May 19

Two medical treatment disputes: hormones for healthy women; statins for healthy men & women

I. Hormone replacement therapy (HRT)

greatest_experiment_ever performed on women
The Greatest Experiment Ever Performed On Women by Barbara Seaman

For decades the norm in clinical practice was to prescribe hormone replacement therapy, a combination of estrogen plus progestin to menopausal women – despite the lack of scientific evidence of its safety and benefits. Science journalist, Barbara Seaman, founder of the Women’s Health Initiative, had examined the evidence and for decades issued warnings about HRT risks for women’s health. Her book, The Greatest Experiment Ever Performed on Women: Exploding the Estrogen Myth (2009) remains a valuable historical source.

The serious risks of HRT were recently confirmed by Professor Valerie Beral, an epidemiologist, and colleagues at Oxford University who conducted a Million Women Study between 1995 – 2001. Her conclusions according to a detailed re-analysis (2015) of all the available evidence, which includes a meta-analysis of 52 epidemiological studies involving 21,488 women with ovarian cancer:

“Taking hormone replacement therapy (HRT) for menopause, even for just a few years, is associated with a significantly increased risk of developing the two most common types of ovarian cancer … The definite risk of ovarian cancer even with less than 5 years of HRT is directly relevant to today’s patterns of use–with most women now taking HRT for only a few years–and has implications for current efforts to revise UK and worldwide guidelines.” (Science Daily; Read more, The Lancet, 2015)

Read difference between NICE Guidelines and warning by Cancer scientists who have expressed concern that the effect of the NICE Guideline might be to rehabilitate HRT without sufficient recognition of the long-term potential harm.

Dame Valerie Beral
Dame Valerie Beral

Prof Valerie Beral has concluded that “It is very clear there’s an increased risk of cancer of the breast, cancer of the ovary, blood clots and strokes in women who have taken HRT, compared to women who have not.” She told the Guardian:

“About one million UK women are currently using hormones for the menopause,” she said. “Among them, about 10,000 extra breast cancers are estimated to occur in the next 10 years [40,000 in total, instead of 30,000 if the women had not used the hormones]. Also about 1,000 extra ovarian cancers are estimated to occur among them in the next 10 years [6,000 in total].” (The Guardian)

Critics point out that a HRT media campaign underplays cancer risks. Jane Greer, professor of epidemiology at Oxford University, said she and her colleagues did not want an “us and them” battle with gynecologists who advocate greater use of HRT, which would further confuse women. “The thing that makes me so angry about all this is that the message that goes out is [that] nobody can agree. We are squabbling among ourselves. But we do know some facts and that it is complex.” The Guardian

II. Are U.S. Guidelines for treating healthy adults with cholesterol lowering statins “evidence based medicine”?

US cholesterol guidelines recommend prescribing statins to reduce elevated cholesterol for healthy adults with no history or risks for cardiovascular disease, on the assumption that this will prevent heart disease. But critics argue that there is no scientific evidence to back up the guideline recommendations. In fact, clinical guidelines on both sides of the Atlantic and even a Cochrane review have flip-flopped over the years in favor of statins with no additional scientific evidence. John Abramson, MD,* has examined the limited data that is accessible for independent review; and he challenges the claim that scientific evidence supports the recommended wide use of statins in healthy people. He reviews the updated versions of the U.S. guidelines issued in 2001, 2004, 2007, 2011, 2012-2013 (here and here). He argues that each of these guidelines was misrepresented to physicians and the public as “evidence based medicine.”

The 2001 guidelines were published in the Journal of the American Medical Association.

The updated guidelines instantly became “the law of the land,” defining the threshold of treatment that would be used to judge the quality of physicians’ patient-care as well as provide a (purportedly) objective standard that could be introduced as evidence in malpractice litigation.  But did the evidence support almost 20% of American adults being treated daily with statin therapy?”

