Cardiology

Bacteremia is common and associated with significant morbidity and mortality. Bloodstream infections rank among the leading causes of death in North America and Europe.¹

See related article

In this issue, Mushtaq et al² contend that follow-up blood cultures after initial bacteremia are not needed for most hospitalized patients. Not repeating blood cultures after initial bacteremia has been proposed to decrease hospitalization length, consultations, and healthcare costs in some clinical settings. However, without follow-up cultures, it can be difficult to assess the adequacy of treatment of bacteremia and associated underlying infections.

GRAM-NEGATIVE ORGANISMS

Results of retrospective studies indicate that follow-up cultures may not be routinely needed for gram-negative bacteremia. In a review by Canzoneri et al of 383 cases with subsequent follow-up cultures,³ 55 (14%) were positive. The mean duration of bacteremia was 2.8 days (range 1 to 15 days). Of the 55 persistently positive blood cultures, only 8 (15%) were caused by gram-negative organisms. Limitations to this study included the lack of patient outcome data, a low event rate, and the retrospective design.⁴

In a retrospective case-control study of follow-up cultures for 862 episodes of Klebsiella pneumoniae bacteremia,⁵ independent risk factors for persistent bacteremia were intra-abdominal infection, higher Charlson comorbidity index score, solid-organ transplant, and unfavorable treatment response.

These studies confirm that persistent bacteremia is uncommon with gram-negative organisms. They also support using comorbidities and treatment response to guide the ordering of follow-up blood cultures.

WHEN IS FOLLOW-UP CULTURE USEFUL?

Although follow-up blood cultures may not be needed routinely in patients with gram- negative bacteremia, it would be difficult to extrapolate this to gram-positive organisms, especially Staphylococcus aureus.

In Canzoneri et al,³ 43 (78%) of the 55 positive follow-up cultures were due to gram-positive organisms. Factors associated with positive follow-up cultures were concurrent fever, presence of a central intravenous line, end-stage renal disease on hemodialysis, and diabetes mellitus. In addition, infectious disease consultation to decide the need for follow-up cultures for S aureus bacteremia has been associated with fewer deaths, fewer relapses, and lower readmission rates.^6,7

In certain clinical scenarios, follow-up blood cultures can provide useful information, such as when the source of bacteremia is endocarditis or cardiac device infection, a vascular graft, or an intravascular line. In the Infectious Diseases Society of America guidelines for diagnosis and management of catheter-related bloodstream infections, persistent or relapsing bacteremia for some organisms is a criterion for removal of a long-term central venous catheter.⁸

Follow-up cultures are especially useful when the focus of infection is protected from antibiotic penetration, such as in the central nervous system, joints, and abdominal or other abscess. These foci may require drainage for cure. In these cases or in the setting of unfavorable clinical treatment response, follow-up blood cultures showing persistent bacteremia can prompt a search for unaddressed or incompletely addressed foci of infection and allow for source control.

The timing of follow-up cultures is generally 1 to 2 days after the initial culture. Although Mushtaq et al propose a different approach, traditional teaching has been that the last blood culture should not be positive, and this leads to ordering follow-up blood cultures until clearance of bacteremia is documented.

Bacteremia is common and associated with significant morbidity and mortality. Bloodstream infections rank among the leading causes of death in North America and Europe.¹

See related article

In this issue, Mushtaq et al² contend that follow-up blood cultures after initial bacteremia are not needed for most hospitalized patients. Not repeating blood cultures after initial bacteremia has been proposed to decrease hospitalization length, consultations, and healthcare costs in some clinical settings. However, without follow-up cultures, it can be difficult to assess the adequacy of treatment of bacteremia and associated underlying infections.

GRAM-NEGATIVE ORGANISMS

Results of retrospective studies indicate that follow-up cultures may not be routinely needed for gram-negative bacteremia. In a review by Canzoneri et al of 383 cases with subsequent follow-up cultures,³ 55 (14%) were positive. The mean duration of bacteremia was 2.8 days (range 1 to 15 days). Of the 55 persistently positive blood cultures, only 8 (15%) were caused by gram-negative organisms. Limitations to this study included the lack of patient outcome data, a low event rate, and the retrospective design.⁴

In a retrospective case-control study of follow-up cultures for 862 episodes of Klebsiella pneumoniae bacteremia,⁵ independent risk factors for persistent bacteremia were intra-abdominal infection, higher Charlson comorbidity index score, solid-organ transplant, and unfavorable treatment response.

These studies confirm that persistent bacteremia is uncommon with gram-negative organisms. They also support using comorbidities and treatment response to guide the ordering of follow-up blood cultures.

WHEN IS FOLLOW-UP CULTURE USEFUL?

Although follow-up blood cultures may not be needed routinely in patients with gram- negative bacteremia, it would be difficult to extrapolate this to gram-positive organisms, especially Staphylococcus aureus.

In Canzoneri et al,³ 43 (78%) of the 55 positive follow-up cultures were due to gram-positive organisms. Factors associated with positive follow-up cultures were concurrent fever, presence of a central intravenous line, end-stage renal disease on hemodialysis, and diabetes mellitus. In addition, infectious disease consultation to decide the need for follow-up cultures for S aureus bacteremia has been associated with fewer deaths, fewer relapses, and lower readmission rates.^6,7

In certain clinical scenarios, follow-up blood cultures can provide useful information, such as when the source of bacteremia is endocarditis or cardiac device infection, a vascular graft, or an intravascular line. In the Infectious Diseases Society of America guidelines for diagnosis and management of catheter-related bloodstream infections, persistent or relapsing bacteremia for some organisms is a criterion for removal of a long-term central venous catheter.⁸

Follow-up cultures are especially useful when the focus of infection is protected from antibiotic penetration, such as in the central nervous system, joints, and abdominal or other abscess. These foci may require drainage for cure. In these cases or in the setting of unfavorable clinical treatment response, follow-up blood cultures showing persistent bacteremia can prompt a search for unaddressed or incompletely addressed foci of infection and allow for source control.

The timing of follow-up cultures is generally 1 to 2 days after the initial culture. Although Mushtaq et al propose a different approach, traditional teaching has been that the last blood culture should not be positive, and this leads to ordering follow-up blood cultures until clearance of bacteremia is documented.

Bacteremia is common and associated with significant morbidity and mortality. Bloodstream infections rank among the leading causes of death in North America and Europe.¹

See related article

In this issue, Mushtaq et al² contend that follow-up blood cultures after initial bacteremia are not needed for most hospitalized patients. Not repeating blood cultures after initial bacteremia has been proposed to decrease hospitalization length, consultations, and healthcare costs in some clinical settings. However, without follow-up cultures, it can be difficult to assess the adequacy of treatment of bacteremia and associated underlying infections.

GRAM-NEGATIVE ORGANISMS

Results of retrospective studies indicate that follow-up cultures may not be routinely needed for gram-negative bacteremia. In a review by Canzoneri et al of 383 cases with subsequent follow-up cultures,³ 55 (14%) were positive. The mean duration of bacteremia was 2.8 days (range 1 to 15 days). Of the 55 persistently positive blood cultures, only 8 (15%) were caused by gram-negative organisms. Limitations to this study included the lack of patient outcome data, a low event rate, and the retrospective design.⁴

In a retrospective case-control study of follow-up cultures for 862 episodes of Klebsiella pneumoniae bacteremia,⁵ independent risk factors for persistent bacteremia were intra-abdominal infection, higher Charlson comorbidity index score, solid-organ transplant, and unfavorable treatment response.

These studies confirm that persistent bacteremia is uncommon with gram-negative organisms. They also support using comorbidities and treatment response to guide the ordering of follow-up blood cultures.

WHEN IS FOLLOW-UP CULTURE USEFUL?

Although follow-up blood cultures may not be needed routinely in patients with gram- negative bacteremia, it would be difficult to extrapolate this to gram-positive organisms, especially Staphylococcus aureus.

In Canzoneri et al,³ 43 (78%) of the 55 positive follow-up cultures were due to gram-positive organisms. Factors associated with positive follow-up cultures were concurrent fever, presence of a central intravenous line, end-stage renal disease on hemodialysis, and diabetes mellitus. In addition, infectious disease consultation to decide the need for follow-up cultures for S aureus bacteremia has been associated with fewer deaths, fewer relapses, and lower readmission rates.^6,7

In certain clinical scenarios, follow-up blood cultures can provide useful information, such as when the source of bacteremia is endocarditis or cardiac device infection, a vascular graft, or an intravascular line. In the Infectious Diseases Society of America guidelines for diagnosis and management of catheter-related bloodstream infections, persistent or relapsing bacteremia for some organisms is a criterion for removal of a long-term central venous catheter.⁸

Follow-up cultures are especially useful when the focus of infection is protected from antibiotic penetration, such as in the central nervous system, joints, and abdominal or other abscess. These foci may require drainage for cure. In these cases or in the setting of unfavorable clinical treatment response, follow-up blood cultures showing persistent bacteremia can prompt a search for unaddressed or incompletely addressed foci of infection and allow for source control.

The timing of follow-up cultures is generally 1 to 2 days after the initial culture. Although Mushtaq et al propose a different approach, traditional teaching has been that the last blood culture should not be positive, and this leads to ordering follow-up blood cultures until clearance of bacteremia is documented.

From the Division of Rheumatology & Immunology, University of Nebraska Medical Center, and Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE.

Abstract

• Objective: To review cardiovascular disease (CVD) risk assessment in patients with rheumatoid arthritis (RA).
• Methods: Literature review of the assessment of CVD risk in RA.
• Results: CVD is the leading cause of death among RA patients. Because of the increased risk of CVD events and CVD mortality in patients with RA, regular assessment of CVD risk and aggressive management of CVD risk in these patients is crucial. CVD risk estimation typically centers on the use of well-established CVD risk calculators. Most CVD risk scores from the general population do not contain RA-related factors predictive of CVD but have had more extensive performance testing, while novel RA-derived CVD risk scores that incorporate RA-related factors have had limited external validity testing. Neither set of risk scores incorporates novel imaging modalities or serum biomarkers, which are most likely to be helpful among individuals at intermediate risk.
• Conclusion: Primary care and rheumatology providers must be aware of the increased risk of CVD in RA, a risk that approaches that of diabetic patients. Routine assessment of CVD risk is an essential first step in minimizing CVD risk in this population. Until the performance of RA-specific CVD risk scores can be better established, we recommend the use of nationally endorsed CVD risk scores, with the frequency of reassessment based on CVD risk.

Keywords: rheumatoid arthritis; cardiovascular disease; cardiovascular risk assessment.

Editor’s note: This article is part 1 of a 2-part article. “Management of Cardiovascular Disease Risk in Rheumatoid Arthritis” was published in the March/April 2019 issue.

