Anti-inflammatory agents may have potential in secondary prevention
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Atherosclerotic CVD has long been recognized as an inflammatory disease.
Well-known CV risk factors such as uncontrolled hypertension, diabetes, elevated LDL and cigarette smoking lead to alteration of the normal homeostatic properties of the endothelium. An increase in leukocytes and platelets causes a procoagulable state and stimulates the migration and proliferation of smooth muscle cells that form an intermediate lesion on the arterial wall. With persistent inflammation, the arterial wall becomes thickened and undergoes deleterious remodeling. Macrophages and lymphocytes multiply within the lesion and release hydrolytic enzymes, cytokines, chemokines and growth factors that lead to focal necrosis and ultimately lead to a lesion with a fibrous cap in the coronary artery. Ruptures of these fibrous caps are a major cause of ACS.
Anti-inflammatory medications may offer additional benefits in the secondary prevention of acute MI and affect pathophysiologic pathways that are not targeted with current standard treatment. This column explores three potential anti-inflammatory agents: canakinumab (Ilaris, Novartis), methotrexate and colchicine.
Canakinumab
Biomarkers associated with inflammation such as interleukin-6 (IL-6) and high-sensitivity C-reactive protein are associated with increased risk for CV events.
Canakinumab is a monoclonal antibody that was granted FDA orphan drug status and is currently used for the treatment of inflammatory disorders such as periodic fever syndromes and juvenile arthritis. It is administered as a subcutaneous injection every 6 to 8 weeks. Canakinumab inhibits IL-1 beta, a cytokine responsible for triggering the IL-6 signaling pathway, a key modulator of the inflammatory atherosclerotic process.
CANTOS was a randomized, double-blind, placebo-controlled trial that evaluated the use of canakinumab in patients with elevated hsCRP of at least 2 mg/L and a previous MI at least 30 days before randomization (Table). Patients were randomly assigned to placebo or canakinumab 50 mg, canakinumab 150 mg or canakinumab 300 mg subcutaneously every 3 months.
Patients who received canakinumab 150 mg had a significant decrease in the primary composite endpoint of nonfatal MI, nonfatal stroke or CV death compared with placebo, driven by a decrease in nonfatal MI (3.86 per 100 person-years; HR = 0.85; 95% CI, 0.74-0.98). This trial also showed a dose-dependent decrease in levels of hsCRP and IL-6 in patients receiving canakinumab compared with placebo, with no change in levels of LDL or BP. Of note, the magnitude of risk reduction was greatest among patients with the largest reductions of inflammatory mediators. Use of canakinumab was associated with neutropenia and an increased risk for fatal infection, thrombocytopenia without an increased risk for major bleeding and a modest increase in triglyceride levels.
Besides the increased rate of adverse events with this medication, the adoption of canakinumab into practice is limited by its cost. An economic analysis estimated that the addition of canakinumab to standard of care would yield an incremental cost-effectiveness ratio of $6.4 million per quality-adjusted life-year based on orphan-drug pricing. Despite its limitations, this trial largely supports the inflammatory hypothesis of CAD, since canakinumab works solely through an anti-inflammatory mechanism and had a significant effect on clinical outcomes.
Methotrexate
Methotrexate is a folate antimetabolite that inhibits DNA synthesis, repair and cellular replication. It is currently used for the treatment of various inflammatory conditions, including rheumatoid arthritis and psoriatic arthritis. The potential CV effects of methotrexate can be explained by its antiproliferative, antiatherogenic, immunosuppressive and anti-inflammatory effects.
CIRT was a randomized, double-blind, placebo-controlled trial that assessed the use of methotrexate for the secondary prevention of atherothrombotic events in patients with a history of MI or multivessel CAD with type 2 diabetes or metabolic syndrome; unlike in CANTOS, hsCRP was not a criterion for enrollment in CIRT (Table). Patients were randomly assigned to placebo or weekly oral methotrexate and were entered into a run-in phase in which doses were increased sequentially from 5 mg to 10 mg to 15 mg based on tolerability.
Compared with placebo, methotrexate did not reduce the primary composite outcome of nonfatal MI, nonfatal stroke or hospitalization for unstable angina requiring revascularization (4.13% vs. 4.31%; HR = 0.96; 95% CI, 0.79-1.16), nor did it reduce levels of IL-1 beta, IL-6 or hsCRP. Adverse events were more common in the methotrexate group and included elevations in liver enzyme levels and a decrease in leukocyte count and hematocrit levels. There was no difference in all-cause mortality between groups.
A limitation of this trial is its use of a run-in phase, which may have led to selection bias; only patients who were able to tolerate methotrexate were included, which may reduce the ability to extrapolate these results to the general population. Furthermore, the trial was terminated for futility. Only 4,786 of the 5,500 intended patients completed the run-in phase.
