Sara Conway, MD

ILLUSTRATIVE CASE

A 72-year-old man with well-controlled hypertension and chronic obstructive pulmonary disease is scheduled for right total hip arthroplasty (THA) due to severe arthritis. He will be admitted to the hospital overnight, and his orthopedic surgeon anticipates 2 to 3 days of inpatient recovery time. In addition to medical management of the patient’s comorbid conditions, the surgeon asks if you have any insight regarding VTE prophylaxis for this patient. Specifically, do you think aspirin is equal to LMWH for VTE prophylaxis?

All adults undergoing major orthopedic surgery are considered to be at high risk for postoperative VTE development, with those having lower-limb procedures at highest risk.² Of the more than 2.2 million THAs and total knee arthroplasties (TKAs) performed in the United States between 2012 and 2020, 55% were primary TKAs and 39% primary THAs.³ The American College of Chest Physicians (ACCP) estimated a baseline 35-day risk for VTE of 4.3% in patients undergoing major orthopedic surgery.⁴ The highest VTE risk occurs during the first 7 to 14 days post surgery (1.8% for symptomatic deep vein thrombosis [DVT] and 1% for pulmonary embolism [PE]), with a slightly lower risk during the subsequent 15 to 35 days (1% for symptomatic DVT and 0.5% for PE).⁴

Aspirin’s low cost, availability, and ease of administration make it an attractive choice for VTE prevention in patients post THA and TKA surgery. The Pulmonary Embolism Prevention (PEP) trial evaluated 13,356 patients undergoing hip fracture repair and 4088 patients undergoing arthroplasty and found aspirin to be safe and effective in prevention of VTEs compared with placebo. The investigators concluded that “there is now good evidence for considering aspirin routinely in a wide range of surgical and medical groups at high risk of venous thromboembolism.”⁵ The PEP study, along with others, led to the emergence of aspirin monotherapy for VTE prophylaxis.

Current guidelines for perioperative VTE prophylaxis are based on American Society of Hematology (ASH) and ACCP recommendations. For patients undergoing THA or TKA, ASH suggests using aspirin or anticoagulants for VTE prophylaxis; when anticoagulants are used, they suggest using a direct oral anticoagulant (DOAC) over LMWH.⁶ The ASH guidelines are conditional recommendations based on very low certainty of effects, and the ASH panel recognized the need for further investigation with large, high-quality clinical trials.

The ACCP guidelines are clearer in recommending VTE prophylaxis vs no prophylaxis for major orthopedic surgeries and recommend the use of LMWH over other agents, including aspirin, DOACs, warfarin, and intermittent pneumatic compression (IPC) devices.⁴

Although prophylaxis is widely recommended to mitigate the elevated risk for VTE among patients undergoing orthopedic surgery, aspirin as monotherapy remains controversial.⁷ Many orthopedic surgeons prescribe aspirin as a sole VTE prophylaxis agent; however, this practice is not well supported by data from large, well-conducted, randomized trials or inferiority trials.²

STUDY SUMMARY

Aspirin did not meet the noninferiority criterion for postoperative VTE

The CRISTAL trial compared the use of aspirin vs LMWH (enoxaparin) for VTE prophylaxis in patients ages 18 years or older undergoing primary THA or TKA for osteoarthritis.¹ This Australian study used a cluster-randomized, crossover, registry-nested, noninferiority trial design. Of note, in Australia, aspirin is formulated in 100-mg tablets, equivalent to the standard 81-mg low-dose tablet in the United States.

Continue to: Patients taking prescribed antiplatelet...

Patients taking prescribed antiplatelet medication for preexisting conditions (~20% of patients in each group) were allowed to continue antiplatelet therapy during the trial. Patients were excluded if they were receiving an anticoagulant prior to their procedure or had a medical contraindication to aspirin or enoxaparin.

Thirty-one hospital sites were randomly assigned a treatment protocol using either aspirin or enoxaparin. Once target patient enrollment was met with the initial assigned medication, the site switched to the second/other agent. This resulted in 5675 patients in the aspirin group and 4036 in the enoxaparin group enrolled between April 2019 and ­December 2020, with final follow-up in ­August 2021; of these, 259 in the aspirin group and 249 in the enoxaparin group were lost to follow-up, opted out, or died.

Although this study was designed as a noninferiority trial, analysis showed enoxaparin to be significantly superior to aspirin for postoperative VTE prophylaxis.

The aspirin group was given 100 mg PO daily and the enoxaparin group was given 40 mg SC daily (20 mg daily for patients weighing < 50 kg or with an estimated glomerular filtration rate < 30 mL/min/1.73 m²) for 35 days after THA and 14 days after TKA. Both treatment groups received IPC calf devices intraoperatively and postoperatively, and mobilization was offered on postoperative Day 0 or 1.

