LDL Cholesterol Particle Size and Number What Gives ?

Posted on February 27, 2018

LDL Particle Size and Particle Number, What Gives?

Ron is a 72 year old retired engineer, and has a total cholesterol of 174 which hasn’t changed over the seven years we have been following him. This is quite low. Yet, Ron is concerned because his LDL particle number and LDL particle size are “outside of the lab range”.  He is very worried about this and is concerned about his risk for future heart attack.  I explained to Ron the lab range doesn’t apply to him.  Ron’s Calcium Score is low, and his total cholesterol is 174, and he does not have metabolic syndrome or diabetes, so he doesn’t need to worry about the LDL particle size or particle number.

What does the mainstream cardiology say about the value of LDL particle size and number?

The Quebec Study – Small Dense LDL Associated with Increased Mortality from Coronary Artery Disease

You might say “wait just a minute here”, the Quebec study followed 2072 males over 13 years and found that small dense LDL was associated with increased mortality from cardiovascular disease above chart).(6)  The above chart is very convincing, and the three lines for small dense LDL are nicely separated. (6) However, as pretty as the above chart looks, Correlation is not necessarily causation.  If increased small dense LDL particle number causes coronary artery disease, then an intervention that reduces small dense LDL particles should be preventive.  However we know that it is not. Above image courtesy of Medscape.

Houston, We Have a Problem,  New Drug Reduces Small LDL,

However, No Benefit in Preventing Heart Disease

Treatment with the new cholesterol lowering drug, Evacetrapib, resulted in significant decreases in “total LDL particle number (LDL-P) (up to -54%), and small LDL particle (sLDL) (up to -95%) concentrations”.(5) Yet, according to Dr Lincoff in NEJM 2017,

“treatment with evacetrapib did not result in a lower rate of cardiovascular events than placebo among patients with high-risk vascular disease.”(4)

As a matter of fact, Eli Lilly abandoned drug development after this failed study.(4)  So we see that reducing total LDL particle number, or increasing LDL particle size had no benefit for preventing death from heart disease.  The benefit was same as a placebo.

Dr Allaire  agrees that LDL particle size is not very useful.  Dr Allaire writes in 2017 Current Opinion in Lipidology:(1)

“LDL particle size….has not been independently associated with CVD risk after adjustment for other risk factors such as LDL cholesterol, triglycerides, and HDL-C and that routine use of information pertaining to particle size to determine and manage patients’ risk is not yet justified.”(1)

In other words, according to Dr Allaire,  the LDL particle size is not a good predictor of cardiovascular risk.(1)

Predicting Risk: LDL Subfraction Vs. Calcium Score

The next question you might ask: “If LDL cholesterol is not helpful, then what other test is useful for predicting risk of cardiovascular disease?” 

The answer is the Calcium Score which is an inexpensive test which uses a CAT scan to measure the amount of calcium in the coronary arteries.  Studies show that the higher the number the greater the risk, the lower the number the smaller the risk.  None of the cholesterol subfractions can provide this type of information, and in my opinion should be relegated to the medial museum, as a relic from the past.

Conclusion: When it comes down to a contest between LDL Cholesterol Subfractions and Calcium Score, there is no contest.  The Calcium Score wins every time.

Jeffrey Dach MD
7450 Griffin Road Suite 190
Davie Florida 33314
954 792-4663

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Links and References

Header Image LDL particle courtesy of Drs Wolfson

1) Curr Opin Lipidol. 2017 Jun;28(3):261-266. LDL particle number and size and cardiovascular risk: anything new under the sun? Allaire J1, Vors C, Couture P, Lamarche B.

LDL particle size, on the other hand, has not been independently associated with CVD risk after adjustment for other risk factors such as LDL cholesterol, triglycerides, and HDL-C and that routine use of information pertaining to particle size to determine and manage patients’ risk is not yet justified.

We provide here an up-to-date perspective on the potential use of LDL particle number and size as complementary risk factors to predict and manage cardiovascular disease (CVD) risk in the clinical realm.
RECENT FINDINGS:  Studies show that a significant proportion of the population has discordant LDL particle number and cholesterol indices [non-HDL cholesterol (HDL-C)]. Data also show that risk prediction may be improved when using information on LDL particle number in patients with discordant particle number and cholesterol data. Yet, most of the current CVD guidelines conclude that LDL particle number is not superior to cholesterol indices, including non-HDL-C concentrations, in predicting CVD risk. LDL particle size, on the other hand, has not been independently associated with CVD risk after adjustment for other risk factors such as LDL cholesterol, triglycerides, and HDL-C and that routine use of information pertaining to particle size to determine and manage patients’ risk is not yet justified.
SUMMARY:  Additional studies are required to settle the debate on which of cholesterol indices and LDL particle number is the best predictor of CVD risk, and if such measures should be integrated in clinical practice.

Women with discordant high particle concentration were more likely to have metabolic syndrome (MetS) and diabetes

2) Clin Chem. 2017 Apr;63(4):870-879. doi: 10.1373/clinchem.2016.264515. Epub 2017 Feb 7.  Discordance between Circulating Atherogenic Cholesterol Mass and Lipoprotein Particle Concentration in Relation to Future Coronary Events in Women.
Lawler PR1,2,3,4, Akinkuolie AO1,3, Ridker PM2,3, Sniderman AD5, Buring JE3,4, Glynn RJ3,4, Chasman DI3, Mora S6,2,3.
It is uncertain whether measurement of circulating total atherogenic lipoprotein particle cholesterol mass [non-HDL cholesterol (nonHDLc)] or particle concentration [apolipoprotein B (apo B) and LDL particle concentration (LDLp)] more accurately reflects risk of incident coronary heart disease (CHD). We evaluated CHD risk among women in whom these markers where discordant.
METHODS:Among 27533 initially healthy women in the Women’s Health Study (NCT00000479), using residuals from linear regression models, we compared risk among women with higher or lower observed particle concentration relative to nonHDLc (highest and lowest residual quartiles, respectively) to individuals with agreement between markers (middle quartiles) using Cox proportional hazards models.
RESULTS:Although all 3 biomarkers were correlated (r ≥ 0.77), discordance occurred in up to 20.2% of women. Women with discordant high particle concentration were more likely to have metabolic syndrome (MetS) and diabetes (both P < 0.001). Over a median follow-up of 20.4 years, 1246 CHD events occurred (514725 person-years). Women with high particle concentration relative to nonHDLc had increased CHD risk: age-adjusted hazard ratio (95% CI) = 1.77 (1.56-2.00) for apo B and 1.70 (1.50-1.92) for LDLp. After adjustment for clinical risk factors including MetS, these risks attenuated to 1.22 (1.07-1.39) for apo B and 1.13 (0.99-1.29) for LDLp. Discordant low apo B or LDLp relative to nonHDLc was not associated with lower risk.
CONCLUSIONS:Discordance between atherogenic particle cholesterol mass and particle concentration occurs in a sizeable proportion of apparently healthy women and should be suspected clinically among women with cardiometabolic traits. In such women, direct measurement of lipoprotein particle concentration might better inform CHD risk assessment.

