Payal Kohli, MD

Payal Kohli, MD, is an attending cardiologist for Kaiser Permanente in Denver, Colorado.

	As the number of biomarkers used to assess cardiovascular disease (CVD) risk and promote prevention continues to grow, clinicians are challenged to determine which marker is best used in which circumstance. In general, three criteria are important when evaluating biomarkers:

	The following are the top 5 “biomarkers” every physician involved in CVD prevention must know how and when to use:

Ok, this isn’t a true “biomarker” but ordering it is definitely the first step in assessing a patient’s risk of atherosclerotic CVD (ASCVD). And the ACC’s handy 

 incorporates total cholesterol (TC) and HDL-C into risk estimation. Recent ideological changes are shifting testing away from the  fasting lipid panel, noting that it is no longer needed (rationale: TC, LDL-C, and HDL-C are less impacted by fasting). But beware, non-fasting panels can be difficult to interpret if the triglycerides (TGs) are very high because elevated levels can affect LDL-C calculation by the Friedwald equation). Personally, for primary prevention patients, I generally start with a non-fasting panel and depending on the results (ie, when TGs are very elevated), if need be, I repeat with a fasting panel. For secondary prevention patients, especially those who are very high risk, I still tend to start with a fasting lipid panel.

Another “trick” biomarker. I consider the hemoglobin A1c one of our oldest and most widely utilized biomarkers in CVD prevention, managem ent, and prognosis. Because it reflects the previous 3 months of glycemic control, I know this for sure: 

. The obvious benefit of this measure is its potential to help diagnose diabetes as well as to reflect how well the disease is managed and to gauge overall prognosis. The A1c can also help assess pre-clinical disease, or “prediabetes.” As prediabetes gains credence as a clinical disease entity, recommendations for more aggressive risk control of the condition (ie, with lifestyle changes, pharmacologic therapy) have been incorporated into treatment guidelines. Recent guidelines recommend considering use of metformin in patients with prediabetes (fasting plasma glucose 100-125 mg/dL; 2-hr post-load glucose 140-199 mg/dL; or A1c 5.7-6.4%), especially in those who are age <60 years old, have a BMI >35 kg/m

, or have a history of gestational diabetes.

 Metformin has not been approved for such use by the FDA but may have the potential to prevent progression to diabetes. Large cardiovascular outcome trials with antihyperglycemic medications are ongoing - stay tuned to see if pharmacologic treatment of prediabetes with metformin may reduce MACE.

Hs-CRP (high-sensitivity C-reactive protein). 

Hs-CRP is a biomarker whose characteristics (ie, its constant half-life) make it ideal as an indicator of acute ongoing inflammation. A meta-analysis from the USPSTF demonstrated that hs-CRP >3 mg/dL was associated with 60% increased risk of cardiovascular disease.The biomarker became a prominent topic in CVD prevention in 2008 with results of the JUPITER trial.

 JUPITER was a large outcomes trial that randomized ~18,000 primary prevention patients with LDL-C <130 mg/dL and hs-CRP >2 mg/dL to statin therapy (with rosuvastatin) vs placebo. The trial had to be stopped early in light of a 44% lower hazard for the primary composite endpoint with statin use in the treatment group.

	The ACC/AHA have given hs-CRP screening in the decision to use a statin a Class IIa indication and a Class IIb recommendation for men >50 years and women >60 years.

This is a marker for CVD I tend to use when: (1) cholesterol is well controlled but the patient has a significant family history of premature heart disease, or (2) there are other risk factors that are readily captured by the ACC’s ASCVD risk calculator (eg, a high-risk ethnic group such as South Asians that tends to have elevated Lp(a) levels)

	Lp(a) represents an LDL-like particle and an apolipoprotein (a) and is a genetically determined marker. Ideally, levels should be <14 mg/dL and very high risk (for atherosclerosis and vascular events) is >50 mg/dL. Recently, it has been found that PCSK9 inhibition reduced Lp(a) by ~30% 

(read about PCSK9 inhibition and test your knowledge here)

 BNP belongs to a family of hormones that are upregulated in period of myocardial wall stress and the most common clinical use is in the setting of acute heart failure (usually for diagnosis) or chronic heart failure (usually for prognosis).  In primary prevention, there have been consistent associations with elevated BNP and cardiovascular risk and in multiple analyses, BNP (or its precursor NT-proBNP) has been shown to have independent prognostic value. I don’t check it often unless there is HFPEF or diastolic heart failure present; in these cases, it helps to establish a baseline in patients who are euvolemic.

