Blood pressure: Official guidelines make no sense

These guidelines make no sense because

1. BP increases normally with age, as known for more than half a century; yet guidelines for what is said to be “normal” and what is called “hypertension” ignore the correlation with age.
2. The guidelines are not based on pertinent data because the dependence on age is not properly taken into account.

It’s no wonder, then, that the guidelines were changed in one way in 2013 and in the opposite way just four years later.

At the end of 2013, the most authoritative recommendations for managing blood pressure stated that “There is strong evidence to support treating hypertensive persons aged 60 years or older to a BP goal of less than 150/90 mmHg and hypertensive persons 30 through 59 years of age to a diastolic goal of less than 90 mmHg; however, there is insufficient evidence in hypertensive persons younger than 60 years for a systolic goal, or in those younger than 30 years for a diastolic goal, so the panel recommends a BP of less than 140/90 mmHg for those groups based on expert opinion” [emphases added].

Note first that the criterion for describing someone as “hypertensive” is based on insufficient evidence, which has not prevented modern medicine from being quite dogmatic about calling people of any age hypertensive when their BP exceeds what is the common average in healthy 30-40-year-olds, namely about 140/90.

Then note that the goal of ≤150 systolic not as low as what had been recommended dogmatically for the previous three decades or more.

And then contemplate how to value “expert opinion” that is based on insufficient evidence.

In “Don’t take a pill if you’re not ill”  I made a point I’ve not seen elsewhere: population-average numbers for blood sugar, cholesterol, and BP are taken as the desirable upper limits and medication is administered to lower everyone’s numbers to those levels; yet no consideration is given to raising the numbers if they are lower than the average, even as there is evidence that, for example, higher cholesterol is good for older people since it is associated with lower mortality (1, 2). If the population average is more desirable than higher numbers, why aren’t the averages regarded as better than lower numbers as well?

In “Everyone is sick?” I cited the Institute of Medicine finding that measures like (and including) BP are not symptoms of illness even as they are treated as such; discussed further re BP in “‘Hypertension’: An illness that isn’t illness”.

“60 MINUTES on aging — correlations or causes?” cited the finding that mini-strokes in older people were less frequent with higher blood pressure, the very opposite of the official dogma.

So now in 2017 the guidelines call for significantly lower BP than the 2013-14 set, namely “normal (<120/80 mmHg), elevated (120-129/<80 mmHg), stage 1 hypertension (130-139/80-89 mmHg), or stage 2 hypertension(³140/90 mmHg)”; though it is conceded that this is merely a “strong recommendation” based on “moderate-quality evidence” (3).

Defining hypertension as ≥130 makes it likely that some of this “moderate-quality” evidence came from the SPRINT trial, which concluded (4) that “Among patients at high risk for cardiovascular events but without diabetes, targeting a systolic blood pressure of less than 120 mm Hg, as compared with less than 140 mm Hg, resulted in lower rates of fatal and nonfatal major cardiovascular events and death from any cause, although significantly higher rates of some adverse events were observed in the intensive-treatment group” [emphasis added].

There is here a conundrum: How could there be lower rates of “fatal and nonfatal major cardiovascular events” when Table S5 in the Supplementary Appendix reports only 118 “Serious Adverse Events and Conditions of Interest Classified as Possibly or Definitely Related to the Intervention” under standard treatment (to ≤140) by contrast to 220 under the intensive treatment? With the latter confirming “significantly higher rates of some adverse events were observed in the intensive-treatment group”?

At any rate, all these data are incapable of delivering a meaningful answer about possible risks posed by high BP. Since BP increases with age, the only way to detect its possible risk would be to monitor the health and mortality rates of cohorts of people of the same age, and this is not the case in the SPRINT Trial.

There are plenty of other reasons to be wary of the SPRINT study. The Supplementary Appendix asserts that “All components of the SPRINT study protocol were designed and implemented by the investigators. The investigative team collected, analyzed, and interpreted the data. All aspects of manuscript writing and revision were carried out by the coauthors. The content is solely the responsibility of the authors”. But which ones exactly? There are 6 pages of names; there were 102 clinical sites; a trial coordinating center and centers for MRI reading and electrocardiography reading; an independent data and safety monitoring board; institutional review boards at each clinical site; and a steering committee (13 members) and a writing committee (members not detailed in the Appendix).

When everyone is responsible, then in practice no one is responsible.

Rhetorical questions:

Ø      Who conceived the idea of testing more stringent criteria than formerly for controlling BP?