Rheumatoid arthritis (RA) is a chronic, autoimmune inflammatory arthritis affecting up to 1% of the US population that can lead to joint damage, functional disability, and reduced quality of life.¹ In addition to articular involvement, systemic inflammation accompanying RA may lead to extra-articular manifestations and increase the risk of premature death.² Cardiovascular disease (CVD), accounting for nearly half of all deaths among RA patients, is now recognized as a critical extra-articular manifestation of RA.^2,3 As such, assessment and management of CVD risk is essential to the comprehensive care of the RA patient. This article reviews the approach to assessing CVD risk in patients with RA; the management of both traditional and RA-specific risk factors is discussed in a separate article.

Scope of the Problem

In a large meta-analysis of observational studies that included more than 111,000 patients with RA, CVD-related mortality rates were 1.5 times higher among RA patients than among general population controls.⁴ The risk of overall CVD, including nonfatal events, is similar; a separate meta-analysis of observational studies that included more than 41,000 patients with RA calculated a pooled relative risk for incident CVD of 1.48.⁵ Individual analyses identified heightened risk of acute coronary syndrome (ACS), cerebrovascular accident, and congestive heart failure (CHF).⁵ Perhaps more illustrative of the magnitude of the problem, the risk of CVD in RA approaches that observed among individuals with diabetes mellitus.^6,7

Coronary artery disease (CAD) accounts for a significant portion of the CVD risk in RA, but its presentation may be atypical in RA patients. RA patients are at higher risk of suffering unrecognized myocardial infarction (MI) and sudden cardiac death.⁸ The reasons for silent ischemia in RA are not fully known, but have been hypothesized to include imbalances of inflammatory cytokines, alterations in pain sensitization, or the female predominance of RA (with women more often presenting with atypical symptoms of myocardial ischemia).⁹ Alarmingly, a retrospective chart review study reported that RA patients admitted for an acute MI were less likely to receive appropriate reperfusion therapy as well as secondary prevention with beta-blockers and lipid-lowering agents.¹⁰ Even with appropriate therapy, long-term outcomes such as mortality and recurrent ischemic events are more likely to occur in RA patients after acute MI.^11-13

Independent of ischemic heart disease, RA patients are at increased risk of CHF.^14-16 RA patients are at particular risk for CHF with preserved ejection fraction,¹⁷ which may be a result of systemic inflammation causing left ventricular stiffening.^18,19 Similar to CAD, patients with RA are less likely to present with typical CHF symptoms, are less likely to receive guideline-concordant care, and have higher mortality rates following presentation with CHF.¹⁷

Although accounting for a lower proportion of the excess CVD morbidity and mortality in RA, the risk of noncardiac vascular disease is also increased in RA patients. Large meta-analyses have identified positive associations between RA with both ischemic (odds ratio [OR], 1.64 [95% confidence interval {CI}, 1.32-2.05]) and hemorrhagic (OR, 1.68 [95% CI, 1.11-2.53]) stroke.²⁰ Similarly, RA patients appear to have an approximately twofold higher risk of venous thromboembolic events.²¹ Less frequently studied than other forms of CVD, peripheral arterial disease may be increased in RA patients independent of other CVD and CVD risk factors.^22,23

Assessing CVD Risk in RA

CVD Risk Scores

In order to identify patients who may benefit from primary prevention interventions, such as lipid-lowering therapy, CVD risk estimation typically centers on the use of well-established CVD risk calculators (Table). CVD risk scores such as the Framingham Risk Score (FRS), Systematic Coronary Risk Evaluation (SCORE), and American College of Cardiology/ American Heart Association (ACC/AHA) Pooled Cohort Equation incorporate traditional CVD risk factors, including age, sex, smoking status, blood pressure, lipid levels, and presence of diabetes mellitus.^24,25 However, CVD risk in RA patients appears to be inadequately explained by traditional CVD risk factors,²⁶ with disease activity and inflammation being associated with higher CVD risk. Recognizing that inflammation may contribute to CVD risk even among non-RA patients, the Reynolds Risk Score includes high-sensitivity C-reactive protein (hsCRP) in its calculation.²⁷ In contrast to more robust performance in the general population, these well-established CVD risk scores have had variable predictive potential of incident CVD in RA patients.^28-30

Several models, or adaptations to existing models, have been proposed to improve CVD risk assessment in RA populations (Table). In 2009, the European League Against Rheumatism (EULAR) task force suggested using a correction factor of 1.5 with traditional CVD risk models in RA patients with 2 of the following criteria: disease duration exceeding 10 years, rheumatoid factor or anti-cyclic citrullinated peptide (CCP) antibody positivity, or extra-articular manifestations of RA.³¹ An update to these recommendations in 2015 continued to propose the use of a 1.5 correction factor, but suggested applying this to all RA patients.³² QRISK2, a modification to QRISK1 which was developed to predict CVD in the UK general population, includes the diagnosis of RA as a risk factor, and in early validation efforts more accurately discriminated patients in the general population at increased risk of CVD compared to the FRS.³³ Additional disease-specific risk factors such as systemic lupus, steroid use, severe mental illness, and steroid and atypical antipsychotic use were incorporated in the QRISK3 algorithm, with model performance similar to the QRISK2.³⁴ The Expanded Cardiovascular Risk Prediction Score for RA (ERS-RA) was specifically developed to assess CVD risk in RA patients by including RA disease activity, level of physical disability, RA disease duration, and prednisone use.³⁵ Despite efforts to develop “RA-specific” risk scores, these have not consistently outperformed traditional CVD risk calculators.^36-38 In one study involving more than 1700 RA patients, the ERS-RA performed similarly to the FRS and Reynolds Risk Score, with a net reclassification index of just 2.3% versus the FRS.³⁶

Imaging Modalities

Imaging modalities may assist in characterizing the increased risk of CVD in RA and the subclinical CVD manifestations that occur. For example, RA patients were shown to have more prevalent and unstable coronary plaque, higher carotid intima media thickness, and impaired myocardial function with computed tomography (CT) angiography and carotid ultrasound.^39,40 However, studies harnessing noninvasive imaging to augment CVD risk assessment in RA patients are limited.

Carotid ultrasound has been the most extensively studied imaging modality for CVD risk assessment in RA. In a cohort of 599 RA patients with no history of ACS, rates of ACS were nearly 4 times higher in RA patients with bilateral carotid plaque on carotid ultrasound, and the association with ACS was independent of other traditional and RA-related risk factors.⁴¹ Presence of bilateral carotid plaques was similarly associated with an increased risk of overall CVD events (hazard ratio [HR], 3.34 [95% CI, 1.21-9.22]), ACS alone (HR, 6.31 [95% CI, 1.27-31.40]), and a lower mean CVD event-free survival (13.9 versus 15.2 years, P = 0.01) in a separate inception cohort of 105 RA patients with no prior history of CVD.⁴² The most useful application of carotid ultrasound may be in conjunction with clinical CVD risk models. Use of carotid ultrasound improved CVD risk stratification among RA patients who were considered at moderate risk by the EULAR-modified SCORE calculator.⁴³ Beyond carotid ultrasound, measurement of arterial stiffness through ultrasound could also aid in CVD risk stratification. Aortic pulse wave velocity and augmentation index, measures of arterial stiffness, are predictive of CVD in the general population as well as RA patients and improve with reduction in RA disease activity.^44,45 Peripheral arterial stiffness (brachial-ankle elasticity index) is impaired in RA patients and predictive of CVD morbidity and mortality in the general population.^46,47

CT coronary angiography and coronary artery calcium (CAC) scores are reliable measures of coronary artery atherosclerosis and have been validated for CVD risk assessment in the general population.^48-52 While the association between RA and CT-related findings of atherosclerosis is well established, assessment of CT-mediated evaluation as a prognostic tool for CVD in RA is limited. In one cohort study, CAC predicted higher rates of CVD events in Chinese patients with RA and systemic lupus erythematosus in a pooled analysis, although results were limited by low event rates and the absence of RA-only subanalyses.⁵³

While the aforementioned imaging modalities have focused on enhancing the identification of atherosclerosis, echocardiography or cardiac magnetic resonance imaging (MRI) may be useful for detecting subclinical structural and/or functional abnormalities that predispose to CHF. Structural abnormalities including increased left ventricular mass and hypertrophy are more prevalent in RA patients and predict incident CHF in the general population.^54-56 MRI measures of myocardial inflammation, including T1 mapping and extracellular volume, are associated with higher mortality rates and also appear to be elevated in RA patients.^57,58 Whether identification of these imaging findings influences the cost-effective clinical management of RA patients needs further study.

Biomarkers

Serum biomarkers, such as the anti-CCP antibody, have become crucial to the evaluation of patients suspected to have RA. With the growing understanding of the role pro-inflammatory mediators play in CVD pathogenesis and the relative ease with which they can be measured, serum biomarkers have potential to inform CVD risk assessment. In the general population, hsCRP concentrations are predictive of CVD and are included in the Reynolds Risk Score.²⁷ In RA, CRP concentrations are typically much higher than those observed among individuals in the general population solely at increased CVD risk, yet elevated levels remain predictive of CVD death independent of RA disease activity and traditional CVD risk factors.⁵⁹ Several additional cytokines, chemokines, and adhesion molecules have been associated with surrogate markers of CVD in RA patients, although further study is needed to elucidate thresholds that signify increased CVD risk in a population characterized by the presence of systemic inflammation.⁶⁰

Cardiac biomarkers used frequently in the general population may be useful to assess CVD risk in RA patients. N-terminal-pro brain natriuretic peptide (NT-pro BNP) is a biomarker typically used to evaluate CHF severity, but it may also predict long-term mortality in patients with coronary heart disease.^61,62 Circulating NT-pro BNP concentrations are elevated in RA independent of prevalent CHF and may serve as a useful tool to identify subclinical cardiac disease in RA patients.⁶³ High-sensitivity cardiac troponin I (HS-cTnI) assays are capable of detecting levels of cardiac troponin below the threshold typically used to diagnose ACS. HS-cTnI levels are increased in RA patients independent of additional CVD risk factors, and elevated levels (> 1.5 pg/mL) were associated with more severe CT angiography findings of coronary plaque as well as increased risk of CVD events.^64,65

A fully validated algorithm for CVD risk assessment in RA is lacking. Most CVD risk scores from the general population do not contain RA-related factors predictive of CVD but have had more extensive performance testing. In contrast, novel RA-derived CVD risk scores incorporate RA-related factors, but have had limited external validity testing. Additionally, RA-derived risk scores are less likely to be utilized and adopted by primary care providers and cardiologists involved in RA patients’ care. Neither set of risk scores incorporates novel imaging modalities or serum biomarkers, which are most likely to be helpful among individuals at intermediate risk. Therefore, until the performance of RA-specific CVD risk scores can be better established, we recommend the use of nationally endorsed CVD risk scores, with the frequency of reassessment based on CVD risk.