Articles

Which biomarker is most useful in what situation? Find out how one cardiologist makes these decisions. Do you concur? 

The Top 5 Biomarkers in Cardiovascular Disease Prevention

The debut of the proprotein convertase subtilisin kexin 9 (PCSK9) inhibitors evolocumab (Repatha, Amgen) and alirocumab (Praluent, Sanofi-Regeneron) in mid-2015 has completely changed the landscape of primary and secondary prevention of coronary heart disease (CHD). If ever there were a “Cinderella” story in science, it would be this one which embodies a true “bench to bedside” tale. The drug target for inhibition of PCSK9 was discovered with the identification of both gain of function (GOF) and loss of function (LOF) mutations in this enzyme. The GOF mutation resulted in heterozygous familial hypercholesterolemia (HeFH) and high levels of CHD while LOF mutations resulted in a significantly lower LDL-cholesterol and risk of CHD.

Here is a typical patient with FH you might see in clinical practice (case adapted from Yuan et al

): A 34-year-old man of Irish ancestry was referred for dyslipidemia management. He had been in good general health until the age of 29 years, when routine blood tests returned a plasma total cholesterol (TC) result of 387 mg/dL and an LDL-C concentration of 309 mg/dL. His family history included premature CAD: his father and 2 paternal uncles each had elevated plasma levels of LDL-C and died of MI before 50 years of age.

Answer B. A heterogeneous group of disorders resulting in elevated serum cholesterol and triglyceride concentrations. (NOT consistent with FH)  

Familial hypercholesterolemia is transmitted via autosomal dominant inheritance and results mainly in isolated elevated total cholesterol (due to elevated LDL-C) and is less likely to cause elevations in triglyceride (TG) concentration. TGs are more commonly elevated in related disorders of cholesterol homeostasis, such as familial hypertriglyceridemia, familial combined hyperlipidemia and familial dysbetalipoproteinemia. In homozygous familial hypercholesterolemia (HoFH), diagnostic criteria can include genetic analyses and/or clinical scoring systems. Because of its autosomal dominant transmission, a through family history is important. Clinical manifestations include premature CHD, cutaneous manifestations such as tendon xanthomas, widespread atherosclerosis, and early mortality. HeFH, whose prevalence is higher than was previously appreciated, can also result in clinical characteristics such as tendon thickening, xanthelasmas, xanthomas, and corneal arcus. There are three currently accepted resources for diagnosis of FH: the Simon Broom Criteria, the Med Ped Criteria, and the FH Dutch Lipid Clinic Criteria. Although molecular diagnosis is helpful, it is not essential to diagnosis of this condition and early identification and treatment can have a considerable impact on the natural history of the disease. 

…. At age 33, the patient experienced an acute MI. Angiography showed widespread CAD that required the placement of 3 stents. Daily oral drug therapy was initiated for secondary CAD prevention: atorvastatin (80 mg), ezetimibe (10 mg), ramipril (5 mg), clopidogrel (75 mg), bisoprolol (5 mg) and ASA (81 mg). At 6 months after his MI, his serum TC and LDL-C concentrations were 207 and 145 mg/dL, respectively; trial of rosuvastatin 40 mg resulted in slight improvement of his serum TC to 180 mg/dL and LDL-C to 125 mg/dL.

Is this patient a candidate for PCSK9 inhibitor therapy?

  The answer will follow later. First, how much do you know about PCSK9 and inhibition of this enzyme? Test your knowledge below.

Answer: C. Regulation of LDL receptor glycoprotein on hepatic membrane.

