{"id":41806,"date":"2013-11-24T11:35:21","date_gmt":"2013-11-24T16:35:21","guid":{"rendered":"http:\/\/1boringoldman.com\/?p=41806"},"modified":"2013-11-24T12:51:35","modified_gmt":"2013-11-24T17:51:35","slug":"an-exempler","status":"publish","type":"post","link":"https:\/\/1boringoldman.com\/index.php\/2013\/11\/24\/an-exempler\/","title":{"rendered":"an exempler&#8230;"},"content":{"rendered":"\n<div align=\"justify\">I&#8217;ve been otherwise occupied, and not so vigilant as usual about the things I usually follow. Catching up, there&#8217;s aplenty to report, but this particular issue has an emotional valence for me from a long time ago &#8211; at least forty years. It has to do with small differences in medicine:      <\/div>\n<blockquote>\n<div align=\"center\" class=\"big\"><a href=\"http:\/\/www.bmj.com\/content\/347\/bmj.f6123\" target=\"_blank\">Should people at low risk of cardiovascular disease take a statin?<\/a><\/div>\n<div align=\"center\" class=\"small\">by John D Abramson, Harriet G Rosenberg, and Nicholas Jewell, and<span class=\"name\"> James M Wright<\/span><\/div>\n<div align=\"center\" class=\"middle\"><strong><font color=\"#0066ff\">British Medical Journal<\/font><\/strong>. 2013 347:f6123.<\/div>\n<p align=\"justify\">&#8230;From a pharmacoeconomic perspective, expanding generic  statin therapy to millions of low risk patients would add drug costs of  up to $1\/day or more per person  for no net health benefit. Furthermore, if cholesterol lowering becomes  established in low risk people, the indications for new, more expensive  cholesterol lowering drugs such as the ApoB Antisence drugs and PCSK9  inhibitors currently being tested in clinical trials will probably  expand as well. <\/p>\n<p align=\"justify\">    The dominance of industry sponsored  clinical trials of cardiovascular prevention has produced a body of  scientific evidence that largely limits clinicians&rsquo; interventions to  drug therapy.   Rather than being compelled by guidelines to prescribe statin therapy  for people at low risk of cardiovascular disease, doctors would provide a  far greater service by explaining the magnitude of the benefits and  uncertainty about the harms of statins together with discussion of the  epidemiological evidence showing that behavioural risk factors&mdash;including  tobacco use, lack of physical exercise, and unhealthy diet&mdash;are  responsible for 80% of cardiovascular disease:  <\/p>\n<div><strong><font color=\"#200020\">What low risk patients need to know <\/font><\/strong><\/div>\n<ul>\n<li>\n<div align=\"justify\">Lifestyle factors&mdash;including lack of exercise, tobacco use, and unhealthy diet&mdash;account for 80% of cardiovascular disease<\/div>\n<\/li>\n<li>\n<div align=\"justify\">For  people at low risk of cardiovascular disease [&lt;10% risk over next  five years], statins do not reduce the overall risk of death or serious  illness <\/div>\n<\/li>\n<li>\n<div align=\"justify\">In order to prevent  one heart attack or stroke, 140 low risk people [&lt; 10% five year  risk] must receive statins for five years <\/div>\n<\/li>\n<li>\n<div align=\"justify\">The  side effects of statins&mdash;including  muscle symptoms, increased risk of  diabetes [especially in women], liver inflammation, cataracts, decreased  energy, sexual dysfunction, and exertional fatigue&mdash;occur in about 20%  of people treated with statins<\/div>\n<\/li>\n<\/ul>\n<\/blockquote>\n<blockquote>\n<div align=\"center\" class=\"big\"><a target=\"_blank\" href=\"http:\/\/www.bmj.com\/content\/347\/bmj.f6412\">Statins for all over 50? No<\/a><\/div>\n<div align=\"center\" class=\"small\">by Fiona Godlee, editor BMJ<\/div>\n<div align=\"center\" class=\"middle\"><strong><font color=\"#0066ff\">British Medical Journal<\/font><\/strong>. 