Conclusion

RA patients are at increased risk of CVD and CVD-related mortality relative to the general population. The disproportionate CVD burden seen in RA appears to be multifactorial, owing to the complex effects of systemic inflammation, endothelial dysfunction, and pro-atherogenic lipoprotein modifications. Additionally, many traditional CVD risk factors are more prevalent and suboptimally managed in RA patients. To mitigate the increased risk of CVD in RA, primary care and subspecialty providers alike must be aware of this heightened risk in RA, perform frequent assessment of CVD risk, and aggressively manage both traditional and nontraditional CVD risk factors. The management of CVD risk factors is discussed in detail in the second part of this article.

Corresponding author: Bryant R. England, MD; 986270 Nebraska Medical Center, Omaha, NE 68198-6270; Bryant.england@unmc.edu.

Financial disclosures: Dr. England is supported by UNMC Internal Medicine Scientist Development Award, UNMC Physician-Scientist Training Program, the UNMC Mentored Scholars Program, and the Rheumatology Research Foundation Scientist Development Award. Dr. Mikuls is supported by a VA Merit Award (CX000896) and grants from the National Institutes of Health: National Institute of General Medical Sciences (U54GM115458), National Institute on Alcohol Abuse and Alcoholism (R25AA020818), and National Institute of Arthritis and Musculoskeletal and Skin Diseases (2P50AR60772).

From the Division of Rheumatology & Immunology, University of Nebraska Medical Center, and Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE.

Abstract

• Objective: To review cardiovascular disease (CVD) risk assessment in patients with rheumatoid arthritis (RA).
• Methods: Literature review of the assessment of CVD risk in RA.
• Results: CVD is the leading cause of death among RA patients. Because of the increased risk of CVD events and CVD mortality in patients with RA, regular assessment of CVD risk and aggressive management of CVD risk in these patients is crucial. CVD risk estimation typically centers on the use of well-established CVD risk calculators. Most CVD risk scores from the general population do not contain RA-related factors predictive of CVD but have had more extensive performance testing, while novel RA-derived CVD risk scores that incorporate RA-related factors have had limited external validity testing. Neither set of risk scores incorporates novel imaging modalities or serum biomarkers, which are most likely to be helpful among individuals at intermediate risk.
• Conclusion: Primary care and rheumatology providers must be aware of the increased risk of CVD in RA, a risk that approaches that of diabetic patients. Routine assessment of CVD risk is an essential first step in minimizing CVD risk in this population. Until the performance of RA-specific CVD risk scores can be better established, we recommend the use of nationally endorsed CVD risk scores, with the frequency of reassessment based on CVD risk.

Keywords: rheumatoid arthritis; cardiovascular disease; cardiovascular risk assessment.

Editor’s note: This article is part 1 of a 2-part article. “Management of Cardiovascular Disease Risk in Rheumatoid Arthritis” was published in the March/April 2019 issue.

Rheumatoid arthritis (RA) is a chronic, autoimmune inflammatory arthritis affecting up to 1% of the US population that can lead to joint damage, functional disability, and reduced quality of life.¹ In addition to articular involvement, systemic inflammation accompanying RA may lead to extra-articular manifestations and increase the risk of premature death.² Cardiovascular disease (CVD), accounting for nearly half of all deaths among RA patients, is now recognized as a critical extra-articular manifestation of RA.^2,3 As such, assessment and management of CVD risk is essential to the comprehensive care of the RA patient. This article reviews the approach to assessing CVD risk in patients with RA; the management of both traditional and RA-specific risk factors is discussed in a separate article.

Scope of the Problem

In a large meta-analysis of observational studies that included more than 111,000 patients with RA, CVD-related mortality rates were 1.5 times higher among RA patients than among general population controls.⁴ The risk of overall CVD, including nonfatal events, is similar; a separate meta-analysis of observational studies that included more than 41,000 patients with RA calculated a pooled relative risk for incident CVD of 1.48.⁵ Individual analyses identified heightened risk of acute coronary syndrome (ACS), cerebrovascular accident, and congestive heart failure (CHF).⁵ Perhaps more illustrative of the magnitude of the problem, the risk of CVD in RA approaches that observed among individuals with diabetes mellitus.^6,7

Coronary artery disease (CAD) accounts for a significant portion of the CVD risk in RA, but its presentation may be atypical in RA patients. RA patients are at higher risk of suffering unrecognized myocardial infarction (MI) and sudden cardiac death.⁸ The reasons for silent ischemia in RA are not fully known, but have been hypothesized to include imbalances of inflammatory cytokines, alterations in pain sensitization, or the female predominance of RA (with women more often presenting with atypical symptoms of myocardial ischemia).⁹ Alarmingly, a retrospective chart review study reported that RA patients admitted for an acute MI were less likely to receive appropriate reperfusion therapy as well as secondary prevention with beta-blockers and lipid-lowering agents.¹⁰ Even with appropriate therapy, long-term outcomes such as mortality and recurrent ischemic events are more likely to occur in RA patients after acute MI.^11-13

Independent of ischemic heart disease, RA patients are at increased risk of CHF.^14-16 RA patients are at particular risk for CHF with preserved ejection fraction,¹⁷ which may be a result of systemic inflammation causing left ventricular stiffening.^18,19 Similar to CAD, patients with RA are less likely to present with typical CHF symptoms, are less likely to receive guideline-concordant care, and have higher mortality rates following presentation with CHF.¹⁷

Although accounting for a lower proportion of the excess CVD morbidity and mortality in RA, the risk of noncardiac vascular disease is also increased in RA patients. Large meta-analyses have identified positive associations between RA with both ischemic (odds ratio [OR], 1.64 [95% confidence interval {CI}, 1.32-2.05]) and hemorrhagic (OR, 1.68 [95% CI, 1.11-2.53]) stroke.²⁰ Similarly, RA patients appear to have an approximately twofold higher risk of venous thromboembolic events.²¹ Less frequently studied than other forms of CVD, peripheral arterial disease may be increased in RA patients independent of other CVD and CVD risk factors.^22,23

Assessing CVD Risk in RA

CVD Risk Scores

In order to identify patients who may benefit from primary prevention interventions, such as lipid-lowering therapy, CVD risk estimation typically centers on the use of well-established CVD risk calculators (Table). CVD risk scores such as the Framingham Risk Score (FRS), Systematic Coronary Risk Evaluation (SCORE), and American College of Cardiology/ American Heart Association (ACC/AHA) Pooled Cohort Equation incorporate traditional CVD risk factors, including age, sex, smoking status, blood pressure, lipid levels, and presence of diabetes mellitus.^24,25 However, CVD risk in RA patients appears to be inadequately explained by traditional CVD risk factors,²⁶ with disease activity and inflammation being associated with higher CVD risk. Recognizing that inflammation may contribute to CVD risk even among non-RA patients, the Reynolds Risk Score includes high-sensitivity C-reactive protein (hsCRP) in its calculation.²⁷ In contrast to more robust performance in the general population, these well-established CVD risk scores have had variable predictive potential of incident CVD in RA patients.^28-30

Several models, or adaptations to existing models, have been proposed to improve CVD risk assessment in RA populations (Table). In 2009, the European League Against Rheumatism (EULAR) task force suggested using a correction factor of 1.5 with traditional CVD risk models in RA patients with 2 of the following criteria: disease duration exceeding 10 years, rheumatoid factor or anti-cyclic citrullinated peptide (CCP) antibody positivity, or extra-articular manifestations of RA.³¹ An update to these recommendations in 2015 continued to propose the use of a 1.5 correction factor, but suggested applying this to all RA patients.³² QRISK2, a modification to QRISK1 which was developed to predict CVD in the UK general population, includes the diagnosis of RA as a risk factor, and in early validation efforts more accurately discriminated patients in the general population at increased risk of CVD compared to the FRS.³³ Additional disease-specific risk factors such as systemic lupus, steroid use, severe mental illness, and steroid and atypical antipsychotic use were incorporated in the QRISK3 algorithm, with model performance similar to the QRISK2.³⁴ The Expanded Cardiovascular Risk Prediction Score for RA (ERS-RA) was specifically developed to assess CVD risk in RA patients by including RA disease activity, level of physical disability, RA disease duration, and prednisone use.³⁵ Despite efforts to develop “RA-specific” risk scores, these have not consistently outperformed traditional CVD risk calculators.^36-38 In one study involving more than 1700 RA patients, the ERS-RA performed similarly to the FRS and Reynolds Risk Score, with a net reclassification index of just 2.3% versus the FRS.³⁶

Imaging Modalities

Imaging modalities may assist in characterizing the increased risk of CVD in RA and the subclinical CVD manifestations that occur. For example, RA patients were shown to have more prevalent and unstable coronary plaque, higher carotid intima media thickness, and impaired myocardial function with computed tomography (CT) angiography and carotid ultrasound.^39,40 However, studies harnessing noninvasive imaging to augment CVD risk assessment in RA patients are limited.

Carotid ultrasound has been the most extensively studied imaging modality for CVD risk assessment in RA. In a cohort of 599 RA patients with no history of ACS, rates of ACS were nearly 4 times higher in RA patients with bilateral carotid plaque on carotid ultrasound, and the association with ACS was independent of other traditional and RA-related risk factors.⁴¹ Presence of bilateral carotid plaques was similarly associated with an increased risk of overall CVD events (hazard ratio [HR], 3.34 [95% CI, 1.21-9.22]), ACS alone (HR, 6.31 [95% CI, 1.27-31.40]), and a lower mean CVD event-free survival (13.9 versus 15.2 years, P = 0.01) in a separate inception cohort of 105 RA patients with no prior history of CVD.⁴² The most useful application of carotid ultrasound may be in conjunction with clinical CVD risk models. Use of carotid ultrasound improved CVD risk stratification among RA patients who were considered at moderate risk by the EULAR-modified SCORE calculator.⁴³ Beyond carotid ultrasound, measurement of arterial stiffness through ultrasound could also aid in CVD risk stratification. Aortic pulse wave velocity and augmentation index, measures of arterial stiffness, are predictive of CVD in the general population as well as RA patients and improve with reduction in RA disease activity.^44,45 Peripheral arterial stiffness (brachial-ankle elasticity index) is impaired in RA patients and predictive of CVD morbidity and mortality in the general population.^46,47

CT coronary angiography and coronary artery calcium (CAC) scores are reliable measures of coronary artery atherosclerosis and have been validated for CVD risk assessment in the general population.^48-52 While the association between RA and CT-related findings of atherosclerosis is well established, assessment of CT-mediated evaluation as a prognostic tool for CVD in RA is limited. In one cohort study, CAC predicted higher rates of CVD events in Chinese patients with RA and systemic lupus erythematosus in a pooled analysis, although results were limited by low event rates and the absence of RA-only subanalyses.⁵³

While the aforementioned imaging modalities have focused on enhancing the identification of atherosclerosis, echocardiography or cardiac magnetic resonance imaging (MRI) may be useful for detecting subclinical structural and/or functional abnormalities that predispose to CHF. Structural abnormalities including increased left ventricular mass and hypertrophy are more prevalent in RA patients and predict incident CHF in the general population.^54-56 MRI measures of myocardial inflammation, including T1 mapping and extracellular volume, are associated with higher mortality rates and also appear to be elevated in RA patients.^57,58 Whether identification of these imaging findings influences the cost-effective clinical management of RA patients needs further study.