The primary outcome—development of symptomatic VTE within 90 days of the procedure—occurred in 187 (3.5%) patients in the aspirin group and 69 (1.8%) patients in the enoxaparin group (estimated difference = 1.97%; 95% CI, 0.54%-3.41%). This did not meet the noninferiority criterion for aspirin, based on an estimated assumed rate of 2% and a noninferiority margin of 1%, and in fact was statistically superior for enoxaparin (P = .007). There were no significant differences between the 2 groups in major bleeding or death within 90 days.¹

WHAT’S NEW

Enoxaparin was significantly superior to aspirin for VTE prophylaxis

Although this study was designed as a noninferiority trial, analysis showed enoxaparin to be significantly superior for postoperative VTE prophylaxis compared with aspirin.

Continue to: CAVEATS

Study aspirin dosing differed from US standard

This study showed significantly lower rates of symptomatic VTE in the enoxaparin group compared with the aspirin group; however, the majority of this difference was driven by rates of below-the-knee DVTs, which are clinically less relevant.⁸ Also, this trial used a 100-mg aspirin formulation, which is not available in the United States.

CHALLENGES TO IMPLEMENTATION

Aspirin is far cheaper and administered orally

Aspirin is significantly cheaper than enoxaparin, costing about $0.13 per dose (~$4 for 30 tablets at the 81-mg dose) vs roughly $9 per 40 mg/0.4 mL dose for enoxaparin.⁹ However, a cost-effectiveness analysis may be useful to determine (for example) whether the higher cost of enoxaparin may be offset by fewer DVTs and other sequelae. Lastly, LMWH is an injection, which some patients may refuse.

ILLUSTRATIVE CASE

A 72-year-old man with well-controlled hypertension and chronic obstructive pulmonary disease is scheduled for right total hip arthroplasty (THA) due to severe arthritis. He will be admitted to the hospital overnight, and his orthopedic surgeon anticipates 2 to 3 days of inpatient recovery time. In addition to medical management of the patient’s comorbid conditions, the surgeon asks if you have any insight regarding VTE prophylaxis for this patient. Specifically, do you think aspirin is equal to LMWH for VTE prophylaxis?

All adults undergoing major orthopedic surgery are considered to be at high risk for postoperative VTE development, with those having lower-limb procedures at highest risk.² Of the more than 2.2 million THAs and total knee arthroplasties (TKAs) performed in the United States between 2012 and 2020, 55% were primary TKAs and 39% primary THAs.³ The American College of Chest Physicians (ACCP) estimated a baseline 35-day risk for VTE of 4.3% in patients undergoing major orthopedic surgery.⁴ The highest VTE risk occurs during the first 7 to 14 days post surgery (1.8% for symptomatic deep vein thrombosis [DVT] and 1% for pulmonary embolism [PE]), with a slightly lower risk during the subsequent 15 to 35 days (1% for symptomatic DVT and 0.5% for PE).⁴

Aspirin’s low cost, availability, and ease of administration make it an attractive choice for VTE prevention in patients post THA and TKA surgery. The Pulmonary Embolism Prevention (PEP) trial evaluated 13,356 patients undergoing hip fracture repair and 4088 patients undergoing arthroplasty and found aspirin to be safe and effective in prevention of VTEs compared with placebo. The investigators concluded that “there is now good evidence for considering aspirin routinely in a wide range of surgical and medical groups at high risk of venous thromboembolism.”⁵ The PEP study, along with others, led to the emergence of aspirin monotherapy for VTE prophylaxis.

Current guidelines for perioperative VTE prophylaxis are based on American Society of Hematology (ASH) and ACCP recommendations. For patients undergoing THA or TKA, ASH suggests using aspirin or anticoagulants for VTE prophylaxis; when anticoagulants are used, they suggest using a direct oral anticoagulant (DOAC) over LMWH.⁶ The ASH guidelines are conditional recommendations based on very low certainty of effects, and the ASH panel recognized the need for further investigation with large, high-quality clinical trials.

The ACCP guidelines are clearer in recommending VTE prophylaxis vs no prophylaxis for major orthopedic surgeries and recommend the use of LMWH over other agents, including aspirin, DOACs, warfarin, and intermittent pneumatic compression (IPC) devices.⁴

Although prophylaxis is widely recommended to mitigate the elevated risk for VTE among patients undergoing orthopedic surgery, aspirin as monotherapy remains controversial.⁷ Many orthopedic surgeons prescribe aspirin as a sole VTE prophylaxis agent; however, this practice is not well supported by data from large, well-conducted, randomized trials or inferiority trials.²

STUDY SUMMARY

Aspirin did not meet the noninferiority criterion for postoperative VTE

The CRISTAL trial compared the use of aspirin vs LMWH (enoxaparin) for VTE prophylaxis in patients ages 18 years or older undergoing primary THA or TKA for osteoarthritis.¹ This Australian study used a cluster-randomized, crossover, registry-nested, noninferiority trial design. Of note, in Australia, aspirin is formulated in 100-mg tablets, equivalent to the standard 81-mg low-dose tablet in the United States.