3)   Curr Opin Endocrinol Diabetes Obes. 2018 Jan 10. Discordance between lipoprotein particle number and cholesterol content: an update.
Cantey EP1, Wilkins JT2.
The cholesterol content within atherogenic apolipoprotein-B (apoB) containing lipid particles is the center of consensus guidelines and clinicians’ focus whenever evaluating a patient’s risk for atherosclerotic cardiovascular disease. The pathobiology of atherosclerosis requires the retention of lipoprotein particles within the vascular intima over time followed by maladaptive inflammation resulting in plaque formation and rupture in some. The cholesterol content is widely variable within each particle creating either cholesterol-deplete or cholesterol-enriched particles. This variance in particle cholesterol content varies within and between individuals. Discordance analysis exploits this difference in cholesterol content of particles to demonstrate the differential significance of LDL-cholesterol (LDL-C) and non-HDL-C from measures of lipoprotein particle number in terms of assessing atherosclerotic cardiovascular disease risks.
RECENT FINDINGS:Three studies have added to the growing body of literature of discordance analysis. Despite wide variability of discordance cutoffs, baseline risk of atherosclerotic disease, and populations sampled, the conclusion remains the same: risk of atherosclerotic disease follows apoB lipid particle concentration rather than cholesterol content of lipid particles.
SUMMARY:In addition to traditional lipid fractions, assessments of atherogenic particle number should be strongly considered whenever assessing CVD risk in nontreated and treated individuals. There is a need for clinical trials that focus not only on the reduction in LDL-C but apoB, as well.

4)  Lincoff, A. Michael, et al. “Evacetrapib and cardiovascular outcomes in high-risk vascular disease.” New England Journal of Medicine 376.20 (2017): 1933-1942.

Although treatment with evacetrapib has resulted in reductions of 60 to 70% in the levels of small dense LDL particles,29 effects on the total number of LDL particles and on apolipoprotein B levels (reductions of 22% and 20%, respectively) are considerably less pronounced.

CONCLUSIONS:Although the cholesteryl ester transfer protein inhibitor evacetrapib had favorable effects on established lipid biomarkers, treatment with evacetrapib did not result in a lower rate of cardiovascular events than placebo among patients with high-risk vascular disease.

5)  Nicholls SJ, Ruotolo G, Brewer HB, et al. Evacetrapib alone or in combination with statins lowers lipoprotein(a) and total and small LDL particle concentrations in mildly hypercholesterolemic patients. J Clin Lipidol 2016;10:519-527.e4

Potent CETP inhibitors reduce plasma concentrations of atherogenic lipoprotein biomarkers of cardiovascular risk.
OBJECTIVES:To evaluate the effects of the cholesteryl ester transfer protein (CETP) inhibitor evacetrapib, as monotherapy or with statins, on atherogenic apolipoprotein B (apoB)-containing lipoproteins in mildly hypercholesterolemic patients.
METHODS:VLDL and LDL particle concentrations and sizes (using nuclear magnetic resonance spectroscopy) and lipoprotein(a) concentration (using nephelometry) were measured at baseline and week 12 in a placebo-controlled trial of 393 patients treated with evacetrapib as monotherapy (30 mg/d, 100 mg/d, or 500 mg/d) or in combination with statins (100 mg plus simvastatin 40 mg/d, atorvastatin 20 mg/d, or rosuvastatin 10 mg/d; Clinicaltrials.gov Identifier: NCT01105975).
RESULTS:Evacetrapib monotherapy resulted in significant placebo-adjusted dose-dependent decreases from baseline in Lp(a) (up to -40% with evacetrapib 500 mg), total LDL particle (LDL-P) (up to -54%), and small LDL particle (sLDL) (up to -95%) concentrations. Compared to statin alone, coadministration of evacetrapib and statins also resulted in significant reduction from baseline in Lp(a) (-31%), LDL-P (-22%), and sLDL (-60%) concentrations. The percentage of patients with concentrations above optimal concentrations for LDL-P (>1000 nmol/L) and sLDL (>600 nmol/L) decreased from 88% and 55% at baseline, respectively, to 20% and 12% at week 12, for patients treated with evacetrapib plus statins. Evacetrapib, alone or with statins, significantly increased LDL-P size.

CONCLUSIONS:Evacetrapib, as monotherapy or with statins, significantly reduces the concentrations of atherogenic apoB-containing lipoproteins, including Lp(a), LDL-P, and sLDL.

6) St-Pierre, Annie C., et al. “Low-density lipoprotein subfractions and the long-term risk of ischemic heart disease in men: 13-year follow-up data from the Quebec Cardiovascular Study.” Arteriosclerosis, thrombosis, and vascular biology 25.3 (2005): 553-559.Low density lipoprotein Risk of ischemic heart disease Quebec St Pierre Annie Arterio thrombo vasc bio 2005

The objective of the present study was to investigate the association between large and small low-density lipoprotein (LDL) and long-term ischemic heart disease (IHD) risk in men of the Quebec Cardiovascular Study.
METHODS AND RESULTS:Cholesterol levels in the large and small LDL subfractions (termed LDL-C> or =260A and LDL-C<255a 13="" 2072="" 262="" a="" all="" and="" angina="" at="" baseline="" cardiovascular="" cohort="" coronary="" death="" during="" electrophoresis="" estimated="" events="" examination="" first="" followed-up="" for="" free="" from="" gel="" gradient="" ihd="" in="" infarction="" men="" myocardial="" nbsp="" nonfatal="" of="" pectoris="" period="" plasma="" polyacrylamide="" population-based="" quebec="" recorded.="" respectively="" strong="" study.="" style="border: 0px; font-family: inherit; font-style: inherit; margin: 0px; outline: 0px; padding: 0px; vertical-align: baseline;" the="" unstable="" were="" which="" whole="" years="">Our study confirmed the strong and independent association between LDL-C<255a a="" and="" as="" dense="" ihd="" in="" ldl="" levels="" men="" of="" phenotype="" proxy="" risk="" small="" strong="" the="">, particularly over the first 7 years of follow-up. However, elevated LDL-C> or =260A levels (third versus first tertile) were not associated with an increased risk of IHD over the 13-year follow-up (RR=0.76; P=0.07).

