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Primary Care Corner: A new atherosclerosis risk calculator: QRISK3

2 Aug, 17 | by

by Dr Geoffrey Modest

In prior blogs I commented in a not particularly quantitative fashion that it made sense to have a gestalt about how aggressive to be in coronary artery disease prevention (see or for example). The point was that the available atherosclerotic risk calculators did not include many conditions that confer increased risk, including such things as peripheral artery disease, chronic kidney disease, microalbuminuria, chronic inflammatory conditions, A1c, migraine, etc. (Eg, for someone with a borderline cardiovascular risk in terms of initiating statin or other more aggressive therapies, perhaps the decision to initiate such therapy should include these conditions). A recent article from the UK included many of these conditions in a new quantitative risk calculator QRISK3 (see​ ).



— in the UK, clinicians have been using a 10-year cardiovascular risk tool called QRISK since 2007, which was soon updated to QRISK2 with frequent subsequent updates. This latter risk tool evaluates risk on all people aged 25-84, and includes age, ethnicity, deprivation (the Townsend score, which reflects social class by measuring unemployment levels, non-car ownership, non-home ownership, household overcrowding), systolic blood pressure, BMI, total cholesterol/HDL ratio, smoking, family history of coronary artery disease in a first-degree relative aged less than 60, type I diabetes, type II diabetes, treated hypertension, rheumatoid arthritis, atrial fibrillation, and chronic kidney disease (stage 4 or 5).

— They are now proposing updating this calculator (QRISK3) to include chronic kidney disease (stage 3, 4, or 5), a measure of systolic blood pressure variability (standard deviation of repeated measures), migraine, corticosteroid use, systemic lupus erythematosus, atypical psychotics, severe mental illness, a erectile dysfunction in men, and HIV/AIDS.

— 981 clinical practices we used to derive the prediction scores based on these new parameters, with 7.89 million patients aged 25-84; and 328 clinical practices with 2.67 million patients were used in the validation cohort. All patients were free of cardiovascular disease at baseline and were not on statins.

— Baseline characteristics of these cohorts were similar, mean age 43, Townsend score 0.5, BMI 26, cholesterol/HDL ratio 3.9, systolic blood pressure 126 mmHg, systolic blood pressure variability 9.5 mmHg, non-smoker 45%/former smoker 15%/light smoker 12%/moderate smoker 6%/heavy smoker 4%, family history of heart disease 10%, type I diabetes 0.3%, type II diabetes 2%, treated hypertension 5%, rheumatoid arthritis 1%, atrial fibrillation 0.5%, chronic kidney disease (stage 3, 4, or 5) 0.5%, migraine 2%, steroid use 2%, HIV-AIDS 0.2%, SLE 0.1%, atypical psych antipsychotic use 0.5%, severe mental illness 6%, erectile dysfunction 2%

— The outcome measured was cardiovascular disease defined as the composite outcome of coronary heart disease, ischemic stroke, and TIA.


— in the derivation cohort, for the mulivariate-adjusted model, the hazard ratios were: 5.62 for type 1 diabetes, 4.92 for atrial fibrillation, 2.91 for type 2 diabetes, 2.31 for chronic kidney disease, 2.14 for SLE, 1.81 for steroid use, 1.58 for family history of CHD, 1.35 for migraine, 1.29 for antipsychotic use, 1.24 for RA, 1.13 for severe mental illness, and 1.08 for SBP variability

— there were 363, 565 incident cases of cardiovascular disease from 50.8 million person-years of observation to assess the value of these newly proposed risk factors, and all met the model inclusion criteria (at least a 10% increased or decreased risk) except for HIV/AIDS.

— In women, QRISK3 explained 59.6% of the variation in time to diagnosis of cardiovascular disease

— in men, 54.8% of the risk was explained

— overall performance of the QRISK3 algorithm was similar to the QRISK2 one.



— it is not surprising that adding these risk factors did not significantly change the predictive model, since the overall prevalence of these risk factors was quite small

— In fact, looking at the baseline demographics, this population was pretty young and remarkably devoid of medical comorbidities (quite an apparently healthy population, at least as compared to any I’ve ever worked with) and therefore had a pretty low likelihood of a clinical event in the next 10 years.  and this might affect its generalizability to older/sicker populations.

— It is notable that the basic risk calculator initially used in the UK since 2007 already included several items not in the US risk calculators, such as markers of social class, chronic kidney disease, atrial fibrillation, rheumatoid arthritis.

— The new risk calculator is available online at . It is important to recognize that many patients do not have information on all of the components of this risk calculator (and the risk calculator does not require them). In fact both the derivation and validation cohorts above were often missing pieces of data, and the researchers used the statistically valid technique of multiple imputation whereby the missing data is imputed by assuming different possible scenarios (eg assuming that the missing data was random and not different from the observed data, or perhaps incorporating various models where there are systematic differences between the missing data and the observed data: for fuller description, see Sterne JAC. BMJ 2009; 338: b2393)


— this study did find that all of their proposed conditions that might change the risk of atherosclerotic events, except HIV/AIDS, did in fact confer a significant increased risk on their multivariate-adjusted model

–however, overall this new risk model QRISK3 did not add anything to their prior risk model, which I think is simply because the prevalence of these conditions in their population was so small.  It would have been interesting to look at a population with, for example,  high levels of RA or on lots of antipsychotic meds to see if their calculator were superior to models without these issues (and even high prevalence of HIV/AIDS, to see if that mattered)

–but, I think they are on the right track overall. Studies have shown that these additional risk factors do confer increased risk, controlling for the traditional ones. And the applicability of the older risk calculators is limited: does the Framingham Risk Score really apply to non-white, non-working class patients? (we do know that the Framingham Risk Score does systematically overestimate risk in Japanese people, for example). How about the disabled poor Nicaraguan woman in front of me who has chronic kidney disease from the widespread indiscriminate use of the weed-killer glyphosate on the crops????  My guess is that including as many of the documented risk factors above (social class/poverty, renal failure,…) do add to the predictive model, even if not tested in the specific subgroup of such Nicaraguan women.

