Precision Primary Prevention

If you’re going to indulge in anticipatory medicine, it is best to anticipate those at highest risk. An elegant study by Wald et al in the NEJM shows how precision primary prevention can be done. The researchers screened toddlers, who presented routinely to their general practitioners for vaccinations, for an uncommon, but not rare, familial predisposition to high cholesterol known as heterozygous familial hypercholesterolemia (FH), in which premature cardiovascular death can be deferred by statins and lifestyle changes. Blood drawn from the toddlers by a heel prick was tested for serum cholesterol and genetic mutations indicative of heterozygous familial hypercholesterolemia (FH). The parents of toddlers who met criteria for FH were also tested for cholesterol and genetic mutations. Obviously identifying affected parents, and increasing their longevity, is also beneficial for their children.

Researchers defined familial hypercholesterolemia in two ways.

  1. Elevated cholesterol and a gene mutation – phenotype positive, genotype positive group.
  2. Elevated cholesterol on two occasions but no mutation – phenotype positive, genotype unknown group. It was assumed that children in this group have genetic mutations which we’re presently unaware of.

The mutations (there are 48), present in 37 out of 10,095 children, were picked up in 20/37 children when high cholesterol was defined at the 99.2nd percentile, and in 32/37 children when high cholesterol was defined at the 95th percentile. The more stringent threshold for high cholesterol missed 46 % (nearly half), and the less stringent missed 14 %, of carriers of known mutations for FH. The frequency of the “phenotype positive, genotype unknown” – i.e. those who had elevated cholesterol on two occasions, but did not have the known mutations for FH, was 8 out 10, 095 children (0.08 %) – I suspect this number may be higher when screening is rolled out en masse.

What threshold for “high cholesterol” should be used? If we’re going to screen for familial hypercholesterolemia there’s no point missing half the children who carry the mutations. It makes sense using the lower threshold of 95th percentile of population serum cholesterol to define hypercholesterolemia.

At first, it seems we’re throwing a wide net to catch rare trout. However, the net is no wider than other screening nets. Applying the more liberal threshold for elevated cholesterol, 40 cases of FH were found in 10 095 kids, which is a number-needed-to screen (NNS) of 250. When you include the parents who, unbeknownst, had FH or high cholesterol, that’s an NNS of 125 – hardly an unrespectable NNS compared with cancer screening – for smokers at high risk for lung cancer, the NNS is 320 with screening with low dose CT.

There are still uncertainties because of the “inverse problem” which haunts genomics. Just because people who die prematurely from CV disease have certain genetic mutations which elevate cholesterol, doesn’t mean that everyone with that genetic mutation will die prematurely. This genotype-phenotype-outcome mismatch is nicely explained by Siddhartha Mukherjee in The Gene.

The authors make clear that mutation alone doesn’t maketh risk and cholesterol must also be elevated to define familial hypercholesterolemia. Because we must assume that anyone with a mutation and high cholesterol may die prematurely – we must assume something –  and that they’d benefit from lifestyle changes and statins, inevitably, some will be overtreated. The natural histories of the “phenotype positive, genotype positive” and “phenotype positive, genotype unknown” – by natural history, I mean how many in these cohorts die prematurely and at what age – is a knowledge gap that’ll likely, and unsurprisingly, be permanent. Would you volunteer your child, who just had FH detected, to remain untreated to study this intriguing question for mankind? I wouldn’t.

The study asks a probing philosophical question. Is familial hypercholesterolemia a disease or a risk-factor, or is the distinction between risk factor and disease a distinction without a difference? It will be tempting to start adolescents with FH on statins, whilst encouraging them to swing on monkey bars. It is hard to see how statins can be avoided in adolescents known to have FH, and for their management to be largely lifestyle based. Prescribing exercise to children at high risk of premature death from cardiovascular disease sounds good in theory, but if participating in sports requires a doctor’s prescription, how successful can that prescription be? I mean getting off the couch surely doesn’t need shared decision making, and whether the children get off the couch, sooner or later, their parents might ask for pharmacological means to reduce their risk of premature death, which I believe would be wholly justified.

I’ve been told by some cardiologists that in those genetically-predisposed to high cholesterol, running, or swinging on monkey bars, though helpful, won’t alone reduce their risk of dying early, at least not without a little help from statins. I always take cardiologists at their word. What choice have I? My life could depend on them.

Nevertheless, statin-skeptics should occasionally suspend their skepticism. The group uncovered by Wald and colleagues is an apt group for suspending skepticism about statins and primary prevention.

Saurabh Jha is a radiologist and contributing editor. He can be reached @RogueRad

Categories: Uncategorized

2 replies »

  1. Prior to the primary prevention study on the use of pravastatin, the previous trials using niacin and later, gemfibrozil, demonstrated no long term benefit. Remember, there was a decrease in the cardiovascular morbidity for the treated men as opposed to the placebo treated men in the first two trials. But, the “all other” cause of death was higher in the treated group, for both the niacin AND the gemfibrozil trial. Interestingly, the principal worsening in morbidity for the treated men in both studies involved accidents and cancer. Eventually, the pravastatin trial reported in 1997 demonstrated no increased morbidity in the medication treated men as compared to the placebo treated men. And finally, you will need to treat 1000 men with a statin to affect the health of “7” through primary prevention. Oh yes, there are no primary prevention trials in women. So then, given these levels of uncertainty, I am not at all certain that we should be screening any person until they are nineteen years of age, can give their own informed consent AND have the demonstrated capability to take a medication regularly over a long period of time.

    All in all, primary prevention with medication for ASHD really does not have a substantial level of precision for children. More importantly, none of this changes our responsibilities to form the caring relationships with families, in ten minutes a visit, and their children that are required to have an impact on the other issues for cardiovascular risk reduction.

    Our nation’s healthcare industry continues to chase the antibiotic theory of disease, a cure by a medication prescription. Really, we should be chasing the incredible level of uncertainty underlying the HEALTH of each person. As we respond to each person’s over-all health, what is the institutional governance that is required to sustain this every hour of the day for each citizen? With no time to waste, what institutional changes will our nation need to undertake for reducing our nation’s maternal mortality ratio by 75%, that would be required for our nation to rank within the best ten of the world’s developed nations?

  2. We do know cost-effectiveness of screening for lung ca–depending on assumptions and what you believe. NNS for adolescent FH might fall within values we usually accept, but lifelong costs of treatment not available. it is too early to endorse the strategy.