CONCLUSIONS:These results indicated that estimated cholesterol levels in the large LDL subfraction were not associated with an increased risk of IHD in men and that the cardiovascular risk attributable to variations in the LDL size phenotype was largely related to markers of a preferential accumulation of small dense LDL particles.

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Read the complete article here.

Evacetrapib and Cardiovascular Outcomes in High-Risk Vascular Disease - Gibson

Evacetrapib and Cardiovascular Outcomes in High-Risk Vascular Disease


C. Michael Gibson MD‏           

 

Proud to be co-author of this New England Journal Med article showing lowering LDL does not always improve outcomes

Background

The cholesteryl ester transfer protein inhibitor evacetrapib substantially raises the high-density lipoprotein (HDL) cholesterol level, reduces the low-density lipoprotein (LDL) cholesterol level, and enhances cellular cholesterol efflux capacity. We sought to determine the effect of evacetrapib on major adverse cardiovascular outcomes in patients with high-risk vascular disease.

Conclusions

Although the cholesteryl ester transfer protein inhibitor evacetrapib had favorable effects on established lipid biomarkers, treatment with evacetrapib did not result in a lower rate of cardiovascular events than placebo among patients with high-risk vascular disease.

 (Funded by Eli Lilly; ACCELERATE ClinicalTrials.gov number, NCT01687998.)


Read the complete article here.

More SALT Controversy - Nestle

It’s salt war time again: new research, arguments over public health recommendations, and issues of conflicts of interest

Here are the burning questions about sodium (which is 40% of salt) intake:
(a) Does too much dietary sodium cause high blood pressure?   Answer: an unambiguous yes (although not necessarily in everyone).
(b) Are public health recommendations to reduce salt intake warranted?  I think so, but others disagree.
(c) If so, to what level?  Although virtually all committees reviewing the evidence on salt and hypertension view public health recommendations as warranted, and advise an upper limit of about 2 grams of sodium (5 grams of salt, a bit more than a teaspoon (see table from the Wall Street Journal), these too are under debate.

These recommendations are strongly opposed by The Salt Institute, the trade association for the salt industry, its industry supporters, and some groups of investigators.
Now the New England Journal of Medicine weighs in with three new studies, an editorial, and a cartoon video.  The papers:

• Association of Urinary Sodium and Potassium Excretion with Blood Pressure: A. Mente and Others | N Engl J Med 2014;371:601-611
• Urinary Sodium and Potassium Excretion, Mortality, and Cardiovascular Events: M. O’Donnell and Others | N Engl J Med 2014;371:612-623
• Global Sodium Consumption and Death from Cardiovascular Causes: D. Mozaffarian and Others | N Engl J Med 2014;371:624-634

Start with the video,  narrated by the editor, Dr. Jeffrey Drazen (click on video link on the right side).  It gives an excellent summary of the three papers.  Despite their methodological differences, all confirm (a).  They disagree on (c) and, therefore, (b).

Are public health recommendations warranted?
But note Dr. Drazen’s suggestion: “throw away the salt shaker.”
He is in favor of reducing salt intake.  But the salt shaker is not where most dietary salt comes from.  At least 75% of salt in American diets comes from restaurant and processed foods.   As Dr. Yoni Freedhoff explains:

If you’d like to reduce the sodium in your diet, rather than keep a running tally of how much you’re actually consuming, why not try instead to determine what percentage of your diet comes from restaurants and boxes? Sure, there’s data to suggest you might simply find other ways to add salt to your diet. But visit restaurants and consume processed foods less frequently, and I’d be willing to wager that you’ll be far more likely to see health benefits than were you to simply fill your grocery cart with low-sodium versions of highly processed foods.

Individuals cannot cut down on salt on their own.  That’s one reason why public health policies are needed—to get restaurants and processed food manufacturers to reduce salt content.
Two of the papers say that the only people who need to cut down on salt are those with hypertension and older people (one of the studies says that means people over age 55).

• How many Americans have hypertension?  67 million (1 out of every 3 adults) according to the CDC.
• How many Americans are over age 55?  More than 80 million, and rising.

You can’t expect 70 or 80 million people to reduce salt intake on their own.  Hence: public health recommendations.

Conflict of interest alert
Some of the investigators report receiving grants or fees from companies that make anti-hypertensive drugs but the editorial accompanying the papers is of special concern.   Written by Dr. Suzanne Oparil, it says about one of the studies:

These provocative findings beg for a randomized, controlled outcome trial to compare reduced sodium intake with usual diet. In the absence of such a trial, the results argue against reduction of dietary sodium as an isolated public health recommendation.

These conclusions sent me right to her conflict-of-interest disclosure statement.  Although Dr. Oparil reports receiving grants or fees from companies making anti-hypertensive drugs—-and, even more remarkable, from The Salt Institute—she states that she has no conflicts of interest.
I think she does.

Implications
Her editorial is especially unfortunate because it influences the way reporters write about the studies.
The Associated Press account, for example, begins:

A large international study questions the conventional wisdom that most people should cut back on salt, suggesting that the amount most folks consume is OK for heart health — and too little may be as bad as too much. The findings came under immediate attack by other scientists.

As well they should.  Blood pressure rises with age and huge swaths of the population would be healthier eating less salt.   The AP reporter quoted me saying so:

“People don’t eat salt, they eat food,” she said. “Lots of people have high blood pressure and lots of people are getting older,” making salt a growing concern, she said. “That’s the context in which this is taking place.”

The three studies are complicated to interpret because of differences in methods and discrepancies in outcomes.  They agree that if you already have hypertension or are “elderly,” or eat a lot of salt, you should cut down.

This seems like a good idea for just about anyone.   People don’t eat salt; they eat foods containing salt, and foods high in salt tend to be high in other things best consumed in small amounts.
The studies also talk about the protective effects of potassium, best obtained from vegetables.
Eat a lot of vegetables and not too much junk food, and you don’t have to worry about any of this.
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Read the complete article here.

Ezetimibe Prescribing Fails to Keep Up With Evidence - JAMA

Ezetimibe Prescribing Fails to Keep Up With Evidence     

Mike Mitka, MSJ 

             

JAMA. Published online March 19, 2014. doi:10.1001/jama.2014.2896

          

 

Although physicians like to think they practice evidence-based medicine, that appears to not be the case with prescribing the cardiovascular drug ezetimibe. And some critics say that use of surrogate markers to guide practice rather than clinical outcomes such as occurrence of myocardial infarction, stroke, or death has likely played a role.

