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Risk factors vs. risks: Who will develop cardiovascular disease -- and could a new polypill help prevent it?

Most people understand that conditions like hypertension, diabetes and elevated cholesterol are risk factors that lead to cardiovascular disease, primarily heart attacks and strokes. But you might be surprised to understand how poorly we use that knowledge in our quest to prevent such life-threatening events.  

Dr. Richard Grimm, a University of Minnesota preventive cardiologist and researcher, isn't surprised. As director of the Berman Center for Outcomes and Clinical Research in Minneapolis, he's directed the local arm of numerous national studies investigating different elements of cardiovascular disease. He understands the risk data, and he's long been perplexed at how we've chosen to apply it.

"Almost half of all heart attacks occur in people that don't have risk factors," Dr. Grimm explained. "They don't have risk factors, but they do have risks."

Risks but not risk factors? Try the Grimm Meter.

To see Grimm's point, you need to understand that risk factors are a clumsy, binary view of things. They promote a "yes" or "no," you-either-have-it-or-you-don't view of risk. Take hypertension for example, where the current upper limit of normal for systolic blood pressure (the top number in a blood pressure measurement) is 140. At that level, your neighbor would be considered hypertensive and worthy of medication at 146, while you'd be scot-free at 138.

Using risk factors in this way is an all-or-nothing proposition that flies in the face of what research tells us. As Grimm puts it, "the risks of cardiovascular disease imparted by elevated blood pressure or cholesterol are graded and continuous." Risk factors behave like an on/off light switch, but the risks associated with having a heart attack or stroke are more like a dimmer switch: As risks gradually increase, the likelihood of having an event increases.

If you can't put your head around all this, perhaps a Grimm Meter could help. It's a circular slide rule that uses specific risk-factor data to help patients calculate their individual cumulative risk. Working with the biostatistician Kenneth Svendsen, Grimm has used data from published cardiovascular disease trials to refine the device since its inception in the early 1980s. I used the Grimm Meter to create the following two patient scenarios.

Dr. Richard Grimm
Dr. Richard Grimm

A 50-year-old female has a high normal systolic blood pressure of 135. She has a low but normal HDL cholesterol of 45 (HDL is the "good" cholesterol and normal is >40); she has a high but normal "bad" cholesterol, with an LDL of 150 (<160 normal); and she doesn't smoke or have diabetes. Compare her to a 50-year-old male who has high blood pressure, with a systolic blood pressure of 150; a good HDL of 60 and a reasonably good LDL of 120; he smokes about 15 cigarettes a day but he's not diabetic.

So which one of these two is at the greatest risk of developing cardiovascular disease? The 50-year-old woman with no risk factors, or the 50-year-old man who smokes and has high blood pressure? Answer: They are at equal risk. Both have a 9 percent chance of dying of a stroke or heart attack before they reach age 70. Their risk of having a nonfatal cardiovascular event in the same time frame is 2-3 times that.

How can this be? The woman has multiple risks, but none of them reach the threshold for being termed an "abnormal risk factor;" and since we have a health-care system focused on abnormal single risk factors and not on cumulative risk, she wouldn't warrant treatment.

Who decides what 'normal' is?
The obvious question then is, "Who sets these risk factor thresholds, and how do they come up with the numbers?"

The "who" is generally a panel of experts made up of physicians, researchers and other health scientists. The "how" is not so easily answered. "For each of these risk factors that are on the Grimm Meter, the levels that we call 'normal' are basically totally arbitrary," Grimm explained, "and it's hard to go back into the medical literature and figure out where they came from."

He explains that physicians have been rather slow to pick up on the idea of risk factors in disease (look how long it took to clearly recognize the dangers of smoking). And when we did figure it out, the levels chosen to define "normal" were very cautious, a soft tentative punch, as if we weren't sure this thing was worth fighting.

Early risk-factor data on cardiovascular disease came from the likes of the Framingham Heart Study, which Grimm describes as "very famous; but as a study it was tiny by today's comparisons, and it included essentially no blacks and very few women." According to Grimm, it wasn't until the early 1980s that we began to get the bigger, more powerful studies that were needed.

"When we finally got a study like the 'MRFIT' — almost 13,000 men they've been following since 1973 — it was very clear that these risk factors are graded and continuous. If your blood pressure is 115 and you go to 135, which is still normotensive, you double your risk," Grimm explained.

As study data have trickled in, the established "normal" levels for blood pressure and cholesterol have been slowly lowered. At this point, we're not sure where the bottom is, but an article in the British Medical Journal titled "Risk Factor Thresholds: Their Existence Under Scrutiny" tried to make a guestimate.

Using data from studies of isolated groups of people who are still living a hunter-gatherer lifestyle, they found that at age 60, these people had a systolic blood pressure of 110, a total cholesterol of 125, and a body mass index of 22 (>25 is overweight). Less than 1 percent of current Western populations have blood pressures or cholesterol below that level, and less than 10 percent are thinner than these people. So we're nowhere close to bottoming out.

