Making it up on volume

A major medical paper on primary heart disease prevention admitted that cardiovascular disease risk factors have proven useless for predicting heart disease among our population and that reducing risks factors doesn’t translate into reduced clinical disease or fewer premature deaths.

But the solutions to this conundrum were the most unbelievable examples of ad-hoc reasoning.

The paper was the American Heart Association’s new Guidelines for Cardiovascular Disease Prevention in Women. It differed from its 2004 Guidelines in one significant way: women previously classified as low or intermediate risk are now all labeled as “at risk” and targeted for intervention. They arrived at this plan because virtually all heart disease occurs in women without “risk factors” and of low risk.

Instead of acknowledging what the medical literature has shown for decades — that these risk factors themselves are problematic and that relying on them to predict who will succumb to disease or premature death is insupportable — they took a unique twist.

The guidelines previously developed for women of “high risk” — “preventive” measures, including “heart-healthy” diets, physical activity, weight management; and pharmaceuticals to address health indices considered risk factors — have been made universal to all women. Their reasoning was that all women have a “high” lifetime risk for cardiovascular disease.

The point they neglect to say is that it’s because cardiovascular disease is associated with advanced aging and we’re all going to die eventually! Cardiovascular disease is the most common cause of death with aging. According to the March issue of American Family Physicians, using U.S. National Center for Health Statistics, a woman’s risk of dying in 10 years from a heart attack rises with age: from 0.4% at age 50, 1.4% at age 60, 5% at age 70, 15.3% at age 80, to 27.2% by age 90 among nonsmokers.

By comparison, the 10-year risk of dying from breast cancer is 1% at age 90. Among men, 10-year risks of dying from a heart attack are 3.2% at age 50, 8.4% at age 60, 9.3% at age 70, 19.6% at age 80 and 22.3% at age 90.

“Population-wide strategies are necessary to combat the pandemic of CVD in women,” the AHA wrote, “because individually tailored interventions alone are likely insufficient to maximally prevent and control CVD.”

Yes, it is reminiscent of that business joke of losing money on each individual sale, but hoping to make it up on volume.

Was this paper marketing or science? As we’ve already seen, there is no “pandemic of cardiovascular disease” and rates have been dropping steadily for more than half a century.

Never the less, they say these new primary prevention guidelines are necessary to save lives. Before we look at them more closely, let’s clarify what they mean by primary prevention. According to the AHA: “Primary prevention means the effort to modify risk factors or prevent their development with the aim of delaying or preventing new-onset coronary heart disease.” In contrast, “secondary prevention” is individual treatment efforts to reduce the recurrence of coronary events and reduce mortality among patients who already have heart disease.

The most commonly used measure to predict our 10-year risks of dying from heart disease has long been the Framingham Risk Score. This simple assessment tool is based on the popular risk factors such as cholesterol, smoking status, blood pressure, age and gender. The AHA guidelines also address other popular ones, such as body mass index, fasting glucose and depression. “Healthy lifestyle” interventions are recommended for everyone, and intensive Class I clinical management (drugs) are recommended for all women, even at low-risk, for management of blood pressure and cholesterol. For life.

Were these guidelines evidence-based? An examination of the studies the AHA used to support its new Guidelines were not nearly the slam dunk most healthcare professionals, and certainly most consumers, probably believe.

Since we’ve already examined at Junkfood Science, the shortfalls in the evidence surrounded several of the popular “risk factors,” such as BMI, salt-reduction and blood pressure management, let’s look more closely at another one of the biggies: serum lipid (“cholesterol”) levels. The clinical trials on the primary prevention of cardiovascular disease deaths by managing serum “cholesterol” levels that the AHA used as evidence, all involved prescription medications. Briefly, the studies were:

· 1978 Report from the Committee of Principal Investigators on clofibrate, only on men, that reported no mortality figures

· 1984 Lipid Research Clinical trial of cholestyramine, only on men, yet found mortality rates of 3.6% in the treatment group and 3.7% in the placebo — actual mortality difference of 0.1%

· 1993 Helsinki Heart Study trial of Gemfibrozil, also only on men, which found mortality of 2.5% among treatment group and 2.2% among placebo — actual mortality difference of 0.3%

· 1995 WOS-COP trial on pravastatin, also only on men, which found mortality of 3.2% in the treatment group and 4.1% among placebo — a mere 0.9% difference

What about women? Women have long presented a quandary for traditional heart disease risk factors because we generally have lower rates of heart disease than men, despite having higher levels of serum lipids (“cholesterol” levels), body fat, etc. Back in 1995, an article examining the health risks and higher death rates among people with low cholesterol levels had been published in the AHA journal, Circulation, which specifically noted concern about the exclusion of women in studies. It cautioned:

The dearth of information on the effects of low cholesterol and cholesterol lowering in women and children is one rationale for not supporting population-based efforts to reduce cholesterol levels.