2013 347:f6412<\/div>\n<p align=\"justify\">&#8230;There is a concern underlying their critique that will be familiar to <em>BMJ<\/em>  readers. It is that all of the trials included in the CTT meta-analysis  were funded by the manufacturer of the statin being studied. They list  the various ways in which these trials might have exaggerated the  benefits of statins and minimised the harms, and they summarise what low  risk patients need to know. Top of the list is the benefit of lifestyle  change, something that the dominance of industry sponsored clinical  trials too often obscures.<\/p>\n<p align=\"justify\">None of this does much to  bolster confidence in the published literature. Nor am I reassured by  discussions at two recent meetings co-hosted by the European Federation  of Pharmaceutical Industry Associations (EFPIA). Drug company AbbVie is  suing the European Medicines Agency to stop summary reports of its  clinical trials becoming publicly available [doi:<a target=\"_blank\" href=\"http:\/\/www.bmj.com\/lookup\/doi\/10.1136\/bmj.f1636\">10.1136\/bmj.f1636]<\/a>.  AbbVie&rsquo;s lawyer made clear that the company considers even the data on  adverse events to be commercially confidential. Despite industry&rsquo;s  claims to be in favour of greater transparency, EFPIA and its American  counterpart PhRMA are supporting Abbvie. The <em>BMJ<\/em> and BMA have joined forces to intervene on behalf of the EMA [doi:<a target=\"_blank\" href=\"http:\/\/www.bmj.com\/lookup\/doi\/10.1136\/bmj.f4728\">10.1136\/bmj.f4728]<\/a>.<\/p>\n<div align=\"justify\">As  for a way forward, I can&rsquo;t improve on the list of solutions proposed by  Richard Lehman when emailing out his journal review blog this week [<a target=\"_blank\" href=\"http:\/\/bit.ly\/HcKvjy\">http:\/\/bit.ly\/HcKvjy<\/a>]:  &ldquo;All phase 3 trials to be designed and conducted independently of  manufacturers, using the best available comparator. Research priorities  to be determined by patients (James Lind Alliance). Value-based pricing.  All data available from all trials, with meta-data: IPD [individual  patient data] level for qualified independent centres. Big increase in  comparative effectiveness research, much more research into  non-pharmacological treatments.&rdquo;<\/div>\n<\/blockquote>\n<div align=\"justify\">After four whirlwind years of clinical training in a big-city [desparate illness] charity hospital and doing a research fellowship along with clinical responsibilities, I found myself in 1971 working regular hours in a military hospital seeing patients from a more or less healthy population. It was the era when guidelines were coming into vogue &#8211; when do you treat blood pressure? how tightly do you control blood sugar? what&#8217;s the upper limit of cholesterol? weight? The &#8216;executive physical&#8217; had become popular with stress tests, pap smears, and sigmoidoscopies. Preventive medicine had moved from the world of immunizations to the &quot;healthy lifestyle&quot; doctoring of the present. I was a young contientious doctor, doing the right things. And I didn&#8217;t much like that part of it. The blood pressure medications I gave to people with minimum elevations had a heavy downside. The burden of tight diabetic control was pretty limiting. Trying to get overweight Air Force Sergeants to slim down was something of a lesson in futility. I didn&#8217;t know how to do some of the calculations back then, but I had a feeling that we were in the range of some very small differences [and in many cases, we were]. I just didn&#8217;t feel genuine when I passed on many of the guidelines I was given. And over time, it has gotten worse. And I didn&#8217;t enjoying focusing on the numbers so much. I think that was part of my decision to change specialties. The patient&#8217;s lives seemed so much more relevant than decremental changes in their diastolic blood pressure.     <\/div>\n<p align=\"justify\"><em>A Vignette<\/em>: A friend down the road had been having a lot of muscle pain and stiffness and had been &quot;sentenced&quot; to Yoga Classes by his wife [which massively increased his symptoms]. On another day, he was talking about medication costs. He mentioned he&#8217;s taking a Statin that&#8217;s not yet generic. It costs a &quot;mint,&quot; but his doctor says that it&#8217;s the &quot;best one.