Why the cardiovascular community needs to take a closer look at inflammation
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Key takeaways:
- Inflammation is a major contributor to atherosclerotic heart disease.
- Anti-inflammatory therapy may reduce cardiovascular events in patients with residual inflammatory risk already on lipid-lowering therapy.
Heart disease continues to be the leading cause of death and disability in the U.S. and worldwide. Atherosclerotic CVD, which is caused by plaque buildup in arterial walls, contributes to multiple life-threatening conditions.
This is due in part to the fact that atherosclerosis may go virtually unnoticed until a major CV event happens.
Patients with ASCVD are at a higher risk for major adverse CV events, including heart attack (also known as MI), stroke and death. In the U.S. alone, more than 800,000 of these people are at risk for MI, and for approximately 200,000 of them, this may well be their second life-threatening cardiac event. More importantly, nearly 20% of those people who have had a MI will be hospitalized again within 5 years due to a second event.
Cardiologists and other health care providers have made significant progress in preventing MI or strokes due to high cholesterol. However, many patients at risk for ASCVD remain inadequately treated, leaving them vulnerable to disease progression.
A well-recognized goal in preventive cardiology is cholesterol reduction to reduce patients’ overall risk for heart disease and future CV events. Statin therapy is first-line treatment for primary prevention of ASCVD in patients with LDL levels ( 190 mg/dL), those with diabetes aged 40 to 75 years and those determined to be at sufficient ASCVD risk after a clinician-patient risk discussion. Yet, cholesterol management alone is not sufficient to prevent ASCVD-related disease, as many statin-treated patients continue to experience acute CV events.
A second look at inflammation in ASCVD
It is important to treat all known risk factors that contribute to ASCVD, including high BP, hyperlipidemia, diabetes and obesity, but physicians also need to recognize that inflammation is another major and mostly untreated contributing factor to this disease. As a CV surgeon, as well as an immunologist, I know the role systemic inflammation plays in increasing a patient’s risk for CVD.
I have observed patients with various systemic inflammatory disorders, and although each of these diseases are different from one another, all have been linked to an increased risk for atherosclerosis. For example, psoriasis, a chronic inflammatory disease of the skin and joints that affects 2% to 3% of the world’s population, has been clearly linked to multiple associated comorbidities, including an increased prevalence of CV risk factors.
Similarly, patients with rheumatoid arthritis (RA), an autoimmune disease that predominately affects the joints, have an increased mortality rate due to CV events. Most notably, women living with RA have up to a threefold increased risk for heart attack even without the traditional CV risk factors. As such, targeting inflammation in the context of CVD is of the utmost importance for me and my patients.
Previously seen as the result of passive lipid accumulation in the vessel wall, immune cells and inflammation are now known to play a key role in atherosclerosis in conjunction with hyperlipidemia and elevated LDL levels. However, research has now shown inflammation plays a significant role in the development of atherosclerosis and ASCVD and even the formation of plaque.
Although the link between inflammation and CVD has been proved, most physicians have focused on treating high-risk patients with lipid-lowering therapies, including statin therapy.
Inflammation driven by signaling cytokines, circulating immune cells, and oxidized LDL leads to atherosclerotic plaque development, plaque progression and eventual rupture. The NLRP3 inflammasome has been implicated in ASCVD, as it leads to the activation of proinflammatory cytokines triggering signaling through interleukin-6 (IL-6) and inducing production of C-reactive protein, a biomarker for inflammation.
Major clinical trials have now shown that physicians may further reduce the risk for CV events in patients by addressing inflammation as a crucial therapeutic target for secondary prevention in high-risk patients.
In 2017, the CANTOS trial proved that inflammation inhibition without lipid-lowering medications can significantly reduce CV event rates and helped to define the IL-1 to IL-6 to CRP pathway as a central target in CVD. More recently, residual inflammatory risk was found to be a more powerful determinant of recurrent CV events, CV death and all-cause mortality than by LDL in patients with or at high risk for atherosclerotic disease who were receiving contemporary statins.
Detecting and treating inflammation in ASCVD
It is necessary to address both cholesterol risk and inflammation to reduce the risk for a heart attack or stroke, each of which can be measured by simple blood tests. Most patients and practitioners are aware of blood tests measuring LDL to predict CV risk, but fewer know or measure high-sensitivity CRP to determine residual inflammatory risk.
HsCRP is a nonspecific inflammatory marker and an acute phase reactant that predicts the likelihood of MI, stroke, peripheral artery disease and sudden cardiac death among healthy individuals with no history of CVD, and recurrent events and death in patients with known ASCVD. Generally, hsCRP values above 2 mg/L are linked to increased risk for MIs or risk for a repeat MI.