–and, another issue is the real utility of a 10-year risk calculator (which QRISK-3 does not challenge). one of the positives in the 2013 AHA/ACC risk calculator is that they did include a longterm risk calculator for 30-year/lifetime risk (not based on rigorous data, though). the obvious reality is that a prime target for hyperlipidemia intervention is people in their 40s, who have a pretty low likelihood of a cardiovascular event in the next 10 years.

–to me, the real positive of QRISK3 is that it challenges the traditional risk calculators, reinforcing the need to look at the individual patient in a more global way than a few medical components. And it would be great to have more studies which validate this in lots of different populations of different ages and prevailing comorbidities.

Primary Care Corner with Geoffrey Modest MD: fenofibrate,not so effective

30 Mar, 17 | by

There was extended followup of ACCORD-Lipid study for 5 years after the study ended, which confirmed the original conclusions that adding fenofibrate to simvastatin in diabetic patients did not improve cardiovascular outcomes, and that the assessment of prespecified outcomes also found that the subgroup with low HDL/high triglycerides did better with fenofibrate, but women overall did worse (see doi:10.1001/jamacardio.2016.4828 )



–4644 patients (90% of surviving participants) agreed to the 5-year followup of the ACCORD-lipid trial, after the fenofibrate vs placebo intervention was finished (all patients received simvastatin)

–this cohort was similar to the original study (these are the pre-trial baselines): 31% women, 66% white/14% black/7% Hispanic, 35% previous cardiovascular event, 4% heart failure, 14% current smoker/46% former, BMI 32, 11 year duration of diabetes, A1c=8.25%, LDL 100, HDL 42 in women/37 men, TG 188



–simvastatin treatment (20 or 40mg dose, titrated) did lead to a mean decrease of LDL to 80 mg/dl, which basically continued in the post-trial period. The TG (triglyceride) decreased to 145 in those on fenofibrate and 170 on placebo, with both achieving 161 mg/dL in the post-trial period. HDL increased during the ACCORD trial to about 41 mg/dl in both groups, and pretty much stayed the same in the post-trial period.

–primary outcome (nonfatal MI, nonfatal stroke, fatal CV event): essentially the same non-significant 7% difference as found in the trial

–secondary outcomes (individual components of the primary outcome, plus revascularization, hospitalization for heart failure, all-cause mortality): all continued to be nonsignficant

–prespecified subgroups, primary outcome in all of them were nonsignificant, other than in:

–female: 30% increase, HR 1.30 (1.01-1.68)

–male: 16% decrease, HR 0.84 (0.73-0.96)


–this trial adds to several others suggesting that fenofibrate does not have much cardiovascular benefit, including the FIELD trial. Gemfibrozil, however, either singly or in addition to statins, does confer clinical benefit in several studies. I am  unaware of any trials directly comparing different fibrates, but one meta-analysis of fibrates and CAD outcomes did find significant clinical benefit with gemfibrozil (23% decrease) vs none with fenofibrate or benzafibrate (see Lancet 2010; 375:1875)

–on secondary analyses, however, there is some consistency in finding that fenofibrate is clinically helpful in those with diabetic dyslipidemia (low HDL, high TG), which occurs in up to 35% of diabetic patients (though only 17% of the ACCORD cohort)

–the male/female difference found here is concerning, though was not found in the FIELD trial, which did have more female participants. And I am unaware of any male/female differences in trials with other fibrates.

–the above “legacy” study is important, since it does show that using fenofibrate for a pretty long trial (4.7 years) did not show any residual benefit 5 years later. Several other trials, such as the Coronary Drug Project, did show benefit on longer-term followup after the trial ended (with niacin, in the case of the CDP), confirming the utility of these legacy trials (and they might also show delayed adverse events).

–so, one concern is what agent to add when a statin does not give adequate cardioprotection, especially in diabetics with dyslipidemia and very high triglycerides? The fact that 2 trials did find some benefit for fenofibrate in this subgroup is reassuring, but not definitive since this was a subgroup analysis (though prespecified).  It does seem that gemfibrozil is a more potent fibrate, though there is the  concern of drug-drug interactions with statins: increased myopathy/ rhabdomyolysis. A recent article, however, did suggest that this consideration may be overblown (see here which looks at drug-drug interactions, suggesting that it is safe to use either atorvastatin or rosuvastatin with gemfibrozil, though perhaps best at lower doses. And that may well be the best alternative…

Primary Care Corner with Geoffrey Modest MD: More Data Supporting Treat-to-Target

29 Nov, 16 | by EBM

By Dr. Geoffrey Modest

A recent article looked at the relationship between achieved LDL cholesterol levels and changes in coronary artery atherosclerosis progression, as determined by coronary CT angiography, CTA (see


  • 147 patients with evident atherosclerotic plaques on CTA had quantitative plaque size measured both at baseline and at follow-up CTA two years later (median 3.2 years)
  • Baseline characteristics: mean age 62, 57% male, 65% with hypertension, 33% diabetes, 20% active smoking, 27% dyslipidemia (defined as total cholesterol >240 mg/dL, LDL >130, HDL <40, triglycerides >150, and/or treatment with lipid-lowering agents), cardiac risk score by both the ATP III and Framingham risks:60% low risk (<10% over 10 years), 30% intermediate (10 to 20%), and 10% high risk (>20%). Number risk factors = 1.6
  • Multi-center, observational study, assessing those who had LDL <70, versus >70, to assess changes in quantitative measurement of plaque volume, usingthe modified 17-segment American Heart Association model for coronary segment classification
  • This was an industry-supported study done in 4 Korean  centers