Continue to: Patients taking prescribed antiplatelet...

Patients taking prescribed antiplatelet medication for preexisting conditions (~20% of patients in each group) were allowed to continue antiplatelet therapy during the trial. Patients were excluded if they were receiving an anticoagulant prior to their procedure or had a medical contraindication to aspirin or enoxaparin.

Thirty-one hospital sites were randomly assigned a treatment protocol using either aspirin or enoxaparin. Once target patient enrollment was met with the initial assigned medication, the site switched to the second/other agent. This resulted in 5675 patients in the aspirin group and 4036 in the enoxaparin group enrolled between April 2019 and ­December 2020, with final follow-up in ­August 2021; of these, 259 in the aspirin group and 249 in the enoxaparin group were lost to follow-up, opted out, or died.

Although this study was designed as a noninferiority trial, analysis showed enoxaparin to be significantly superior to aspirin for postoperative VTE prophylaxis.

The aspirin group was given 100 mg PO daily and the enoxaparin group was given 40 mg SC daily (20 mg daily for patients weighing < 50 kg or with an estimated glomerular filtration rate < 30 mL/min/1.73 m²) for 35 days after THA and 14 days after TKA. Both treatment groups received IPC calf devices intraoperatively and postoperatively, and mobilization was offered on postoperative Day 0 or 1.

The primary outcome—development of symptomatic VTE within 90 days of the procedure—occurred in 187 (3.5%) patients in the aspirin group and 69 (1.8%) patients in the enoxaparin group (estimated difference = 1.97%; 95% CI, 0.54%-3.41%). This did not meet the noninferiority criterion for aspirin, based on an estimated assumed rate of 2% and a noninferiority margin of 1%, and in fact was statistically superior for enoxaparin (P = .007). There were no significant differences between the 2 groups in major bleeding or death within 90 days.¹

WHAT’S NEW

Enoxaparin was significantly superior to aspirin for VTE prophylaxis

Although this study was designed as a noninferiority trial, analysis showed enoxaparin to be significantly superior for postoperative VTE prophylaxis compared with aspirin.

Continue to: CAVEATS

Study aspirin dosing differed from US standard

This study showed significantly lower rates of symptomatic VTE in the enoxaparin group compared with the aspirin group; however, the majority of this difference was driven by rates of below-the-knee DVTs, which are clinically less relevant.⁸ Also, this trial used a 100-mg aspirin formulation, which is not available in the United States.

CHALLENGES TO IMPLEMENTATION

Aspirin is far cheaper and administered orally

Aspirin is significantly cheaper than enoxaparin, costing about $0.13 per dose (~$4 for 30 tablets at the 81-mg dose) vs roughly $9 per 40 mg/0.4 mL dose for enoxaparin.⁹ However, a cost-effectiveness analysis may be useful to determine (for example) whether the higher cost of enoxaparin may be offset by fewer DVTs and other sequelae. Lastly, LMWH is an injection, which some patients may refuse.

ILLUSTRATIVE CASE

A 72-year-old man with well-controlled hypertension and chronic obstructive pulmonary disease is scheduled for right total hip arthroplasty (THA) due to severe arthritis. He will be admitted to the hospital overnight, and his orthopedic surgeon anticipates 2 to 3 days of inpatient recovery time. In addition to medical management of the patient’s comorbid conditions, the surgeon asks if you have any insight regarding VTE prophylaxis for this patient. Specifically, do you think aspirin is equal to LMWH for VTE prophylaxis?

All adults undergoing major orthopedic surgery are considered to be at high risk for postoperative VTE development, with those having lower-limb procedures at highest risk.² Of the more than 2.2 million THAs and total knee arthroplasties (TKAs) performed in the United States between 2012 and 2020, 55% were primary TKAs and 39% primary THAs.³ The American College of Chest Physicians (ACCP) estimated a baseline 35-day risk for VTE of 4.3% in patients undergoing major orthopedic surgery.⁴ The highest VTE risk occurs during the first 7 to 14 days post surgery (1.8% for symptomatic deep vein thrombosis [DVT] and 1% for pulmonary embolism [PE]), with a slightly lower risk during the subsequent 15 to 35 days (1% for symptomatic DVT and 0.5% for PE).⁴

Aspirin’s low cost, availability, and ease of administration make it an attractive choice for VTE prevention in patients post THA and TKA surgery. The Pulmonary Embolism Prevention (PEP) trial evaluated 13,356 patients undergoing hip fracture repair and 4088 patients undergoing arthroplasty and found aspirin to be safe and effective in prevention of VTEs compared with placebo. The investigators concluded that “there is now good evidence for considering aspirin routinely in a wide range of surgical and medical groups at high risk of venous thromboembolism.”⁵ The PEP study, along with others, led to the emergence of aspirin monotherapy for VTE prophylaxis.