Importantly, hsCRP levels vary over time and a CAD risk assessment should be based on the average of two hsCRP tests. For hsCRP, when values are very high (above 10 mg/L), it is likely that the body is responding to a cold or infectious disease, and so another test should be performed to confirm the biomarker. Among statin-treated patients with hsCRP greater than 2 mg/L, risks for CV death were high regardless of LDL level.
Nearly half of all patients on aggressive statin therapy have residual inflammatory risk. More than one-third of patients with ASCVD have hsCRP levels above 2 mg/L, which indicates a higher risk for heart disease. In contemporary trials, roughly twice as many individuals were found to have residual inflammatory risk compared with residual cholesterol risk.
The potential of low-dose colchicine
There was not an agent specifically approved by the FDA for reduction of CV events in high-risk patients with residual inflammatory risk until June, when the agency approved colchicine 0.5 mg (Lodoco, Agepha Pharma) to reduce risk for heart attack, stroke, coronary revascularization and CV death.
Colchicine 0.5 mg reduces multiple pro-inflammatory mechanisms and has been shown to inhibit migration of neutrophils to inflamed areas. Colchicine suppresses the NLRP3 inflammasome and reduces IL-6 and CRP levels.
Colchicine 0.5 mg has been shown to safely lower MACE compared with placebo and on top of standard care, including statin therapy. The LoDoCo2 trial in patients with clinically stable CAD, most of whom were on statin therapy, showed during a median follow-up of 29 months that colchicine 0.5 mg reduced the risk for CV death, MI, ischemic stroke or ischemia-driven coronary revascularization by 31% compared with placebo.
In the COLCOT trial, colchicine 0.5 mg also showed clinical benefits in patients following a recent MI. In the study, patients treated with colchicine 0.5 mg experienced a 23% lower incidence of death from CV causes, resuscitated cardiac arrest, MI, stroke or urgent hospitalization for angina leading to coronary revascularization in a time-to-event analysis compared with those assigned placebo. The benefit was most significant in reducing the incidence of stroke and angina requiring revascularization.
Importantly, colchicine 0.5 mg is associated with a 30% to 40% reduction in median hsCRP levels and a 16% reduction in median IL-6 levels in patients with chronic coronary disease.
Colchicine has been proven to be safe and effective in patients taking high-intensity statins. The most common adverse events in patients treated with colchicine 0.5 mg are diarrhea, nausea and abdominal pain in up to 10% of those initiating therapy. For most individuals, these gastrointestinal effects markedly attenuate with longer-term therapy. Colchicine has been used safely for almost 2,000 years. In clinical studies, myotoxicity was reported at the same rate in those treated with colchicine or placebo.
It is important to note that colchicine 0.5 mg should not be prescribed to individuals with clinically significant chronic kidney disease or hepatic dysfunction and should not be used in combination with strong inhibitors of CYP3A4 or P-glycoprotein. Certain immunosuppressive medications should be avoided in patients on colchicine.
Inflammatory risk and CVD reduction strategies
Substantial progress has been made in preventing MI and stroke in patients. However, until recently, the significant role inflammation plays in heart disease has not been well recognized, even by physicians. Research has shown that inflammation contributes to ASCVD in conjunction with hyperlipidemia and elevated LDL levels, and that addressing residual inflammatory risk may be able to significantly lower the likelihood of MI and stroke.
Cardiologists and primary care providers alike should measure hsCRP as well as LDL to get the complete picture of a patient’s residual risk. For most patients, the best care is likely to include combined use of aggressive LDL-lowering and inflammation-inhibiting therapies, as targeting LDL alone is unlikely to eliminate ASCVD risk. Physicians can now address systemic inflammation as an underlying factor in ASCVD by adding anti-inflammatory therapy to lipid-lowering medications to reduce the risk for life-threatening CV events in patients.
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For more information:
Robert L. Quigley, MD, DPhil, is an international health care consultant and a senior consultant for International SOS. He is the co-founder and executive chairman of the International Corporate Health Leadership Council, a 501(c)(6) organization. He formerly served as senior vice president and global medical director, corporate health solutions, at International SOS Assistance & MedAire, Americas Region, and was responsible for leading the delivery of high-quality medical assistance, health care management and medical transportation services. Before joining International SOS, Quigley was a triple board re-certified cardiovascular and thoracic surgeon who directed two open heart programs within the Jefferson Health System in Philadelphia, where he was a professor of surgery at Jefferson Medical College. He can be reached at robertlquigley8@gmail.com.
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