&quot; Last night they were over and he mentioned he&#8217;d gotten back his most recent <em>cholesterol count<\/em> and said the number. His LDL [<em>bad cholesterol<\/em>] was &quot;way down&quot; [from <em>normal<\/em> to even<em> more normal<\/em>].  <\/p>\n<table width=\"95%\" cellspacing=\"0\" cellpadding=\"0\" border=\"0\" align=\"center\">\n<tr>\n<td align=\"justify\" class=\"small\"><u><strong><font color=\"#200020\">The bottom line<\/font><\/strong><\/u><br \/>    Our calculations using data  presented in the 2012 CTT patient level meta-analysis show that statin  therapy prevents one serious cardiovascular event per 140 low risk  people (five year risk &lt;10%) treated for five years. Statin therapy  in low risk people does not reduce all cause mortality or serious  illness and has about an 18% risk of causing side effects that range  from minor and reversible to serious and irreversible. Broadening the  recommendations in cholesterol lowering guidelines to include statin  therapy for low risk individuals will unnecessarily increase the  incidence of adverse effects without providing overall health benefit&#8230;from <em>Abramson et al<\/em> [above]  <\/td>\n<\/tr>\n<\/table>\n<p align=\"justify\">After looking at all these psychoactive drug trials, I am learning more precise ways of thinking about all of this. For a drug to have a demonstrable <em><strong><font color=\"#200020\">statistical<\/font><\/strong><\/em> superiority over sugar is certainly of interest, but hardly justifies it being turned into a multi&middot;billion dollar phenome &#8211; which is exactly what has happened repeatedly. There&#8217;s something else that can be said about such comparisons, the <em><strong><font color=\"#200020\">strength of effect<\/font><\/strong><\/em> being one. Just because a drug has antidepressant properties in a large cohort, doesn&#8217;t mean it will be a clinically meaningful effect in many depressed people. And those numbers are frequently omitted from articles &#8211; things like <em><strong><font color=\"#200020\">odds ratio<\/font><\/strong><\/em>, <em><strong><font color=\"#200020\">number needed to treat [NNT]<\/font><\/strong><\/em>, <em><strong><font color=\"#200020\">effect size<\/font><\/strong><\/em>, etc. And then there are <em><strong><font color=\"#200020\">adverse effects<\/font><\/strong><\/em> [side effects] and <em><strong><font color=\"#200020\">serious adverse effects [SAEs]<\/font><\/strong><\/em>. They can be quantified as things like <em><strong><font color=\"#200020\">risk ratio<\/font><\/strong><\/em>, <em><strong><font color=\"#200020\">relative risk<\/font><\/strong><\/em>, or <em><strong><font color=\"#200020\">number needed to harm [NNT]<\/font><\/strong><\/em>. In the end, all of these things can be combined into a <em><strong><font color=\"#200020\">risk&middot;benefit ratio<\/font><\/strong><\/em>, and while there are some ways to quantitate this, it&#8217;s usually discussed subjectively as in these articles.<\/p>\n<p align=\"justify\">I grew into doctor&middot;hood when such things were more narrative than&nbsp; mathematical. Digitalis could be a life&middot;saver or a poison, and I could say that in words to patients and explain why it was both. I thought of drugs categorically, as powerful or weak, as safe or dangerous, with not much in between on either axis. I thought of classes of drugs [the <em><strong><font color=\"#200020\">penicillin<\/font><\/strong><\/em>s] more in terms of their similarities than their differences. Now, in the <em><strong><font color=\"#200020\">Age of Clinical Trials<\/font><\/strong><\/em>, we are bombarded with articles that are preoccuppied with small effects and small differences among members of a similar class. One frequently sees patients who have tried every known SSRI without success, but come seeking another <em>new<\/em> one. Rather than concluding the obvious, no chemical help in sight and likely there&#8217;s something wrong in their life. They think they just haven&#8217;t tried the right antidepressant [after all, they are <em>anti&middot;depressants<\/em>].