A more inclusive approach to preventing heart disease
One of the major implications of a system that is built to respond to risk factors and not to cumulative risk is that treatment and prevention are focused on the minority of people who are perceived to be at the highest risk for stroke or heart attack, or those who have already suffered one. There's a certain logic there — focusing our resources on those at the highest risk. But as Grimm points out, from an absolute numbers standpoint, many new heart attacks and strokes come from those at moderate risk; as an example, a group with half the risk of another group but with twice as many members will produce the same number of sick patients.

Under the current system, those at moderate risk often fly under the radar, until they either have an event or reach established risk factor thresholds. According to the National Health and Nutrition Examination Survey (NHANES), over half of those people in the United States with a greater than 7.5 percent risk of having a stroke or heart attack in the next five years (considered moderate) do not receive medications to lower their blood pressure or cholesterol. A better option might be to use treatment to keep them from developing disease, except that it is a huge group and that would cost a lot of money. Or would it? What if there were a single, affordable pill to help prevent cardiovascular disease?

A PILL, or rather, a Program to Improve Life and Longevity
Dr. Grimm is now beginning a local pilot for an international, multicenter study involving what is referred to as a "polypill," a single pill containing several medications. Titled the Program to Improve Life and Longevity (PILL), the polypill being investigated contains low doses of an aspirin, simvastatin (a cholesterol-lowering medication) and two blood pressure-lowering medications. The pilot will run 12 weeks and will monitor blood pressure, cholesterol and tolerability. None of these four medications are novel — they are among the most frequently prescribed drugs today — and so Grimm and his colleagues aren't anticipating any problems.

If all goes well with the pilot, a multimillion-dollar trial will likely follow, taking aim at treating those at above-average risk for cerebrovascular disease. It has been estimated that using such a combination pill could reduce heart attacks and strokes in that group by as much as 60-80 percent.

Regarding our current system, which treats only those at high risk, Grimm notes, "We can treat all of that group's risk factors perfectly, and get them down to normal level, but we just make a little dent in the disease incidence rates in the population because there are just not that many people who have high risk factors."

Can we afford the cure? And will we take it?
Now, more than ever, it's all about the money. Can we really afford to treat everyone in the moderate risk group? We can if it's as affordable as the PILL study's polypill.

"If it's marketed in the U.S., it might cost $50 a year," Grimm told me. "And that's kind of a high estimate." The pill is being manufactured in an FDA-approved facility in India, where a growing number of people are enjoying the incidental "fruits" of a Western lifestyle.

"India has a middle class of about 400 million people. It's bigger than the U.S. population," Grimm explained. "The most common cause of death in India now is cardiovascular disease. It was for years and years and years infectious disease. In India the polypill will cost a buck or two every month, so it really is feasible to do on a broad-scale basis."

The idea of a polypill has been around for years, but it's never gotten this far — that is, into a trial phase. One of the problems with any medication is that you have to take it to receive any benefit. The more pills you take, the harder it is to take them all. But with the polypill, compliance could be dramatically improved.

"The literature is pretty strong that if you take one pill once a day, compliance is going to be much better than if you take multiple pills once a day, or particularly if you have to take it more than once a day," Grimm explained.

"Part of the problem is patients remembering, but another big part of it is, you're taking four pills, which means you're responsible for getting four things renewed. And sometimes, the way our system works, you've got to go every month to get your pills, and it is not necessarily coordinated. So it's a big burden on the patient to be responsible for taking their drug, and getting their drug, and most people can't handle it very well," Grimm said. "I take three medications for my blood pressure and it is sort of hard for me," he admitted with a laugh.

If you're interested in being a part of the PILL study pilot, you can contact the Berman Center for Outcomes and Clinical Research by calling 612-341-7900 or emailing acamarena@bermancenter.org.

Dr. Craig Bowron is a Twin Cities internist and writer who reports on medical topics for MinnPost.

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Comments (2)

Does the low cost mean the polypill will be imported and sold in the U.S. without a U.S. drug company getting to patent it, advertise it to possible patients on TV and in magazines and newspapers, and price it at mega-bucks levels to pay for the advertising? (Good work.)

The Framington Heart study was essentially all "white" in the beginning but the majority of the original participants were women, contrary to what is written. This is very relevant to the "second hand smoke" debate because back in 1948 most men smoked and few women did. Also, most women didn't work out side the home so we have an good, long tern study of the effects of second hand smoke that is ignored by things like the Surgeon Generals report on second hand smoke. Framingham asked about these things.

Here is a breakdown of the "charter" 1948 participants.

Age 29-39 40-49 50-62 Totals
Men 835 779 722 2,336
Women 1,042 962 869 2,873
Totals 1,877 1,741 1,591 5,209

http://www.framinghamheartstudy.org/participants/original.html