Yet, it’s more than a decade later and none of the studies that the AHA used as evidence in their 2007 guidelines for women had been conducted only on women. A few had at least included women. Women were lumped together with men in these primary prevention trials:

· 1993 Prevastatin Multi-national study was conducted only on a high-risk population and reported no mortality figures

· 1994 Furberg study on Lovastatin reported no deaths among treatment group and 1.1% among placebo group; but heart attacks were identical at 1.1%

· 1995 Downs study of Lovastatin reported mortality among treatment group of 0.5% and among placebo of 0.7% — a mortality difference of 0.2%

· 2002 ALLHAT trial of pravastatin reported overall deaths of 12.2% among treatment group and 12.4% in the control — actual mortality difference of 0.2%

· 2003 report on the ASCOT-LL study on atorvastatin on hypertensive patients reported mortalities of 3.6% among treatment group and 4.1% among placebo group — 0.5% difference

· 2005 ASCOT-LL study on atorvastatin for type 2 diabetics with hypertension reported 17 deaths among the 289 treated (0.058%) and 10 among the 311 controls (0.03%) — a 0.02% difference.

These findings may come as a surprise to both men and women in the general public, unaware of how small the actual benefits of even intense medical management are, and of the controversy that’s been going on within the medical community for many years. Dr. Donald L. Vine, M.D., a cardiologist and professor at the University of Kansas School of Medicine in Wichita, reviewed a number of those earlier studies on the AHA evidence list. In a strong editorial in a 1994 issue of the American Family Physician, he described how he was perplexed by the conflicting information in the Helsinki and Lipid Research Clinic studies because their abstracts “described a greater degree of benefit than that calculated from the methods and results.” He explained that consumers are frequently misled by reports based on relative risks — hearing of a 34% reduction in risk for death sounds impressive — when the actual numbers are much smaller.

The literature gives the impression of greater benefits of cholesterol reduction than there really are, he said, because “studies with favorable outcomes are cited nearly six times as frequently as studies with unfavorable outcomes and because the results are often reported in terms of relative risk reduction, which amplifies the appearance of benefit.” He added:

The combined data from nine randomized primary prevention trials (a total of 96,781 males) point to a -0.07 percent difference in the risk of death from any cause between control and treatment groups.... While one might argue that a longer period of observation would improve outcomes..., similar calculations from four trials with an average follow-up of 12 years ...results in a difference in all-cause mortality of only 0.5 percent.

We should realize that, after primary prevention trials involving nearly 100,000 participants, the debate about the value of cholesterol lowering would be over if the differences between treatment and control groups were sizable. The literature on the subject should be read with skepticism.

Yet, as the 2007 AHA evidence review shows, even more than a decade later, the results aren’t much different. Nor is the sentiment among many doctors. As Dr. Vine concluded:

In my opinion, the importance of the serum cholesterol level as a modifiable risk factor for coronary artery disease has been overemphasized and overmarketed. Asymptomatic men with no evidence of coronary heart disease should be advised that the demonstrated benefits of cholesterol reduction are modest at best....Finally, drug therapy, which is expensive and may carry unanticipated risks, should probably be reserved for those individuals with substantially elevated cholesterol levels, familial hyperlipidemia or demonstrated coronary heart disease.

Interestingly, one of the biggest clinical studies probably ever conducted in the world to examine popular cardiac risk factors and the deaths was not included among the AHA evidence. This study was the Vorarlberg Health Monitoring and Promotion Programme, led by Dr. Hanno Ulmera at the Agency for Social and Preventive Medicine at Bregenz, Austria. It was an incredible project involving 149,600 men and women followed for over 15 years and involved 454,448 medical examinations which included blood pressures, BMI measurements, fasting cholesterol panels and blood glucose levels. After age 50, when most heart disease deaths occur, only a borderline association between cholesterol and CVD mortality was found in men, while in women, low cholesterols were significantly associated with higher all-cause mortality. “The low cholesterol effect occurs even among younger respondents, contradicting the previous assessments among cohorts of older people that this is a proxy or marker for frailty occurring with age,” they concluded.