Biomarkers

Serum biomarkers, such as the anti-CCP antibody, have become crucial to the evaluation of patients suspected to have RA. With the growing understanding of the role pro-inflammatory mediators play in CVD pathogenesis and the relative ease with which they can be measured, serum biomarkers have potential to inform CVD risk assessment. In the general population, hsCRP concentrations are predictive of CVD and are included in the Reynolds Risk Score.²⁷ In RA, CRP concentrations are typically much higher than those observed among individuals in the general population solely at increased CVD risk, yet elevated levels remain predictive of CVD death independent of RA disease activity and traditional CVD risk factors.⁵⁹ Several additional cytokines, chemokines, and adhesion molecules have been associated with surrogate markers of CVD in RA patients, although further study is needed to elucidate thresholds that signify increased CVD risk in a population characterized by the presence of systemic inflammation.⁶⁰

Cardiac biomarkers used frequently in the general population may be useful to assess CVD risk in RA patients. N-terminal-pro brain natriuretic peptide (NT-pro BNP) is a biomarker typically used to evaluate CHF severity, but it may also predict long-term mortality in patients with coronary heart disease.^61,62 Circulating NT-pro BNP concentrations are elevated in RA independent of prevalent CHF and may serve as a useful tool to identify subclinical cardiac disease in RA patients.⁶³ High-sensitivity cardiac troponin I (HS-cTnI) assays are capable of detecting levels of cardiac troponin below the threshold typically used to diagnose ACS. HS-cTnI levels are increased in RA patients independent of additional CVD risk factors, and elevated levels (> 1.5 pg/mL) were associated with more severe CT angiography findings of coronary plaque as well as increased risk of CVD events.^64,65

A fully validated algorithm for CVD risk assessment in RA is lacking. Most CVD risk scores from the general population do not contain RA-related factors predictive of CVD but have had more extensive performance testing. In contrast, novel RA-derived CVD risk scores incorporate RA-related factors, but have had limited external validity testing. Additionally, RA-derived risk scores are less likely to be utilized and adopted by primary care providers and cardiologists involved in RA patients’ care. Neither set of risk scores incorporates novel imaging modalities or serum biomarkers, which are most likely to be helpful among individuals at intermediate risk. Therefore, until the performance of RA-specific CVD risk scores can be better established, we recommend the use of nationally endorsed CVD risk scores, with the frequency of reassessment based on CVD risk.

Conclusion

RA patients are at increased risk of CVD and CVD-related mortality relative to the general population. The disproportionate CVD burden seen in RA appears to be multifactorial, owing to the complex effects of systemic inflammation, endothelial dysfunction, and pro-atherogenic lipoprotein modifications. Additionally, many traditional CVD risk factors are more prevalent and suboptimally managed in RA patients. To mitigate the increased risk of CVD in RA, primary care and subspecialty providers alike must be aware of this heightened risk in RA, perform frequent assessment of CVD risk, and aggressively manage both traditional and nontraditional CVD risk factors. The management of CVD risk factors is discussed in detail in the second part of this article.

Corresponding author: Bryant R. England, MD; 986270 Nebraska Medical Center, Omaha, NE 68198-6270; Bryant.england@unmc.edu.

Financial disclosures: Dr. England is supported by UNMC Internal Medicine Scientist Development Award, UNMC Physician-Scientist Training Program, the UNMC Mentored Scholars Program, and the Rheumatology Research Foundation Scientist Development Award. Dr. Mikuls is supported by a VA Merit Award (CX000896) and grants from the National Institutes of Health: National Institute of General Medical Sciences (U54GM115458), National Institute on Alcohol Abuse and Alcoholism (R25AA020818), and National Institute of Arthritis and Musculoskeletal and Skin Diseases (2P50AR60772).

From the Division of Rheumatology & Immunology, University of Nebraska Medical Center, and Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE.

Abstract

• Objective: To review cardiovascular disease (CVD) risk assessment in patients with rheumatoid arthritis (RA).
• Methods: Literature review of the assessment of CVD risk in RA.
• Results: CVD is the leading cause of death among RA patients. Because of the increased risk of CVD events and CVD mortality in patients with RA, regular assessment of CVD risk and aggressive management of CVD risk in these patients is crucial. CVD risk estimation typically centers on the use of well-established CVD risk calculators. Most CVD risk scores from the general population do not contain RA-related factors predictive of CVD but have had more extensive performance testing, while novel RA-derived CVD risk scores that incorporate RA-related factors have had limited external validity testing. Neither set of risk scores incorporates novel imaging modalities or serum biomarkers, which are most likely to be helpful among individuals at intermediate risk.
• Conclusion: Primary care and rheumatology providers must be aware of the increased risk of CVD in RA, a risk that approaches that of diabetic patients. Routine assessment of CVD risk is an essential first step in minimizing CVD risk in this population. Until the performance of RA-specific CVD risk scores can be better established, we recommend the use of nationally endorsed CVD risk scores, with the frequency of reassessment based on CVD risk.

Keywords: rheumatoid arthritis; cardiovascular disease; cardiovascular risk assessment.

Editor’s note: This article is part 1 of a 2-part article. “Management of Cardiovascular Disease Risk in Rheumatoid Arthritis” was published in the March/April 2019 issue.

Rheumatoid arthritis (RA) is a chronic, autoimmune inflammatory arthritis affecting up to 1% of the US population that can lead to joint damage, functional disability, and reduced quality of life.¹ In addition to articular involvement, systemic inflammation accompanying RA may lead to extra-articular manifestations and increase the risk of premature death.² Cardiovascular disease (CVD), accounting for nearly half of all deaths among RA patients, is now recognized as a critical extra-articular manifestation of RA.^2,3 As such, assessment and management of CVD risk is essential to the comprehensive care of the RA patient. This article reviews the approach to assessing CVD risk in patients with RA; the management of both traditional and RA-specific risk factors is discussed in a separate article.

Scope of the Problem

In a large meta-analysis of observational studies that included more than 111,000 patients with RA, CVD-related mortality rates were 1.5 times higher among RA patients than among general population controls.⁴ The risk of overall CVD, including nonfatal events, is similar; a separate meta-analysis of observational studies that included more than 41,000 patients with RA calculated a pooled relative risk for incident CVD of 1.48.⁵ Individual analyses identified heightened risk of acute coronary syndrome (ACS), cerebrovascular accident, and congestive heart failure (CHF).⁵ Perhaps more illustrative of the magnitude of the problem, the risk of CVD in RA approaches that observed among individuals with diabetes mellitus.^6,7

Coronary artery disease (CAD) accounts for a significant portion of the CVD risk in RA, but its presentation may be atypical in RA patients. RA patients are at higher risk of suffering unrecognized myocardial infarction (MI) and sudden cardiac death.⁸ The reasons for silent ischemia in RA are not fully known, but have been hypothesized to include imbalances of inflammatory cytokines, alterations in pain sensitization, or the female predominance of RA (with women more often presenting with atypical symptoms of myocardial ischemia).⁹ Alarmingly, a retrospective chart review study reported that RA patients admitted for an acute MI were less likely to receive appropriate reperfusion therapy as well as secondary prevention with beta-blockers and lipid-lowering agents.¹⁰ Even with appropriate therapy, long-term outcomes such as mortality and recurrent ischemic events are more likely to occur in RA patients after acute MI.^11-13

Independent of ischemic heart disease, RA patients are at increased risk of CHF.^14-16 RA patients are at particular risk for CHF with preserved ejection fraction,¹⁷ which may be a result of systemic inflammation causing left ventricular stiffening.^18,19 Similar to CAD, patients with RA are less likely to present with typical CHF symptoms, are less likely to receive guideline-concordant care, and have higher mortality rates following presentation with CHF.¹⁷

Although accounting for a lower proportion of the excess CVD morbidity and mortality in RA, the risk of noncardiac vascular disease is also increased in RA patients. Large meta-analyses have identified positive associations between RA with both ischemic (odds ratio [OR], 1.64 [95% confidence interval {CI}, 1.32-2.05]) and hemorrhagic (OR, 1.68 [95% CI, 1.11-2.53]) stroke.²⁰ Similarly, RA patients appear to have an approximately twofold higher risk of venous thromboembolic events.²¹ Less frequently studied than other forms of CVD, peripheral arterial disease may be increased in RA patients independent of other CVD and CVD risk factors.^22,23

Assessing CVD Risk in RA

CVD Risk Scores

In order to identify patients who may benefit from primary prevention interventions, such as lipid-lowering therapy, CVD risk estimation typically centers on the use of well-established CVD risk calculators (Table). CVD risk scores such as the Framingham Risk Score (FRS), Systematic Coronary Risk Evaluation (SCORE), and American College of Cardiology/ American Heart Association (ACC/AHA) Pooled Cohort Equation incorporate traditional CVD risk factors, including age, sex, smoking status, blood pressure, lipid levels, and presence of diabetes mellitus.^24,25 However, CVD risk in RA patients appears to be inadequately explained by traditional CVD risk factors,²⁶ with disease activity and inflammation being associated with higher CVD risk. Recognizing that inflammation may contribute to CVD risk even among non-RA patients, the Reynolds Risk Score includes high-sensitivity C-reactive protein (hsCRP) in its calculation.²⁷ In contrast to more robust performance in the general population, these well-established CVD risk scores have had variable predictive potential of incident CVD in RA patients.^28-30

Several models, or adaptations to existing models, have been proposed to improve CVD risk assessment in RA populations (Table). In 2009, the European League Against Rheumatism (EULAR) task force suggested using a correction factor of 1.5 with traditional CVD risk models in RA patients with 2 of the following criteria: disease duration exceeding 10 years, rheumatoid factor or anti-cyclic citrullinated peptide (CCP) antibody positivity, or extra-articular manifestations of RA.³¹ An update to these recommendations in 2015 continued to propose the use of a 1.5 correction factor, but suggested applying this to all RA patients.³² QRISK2, a modification to QRISK1 which was developed to predict CVD in the UK general population, includes the diagnosis of RA as a risk factor, and in early validation efforts more accurately discriminated patients in the general population at increased risk of CVD compared to the FRS.³³ Additional disease-specific risk factors such as systemic lupus, steroid use, severe mental illness, and steroid and atypical antipsychotic use were incorporated in the QRISK3 algorithm, with model performance similar to the QRISK2.³⁴ The Expanded Cardiovascular Risk Prediction Score for RA (ERS-RA) was specifically developed to assess CVD risk in RA patients by including RA disease activity, level of physical disability, RA disease duration, and prednisone use.³⁵ Despite efforts to develop “RA-specific” risk scores, these have not consistently outperformed traditional CVD risk calculators.^36-38 In one study involving more than 1700 RA patients, the ERS-RA performed similarly to the FRS and Reynolds Risk Score, with a net reclassification index of just 2.3% versus the FRS.³⁶

Imaging Modalities

Imaging modalities may assist in characterizing the increased risk of CVD in RA and the subclinical CVD manifestations that occur. For example, RA patients were shown to have more prevalent and unstable coronary plaque, higher carotid intima media thickness, and impaired myocardial function with computed tomography (CT) angiography and carotid ultrasound.^39,40 However, studies harnessing noninvasive imaging to augment CVD risk assessment in RA patients are limited.

