Primary Prevention with Statin Therapy

JAMA logo

I have reproduced this article EXACTLY from the Journal of the American Medical Association (JAMA) in response to the AHA 2013 NEW lipid guidelines.

JAMA Weighs In on CVD Guidance, Statins in Primary Prevention Shelley Wood November 25, 2013

CHICAGO, IL – Another week and another flurry of insights and opinions on the new CVD prevention guidelines, this time in the journal that once cornered the market on cholesterol guidance.

Back in 2001, when the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults released their third report (ATP III), it was the Journal of the American Medical Association (JAMA) that published the report. Ditto the previous edition, ATP II, in 1993.

This time around, in the wake of the partnership struck between the American Heart Association (AHA), American College of Cardiology (ACC), and the original guidelines developer, the National Heart, Lung, and Blood Institute (NHLBI), the new guidelines and accompanying risk calculator were simultaneously published in the flagship journals of the two cardiology organisations.

Seemingly keen to get in on a piece of the action, JAMA has today published online a Clinical Evidence Synopsis[1], accompanied by a commentary by Dr Jennifer Robinson, vice chair for the new cholesterol guidelines and a co-author of the guidelines for assessing CV risk[2]. Both the clinical evidence synopsis and Robinson’s commentary zero in on what has emerged as the most controversial aspect of the new four-part CVD guideline packet: the use of statins in primary prevention. Specifically, experts have raised concerns that too many patients will be swept into drug therapy by the new CV risk calculator.

The clinical evidence synopsis, by Dr Fiona Taylor (London School of Hygiene and Tropical Medicine) and colleagues, sums up their 2013 Cochrane meta-analysis that updated a 2011 meta-analysis reviewing the evidence on statin use in primary prevention[3]. Taylor et al’s analysis included 18 trials conducted between 1994 and 2008 and published between 2011 and 2013, enrolling almost 57 000 patients. Compared with placebo, statins reduced LDL by 39 mg/dL, all-cause mortality by 14%, fatal and non-fatal CVD by 22%, coronary heart disease by 27%, stroke by 22%, and coronary revascularisation by 38%. Risk of cancer, myalgia, rhabdomyolysis, liver-enzyme elevations, renal dysfunction, or arthritis were no different between the patients taking statins and those on placebo, nor was drug discontinuation. An increased risk of diabetes with statins was seen “in one of the two trials reporting this outcome.”

Dr Rita Redberg (University of California, San Francisco), who recently co authored a New York Times Op-Ed expressing concern that the new cholesterol guidelines would lead to statin over treatment, commented on the JAMA articles for heartwire .

Redberg pointed out that this latest Cochrane analysis comes to starkly different conclusions than the 2011 Cochrane review, despite having many of the same authors. That may be in part due to the “elimination of major trials,” something also at odds with a 2009 meta-analysis by Ray et al that found no benefit of statins in reducing all-cause mortality.

In her commentary, Robinson notes that the 2013 Cochrane meta-analysis was one of the pieces of evidence reviewed by the ACC/AHA guideline writers, along with other “high-quality randomized trials and systematic reviews and meta-analysis of randomized trials.” These included the 2010 and 2012 Cholesterol Treatment Trialists meta-analysis, as well as the AFCAPS/TexCAPS, MEGA , and JUPITER trials. It was from these studies, she notes, that the cut points of a 5% and 7.5% or greater 10-year risk of atherosclerotic cardiovascular disease were derived, and not plucked from thin air, as some critics have alleged.

The recent studies, writes Robinson, “provide evidence that largely refutes the major criticisms against statins used for primary prevention. Statins are well tolerated in properly selected individuals. Statins reduce total mortality as well as atherosclerotic cardiovascular disease events in lower-risk individuals. Concerns about cost are no longer relevant with five of the currently available statins available as generic drugs. . . . The accumulated evidence should convince those with a philosophical aversion to statin therapy for primary prevention to reconsider their stance.”

