are we now?

The second paragraph shows many, interesting, graphs (figs 2-4).

Annoyingly, PLOS only allows one sentence-legends. The details are in the (WORD) supplement without proper referral to the actual figure numbers. Grrrr..!  This is completely unnecessary in reviews/editorials/policy forums. And -as said- annoying, because you have to read a Word file to understand where the data actually come from.

Bastian et al. have used MEDLINE’s publication types (i.e. case reports [pt], reviews[pt], Controlled Clinical Trial[pt] ) and search filters (the Montori SR filter and the Haynes narrow therapy filter, which is built-in in PubMed’s Clinical Queries) to estimate the yearly rise in number of study types. The total number of Clinical trials in CENTRAL (the largest database of controlled clinical trials, abbreviated as CCTRS in the article) and the Cochrane Database of Systematic Reviews (CDSR) are easy to retrieve, because the numbers are published quaterly (now monthly) by the Cochrane Library. Per definition, CDSR only contains SR’s and CENTRAL (as I prefer to call it) contains almost invariably controlled clinical trials.

In short, these are the conclusions from their three figures:

  • Fig 2: The number of published trials has raised sharply from 1950 till 2010
  • Fig 3: The number of systematic reviews and meta-analysis has raised tremendously as well
  • Fig 4: But systematic reviews and clinical trials are still far outnumbered by narrative reviews and case reports.

O.k. that’s clear & they raise a good point : an “astonishing growth has occurred in the number of reports of clinical trials since the middle of the 20th century, and in reports of systematic reviews since the 1980s—and a plateau in growth has not yet been reached.
Plus indirectly: the increase in systematic reviews  didn’t lead to a lower the number of trials and narrative reviews. Thus the information overload is still increasing.
But instead of discussing these findings they go into an endless discussion on the actual data and the fact that we “still do not know exactly how many trials have been done”, to end the discussion by saying that “Even though these figures must be seen as more illustrative than precise…” And than you think. So what? Furthermore, I don’t really get their point of this part of their article.

 

Fig. 2: The number of published trials, 1950 to 2007.

 

 

With regard to Figure 2 they say for instance:

The differences between the numbers of trial records in MEDLINE and CCTR (CENTRAL) (see Figure 2) have multiple causes. Both CCTR and MEDLINE often contain more than one record from a single study, and there are lags in adding new records to both databases. The NLM filters are probably not as efficient at excluding non-trials as are the methods used to compile CCTR. Furthermore, MEDLINE has more language restrictions than CCTR. In brief, there is still no single repository reliably showing the true number of randomised trials. Similar difficulties apply to trying to estimate the number of systematic reviews and health technology assessments (HTAs).

Sorry, although some of these points may be true, Bastian et al. don’t go into the main reason for the difference between both graphs, that is the higher number of trial records in CCTR (CENTRAL) than in MEDLINE: the difference can be simply explained by the fact that CENTRAL contains records from MEDLINE as well as from many other electronic databases and from hand-searched materials (see this post).
With respect to other details:. I don’t know which NLM filter they refer to, but if they mean the narrow therapy filter: this filter is specifically meant to find randomized controlled trials, and is far more specific and less sensitive than the Cochrane methodological filters for retrieving controlled clinical trials. In addition, MEDLINE does not have more language restrictions per se: it just contains a (extensive) selection of  journals. (Plus people more easily use language limits in MEDLINE, but that is besides the point).

Elsewhere the authors say:

In Figures 2 and 3 we use a variety of data sources to estimate the numbers of trials and systematic reviews published from 1950 to the end of 2007 (see Text S1). The number of trials continues to rise: although the data from CCTR suggest some fluctuation in trial numbers in recent years, this may be misleading because the Cochrane Collaboration virtually halted additions to CCTR as it undertook a review and internal restructuring that lasted a couple of years.

As I recall it , the situation is like this: till 2005 the Cochrane Collaboration did the so called “retag project” , in which they searched for controlled clinical trials in MEDLINE and EMBASE (with a very broad methodological filter). All controlled trials articles were loaded in CENTRAL, and the NLM retagged the controlled clinical trials that weren’t tagged with the appropriate publication type in MEDLINE. The Cochrane stopped the laborious retag project in 2005, but still continues the (now) monthly electronic search updates performed by the various Cochrane groups (for their topics only). They still continue handsearching. So they didn’t (virtually?!) halted additions to CENTRAL, although it seems likely that stopping the retagging project caused the plateau. Again the author’s main points are dwarfed by not very accurate details.