John Abramson, MD
John Abramson, MD

Dr. Abramson explains the difference between “relative risk reduction” – which refers to the percent reduction in risk of developing heart disease (of 25 -30%); compared to “absolute risk reduction” – which refers to the chance that statin therapy would actually protect an individual from developing heart disease. To prevent one heart attack or cardiac death, 50 men at increased risk of heart disease would have to take statins for five years. So, the ratio is one chance out of 50 in preventing a heart attack and 49 chances out of 50 of gaining no health benefit. Not considered in the guidelines is the evidence of risk of serious adverse effects which the proponents of statins seem to overlook. These include, muscle problems, diabetes, liver dysfunction, acute renal failure, cataracts, sexual dysfunction and psychiatric symptoms. (Pharmaceutical Journal, 2015)

The 2001 guidelines claimed that seven clinical trials had shown that statin therapy effectively reduced the risk of heart disease in women with no pre-existing heart disease. However, Dr. Abramson has dissected the guidelines and found an acknowledgement buried (on page 211 of the 284 page guidelines) indicating that the recommendation for women is not supported by any evidence: “clinical trials of LDL lowering generally are lacking for this category [i.e., women]….the rationale for therapy is based on extrapolation of benefit from men of similar condition.”

He also found that the statement, “aggressive LDL-lowering therapy is effective in reducing CHD [coronary heart disease in people over the age of 65] is also not backed by evidence in the nine clinical trials cited in the guidelines. In other words, the guidelines are not “evidence based“, they are merely the opinion of the designated “experts” who crafted them. And those experts were not unbiased: five of the 14 experts including the chair of the panel, had financial ties with statin drug manufacturers.  Four of these five, including the chair of the panel, disclosed relationships with all three manufacturers of the best-selling statins. Furthermore, according to the Center for Science in the Public Interest, several members of the panel had financial ties to the American Egg Board, the National Cattlemen’s Association and the National Dairy Promotion & Research Board. This may explain the lack of mention in the guidelines any recommendation to reduce the ingestion of eggs, beef, and dairy which are known to increase cholesterol. (Read also AHRP: Statin-Cholesterol Guidelines—Industry Influenced?)

Findings of NIH Antihypertensive / Lipid-Lowering Treatment to Prevent Heart Attack trial
As fate would have it, the findings of a major government-sponsored trial, Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT-LLT) were completed and published in JAMA in 2002. ALLHAT was a landmark 8-year hypertension trial involving 33,000 patients with hypertension who were at increased risk of heart disease. The number of men and women aged 55 and older was equally divided. Ten thousand of the patients were a subset in which the efficacy of the expanded use of statins was tested. The report was published in JAMA in 2002.

 “The study found that quadrupling the number of people on statins prevented no more heart disease, nor did it decrease the overall risk of death.  There was no benefit to increasing the number of patients taking statins beyond the community norm of the mid 1990s: not for people 55-64 or 65 or older, not for men or women, not for those with or without diabetes, not for those with or without heart disease, and among those without heart disease, not for those with LDL-cholesterol higher or lower than 130 mg/dL. The only group that derived any significant benefit from more statins were African Americans, who had fewer episodes of heart disease, but no fewer deaths.

…one would expect that the results ALLHAT-LLT – showing that increasing the number of Americans being treated with statins from 13 to 36 million might not be such a good idea – would have gotten a lot of attention.” (BIG PHARMA, 2013)

But the multiple ALLHAT findings posed a major threat to statin and blood pressure drug manufacturers by documenting that a cheap diuretic lowered blood pressure better than the biggest selling class of drugs; and by documenting that increased use of statins did not decrease the overall risk of death. As Ron Winslow wrote in The Wall Street Journal: “In a finding sure to shake up the $20 billion market for blood-pressure medicines, a 10-cents-a-pill diuretic proved superior to two of the pharmaceutical industry’s biggest selling classes of drugs…

Presentation of the ALLHAT findings was delayed; the findings were not presented at the November 2002 meeting of the American Heart Association. Manufacturers of these drugs were given an advance copy and adequate time to prepare their response. Few of the news media reported the findings – except for the Wall Street Journal; and most experts writing in the medical journals rejected the ALLHAT study findings which raised doubt about the validity of the cholesterol clinical practice guidelines.

