Thursday, March 06, 2008


The headline on the article below is misleading. What it refers to is the controversial WHI study -- in which a clinical trial was stopped after old ladies on HRT pills seemed to be getting more cancer. Subsequent analyses, however concluded that the panic was unwarranted. So the claim that cancer risk "continues" is ill-informed. Any cancer risk shown in the original study was vanishingly small. See here and here for instance.

The panic reaction did however set the scene for another interesting study -- of what happens when women go off HRT. Are women who once took HRT more at risk than those on placebo? It was found that such women were at NO greater risk of heart events but did get more breast cancer (3.5% of the HRT group got cancer versus 2.7% for the non-HRT group). Clearly, however, the degree of risk was small in any case and the elevation of risk would be unlikely to be of much concern to most women. Taking ANY drug entails some risk of side effects and it is the balance between benefit and harm that rational users have to consider.

Of greater interest was the study of what happens when you consider ALL the illnesses that the old ladies concerned got. HRT therapy has some apparent favourable impacts on disease as well as adverse impacts. It was reported that the difference in disease incidence overall was quite minute (2.9% versus 2.4%). Once again, then, we see quite unjustified panic. Popular article followed by journal abstract below

Cancer risk continues even after women stop hormone treatment

Hormone replacement therapy continues to increase the risk of cancer even after a woman stops taking it, a study has shown. Three years after treatment ceased, the risk of breast cancer remained 27 per cent higher while risks of any type of cancer were 24 per cent higher. The findings, published in the Journal of the American Medical Association, imply that cancer risks persist, while other health risks such as blood clots and strokes - which are elevated while the women were taking the pills - returned to normal.

The results come from a follow-up to the Women's Health Initiative study, which gave warning in 2002 of cancer risks while taking HRT. After those findings were published and backed by results from the Million Women Study in 2003, about half the two million British women who had been taking HRT stopped. More recently, the health initiative study has been criticised for failing to break down the results by age. Among women in their fifties, defenders of HRT said, the risks were much smaller.

The new study, led by Gerardo Heiss, of the University of North Carolina, follows 15,730 women originally included in the trial, with an average age of 63. All had been randomised to take either the combined HRT pill (oestrogen plus progestagen, called progestin in the US) or a placebo.

In 2002, when researchers discovered an increased risk of breast cancer and heart and artery disease in women assigned to HRT, the trial was terminated. All the women were advised to stop taking the pills. The study looks at what happened in the following three years, up to 2005. At the end of that time the numbers of heart attacks, strokes and blood clots in women from both the active and placebo treatment groups were similar, showing that the risk of cardio-vascular disease had fallen substantially for former HRT users. While taking the treatment, the women had experienced a 29 per cent increased risk of heart attacks, a 41 per cent increased risk of strokes and nearly twice the normal risk of serious blood clots. These returned to normal after stopping.

But the increased risk of breast cancer remained at about the same level. During the follow-up study there were 63 more diagnoses of cancer among former HRT users than among women who did not have the treatment, or three per 1,000 participants per year. Marcia Stefanick, one of the study authors, from Stanford University, California, said: "The continued increased risk of breast cancer clearly plays a role in the increased overall risk of cancer, years after stopping long-term oestrogen plus progestin therapy, and it is important that we continue to follow these women." Leslie Ford, from the US National Institutes of Health, which funded the Women's Health Initiative, said: "The hormones' effects on breast cancer appear to linger. These findings reinforce the importance of women getting regular breast exams and mammograms even after they stop hormone therapy."

A summary of risks and benefits, called the "global index", was included in the results and covered outcomes for heart disease, invasive breast cancer, stroke, lung blood clots, cancer of the womb lining, bowel cancer, hip fracture and death. This overall measure showed an increased risk of 12 per cent for women taking HRT, which did not change after treatment stopped.

Michael Lauer, director of the National Heart Lung and Blood Institute at the US National Institutes of Health, said: "This study provides further evidence that five years of combination hormone therapy is harmful. All the accumulated risks do not simply disappear."

The advice from drug regulators in Britain is that HRT should be used for the control of symptoms of the menopause at the minimum effective dose and for the shortest possible time. That maximises the benefit and reduces the risks, since the evidence is that most of the damaging effects of HRT occur after the age of 60. In particular, HRT in younger women appears to cut heart attacks rather than increase them.

The new study does not attempt to break down the results by age so it is impossible to tell whether the persistent cancer risk is age-related. In the US, some researchers have linked a rapid fall in breast-cancer rates of 6.3 per cent in 2003 to the abandonment of HRT by so many women. The new trial fails to corroborate this claim because it contained too few women to detect a change of this order. Further follow-up was needed, the authors said.


Health Risks and Benefits 3 Years After Stopping Randomized Treatment With Estrogen and Progestin

By Gerardo Heiss et al.

Context: The Women's Health Initiative (WHI) trial of estrogen plus progestin vs placebo was stopped early, after a mean 5.6 years of follow-up, because the overall health risks of hormone therapy exceeded its benefits.