Carotid ultrasound has been the most extensively studied imaging modality for CVD risk assessment in RA. In a cohort of 599 RA patients with no history of ACS, rates of ACS were nearly 4 times higher in RA patients with bilateral carotid plaque on carotid ultrasound, and the association with ACS was independent of other traditional and RA-related risk factors.⁴¹ Presence of bilateral carotid plaques was similarly associated with an increased risk of overall CVD events (hazard ratio [HR], 3.34 [95% CI, 1.21-9.22]), ACS alone (HR, 6.31 [95% CI, 1.27-31.40]), and a lower mean CVD event-free survival (13.9 versus 15.2 years, P = 0.01) in a separate inception cohort of 105 RA patients with no prior history of CVD.⁴² The most useful application of carotid ultrasound may be in conjunction with clinical CVD risk models. Use of carotid ultrasound improved CVD risk stratification among RA patients who were considered at moderate risk by the EULAR-modified SCORE calculator.⁴³ Beyond carotid ultrasound, measurement of arterial stiffness through ultrasound could also aid in CVD risk stratification. Aortic pulse wave velocity and augmentation index, measures of arterial stiffness, are predictive of CVD in the general population as well as RA patients and improve with reduction in RA disease activity.^44,45 Peripheral arterial stiffness (brachial-ankle elasticity index) is impaired in RA patients and predictive of CVD morbidity and mortality in the general population.^46,47

CT coronary angiography and coronary artery calcium (CAC) scores are reliable measures of coronary artery atherosclerosis and have been validated for CVD risk assessment in the general population.^48-52 While the association between RA and CT-related findings of atherosclerosis is well established, assessment of CT-mediated evaluation as a prognostic tool for CVD in RA is limited. In one cohort study, CAC predicted higher rates of CVD events in Chinese patients with RA and systemic lupus erythematosus in a pooled analysis, although results were limited by low event rates and the absence of RA-only subanalyses.⁵³

While the aforementioned imaging modalities have focused on enhancing the identification of atherosclerosis, echocardiography or cardiac magnetic resonance imaging (MRI) may be useful for detecting subclinical structural and/or functional abnormalities that predispose to CHF. Structural abnormalities including increased left ventricular mass and hypertrophy are more prevalent in RA patients and predict incident CHF in the general population.^54-56 MRI measures of myocardial inflammation, including T1 mapping and extracellular volume, are associated with higher mortality rates and also appear to be elevated in RA patients.^57,58 Whether identification of these imaging findings influences the cost-effective clinical management of RA patients needs further study.

Biomarkers

Serum biomarkers, such as the anti-CCP antibody, have become crucial to the evaluation of patients suspected to have RA. With the growing understanding of the role pro-inflammatory mediators play in CVD pathogenesis and the relative ease with which they can be measured, serum biomarkers have potential to inform CVD risk assessment. In the general population, hsCRP concentrations are predictive of CVD and are included in the Reynolds Risk Score.²⁷ In RA, CRP concentrations are typically much higher than those observed among individuals in the general population solely at increased CVD risk, yet elevated levels remain predictive of CVD death independent of RA disease activity and traditional CVD risk factors.⁵⁹ Several additional cytokines, chemokines, and adhesion molecules have been associated with surrogate markers of CVD in RA patients, although further study is needed to elucidate thresholds that signify increased CVD risk in a population characterized by the presence of systemic inflammation.⁶⁰

Cardiac biomarkers used frequently in the general population may be useful to assess CVD risk in RA patients. N-terminal-pro brain natriuretic peptide (NT-pro BNP) is a biomarker typically used to evaluate CHF severity, but it may also predict long-term mortality in patients with coronary heart disease.^61,62 Circulating NT-pro BNP concentrations are elevated in RA independent of prevalent CHF and may serve as a useful tool to identify subclinical cardiac disease in RA patients.⁶³ High-sensitivity cardiac troponin I (HS-cTnI) assays are capable of detecting levels of cardiac troponin below the threshold typically used to diagnose ACS. HS-cTnI levels are increased in RA patients independent of additional CVD risk factors, and elevated levels (> 1.5 pg/mL) were associated with more severe CT angiography findings of coronary plaque as well as increased risk of CVD events.^64,65

A fully validated algorithm for CVD risk assessment in RA is lacking. Most CVD risk scores from the general population do not contain RA-related factors predictive of CVD but have had more extensive performance testing. In contrast, novel RA-derived CVD risk scores incorporate RA-related factors, but have had limited external validity testing. Additionally, RA-derived risk scores are less likely to be utilized and adopted by primary care providers and cardiologists involved in RA patients’ care. Neither set of risk scores incorporates novel imaging modalities or serum biomarkers, which are most likely to be helpful among individuals at intermediate risk. Therefore, until the performance of RA-specific CVD risk scores can be better established, we recommend the use of nationally endorsed CVD risk scores, with the frequency of reassessment based on CVD risk.

Conclusion

RA patients are at increased risk of CVD and CVD-related mortality relative to the general population. The disproportionate CVD burden seen in RA appears to be multifactorial, owing to the complex effects of systemic inflammation, endothelial dysfunction, and pro-atherogenic lipoprotein modifications. Additionally, many traditional CVD risk factors are more prevalent and suboptimally managed in RA patients. To mitigate the increased risk of CVD in RA, primary care and subspecialty providers alike must be aware of this heightened risk in RA, perform frequent assessment of CVD risk, and aggressively manage both traditional and nontraditional CVD risk factors. The management of CVD risk factors is discussed in detail in the second part of this article.

Corresponding author: Bryant R. England, MD; 986270 Nebraska Medical Center, Omaha, NE 68198-6270; Bryant.england@unmc.edu.

Financial disclosures: Dr. England is supported by UNMC Internal Medicine Scientist Development Award, UNMC Physician-Scientist Training Program, the UNMC Mentored Scholars Program, and the Rheumatology Research Foundation Scientist Development Award. Dr. Mikuls is supported by a VA Merit Award (CX000896) and grants from the National Institutes of Health: National Institute of General Medical Sciences (U54GM115458), National Institute on Alcohol Abuse and Alcoholism (R25AA020818), and National Institute of Arthritis and Musculoskeletal and Skin Diseases (2P50AR60772).

This week in cardiology news, revised atrial fibrillation guidelines revamp anticoagulation, the SPRINT MIND results showing that tight BP control staves off mild cognitive impairment are published, the FDA discovers that nitrosamine-contaminated ARBs have been on the market for years, and subclinical hypothyroidism boosts the immediate risk of heart failure.

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This week in cardiology news, revised atrial fibrillation guidelines revamp anticoagulation, the SPRINT MIND results showing that tight BP control staves off mild cognitive impairment are published, the FDA discovers that nitrosamine-contaminated ARBs have been on the market for years, and subclinical hypothyroidism boosts the immediate risk of heart failure.

Amazon Alexa
Apple Podcasts
Google Podcasts
TuneIn






 

This week in cardiology news, revised atrial fibrillation guidelines revamp anticoagulation, the SPRINT MIND results showing that tight BP control staves off mild cognitive impairment are published, the FDA discovers that nitrosamine-contaminated ARBs have been on the market for years, and subclinical hypothyroidism boosts the immediate risk of heart failure.

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Apple Podcasts
Google Podcasts
TuneIn






 

The purpose of this guideline is to provide direction for the management of patients with high blood cholesterol to decrease the incidence of atherosclerotic vascular disease. The update was undertaken because new evidence has emerged since the publication of the 2013 ACC/AHA cholesterol guideline about additional cholesterol-lowering agents including ezetimibe and PCSK9 inhibitors.

Measurement and therapeutic modalities

In adults aged 20 years and older who are not on lipid-lowering therapy, measurement of a lipid profile is recommended and is an effective way to estimate atherosclerotic cardiovascular disease (ASCVD) risk and documenting baseline LDL-C.

Statin therapy is divided into three categories: High-intensity statin therapy aims for lowering LDL-C levels by more than 50%, moderate-intensity therapy by 30%-49%, and low-intensity therapy by less than 30%.
 

Cholesterol management groups

In all individuals at all ages, emphasizing a heart-healthy lifestyle, meaning appropriate diet and exercise, to decrease the risk of developing ASCVD should be advised.

Individuals fall into groups with distinct risk of ASCVD or recurrence of ASCVD and the recommendations are organized according to these risk groups.

Secondary ASCVD prevention: Patients who already have ASCVD by virtue of having had an event or established diagnosis (MI, angina, cerebrovascular accident, or peripheral vascular disease) fall into the secondary prevention category:

• Patients aged 75 years and younger with clinical ASCVD: High-intensity statin therapy should be initiated with aim to reduce LDL-C levels by 50%. In patients who experience statin-related side effects, a moderate-intensity statin should be initiated with the aim to reduce LDL-C by 30%-49%.
• In very high-risk patients with an LDL-C above 70 mg/dL on maximally tolerated statin therapy, it is reasonable to consider the use of a non–statin cholesterol-lowering agent with an LDL-C goal under 70 mg/dL. Ezetimibe (Zetia) can be used initially and if LDL-C remains above 70 mg/dL, then consideration can be given to the addition of a PCSK9-inhibitor therapy (strength of recommendation: ezetimibe – moderate; PCSK9 – strong). The guideline discusses that, even though the evidence supports the efficacy of PCSK9s in reducing the incidence of ASCVD events, the expense of PCSK9 inhibitors give them a high cost, compared with value.
• For patients more than age 75 years with established ASCVD, it is reasonable to continue high-intensity statin therapy if patient is tolerating treatment.

Severe hypercholesterolemia:

• Patients with LDL-C above 190 mg/dL do not need a 10-year risk score calculated. These individuals should receive maximally tolerated statin therapy.
• If patient is unable to achieve 50% reduction in LDL-C and/or have an LDL-C level of 100 mg/dL, the addition of ezetimibe therapy is reasonable.
• If LDL-C is still greater than 100mg/dL on a statin plus ezetimibe, the addition of a PCSK9 inhibitor may be considered. It should be recognized that the addition of a PCSK9 in this circumstance is classified as a weak recommendation.

Diabetes mellitus in adults:

• In patients aged 40-75 years with diabetes, regardless of 10-year ASCVD risk, should be prescribed a moderate-intensity statin (strong recommendation).
• In adults with diabetes mellitus and multiple ASCVD risk factors, it is reasonable to prescribe high-intensity statin therapy with goal to reduce LDL-C by more than 50%.
• In adults with diabetes mellitus and 10-year ASCVD risk of 20% or higher, it may be reasonable to add ezetimibe to maximally tolerated statin therapy to reduce LDL-C levels by 50% or more.
• In patients aged 20-39 years with diabetes that is either of long duration (at least 10 years, type 2 diabetes mellitus; at least 20 years, type 1 diabetes mellitus), or with end-organ damage including albuminuria, chronic renal insufficiency, retinopathy, neuropathy, or ankle-brachial index below 0.9, it may be reasonable to initiate statin therapy (weak recommendation).