 

Ezetimibe is an intestinal cholesterol absorption inhibitor found to reduce low-density lipoprotein cholesterol (LDL-C) levels by about 20% when given alone. It also further reduces LDL-C levels when added to statin therapy, which blocks cholesterol synthesis in the liver by inhibiting HMG-CoA reductase.

 

The Food and Drug Administration approved ezetimibe in 2002 for use in the United States primarily because it lowered LDL-C levels, a surrogate marker for prevention of cardiovascular disease. Whether ezetimibe improved clinically meaningful outcomes remained a question.

 

That question was somewhat answered in January 2008, with the announcement that the Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression (ENHANCE) trial, sponsored and conducted by industry, found that the addition of ezetimibe failed to reduce atherosclerosis progression compared with simvastatin alone, despite lowering LDL-C levels. Atherosclerosis progression was determined by a change in the intima-media thickness of the walls of the carotid and femoral arteries—yet another surrogate end point (Kastelein JJP et al. N Engl J Med. 2008;358[14]:1431-1443).

Place holder to copy figure label and caption

Graphic Jump Location

US and Canadian physicians continue to prescribe ezetimibe even after a study found giving the drug with a statin failed to reduce atherosclerosis progression compared with the statin alone.

 

 

The ENHANCE result prompted some leaders in the cardiology community to question ezetimibe’s place in cardiovascular disease treatment. Harlan Krumholz, MD, professor of medicine and epidemiology and public health at Yale University in New Haven, Connecticut, said the study should change practice. “Although not definitive, [ENHANCE] increases our uncertainty about the clinical value of this novel drug. Without some evidence of improved outcomes associated with its use, ezetimibe should be relegated to a last option for patients who need medication for hypercholesterolemia, and even in these cases, it is reasonable for clinicians and their patients to wait for further information before considering it,” he wrote in NEJM Journal Watch (http://tinyurl.com/pk9xr29).

 

So did the ENHANCE results change practice? In the United States, the answer is “somewhat,” while in Canada, the answer appears to be “no.”

 

In a study published in the American Heart Journal, researchers looked at ezetimibe prescription trends before and after ENHANCE, using data collected from CompuScript in Canada and IMS Health in the United States from January 1, 2002, to December 31, 2009. The researchers found the monthly number of ezetimibe prescriptions per 100 000 population rose from 6 to 1082 in the United States from November 2002 to January 2008 and then declined to 572 per 100 000 population by December 2009, a decrease of 47.1%. In Canada, however, use continuously increased from 2 to 495 per 100 000 from June 2003 (when the drug was approved in Canada) to December 2009 (Lu L et al. Am Heart J. doi:10.1016/j.ahj.2014.01.014 [published online February 27, 2014]).

 

Coauthor Cynthia A. Jackevicius, PharmD, MSc, a professor of pharmacy practice and administration at Western University of Health Sciences in Pomona, California, and an adjunct scientist, Institute for Clinical Evaluative Sciences, in Toronto, said her team was initially surprised by the Canadian results.

 

“Previous findings showed ezetimibe use in Canada experienced a more conservative uptake, so we expected to see a decrease in use in response to the ENHANCE study,” Jackevicius said. “So we looked for different factors, and one is the Canadian lipid guidelines, which specifically said ezetimibe could be added to statins, and that didn’t change after ENHANCE came out.”

A study of ezetimibe use in Saskatchewan, the only Canadian province that lists the drug for open formulary access, even though guidelines say it’s a second-line agent for lowering cholesterol, reflects Jackevicius’s team’s findings. Using data from provincial health administrative databases, the Saskatchewan researchers found that ezetimibe prescriptions were 2.5% of cholesterol-lowering dispensations in 2004 and 8.8% of such dispensations in 2011 (Alsabbagh WM et al. Can J Cardiol. 2014;30[2]:237-243). The authors concluded that allowing unrestricted use of ezetimibe in Saskatchewan may have led to a large number of inappropriate prescriptions, at odds with Canadian clinical guidelines.

 

And although ezetimibe use declined in the United States, its use per 100 000 population is still greater than Canada’s, generating US expenditures of more than $2.2 billion in 2009.

 

Krumholz, one of the coauthors on the study with Jackevicius, remains perplexed as to the continuing popularity of ezetimibe. “The drug continues to defy gravity, and that’s probably a result of really strong marketing and the singular focus on cholesterol numbers,” he said.

 

Krumholz said heart health campaigns urging patients to “know your numbers” and treatment goals based on cholesterol measurements, such as getting asymptomatic individuals’ LDL-C levels below 130 mg/dL, have worked in ezetimibe’s favor at the expense of evidence-based medicine. “Is this the drug that lowers your LDL-C and helps you? We don’t know that,” he said. “The comfort of hitting a target offers little benefit if you don’t know that it is really protecting you.”

 

Although ENHANCE has not derailed ezetimibe prescribing, the newest cholesterol management guidelines just might. The guidelines, issued late last year by the American College of Cardiology and the American Heart Association, abandon the idea of reaching a target level for LDL-C, instead recommending the use of statins to reduce LDL-C levels only for certain types of patients.

Will this change in the guidelines affect ezetimibe prescribing? “It will be interesting to see what the guidelines will do,” Krumholz said.

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Read the complete article here.

Putting "Relative Risk" in perspective - Eades

Absolute risk versus relative risk: Why you need to know the difference

30. December 2013,

Six years ago, the airwaves were alive with Lipitor ads. Lipitor, a statin and the largest selling drug in the world at that time, was being challenged by other less expensive statins that had gone off patent, so Pfizer, the manufacturer, was blanketing the media in an effort to keep sales humming.

Pfizer had a series of ads featuring Dr. Robert Jarvik, one of the developers of the first artificial heart. These ads were a first in that a real doctor had never appeared in an ad touting a drug. As I posted at the time, Pfizer and Dr. Jarvik got into some trouble because they all played a little fast and loose with the truth about Dr. Jarvik’s credentials.



Aside from the misrepresentation by both Pfizer and Jarvik, one of the claims many of these ads made was that by taking Lipitor you could reduce your risk of heart disease by 36 percent. Sounds pretty good. I would like to reduce my risk of heart disease by 36 percent as did millions of people who went on the drug.

These ads weren’t technically misleading, but they didn’t tell the whole truth, because the 36 percent reduction in heart attack risk was what’s called a relative risk reduction.