PCSK9, is a part of a family of proprotein convertase enzymes that work to maintain homeostasis. PCSK9 directly regulates the cell-surface expression and degradation of low-density lipoprotein receptors (LDL-R) in the liver. When this enzyme is inhibited with a monoclonal antibody or siRNA (a PCSK9 inhibitor), the LDL-R does not bind PCSK9 and so can be recycled back to the cell surface to scavenge more circulating LDL-C. Hence, PCSK9 inhibition (or LOF mutations in PCSK9) leads to clinically lower levels of circulating cholesterol. Additional physiologic effects of PCSK9 have not yet been identified although animal studies have suggested a role in non-hepatic tissue, such as intestinal and adipocyte lipid metabolism, atherosclerotic plaque, apoptotic cell death, and regulation of glycemic control. 

 is the mechanism of action of statins, which competitively inhibit HMG-CoA reductase, which is the first and rate-limiting enzymatic step of the cholesterol biosynthetic pathway. 

 is the mechanism of action of ezetemibe (Zetia) and 

In recent years, increasing attention has been turned towards familial lipid disorders, a risk factor that had previously been thought to not be readily modifiable.

Answer: B. As an adjunct to diet and maximally tolerated statin therapy for adults with HeFH or with clinical ASCVD.

are the only currently approved indications for use of alirocumab in the United States. 

 is incorrect as this agent is not recommended as an alternative to statin therapy in patients who have no history of statin intolerance – statins remain the first line therapy for hyperlipidemia.. In Europe, alirocumab is approved for use as a stand-alone agent for adult patients with primary hypercholesterolemia (HeFH and non-familial) or mixed dyslipidemia as an adjunct to diet: 

a) in combination with a statin, or statin with other lipid-lowering therapies in patients unable to reach their LDL-C goals with the maximally-tolerated statin, or 

b) alone or in combination with other lipid-lowring therapies for patients who are statin intolerant, or for whom a statin is contraindicated. 

Alirocumab is not yet approved in primary prevention populations (

) unless there is clinical ASCVD or FH present.

The ODYSSEY-OUTCOMES trial, a prospective trial of ~18,000 patients after acute coronary syndrome (acute ischemic population) during treatment with alirocumab is expected to report results at the American College of Cardiology Conference in March 2018. However, outcome data are available from the FOURIER trial

which reported on cardiovascular outcomes with the use of the evolcumab (Repatha, Amgen) in a secondary prevention population (stable CAD). At median follow up of 2.2 years, the results showed that there was a sustained reduction in LDL-C and a resulting reduction in the primary endpoint (composite of CVD, MI, stroke, hospitalization for unstable angina, or coronary revascularization) and the secondary endpoint (CVD, MI, stroke) with the benefit being driven primarily by reduction of non-fatal events such as stroke (lower by 0.4%), myocardial infarction (lower by 1.2%), coronary revascularization (lower by 1.5%). There was no mortality benefit. Some suggest that a mortality benefit may emerge with longer follow-up. No apparent safety signals emerged.

Overall, the two FDA-approved PCSK9 inhibitors are very well tolerated and there have been rare serious side effects. The mechanism of alirocumab and evolocumab is a humanized monoclonal antibody against PCSK9. Common side effects include injection site reactions and cold or flu and flu-like symptoms.  Serious side effect such as severe systemic allergic reactions/hypersesnitivity and hypersensitivity vasculitis, have been reported but are rare. Neurocognitive events were reported in 0.8% of patients treated with alirocumab and 0.7% of patients treated with placebo. Confusion or memory impairment were reported more frequently by those in the alirocumab group (0.2% for each) vs those in the placebo group (<0.1% for each). Liver-related disorders (primarily related to abnormalities in liver enzymes) were reported in 2.5% of alirocuman-treated patients and 1.8% of patients treated with placebo, leading to treatment discontinuation in 0.4% and 0.2% of patients, respectively. Increases in serum transaminases to greater than 3 times the upper limit of normal occurred in 1.7% of patients treated with alirocumab vs 1.4% of patients treated with placebo. 