Primary prevention in adults: Adults with LDL 70-189 mg/dL and a 10-year risk of a first ASCVD event (fatal and nonfatal MI or stroke) should be estimated by using the pooled cohort equation. Adults should be categorized according to calculated risk of developing ASCVD: low risk (less than 5%), borderline risk (5% to less than 7.5%), intermediate risk (7.5% and higher to less than 20%), and high risk (20% and higher) (strong recommendation:

• Individualized risk and treatment discussion should be done with clinician and patient.
• Adults in the intermediate-risk group (7.5% and higher to less than 20%), should be placed on moderate-intensity statin with LDL-C goal reduction of more than 30%; for optimal risk reduction, especially in high-risk patients, an LDL-C reduction of more than 50% (strong recommendation).
• Risk-enhancing factors can favor initiation of intensification of statin therapy.
• If a decision about statin therapy is uncertain, consider measuring coronary artery calcium (CAC) levels. If CAC is zero, statin therapy may be withheld or delayed, except those with diabetes as above, smokers, and strong familial hypercholesterolemia with premature ASCVD. If CAC score is 1-99, it is reasonable to initiate statin therapy for patients older than age 55 years; If CAC score is 100 or higher or in the 75th percentile or higher, it is reasonable to initiate a statin.

Statin safety: Prior to initiation of a statin, a clinician-patient discussion is recommended detailing ASCVD risk reduction and the potential for side effects/drug interactions. In patients with statin-associated muscle symptoms (SAMS), a detailed account for secondary causes is recommended. In patients with true SAMS, it is recommended to check a creatine kinase level and hepatic function panel; however, routine measurements are not useful. In patients with statin-associated side effects that are not severe, reassess and rechallenge patient to achieve maximal lowering of LDL-C with a modified dosing regimen.
 

The bottom line

Lifestyle modification is important at all ages, with specific population-guided strategies for lowering cholesterol in subgroups as discussed above. Major changes to the AHA/ACC Cholesterol Clinical Practice Guidelines now mention new agents for lowering cholesterol and using CAC levels as predictability scoring.

Reference

Grundy SM et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the management of blood cholesterol: Executive Summary: A report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2018 Nov 10.

Dr. Skolnik is a professor of family and community medicine at Jefferson Medical College, Philadelphia, and an associate director of the family medicine residency program at Abington (Pa.) Jefferson Health. Dr. Palko is a second-year resident in the family medicine residency program at Abington Jefferson Hospital.

The purpose of this guideline is to provide direction for the management of patients with high blood cholesterol to decrease the incidence of atherosclerotic vascular disease. The update was undertaken because new evidence has emerged since the publication of the 2013 ACC/AHA cholesterol guideline about additional cholesterol-lowering agents including ezetimibe and PCSK9 inhibitors.

Measurement and therapeutic modalities

In adults aged 20 years and older who are not on lipid-lowering therapy, measurement of a lipid profile is recommended and is an effective way to estimate atherosclerotic cardiovascular disease (ASCVD) risk and documenting baseline LDL-C.

Statin therapy is divided into three categories: High-intensity statin therapy aims for lowering LDL-C levels by more than 50%, moderate-intensity therapy by 30%-49%, and low-intensity therapy by less than 30%.
 

Cholesterol management groups

In all individuals at all ages, emphasizing a heart-healthy lifestyle, meaning appropriate diet and exercise, to decrease the risk of developing ASCVD should be advised.

Individuals fall into groups with distinct risk of ASCVD or recurrence of ASCVD and the recommendations are organized according to these risk groups.

Secondary ASCVD prevention: Patients who already have ASCVD by virtue of having had an event or established diagnosis (MI, angina, cerebrovascular accident, or peripheral vascular disease) fall into the secondary prevention category:

• Patients aged 75 years and younger with clinical ASCVD: High-intensity statin therapy should be initiated with aim to reduce LDL-C levels by 50%. In patients who experience statin-related side effects, a moderate-intensity statin should be initiated with the aim to reduce LDL-C by 30%-49%.
• In very high-risk patients with an LDL-C above 70 mg/dL on maximally tolerated statin therapy, it is reasonable to consider the use of a non–statin cholesterol-lowering agent with an LDL-C goal under 70 mg/dL. Ezetimibe (Zetia) can be used initially and if LDL-C remains above 70 mg/dL, then consideration can be given to the addition of a PCSK9-inhibitor therapy (strength of recommendation: ezetimibe – moderate; PCSK9 – strong). The guideline discusses that, even though the evidence supports the efficacy of PCSK9s in reducing the incidence of ASCVD events, the expense of PCSK9 inhibitors give them a high cost, compared with value.
• For patients more than age 75 years with established ASCVD, it is reasonable to continue high-intensity statin therapy if patient is tolerating treatment.

Severe hypercholesterolemia:

• Patients with LDL-C above 190 mg/dL do not need a 10-year risk score calculated. These individuals should receive maximally tolerated statin therapy.
• If patient is unable to achieve 50% reduction in LDL-C and/or have an LDL-C level of 100 mg/dL, the addition of ezetimibe therapy is reasonable.
• If LDL-C is still greater than 100mg/dL on a statin plus ezetimibe, the addition of a PCSK9 inhibitor may be considered. It should be recognized that the addition of a PCSK9 in this circumstance is classified as a weak recommendation.

Diabetes mellitus in adults:

• In patients aged 40-75 years with diabetes, regardless of 10-year ASCVD risk, should be prescribed a moderate-intensity statin (strong recommendation).
• In adults with diabetes mellitus and multiple ASCVD risk factors, it is reasonable to prescribe high-intensity statin therapy with goal to reduce LDL-C by more than 50%.
• In adults with diabetes mellitus and 10-year ASCVD risk of 20% or higher, it may be reasonable to add ezetimibe to maximally tolerated statin therapy to reduce LDL-C levels by 50% or more.
• In patients aged 20-39 years with diabetes that is either of long duration (at least 10 years, type 2 diabetes mellitus; at least 20 years, type 1 diabetes mellitus), or with end-organ damage including albuminuria, chronic renal insufficiency, retinopathy, neuropathy, or ankle-brachial index below 0.9, it may be reasonable to initiate statin therapy (weak recommendation).

Primary prevention in adults: Adults with LDL 70-189 mg/dL and a 10-year risk of a first ASCVD event (fatal and nonfatal MI or stroke) should be estimated by using the pooled cohort equation. Adults should be categorized according to calculated risk of developing ASCVD: low risk (less than 5%), borderline risk (5% to less than 7.5%), intermediate risk (7.5% and higher to less than 20%), and high risk (20% and higher) (strong recommendation:

• Individualized risk and treatment discussion should be done with clinician and patient.
• Adults in the intermediate-risk group (7.5% and higher to less than 20%), should be placed on moderate-intensity statin with LDL-C goal reduction of more than 30%; for optimal risk reduction, especially in high-risk patients, an LDL-C reduction of more than 50% (strong recommendation).
• Risk-enhancing factors can favor initiation of intensification of statin therapy.
• If a decision about statin therapy is uncertain, consider measuring coronary artery calcium (CAC) levels. If CAC is zero, statin therapy may be withheld or delayed, except those with diabetes as above, smokers, and strong familial hypercholesterolemia with premature ASCVD. If CAC score is 1-99, it is reasonable to initiate statin therapy for patients older than age 55 years; If CAC score is 100 or higher or in the 75th percentile or higher, it is reasonable to initiate a statin.

Statin safety: Prior to initiation of a statin, a clinician-patient discussion is recommended detailing ASCVD risk reduction and the potential for side effects/drug interactions. In patients with statin-associated muscle symptoms (SAMS), a detailed account for secondary causes is recommended. In patients with true SAMS, it is recommended to check a creatine kinase level and hepatic function panel; however, routine measurements are not useful. In patients with statin-associated side effects that are not severe, reassess and rechallenge patient to achieve maximal lowering of LDL-C with a modified dosing regimen.
 

The bottom line

Lifestyle modification is important at all ages, with specific population-guided strategies for lowering cholesterol in subgroups as discussed above. Major changes to the AHA/ACC Cholesterol Clinical Practice Guidelines now mention new agents for lowering cholesterol and using CAC levels as predictability scoring.

Reference

Grundy SM et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the management of blood cholesterol: Executive Summary: A report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2018 Nov 10.

Dr. Skolnik is a professor of family and community medicine at Jefferson Medical College, Philadelphia, and an associate director of the family medicine residency program at Abington (Pa.) Jefferson Health. Dr. Palko is a second-year resident in the family medicine residency program at Abington Jefferson Hospital.

The purpose of this guideline is to provide direction for the management of patients with high blood cholesterol to decrease the incidence of atherosclerotic vascular disease. The update was undertaken because new evidence has emerged since the publication of the 2013 ACC/AHA cholesterol guideline about additional cholesterol-lowering agents including ezetimibe and PCSK9 inhibitors.

Measurement and therapeutic modalities

In adults aged 20 years and older who are not on lipid-lowering therapy, measurement of a lipid profile is recommended and is an effective way to estimate atherosclerotic cardiovascular disease (ASCVD) risk and documenting baseline LDL-C.

Statin therapy is divided into three categories: High-intensity statin therapy aims for lowering LDL-C levels by more than 50%, moderate-intensity therapy by 30%-49%, and low-intensity therapy by less than 30%.
 

Cholesterol management groups

In all individuals at all ages, emphasizing a heart-healthy lifestyle, meaning appropriate diet and exercise, to decrease the risk of developing ASCVD should be advised.

Individuals fall into groups with distinct risk of ASCVD or recurrence of ASCVD and the recommendations are organized according to these risk groups.

Secondary ASCVD prevention: Patients who already have ASCVD by virtue of having had an event or established diagnosis (MI, angina, cerebrovascular accident, or peripheral vascular disease) fall into the secondary prevention category:

• Patients aged 75 years and younger with clinical ASCVD: High-intensity statin therapy should be initiated with aim to reduce LDL-C levels by 50%. In patients who experience statin-related side effects, a moderate-intensity statin should be initiated with the aim to reduce LDL-C by 30%-49%.
• In very high-risk patients with an LDL-C above 70 mg/dL on maximally tolerated statin therapy, it is reasonable to consider the use of a non–statin cholesterol-lowering agent with an LDL-C goal under 70 mg/dL. Ezetimibe (Zetia) can be used initially and if LDL-C remains above 70 mg/dL, then consideration can be given to the addition of a PCSK9-inhibitor therapy (strength of recommendation: ezetimibe – moderate; PCSK9 – strong). The guideline discusses that, even though the evidence supports the efficacy of PCSK9s in reducing the incidence of ASCVD events, the expense of PCSK9 inhibitors give them a high cost, compared with value.
• For patients more than age 75 years with established ASCVD, it is reasonable to continue high-intensity statin therapy if patient is tolerating treatment.