Ø      What data stimulated that idea, given that the 2013 guidelines cited above revealed a lack of evidence for a systolic goal in persons younger than 60?

Ø      Why are there no statements about conflicts of interest? Biomedical research requires funding. Research articles typically list potential conflicts of interest, and it is well known that most biomedical scientists have some sort of consulting or other relationship with drug companies. Here the only possible clue lies in the Acknowledgments: “The SPRINT investigators acknowledge the contribution of study medications (azilsartan and azilsartan combined with chlorthalidone) from Takeda Pharmaceuticals International, Inc.”

The official BP guidelines make no sense because

1. BP increases normally with age, as known for more than half a century; yet guidelines for what is said to be “normal” ignore the correlation with age.
2. The guidelines are not based on pertinent data but on admittedly “moderate-quality” evidence; that is actually of much lower quality than that because it does not offer age-specific information.

**************************************************************************

1. Schatz et al., “Cholesterol and all-cause mortality in elderly people from the Honolulu Heart Program: a cohort study”, Lancet, 358 (2001) 351-5.
2. Chapter 3 in Joel M. Kaufmann, Malignant Medical Myths, Infinity Publishing, 2006; ISBN 0-7414-2909-8.
3. Adam S. Cifu & Andrew M. Davis, “JAMA Clinical Guidelines Synopsis: Prevention, detection, evaluation, and management of high blood pressure in adults”, JAMA; published online 20 November 2017; Clinical Review & Education, E1-3.
4. The SPRINT Research Group, “A randomized trial of intensive versus standard blood-pressure control”, New England Journal of Medicine, 373 (2015) 2103-16.

 

Fog Facts: Side effects and re-positioning of drugs

Fog Facts: things that are known and yet not known —
[not known to the conventional wisdom, the general public, the media
but known to those (few) who are genuinely informed about the subject]

For that delightful term, Fog Facts, I’m grateful to Larry Beinhart who introduced me to it in his novel “The Librarian”. There it’s used in connection with political matters, but it’s entirely appropriate for the disconnect between “what everyone knows” about blood pressure, cholesterol, prescription drugs, and things of that ilk, and what the actual facts are in the technical literature.

For example, the popular shibboleth is that drug companies spend hundreds of millions of dollars in the development of a new drug, and that’s why they need to make such large profits to plough back into research. The truth of the matter is that most new drugs originate in academic research, conducted to a great extent at public expense; and drug companies spend more on advertising and marketing than they do on research. All that is known to anyone who cares to read material other than what the drug-company ads say and what the news media disseminate; and yet it’s not known because too few people read the right things, even books by former editors of medical journals and academic researchers at leading universities and published by mainstream publishers; see “What’s wrong with modern medicine”.

When it comes to drug “development”, the facts are all hidden in plain view. There’s even a whole journal about it, Nature Reviews — Drug Discovery, that began publication in 2002. I came to learn about this because Josh Nicholson had alerted me to an article in that journal, “Drug repositioning: identifying and developing new uses for existing drugs” (by Ted T. Ashburn and Karl B. Thor, 3 [2004] 673-82). I had never heard of “drug repositioning”. What could it mean?

Well, it means finding new uses for old drugs. And the basic reason for doing so is that it’s much easier and more profitable than trying to design or discover a new drug, because old drugs have already been approved as safe, and it’s already known how to manufacture them.

What seems obvious, however — albeit only as a Fog Fact — is that the very success of repositioning drugs should be a red flag warning against the drug-based medicine or drug-first medicine or drug-besotted medicine that has become standard practice in the United States. The rationale for prescribing a drug is that it will fix what needs attending to without seriously and adversely affecting anything else, in other words that there are no serious “side” effects. But repositioning a drug shows that it has a comparably powerful effect on something other than its original target. In other words, “side” effects may be as powerful and significant as the originally intended effect. Ashburn and Thor give a number of examples:

Cymbalta was originally prescribed to treat depression, anxiety, diabetic peripheral neuropathy, and fibromyalgia (all at about the same dosage, which might cause one to wonder how many different mechanisms or systems are actually being affected besides the intended one). The listed side effects do not include anything about urination, yet the drug has been repositioned as Duloxetine SUI to treat “stress urinary incontinence (SUI), a condition characterized by episodic loss of urine associated with sharp increases in intra-abdominal pressure (for example, when a person laughs, coughs or sneezes)”; and “Lilly is currently anticipating worldwide sales of Duloxetine SUI to approach US $800 million within four years of launch”.

Dapoxetine was not a success for analgesia or against depression, but came into its own to treat premature ejaculation.