  • Of note, those that had a follow-up LDL <70 had a higher prevalence of diabetes (p=0.002) [i.e., were likely at even higher risk of progressive disease]
  • Those with an LDL <70 had significant attenuation in plaque progression: 12.7 mm³ versus 44.2 mm³, p=0.014.
  • Multivariate analysis found that the only factor influencing plaque progression was the follow-up LDL level (p=0.021), controlling for age, hypertension, active smoking, and follow-up LDL <70.
  • All patients who achieved an LDL <70 were on a statin (n=37), whereas 63% (n= 70) of those with follow-up LDL >70 were on a statin; those actually taking a statin had similar plaque progression as the overall group, with plaque progression of 12.7 versus 41.8 mm³
  • Subgroup analysis showed that annual plaque volume could be attenuated with aggressive LDL control (4.6 mm³ versus 14.5 mm³)


  • Coronary atherosclerosis remains a major cause of global morbidity and mortality (though decreasing in many resource-rich countries, but increasing in resource poor countries), with an estimated global burden of 17 million deaths annually.
  • Prior studies looking at intravascular ultrasound (IVUS) have shown that intensive LDL lowering can halt the progression of atherosclerosis and even promote some regression. CTA provides a noninvasive assessment of CAD with high reproducibility and a diagnostic performance correlating well with that of the invasive IVUS.
  • As noted by the editorialists (see doi:10.1016/j.jcmg.2016.08.002), several coronary angiography and IVUS studies have found that LDL levels need to be brought down to the 70-80 mm/dL range in order to decrease plaque progression, and even lower LDLs were needed for plaque volume reduction. The above study found almost a 70% decrease in the annual rate of plaque progression in those with LDL <70.
  • Plaque progression is in fact a reasonable surrogate marker for future cardiac events. One study found that plaque progression over time was associated with a 28% likelihood of a cardiac event versus 10% in those without plaque progression. Other studies have shown that plaques with rapid progression were much more likely to be the culprit lesions in cardiac events (i.e., the lesions that rupture and cause an acute cardiac event)
  • A few additional comments:
    • This was not an intervention study. As with other studies looking at achieved LDL and cardiac events, these patients were not randomized to specific LDL targets, so one cannot definitively conclude that it is beneficial to treat-to-target. For example, perhaps those who more easily achieve a lower LDL target have a less malignant atherosclerotic course. However, there are a few lines of argument which suggest that treating to lower LDL targets is highly likely to be beneficial:
      • The Treating to New Targets trial (Barter P. N Engl J Med 2007; 357:1301-1310), which compared the effects of atorvastatin 10 versus atorvastatin 80 mg, found that though the number of clinical cardiac events was lower overall in the group on 80 mg, there was no difference between the two groups if one looked at achieved LDL levels (by the way, this trial also showed that the number of cardiac events was also related to the HDL level: those with LDL >100 but HDL >55 had the same 5-year risk of a cardiovascular event as those with achieved LDL<70, but HDL <38. and statins had essentially no effect on HDL, independent of their dose). see first graph below
      • Data from the constellation of many lipid trials, looking at both the achieved LDL on statins and the natural LDL of patients, show a straight line relationship: those with lower achieved or natural LDL down to 70 had fewer cardiac events. See second graph below. This also suggests, as seen in several studies, that it is the on-statin achieved LDL that matters, and the “pleotrophic” non-lipid effects don’t seem to matter so much.
      • The editorialists had a very similar graph to the second one below (see reference above), showing that achieved LDL targets were associated both with changes in percent of atheroma volume as well as angiographic mean luminal diameter/extent of stenosis
      • The data from the ezetimibe trial (see ) showed that adding ezetimibe to simvastatin decreased cardiac events, more so than simvastatin itself, again suggesting further decreases in LDL were beneficial. The data on PCSK9 inhibitors is more preliminary, but have shown a dramatic decrease in LDL over just using statins, and a decreased cardiac event rate (Robinson JG. N Engl J Med 2015; 372: 1489 studied high-risk patients on max dose statin but LDL >70, then randomized to PCSK9 inhibitor plus statin vs continued statin, and found a 62% further decrease in LDL by the PCSK9 inhibitor and a 48% decrease in cardiac events over 78 weeks). These studies further support a low LDL target
    • So, despite the lack of rock-solid studies, there is a remarkable convergence of data from different types of studies suggesting that targeting a lower LDL is the appropriate approach. The graph in the editorialists’ article shows that the achieved LDL correlates very well with changes in atheroma volume as well as the residual luminal diameter of coronary arteries. The second graph below that shows that clinical events track with the achieved LDL. And the Targeting New Targets trial showed that it was the achieved LDL and not the dosage of atorvastatin (10 vs 80mg, which correspond to “moderate” and “high” intensity statins by the 2013 ACC guidelines) that was associated with clinical outcomes (though the lower achieved LDL was more common with the 80 mg dosage)
  • So why did the new AHA guidelines in 2013 make a point of eliminating the treating-to-target approach? They state that this was because there was not enough rigorous data to show that treating-to-target really mattered (as noted above: no specific trials looked at this). However, many of their other recommendations had much less data to support them, including looking at the individual’s 30-year risk profile or treating a 21 year-old with LDL >190 aggressively (both of which I support, it is just that there really are no data to support these by RCTs, as opposed to the above data which i think pretty strongly support a targeted LDL). My best guess is that they feel that statins are used insufficiently overall, so they wanted to develop the easiest algorithm to reinforce using statins in people at increased cardiovascular risk (in fact, in the above Korean study only 56% of really high-risk patients who were not on a statin initially were actually put on a statin by their clinicians). But there are several studies showing that applying the 2013 recommendations would lead to dramatic overtreatment (eg, the AHA/ACC 2013 guidelines would recommend statins for nearly all men and two thirds of women >55 years old). In addition to exposing lots of people probably unnecessarily to statins, the approach of stratifying patients into needing either intensive- vs moderate-dose statin therapy does potentially create unfortunate clinical consequences in those who clearly need statins:
    • I have seen several patients with clinical CAD who, when put on atorvastatin 10 mg, achieve an LDL in the 40s. Should I really be putting them on high intensity statin? There are more adverse events taking higher dose statins, and what is likely to be the benefit?? (and there are animal data, and old human data on lipid-lowering therapies, as well as the recent PCSK9 studies, finding that there may be neurocognitive issues with too-low an LDL…. Cholesterol is part of the cell membranes of neurons, which is integral to neural transmission)
    • I have also seen many very high-risk patients on atorvastatin 80 mg who do not achieve an acceptable LDL level (specifically, <70). In many cases, by switching them to rosuvastatin 40 mg they have done much better. I have not seen this as a tested clinical strategy, but given our understanding of statins and the above data on the benefit of LDL <70, I think this is a reasonable strategy. And I would try this before adding ezetimibe, or PCSK9 inhibitors…
  • So, I am concerned about the clinical implications of adopting a simple algorithm of “high” vs “moderate” intensity statins: we may be overtreating some patients, as well as undertreating others, in a disease with potentially very bad outcomes and with tried-and-true meds which are quite effective in lowering the likelihood of these events, and with minimal adverse effects. I do in general support an aggressive approach to LDL management, especially in those at higher risk of clinical cardiac events, and I strongly suspect that the clinical risk of undertreating with statins is much higher than that of overtreating. However, I also think we should be tracking and following lipid levels, both to make sure that the patients are taking their statins appropriately, and also to titrate the statin dose to the individual.