Severe hypercholesterolemia:

• Patients with LDL-C above 190 mg/dL do not need a 10-year risk score calculated. These individuals should receive maximally tolerated statin therapy.
• If patient is unable to achieve 50% reduction in LDL-C and/or have an LDL-C level of 100 mg/dL, the addition of ezetimibe therapy is reasonable.
• If LDL-C is still greater than 100mg/dL on a statin plus ezetimibe, the addition of a PCSK9 inhibitor may be considered. It should be recognized that the addition of a PCSK9 in this circumstance is classified as a weak recommendation.

Diabetes mellitus in adults:

• In patients aged 40-75 years with diabetes, regardless of 10-year ASCVD risk, should be prescribed a moderate-intensity statin (strong recommendation).
• In adults with diabetes mellitus and multiple ASCVD risk factors, it is reasonable to prescribe high-intensity statin therapy with goal to reduce LDL-C by more than 50%.
• In adults with diabetes mellitus and 10-year ASCVD risk of 20% or higher, it may be reasonable to add ezetimibe to maximally tolerated statin therapy to reduce LDL-C levels by 50% or more.
• In patients aged 20-39 years with diabetes that is either of long duration (at least 10 years, type 2 diabetes mellitus; at least 20 years, type 1 diabetes mellitus), or with end-organ damage including albuminuria, chronic renal insufficiency, retinopathy, neuropathy, or ankle-brachial index below 0.9, it may be reasonable to initiate statin therapy (weak recommendation).

Primary prevention in adults: Adults with LDL 70-189 mg/dL and a 10-year risk of a first ASCVD event (fatal and nonfatal MI or stroke) should be estimated by using the pooled cohort equation. Adults should be categorized according to calculated risk of developing ASCVD: low risk (less than 5%), borderline risk (5% to less than 7.5%), intermediate risk (7.5% and higher to less than 20%), and high risk (20% and higher) (strong recommendation:

• Individualized risk and treatment discussion should be done with clinician and patient.
• Adults in the intermediate-risk group (7.5% and higher to less than 20%), should be placed on moderate-intensity statin with LDL-C goal reduction of more than 30%; for optimal risk reduction, especially in high-risk patients, an LDL-C reduction of more than 50% (strong recommendation).
• Risk-enhancing factors can favor initiation of intensification of statin therapy.
• If a decision about statin therapy is uncertain, consider measuring coronary artery calcium (CAC) levels. If CAC is zero, statin therapy may be withheld or delayed, except those with diabetes as above, smokers, and strong familial hypercholesterolemia with premature ASCVD. If CAC score is 1-99, it is reasonable to initiate statin therapy for patients older than age 55 years; If CAC score is 100 or higher or in the 75th percentile or higher, it is reasonable to initiate a statin.

Statin safety: Prior to initiation of a statin, a clinician-patient discussion is recommended detailing ASCVD risk reduction and the potential for side effects/drug interactions. In patients with statin-associated muscle symptoms (SAMS), a detailed account for secondary causes is recommended. In patients with true SAMS, it is recommended to check a creatine kinase level and hepatic function panel; however, routine measurements are not useful. In patients with statin-associated side effects that are not severe, reassess and rechallenge patient to achieve maximal lowering of LDL-C with a modified dosing regimen.
 

The bottom line

Lifestyle modification is important at all ages, with specific population-guided strategies for lowering cholesterol in subgroups as discussed above. Major changes to the AHA/ACC Cholesterol Clinical Practice Guidelines now mention new agents for lowering cholesterol and using CAC levels as predictability scoring.

Reference

Grundy SM et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the management of blood cholesterol: Executive Summary: A report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2018 Nov 10.

Dr. Skolnik is a professor of family and community medicine at Jefferson Medical College, Philadelphia, and an associate director of the family medicine residency program at Abington (Pa.) Jefferson Health. Dr. Palko is a second-year resident in the family medicine residency program at Abington Jefferson Hospital.

SNOWMASS, COLO. – The decades-long belief that aspirin is beneficial for primary prevention of cardiovascular events was utterly dashed by three major randomized clinical trials during the space of a few short weeks in autumn 2018.

“Is aspirin safe and effective for primary prevention? The short answer here is no,” Patrick T. O’Gara, MD, declared at the annual Cardiovascular Conference at Snowmass sponsored by the American College of Cardiology.

“Think of all those decades of aspirin therapy in the hopes of making ourselves healthier,” added Dr. O’Gara, professor of medicine at Harvard Medical School, Boston, and a past president of the American College of Cardiology.

He cited the results of three placebo-controlled randomized trials totaling more than 47,000 patients without known cardiovascular disease: ARRIVE, published in late September 2018, followed in October by ASPREE and ASCEND.

• ARRIVE. This double-blind study conducted in seven countries included 12,546 patients deemed at moderate cardiovascular risk, with an estimated 10-year cardiovascular event risk of 17%. Eligibility was restricted to men aged 55 and up and women aged 60 or older. After a median follow-up of 5 years, there was no difference between patients assigned to enteric-coated aspirin at 100 mg/day versus placebo in the incidence of major adverse cardiovascular events, with a hazard ratio of 0.96. However, GI bleeding events were 2.1-fold more common in the aspirin group (Lancet. 2018 Sep 22;392[10152]:1036-46).

• ASPREE. This double-blind trial, conducted in Australia and the United States, included 19,114 community-dwelling participants aged 70 years or older, or 65 years or older for Hispanics and blacks in the United States. After a median 4.7 years of follow-up, there was no difference in major adverse cardiovascular events between subjects randomized to 100 mg/day of enteric-coated aspirin and those on placebo. So, as in ARRIVE, no benefit. However, the rate of major hemorrhage was 38% greater in the aspirin group (N Engl J Med. 2018 Oct 18;379[16]:1509-18).

Moreover, the rate of all-cause mortality was 14% greater in the aspirin group, a statistically significant difference, compared with controls. Drilling down, the investigators showed that the major contributor to this excess mortality in the aspirin group was their 31% greater rate of cancer-related death (N Engl J Med. 2018 Oct 18;379[16]:1519-28).

“Remember, we used to think that taking aspirin reduced the incidence of GI cancer, and, in particular, colon adenocarcinoma? Well, here’s a very startling observation in 19,114 healthy elderly patients showing an increase in cancer-associated death with the use of aspirin,” commented Dr. O’Gara.

• ASCEND. This study randomized 15,480 subjects with diabetes but no known cardiovascular disease to 100 mg/day of aspirin or placebo and followed them for a mean of 7.4 years. There was a significant 12% relative risk reduction in the composite endpoint of serious vascular events in the aspirin group; however, the aspirin-treated patients also had a 29% greater rate of major bleeding events (N Engl J Med. 2018 Oct 18;379[16]:1529-39).

“So in dealing with our diabetic patients, we could perhaps say there is a small reduction in the risk of cardiovascular outcomes that is overwhelmed by more than a factor of two with regard to an increase in the risk of bleeding,” the cardiologist observed.

How did physicians get the aspirin story for primary prevention so wrong for so long? Dr. O’Gara pointed to the Physicians’ Health Study, conducted mainly back in the 1970s, as one of the benchmark studies that led to the widespread use of aspirin in this way.

“I think the aspirin story has now been put into sharp focus just within the course of the last 6 months and should force all of us to reassess what it is that we advise patients,” he concluded.

Dr. O’Gara’s presentation was the talk of the meeting, as many attendees hadn’t yet caught up with the latest aspirin data.

During an Q&A session, Robert A. Vogel, MD, a preventive cardiology authority at the University of Colorado, Denver, was asked, given the new emphasis placed upon coronary artery calcium as a supplemental risk assessment tool in the latest guidelines, at what magnitude of coronary artery calcium score in a patient with no history of coronary disease he would give aspirin for secondary prevention.

“I know I don’t know the answer to that question,” Dr. Vogel replied. “I no longer reflexively give aspirin to, say, a 60-year-old with a calcium score of 200. I will give a statin. Statins in my book are so effective and safe that my threshold for giving a statin in a 60-year-old is virtually nothing. But with a calcium score of 2,000 or 5,000, I worry just like you worry.”

He noted that the primary prevention patients in the three recent major trials were mostly 60-70 years of age or older. It’s safe to assume that by that point in life many of them had silent atherosclerosis and would have had a non-zero coronary artery calcium score, had they been tested. And yet, aspirin didn’t provide any net benefit in those groups, unlike the drug’s rock-solid proven value in patients who have actually experienced a cardiovascular event.

Dr. O’Gara reported receiving funding from the National Heart, Lung and Blood Institute, the National Institute of Dental and Craniofacial Research, from Medtronic in conjunction with the ongoing pivotal APOLLO transcatheter mitral valve replacement trial, and from Edwards Lifesciences for the ongoing EARLY TAVR trial.

bjancin@mdedge.com

This article was updated 1/31/19.

SNOWMASS, COLO. – The decades-long belief that aspirin is beneficial for primary prevention of cardiovascular events was utterly dashed by three major randomized clinical trials during the space of a few short weeks in autumn 2018.

“Is aspirin safe and effective for primary prevention? The short answer here is no,” Patrick T. O’Gara, MD, declared at the annual Cardiovascular Conference at Snowmass sponsored by the American College of Cardiology.

“Think of all those decades of aspirin therapy in the hopes of making ourselves healthier,” added Dr. O’Gara, professor of medicine at Harvard Medical School, Boston, and a past president of the American College of Cardiology.

He cited the results of three placebo-controlled randomized trials totaling more than 47,000 patients without known cardiovascular disease: ARRIVE, published in late September 2018, followed in October by ASPREE and ASCEND.

• ARRIVE. This double-blind study conducted in seven countries included 12,546 patients deemed at moderate cardiovascular risk, with an estimated 10-year cardiovascular event risk of 17%. Eligibility was restricted to men aged 55 and up and women aged 60 or older. After a median follow-up of 5 years, there was no difference between patients assigned to enteric-coated aspirin at 100 mg/day versus placebo in the incidence of major adverse cardiovascular events, with a hazard ratio of 0.96. However, GI bleeding events were 2.1-fold more common in the aspirin group (Lancet. 2018 Sep 22;392[10152]:1036-46).

• ASPREE. This double-blind trial, conducted in Australia and the United States, included 19,114 community-dwelling participants aged 70 years or older, or 65 years or older for Hispanics and blacks in the United States. After a median 4.7 years of follow-up, there was no difference in major adverse cardiovascular events between subjects randomized to 100 mg/day of enteric-coated aspirin and those on placebo. So, as in ARRIVE, no benefit. However, the rate of major hemorrhage was 38% greater in the aspirin group (N Engl J Med. 2018 Oct 18;379[16]:1509-18).