To heartwire , Robinson pointed out that much of the criticism of the new guidelines and risk calculator has centred on the idea that millions more Americans will be encouraged to take statins. In fact, she points out, “in 2005, 35 million Americans were already on a statin, so if you apply our CV risk calculator, you’d see 32 million on a statin. There are [still] a lot of people being treated, but [with these new guidelines] you are not going to see more people being treated, it may just not be the same people.”

She also addressed the controversial Ridker and Cook analysis, which came out with much fanfare during last week’s AHA meeting, as well as its call to treat only subjects who are similar to those enrolled in the major clinical trials rather than use an untested global risk-prediction score.

“We tried that,” Robinson said, “and what you get when you apply clinical-trial inclusion criteria is that you fail to identify about 40% of high-risk people [who would benefit from statin therapy] and you overtreat about 35% of people who have less than a 5% 10-year risk of CVD.”

The four major criticisms of the guidelines as they pertain to statin therapy are concerns about adverse effects, lack of a total mortality benefit, cost, and a “philosophical aversion to drug therapy,” Robinson writes.

“None of these really stand up under the light of evidence anymore,” she told heartwire . “It’s fine to have a philosophical aversion to statins, but when all the evidence flies in the face of that, it seems like that’s an attitude that should fall by the wayside.”

Asked if she’s concerned that all the focus on statins in the cholesterol guidelines has eclipsed important information in the lifestyle and obesity guidelines, released the same day, Robinson maintained that statins deserve the attention they’ve been basking in over the last few weeks.

“Only 10% of Americans have optimal CV health: that’s why we need statins. We’ve been telling people to diet and exercise for at least 50 years; this is not a new thing. I think the problem with this approach is that if we wait until people do what we tell them to do for diet and exercise and smoking cessation, we are going to be withholding a lifesaving therapy from exactly the people who will benefit. Of course, keep telling people to diet, exercise, and quit smoking, but when people can’t or won’t do that, we can’t withhold therapy.”

Redberg for her part, remains adamant that the focus of primary-prevention efforts should be on promoting healthy lifestyle, not prescribing drugs. “Healthy-lifestyle measures such as healthy diet, regular physical activity, and smoking cessation . . . have been shown to reduce heart disease and cancer and are associated with living longer as well as better. The multiple adverse effects-fatigue, weakness, muscle problems, memory loss, and diabetes risk-and concern for underreporting of adverse events in current trials noted in the current and previous Cochrane meta-analysis (all industry-sponsored [based on] data that are not publicly available) all mean that the chance of benefit from statins in primary prevention is still dwarfed by the chance of harms. ”

Robinson, however, pointed to the fact that one of the most vocal critics of specific high-profile drugs and their expanded use was also invited by JAMA to respond to the new cholesterol guidance. The Viewpoint by Dr Bruce Psaty with Dr Noel S Weiss (University of Washington, Seattle) was published online in JAMA last week on a day many cardiologists were travelling home from the AHA meeting[4]. 

In it, notes Robinson, Psaty was “highly supportive” of the new guidelines. He writes: “Overall, the revised 2013 ACC/AHA guidelines represent a strong fit with the clinical-trial evidence: treatment thresholds resemble eligibility criteria of the trials; statins are clearly identified as the first-line drug therapy; and treatment targets are abandoned.”

“We were pretty pleased,” Robinson told heartwire .

That’s not enough to reassure Redberg, who insists all research into statins in primary prevention should be reviewed “by groups that do not have conflicts of interest and that make their data freely available to the research community and clinicians for independent analysis.”

Cardiologydoc

Grain Intake – and Cardiovascular Disease

Epidemiological studies have suggested that whole-grain intake is protectivefood_0320 against cancer, cardiovascular disease, diabetes and obesity. Just about every health care system worldwide recommends consuming three servings of whole grains daily.

Whole grains are rich in nutrients and phytochemicals; have high concentrations of dietary fibre, resistant starch, and oligosaccharides. Whole grains are rich in antioxidants including trace minerals and phenolic compounds and these compounds have been linked to disease prevention. Other protective compounds in whole grains include phytate, phyto-oestrogens such as lignan, plant stanols and sterols, and vitamins and minerals. t1larg.gluten.foods.giAlthough it is difficult to separate the protective properties of whole grains from dietary fibre and other components, the disease protection seen from whole grains in prospective epidemiological studies far exceeds the protection from isolated nutrients and phytochemicals in whole grains.