Thalidomide was originally marketed to treat morning sickness, but it produced limb defects in babies. Later it was found effective against “erythema nodosum laprosum (ENL), an agonizing inflammatory condition of leprosy”. Moreover, since the birth defects may have been associated with blocking development of blood vessels, thalidomide might work against cancer; and indeed “Celgene recorded 2002 sales of US $119 million for Thalomid, 92% of which came from off-label use of the drug in treating cancer, primarily multiple myeloma . . . . Sales reached US $224 million in 2003 . . . . The lesson from the thalidomide story is that no drug is ever understood completely, and repositioning, no matter   how unlikely, often remains a possibility” [emphasis added: once the FDA has approved drug A to treat condition B, individual doctors are allowed to prescribe it for other conditions as well, although drug companies are not allowed to advertise it for those other uses. That legal restriction is far from always honored, as demonstrated by the dozens of settlements paid by drug companies for breaking the law.]

Perhaps the prize for repositioning (so far) goes to Pfizer, which turned sildenafil, an unsuccessful treatment for angina, into Viagra, a very successful treatment for “erectile dysfunction”: “By 2003, sildenafil had annual sales of US $1.88 billion and nearly 8 million men were taking sildenafil in the United States alone”.

At any rate, Ashburn and Thor could not be more clear: The whole principle behind repositioning is that it’s more profitable to see what existing drugs might do than to look for what might be biologically speaking the best treatment for a given ailment. So anti-depressants get approved and prescribed against smoking, premenstrual dysphoria, or obesity; a Parkinson’s drug and a hypertension drug are prescribed for ADHD; an anti-anxiety medication is prescribed for irritable bowel syndrome; Alzheimer’s, whose etiology is not understood, gets treated with Reminyl which, as Nivalin, (generic galantamine) is also supposed to treat polio and paralysis. Celebrex, a VIOXX-type anti-arthritic, can be prescribed against breast and colon cancer; treatment of enlarged prostate is by the same drug used to combat hair loss; the infamous “morning after” pill for pregnancy termination can treat “psychotic major depression”; Raloxifene to treat breast and prostate cancer is magically able also to treat osteoporosis.

And so on and so forth. This whole business of drug repositioning exposes the fallacy of the concept that it is possible to find “a silver bullet”, a chemical substance that can be introduced into the human body to accomplish just one desired thing. That concept ought to be recognized as absurd a priori, since we know that human physiology is an interlocking network of signals, feedback, attempted homeostasis, defenses against intruders.

It is one thing to use, for brief periods of time, toxins that can help the body clear infections — sulfa drugs, antibiotics. It is quite another conceit and ill-founded hubris to administer powerful chemicals to decrease blood pressure, lower cholesterol, and the like, in other words, to attempt to alter interlocking self-regulating systems as though one single aspect of them could be altered without doing God-only-knows-what-else elsewhere.

The editorial in the first issue (January 2002) of Nature Reviews Drug Discovery was actually clear about this: “drugs need to work in whole, living systems”.

But that editorial also gave the reason for the present-day emphasis on medicine by drugs: “Even with vastly increased R & D spending, the top 20 pharmaceutical companies still churn out only around 20 drugs per year between them, far short of the 4-5 new drugs that analysts say they each need to produce to justify their discovery and development costs”.

And the editorial also mentions one of the deleterious “side” effects of the rush to introduce new drugs: “off-target effects . . . have led to the vastly increased number of costly late-stage failures seen in recent years (approximately half the withdrawals in the past 20 years have occurred since 1997)” — “off-target effects” being a synonym for “side” effects.

It’s not only that new drugs are being rushed to market. As a number of people have pointed out, drug companies also create their own markets by inventing diseases like attention-deficit disorder, erectile dysfunction, generalized anxiety disorder, and so on and on. Any deviation of behavior from what might naively be described as “normal” offers the opportunity to discover a new disease and to re-position a drug.

The ability of drug companies to sell drugs for new diseases is helped by the common misconception about “risk factors”. Medication against hypertension or high cholesterol, for example, is based on the presumption that both those raise the risk of heart attack, stroke, and other undesirable contingencies because both are “risk factors” for such contingencies. But “risk factor” describes only an observed association, a correlation, not an identified causation. Correlation never proves causation. “Treating” hypertension or high cholesterol makes sense only if those things are causes, and they have not been shown to be that. On the other hand, lifelong ingestion of drugs is certainly known to have potentially dangerous consequences.

Modern drug-based, really drug-obsessed medical practice is as misguided as “Seeking Immortality”.