A study just published in the March issue of the Journal of the American Medical Association actually tested the AHA’s proposals, among men and women. The METEOR Trial was a randomized, double-blind, placebo-controlled study conducted across 61 primary care centers in the U.S. and Europe. It examined 984 adults, with an average age of 57, who were all considered to have low risk factors for heart disease based on the Framingham Risk Score. Some received the statin, rosuvastatin, and the rest a placebo and after two years the progression of atherosclerosis was assessed by carotid intima-media thicknesses, measured by ultrasound. While the statin reduced LDL-cholesterol by 49% and resulted in small reductions in intima-media thickness, there was no regression of atherosclerosis or change in clinical outcomes.

We could be tempted to find a way to explain away the findings. And, indeed, this study had several weaknesses; and it is reasonable to question if greater benefits might be seen down the road or that perhaps intima-media thickness evaluations might not be good measures of atherosclerosis. A recent study published in Stroke, for example, evaluated the relationship between plaque formation and these ultrasound measurements in 319 healthy adults from ages 21 to 105 and found “intima-media thickness is a physiological effect of aging...and is distinct from pathological plaque formation.” Given this question, it makes those null results in actual clinical outcomes especially important.

An editorial in the same issue of JAMA reporting the METEOR trial was written by Dr. Michael S. Lauer, M.D. of the Cleveland Clinic. He said that clinical guidelines for primary heart disease prevention for asymptomatic adults have long focused on assessing an individual’s risk and applying lifestyle interventions and pharmacological strategies, with aggressive interventions reserved to high-risk patients. But, he wrote, “the major, yet highly underappreciated, problem with this high-risk strategy is that it has a relatively minor effect on overall population incidence of disease.” Most disease is found in low-risk people with relatively “normal” levels of cholesterol or blood pressure, he noted. And by far, most Americans are actually of low risk:

According to recent National Health and Nutrition Examination Survey data, among healthy adults aged 20 to 79 years, 85% had low-risk Framingham scores while only 2% had high-risk scores.

In other words, these risk factors aren't very good measures and we give them more credence than the evidence can support. That doesn't mean we should run screaming into the hills, thinking we're all going die and are all at risk, but that the evidence indicates that our obsession with these popular risk factors and numbers is not especially helpful, healthful or necessary for virtually all of us.

While Dr. Lauer described proposals to institute population-wide strategies outside of traditional medical care, such as mass screenings, smoking bans, trans-fat bans, and physical activity initiatives, he noted that the effectiveness of community and life-style interventions haven’t worked well. He also questioned the use of surrogate end points, such as intima-media thickness measurements, in primary prevention trials as they’ve been difficult to demonstrate a link to actual clinical outcomes. He acknowledged that no randomized trial to date has been able to show this statin reduces actual clinical events (heart attacks, deaths, etc.).

While it’s become popular to believe that certain health indices (BMI, blood “cholesterol,” blood sugar, or blood pressure) and lifestyles can predict who will succumb to disease or premature death, it’s not supported in the medical literature. As Dr. P.K. Shah, director of cardiology at Cedars-Sinai Medical Center explained to the Los Angeles Times on February 28, 2005, people with risk factors don’t all have a heart attack. “Our traditional risk factors are very weak overall predictors of future risk.”

Another popular misconception is that cholesterol in our blood is something to fear and less is always best. In fact, almost every system in our body actually needs it and if we don’t eat enough of it, our livers will just make more. Our brain synapses are mostly made of cholesterol, our body needs cholesterol to make Vitamin D, all our cells need it for structural integrity, it’s critical in bile to digest foods, and it’s essential for most of our sex hormones. It's not all bad.

Also little known, is that there are countless “paradoxes” to the significance of cholesterol and other risk factors in the development of heart disease. The World Health Organization’s MONICA project, which is an impressive 10-year study that measured cardiovascular disease mortality and disease incidences and risk factors among 10 million people in 21 countries, was also not included in the AHA evidence review. This study data continues to reveal no statistical connections between reductions in standard risk factors (obesity, smoking, blood pressure or cholesterol levels) and heart disease. A report in the International Journal of Epidemiology, found that there was “a large variability in the risk factor patterns among the MONICA populations.” The blood pressures and serum lipid levels, and levels of medications, for example, are all over the place. As Dr. Caroline Morrison, on one of the investigators said:

Changing rates of coronary heart disease in different populations did not appear to relate at all well to the change in the standard risk factors. This will be a big surprise for many people.

You’ll also find entire populations where women have higher rates of heart disease than men, so it shouldn’t be surprising that even the popular belief that female hormones are somehow protective has never been able to be confirmed in a study. In fact, the evidence against it has only grown since 1963, when a meticulously-conducted clinical study by Cornell University researchers was published in Circulation. It found no difference in arteriosclerotic heart disease among women who’d had their ovaries removed during a hysterectomy and those who hadn’t, concluding it was something apart from ovarian function responsible for the relative freedom from coronary heart disease in women.