Dr. Scott Grundy, the chair of the panel that wrote the 2001 and 2004 cholesterol guidelines, reported having received money from 10 drug companies when he chaired the update of the cholesterol-lowering guidelines in 2004. (NIH Heart, Lung, Blood, Institute (NHLBI), Cholesterol Guidelines, 2013) He explained to the Wall Street Journal, “You can have the experts involved, or you could have people who are purists and impartial judges, but you don’t have the expertise.” Dr. Grundy spun the actual findings, stating:

“Physicians might be tempted to conclude that this large study demonstrates that statins do not work; however, it is well known that they do. Rather, it appears that statins are less effective in the primary care setting in which they were used in ALLHAT-LLT. Statins have been proven efficacious in a wide array of primary and secondary prevention randomized, blinded, controlled trials. ALLHAT-LLT shows that the effectiveness may be limited in a setting that more closely mirrors clinical practice.”

But Dr. Robert M Califf (Duke University Medical Center), a member of the Data and Safety Monitoring Committee for ALLHAT, stated in an interview:

“I do think [the finding] raises an interesting question, because it’s basically an effectiveness trial, the kind of trial that we talk about a lot but hasn’t been done all that often. It does raise the question if, in the real world, you started out treating a bunch of people with pravastatin, how well they’re really going to do.” (ALLHAT Lipid-Lowering Trial Show No Benefit From Prevastatin, Medscape, 2002) (Read more here and here)

In 2004, the National Cholesterol Education Program of the National Heart, Lung, Blood Institute (NHLBI) lowered the threshold for initiating treatment with statins for men and women to a cholesterol level of 130 mg/dL and a 10-20% risk of coronary heart disease within 10 years. The updated guidelines were proclaimed “evidence based”, but like the 2001 guidelines, they were not substantiated by scientific evidence. The guidelines were published in the journal Circulation, 2004. The guidelines for women were updated in 2007.

Dr. Abramson published an article in The Lancet challenging the claim that the recommendations were “evidence based”:

the clinical trials of primary prevention for which data were available had shown that neither the overall risk of death nor the risk of serious illness was reduced by statin therapy…the primary prevention trials for which data were available included 10,990 women, and showed that statins provided no reduction in total coronary heart disease events.” (Are Lipid-Lowering Guidelines Evidence-Based? The Lancet, 2007)

In 2011, women got somewhat of a reprieve from aggressive statin intervention; it was no longer recommended to prescribe statins for women with less than a 20% risk of developing heart disease within the next 10 years. This changed recommendation was made without explanation or any announcement; it was noted in the fine print, lest attention be drawn and questions raised.

The same year, the Cochrane Heart Group updated its 2007 review of statin therapy for the prevention of cardiovascular disease which agreed with the US revised guidelines which did not recommend statins for people with less than a 20% risk of coronary heart disease, concluding:

“Only limited evidence showed that primary prevention with statins may be cost effective and improve patient quality of life. Caution should be taken in prescribing statins for primary prevention among people at low cardiovascular risk.” (Cochrane Systematic Reviews, 2011)

The integrity of clinical guidelines crafted by “experts” with deep financial ties to drug manufacturers is highly suspect
The editorial in JAMA accompanying  the 2001 guidelines was written by Dr. Richard Pasternak (Massachusetts General Hospital, Harvard Medical School, whose copious financial conflicts of interest  include: “has served as a speaker for or on the speakers bureau for Merck, Schering-Plough, Kos, Pfizer, and Bristol-Myers Squibb, Sanofi; has served as a consultant to or on the advisory board for Merck, Pfizer Health Solutions, AstraZeneca, Kos, Johnson & Johnson, and Bristol-Myers Squibb; and has received a research grant from Merck-Medco”

In 2008, the results of Harvard’s JUPITER study were published by the NEJM. The study tested the rationale for prescribing statins to prevent a cardiovascular event in healthy individuals. JUPITER involved 17,802 healthy men and women with low-density lipoprotein (LDL) cholesterol levels who were randomly prescribed 20 mg. of rosuvastatin daily. After a follow-up of one year and nine months, the study was stopped due to the claimed positive results in lowering myocardial infarction, stroke, or death from cardiovascular causes.

