Case Study: Identifying and Managing the Patient with High Inflammatory Burden

CASE STUDY

This case has unanswered questions but shows how a cardiologist and nurse practitioner who became certified lipid specialists create a team approach for their patient.

MS. TAYLOR AND DR. GREENFIELD:

Ms. C is a 59-year-old woman relocating from another state and seeking a cardiology follow-up evaluation two years after suffering an ST-segment elevation myocardial infarction (STEMI) that was successfully stented. Aside from being an ex-smoker who quit 35 years ago, there is no history of diabetes or hypertension and no family history for premature heart disease. At the time of her MI, she was placed on atorvastatin 80 mg daily. Six months later, the dose was reduced to 40 mg daily because of complaints of myalgias. Other medications included ASA 81 mg daily, metoprolol XL 25 mg daily and losartan 25 mg daily. A lipid profile one month ago demonstrated these results (Table 1).

One month after her initial appointment, she was admitted through the emergency department (ED) with an acute anterior wall myocardial infarction treated with placement of two drug-eluting stents. The following morning, as we approached her bedside, she asked us, “Why did I have another heart attack?”

MS. TAYLOR: A significant percentage of residual ASCVD risk exists in patients treated with high-intensity statin, especially if inflammation still may be present.(1) While Ms. C was not obese, remained a non-smoker and was normotensive with a normal fasting blood glucose, her elevated hs-CRP suggests the presence of an inflammatory component in her ongoing cardiovascular risk. In 2008, the Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) (2) took patients free of atherosclerotic cardiovascular disease (ASCVD) with

hs-CRP > 2 mg/L and relatively normal LDL levels <130mg/dl. Treatment with rosuvastatin resulted in a 44% reduction in the primary endpoint of nonfatal MI, stroke or death. In addition, the lowest event rates in JUPITER were shown in those with both an LDL-C < 70 mg/dl and an hs-CRP < 2 mg/L.

The National Lipid Association (NLA) Recommendations for Patient-Centered Management of Dyslipidemia: Part 2 comprehensively outlines therapeutic lifestyle changes and the appropriateness of discussing it as initial management. (1) While our patient often consumed red meat and bakery products, the NLA recommendations suggest a diet emphasizing fish consumption — preferably high in omega-3 fatty acids — poultry, nuts, seeds, grains, fruits and vegetables, and limited saturated fats found in red meat and whole milk products, as well as processed meats and sugar.

Residual risk often remains in patients treated with statins, especially if hs-CRP remains elevated(2) and despite wellcontrolled blood pressure and glucose, as is the case on our patient. Investigators from the Cleveland Clinic also have identified the gut microbiome as playing a role in inflammation and cardiovascular disease.(3) Consumption of red meat, egg yolks and energy drinks and substances that contain choline, L-carnitine and betaine can result in production of trimethylamine (TMA) that when oxidized in the liver is converted to trimethylamine oxide (TMAO), a substance that is pro-inflammatory. Higher levels of TMAO are predictive of increased risk of major cardiovascular events.(4) Vegans and vegetarians have much lower TMA levels than omnivores, which may in part explain their lower risk for major adverse cardiovascular events. Increased physical activity with 150 minutes/week of moderate exercise such as brisk walking, as recommended by the ACC/AHA Lifestyle Management Guidelines(5), also can help promote normal levels of lipids and blood pressure, addressing residual ASCVD risk in our patients.

DR. GREENFIELD: As healthcare providers, we become distressed when we can’t find a plausible explanation as to why our patient has suffered a cardiovascular event. She is very well treated with a high-intensity statin and has a low LDL-C, but she still suffered recurrent MI. Her persistent elevated hs-CRP suggested a marker of residual cardiovascular risk. I took this time to review the medical literature with our patient. I wanted to show her that there is clinical trial evidence demonstrating that residual ASCVD risk is associated with elevated hsCRP, even in patients on maximal medical therapy and who have achieved high-intensity LDL-C reduction.