For prior critiques of the 2013 ACC/AHA guidelines, see , and,

Primary Care Corner with Geoffrey Modest MD: Omega-3 Fatty Acids and Cardiovascular Disease

1 Sep, 16 | by EBM

By Dr. Geoffrey Modest

AHRQ (Agency for Healthcare Research and Quality) just released their updated systematic review on omega-3 fatty acids and cardiovascular disease (see ).


  • Omega-3 fatty acids (n-3 FA) include both marine oils, predominantly EPA (eicosapentaenoic acid) and DHA (docosahexaenoic acid) which come from fish, seafood, other ocean life; and ALA (alphalinolenic acid) which comes from vegetable oils (esp soybean, canola and flaxseed oils) and nuts (esp walnuts)
  • There are large differences in consumption of these n-3FAs overall: though ALA ingestion is pretty consistent across developed countries at about 0.3-1.0% of energy (in the US it is 0.6%), EPA and DHA consumption vary a lot (0.13 g/d combined in the US, vs 0.4 g/d in South Korea)
  • Older epidemiological observational studies have found significantly less cardiovascular disease in those on high fish diets. The rates of cardiovascular disease in the US has declined sharply in the past several decades, likely related to more use of statins, antihypertensives and aspirin


  • RCTs (essentially all done with marine oils):
    • For many of these trials, there were very mixed results, with a few studies finding efficacy, others none, and the meta-analyses combining them therefore not finding significant benefit
    • All-cause death: 2 of 17 trial found lower all-cause death, others not, so overall no benefit
    • Major Adverse Cardiovascular Events (MACE): 2 of 10 trials found significant reductions, so meta-analysis found no significant benefit
    • Total MI: no trials found benefit
    • CVD death: 2 of 7 trial found significant benefit, so meta-analysis found no significant benefitin those with existing CVD
    • Sudden cardiac death: no trials found benefit
    • Angina: 1 trial found benefit along with statins for unstable angina after 5 years in patients with dyslipidemia, other trials without benefit. Same for heart failure
    • No benefit in RCTs for total stroke death, revascularization, CHD deaths, atrial fibrillation, heart failure deaths
    • BP: no  benefit for blood pressure, in 19 RCTs
    • Lipids: many trials. Increase in LDL of 1.98 mg/dL, increase of HDL of 0.92 mg/dL. Triglycerides more complex: each increase in baseline Tg level by 1 mg/dL was associated with a net decrease by marine oils of -0.15 mg/dL; and each increase of EPA+DHA dose by 1 g/d was associated with a greater decrease in Tg of -5.9 mg/L (i.e.: more effect of marine oils if higher Tg level to start with, and with higher doses marine oils.) And EPA may be more effective than DHA
  • Observational studies (meta-analysis of 21 studies):
    • CVD death: statistically significant benefit with marine oil intake
    • CHD death: non-significant
    • All-cause death: overall non-significant, but there was decrease in those on high dose marine oil intake. Same with CHD itself
    • Stroke: significant, and more protective at higher doses of marine oils. Same for ischemic stroke. No change in hemorrhagic strokes
    • Heart failure: significant benefit of marine oils
  • There was insufficient evidence of benefit in studies looking at only EPA or DHA individually (or other n-3FAs DPA, SDA; or if look at marine oils vs ALA (though very few studies looked at ALA, and not many looking at the individual marine oils)
  • Adverse events: no serious adverse events felt to be related to the study interventions in 25 RCTs.

Overall conclusions

  • Omega-3 fatty acids raised HDL and LDL a little (<2gm/dL) but did lower triglycerides, more so in those with higher baseline triglyceride levels and higher doses of n-3 FAs, based on RCTs
  • In those at increased risk of cardiovascular disease, RCTs found that omega-3 fatty acids do not change one’s risk for: overall major adverse cardiovascular events, all-cause death, sudden cardiac death, coronary revascularization, or atrial fibrillation
  • Observational studies do find that those with higher intake of fish high in omega-3 fatty acids may lower one’s risk of ischemic stroke due to atherosclerosis
  • RCTs and observational studies differ in benefit for cardiovascular death, and total stroke (fatal and nonfatal, ischemic and hemorrhagic stroke) outcomes. RCTs show no benefit, observational studies show some possible benefit.