So what is going wrong with the failure to prevent atherosclerotic cardiovascular disease (ASCVD)?

Despite all the preventative lifestyle and nutritional guidelines, ASCVD remains the biggest killer worldwide with the epidemic of vascular disease closely associated with diets predominantly carbohydrate based, including high intake of grains.  Confirming my personal experience as a non invasive preventative cardiologist for the past 20 years, I find it extremely hard to find truly healthy 50+ men or women. Published in Circulation 2011 it seems “ideal cardiovascular health” in healthy American 50+ men and women is equally impossibly hard to achieve despite the prevailing lifestyle wisdom and nutritional information available to all.  

Ideal CV Health  Circulation

In this study only 1/1000 “healthy individuals” (average age 57) achieved all 7 of the health behaviors and health factors.

  1. Non-smoking
  2. Body Mass Index < 25 m2/kg
  3. Moderate physical activity 150 minutes/ week
  4. 4-5 key components of the AHA Dietary guidelines
  5. Total Cholesterol < 5.0 mmol/l (<200 mg/dL)
  6. BP ~ < 120/80
  7. Fasting Glucose < 6.0 mmol/l (< 100 mg/dL)

Ideal CV Health  Circulation results

Also confirming what I see every day is a high prevalence of “sub clinical” atherosclerosis and cardiovascular disease in “so-called” healthy 50+ individuals.  Note the high background prevalence of sub clinical disease even in normal BMI and normal waist measurement in American men and women (average age 57).

Burden of sub clinical CVD

Prev sub clinical CVD

A very famous paper by Boyd Eaton in The New England Journal of Medicine in 1985 suggested that humans, before agricultural times (>10 000 years ago), basically, did not consume cereal grains. 

Since then a number of toxic components that affect many people beyond celiac disease have been identified.  Cereal grains, particularly gluten-containing grains, have a variety of elements or compounds that are toxic, not just to humans, but to other mammals, birds, and insects. This is precisely why cereal grains have evolved, as these antinutrients protect them from predation. Grains are basically grass seeds and are the reproductive material of a plant responsible for the survival of the species.

Grass family

Plants have taken a number of evolutionary strategies to prevent predation by birds and insects and even pathogens, fungus, and bacteria and perhaps humans. One is that they evolve structures like thorns and hard shells and physical barriers making it very difficult for the predator to get to the seed. To avoid being eaten, cereal grains and legumes have taken on another strategy in which they have evolved toxic compounds (anti-nutrients), essentially to make them unpalatable. PicofWheatThe effect of some of these anti-nutrients is to increase intestinal permeability so that the toxic compound can get past the gastrointestinal barrier and into the bloodstream to interact with our physiology to produce pathological effects.

These toxic compounds in the seeds are more concentrated in the finished product that humans eat in terms of flour-produced products or flour-containing foods and in susceptible individuals cause increased gastrointestinal permeability and multi system pathologies.

There are three compounds in wheat which we know cause intestinal permeability. The best studied of which gluten or, actually, a protein is called gliadin (and related proteins derived from grass seeds). All seem to increase intestinal permeability by a mechanisms elucidated by Alessio Fasano’s group at the University of Maryland. gluten-sensitivityPublished in 2009 these scientists linked a human protein (zonulin) to inflammatory and autoimmune disorders like celiac disease; multiple sclerosis; Thyroiditis; arthritis and diabetes. Alessio Fasano identified zonulin as a molecule in the human body called “haptoglobin 2 precursor”.

Haptoglobin is a molecule that has been known to scientists for many years, identified as a marker of inflammation in the body. Haptoglobin 1 is the original form of the haptoglobin molecule, and scientists believe it evolved 800 million years ago. Haptoglobin 2 is a permutation found only in humans. It’s believed the mutation occurred in India about 2 million years ago, spreading gradually among increasing numbers of people throughout the world.