Current guidelines for perioperative VTE prophylaxis are based on American Society of Hematology (ASH) and ACCP recommendations. For patients undergoing THA or TKA, ASH suggests using aspirin or anticoagulants for VTE prophylaxis; when anticoagulants are used, they suggest using a direct oral anticoagulant (DOAC) over LMWH.⁶ The ASH guidelines are conditional recommendations based on very low certainty of effects, and the ASH panel recognized the need for further investigation with large, high-quality clinical trials.

The ACCP guidelines are clearer in recommending VTE prophylaxis vs no prophylaxis for major orthopedic surgeries and recommend the use of LMWH over other agents, including aspirin, DOACs, warfarin, and intermittent pneumatic compression (IPC) devices.⁴

Although prophylaxis is widely recommended to mitigate the elevated risk for VTE among patients undergoing orthopedic surgery, aspirin as monotherapy remains controversial.⁷ Many orthopedic surgeons prescribe aspirin as a sole VTE prophylaxis agent; however, this practice is not well supported by data from large, well-conducted, randomized trials or inferiority trials.²

STUDY SUMMARY

Aspirin did not meet the noninferiority criterion for postoperative VTE

The CRISTAL trial compared the use of aspirin vs LMWH (enoxaparin) for VTE prophylaxis in patients ages 18 years or older undergoing primary THA or TKA for osteoarthritis.¹ This Australian study used a cluster-randomized, crossover, registry-nested, noninferiority trial design. Of note, in Australia, aspirin is formulated in 100-mg tablets, equivalent to the standard 81-mg low-dose tablet in the United States.

Continue to: Patients taking prescribed antiplatelet...

Patients taking prescribed antiplatelet medication for preexisting conditions (~20% of patients in each group) were allowed to continue antiplatelet therapy during the trial. Patients were excluded if they were receiving an anticoagulant prior to their procedure or had a medical contraindication to aspirin or enoxaparin.

Thirty-one hospital sites were randomly assigned a treatment protocol using either aspirin or enoxaparin. Once target patient enrollment was met with the initial assigned medication, the site switched to the second/other agent. This resulted in 5675 patients in the aspirin group and 4036 in the enoxaparin group enrolled between April 2019 and ­December 2020, with final follow-up in ­August 2021; of these, 259 in the aspirin group and 249 in the enoxaparin group were lost to follow-up, opted out, or died.

Although this study was designed as a noninferiority trial, analysis showed enoxaparin to be significantly superior to aspirin for postoperative VTE prophylaxis.

The aspirin group was given 100 mg PO daily and the enoxaparin group was given 40 mg SC daily (20 mg daily for patients weighing < 50 kg or with an estimated glomerular filtration rate < 30 mL/min/1.73 m²) for 35 days after THA and 14 days after TKA. Both treatment groups received IPC calf devices intraoperatively and postoperatively, and mobilization was offered on postoperative Day 0 or 1.

The primary outcome—development of symptomatic VTE within 90 days of the procedure—occurred in 187 (3.5%) patients in the aspirin group and 69 (1.8%) patients in the enoxaparin group (estimated difference = 1.97%; 95% CI, 0.54%-3.41%). This did not meet the noninferiority criterion for aspirin, based on an estimated assumed rate of 2% and a noninferiority margin of 1%, and in fact was statistically superior for enoxaparin (P = .007). There were no significant differences between the 2 groups in major bleeding or death within 90 days.¹

WHAT’S NEW

Enoxaparin was significantly superior to aspirin for VTE prophylaxis

Although this study was designed as a noninferiority trial, analysis showed enoxaparin to be significantly superior for postoperative VTE prophylaxis compared with aspirin.

Continue to: CAVEATS

Study aspirin dosing differed from US standard

This study showed significantly lower rates of symptomatic VTE in the enoxaparin group compared with the aspirin group; however, the majority of this difference was driven by rates of below-the-knee DVTs, which are clinically less relevant.⁸ Also, this trial used a 100-mg aspirin formulation, which is not available in the United States.