Objective: To report health outcomes at 3 years (mean 2.4 years of follow-up) after the intervention was stopped.

Design, Setting, and Participants: The intervention phase was a double-blind, placebo-controlled, randomized trial of conjugated equine estrogens (CEE) 0.625 mg daily plus medroxyprogesterone acetate (MPA) 2.5 mg daily, in 16 608 women aged 50 through 79 years, recruited by 40 centers from 1993 to 1998. The postintervention phase commenced July 8, 2002, and included 15,730 women.

Main Outcome Measures: Semi-annual monitoring and outcomes ascertainment continued per trial protocol. The primary end points were coronary heart disease and invasive breast cancer. A global index summarizing the balance of risks and benefits included the 2 primary end points plus stroke, pulmonary embolism, endometrial cancer, colorectal cancer, hip fracture, and death due to other causes.

Results: The risk of cardiovascular events after the intervention was comparable by initial randomized assignments, 1.97% (annualized rate) in the CEE plus MPA (343 events) and 1.91% in the placebo group (323 events). A greater risk of malignancies occurred in the CEE plus MPA than in the placebo group (1.56% [n = 281] vs 1.26% [n = 218]; hazard ratio [HR], 1.24; 95% confidence interval [CI], 1.04-1.48). More breast cancers were diagnosed in women who had been randomly assigned to receive CEE plus MPA vs placebo (0.42% [n = 79] vs 0.33% [n = 60]; HR, 1.27; 95% CI, 0.91-1.78) with a modest trend toward a lower HR during the follow-up after the intervention. All-cause mortality was somewhat higher in the CEE plus MPA than in the placebo group (1.20% [n = 233] vs 1.06% [n = 196]; HR, 1.15; 95% CI, 0.95-1.39). The global index of risks and benefits was unchanged from randomization through March 31, 2005 (HR, 1.12; 95% CI, 1.03-1.21), indicating that the risks of CEE plus MPA exceed the benefits for chronic disease prevention.

Conclusions: The increased cardiovascular risks in the women assigned to CEE plus MPA during the intervention period were not observed after the intervention. A greater risk of fatal and nonfatal malignancies occurred after the intervention in the CEE plus MPA group and the global risk index was 12% higher in women randomly assigned to receive CEE plus MPA compared with placebo.

JAMA. 2008;299(9):1036-1045


I commented recently on the inconclusive study of Prozac and similar drugs which showed that in some groups the drugs helped a lot but in others the drugs seemed to help not at all. I concluded that the real challenge of the finding lay in sorting out which patients would be in the benefited group.

The study below gets an opportunistic boost off that finding. "If the pills don't work, what does?" is their question. It is however a most incompetent study with no placebo group so should be disregarded. One might remark in fact that the apparent benefits reported for psychological therapy were rather what one would expect from a placebo effect. Popular article followed by journal abstract below

Depressed teenagers whose medication is not working should switch medications and start cognitive behavioural therapy (CBT), a specific type of psychotherapy, according to a new study in the Journal of the American Medical Association. The study involved 334 patients with major depressive disorder, aged 12 to 18 years. All of the participants had taken an antidepressant called an SSRI (selective serotonin re-uptake inhibitor) for two months, with no improvement in symptoms. For the next 12 weeks, they were divided into four groups. The first group switched to a different SSRI (paroxetine, citalopram or fluoxetine); the second group switched to a different SSRI and were given CBT, while the third group switched to venlafaxine -- a different type of antidepressant called an SNRI (serotonin and noradrenaline reuptake inhibitor) -- and the fourth group switched to venlafaxine and were also given CBT. Of those who switched to a combination of medication and CBT, 55 per cent showed improvement, regardless of the drug type. Only 41 per cent of those who simply switched medication showed an improvement in symptoms after 12 weeks.


Switching to Another SSRI or to Venlafaxine With or Without Cognitive Behavioral Therapy for Adolescents With SSRI-Resistant Depression

By David Brent et al.

Context: Only about 60% of adolescents with depression will show an adequate clinical response to an initial treatment trial with a selective serotonin reuptake inhibitor (SSRI). There are no data to guide clinicians on subsequent treatment strategy.

Objective: To evaluate the relative efficacy of 4 treatment strategies in adolescents who continued to have depression despite adequate initial treatment with an SSRI.

Design, Setting, and Participants: Randomized controlled trial of a clinical sample of 334 patients aged 12 to 18 years with a primary diagnosis of major depressive disorder that had not responded to a 2-month initial treatment with an SSRI, conducted at 6 US academic and community clinics from 2000-2006.

Interventions Twelve weeks of: (1) switch to a second, different SSRI (paroxetine, citalopram, or fluoxetine, 20-40 mg); (2) switch to a different SSRI plus cognitive behavioral therapy; (3) switch to venlafaxine (150-225 mg); or (4) switch to venlafaxine plus cognitive behavioral therapy.

