To Further Impede the Progression of Heart Disease, We Must Treat Patients With Anti-Inflammatory Drugs in Combination With Statin Therapy

Heart disease continues to be the leading cause of death and disability in the U.S. and worldwide. Atherosclerotic cardiovascular disease (ASCVD), which is caused by plaque buildup in arterial walls, puts patients at risk of multiple life-threatening conditions and may go virtually overlooked until a major cardiovascular (CV) event, such as a heart attack or stroke, happens.

In the U.S. alone, more than 805,000 people are at risk of a heart attack, and for approximately 200,000 of them, this may be their second life-threatening cardiac event. More importantly, nearly 20% of those people who have had a heart attack will be hospitalized again within five years due to a second event. These alarming statistics not only impact patients and their families but the workforce and economy.

Cardiologists have made significant progress in preventing heart attacks or stroke due to high cholesterol. Even so, many patients remain at risk for ASCVD due to inadequate treatment leaving them vulnerable to disease progression and potentially catastrophic events.

Statin therapy is the first-line treatment for primary prevention of ASCVD in patients. Yet, cholesterol management alone is not sufficient to prevent ASCVD-related disease, as many statin-treated patients continue to suffer from acute CV events. Most physicians have continued to focus on lowering patients’ risk of CV events with additional lipid lowering therapies rather than targeting systemic inflammation as a contributing factor to ASCVD progression. 

Every doubling of statin dose develops, on average, a further reduction in LDL cholesterol (a major culprit in ASCVD) however this “rule of 6” strategy can result in, among other consequences, an increase in side effects. Furthermore, even if the increasing statin therapy normalizes LDL levels there remains a risk for a CV event. It’s therefore very important that physicians begin to recognize the impact of inflammation as a mostly untreated contributing factor to this disease.

For more than two decades, research has shown inflammation plays a significant role in the development of atherosclerosis and ASCVD. Since then, several clinical trials have shown that physicians may further reduce the risk of CV events in patients by addressing inflammation as a crucial therapeutic target for secondary prevention in high-risk patients.

Most importantly, a recent analysis published in The Lancet found residual inflammatory risk to be a more powerful determinant of recurrent cardiovascular events, cardiovascular death, and all-cause mortality than by LDL-C. 

With this abundance of data showing the importance of inflammation in CVD, it’s time we cardiologists and physicians treat high-risk patients by adding inflammation-inhibiting therapies along with aggressive lipid-lowering medications to further reduce the progression of atherosclerosis.

The good news is that last year the U.S. Food and Drug Administration (FDA)-approved the first anti-inflammatory therapeutic option known as LODOCO^® (colchicine, 0.5 mg) to reduce cardiac event risk in patients with established cardiac risk factors. The drug is safe, and efficacious on top of conventional statin therapy. Most importantly, it is cost effective and can easily be made available to any and all patients with ASCVD whom historically may not have had access to equitable health care.

The data supporting this approval included the LoDoCo2 trial which showed colchicine significantly reduced the risk of cardiovascular death, heart attack, ischemic stroke, or ischemia-driven coronary revascularization by 31% compared with placebo. This represents an astonishing effect and one that surpasses the reductions seen in contemporary secondary prevention trials of adjunctive lipid-lowering agents. 

However, one approved anti-inflammatory treatment is not enough. 

For example, people with chronic kidney disease or hepatic dysfunction should not be prescribed colchicine. These people represent a significant population that currently remains at risk of life-threatening CV events. As such, we must continue to research anti-inflammatory agents that may work synergistically with statins, without compromise to hepatic or renal function to mitigate ASCVD.

In 2017, the CANTOS trial proved that inflammation inhibition using canakinumab, without lipid lowering medications, can significantly reduce CV event rates by helping to define the IL-1 to IL-6 to CRP pathway as a central target in CV disease. Colchicine has also been shown to reduce multiple pro-inflammatory mechanisms by suppressing the NLRP3 inflammasome and inhibiting migration of neutrophils to inflamed areas. 

Several systematic reviews of anti-inflammatory drugs have been performed to explore the potential beneficial effects in patients with ASCVD. Nonetheless more research is required to ensure we are providing patients with CV disease with the best care that we can by also addressing underlying systemic inflammation. 

Although considerable progress has been made in preventing heart attacks or stroke in patients, until recently, even physicians did not recognize the significant role inflammation plays in contributing to heart disease. As such, cardiologists and other physicians who treat patients with ASCVD have continued to focus on additional aggressive lipid-lowering medications with little success in further reducing the risk of a life-threatening CV event in their patients. However, it is paramount that we as clinicians address both cholesterol risk and inflammation to further reduce the risk of a heart attack or stroke successfully.

In the past year, we’ve made significant advancements with one FDA-approved anti-inflammatory drug (LODOCO) that can effectively treat heart disease in combination with lipid-lowering medications. However, it’s essential that we continue to research the potential beneficial effects of inflammatory-inhibiting agents so that more patients can prevent life-threatening cardiac events.

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