However, more patients treated with statins developed diabetes compared to those on placebo. New cases of diabetes occurred at a rate equal to 16 patients per 1,000 treated for five years. And in women the rate was 28 new cases for every 1,000 women. (S. Mora, RJ Glynn, et al. Circulation, 2010)

Eleven of the fourteen JUPITER investigators had copious financial ties to drug manufacturers. The chair, Dr. Paul Ridker is also listed as a co-inventor on patents that relate to the use of inflammatory biomarkers in cardiovascular disease, including the use of high-sensitivity C-reactive protein in the evaluation of patients’ risk of cardiovascular disease. (NEJM, 2008)

In 2012, The Lancet claimed statins benefit people at low risk of cardiovascular disease  Doctoring Data_Dr. Malcolm KendrickThe Lancet published a meta-analysis of the effect of statins in 27 randomized trials by the Oxford Cholesterol Treatment Trialists (CTT) Collaborations which concluded that statins will prevent 11 “major vascular events” for every 1,000 low risk adults treated for five years. The article claimed the benefit was 20 times greater than the risk of muscle toxicity or diabetes. The data show that the overall risk of death in people at low risk of cardiovascular disease is not significantly reduced by statins. The CTT authors calculate that 91 people need to be treated with a statin for five years in order to prevent one cardiovascular event. So, 90 people will have been treated with a statin for five years with absolutely no benefit because statins play no role in reducing any other serious illnesses that result in death, prolonged hospitalization, cancer or permanent disability.

The CTT authors relied on data about side-effects from industry clinical trials which have been shown during litigation procedures to understate – or more accurately, to conceal adverse effects. On the other hand, a study that examined population-based health statistics in the U.S. showed that painful muscle symptoms occurred in 53 out of every 1,000 patients treated with statins – 100 times more frequently than had been reported within the clinical trials in the Lancet meta-analysis.

The argument Dr. Abramson makes is that “reducing the risk of cardiovascular events is an important benefit only if this improves overall health at the same time.” He buttresses his argument by citing global public health statistics which show that while more Americans ingested statins than all others combined in 2013 – 13 million Americans out of a total of 25 million globally – they were undergoing more frequent angiograms to open up blocked coronary arteries. And the U.S. death rate from coronary heart disease is so high, the US ranks 25th. (OECD, Health at a Glance, 2011)

An editorial accompanied the CTT meta-analysis in the Lancet with the provocative title “Statins For All By the Age of 50 Years?” It declared that the CTT trial should “dissipate uncertainty about any potential serious adverse risks of statins…[and] provide reassurance for general practitioners to prescribe higher doses of statins to achieve greater benefit.” This blanket endorsement has the tone of a promo written by a hired professional PR firm such as pharmaceutical companies use.

The exaggerated CTT claims and endorsement by the Lancet led the Cochrane Review to radically revise its recommendations in 2013, stating: “Our previous conclusion urging caution in the use of statins in people at low risk of cardiovascular events is no longer tenable in light of the CTT Collaboration findings.” The Cochrane goes so far as to lend credibility to the implied editorial recommendation of treating most people “over the age of 50 with a statin.”

Patient outcomes in clinical trials are mostly unreported in published articles
It is noteworthy that in 2014, the author of the 2012 Lancet editorial, Professor Shah Ebrahim, after conducting a systematic meta-analysis of 90 studies each involving more than 1,000 patients acknowledged the absence of unbiased RCT adverse effects assessments:

Efficacy of statins has been extensively studied, with much less information reported on their unintended effects. Evidence from randomized controlled trials (RCTs) on unintended effects is often insufficient to support hypotheses generated from observational studies. We aimed to systematically assess unintended effects of statins from observational studies in general populations with comparison of the findings where possible with those derived from randomized trials.”