Science is broken

Science is broken: Perverse incentives and the misuse of quantitative metrics have undermined the integrity of scientific research is the full title of an article published in the on-line journal AEON . I learned of it through a friend who was interested in part because the authors are at the university from which I retired some 17 years ago.

The article focuses on the demands on researchers to get grants and publish, and that their achievements are assessed quantitatively rather than qualitatively, through computerized scoring of such things as Journal Impact Factor and numbers of citations of an individual’s work.

I agree that those things are factors in what has gone wrong, but there are others as well.

The AEON piece is an abbreviated version of the full article in Environmental Engineering Science (34 [2017] 51-61; DOI: 10.1089/ees.2016.0223). I found it intriguing that the literature cited in it overlaps very little with the literature with which I’ve been familiar. That illustrates how over-specialized academe has become, and with that the intellectual life of society as a whole. There is no longer a “natural philosophy” that strives to integrate knowledge across the board, from all fields and specializations; and there are not the polymath public intellectuals who could guide society through the jungle of ultra-specialization. So it is possible, as in this case of “science is broken”, for different folk to reach essentially the same conclusion by extrapolating from quite different sets of sources and quite independently of one another.

I would add more factors, or perhaps context, to what Edwards and Roy emphasized:

The character of research activity has changed out of sight since the era or “modern science” began; for example, the number of wannabe “research universities” in the USA has tripled or quadrupled since WWII — see “Three stages of modern science”; “The science bubble”; chapter 1 in Science Is Not What You Think [McFarland 2017].

This historical context shows how the perverse incentives noted by Edwards and Roy came about. Honesty and integrity, dedication to truth-seeking above all, were notable aspects of scientific activity when research was something of an ivory-tower avocation; nowadays research is so integrated with government and industry that researchers face much the same difficulties as professionals who seek to practice honesty and integrity while working in the political realm or the financial realm: the system makes conflicts of interest, institutional as well as personal, inevitable. John Ziman (Prometheus Bound, Cambridge University Press) pointed out how the norms of scientific practice nowadays differ from those traditionally associated with science “in the good old days” (the “Mertonian” norms of communality, universality, disinterestedness, skepticism).

My special interest has long been in the role of unorthodoxies and minority views in the development of science. The mainstream, the scientific consensus, has always resisted drastic change (Barber, “Resistance by scientists to scientific discovery”, Science, 134 [1961] 596–602), but nowadays that resistance can amount to suppression; see “Science in the 21^st century”; Dogmatism in Science and Medicine: How Dominant Theories Monopolize Research and Stifle the Search for Truth [McFarland, 2012]). Radical dissent from mainstream views is nowadays expressed openly almost only by long-tenured full professors or by retired people.

I’m in sympathy with the suggestions at the end of the formal Edwards and Roy paper, but I doubt that even those could really fix things since the problem is so thoroughgoingly systemic. Many institutions and people are vested in the status quo. Thus PhD programs will not change in the desired direction so long as the mentoring faculty are under pressure to produce more publications and grants, which leads to treating graduate students as cheap hired hands pushing the mentor’s research program instead of designing PhD research as optimum for neophytes to learn to do independent research. The drive for institutional prestige and status and rankings seems the same among university leaders, and they seek those not by excelling in “higher education” but by winning at football and basketball and by getting and spending lots of grant money on “research”. How to change that obsession with numbers: dollars for research, games won in sports?

That attitude is not unique to science or to academe. In society as a whole there has been increasing pressure to find “objective” criteria to avoid the biases inherent inevitably in human judgments. Society judges academe by numbers — of students, of research expenditures, of patents, of magnitude of endowment , etc. — and we compare nations by GDP rather than level of satisfaction among the citizens. In schools we create “objective” and preferably quantifiable criteria like “standards of learning” (SOLs), that supersede the judgments of the teachers who are in actual contact with actual students. Edwards and Roy cite Goodhart’s Law, which states that “when a measure becomes a target, it ceases to be a good measure”, which was new to me and which encapsulates so nicely much of what has gone wrong. For instance, in less competitive times, the award of a research grant tended to attest the quality of the applicant’s work; but as everything increased in size, and the amount of grants brought in became the criterion of quality of applicant and of institution, the aim of research became to get more grants rather than to do the most advancing work that would if successful bring real progress as well as more research funds. SOLs induced teachers to cheat by sharing answers with their students before giving the test. And so on and on. The cart before the horse. The letter of every law becomes the basis for action instead of the human judgment that could put into practice the spirit of the law.