<\/p>\n<p align=\"justify\">So back to the Statins, this is a multi&middot;billion dollar phenome extra&middot;ordinaire, and in large measure is as big a <em>much&middot;ado&middot;about&middot;nothing<\/em> as it was in 1971 when I found myself balking at all the guidelines that kept coming. To me, Statins are for high risk patients, side effects or not. The rest of us should drive carefully, and stick to the basics [&quot;<em>Lifestyle factors&mdash;including lack of exercise, tobacco use, and unhealthy diet&mdash;account for 80% of cardiovascular disease<\/em>&quot;]. Dr. David Healy&#8217;s book, <a href=\"http:\/\/www.google.com\/url?sa=t&#038;rct=j&#038;q=&#038;esrc=s&#038;source=web&#038;cd=1&#038;cad=rja&#038;ved=0CCwQFjAA&#038;url=http%3A%2F%2Fwww.amazon.com%2FPharmageddon-David-Healy%2Fdp%2F0520275764&#038;ei=DCeSUsvAINGjkQevjoCACg&#038;usg=AFQjCNHPdtqw8Q2zaRFC4UERJYsYxbRk5Q&#038;sig2=OJiYBQ19jWGn-c8I4ptanQ&#038;bvm=bv.56988011,d.eW0\" target=\"_blank\"><font color=\"#990000\">Pharmageddon<\/font><\/a>, makes this point more eloquently than I, but, in my words, we have become a culture of small differences &#8211; differences that don&#8217;t really matter [and they even fudge on that eg Paxil Study 329]. And the Pharmaceutical Industry and the proliferation of Clinical Trials have had a big part in making us that way &#8211; by design.&nbsp;<\/p>\n<div align=\"justify\">Back in 1971, I felt guilty about balking at following those many guidelines in my clinical work &#8211; in fact, too guilty not to do it. But it wasn&#8217;t how I wanted to spend my life. And back then was nothing compared to today. I don&#8217;t feel guilty anymore. The prescription of <em>small differences<\/em> medication and the doing of <em>low yield<\/em> medical tests accounts for a <em>beyond sizable<\/em> fraction of our overall medical cost burden, and this Statin escalation is a negative exempler of exactly why. At least that&#8217;s what I think. The good news is that the current focus on honest Clinical Trial reporting is a positive step towards doing something about it&#8230;<\/div>\n","protected":false},"excerpt":{"rendered":"<p>I&#8217;ve been otherwise occupied, and not so vigilant as usual about the things I usually follow. Catching up, there&#8217;s aplenty to report, but this particular issue has an emotional valence for me from a long time ago &#8211; at least forty years. It has to do with small differences in medicine: Should people at low [&hellip;]<\/p>\n","protected":false},"author":2,"featured_media":0,"comment_status":"open","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"_bbp_topic_count":0,"_bbp_reply_count":0,"_bbp_total_topic_count":0,"_bbp_total_reply_count":0,"_bbp_voice_count":0,"_bbp_anonymous_reply_count":0,"_bbp_forum_subforum_count":0,"footnotes":""},"categories":[5],"tags":[],"class_list":["post-41806","post","type-post","status-publish","format-standard","hentry","category-opinion"],"_links":{"self":[{"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/posts\/41806","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/users\/2"}],"replies":[{"embeddable":true,"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/comments?post=41806"}],"version-history":[{"count":31,"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/posts\/41806\/revisions"}],"predecessor-version":[{"id":41837,"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/posts\/41806\/revisions\/41837"}],"wp:attachment":[{"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/media?parent=41806"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/categories?post=41806"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/tags?post=41806"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}