Some interesting points in this paragraph:

  • We still do not know exactly how many trials have been done.
  • For a variety of reasons, a large proportion of trials have remained unpublished (negative publication bias!) (note: Cochrane Reviews try to lower this kind of bias by applying no language limits and including unpublished data, i.e. conference proceedings, too)
  • Many trials have been published in journals without being electronically indexed as trials, which makes them difficult to find. (note: this has been tremendously improved since the Consort-statement, which is an evidence-based, minimum set of recommendations for reporting RCTs, and by the Cochrane retag-project, discussed above)
  • Astonishing growth has occurred in the number of reports of clinical trials since the middle of the 20th century, and in reports of systematic reviews since the 1980s—and a plateau in growth has not yet been reached.
  • Trials are now registered in prospective trial registers at inception, theoretically enabling an overview of all published and unpublished trials (note: this will also facilitate to find out reasons for not publishing data, or alteration of primary outcomes)
  • Once the International Committee of Medical Journal Editors announced that their journals would no longer publish trials that had not been prospectively registered, far more ongoing trials were being registered per week (200 instead of 30). In 2007, the US Congress made detailed prospective trial registration legally mandatory.

The authors do not discuss that better reporting of trials and the retag project might have facilitated the indexing and retrieval of trials.

How Close Are We to Archie Cochrane’s Goal?

According to the authors there are various reasons why Archie Cochrane’s goal will not be achieved without some serious changes in course:

  • The increase in systematic reviews didn’t displace other less reliable forms of information (Figs 3 and 4)
  • Only a minority of trials have been assessed in systematic review
  • The workload involved in producing reviews is increasing
  • The bulk of systematic reviews are now many years out of date.

Where to Now?

In this paragraph the authors discuss what should be changed:

  • Prioritize trials
  • Wider adoption of the concept that trials will not be supported unless a SR has shown the trial to be necessary.
  • Prioritizing SR’s: reviews should address questions that are relevant to patients, clinicians and policymakers.
  • Chose between elaborate reviews that answer a part of the relevant questions or “leaner” reviews of most of what we want to know. Apparently the authors have already chosen for the latter: they prefer:
    • shorter and less elaborate reviews
    • faster production ànd update of SR’s
    • no unnecessary inclusion of other study types other than randomized trials. (unless it is about less common adverse effects)
  • More international collaboration and thereby a better use  of resources for SR’s and HTAs. As an example of a good initiative they mention “KEEP Up,” which will aim to harmonise updating standards and aggregate updating results, initiated and coordinated by the German Institute for Quality and Efficiency in Health Care (IQWiG) and involving key systematic reviewing and guidelines organisations such as the Cochrane Collaboration, Duodecim, the Scottish Intercollegiate Guidelines Network (SIGN), and the National Institute for Health and Clinical Excellence (NICE).

Summary and comments

The main aim of this paper is to discuss  to which extent the medical profession has managed to make “critical summaries, by speciality or subspeciality, adapted periodically, of all relevant randomized controlled trials”, as proposed 30 years ago by Archie Cochrane.

Emphasis of the paper is mostly on the number of trials and systematic reviews, not on qualitative aspects. Furthermore there is too much emphasis on the methods determining the number of trials and reviews.

The main conclusion of the authors is that an astonishing growth has occurred in the number of reports of clinical trials as well as in the number of SR’s, but that these systematic pieces of evidence shrink into insignificance compared to the a-systematic narrative reviews or case reports published. That is an important, but not an unexpected conclusion.

Bastian et al don’t address whether systematic reviews have made the growing number of trials easier to access or digest. Neither do they go into developments that have facilitated the retrieval of clinical trials and aggregate evidence from databases like PubMed: the Cochrane retag-project, the Consort-statement, the existence of publication types and search filters (they use themselves to filter out trials and systematic reviews). They also skip other sources than systematic reviews, that make it easier to find the evidence: Databases with Evidence Based Guidelines, the TRIP database, Clinical Evidence.
As Clay Shirky said: “It’s Not Information Overload. It’s Filter Failure.”

It is also good to note that case reports and narrative reviews serve other aims. For medical practitioners rare case reports can be very useful for their clinical practice and good narrative reviews can be valuable for getting an overview in the field or for keeping up-to-date. You just have to know when to look for what.