CHALLENGES TO IMPLEMENTATION

Aspirin is far cheaper and administered orally

Aspirin is significantly cheaper than enoxaparin, costing about $0.13 per dose (~$4 for 30 tablets at the 81-mg dose) vs roughly $9 per 40 mg/0.4 mL dose for enoxaparin.⁹ However, a cost-effectiveness analysis may be useful to determine (for example) whether the higher cost of enoxaparin may be offset by fewer DVTs and other sequelae. Lastly, LMWH is an injection, which some patients may refuse.

ILLUSTRATIVE CASE

A 62-year-old woman with a past medical history of type 2 diabetes, hyperlipidemia, hypertension, and remote myocardial infarction (MI) presents to her primary care office for a preventive visit. She is a nonsmoker and has been taking her daily medications as prescribed, including an angiotensin-converting enzyme inhibitor, high-intensity statin, and aspirin. Her diabetes is well controlled. What else would you consider recommending to decrease this patient’s risk for future CVEs?

Cardiovascular disease (CVD) is a major contributor to morbidity and mortality, affecting more than 50% of patients older than 60.² Despite control of risk factors with standard treatment modalities, patients with established CVD remain at high risk for future events, which makes elucidating and targeting other causative pathways essential.³

Inflammation has been identified as a key player in the development and progression of atherosclerosis and its downstream effects, with increased inflammatory markers correlating with increased risk for CVEs.⁴ Due to these findings, anti-inflammatory treatments have been under investigation as agents to further reduce risk for CVEs. In 1 such trial, the Canakinumab Antiinflammatory Thrombosis Outcome Study (CANTOS), patients with MI and elevated C-reactive protein levels treated with the interleukin-1 beta inhibitor canakinumab showed reduced risk for future CVEs compared to those receiving placebo.⁵ However, due to canakinumab’s high cost, inconvenient subcutaneous administration, and increased incidence of fatal infections, other agents are under investigation.

Colchicine is a potent anti-inflammatory agent, with approval in the United States for treatment of gout and familial Mediterranean fever. It works broadly to reduce inflammation by disrupting tubulin polymerization.^6,7 Colchicine decreases interleukin-1 beta production through inactivation of the NLRP3 inflammasome pathway, which has been associated with the inflammatory component driving atherosclerotic plaque progression and instability.^5,8 Colchicine’s oral administration, relative cost-effectiveness, and safety profile make it an attractive option for potential use in secondary prevention of CVEs.

The Low-Dose Colchicine (LoDoCo) trial, published in 2013, demonstrated a reduction in CVEs in those with CVD taking guideline-directed medical therapy (GDMT) plus colchicine 0.5 mg/d, compared with those taking GDMT alone.⁹ However, the LoDoCo study enrolled only 532 patients and was not placebo controlled. The Colchicine Cardiovascular Outcomes Trial (COLCOT), published in 2019, was a randomized, ­double-blind, placebo-controlled trial that aimed to further evaluate the effects of colchicine on CVEs on a larger scale and to assess its longer-term safety.¹⁰ In this study, the colchicine group had a significantly lower risk of CVEs vs placebo, with a comparable safety profile.¹⁰

STUDY SUMMARY

Fewer CVEs occurred when colchicine was added to the regimen

The randomized, multicenter, double-blind Low Dose Colchicine 2 (LoDoCo2) trial evaluated whether colchicine 0.5 mg daily reduces CV death, spontaneous (nonprocedural) MI, ischemic stroke, or ischemia-driven coronary revascularization in patients with chronic CAD (composite primary endpoint). This trial included 5522 patients, ages 35 to 82, in Australia and the Netherlands. Patients were eligible to participate if they had evidence of CAD by invasive coronary angiography, coronary calcium score, or computed tomography angiography, as well as evidence of clinical stability for 6 months. Exclusion criteria included moderate-to-severe renal impairment, severe heart failure, severe valvular disease, or intolerance to colchicine.

Patients (N = 6528) took colchicine 0.5 mg daily as part of a 1-month, open-label run-in phase; 1006 patients stopped taking colchicine during this time. Perceived adverse effects were observed in 611 of these patients, the most common being gastrointestinal (GI) upset (437 patients). After the run-in phase, the remaining 5522 patients were randomized to either the colchicine or placebo group. Both groups continued to receive GDMT for CVD, including antiplatelet therapy, anticoagulants, and hypertensive therapy as indicated. Lipid-lowering therapies were continued in 96.7% of the colchicine group and 96.6% of the placebo group. These patients were then followed for a minimum of 1 year (median duration, 28.6 months).

Continue to: The primary endpoint...