Relative Risk
Relative risk is always stated as a percentage. Let’s say we do a study in which we randomize 200 subjects in two groups of 100. One group (the study group) takes a drug, and the other (the control group) takes a sugar pill. We keep the subjects in the two groups on their pill regimen and wait for, say, ten years to see what happens. After ten years, we find that 90 people in the group taking the sugar pill died while only 60 people taking the drug died.

We can then do the following calculation. 90 − 60 = 30. 30 divided by 90 = 0.33. Converting 0.33 to a percentage = 33 percent. Which is the relative risk. If this were an actual study, you could say people taking the drug reduced their risk of dying by 33 percent.

Would this be important? Absolutely. In this case as least. Why? Because 150 people out of 200 died. This means most of the people in the study died, so a 33 percent reduction in risk is huge. I would be all over this drug in a heartbeat.

So what’s the problem, then, with the 36 percent reduction in risk found in the Lipitor study? And why shouldn’t people be begging to go on Lipitor?

Because they need to know the absolute risk before the relative risk becomes important.

Absolute Risk
The absolute risk is simply the total risk for whatever is being studied. In our made up example above, the study end point we were looking for was death. In that example, 150 out of 200 died. So if you were a subject in that study, your absolute risk of dying would be 150 divided by 200 or 75 percent, which is very high.

If your absolute risk of crashing during a commercial airline flight were 75 percent, you would never fly. But if you absolutely had to fly, and one airline offered a 33 percent reduction in risk of crashing (relative risk), you would be stupid not to fly that airline.

To make sense out of relative risk, you’ve got to know the absolute risk.

Let’s go back to our Lipitor claim.

The 36 percent relative risk reduction figure came from a study published in Drugs titled Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial–Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial.

This study was a subset of a larger study in which about 20,000 subjects with high blood pressure and three other cardiovascular risk factors were randomized into two groups, the subjects in each of which got one of two blood pressure lowering medications. From this larger group, a little over 10,000 subjects were found who had cholesterol levels at or below 250 mg/dl (6.5 mmol/l). In addition to the blood pressure medications, half of this group got 10 mg of Lipitor (atorvastatin) per day while the other half got a placebo along with their blood pressure medication.

In the Lipitor/placebo arm of this study, the endpoint was defined as a non-fatal heart attack or death from heart disease.

After about 3.3 years, this arm of the study was discontinued because there were a significant number of either heart attacks of deaths from heart disease in the placebo group, and the researchers felt it was unethical to continue the study.

When the data were examined, it turned out that the group taking Lipitor experienced a 36 percent decrease in relative risk for heart disease. Thus the barrage of ads for Lipitor that followed.
Even websites aimed at doctors, using info from the Lipitor package insert, showed graphics designed to make any doctor grab for the Lipitor pre-printed prescription pad. This graph is 100 percent accurate, but, as we shall see, hugely misleading.


Figure 1 below is a graphic showing what that 36 percent relative risk looks like.

Figure 1. Relative risk of 36 percent with a large absolute risk.

 

Pretty impressive, isn’t it? Makes you wonder why anyone wouldn’t want to take Lipitor. Problem is, Figure 1, which I made up, shows a relative risk differential of 36 percent, but it also shows a large absolute risk.

Looking at Figure 2 below, which shows the actual absolute risk of experiencing a heart attack or dying from heart disease in this study, you can see that the 36 percent relative risk reduction is accurate. But does it really make you want to stampede to the pharmacy to pick up your Lipitor? Remember, these subjects all had high blood pressure and two other risk factors for heart disease, yet their absolute risk is pretty low. Would you want to take a medicine that could give you muscle aches and pains along with muscle wasting, short term memory loss and possibly fatal liver or kidney damage based on the absolute risk shown in Figure 2?

Figure 2.  Relative risk of 36 percent with actual absolute risk in the Lipitor study. 

 

If you compare Figure 1 to Figure 2 above, both of which have the same relative risk, you can readily see that the absolute risk is extremely important. If the absolute risk is high, as it is in Figure 1 at the top, then the relative risk becomes important.

If, as in Figure 2, the real Lipitor vs placebo graphic, the absolute risk is small, then not so much so. Both Figure 1 and Figure 2 show the same relative risk, but not anywhere close to the same absolute risk. Which is why you always want to know the absolute risk before you make a decision on anything based on relative risk. Because absolute risk is usually pretty low in drug studies, the pharmaceutical industry typically uses the relative risk number to sell their medicines.

In the case of statins, most people go on statins because what they really fear is dropping dead of a heart attack, and they feel the statins are protective.

What happened in this study? There were two more deaths in the placebo group than in the Lipitor group, but that number wasn’t statistically significant. Figure 3 below is a graphic showing the absolute risk of having a fatal heart attack in the Lipitor trial.

Figure 3. Relative and absolute risk of fatal heart attack in the Lipitor study.

 

Not a huge absolute risk.

Let’s look at another example that is much more dramatic than the Lipitor study above.

I pulled a paper from the New England Journal of Medicine (NEJM) looking at coronary artery calcification (CAC) scores and risk for having a heart attack.

Approximately 20 percent of the plaque in coronary arteries is composed of calcium, which shows up on X-rays. But since the heart is constantly in motion, it’s difficult to see the calcium in standard X-rays of the chest. Specialized CT machines, however, can take extremely fast photos of the heart and actually see the calcium in the coronary arteries. A computer program then converts this calcium into a score, which is simply a number. If you have a zero score, you have no calcium accumulation, which means you probably don’t have any plaque to speak of. You could have some soft plaque that hasn’t yet calcified, but a zero CAC score is definitely a good one.

The NEJM study looked at CAC scores of 6,722 subjects and broke them out into one of four groups. Zero, CAC score of 1-100, CAC score of 101-300, and CAC score of greater than 300. These groups were followed for about 4 years on average for the main endpoint of the study, which was a major coronary event, defined as a heart attack or death from coronary heart disease.

You can see the relative and absolute risk in the graphics below. Upper left is zero CAC score. Upper right, 1-100 CAC score. The lower left is 101-300 CAC score, and the lower right is greater than a 300 CAC score.

Figure 4. Relative and absolute risks for various CAC scores.  Zero upper left. 1-100 CAC upper right.

101-300 CAC lower left.  Greater than 300 lower right.

 

As you can see, the risk for a major coronary event is negligible with a CAC score of zero. And the risk increases as the CAC scores go up. The subjects in this study who had CAC scores above 300 experienced 19 times more major coronary events than did those with zero CAC scores. Which would mean a 300+ CAC score carries a relative risk of 1900 percent* as compared to a zero, which is humongous. But looking at the absolute risk tells a different story.