“Reporting of unintended effects in RCTs is not done consistently and failure to report such findings introduces bias into evaluations of the benefits and harms of treatments. Considerable adverse event data are collected in most RCTs but are not readily available to include in systematic reviews. Future research in this area will need to engage with pharmaceutical companies to obtain relevant data to enable unbiased assessments of the true levels of common unintended effects of statins.” (Systematic Review and Meta-Analysis, BioMed Central, 2014)

In 2014, an article co-authored by Dr. Ben Goldacre was widely publicized as claiming that “statins had no side effects.” Goldacre criticized his own study on his blog stating:

“the central flaw in our study… the side effects information we were able to work with, from trial publications, is likely to be incomplete: the trial reports varied in what side effects they reported, they often failed to describe their methods for spotting and reporting side effects very well, and companies may not be highly motivated to put a lot of side effects data into their academic papers..”

He goes on to criticize the World Health Organization’s side effects monitoring center in Uppsala, Sweden and the European Medicines Agency for withholding adverse effect information from researchers. He called this secrecy “silly and rather self-defeating.”

In an editorial in the BMJ (2014), Dr. Goldacre emphasized the fact that preventive medicine is “a new kind of medicine” requiring clarity in the form of “clean, clear data showing the risks and benefits of preventive treatments on real world outcomes.” He also emphasized that preventive medicine cannot be dictated [presumably by “expert” guidelines]; preventive medical interventions must be made as a discretionary choice that each patient makes and that doctors must respect a patient’s preference.

if there is any uncertainty at all about the risks and benefits of statins – and there is – then we have failed to competently implement the most basic principles of evidence based medicine. Statins are the single most commonly prescribed class of treatment in the developed world, taken by tens if not hundreds of millions of patients every day. That would be more than enough clinical experience to resolve any research questions, if we were competently identifying all outstanding uncertainties, and conducting well-designed trials to answer those questions in routine clinical care.

When we offer statins, or any preventive treatment, we are practicing a new kind of medicine, very different to the doctor treating a head injury in A&E. We are less like doctors, and more like a life insurance sales team: offering occasional benefits, many years from now…

this new kind of medicine needs perfect information. We need clean, clear data showing the risks and benefits of preventive treatments, on real world outcomes, beyond any reasonable doubt, at every level of risk, and for as many subgroups as possible. We need shared decision making products that are universally available, carefully validated, and seamlessly integrated into routine clinical care, to help all patients make their own truly informed decisions. Lastly, we need to recognise that different patients have different priorities: different to each other and, sometimes, very different to our own.”

BIG PHARMA 2013A fundamental issue that raises doubts about the integrity of evidence from company controlled clinical trials
Dr. Abramson points to the essential problem that confounds the integrity of the statins evidence; including the evidence presented in The Lancet. The only scientists who have access to the raw, patient-level data belong to the Cholesterol Treatment Trialists’ (CTT) Collaboration. CTT is part of the Oxford Clinical Trial Service, which is dependent on pharmaceutical money for its research: “industry funding helps to ensure that the trials are of sufficient size and scope to assess the safety and efficacy of treatments reliability…seeks reimbursement to the University of Oxford of the costs of travel and accommodation to participate in scientific meetings. ” (CTSU funding sources, 2014)

CTT indicates that the individual patient data “will be held in strict confidence and would not be released to others.” Thus, there is no possibility of an independent arm’s length peer review of CTT’s published meta-analysis of company trials that are kept secret. Dr. Abramson concluded:

“The evolution of cholesterol-lowering guidelines since 2001 provides an important example of just how far the pendulum has swung toward the interests of the drug companies…The bottom line is that practically all that we think we know about the efficacy and safety of statins has been brought to us by commercial interests that hold the actual data as proprietary secrets. Since we cannot verify commercial claims of efficacy and safety, healthy people should use statins with caution… Although the situation with statins seems singularly chaotic, the bad news is that it is not at all unique.

It is just the example du jour of the extent to which the primary function of medical information has become tipped toward serving commercial rather than public interest. Medical science will not best serve the public interest until its findings are completely transparent.” (John Abramson, MD, Pharmaceutical Journal, 2015)

*Dr. Abramson is a member of the Board of directors of the Alliance for Human Research Protection.

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