The primary endpoint occurred less frequently in the colchicine group than in the placebo group (6.8% vs 9.6%; P < .001; number needed to treat = 36). The incidence rates for 2 of the individual outcomes in the composite, MI (hazard ratio [HR] = 0.7; 95% CI, 0.53-0.93) and ischemia-driven coronary revascularization (HR = 0.75; 95% CI, 0.60-0.94), were significantly lower in the colchicine group. The other outcomes were no different from placebo.¹

There was a similar incidence of serious adverse events, such as noncardiovascular death, cancer diagnosis, and hospitalization for infection, pneumonia, or GI issues. High-dose statins were used by 3413 patients (61.8%). Myalgia (data collected only from the Netherlands cohort) was reported more commonly in the colchicine group than the placebo group (21.2% vs 18.5%; cumulative incidence ratio = 1.15; 95% CI, 1.01-1.31). Myotoxic effects were rare in both groups.¹

WHAT’S NEW

RCT supports potential for anti-inflammatory therapy in CAD

This large RCT demonstrated that the addition of daily colchicine reduces CVE risk in patients with known CAD while maintaining a good safety profile.¹

CAVEATS

Watch for potential drug interactions in patients with renal dysfunction

Prescribers should be aware of potential drug interactions, especially in those with renal or hepatic dysfunction, when prescribing colchicine, as it is metabolized through cytochrome P450 3A4 (CYP3A4) and excreted via the P-glycoprotein transport system, by which many statins are also metabolized and act as a competitive substrate.⁷ In addition, simvastatin, and to a lesser degree atorvastatin, are CYP3A4 inhibitors.

Also of note, the 0.5-mg colchicine tablet is not available in some countries—including the United States, where only 0.6-mg tablets are available. The 0.6-mg dose would likely have the same benefit and similar adverse effect profile but was not included in the study.

CHALLENGES TO IMPLEMENTATION

GI tolerability may be an issue

Colchicine is widely available and relatively low in cost, at approximately $32 per month for the 0.6-mg daily tablets. A major limitation is lack of tolerability, as adverse effects such as nausea, vomiting, diarrhea, and abdominal pain are frequently reported.

ILLUSTRATIVE CASE

A 62-year-old woman with a past medical history of type 2 diabetes, hyperlipidemia, hypertension, and remote myocardial infarction (MI) presents to her primary care office for a preventive visit. She is a nonsmoker and has been taking her daily medications as prescribed, including an angiotensin-converting enzyme inhibitor, high-intensity statin, and aspirin. Her diabetes is well controlled. What else would you consider recommending to decrease this patient’s risk for future CVEs?

Cardiovascular disease (CVD) is a major contributor to morbidity and mortality, affecting more than 50% of patients older than 60.² Despite control of risk factors with standard treatment modalities, patients with established CVD remain at high risk for future events, which makes elucidating and targeting other causative pathways essential.³

Inflammation has been identified as a key player in the development and progression of atherosclerosis and its downstream effects, with increased inflammatory markers correlating with increased risk for CVEs.⁴ Due to these findings, anti-inflammatory treatments have been under investigation as agents to further reduce risk for CVEs. In 1 such trial, the Canakinumab Antiinflammatory Thrombosis Outcome Study (CANTOS), patients with MI and elevated C-reactive protein levels treated with the interleukin-1 beta inhibitor canakinumab showed reduced risk for future CVEs compared to those receiving placebo.⁵ However, due to canakinumab’s high cost, inconvenient subcutaneous administration, and increased incidence of fatal infections, other agents are under investigation.

Colchicine is a potent anti-inflammatory agent, with approval in the United States for treatment of gout and familial Mediterranean fever. It works broadly to reduce inflammation by disrupting tubulin polymerization.^6,7 Colchicine decreases interleukin-1 beta production through inactivation of the NLRP3 inflammasome pathway, which has been associated with the inflammatory component driving atherosclerotic plaque progression and instability.^5,8 Colchicine’s oral administration, relative cost-effectiveness, and safety profile make it an attractive option for potential use in secondary prevention of CVEs.

The Low-Dose Colchicine (LoDoCo) trial, published in 2013, demonstrated a reduction in CVEs in those with CVD taking guideline-directed medical therapy (GDMT) plus colchicine 0.5 mg/d, compared with those taking GDMT alone.⁹ However, the LoDoCo study enrolled only 532 patients and was not placebo controlled. The Colchicine Cardiovascular Outcomes Trial (COLCOT), published in 2019, was a randomized, ­double-blind, placebo-controlled trial that aimed to further evaluate the effects of colchicine on CVEs on a larger scale and to assess its longer-term safety.¹⁰ In this study, the colchicine group had a significantly lower risk of CVEs vs placebo, with a comparable safety profile.¹⁰

STUDY SUMMARY

Fewer CVEs occurred when colchicine was added to the regimen

The randomized, multicenter, double-blind Low Dose Colchicine 2 (LoDoCo2) trial evaluated whether colchicine 0.5 mg daily reduces CV death, spontaneous (nonprocedural) MI, ischemic stroke, or ischemia-driven coronary revascularization in patients with chronic CAD (composite primary endpoint). This trial included 5522 patients, ages 35 to 82, in Australia and the Netherlands. Patients were eligible to participate if they had evidence of CAD by invasive coronary angiography, coronary calcium score, or computed tomography angiography, as well as evidence of clinical stability for 6 months. Exclusion criteria included moderate-to-severe renal impairment, severe heart failure, severe valvular disease, or intolerance to colchicine.