Dr. Fasano’s study revealed that zonulin is the precursor molecule for haptoglobin 2 – that is, it is an immature molecule that matures into haptoglobin 2. It was previously believed that such precursor molecules served no purpose in the body other than to mature into the molecules they were destined to become. But Dr. Fasano’s study identifies precursor haptoglobin 2 as the first precursor molecule that serves another function entirely – opening a gateway in the gut, or intestines, to let gluten in. 

Apes, monkeys and chimpanzees do not have haptoglobin 2 but 80 percent of humans have it. Apes, monkeys and chimpanzees rarely develop autoimmune disorders whilst humans suffer from more than 70 different kinds of such autoimmune conditions. 

This molecule could be a critical piece of the puzzle in celiac disease, non-celiac gluten sensitivity, other autoimmune disorders and allergies and even cancer, all of which are related to an exaggerated production of zonulin/pre-haptoglobin 2 in response to gluten and other grain proteins, leading to the loss of the protective barrier of cells lining the gut and other areas of the body, like the blood brain barrier.

Gluten_Induced_Disease_Chart

People who suffer from celiac disease and non-celiac gluten sensitivity (NCGS) have sensitivity to gluten and therefore suffer gastrointestinal symptoms and other systemic symptoms when they eat it.

Seemingly in sensitive people, gluten generates an exaggerated release of zonulin that makes the gut more permeable to large molecules, including gluten itself. The permeable gut allows these macromolecules access to the rest of the body triggering an autoimmune response in which a celiac patient’s immune system identifies gluten as an intruder and responds with an attack targeting the intestine instead of the intruder producing the typical small intestine villous atrophy. An inappropriately high level of production of zonulin also seems responsible for the passage through the intestine of other intruders (other antigens) linking other conditions such as type 2 diabetes, metabolic syndrome, multiple sclerosis and many allergies and autoimmune disease.

Whilst celiac disease is relatively uncommon (~1%) the prevalence of non-celiac gluten sensitivity (NCGS) seems much higher and may be grossly underestimated in the general population.

There are other compounds in wheat that increase intestinal permeability. Extensively studied is wheat germ agglutinin or WGA (a lectin). WGA seems to increase intestinal permeability through two pathways: paracellular and transcellular pathways. In other words the WGA or the lectin can go between cells or it can go through cells through receptor-mediated pathways.

pathogenesis_autoimmune-resized-600

The third component in wheat that increases intestinal permeability is an obscure protein called thaumatin-like proteins. This has been studied in other plant products, but not so much so in wheat. So, we suspect that wheat actually has three compounds: gliadin, WGA, and thaumatin-like proteins that seem to act synergistically to increase intestinal permeability in some people to some degree leading to activation of our immune systems leading to autoimmunity and chronic inflammation with pathological effects on cardiovascular disease, cancers, and other diseases.

WGA is a powerful lectin which seemingly binds to everything including interfering (amongst others) with Vitamin D metabolism. One of the animal models back in the 1980s to study rickets was to feed puppy’s whole grains (wheat).  When the diets comprised 45 to 50% of total energy from grains, they could induce rickets.  Relevant to the development of cardiovascular disease is the association outlined nicely by David S.H. Bell, MD (South Med J. 2011;104 (5):340-344) that Vitamin D deficiency is associated with the risk factors of inflammation, insulin resistance and endothelial dysfunction, and left ventricular hypertrophy. As a result there is an increase in cardiovascular events (CVEs) associated with vitamin D deficiency. Deficiency of vitamin D results in an increased expression of genes that are associated with activation of the renin-angiotensin system and genes that are associated with malfunction of calcium channels.  Therefore, activation of these genes is likely to lead to hypertension, left ventricular hypertrophy and congestive heart failure.

Vitamin D replacement has also been shown to increase high-density lipoprotein levels mainly due to an increase in the size of the high-density lipoprotein particle.  The increase in high-density lipoprotein particle size improves reverse cholesterol transportation (protective to the arterial wall) which has also been shown to improve with vitamin D replacement. 

Epithelial cells contain on their outer surface a glycocalyx.  When you look at a cross-section of flow in an artery, the red blood cells and white blood cells that flow through the artery never touch the endothelial cells because of the surface glycocalyx. The gut is lined with similar epithelial cells preventing macromolecule absorption due in part to the glycocalyx barrier. It prevents large macromolecules (and other antigens) from being absorbed inappropriately. So, we only absorb fatty acids; sugar molecules and amino acids.

