Why Me?

After surviving a heart attack, patients understandably want answers. The question typically comes in the form of “why did I have a heart attack?” Or, “I’ve been seeing my doctor regularly, wouldn’t this have been detected?”

The answers are complicated but best summed up by a slide Dr. Matthew Budoff, preventive cardiologist, frequently puts up during his lectures:

“Superior doctors prevent the disease. Mediocre doctors treat the disease before evident. Inferior doctors treat the full-blown disease” – Huang Dee Nai-Chang ( 2600 BC 1st Chinese Medical Text)

Atherosclerosis develops over several decades. There are multiple opportunities along the way to recognize risk factors, identify its presence and get in front of the disease.

But once it fully manifests, it becomes much more challenging to stabilize or reverse. We now have the tools and it can be done. It’s been a process.

History 

In 1964 the US Surgeon General issued a report concluding that smoking was a “probable” cause of coronary heart disease. Since then various other lifestyle recommendations have been made, such as reducing saturated fats, getting plenty of exercise and reducing stress. 

In 1987, arguably the greatest therapeutic advancement in modern medicine beyond vaccinations and antibiotics was released in the United States. Statins. Lovastatin, under the trade name Mevacor hit the stage  (and just in time for this author’s father, who at age 46, 1 year after quitting smoking, developed angina while carrying a 10 lb bag up a flight of stairs and required balloon angioplasty in 5 locations). In the 80’s and 90’s we were just hoping to slow down the disease. Give patients a few more years. 

In 2004 we first saw evidence of halting of the progression of plaque in the REVERSAL trial (JAMA. 2004;291(9):1071-1080. doi:10.1001/jama.291.9.1071) which used IVUS (Intravascular Ultrasound). Patients treated with the highest intensity statin at that time, Lipitor (atorvastatin) 80 mg daily to achieve a mean LDL-C ~ 70 mg/dL (mean 79) vs Pravachol (pravastatin) 40 mg daily to achieve LDL-C ~ 100 mg/dL (mean 110) showed plaque regression in a small percentage of patients. 

In 2006 the ASTEROID trial (JAMA. 2006;295(13):1556-1565. doi:10.1001/jama.295.13.jpc60002) showed evidence for the first time, of plaque regression when using Crestor (rosuvastatin) 40 mg daily to achieve a mean LDL-C of 60 mg/dL. 

Fast forward to 2016, when the GLAGOV trial (JAMA. 2016;316(22):2373-2384. doi:10.1001/jama.2016.16951), using evolocumab (Praluent - link to company website) demonstrated plaque regression in ~ ⅔  of patients achieved atheroma regression, after achieving a mean LDL-C of 36 mg/dL, whereas the placebo group (statin only) showed no evidence of regression at a mean LDL-C of 93 mg/dL.

Do you see the trend here? With every iteration of these clinical trials, therapies capable of greater LDL-C reduction yield not only greater reductions in ASCVD outcomes (less heart attacks and heart deaths), but mechanistically demonstrate the evolution from slowing the progression, to halting plaque developement, to regression of the disease.

So what causes atherosclerosis?

Blood cholesterol, trafficked in “atherogenic” lipoprotein particles - predominantly Low Density Lipoprotein (LDL) is causal to atherosclerosis, all by itself. This fact is recognized by every cardiovascular organization in the world.

Cumulative exposure to atherogenic lipoproteins is all that is needed to produce atherosclerosis. By checking someone’s blood concentration of LDL-C in mg/dL, which is a surrogate for the LDL-particles, we get a good approximation of what is and has been traveling through the bloodstream of that individual every second or every day of their life.  That lifetime exposure to ApoB containing particles (atherogenic particles) is largely what drives the risk for atherosclerosis. 

In a population, the higher the LDL-C, the higher the risk of atherosclerosis. But even “normal LDL-C” levels are plenty. This comes as a surprise to many of our patients following that first heart attack when they declaire “But I’ve always been told my cholesterol was normal!”

Bell-shaped curves showing the cholesterol levels of those admitted with their first heart attack compared with bell-shaped curves of those of the general population are nearly superimposable. Meaning, the only levels of LDL-C that essentially guarantee a life free of atherosclerosis, is maintaining LDL-C in the pediatric range of 20-40 mg/dL. Heart disease is the #1 killer for a reason. It’s damn common.