Bastian et al have several suggestions for improvement, but these suggestions are not always underpinned. For instance, they propose access to all systematic reviews and trials. Perfect. But how can this be attained? We could stimulate authors to publish their trials in open access papers. For Cochrane reviews this would be desirable but difficult, as we cannot demand from authors who work for months for free to write a SR to pay the publications themselves. The Cochrane Collab is an international organization that does not receive subsidies for this. So how could this be achieved?

In my opinion, we can expect the most important benefits from prioritizing of trials ànd SR’s, faster production ànd update of SR’s, more international collaboration and less duplication. It is a pity the authors do not mention other projects than “Keep up”.  As discussed in previous posts, the Cochrane Collaboration also recognizes the many issues raised in this paper, and aims to speed up the updates and to produce evidence on priority topics (see here and here). Evidence aid is an example of a successful effort.  But this is only the Cochrane Collaboration. There are many more non-Cochrane systematic reviews produced.

And then we arrive at the next issue: Not all systematic reviews are created equal. There are a lot of so called “systematic reviews”, that aren’t the conscientious, explicit and judicious created synthesis of evidence as they ought to be.

Therefore, I do not think that the proposal that each single trial should be preceded by a systematic review, is a very good idea.
In the Netherlands writing a SR is already required for NWO grants. In practice, people just approach me, as a searcher, the days before Christmas, with the idea to submit the grant proposal (including the SR) early in January. This evidently is a fast procedure, but doesn’t result in a high standard SR, upon which others can rely.

Another point is that this simple and fast production of SR’s will only lead to a larger increase in number of SR’s, an effect that the authors wanted to prevent.

Of course it is necessary to get a (reliable) picture of what has already be done and to prevent unnecessary duplication of trials and systematic reviews. It would the best solution if we would have a triplet (nano-publications)-like repository of trials and systematic reviews done.

Ideally, researchers and doctors should first check such a database for existing systematic reviews. Only if no recent SR is present they could continue writing a SR themselves. Perhaps it sometimes suffices to search for trials and write a short synthesis.

There is another point I do not agree with. I do not think that SR’s of interventions should only include RCT’s . We should include those study types that are relevant. If RCT’s furnish a clear proof, than RCT’s are all we need. But sometimes – or in some topics/specialties- RCT’s are not available. Inclusion of other study designs and rating them with GRADE (proposed by Guyatt) gives a better overall picture. (also see the post: #notsofunny: ridiculing RCT’s and EBM.

The authors strive for simplicity. However, the real world isn’t that simple. In this paper they have limited themselves to evidence of the effects of health care interventions. Finding and assessing prognostic, etiological and diagnostic studies is methodologically even more difficult. Still many clinicians have these kinds of questions. Therefore systematic reviews of other study designs (diagnostic accuracy or observational studies) are also of great importance.

In conclusion, whereas I do not agree with all points raised, this paper touches upon a lot of important issues and achieves what can be expected from a discussion paper:  a thorough shake-up and a lot of discussion.

References

  1. Bastian, H., Glasziou, P., & Chalmers, I. (2010). Seventy-Five Trials and Eleven Systematic Reviews a Day: How Will We Ever Keep Up? PLoS Medicine, 7 (9) DOI: 10.1371/journal.pmed.1000326

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#Cochrane Colloquium 2009: Better Working Relationship between Cochrane and Guideline Developers

19 10 2009

singapore CCLast week I attended the annual Cochrane Colloquium in Singapore. I will summarize some of the meetings.

Here is a summary of an interesting (parallel) special session: Creating a closer working relationship between Cochrane and Guideline Developers. This session was brought together as a partnership between the Guidelines International Network (G-I-N) and The Cochrane Collaboration to look at the current experience of guideline developers and their use of Cochrane reviews (see abstract).

Emma Tavender of the EPOC Australian Satellite, Australia reported on the survey carried out by the UK Cochrane Centre to identify the use of Cochrane reviews in guidelines produced in the UK ) (not attended this presentation) .

Pwee Keng Ho, Ministry of Health, Singapore, is leading the Health Technology Assessment (HTA) and guideline development program of the Singapore Ministry of Health. He spoke about the issues faced as a guideline developer using Cochrane reviews or -in his own words- his task was: “to summarize whether guideline developers like Cochrane Systematic reviews or not” .

Keng Ho presented the results of 3 surveys of different guideline developers. Most surveys had very few respondents: 12-29 if I remember it well.

Each survey had approximately the same questions, but in a different order. On the face of it, the 3 surveys gave the same picture.