WGA like many lectins, bind the glycocalyx causing it to be shed exposing the bare epithelial cells to the gut contents, or in the case of the artery, the contents of the bloodstream. Whenever the glycocalyx is shed in epithelial cells, it causes pro-inflammatory cytokines (TNF alpha, interleukin-2; interleukin-6) that also increases intestinal permeability and compromise vascular integrity (endothelial dysfunction) increasing permeability of the arteries to atherosclerotic lipoproteins causing atherosclerotic cardiovascular disease (ASCVD).

Conventional diets with 60% of daily calories from carbohydrates including a large proportion of grains, may therefore compound (paradoxically) some of the risk for ASCVD with leaky-gut syndrome; dyslipidaemia and high systemic inflammatory burden and autoimmune disease.  h_LDLpathwayThere is a tendency towards lower HDL and to small dense LDL particles size in people consuming high carbohydrate diets including high (often refined) grain intake.  The increased systemic inflammation (high us-CRP) promoting oxidation of the small dense LDL molecules is the typical atherogenic environment to potentiate ASCVD.What-is-Paleolithic-Diet

Perhaps some very good reasons to re-visit a Paleolithic low carbohydrate style diet.

Blessings

Cardiologydoc

Understanding the 2013 AHA Lipid guidelines

AHA 2013 lipid guidelines manuscript 2

The goals of the American College of Cardiology (ACC) and the American Heart Association (AHA) are to prevent cardiovascular (CV) diseases, improve the management of people who have these diseases through professional education and research, and develop guidelines, standards and policies that promote optimal patient care and cardiovascular health. Recommendations are derived from randomized trials, meta-analyses, and observational studies evaluated for good quality.

The Expert Panel was charged with updating the clinical practice recommendations for the treatment of blood cholesterol levels to reduce atherosclerotic cardiovascular disease (ASCVD) risk using data from randomized controlled trials (RCTs) and systematic reviews and meta-analyses of RCTs. ASCVD includes coronary heart disease (CHD), stroke, and peripheral arterial disease, all of presumed atherosclerotic origin. The recommendations are intended to provide a strong evidence-based foundation for the treatment of cholesterol for the primary and secondary prevention of ASCVD in women and men the great cause of morbidity and mortality worldwide including South Africa.

The summary of the guidelines are:

1. Focus on ASCVD Risk Reduction: 4 statin benefit groups: based on a comprehensive set of data from RCTs that identified 4 statin benefit groups which focus efforts to reduce ASCVD events in secondary and primary prevention. Identifies high-intensity and moderate-intensity statin therapy for use in secondary and primary prevention.

2. A New Perspective on LDLC and/or Non-HDLC Treatment Goals: The Expert Panel was unable to find RCT evidence to support continued use of specific LDL–C and/or Non-HDL targets. The appropriate intensity of statin therapy should be used to reduce ASCVD risk in those most likely to benefit. Non Statin therapies do not provide acceptable ASCVD risk reduction benefits compared to their potential for adverse effects in the routine prevention of ASCVD.

3. Global Risk Assessment for Primary Prevention: The guideline recommends use of the new Pooled Cohort Equations to estimate 10-year ASCVD risk in both white and black men and women. By more accurately identifying higher risk individuals for statin therapy, the guideline focuses statin therapy on those most likely to benefit. It also indicates, based on RCT data, those high-risk groups that may not benefit. Before initiating statin therapy, this guideline recommends a discussion by clinician and patients.

4. Safety Recommendations: The guideline used RCTs to identify important safety considerations in individuals receiving treatment of blood cholesterol to reduce ASCVD risk. Using RCTs to determine statin adverse effects facilitates the understanding of the net benefit from statin therapy. Provides expert guidance on management of statin-associated adverse effects, including muscle symptoms.

5. Role of Biomarkers and Noninvasive Tests: Treatment decisions in selected individuals who are not included in the 4 statin benefit groups may be informed by other factors as recommended by the Risk Assessment working Group guideline.