Although methotrexate is inexpensive, is given orally and is widely used as an agent for other inflammatory conditions, the lack of efficacy and concerning adverse event profile preclude its use for the secondary prevention of ASCVD.
Colchicine
Colchicine inhibits beta-tubulin polymerization into microtubules and is currently indicated for gout, familial Mediterranean fever and pericarditis. In the LoDoCo trial, patients with stable CAD on optimal medical therapy who received colchicine 0.5 mg once daily had lower risk for ACS, cardiac arrest and stroke compared with a control group. This study, however, enrolled only 532 patients, was unblinded and lacked a placebo group.
The more recent COLCOT trial was a randomized, double-blind, placebo-controlled trial that evaluated the use of colchicine 0.5 mg daily compared with placebo in patients who experienced an MI within 30 days of enrollment (Table on page 22). Patients receiving colchicine had a significantly lower rate of the primary composite outcome of death from CV causes, resuscitated cardiac arrest, MI, stroke or urgent hospitalization for angina leading to coronary revascularization (5.5% vs. 7.1%; HR = 0.77; 95% CI, 0.61-0.96); these results were primarily driven by lower risk for angina and stroke. Of note, nausea, flatulence and pneumonia occurred more frequently in the colchicine group.
Only 4% patients in COLCOT underwent inflammatory biomarker testing and patients were not randomly assigned to evaluate outcomes based on initial hsCRP levels. At enrollment, patients had a median hsCRP level of 4.28 mg/L, and no difference in change from baseline was detected between the groups at 6 months. The small subset of patients and the resolution of the acute elevation of biomarkers, however, may have obscured evidence of an anti-inflammatory effect.
At this time, this trial does not support the routine use of colchicine for all patients for secondary prevention of ASCVD. Given its safety and low cost, however, colchicine may be considered for patients in whom other secondary prevention medications are optimized to prevent stroke and hospitalization for angina.
None of the aforementioned trials evaluated whether timing following an acute event affected the benefit.
More convincing data needed
Although canakinumab reduced inflammatory biomarker levels and CV events, it cannot be recommended for CV indications.
Methotrexate and colchicine, however, are ostensibly more appealing options due to their low cost and oral route of administration, but methotrexate did not demonstrate efficacy in reducing CV events in the population enrolled in CIRT. Of these two drugs, colchicine reduced the risk for stroke and hospitalization for angina and demonstrated a more favorable side effect profile than methotrexate.
Inflammation plays a key role in the development of atherosclerosis, but, at this time, more convincing data are needed before agents that target inflammatory pathways become a standard of care in the secondary prevention of ASCVD. Anti-inflammatory medications such as colchicine should be considered as adjunct therapy to medications with proven benefits, such as statins. We await the results of the LoDoCo 2 study, to be unveiled shortly, to confirm the results of COLCOT. Because of its demonstrated anti-inflammatory actions, investigators have begun small exploratory trials to evaluate whether canakinumab may offer benefits in treating respiratory failure and pneumonia associated with COVID-19.
- References:
- Colcrys (colchicine). Package insert. Takeda Pharmaceuticals; 2009.
- Cremer PC, et al. Canakinumab to Reduce Deterioration of Cardiac and Respiratory Function Due to COVID-19. NCT04365153; currently recruiting.
- Hansson GK, et al. N Engl J Med. 2005;doi:10.1056/NEJMra043430.
- Harrington RA, et al. N Engl J Med. 2017;doi:10. 1056/NEJMe1709904.
- Ilaris (canakinumab). Package insert. Novartis International AG; 2019.
- Methotrexate. Package insert. 2019.
- Newby LK, et al. N Engl J Med. 2019;doi:10.1056/NEJMe1914378.
- Nidorf SM, et al. N Engl J Med. 2013;doi:10.1016/ j.jacc.2012.10.027.
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- Ridker PM, et al. Lancet. 2017;doi:10.1016/S0140- 6736(17)32247-X.
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- Sehested TSG, et al. JAMA Cardiol. 2019;doi:10. 1001/jamacardio.2018.4566.
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- For more information:
- Melanie R. Madorsky, PharmD, BCPS, BCCP, is a clinical pharmacy specialist in the cardiac care unit at Memorial Hermann-Texas Medical Center in Houston.
- Thomas Szymanski, PharmD, BCCP, is a clinical pharmacy specialist in cardiothoracic surgery at WVU Medicine.
- Sarah A. Spinler, PharmD, FCCP, FAHA, FASHP, AACC, BCPS (AQ Cardiology), is the Cardiology Today Pharmacology Consult column editor. She is professor and chair of the department of pharmacy practice in the School of Pharmacy and Pharmaceutical Sciences at Binghamton University. She can be reached at sspinler@binghamton.edu.
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Ridker PM, et al. N Engl J Med. 2017;doi:10.1056/NEJMoa1707914.
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