Patients (N = 6528) took colchicine 0.5 mg daily as part of a 1-month, open-label run-in phase; 1006 patients stopped taking colchicine during this time. Perceived adverse effects were observed in 611 of these patients, the most common being gastrointestinal (GI) upset (437 patients). After the run-in phase, the remaining 5522 patients were randomized to either the colchicine or placebo group. Both groups continued to receive GDMT for CVD, including antiplatelet therapy, anticoagulants, and hypertensive therapy as indicated. Lipid-lowering therapies were continued in 96.7% of the colchicine group and 96.6% of the placebo group. These patients were then followed for a minimum of 1 year (median duration, 28.6 months).

Continue to: The primary endpoint...

The primary endpoint occurred less frequently in the colchicine group than in the placebo group (6.8% vs 9.6%; P < .001; number needed to treat = 36). The incidence rates for 2 of the individual outcomes in the composite, MI (hazard ratio [HR] = 0.7; 95% CI, 0.53-0.93) and ischemia-driven coronary revascularization (HR = 0.75; 95% CI, 0.60-0.94), were significantly lower in the colchicine group. The other outcomes were no different from placebo.¹

There was a similar incidence of serious adverse events, such as noncardiovascular death, cancer diagnosis, and hospitalization for infection, pneumonia, or GI issues. High-dose statins were used by 3413 patients (61.8%). Myalgia (data collected only from the Netherlands cohort) was reported more commonly in the colchicine group than the placebo group (21.2% vs 18.5%; cumulative incidence ratio = 1.15; 95% CI, 1.01-1.31). Myotoxic effects were rare in both groups.¹

WHAT’S NEW

RCT supports potential for anti-inflammatory therapy in CAD

This large RCT demonstrated that the addition of daily colchicine reduces CVE risk in patients with known CAD while maintaining a good safety profile.¹

CAVEATS

Watch for potential drug interactions in patients with renal dysfunction

Prescribers should be aware of potential drug interactions, especially in those with renal or hepatic dysfunction, when prescribing colchicine, as it is metabolized through cytochrome P450 3A4 (CYP3A4) and excreted via the P-glycoprotein transport system, by which many statins are also metabolized and act as a competitive substrate.⁷ In addition, simvastatin, and to a lesser degree atorvastatin, are CYP3A4 inhibitors.

Also of note, the 0.5-mg colchicine tablet is not available in some countries—including the United States, where only 0.6-mg tablets are available. The 0.6-mg dose would likely have the same benefit and similar adverse effect profile but was not included in the study.

CHALLENGES TO IMPLEMENTATION

GI tolerability may be an issue

Colchicine is widely available and relatively low in cost, at approximately $32 per month for the 0.6-mg daily tablets. A major limitation is lack of tolerability, as adverse effects such as nausea, vomiting, diarrhea, and abdominal pain are frequently reported.

ILLUSTRATIVE CASE

A 62-year-old woman with a past medical history of type 2 diabetes, hyperlipidemia, hypertension, and remote myocardial infarction (MI) presents to her primary care office for a preventive visit. She is a nonsmoker and has been taking her daily medications as prescribed, including an angiotensin-converting enzyme inhibitor, high-intensity statin, and aspirin. Her diabetes is well controlled. What else would you consider recommending to decrease this patient’s risk for future CVEs?

Cardiovascular disease (CVD) is a major contributor to morbidity and mortality, affecting more than 50% of patients older than 60.² Despite control of risk factors with standard treatment modalities, patients with established CVD remain at high risk for future events, which makes elucidating and targeting other causative pathways essential.³

Inflammation has been identified as a key player in the development and progression of atherosclerosis and its downstream effects, with increased inflammatory markers correlating with increased risk for CVEs.⁴ Due to these findings, anti-inflammatory treatments have been under investigation as agents to further reduce risk for CVEs. In 1 such trial, the Canakinumab Antiinflammatory Thrombosis Outcome Study (CANTOS), patients with MI and elevated C-reactive protein levels treated with the interleukin-1 beta inhibitor canakinumab showed reduced risk for future CVEs compared to those receiving placebo.⁵ However, due to canakinumab’s high cost, inconvenient subcutaneous administration, and increased incidence of fatal infections, other agents are under investigation.