6. Future Updates to the Blood Cholesterol Guideline: The comprehensive guideline is for the evidence-based treatment of blood cholesterol to reduce ASCVD risk. Future updates will build on this foundation to provide expert guidance on the management of complex lipid disorders and incorporate refinements in risk stratification based on critical review of emerging data.  RCTs comparing alternate treatment strategies are needed in order to inform future evidence-based guidelines for the optimum ASCVD risk reduction approach.

AHA 2013 lipid guidelines 1

AHA 2013 lipid guidelines 2

AHA 2013 lipid guidelines 3

The move away from a singular focus on LDL levels, with an emphasis on treating RISK instead of LDL level is refreshing as we are very familiar with some individuals with ADVANCED ASCVD with essentially “normal” LDL levels. The lipid hypothesis is not being impugned in any matter or form, but we are realizing that pursuing targets at all costs may lead to the use of medications and or strategies that are not known to benefit patients.

Second, the emphasis on proven medications is extremely important. We have learned that not all medications that favourably affect lipids result in risk reduction for patients. We have learnt this from hormone therapy in postmenopausal women where whilst the lipogram may improve favourably on “paper” the risk of the woman may actually worsen.  We have very poor results with the HDL elevating drugs confirmed in RCT’s to worsen prognosis and there are may “naturopathic” agents that have absolutely no evidence-base to reduce ASCVD.

So we can use lipids to understand risk, but just because a medication improves a lipid profile does not mean that it has reduced the risk of heart attacks or dying of vascular disease. So the guidelines suggest moving away from LDL and emphasised the use of proven medications to reduce risk – and statins are the class that has been shown most conclusively to reduce risk. Moreover, they reduce risk regardless of the LDL level. Also, the trials tested the drug – not a strategy based on a target. So the guidelines de-emphasize non-statins, like ezetimibe, and emphasise the Statin class.

The guidelines direct attention to RISK STRATIFICATION. I have advocated this approach for over a two decades and whist there may be controversy over the risk calculator to use – and the threshold that makes it worth it to receive treatment – the principle of being cognizant of the size of the potential benefit will endure. Work is still needed as to what tools best define a person’s risk of ASCVD but ultimately the decision about whether treatment is worthwhile should reside with a patient who is informed about the risks and benefits. We do need to be sure we are accurately estimating risk and finding ways to communicate information about the decision to patients, but we should not impose a decision on patients. It is up to us to include the patient in all decision-making.

Cardiovascular risk stratification I believe is more than just plugging values (age; sex; race group; total cholesterol; HDL cholesterol; systolic blood pressure; smoking history; diabetes history) into a risk calculator but includes the genetic risk of an individual  as family members with premature vascular events (males < 55 years and females < 65 years) significantly increase an individuals risk. Biological markers of risk with ultra sensitive C reactive protein (us-CRP) and the “metabolic syndrome” influence risk tremendously. Finally any individual with “sub clinical” vascular disease risk stratifies into a POOR future prognostic category and would warrant Statin therapy despite normal LDL values.  

One of the important strengths of the “new risk calculator” (http://my.americanheart.org/cvriskcalculator and http://www.cardiosource.org/science-and-quality/practiceguidelines-and-quality-standards/2013-prevention-guideline-tools.aspx for risk equations), is that it calculates your LIFETIME risk of ASCVD and how you compare to the “God-given” individual of your age/sex with optimal risk reduction.  This provides really good insight into your future risk for vascular events and where you could target the most benefit in reducing risk for lifetime events.

I am really encouraged the movement away from lab cholesterol values, the emphasis on proven medications (Statins) and the emphasis on treatment for those with the most to gain are terrific aspects of the guidelines. Now is the time to turn to implementation and tools. We do need to determine what is the best way to estimate risk to risk stratify more accurately and communicate it with patients. And most importantly, we need to learn how best to engage patients in the decision. But the guidelines have laid out some important principles to guide the development of these tools – and ultimately help us all to make wiser decisions about prevention.

Conclusion

Risk stratify

Annie Johnson 2

Blessings Cardiologydoc