  • Meta-analyses are often hard to interpret. They are usually considered the definitive determination of benefit by including lots more patients and then averaging all of the studies with their individual biases and differing patient characteristics to achieve a real, representative average, and one which might compensate for the individual biases of the different studies. But the reality is that meta-analyses are usually trying to combine mathematically very different studies, often with mathematical correction for comorbidities, etc. (e.g., propensity scoring). In the above case, the meta-analysis used different n-3 FAs, in different doses, in different patients from different backgrounds, with different comorbidities, and for different follow-up times. So, it might be that an individual well-done study which more closely reflects the patient you are seeing might be much more useful than a meta-analysis which dilutes the effect by adding in other non-applicable studies (which perhaps exclude patients like you are seeing, have too small a dose of n-3FAs, don’t last long enough to see an effect….). So, a meta-analysis of 7 trials with 2 showing benefit (as in CVD death above), may be meaningless: perhaps the 2 trials with benefit are much more rigorous, with longer follow-up, higher dose of meds, etc., are really more useful and applicable than the mathematical combination with less appropriate studies. [Another issue, not in the above meta-analysis, is that sometimes a huge study will dwarf many smaller studies by being disproportionately represented in the mathematical combination. The bottom line: don’t just accept the meta-analysis; it is important to look at the individual studies to see if the meta-analysis makes sense to you. And it is not so uncommon that there are almost simultaneous meta-analyses on a subject, printed in different journals, coming out with different conclusions, based on how they do their statistics or which studies they decide to include as appropriate]
  • One reason why observational studies and RCTs may differ in their results on omega-3 fatty acids is that almost all of the observational studies were done in healthy populations and almost all of the RCTs were in those at high risk of CVD. And so many people in the US in the high risk group are on statins, antihypertensives, and low-dose aspirin; these drugs act on metabolic and biochemical pathways that the n-3FAs also impact (anti-lipid, anti-inflammatory, anti-coagulant, improved endothelial function). So the studies on patients at high cardiovascular risk are less likely to show benefit from n-3FAs, since the patients are likely on the above drugs, and any incremental benefit of the n-3’s may have been too small to measure. For low risk patients not on these medications (as in the observational studies), it would take a very long and large study of these patients randomized to n-3 FAs vs placebo to show clinical benefit (the event rate is so low in the short- to moderate-term), and I suspect this study will never happen. The data on intermediate outcomes (lipids, blood pressure) were from both average and high cardiovascular risk populations.
  • Nonetheless, it is pretty clear to me that n-3 FAs do have a role in those with high triglycerides, and I have had some success in lowering Tg levels in some patients with very high Tg’s. And I do encourage increased fish consumption when possible and do not discourage the use of supplemental fish oil to patients who ask about them (the concern with fatty fish, as mentioned in prior blogs, is that many environmental toxins released into the water are lipid-soluble and concentrated in the fat of fish, e.g. PCBs, or mercury. So I do encourage eating wild fish, when possible)


Primary Care Corner with Geoffrey Modest MD: USPSTF Recommendations on Lipid Screening in Adolescents

30 Aug, 16 | by EBM

By Dr. Geoffrey Modest

The USPSTF just came out with their lipid screening recommendations for children and adolescents (see JAMA 2016; 316(6): 625), giving them an “I” rating (current evidence insufficient to recommend screening). For full supporting documents of the USPSTF recommendations, see JAMA 2016; 316(6): 645). Their points:

  • They consider both dyslipidemia from genetic heterozygous familial hypercholesterolemia, FH, (1 in 200-500 people in North America and Europe), where there are really high cholesterol levels (LDL>190 mg/dl, often 2-3x that of unaffected people) and evidence of increased cardiovascular risk (though not typically until age 30: 1 in 6 men and 1 in 10 women have ischemic heart disease by age 40, 25% of women and 50% of men by age 50), as well as multifactorial dyslipidemia, MD, (may have genetic component as well as environmental, esp obesity, where the LDL is lower but >130). Several studies show that there is moderately good tracking of childhood hyperlipidemia into adulthood. But they comment that there are no long-term data that adolescent hyperlipidemia from MD leads to clinical cardiac events in adults. Or that treatment of the MD changes those hard clinical outcomes [i.e., no RCTs have been done, and it is hard to imagine that they ever will be. Would require lots of kids randomized into different treatment wings, maintaining those treatments for decades, and then being able to follow them until they were 50+ years old when more clinical events happen]
  • NHANES data suggest that 7.8% of children 8-17 yo have total cholesterol >200 mg/dl, and 7.4% of those 12-19 have LDL >130 [i.e., pretty common]
  • For those with FH there are data that short-term (<2 year) treatment leads to decreased LDL and decreases the early surrogate marker of carotid intima-media thickness [which actually seems to be a good predictor of future atherosclerotic disease, especially in kids]. There are no compelling data on the long-term benefit of statins through a randomized-controlled trial, since in those with FH it is considered unethical not to use statins. However, a retrospective analysis looked at children with FH who were put on statins for a mean of 10 years starting at age of 14, and compared them to the adults with FH not on statins (they predated the use of statins); they assessed outcomes by age 30 , finding that the adults had many more cardiovascular events at a younger age than the kids (at the age of 30, the cumulative CVD survival was about 90%, vs 100% in the kids, even though 28% of the kids were smokers. See Braamskamp MJ. Am J Coll Cardiol 2016; 67(4): 455). It was notable in this study that the youngest parent with an MI was 20 years old and died at age 23.
  • Harms of screening. Also inadequate evidence, though mostly concerns about medicalization (anxiety about diagnosis, labeling, potentially harmful therapy). Statins are well tolerated with transient adverse effects in kids (increased liver enzymes). And though cardiovascular disease is still the number one killer, there is concern about overdiagnosis (i.e., some people treated may never develop cardiovascular disease)
  • Therapy: statins are typically used, given the adult data. But no consensus on when to start in kids with FH (some say age 8-10, some age 20). No data on long-term use in kids [though there are potential issues concerning taking statins with pregnancy, which they did not mention….]
  • They do acknowledge the rationale for screening kids:
    • Atherosclerosis is a known progressive process which starts in kids, with autopsy studies showing that [my data, not in their document]:
      • Everyone has fatty streaks in their coronaries by age 15-34
      • Advanced atherosclerotic lesions are found in 2% of men and 0% of women aged 15-19, but
      • Advanced atherosclerotic lesions are found in 20% of men and 8% of women aged 30-34
      • The Bogalusa Heart Study found that in adolescents dying mostly from trauma at median age of 19.6, there was a strong correlation between the levels of cardiovascular risk factors (BMI, lipids, and BP) and the degree of atherosclerosis
    • Lipid levels in kids are associated with the extent of adult atherosclerosis
    • Familial hypercholesterolemia, FH, is associated with premature ischemic cardiovascular disease
    • Short-term treatment of patients with FH leads to substantially lower LDL levels and some evidence of improvement in atherosclerosis (see below)
    • Abnormal lipid levels in adults is strongly associated with coronary heart disease events
    • Early identification and intervention in adults can prevent such events
    • And, I would add, prevention of more advanced lesions upfront not only decreases mortality (still a significant number of patients die with their first MI, and more are chronically disabled), but also helps long-term, since statins do not reverse atherosclerosis (just stabilizes it and makes the plaques less likely to rupture), but the residual recurrent cardiac risk in those who sustain an MI (secondary prevention) even with statins remains much higher than in those on statins who are just at elevated cardiovascular risk (i.e., primary prevention)
  • Although there are some potential benefits of identifying and treating those with FH, there are no good data for those with multifactorial dyslipidemia. An Ohio universal screen program (n=6500) looked at nonfasting total cholesterol screening, finding elevated levels >200 in 8.5%. This cohort then had fasting lipids, finding 5.8% had LDL>130. The USPSTF review found that those with the highest likely yield for hyperlipidemia are kids with obesity (12.3%), overweight (8.9%), children 9-11yo (7.2%) and those 16-19 yo (7.2%) [There is an unexplained typical 10-15% decrease in cholesterol levels during puberty].


  • When reading guidelines, it is important to remember that USPSTF overall is an independent governmental agency (so less influenced by drug companies, etc., than some of the professional society recommendations), is very focused on rigorous data (so will not make recommendations if the issue has not been studied well. They say the same thing about blood pressure screening in kids: no data that screening leads to decreased future cardiovascular events, so an “I” rating). In fact, for pretty much the same reasons (lack of clearcut studies), USPSTF does not recommend screening average risk males until age 35 and women till 45. All of these USPSTF recommendations are much less aggressive than the Am Acad of Pediatrics (screen at age 2-10 in all obese kids or if family history of dyslipidemia, etc.), NCEP (screen at age 20), Am College of Physicians, etc.
  • And, as a perspective, we all screen for phenylketonuria in newborns, with a prevalence of 1 in 10,000, but not for familial hypercholesterolemia, with 50x the prevalence (>500,000 born each year)… though I do realize the rigor of studies showing benefit is different)
  • It is pretty clear that targeted screening of those considered to be high risk is not successful: in a few pediatric epidemiologic studies, 1/2 the kids would be missed by relying on parental information/ family history of dyslipidemia or premature cardiovascular disease (e.g., see Ritchie SK. Pediatrics 2010; 126(2):260). And, pretty surprisingly, only about 1/4 of FH patients receive their appropriate diagnosis by middle age (see Neil HA. BMJ 2000; 3212:148). From other organizations (e.g. Am Acad of Pediatrics), screening has been recommended as universal. Universal screening is also much easier to integrate into care than targeted screening.
  • I do definitely think that discussing diet and exercise is really important at all age groups (though adolescents may be the most resistant of them….). But I also do think, from my clinical experience, that this discussion is more effective, at least in some people, if there are personal specific markers that suggest that the individual may be at higher risk. And knowing the lipid levels of adolescents may be very helpful in changing behavior. For example, I think that knowing a person smokes helps individualize their treatment recommendations and is likely to be more effective than just telling everyone they should not smoke (of course, finding out that someone smokes is a bit less invasive than doing a blood test).
  • So, to me, the rationale to do testing wins out. One may pick up the relatively unusual cases of familial hypercholesterolemia, and it seems pretty intuitive that they need meds as supported by our understanding of their physiology and supplemented by some limited data. But one will mostly pick up the pretty common multifactorial hyperlipidemia, and I personally would pursue these patients aggressively with diet and exercise, based on logic but without definitive studies to prove it. I.e., I would use the found high lipid levels to talk with the patient (motivational interviewing) about diet and exercise and suggest much more aggressive follow-up than on their non-dyslipidemic peers. I would not start meds in this group, but if they were able to improve their lifestyle, would track their lipids and give them feedback. And, it turns out that most adolescents do not have optimal lifestyles (see next study)


Not so surprisingly to those in clinical practice with kids/adolescents, there are very impressive data that adolescents have pretty bad lifestyles in terms of cardiovascular health. A recent AHA scientific statement (see DOI: 10.1161/CIR.0000000000000441) noted:

  • 91% had poor diets, 9% intermediate diets: specifically, overconsumption of sodium, sugar, solid fats, refinded carbohydrates; under consumption of fruits, vegetables, whole grains, dairy, dietary fiber
  • Only 10% of boys and 5% of girls aged 16-19 years old had the recommended 60 minutes of moderate-to-vigorous exercise per day (including muscle-strengthening and bone-loading activities at least 3 days/week. [By the way, my untested hypothesis is that kids can use their cellphones, which seem to be pretty ubiquitous even in poorer communities, to track their “numbers of steps” they take each day, in order both to quantify an important aspect of exercise and give direct feedback to them]
  • 27% of12-19 year olds are obese (BMI>95th percentile)
  • This document does promote “early identification and control of dyslipidemia, including heterozygous familial hypercholesterolemia, throughout youth and into adulthood can reduce clinical cardiovascular disease risk beginning in young adult life”. Also it is typical that total cholesterol decreases 10-15% around puberty, independent of diet (suggesting that we should check lipids when kids are 9-11 yo, before these pubertal changes). Non-HDL is more predictive than any single lipid marker. NHANES data suggest that 26-35% of adolescents have “intermediate or poor” levels of total cholesterol overall (worst in Mexican-Americans, best in non-Hispanic whites)
  • Blood pressure. Use sex/height-specific percentile charts. 9-12% have intermediate or poor BP status
  • Fasting glucose <100 mg/dL. Part of the AHA’s Strategic Impact Goal Through 2020 and Beyond, though they note that this metric is not currently used in pediatric practice, misses the boat in obese children since hyperinsulinemia is the first sign of metabolic derangement, and does not adhere to the Am Diabetes Assn definitions (which are the same as for adults). By the fasting blood glucose <100 metric, 20-38% of 12-19 year olds have intermediate or poor levels in the NHANES study.
  • Smoking (twice as common in adolescents exposed to second-hand smoke: reinforcing the need to get parents/caregivers not to smoke, at least in the house). NHANES data suggest that about 1/3 of 12-19 year olds have tried cigarettes within the prior 30 days.


So, this all reinforces the approach of lipid screening in adolescents, despite the lack of clinical outcome data. To me, the reasons to screen younger people are not just to pick up the extreme cases of familial hypercholesterolemia (which typically requires meds) but to use the results as a concrete means to educate adolescents/families about the need for lifestyle changes, with a focus on diet, exercise and obesity, for anyone with hyperlipidemia.




A Response to: USPSTF Does Not Back Lipid Screening in Adolecents

See the response below, sent around with Holly’s permission. Her study (hyperlink below) in 3 sets of adolescents/young adults aged 17-21 and their parents (including some with familial hypercholesterolemia, obesity, and generally healthy) posited different cholesterol screening scenarios, finding that in each of these 3 groups, both the adolescents and the parents saw worse cholesterol results as signifying poorer health, with several commenting about the need to change their lifestyles. This provides support for universal cholesterol screening and using the results to try to influence behavior.  Even in adolescents.



Awesome summary Geoff about an issue near and dear to my heart (pun intended!).

I am interested in whether knowing about heart health/heart disease risk changes teens behavior.  Probably not but certainly gives us something to anchor our counseling on as you note.  You might find this qualitative study we did asking teens about their hypothetical response to lipid screening interesting –

Thanks as always for such an awesome blog!!!

Holly Gooding, MD, MSc

Division of Adolescent/Young Adult Medicine, Boston Children’s Hospital

Division of General Internal Medicine, Brigham and Women’s Hospital

Harvard Medical School, Boston, MA


Primary Care Corner with Geoffrey Modest MD: Home Blood Pressure Monitoring

3 May, 16 | by EBM

By Dr. Geoffrey Modest

A Japanese study was just done of hypertensive patients, comparing clinic blood pressure readings to home-based monitoring, and finding that home-based monitoring was better overall, especially for coronary artery disease. (See Kario K. J Am Coll Cardiol 2016; 67: 1519).


  • 21,591 treated hypertensive patients (mean age 64.9, 51% women, BMI 24, mean followup 2.02 years) were followed in the HONEST study.
  • Patients were asked to measure their home BP (HBP) twice in the AM and twice in the PM on 2 different days in each measurement period and average the 2 measurements for each timeframe; done at 1, 4, 16 weeks, then at 6, 12, 18, and 24 months
  • Clinic blood pressure CBP) was done by the “usual methods of each institution”, without further clarification


  • 127 strokes (2.92/1000 patient-years) and 121 CAD events (2.78/1000 patient-years)
  • For strokes:
    • Higher incidence if morning home systolic BP (HSBP) ≥145 mmHg vs <125 mmHg [HR 6.01 (2.85-12.68)]. There was a graded increase in strokes as the morning HSBP increased, reaching significance at the 145-155 range (HR 3.97), then increasing in the ≥155 range to HR 12.57.
    • Higher incidence if clinic systolic BP (CSBP) ≥150 mmHg vs <130 mmHg [HR 5.85 (3.17-10.67)]. There was a graded increase in strokes as the morning CSBP increased, reaching significance at the 150-160 range (HR 4.88), then increasing in the ≥160 range to HR 14.17.
  • For CAD events (defined as MI and angina with coronary revascularization):
    • Higher incidence if morning HSBP ≥145 mmHg vs <125 mmHg [HR 6.24(2.82-13.84)]. There was a graded increase in strokes as the morning HSBP increased, reaching significance at the 145-155 range (HR 4.15), then increasing in the ≥155 range to HR 12.61.
    • Higher incidence if CSBP ≥150 mmHg vs <130 mmHg [HR 3.51 (1.71-7.20)]. There was a graded increase in strokes as the morning CSBP increased, reaching significance only at the ≥160 range to HR 8.82.
    • In terms of diastolic BP, there were only significant increases in stroke in the ≥90 mmHg group by HBP, and ≥95 mmHg group by CBP. No difference in CAD events in any diastolic BP group.
  • There did not appear to be a J-shaped curve in the relationship between HBP and stroke or CAD events (the numbers of events at the lower blood pressures was pretty small, so wide confidence intervals for these outcomes, but there was no apparent increase as the morning SBP decreased to 110 mmHg)
  • A statistical analysis (goodness-to-fit) found that for stroke events, both HSBP and CSBP predicted events pretty equally. BUT for CAD events, the morning HSBP far outperformed the CSBP