More Evidence of Residual Risk: FOURIER, GLAGOV and CANTOS:More recent literature sheds additional light on this conundrum of inflammation. The Global Assessment of Plaque Regression With a PCSK9 Antibody as Measured by Intravascular Ultrasound (GLAGOV) (figure 1) (6) illustrated that, even when the LDL-C level had been reduced to below 50 mg/dl by using a high-intensity statin in combination with the PCSK-9 inhibitor evolocumab, atherosclerosis still continued to progress in more than one-third of these patients, demonstrating that the disease was not halted in these high-risk patients despite such aggressive therapy.

Moreover, in the landmark FOURIER cardiovascular outcomes trial(7) of evolocumab, the modest 15% relative risk reduction indicates many ASCVD events still occur despite aggressive therapy. When these results were stratified by baseline levels of hs-CRP in those with higher levels of hs-CRP, risk reduction was attenuated despite aggressive LDL-C reduction down to 20 mg/dL.(8) (Figure 2)

Finally, Canakinumab Anti-inflammatory Thrombosis Study (CANTOS) evaluated the response to interleukin 1-beta (IL-1β) monoclonal antibody in stable ASCVD (prior MI) patients with hs-CRP levels >/= 2 mg/L and mean LDL-C 82 mg/ dl.(9) From canakinumab injected at a dose of 150 mg or 300 mg every three months, there was no change in LDL-C, but there was a 41% decrease in hs-CRP and a 15% relative risk reduction for the composite primary endpoint of nonfatal MI, stroke and CV death over 3.7 years of follow-up. There was a higher rate of fatal infections in the canakinumab compared to placebo group, however. This medicine recently was rejected by the United States Food and Drug Administration (FDA) as directed therapy for cardiovascular risk reduction, but the results of CANTOS support the concept that anti-inflammatory pharmacotherapy may have a future role in care.

MS. TAYLOR AND DR. GREENFIELD: What does the future hold? The future development of targets for inflammation remains an active area of investigation.(10) Recent research reveals other potential anti-inflammatory candidates, including colchicine, a drug used in treatment of gout(11), a crystalinduced disease that may share a similar mechanism of action as cholesterol crystals do in coronary plaques. The Cardiovascular Inflammation Reduction Trial (CIRT) of low-dose methotrexate in individuals at high risk for cardiovascular disease who have diabetes or the metabolic syndrome was stopped early because of futility.(12) Observers of this study point out that the mean hs-CRP level in study subjects was normal and failure to demonstrate improved outcome may be because of selection of the wrong patient type. They noted that observational data of methotrexate benefits in rheumatoid and psoriatic arthritis patients provides hope for benefit in others. There also are animal studies of investigational agents looking at other inflammatory cytokines, such as interleukin 18 (IL-18), tumor necrosis factor (TNF-alpha), and even studies looking at promoting natural inhibitors of interleuken 1 (IL-1) (IL-receptor antagonists).

Take-home messages Ms. C has residual ASCVD risk suggested by elevated hs-CRP despite optimal medical therapy and LDL-C reduction. Presently, the only available therapy for this is intensification of therapies, especially therapeutic lifestyle changes and possibly specific diets shown to reduce inflammation. Moreover, addressing residual risk needs to be a team approach. While many cardiologists often are most concerned about the immediate result of the success of a percutaneous intervention, spending time and collaborating with other providers and the greater healthcare team — including nurses, nurse practitioners and lifestyle “interventionalists” such as registered dietitian nutritionists and exercise physiologists who best can work out a long-term plan to reduce risk over a lifetime — is crucial. Optimism also remains for the future development of newer therapies to target inflammation. “Optimism is the faith that leads to achievement. Nothing can be done without hope and confidence.” — Helen Keller

Disclosure Statement: Dr. Greenfield has received honoraria from Sanofi, Regeneron and Amgen. Dr. Taylor has no financial disclosures to report.