Main Outcome Measures: Clinical Global Impressions-Improvement score of 2 or less (much or very much improved) and a decrease of at least 50% in the Children's Depression Rating Scale-Revised (CDRS-R); and change in CDRS-R over time.

Results: Cognitive behavioral therapy plus a switch to either medication regimen showed a higher response rate (54.8%; 95% confidence interval [CI], 47%-62%) than a medication switch alone (40.5%; 95% CI, 33%-48%; P = .009), but there was no difference in response rate between venlafaxine and a second SSRI (48.2%; 95% CI, 41%-56% vs 47.0%; 95% CI, 40%-55%; P = .83). There were no differential treatment effects on change in the CDRS-R, self-rated depressive symptoms, suicidal ideation, or on the rate of harm-related or any other adverse events. There was a greater increase in diastolic blood pressure and pulse and more frequent occurrence of skin problems during venlafaxine than SSRI treatment.

Conclusions: For adolescents with depression not responding to an adequate initial treatment with an SSRI, the combination of cognitive behavioral therapy and a switch to another antidepressant resulted in a higher rate of clinical response than did a medication switch alone. However, a switch to another SSRI was just as efficacious as a switch to venlafaxine and resulted in fewer adverse effects.

JAMA. 2008;299(8):901-913.


Just some problems with the "Obesity" war:

1). It tries to impose behavior change on everybody -- when most of those targeted are not obese and hence have no reason to change their behaviour. It is a form of punishing the innocent and the guilty alike. (It is also typical of Leftist thinking: Scorning the individual and capable of dealing with large groups only).

2). The longevity research all leads to the conclusion that it is people of MIDDLING weight who live longest -- not slim people. So the "epidemic" of obesity is in fact largely an "epidemic" of living longer.

3). It is total calorie intake that makes you fat -- not where you get your calories. Policies that attack only the source of the calories (e.g. "junk food") without addressing total calorie intake are hence pissing into the wind. People involuntarily deprived of their preferred calorie intake from one source are highly likely to seek and find their calories elsewhere.

4). So-called junk food is perfectly nutritious. A big Mac meal comprises meat, bread, salad and potatoes -- which is a mainstream Western diet. If that is bad then we are all in big trouble.

5). Food warriors demonize salt and fat. But we need a daily salt intake to counter salt-loss through perspiration and the research shows that people on salt-restricted diets die SOONER. And Eskimos eat huge amounts of fat with no apparent ill-effects. And the average home-cooked roast dinner has LOTS of fat. Will we ban roast dinners?

6). The foods restricted are often no more calorific than those permitted -- such as milk and fruit-juice drinks.

7). Tendency to weight is mostly genetic and is therefore not readily susceptible to voluntary behaviour change.

8). And when are we going to ban cheese? Cheese is a concentrated calorie bomb and has lots of that wicked animal fat in it too. Wouldn't we all be better off without it? And what about butter and margarine? They are just about pure fat. Surely they should be treated as contraband in kids' lunchboxes! [/sarcasm].

9). And how odd it is that we never hear of the huge American study which showed that women who eat lots of veggies have an INCREASED risk of stomach cancer? So the official recommendation to eat five lots of veggies every day might just be creating lots of cancer for the future! It's as plausible (i.e. not very) as all the other dietary "wisdom" we read about fat etc.

10). And will "this generation of Western children be the first in history to lead shorter lives than their parents did"? This is another anti-fat scare that emanates from a much-cited editorial in a prominent medical journal that said so. Yet this editorial offered no statistical basis for its opinion -- an opinion that flies directly in the face of the available evidence.

Even statistical correlations far stronger than anything found in medical research may disappear if more data is used. A remarkable example from Sociology:
"The modern literature on hate crimes began with a remarkable 1933 book by Arthur Raper titled The Tragedy of Lynching. Raper assembled data on the number of lynchings each year in the South and on the price of an acre's yield of cotton. He calculated the correlation coefficient between the two series at -0.532. In other words, when the economy was doing well, the number of lynchings was lower.... In 2001, Donald Green, Laurence McFalls, and Jennifer Smith published a paper that demolished the alleged connection between economic conditions and lynchings in Raper's data. Raper had the misfortune of stopping his analysis in 1929. After the Great Depression hit, the price of cotton plummeted and economic conditions deteriorated, yet lynchings continued to fall. The correlation disappeared altogether when more years of data were added."
So we must be sure to base our conclusions on ALL the data. But in medical research, data selectivity and the "overlooking" of discordant research findings is epidemic.

"What we should be doing is monitoring children from birth so we can detect any deviations from the norm at an early stage and action can be taken". Who said that? Joe Stalin? Adolf Hitler? Orwell's "Big Brother"? The Spanish Inquisition? Generalissimo Francisco Franco Bahamonde? None of those. It was Dr Colin Waine, chairman of Britain's National Obesity Forum. What a fine fellow!


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