To date, despite thousands of patients being treated with monoclonal antibodies against PCSK9, there have been no significant unexpected adverse effects. Notably, no significant neurocognitive effects have emerged (a theoretical concern of achieving very low LDL concentrations) in a post-hoc analysis of the FOURIER randomized trial

And here's one to keep you on your toes...

Finally, to answer the question about the patient introduced earlier

: Yes, he is most definitely a candidate for PCSK9 inhibitor therapy.  For this patient, he has already had clinical ASCVD (an MI) and he continues to have elevated LDL-C despite maximal dose of high intensity statin and ezetemibe. It is likely that he has HeFH driving his hyperlipidemia and PCSK9 inhibitors would be the most reasonable next step in optimal secondary prevention therapy.

Heterozygous familial hypercholesterolemia: an underrecognized cause of early cardiovascular disease. 

CMAJÃ¢€¯: Canadian Medical Association Journal

 Sabatine MS, Giugliano RP, Keech AC, et al.

 Evolocumab and clinical outcomes in patients with cardiovascular disease. 

2017; 376:1713-1722. DOI: 10.1056/NEJMoa1615664. 

 Giugliano RP, Pedersen TR, Park J-G, et al. 

Clinical efficacy and safety of achieving very low LDL-cholesterol concentrations with the PCSK9 inhibitor evolocumab: a prespecified secondary analysis of the FOURIER trial

The PCSK9 inhibitor class is here to stay. Find out what you know about the enzyme and how its inhibition is revolutionizing CHD prevention.

PCSK9 Inhibitors: A 5-Question Quiz

	The updates from the ACC, AHA, and 9 other professional organizations to the hypertension guidelines were eagerly anticipated. The slides that follow offer a user-friendly summary.

Click through our topline review of the key takeaways from this long-awaited update.  

2017 ACC/AHA Hypertension Guidelines: The Takeaways

Patients with atrial fibrillation (AF), who meet the indication for oral anticoagulation (ie, CHA

-VASC ≥2), and have concomitant coronary artery disease (CAD) with an indication for percutaneous coronary intervention (PCI) (which necessitates the use of dual anti-platelet therapy) continue to pose an important clinical challenge for physicians. It is not at all unusual for clinicians to be left wondering which combination of the following drugs provides the greatest efficacy for these patients along with the lowest risk for bleeding: aspirin, clopidogrel, a direct-acting anticoagulant (DOAC), and warfarin.

Take the quiz below to assess your current knowledge of the latest in the field.

There is a contemporary strategy among physicians for patients with AF and CAD to use “triple therapy” (aspirin, clopidogrel, and oral anticoagulation) for a short period of time following PCI, then drop the aspirin and use only clopidogrel and oral anticoagulation for the duration of the required antiplatelet therapy.

Dewilde WJ, Oirbans T, Verheugt FW, et al. 

Use of clopidogrel with or without aspirin in patients taking oral anticoagulant therapy and undergoing percutaneous coronary intervention: an open-label, randomised, controlled trial. 

 2013 30;381 (9872):1107-15. doi: 10.1016/S0140-6736(12)62177-1. Epub 2013 Feb 13

2. Dans AL, Connolly SJ, Wallentin L, et al. 

Concomitant use of antiplatelet therapy with dabigatran or warfarin in the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial

3. Cannon CP, Bhatt DL, Oldgren J, et al for the RE-DUAL PCI Steering Committee and Investigators. Dual antithrombotic therapy with dabigatran after PCI in atrial fibrillation. NEJM. Published online August 27, 2017. Available at: 

http://www.nejm.org/doi/full/10.1056/NEJMoa1708454#t=article

Quick Quiz: Which antiplatelet/antithrombin combination provides greatest efficacy with least risk for bleeding?

Payal Kohli, MD

Articles

The Top 5 Biomarkers in Cardiovascular Disease Prevention

PCSK9 Inhibitors: A 5-Question Quiz

2017 ACC/AHA Hypertension Guidelines: The Takeaways

Aspirin, Clopidogrel, DOAC, Warfarin: What Combination after PCI in Patients with AF?