I’ve seen patients with 300+ CAC scores come unglued. Granted, it’s not a score you want to see, but it doesn’t mean you’re going to die the next day. A lot of people feel that way, though. Which is why knowing the absolute risk is important before you decompensate over a high relative risk for this or any condition.

If you would like to play around with these absolute and relative risk graphics, you can do so at this site.  Keep the site bookmarked, so the next time you come across a relative risk, look up the actual risk and graph it.  Only then will you know the true risk involved.

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*I used a relative risk score based on the raw data from the study.  If you look at the actual study (linked above), you see different relative risks than what I have.  The ones in the study are lower because the authors extrapolate the data out longer and take into account when the events happened.  So, if you happen to have a high CAC score, your risk is lower than what I show above, which was strictly for illustrative purposes.
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Read the complete article here.

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20140721 Added this link to good video on relative risk. Well worth the watch.

An incredible teaching opportunity on the basics of heart disease - Mandrola

The George W Bush stent case: An incredible teaching opportunity on the basics of heart disease

John Mandrola, MD August 11, 2013

 

The wrist artery hardly had time to seal. (Surely it was a radial.) The controversy came that fast.
The drumbeat of naysayers seemed to start only minutes after a prideful press release announced that George W Bush had undergone successful cardiac stent placement. The ever-quotable cardiologist from Cleveland Clinic, Dr. Steven Nissen, said, “This is really American medicine at its worst.” Dr. David L Brown, from Stony Brook University, and author of an important 2012 study on stents, added that GWB was “now the poster child for the inappropriate use of stenting.”

How could this be? It must be a good thing to uncover and treat heart problems before damage occurs. What do you mean he shouldn’t have had a blockage ‘fixed’ with a stent? Blockages are bad; let’s get them cleaned up. A clear artery is better than an obstructed one, right?

These common sense notions and the intense debate surrounding GWB’s stent offers us an incredible teaching moment for heart disease. It’s hard to believe our number one killer could be this misunderstood. But it is. Both doctors and patients struggle with the basics of atherosclerosis (hardening of the arteries).

This is big. Hidden in the nuances of the GWB case are important messages about the process of atherosclerosis and the significance of the vulnerable plaque. I believe advancing the knowledge of basic atherosclerosis would go far in correcting much of the over-treatment in cardiology today. The false expectations of screening stress tests and the surprise over the lack of benefit of stenting non-symptomatic disease illustrates the wide swath of misinformation out there.

My aim is to use this controversy to spread the facts and fundamentals about atherosclerosis and heart disease.

Consider this question as you read: If you had the choice between two types of blockages in one of the three main coronary arteries (the arteries that supply the heart), which would you choose: Choice A is a thick smooth 80% blockage. Choice B is a thin-walled 10% blockage.

The GWB story:
A former president of the United States gets careful medical attention. In the course of this quite careful care, a significant coronary blockage was discovered. Like many patients with heart disease, Mr. Bush had no symptoms. He did not report chest pain, shortness of breath or dizziness. He is known to be an avid cyclist, a mountain biker even. I don’t know the former president, but I know mountain bikers. He likely demanded a lot from his heart at times. GWB is also special in that it’s hard to quantify the inflammation of 8-years in the White House. (You writers know how much criticism inflames; imagine half the free world thinking badly of you.)

The controversy in this case centers on two issues: First, why did a non-symptomatic patient get an exercise study in the first place? Second, why was a stent used to treat a blockage that was not causing symptoms?

Lack of benefit for stents in stable coronary artery disease:
Let’s begin with the second issue and work backwards. To understand the stent debate, we need to start with the aptly named COURAGE trial, published in 2007 in the New England Journal of Medicine. Researchers screened many thousands of patients to come up with about 2300 study subjects with significant coronary artery disease–similar to the former president’s. COURAGE studied two treatment strategies: about 1100 patients were randomized to optimal medical therapy and another 1100 had optimal medical therapy plus a stent placed in any blockage greater than 70%. Researchers made sure both groups had intense medical therapy, including regularly scheduled nurse-managed visits, free medicines, and dietary and exercise counseling. They then followed patients for five years and compared hard outcomes. COURAGE got its acronym because it was felt courageous to leave patients with major blockages on medicine alone. Prevailing wisdom held that major blockages needed to be stented. (But you know how prevailing wisdom often turns out.)

COURAGE investigators showed that adding a stent to optimal medical therapy and lifestyle changes made no difference in the risk of death, heart attack or stroke. Criticism of COURAGE was robust. The trial enrolled mostly white male patients and bare metal (not drug-eluting) stents were used. Some said the intensity of medical therapy was unrealistic in the real world. (A highly relevant criticism in this era of lean healthcare delivery.) Applicability of COURAGE was also called into question as the investigators had to screen many thousands of patients to get down to 2300 subjects.
These findings, however, turned out to be no fluke. In 2012, a meta-analyses of 8 similar stent trials (JAMA –IM), including 7229 patients, confirmed the lack of benefit for stents in patients with stable coronary artery disease.

It was settled then; stents should only be used in symptomatic patients, like those having heart attacks, chest pain, arrhythmia, or in those with weak hearts and congestive heart failure. Using stents pre-emptively did not work to prevent heart attacks, strokes or death. For the record, when angioplasty (the precursor of stents) was used in asymptomatic patients, it did not prevent heart attack, stroke or death either.

The explanation: Consider basic atherosclerosis.
Coronary artery disease stems from diffuse disease of the blood vessel wall. (We call the inner lining of the blood vessel the endothelium.) Wrong thinking holds that blood vessels are inert pipes that carry blood to organs. So, if a blockage exists, squish it open and voila, it’s fixed. This is total nonsense. The blood vessel wall, the blood itself, and their interaction are wildly active in a biologic sense. (I hate the word dynamic, so let’s just say the endothelial-blood interface is far from static.) Sticky platelets, irritable endothelium, the two together–this is heart disease.

Think of the things that can happen in a blood vessel: One possibility is that overtime a slow-growing thick-walled plaque accumulates cholesterol and fat. The growth may enlarge enough to obstruct blood flow to the heart (or any organ). These ‘stable’ blockages can cause angina—a short supply of nutrients at times of high demand. Though impressive to look at, because of the degree of obstruction, these plaques are less of a problem. We say they are less vulnerable to rupture. What’s more, not only are these thick stable plaques unlikely to rupture, but the downstream heart muscle gets accustomed to periods of low nutrients–ischemia. We say that part of the heart is pre-conditioned for ischemia. (I’ll come back to that.)

