Heart disease - the 7.5% solution?

Statins are in the news again, and not just because of the new PCSK9-based drugs, at least one of which is likely to be approved by the FDA this week, probably for a small class of at-risk patients.  These drugs will drive LDL cholesterol levels through the floor, while generating an estimated 17.8 billion for pharma by the year 2023 (and that's before we even know whether they will reduce risk of heart attack and stroke).

No, this is about your run-of-the-mill class of LDL-lowering statins.  In late 2013, the American Heart Association and the American College of Cardiology recommended new guidelines for determining who should be on statins.

• anyone who has cardiovascular disease, including angina (chest pain with exercise or stress), a previous heart attack or stroke, or other related conditions

• anyone with a very high level of harmful LDL cholesterol (generally an LDL above greater than 190 milligrams per deciliter of blood [mg/dL])

• anyone with diabetes between the ages of 40 and 75 years

• anyone with a greater than 7.5% chance of having a heart attack or stroke or developing other form of cardiovascular disease in the next 10 years.

Risk score is based on the ASCVD calculator, which uses basic data (age, sex, total cholesterol, HDL cholesterol, systolic blood pressure, and smoking and diabetes status) to calculate risk.  Unlike the previous Adult Treatment Panel III (ATP III) guidelines which were based on a target LDL level and risk factors determined by the long-term Framingham heart disease study (using the Framingham Risk Calculator), these new guidelines were based on a risk profile.  With these new guidelines, it was thought that about 13 million additional Americans would benefit from statins, for a total of a third of all Americans.

A study published in the Journal of the American Medical Association last week asks whether these guidelines were better at identifying at-risk individuals than the old ATP III guidelines.  The prospective study followed up 2435 people from the Framingham study who had never taken statins.  Based on the ATP III guidelines, 14% would have been 'eligible' compared with 39%, based on the 2013 guidelines.

The median follow-up was 9.4 (interquartile range, 8.1-10.1) years. There were a total of 74 (3.0%) incident CVD events (40 nonfatal myocardial infarctions, 31 nonfatal strokes, and 3 with fatal CHD) and 43 (1.8%) incident CHD events (40 nonfatal myocardial infarctions and 3 with fatal CHD).

Among those eligible for statin treatment by the ATP III guidelines, 6.9% (24/348) developed incident CVD compared with 2.4% (50/2087) among noneligible participants (HR, 3.1; 95% CI, 1.9-5.0; P less than .001). Applying the ACC/AHA guidelines, among those eligible for statin treatment, 6.3% (59/941) developed incident CVD compared with only 1.0% (15/1494) among those not eligible (HR, 6.8; 95% CI, 3.8-11.9; P less than .001). Therefore, the HR of having incident CVD among statin-eligible vs noneligible participants was significantly higher when applying the ACC/AHA guidelines’ statin eligibility criteria compared with the ATP III guidelines (P less than .001).

That is, according to this study, the 2013 ACC/AHA guidelines identified more people at risk of heart disease than the ATP III guidelines.  That's presumably progress in understanding heart disease risk, and so a good thing. (Does anyone else find the use of the word 'eligible' odd, though?  Like statins are a reward for passing the risk threshold?)

But why don't they ask about family history?  That is one of the most useful bits of data a physician can have about a patient's risk of heart disease (and other things).  Is it too cynical to suggest that acknowledging its usefulness might diminish the importance of what has been learned from the Framingham study?

Less cynically, one reason, though we don't know if the various investigators considered it in this way, is that family history integrates all factors, including those that are being specifically measured (like blood pressure, LDL levels, and so on). Whether they are genetic or environmental, they went into determining whether the relative had heart disease.  So counting family history and LDL, or for that matter, weight and BMI, also not included, may be redundant to an unknown extent.  For risk factors, this would perhaps inflate the apparent risk, but for protective factors the opposite.  But family history is debatably the best single factor, perhaps as important as all the test-battery factors.  At least, it's important to consider why that alone, or that somehow corrected for redundancy, should be a part of all of this.

So, apparently we don't know more about the causes of ASCVD now than we did before 2013, we're just evaluating what we know differently.  So, assuming that statins really do reduce risk of ASCVD, that more people are 'eligible' is thought to be a good thing.  Though, as the JAMA commentary on this article notes in urging increased treatment with statins, "Although a 10-year ASCVD risk threshold of 7.5% or higher might initially seem to be a low threshold, many, indeed most, CVD events occur among the low-risk members of the population."

Wait!  "Low-risk" is defined by us, based on what we know about heart disease!  Our understanding is clearly wrong if all these 'low-risk' people are really high-risk!  Not to mention that there's clearly a huge false-positive pool if a risk estimate of 7.5 out of 100 makes a person eligible for statins!  That means that 92.5 of those 100 people are taking statins even though they weren't going to have a stroke or heart attack.  And, all this means, at least to me, that we really don't understand what causes heart attacks or stroke. The Framingham study identified cholesterol, particularly LDL, as a risk factor, but we're not really sure why, and we don't know what levels are in fact most risky, and people with low LDL can have heart attacks, too.  Statins may or may not work by reducing LDL cholesterol, and lower LDL cholesterol may or may not reduce risk.

And, statins can have serious side effects -- physical as well as the cost burden.  So, if of 100 people taking statins a large majority weren't going to have heart attacks anyway, statins are causing a lot of unnecessary side effects without preventing disease.  Though, to be fair, physicians can't predict the future, and must do their best with the information they have.  They don't know who will or won't have a heart attack, because epidemiology hasn't given them enough information.  They've got to treat people with 7.5% risk as if they are at 100% risk of disease.

So, it's not physicians who are failing here, it's epidemiologists.  But I'll even be fair to epidemiologists -- it's the methods, based on population data and probability (which may not even exist; see our series of posts on this starting here), that are failing.  Epidemiologists are doing their best with what they've got.  We don't know precisely what causes heart attacks, but to prevent them, we've got to treat people with low risk as though they are at high risk, and that's because some people at low risk really are at high risk.

No one has 7.5% of a heart attack.  They have 0% or 100% of a heart attack. Figuring out who is in which group is currently impossible.  What we do know for certain is that putting everyone on statins, as though they have 100% risk is very good for the pharmaceutical companies that make them, and good for people whose heart attack or stroke was prevented, even if we will never know which people these were, and unnecessary and even harmful for everyone else.

This is a lousy way to do medicine.  But it's currently the only way we've got.