Dr. Elizabeth Barrett-Connor, M.D., from the Department of Family and Preventive Medicine at the University of California, San Diego, spoke on coronary heart disease in women at the 1995 Ancel Keys lecture series, reporting:

For years it was thought that the excess male mortality was explained by unhealthy behaviors that were more socially acceptable for men than women. These behaviors might include cigarette smoking, heavy alcohol use, eating more red meat and fewer fruits and vegetables, and exposure to physical hazards. The usual view was that differences in behavior were more important determinants of the higher male mortality. More recent studies, [however, have shown that] risk factors, including lifestyle, lipids, blood pressure and the metabolic syndrome, do not explain the sex difference in CHD.

Nor do they explain heart disease and mortality among any population. The evidence for the lifestyle and “healthy eating” recommendations in the AHA guidelines were so lacking, that a separate post will be devoted to them.

Today’s health risk-frenzied environment promotes the idea that people are responsible (and to blame) for their health problems and have significant control over their health indices. But the simple fact is, such beliefs, including the belief in an ideal way of eating, are far out of proportion to the evidence. Attempting to put the influence of lifestyle factors on health into more reasoned perspectives, New England Journal of Medicine editors, Drs. Jerome Kassirer and Marcia Angell wrote:

Although we would all like to believe that changes in diet or lifestyle can greatly improve our health, the likelihood is that, with few exceptions such as smoking cessation, many if not most such changes will produce only small effects. And the effects may not be consistent. A diet that is harmful to one person may be consumed with impunity by others.

Which brings us to wonder if there is any evidence in support of the AHA’s population-wide efforts at risk factor interventions to prevent cardiovascular disease. For that, we can turn to the latest Cochrane review of 39 clinical trials conducted in multiple countries over the course of three decades, just updated in August 18, 2006. According to its authors:

In many countries, there is enthusiasm for “Healthy Heart Programmes” that use counseling and educational methods to encourage people to reduce their risks for developing heart disease. These risk factors include high cholesterol, excessive salt intake, high blood pressure, excess weight, a high-fat diet, smoking, diabetes, and a sedentary lifestyle. This updated review of all relevant studies found that the approach of trying to reduce more than one risk factor - multiple risk factor intervention - advocated by these Programmes do result in small reductions in blood pressure, cholesterol, salt intake, weight loss, etc. Contrary to expectations, these lifestyle changes had little or no impact on the risk of heart attack or death...

Recent trials examining risk factor changes have cast considerable doubt on the effectiveness of these multiple risk factor interventions....The pooled effects suggest multiple risk factor intervention has no effect on mortality....

Risk factor changes were relatively modest, were related to the amount of pharmacological treatment used, and in some cases may have been over-estimated because of regression to the mean effects, lack of intention to treat analyses, habituation to blood pressure measurement, and use of self-reports of smoking. Interventions using personal or family counselling and education with or without pharmacological treatments appear to be more effective at achieving risk factor reduction and consequent reductions in mortality in high risk hypertensive populations. [However], the evidence suggests that such interventions have limited utility in the general population.

© 2007 Sandy Szwarc

Addendum: Since this post looking at the American Heart Association's guidelines on preventive health for women, an interesting debate has been raging at the British Medical Journal on the use of statins in women. The letter by Dr. Malcolm Kendrick brought up additional arguments that may be of interest to women who might be considering statins for "high" cholesterol. He writes:

As no other cholesterol lowering drug has been shown to improve survival, this discussion is effectively about the use of statins. To date, none of the large trials of secondary prevention with statins has shown a reduction in overall mortality in women. Perhaps more critically, the primary prevention trials have shown neither an overall mortality benefit, nor even a reduction in cardiovascular end points in women. This raises the important question whether women should be prescribed statins at all. I believe that the answer is clearly no....

The Scandinavian simvastatin survival study found the biggest effects of all statin trials—in men. However, what is less publicised is that, overall, three more women died in the statin arm than in the placebo arm. The more recent heart protection study was hailed as a major success for men and women, but despite the hype there was no effect on overall mortality in women.

In the studies of primary prevention neither total mortality nor serious adverse events have been reduced. A meta-analysis published in the Lancet found that statins even failed to reduce coronary heart disease events in women. Of greater concern is that a further meta-analysis of statins in primary prevention suggested that overall mortality may actually be increased by 1% over 10 years (in both men and women).