Main points:

  • some guideline developers are not familiar with Cochrane Systematic Reviews
  • others have no access to it.
  • of those who are familiar with the Cochrane Reviews and do have access to it, most found the Cochrane reviews useful and reliable. (in one survey half of the respondents were neutral)
  • most importantly they actually did use the Cochrane reviews for most of their guidelines.
  • these guideline developers also used the Cochrane methodology to make their guidelines (whereas most physicians are not inclined to use the exhaustive search strategies and systematic approach of the Cochrane Collaboration)
  • An often heard critique of Guideline developers concerned the non-comprehensive coverage of topics by Cochrane Reviews. However, unlike in Western countries, the Singapore minister of Health mentioned acupuncture and herbs as missing topics (for certain diseases).

This incomplete coverage caused by a not-demand driven choice of subjects was a recurrent topic at this meeting and a main issue recognized by the entire Cochrane Community. Therefore priority setting of Cochrane Systematic reviews is one of the main topics addressed at this Colloquium and in the Cochrane Strategic review.

Kay Dickersin of the US Cochrane Center, USA, reported on the issues raised at the stakeholders meeting held in June 2009 in the US (see here for agenda) on whether systematic reviews can effectively inform guideline development, with a particular focus on areas of controversy and debate.

The Stakeholder summit concentrated on using quality SR’s for guidelines. This is different from effectiveness research, for which the Institute of Medicine (IOM) sets the standards: local and specialist guidelines require a different expertise and approach.

All kinds of people are involved in the development of guidelines, i.e. nurses, consumers, physicians.
Important issues to address, point by point:

  • Some may not understand the need to be systematic
  • How to get physicians on board: they are not very comfortable with extensive searching and systematic work
  • Ongoing education, like how-to workshops, is essential
  • What to do if there is no evidence?
  • More transparency; handling conflicts of interest
  • Guidelines differ, including the rating of the evidence. Almost everyone in the Stakeholders meeting used GRADE to grade the evidence, but not as it was originally described. There were numerous variations on the same theme. One question is whether there should be one system or not.
  • Another -recurrent- issue was that Guidelines should be made actionable.

Here are podcasts covering the meeting

Gordon Guyatt, McMaster University, Canada, gave  an outline of the GRADE approach and the purpose of ‘Summary of Findings’ tables, and how both are perceived by Cochrane review authors and guideline developers.

Gordon Guyatt, whose magnificent book ” Users’ Guide to the Medical Literature”  (JAMA-Evidence) lies at my desk, was clearly in favor of adherence to the original Grade-guidelines. Forty organizations have adopted these Grade Guidelines.

Grade stands for “Grading of Recommendations Assessment, Development and Evaluation”  system. It is used for grading evidence when submitting a clinical guidelines article. Six articles in the BMJ are specifically devoted to GRADE (see here for one (full text); and 2 (PubMed)). GRADE not only takes the rigor of the methods  into account, but also the balance between the benefits and the risks, burdens, and costs.

Suppose  a guideline would recommend  to use thrombolysis to treat disease X, because a good quality small RCTs show thrombolysis to be slightly but significantly more effective than heparin in this disease. However by relying on only direct evidence from the RCT’s it isn’t taken into account that observational studies have long shown that thrombolysis enhances the risk of massive bleeding in diseases Y and Z. Clearly the risk of harm is the same in disease X: both benefits and harms should be weighted.
Guyatt gave several other examples illustrating the importance of grading the evidence and the understandable overview presented in the Summary of Findings Table.

Another issue is that guideline makers are distressingly ready to embrace surrogate endpoints instead of outcomes that are more relevant to the patient. For instance it is not very meaningful if angiographic outcomes are improved, but mortality or the recurrence of cardiovascular disease are not.
GRADE takes into account if indirect evidence is used: It downgrades the evidence rating.  Downgrading also occurs in case of low quality RCT’s or the non-trade off of benefits versus harms.

Guyatt pleaded for uniform use of GRADE, and advised everybody to get comfortable with it.

Although I must say that it can feel somewhat uncomfortable to give absolute rates to non-absolute differences. These are really man-made formulas, people agreed upon. On the other hand it is a good thing that it is not only the outcome of the RCT’s with respect to benefits (of sometimes surrogate markers) that count.

A final remark of Guyatt: ” Everybody makes the claim they are following evidence based approach, but you have to learn them what that really means.”
Indeed, many people talk about their findings and/or recommendations being evidence based, because “EBM sells well”, but upon closer examination many reports are hardly worth the name.

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