Many other risk factors may accelerate this process however, such as smoking, hypertension, diabetes, adiposity, becoming sedentary etc.  But the presence of atherogenic lipoprotein particles, even in the absence of all other risk factors is enough.

So why are people STILL dying from this preventable and treatable disease?

Underrecognition of the disease

• Access: For many, it’s an issue of access to health care. Men are less likely to seek it out. Women are less likely to be identified even when they do seek it out. 
• Screening: Appropriate screening is available, but not implemented regularly. Traditional risk calculators often fall short. 3 out of 4 younger patients presenting with their first cardiac event, would have never qualified for a statin using standard risk calculators. So, even if they had reliable check ups, they may not have been recognized.
• • Coronary Artery Calcium Scores offer superior screening when used on top of traditional risk calculators
  • • Highest Net Reclassification Index
    • Highest C-statistic (Receiver Operator Curve)
    • Even benefit low risk patients
• Cost: Many patients lack insurance or cannot even afford the copays to see their doctor or obtain coverage for screening tests
• • Despite Calcium scores being recognized in multiple guidelines, insurance companies refuse to cover them
  • Most calcium score testing has been made affordable ($79 - $199) however some places charge much higher or don’t offer them at all

Undertreatment of the disease

• Guideline Confusion and Popularity: There are many guidelines, some more conservative than others. Some are more popular than others. 
• • This impacts cholesterol treatment goals/thresholds - choosing a more conservative goal/threshold runs the risk of undertreatment
• Misinterpretation of recommendations: Most guidelines recommend that high risk patients achieve a particular threshold or goal LDL-C and > 50% lowering from baseline LDL-C!
• • Many forget that last part - meaning a patient may have an LDL-C of 72 mg/dL and are placed on a low or modest regimen aimed at getting below 70 mg/dL. 
• Adherence:
• • Patients: It’s been well documented that > 50% of patients prescribed statins following an ASCVD event will stop taking their statin by 1 year
  • Providers: By CMS not declaring LDL-C a “Quality Measure” healthcare providers and healthcare systems are not held accountable for achieving LDL-C goals. 
  • Statin intolerance: 
  • • Way over-diagnosed
    • • 90% of patient complaints of statin myalgias are attributable to the “nocebo” effect (insert reference). 
      • But, 10% are real and many patients are simply diagnosed as “statin intolerant” and no treatment alternatives implemented
      • • Both patients and provider become fatigued and simply don’t want to go through the painful process of prior authorization for expensive alternatives
• Insurance denials: Despite a 60% cut in the cost of PCSK9i from ~$15,000/year to $5500/year in 2018, insurance companies continue to deny coverage of life-saving non-statin therapies.
• Provider Education and Awareness:
• •  It takes, on average, 13 years for published guidelines to infiltrate mainstream clinical practice. Medicine moves slowly. As advocates, we can help it move faster. 

• Discordance - Over reliance on LDL-C. Yes, you heard that right. 
• • LDL-C needs to be a “Quality Measure” because it’s by far the more commonly used lipid biomarker and does a pretty good job
  • However LDL-C has limitations
  • • When TG are high and HDL-C is low, LDL-C is discordant to and may drastically underestimate LDL particles and therefore risk. 
  • NonHDL-C is a better biomarker than LDL-C
  • • It’s been in the guidelines for decades - when triglycerides are elevated (now we say > 150 mg/dL), one must look at non-HDL-C (again, discordance).
    • Few clinicians even know what non-HDL-C is
    • Of those that do, few take the time to either calculated it or look at it
    • Non-HDL-C is not always “listed” in lab reports, relying on the clinicians to calculate it themselves
    • Most clinicians (most people) don’t like doing math during a busy visit
  • ApoB (apolipoprotein B) is better when it comes to recognizing residual risk in the presence of discordance
• Ignoring triglycerides
• • Aside from being a visual cue to look for discordance when TG elevated, residually elevated TGs are a prerequisite for a therapy that can reduce ASCVD events by an additional 25%
  • • Icosapent ethyl (Vascepa - insert link to company website)

“Even lower is even better, for even longer”

• “Even lower is even better, for even longer”
• In patients with established ASCVD or prior ACS, the latest clinical trials have demonstrated no LDL-C threshold for which there was not an even greater clinical benefit. Meaning, the lower the achieved level, the greater the risk reduction. Even with LDL-C levels