Another (more worrisome) thing that happens in blood vessels can occur in the earlier phases of heart disease. It’s these younger, less developed, more thin-walled and non-obstructive plaques that cause heart attacks, strokes and sudden death. These are the vulnerable plaques. Because vulnerable plaques don’t obstruct blood flow and rarely have calcium in them, they are neither symptomatic nor detectable by stress testing, coronary CT or heart catheterization. Innocuously termed “lumen irregularities,” these areas of disease are where the danger lies. Here’s why: the thin-walled plaque is more likely to fissure. A tiny crack exposes the inside of the plaque to components of the blood. What happens to your skin when you cut it? It bleeds, and then a clot forms. That’s okay on you arm, but clot formation in the inside of a blood vessel leads to abrupt occlusion of the vessel—a heart attack or stroke. And sudden death due to arrhythmia can occur in this scenario because the supplied heart muscle is not used to low nutrient levels. Non-pre-conditioned heart muscle is electrically irritable. Plaque rupture is why people can die suddenly the day after a normal stress test.
And there’s more. Non-obstructive, possibly vulnerable, plaques occur throughout the three major coronary arteries. Yes, there may be one bad 80% blockage, an eyesore that captures the attention of the cardiologist, but when there is one bad blockage, there are often many other much more vulnerable plaques. So the problem with the major blockage is not just the restriction of downstream blood flow, but rather, it’s a marker for diffuse atherosclerosis. That’s one reason why stents don’t prevent heart attacks or death. The stent treats the blockage least likely to cause the calamity.
But that’s not the only problem with stents. Another issue is that stents create their own disease. The metal cage inside a blood vessel can act as a source of clots. This means patients with stents must take drugs that block platelet function. These “blood thinners” increase the risk of bleeding. The duration of anti-platelet treatment varies depending on patient and stent characteristics, but is often long-term. Stopping an anti-platelet drug shortly after a stent, say in the event of trauma or surgery, greatly increases the risk of abrupt stent closure and heart attack. So stents aren’t free; they come with significant long-term tradeoffs.

The role of Inflammation:
Coronary artery disease equals atherosclerosis. It is a diffuse process involving inflammation in the blood vessel wall. The things that cause atherosclerosis are well-known, and work through chronic inflammation. Smoking is especially terrible. It causes long-term plaque accumulation, increases in platelet stickiness and irritation of the blood vessel wall. Smoking cessation results in near immediate decreases in vulnerable plaque rupture. It’s why you see so many fewer heart attacks with smoking bans; removing exposure from smoke has an immediately soothing effect on blood vessels. High blood pressure exerts its effects on the blood vessel via physics. Imagine 100,000 daily pulses of blood through a soft flexible blood vessel versus a stiff non-complaint hypertensive one. Stiff pipes are more apt to crack. Diabetes wreaks havoc in many ways. Insulin is a real baddie for blood vessels. As a growth factor, insulin causes deposition of fat in plaques. As an inflammation mediator, insulin contributes to the irritability of plaques. You don’t want high insulin levels; this is why a low-calorie diet devoid of simple sugars is so effective. Ask the healthy 90 year-old farmer from Indiana, how much food from packages he eats. Stress takes a toll over time as well. We know chronic angst, unhappiness and anger all associate with heart disease. The common denominator here is also inflammation. When you are inflamed emotionally, so are your platelets and endothelium. Genetics plays a strong role too. We inherit eye color, personality, intelligence, aerobic prowess and so on. We also inherit susceptibility to arterial disease.

I hope you can see why treating and preventing heart disease is not just about squishing low-vulnerability plaques. You can understand why the COURAGE trial showed that adding stents to optimal medical therapy did not lower the risk of heart attack or death. And, if the plaques most likely to kill are not obstructive, you can also understand the limits of stress testing.

Effective treatment of heart disease:
Although we are not close to knowing which of the many thin-walled 10% coronary plaques are vulnerable, we still have a lot that we can do. Note the pronoun, we.
stat
Heart disease therapy means addressing a diffuse disease. It means reducing both the number of plaques and their vulnerability. Ultimately, this is about lowering inflammation. First comes lifestyle. Remember the four legs of the table of health: good food, good exercise, good sleep and good attitudes. Eating less insulin-spiking sugar, inflammatory trans-fats and fewer calories lowers inflammation. The emerging understanding of the importance of gut bacteria gives credence to the saying, we are what we eat. Nutrition is not complicated: eat real food when you are hungry. Exercising every day that you eat soothes the mind, conditions the heart and keeps the body from accumulating fat. Our bodies are beautiful; it’s tragic when humans don’t use their bodies. Getting high quality sleep lowers inflammation. You don’t need me to tell you how good it feels to sleep well. Finally, I’d bet every bike I own that compassion, grace and optimism soothe the vulnerable plaque.

After lifestyle comes medical therapy. Statin drugs don’t prevent heart attacks, strokes and death by lowering cholesterol; that’s just something us humans can easily measure. Statin drugs improve outcomes in patients with established heart disease by reducing inflammation at the arterial wall/blood interface. Beta-blockers and ACE-inhibitors (and ARBs) aren’t just simple blood pressure lowering agents. They have important activity on the neuro-hormonal milieu of the diseased heart and blood vessel. And simple aspirin therapy goes a long way in preventing platelets from accumulating on vulnerable plaques. Science confirms that these classes of drugs lower event rates in patients with established heart disease or those at high-risk of heart disease. I call them the big four heart medications. (BTW: they are all generic!)

Heart disease treatment, however, remains a team sport. Doctors can’t do it alone. Right now, there’s far too much emphasis on treating a diffuse disease with focal therapies. Stents may improve blood flow; bypass surgery may provide a brief reprieve; ICDs offer some protection to selected patients, but it will always be about lowering inflammation. There’s no pill or stent or ICD for that.

JMM
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Drug company kills off another cholesterol-modifying drug - Briffa

Drug company kills of another cholesterol-modifying drug

Dec, Fri 14th, 2012

 

I rarely meet someone who has not heard of cholesterol and does not believe it to be a largely dangerous substance. And increasing number of people seem to be aware of the conventional wisdom regarding the different forms of cholesterol, specifically low density lipoprotein cholesterol (LDL-C) and high density lipoprotein cholesterol (HDL-C). Actually, these names are a bit misleading, as these particles are not cholesterol (though they do contain cholesterol). But, anyway, the conventional wisdom is that LDL-C dumps cholesterol on the inside of our arteries while HDL-C clears cholesterol. As a result, LDL-C and HDL-C are often dubbed ‘bad-’ and ‘good-’ cholesterol.