So, a few points

  • This study supports the importance of home-based blood pressure readings. There is much more data for ambulatory blood pressure monitoring (ABPM), with most but not all studies finding much better predictive value than clinic based measurements, leading to the NICE guidelines in the UK strongly recommending either ABPM or HBP in 2011, and the USPSTF following suit in 2015 [see reviews the USPSTF screening recommendations for blood pressure and includes a Grade A recommendation to screen outside of the clinical setting, but also see a review (Hodgkinson J. BMJ 2011; 342:d3621).
  • But this study adds the following useful insights:
    • They focused on the AM blood pressures, since several studies have looked at blood pressure variability and found that blood pressure tends to be highest in the morning and the incidence of cardiovascular events and strokes is similarly higher then (presumably related to increased activation of the RAS system and increased platelet function/thrombotic tendency). So, from this study which generally found superior predictive value of home-based BP monitoring (especially for CAD), it makes sense for patients to focus just on the morning blood pressures as the decision point on therapy (it turns out in their data that the evening HSBP was also predictive of stroke events but not CAD events). Overall, looking at CSBP or evening HSBP underestimates CAD risk.
  • It should be emphasized how important it is to check the home BP cuff (I ask patients to bring it in, and I simultaneously check one arm as they check the other, then vice versa)
  • One other advantage of home based monitoring is that it empowers the patients around their medical care. In fact, a JAMA study showed that patients who take their BP at home have better blood pressure control (see )
  • So, my bottom line: I really do follow the HBP, which I have lots of patients do (some insurers cover the monitor, otherwise good monitors are about $50, should be appropriately sized upper arm cuffs, and many of my patients have had their kids get one for them). If the patient cannot do HBP monitoring, I ask them to go to a local pharmacy, sit quietly for a few minutes, then check their BP and record it. And I usually do not treat high blood pressure in the clinic if the home pressure is okay (and is done correctly by the patient and with a BP cuff which I find is accurate).

Primary Care Corner with Geoffrey Modest MD: Low LDL and Diabetes Risk

15 Oct, 15 | by EBM

By Dr. Geoffrey Modest

As is evident in several studies, there is a relationship between the use of statins and the development of diabetes (approx 9% increase in diabetes incidence). A recent study looked at the relationship between LDL levels themselves and the development of diabetes (see DOI 10.1007/s00125-015-3762-x).


  • Data from the Framingham Heart Study offspring cohort, with 6011 people and 14120 person-observations (mean age 50, 56% women, mean LDL 125 mg/dl) who were not on any lipid-modifying or antihypertensive medication, followed a mean of 4.5 years
  • Assess the development of diabetes (fasting glucose >125 mg/dl or put on glucose-lowering meds), comparing that to their LDL levels as well as a genetic risk score (GRS) –different genetic changes in single-nucleotide polymorphisms (SNPs) which affect LDL levels


  • 312 people (2.2%) developed diabetes
  • A higher LDL level was associated with a lower risk of diabetes in a graded fashion [OR per SD decrement was 0.81 (0.70-0.93, p=0.004)]
  • The GRS was similarly associated with incident diabetes, both in direction and in magnitude [OR per SD decrement was 0.85 (0.76-0.96, p=0.009)]
  • The increased risk of diabetes was similar across age, sex, BMI, fasting glucose, HDL, or triglyceride levels

A few background issues:

  • It may be more than a coincidence that 2 drugs (niacin and statins) that lower LDL levels are both associated with the development of diabetes
  • Other studies have also found that the GRS for LDL was also associated with diabetes
  • 3 observational studies have found lower LDL levels in people with insulin resistance and diabetes
  • A large Danish database of patients with familial hypercholesterolemia and very high LDL levels (86% of whom had LDL receptor mutations) has found a lower incidence of diabetes (overall OR of 0.45 for those with LDL receptor mutations), with a graded association: the more severe the mutation (assoc with higher LDL levels), the lower the risk of diabetes (see JAMA 2015;313:1029), raising the question that the issue is not statins per se, but the role of the upgraded LDL receptor in predisposing people to diabetes, and raising further the issue of that receptor’s role in glucose homeostasis (see JAMA 2015;313:1016).
  • Patients having variants of the HMG Co-A reductase gene, the enzyme targeted by statins, have increased blood sugar and diabetes risk (i.e., both in those on statins and those with this genetic variant, both of which increase the expression of LDL receptors). the authors postulate that pancreatic β-cells, in the setting of familial hypercholesterolemia, have decreased cholesterol uptake (genetic impairment of LDL receptors) and therefore improved β-cells function and survival (there are a slew of animal studies and some human tissue culture ones supporting the conclusion that those with enhanced LDL receptor activity and the resulting cholesterol-laden pancreatic β-cells have impaired function of the β-cells, see JAMA 2015;313:1029).

So, what does this all mean?? It raises a few issues: perhaps it is not the statins that are causing diabetes, but the lower LDL levels themselves. and, if it turns out that this is mediated through the increased LDL receptors as is likely, and this increase is augmented by statins as well as some mutations, then perhaps developing other drugs which lower LDL levels but do not affect the LDL receptors might be more beneficial (by the way, the PCSK9 inhibitors increase LDL receptor concentrations even more than statins). But at this point, all analyses suggest that lowering of LDL is still beneficial overall, despite the potential development of diabetes. See for a review of statin adverse effects.

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