Colchicine is a potent anti-inflammatory agent, with approval in the United States for treatment of gout and familial Mediterranean fever. It works broadly to reduce inflammation by disrupting tubulin polymerization.^6,7 Colchicine decreases interleukin-1 beta production through inactivation of the NLRP3 inflammasome pathway, which has been associated with the inflammatory component driving atherosclerotic plaque progression and instability.^5,8 Colchicine’s oral administration, relative cost-effectiveness, and safety profile make it an attractive option for potential use in secondary prevention of CVEs.

The Low-Dose Colchicine (LoDoCo) trial, published in 2013, demonstrated a reduction in CVEs in those with CVD taking guideline-directed medical therapy (GDMT) plus colchicine 0.5 mg/d, compared with those taking GDMT alone.⁹ However, the LoDoCo study enrolled only 532 patients and was not placebo controlled. The Colchicine Cardiovascular Outcomes Trial (COLCOT), published in 2019, was a randomized, ­double-blind, placebo-controlled trial that aimed to further evaluate the effects of colchicine on CVEs on a larger scale and to assess its longer-term safety.¹⁰ In this study, the colchicine group had a significantly lower risk of CVEs vs placebo, with a comparable safety profile.¹⁰

STUDY SUMMARY

Fewer CVEs occurred when colchicine was added to the regimen

The randomized, multicenter, double-blind Low Dose Colchicine 2 (LoDoCo2) trial evaluated whether colchicine 0.5 mg daily reduces CV death, spontaneous (nonprocedural) MI, ischemic stroke, or ischemia-driven coronary revascularization in patients with chronic CAD (composite primary endpoint). This trial included 5522 patients, ages 35 to 82, in Australia and the Netherlands. Patients were eligible to participate if they had evidence of CAD by invasive coronary angiography, coronary calcium score, or computed tomography angiography, as well as evidence of clinical stability for 6 months. Exclusion criteria included moderate-to-severe renal impairment, severe heart failure, severe valvular disease, or intolerance to colchicine.

Patients (N = 6528) took colchicine 0.5 mg daily as part of a 1-month, open-label run-in phase; 1006 patients stopped taking colchicine during this time. Perceived adverse effects were observed in 611 of these patients, the most common being gastrointestinal (GI) upset (437 patients). After the run-in phase, the remaining 5522 patients were randomized to either the colchicine or placebo group. Both groups continued to receive GDMT for CVD, including antiplatelet therapy, anticoagulants, and hypertensive therapy as indicated. Lipid-lowering therapies were continued in 96.7% of the colchicine group and 96.6% of the placebo group. These patients were then followed for a minimum of 1 year (median duration, 28.6 months).

Continue to: The primary endpoint...

The primary endpoint occurred less frequently in the colchicine group than in the placebo group (6.8% vs 9.6%; P < .001; number needed to treat = 36). The incidence rates for 2 of the individual outcomes in the composite, MI (hazard ratio [HR] = 0.7; 95% CI, 0.53-0.93) and ischemia-driven coronary revascularization (HR = 0.75; 95% CI, 0.60-0.94), were significantly lower in the colchicine group. The other outcomes were no different from placebo.¹

There was a similar incidence of serious adverse events, such as noncardiovascular death, cancer diagnosis, and hospitalization for infection, pneumonia, or GI issues. High-dose statins were used by 3413 patients (61.8%). Myalgia (data collected only from the Netherlands cohort) was reported more commonly in the colchicine group than the placebo group (21.2% vs 18.5%; cumulative incidence ratio = 1.15; 95% CI, 1.01-1.31). Myotoxic effects were rare in both groups.¹

WHAT’S NEW

RCT supports potential for anti-inflammatory therapy in CAD

This large RCT demonstrated that the addition of daily colchicine reduces CVE risk in patients with known CAD while maintaining a good safety profile.¹

CAVEATS

Watch for potential drug interactions in patients with renal dysfunction

Prescribers should be aware of potential drug interactions, especially in those with renal or hepatic dysfunction, when prescribing colchicine, as it is metabolized through cytochrome P450 3A4 (CYP3A4) and excreted via the P-glycoprotein transport system, by which many statins are also metabolized and act as a competitive substrate.⁷ In addition, simvastatin, and to a lesser degree atorvastatin, are CYP3A4 inhibitors.

Also of note, the 0.5-mg colchicine tablet is not available in some countries—including the United States, where only 0.6-mg tablets are available. The 0.6-mg dose would likely have the same benefit and similar adverse effect profile but was not included in the study.

CHALLENGES TO IMPLEMENTATION

GI tolerability may be an issue

Colchicine is widely available and relatively low in cost, at approximately $32 per month for the 0.6-mg daily tablets. A major limitation is lack of tolerability, as adverse effects such as nausea, vomiting, diarrhea, and abdominal pain are frequently reported.