The most commonly prescribed cholesterol drugs are known as statins, and their main mechanism of action is to lower LDL-C levels. However, other types of cholesterol-modifying drugs exist, including a relatively new class known as cholesterylester transfer protein inhibitors (CEPT inhibitors), which the conversion of supposedly healthy HDL-C into supposedly unhealthy LDL-C. If you believe the conventional wisdom on cholesterol (I don’t), then this should translate into benefits for health with regard cardiovascular disease (e.g. heart disease and stroke).

All this theory is meaningless, however. The only important thing is not the effect drugs (or anything else) have on cholesterol levels, it’s the impact they have on health. Some years back the drug company Pfizer spent in the region of $800 million developing a CEPT inhibitor by the name of torcetrapib. It had ‘positive’ effects on LDL-C and HDL-C levels, but also turned out to kill people. Pfizer promptly and quite rightly ceased development of the drug.

The crashing failure of torcetrapib has not stopped other drug companies seeking to find a commercially viable CEPT inhibitor of their own. More recently, drug company Roche invested in the development of a drug known as dalcetrapib. However, in the middle of this year Roche abandoned plans for further development, and a recently-published study shows us why [1].

In this study, published in the New England Journal of Medicine, almost 16,000 patients who had suffered from ‘acute coronary syndrome’ (e.g. angina or heart attack) were treated with dalcetrapib or placebo for an average of about two and a half years.

These are just the sort of patients one would expect to benefit most from an intervention because, as a group, they would generally be at high risk of future problems. Also, the number of subjects here is huge, and therefore more than big enough to detect any real benefit the drug may have.

The researchers assessed the effects of dalcetrapib using a ‘composite endpoint’ – which essentially means lumping several outcomes together. The composite outcome included death from heart disease, non-fatal heart attack, ischemic stroke (strokes due to blockage of blood vessels rather than bleeding), unstable angina (angina that can come on at rest), and cardiac arrest with resuscitation. The use of composite endpoints ups the odds that a ‘statistically significant’ benefit for a drug will be found (compared to when only one single outcome is chosen).

Biochemical analysis revealed that dalcetrapib did, as expected, have considerable HDL-boosting effect. But the study showed that this drug had no benefits for health at all.

Another interesting thing about the study was that dalcetrapib was found to increase markers of inflammation – a process which is believed to play a key part on the development of heart disease and stroke.

This study was originally designed to run for longer but was terminated early once these results were in. Early termination of studies is known to generally inflate the benefits of drugs and downplay their risks. Who knows what may have happened if they’d continued.

Of course you’re unlikely to hear about the dalcetrapib study because it wasn’t announced with the blaze of publicity usually afforded to more ‘positive’ studies about cholesterol-reducing drugs. But this is often the way with cholesterol-related research in particular: positive results are spun in a way which gives medication seeming miraculous properties, while negative results and inconvenient truths are swept under the carpet.

References:
1. Schwartz GG, et al. Effects of Dalcetrapib in Patients with a Recent Acute Coronary Syndrome. N Engl J Med 29 November 2012 (epub)
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Do statins really reduce the risk of cancer? - Briffa

Do statins really reduce the risk of cancer?

Nov, Fri 9th, 2012 By : Dr John Briffa

 

Yesterday saw the on-line publication of a study in the New England Journal of Medicine (NEJM) that concerns statins and is getting more than its fair share of media attention. The study, conducted in Denmark, analysed the rates of death from cancer in individuals taking statins, and compared them to those in individuals not taking these drugs. Those taking statins were found to be at a statistically significant reduced risk of dying from cancer. Some seem keen to claim that statins may not only be an answer to heart disease, but our cancer woes too. Take this headline for example which you can find here: ‘Statins cut mortality in cancer patients’. The wording of this title on a website dedicated to the education of doctors strongly suggests that statins actually reduce the risk of death from cancer.

But, not so fast. The NEJM study is what is known as ‘epidemiological’ or ‘observational’ study. The study tells us that statin use is associated with a reduced risk of death from cancer, but it can’t tell us whether or not statins actually cut cancer risk.

One fundamental problem with studies of this nature is that they are subject to what is known as the ‘healthy user effect’. Basically, what this means is that healthier, often more health-conscious individuals are more likely to end up on statins than less healthy, not so health-conscious individuals. Because of this, it’s possible that the apparent benefits of statins with regard to cancer (or anything else) are not to do with the drugs themselves, but the health characteristics of those more likely to take statins.

If we really want to know if statins reduce the risk of cancer death then we need to look to what are known as ‘intervention studies’ in which, usually, roughly equivalent groups of individuals are given statins or placebo. These studies, the gold standard of which are ‘randomised controlled trials’ do have the potential of discerning the true effects of drugs and other treatments.

Single studies such as these can provide useful data, but sometimes it makes sense to amass data from several studies to get a decent overview of the impact of a drug or class of drugs. Such grouping of studies together are referred to as ‘meta-analyses’.

One meta-analysis published in 2009 found that statin use was not associated with a reduced risk of cancer [2]. A more recent meta-analysis published this year found the same thing [3]. Meta-analyses of intervention studies are not perfect, but they are much better than (crappy) single epidemiological studies like the one currently doing the rounds. And it’s perhaps worth bearing in mind that there as been at least some concern about the impact statins might have on cancer risk in the elderly. In one study, statin use (compared to placebo) increased the risk of cancer by 25 per cent (statistically significant) [4].

Put in this context, the frothing enthusiasm exhibited by some regarding this latest study seems inappropriate. And for a website dedicated to the education of doctors to proclaim that ‘Statins cut mortality in cancer patients’ is downright negligent.

References:
1. Nielsen SF, et al. Statin Use and Reduced Cancer-Related Mortality. NEJM published online 8 October 2012
2. Brugts JJ, et al. The benefits of statins in people without established cardiovascular disease but with cardiovascular risk factors: meta-analysis of randomised controlled trials. BMJ 2009;338:b2376.
3. Cholesterol treatment trialists’ collaboraton. Lack of effect of lowering LDL cholesterol on cancer: meta-analysis of individual data from 175,000 people in 27 randomised trials of statin therapy. PLoS One 2012;7(1):e29849. Epub 2012 Jan 19.
4. Shepherd J, et al. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet 2002;360(9346):1623-30
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