Moreover, the rate of all-cause mortality was 14% greater in the aspirin group, a statistically significant difference, compared with controls. Drilling down, the investigators showed that the major contributor to this excess mortality in the aspirin group was their 31% greater rate of cancer-related death (N Engl J Med. 2018 Oct 18;379[16]:1519-28).

“Remember, we used to think that taking aspirin reduced the incidence of GI cancer, and, in particular, colon adenocarcinoma? Well, here’s a very startling observation in 19,114 healthy elderly patients showing an increase in cancer-associated death with the use of aspirin,” commented Dr. O’Gara.

• ASCEND. This study randomized 15,480 subjects with diabetes but no known cardiovascular disease to 100 mg/day of aspirin or placebo and followed them for a mean of 7.4 years. There was a significant 12% relative risk reduction in the composite endpoint of serious vascular events in the aspirin group; however, the aspirin-treated patients also had a 29% greater rate of major bleeding events (N Engl J Med. 2018 Oct 18;379[16]:1529-39).

“So in dealing with our diabetic patients, we could perhaps say there is a small reduction in the risk of cardiovascular outcomes that is overwhelmed by more than a factor of two with regard to an increase in the risk of bleeding,” the cardiologist observed.

How did physicians get the aspirin story for primary prevention so wrong for so long? Dr. O’Gara pointed to the Physicians’ Health Study, conducted mainly back in the 1970s, as one of the benchmark studies that led to the widespread use of aspirin in this way.

“I think the aspirin story has now been put into sharp focus just within the course of the last 6 months and should force all of us to reassess what it is that we advise patients,” he concluded.

Dr. O’Gara’s presentation was the talk of the meeting, as many attendees hadn’t yet caught up with the latest aspirin data.

During an Q&A session, Robert A. Vogel, MD, a preventive cardiology authority at the University of Colorado, Denver, was asked, given the new emphasis placed upon coronary artery calcium as a supplemental risk assessment tool in the latest guidelines, at what magnitude of coronary artery calcium score in a patient with no history of coronary disease he would give aspirin for secondary prevention.

“I know I don’t know the answer to that question,” Dr. Vogel replied. “I no longer reflexively give aspirin to, say, a 60-year-old with a calcium score of 200. I will give a statin. Statins in my book are so effective and safe that my threshold for giving a statin in a 60-year-old is virtually nothing. But with a calcium score of 2,000 or 5,000, I worry just like you worry.”

He noted that the primary prevention patients in the three recent major trials were mostly 60-70 years of age or older. It’s safe to assume that by that point in life many of them had silent atherosclerosis and would have had a non-zero coronary artery calcium score, had they been tested. And yet, aspirin didn’t provide any net benefit in those groups, unlike the drug’s rock-solid proven value in patients who have actually experienced a cardiovascular event.

Dr. O’Gara reported receiving funding from the National Heart, Lung and Blood Institute, the National Institute of Dental and Craniofacial Research, from Medtronic in conjunction with the ongoing pivotal APOLLO transcatheter mitral valve replacement trial, and from Edwards Lifesciences for the ongoing EARLY TAVR trial.

bjancin@mdedge.com

This article was updated 1/31/19.

SNOWMASS, COLO. – The decades-long belief that aspirin is beneficial for primary prevention of cardiovascular events was utterly dashed by three major randomized clinical trials during the space of a few short weeks in autumn 2018.

“Is aspirin safe and effective for primary prevention? The short answer here is no,” Patrick T. O’Gara, MD, declared at the annual Cardiovascular Conference at Snowmass sponsored by the American College of Cardiology.

“Think of all those decades of aspirin therapy in the hopes of making ourselves healthier,” added Dr. O’Gara, professor of medicine at Harvard Medical School, Boston, and a past president of the American College of Cardiology.

He cited the results of three placebo-controlled randomized trials totaling more than 47,000 patients without known cardiovascular disease: ARRIVE, published in late September 2018, followed in October by ASPREE and ASCEND.

• ARRIVE. This double-blind study conducted in seven countries included 12,546 patients deemed at moderate cardiovascular risk, with an estimated 10-year cardiovascular event risk of 17%. Eligibility was restricted to men aged 55 and up and women aged 60 or older. After a median follow-up of 5 years, there was no difference between patients assigned to enteric-coated aspirin at 100 mg/day versus placebo in the incidence of major adverse cardiovascular events, with a hazard ratio of 0.96. However, GI bleeding events were 2.1-fold more common in the aspirin group (Lancet. 2018 Sep 22;392[10152]:1036-46).

• ASPREE. This double-blind trial, conducted in Australia and the United States, included 19,114 community-dwelling participants aged 70 years or older, or 65 years or older for Hispanics and blacks in the United States. After a median 4.7 years of follow-up, there was no difference in major adverse cardiovascular events between subjects randomized to 100 mg/day of enteric-coated aspirin and those on placebo. So, as in ARRIVE, no benefit. However, the rate of major hemorrhage was 38% greater in the aspirin group (N Engl J Med. 2018 Oct 18;379[16]:1509-18).

Moreover, the rate of all-cause mortality was 14% greater in the aspirin group, a statistically significant difference, compared with controls. Drilling down, the investigators showed that the major contributor to this excess mortality in the aspirin group was their 31% greater rate of cancer-related death (N Engl J Med. 2018 Oct 18;379[16]:1519-28).

“Remember, we used to think that taking aspirin reduced the incidence of GI cancer, and, in particular, colon adenocarcinoma? Well, here’s a very startling observation in 19,114 healthy elderly patients showing an increase in cancer-associated death with the use of aspirin,” commented Dr. O’Gara.

• ASCEND. This study randomized 15,480 subjects with diabetes but no known cardiovascular disease to 100 mg/day of aspirin or placebo and followed them for a mean of 7.4 years. There was a significant 12% relative risk reduction in the composite endpoint of serious vascular events in the aspirin group; however, the aspirin-treated patients also had a 29% greater rate of major bleeding events (N Engl J Med. 2018 Oct 18;379[16]:1529-39).

“So in dealing with our diabetic patients, we could perhaps say there is a small reduction in the risk of cardiovascular outcomes that is overwhelmed by more than a factor of two with regard to an increase in the risk of bleeding,” the cardiologist observed.

How did physicians get the aspirin story for primary prevention so wrong for so long? Dr. O’Gara pointed to the Physicians’ Health Study, conducted mainly back in the 1970s, as one of the benchmark studies that led to the widespread use of aspirin in this way.

“I think the aspirin story has now been put into sharp focus just within the course of the last 6 months and should force all of us to reassess what it is that we advise patients,” he concluded.

Dr. O’Gara’s presentation was the talk of the meeting, as many attendees hadn’t yet caught up with the latest aspirin data.

During an Q&A session, Robert A. Vogel, MD, a preventive cardiology authority at the University of Colorado, Denver, was asked, given the new emphasis placed upon coronary artery calcium as a supplemental risk assessment tool in the latest guidelines, at what magnitude of coronary artery calcium score in a patient with no history of coronary disease he would give aspirin for secondary prevention.

“I know I don’t know the answer to that question,” Dr. Vogel replied. “I no longer reflexively give aspirin to, say, a 60-year-old with a calcium score of 200. I will give a statin. Statins in my book are so effective and safe that my threshold for giving a statin in a 60-year-old is virtually nothing. But with a calcium score of 2,000 or 5,000, I worry just like you worry.”

He noted that the primary prevention patients in the three recent major trials were mostly 60-70 years of age or older. It’s safe to assume that by that point in life many of them had silent atherosclerosis and would have had a non-zero coronary artery calcium score, had they been tested. And yet, aspirin didn’t provide any net benefit in those groups, unlike the drug’s rock-solid proven value in patients who have actually experienced a cardiovascular event.

Dr. O’Gara reported receiving funding from the National Heart, Lung and Blood Institute, the National Institute of Dental and Craniofacial Research, from Medtronic in conjunction with the ongoing pivotal APOLLO transcatheter mitral valve replacement trial, and from Edwards Lifesciences for the ongoing EARLY TAVR trial.

bjancin@mdedge.com

This article was updated 1/31/19.

The balance between medical research and the pharmaceutical world has always been unsettling. The recent spate of articles in the press reporting the large payments by industry to a number of highly paid medical staff of the Memorial Sloan Kettering Cancer Institute in New York has raised again the continuing issue around that relationship.

When large sums of money are paid to medical leaders for serving on advisory boards, it is reasonable to question whom are they representing: industry or medical science. These relationships are not limited to cancer hospitals and can be presumed to pertain to cardiology and other specialties. One need only look at the disclosure statements of contemporary published articles to become aware of the entanglement of science and industry.

There is little question that both industry and science need to interact to focus direct resources to appropriate targets. No one is better able to do that than well informed scientists working in their disease fields. Industry needs scientific input and scientists need the financial resources of industry. I have been able to see that relationship play out to achieve major impacts on heart disease. But corporate decisions also can be driven by market forces and not altruism. Drug and device research has been redirected or stopped as a result of decisions made by sales forces. At other times, drugs that have great potential in the laboratory have been shelved because of a lack of scientific leadership.


So where is the moral and ethical balance? Published disclosures by authors is not much more than a catharsis in the process where action is required. Medical advisory boards are critical for successful drug and device development. That exchange is crucial to move medical science forward, but the large sums of money raise appropriate questions of what is driving the discussion.

At a more grass roots level, the financial role of investigators and hospitals in clinical trials has raised some concern. Traditionally, the institution and investigators have been reimbursed for their time and expense for recruiting and following patients. Patients, of course, are not reimbursed in clinical trials but are placed at considerable risk of an uncertain result. The reimbursements for marginal expenses seem to be appropriate. More recently, payments to physicians and hospitals have been made at current fee schedules for the implantation of a variety of new devices such as pacemakers and valves. In addition, both physicians and hospitals have invested in the financial success of these clinical trials clouding over their altruistic goals. It has been an incentive for recruiting patients for trials and has been a source of considerable revenue both for the physicians and the institution, without informing the patients of their financial relationship to industry. The image of the patient being placed at risk for the success of a clinical trial of a device by doctors and hospitals seeking financial gain is more than a little disturbing.

There is a lot of money sloshing around in the health care world that has the potential to lead to ethical uncertainty. It is the physician’s responsibility to build up ethical barriers to prevent us from slipping into that morass.

Dr. Goldstein is professor of medicine at Wayne State University and the division head emeritus of cardiovascular medicine at Henry Ford Hospital, both in Detroit.

The balance between medical research and the pharmaceutical world has always been unsettling. The recent spate of articles in the press reporting the large payments by industry to a number of highly paid medical staff of the Memorial Sloan Kettering Cancer Institute in New York has raised again the continuing issue around that relationship.

When large sums of money are paid to medical leaders for serving on advisory boards, it is reasonable to question whom are they representing: industry or medical science. These relationships are not limited to cancer hospitals and can be presumed to pertain to cardiology and other specialties. One need only look at the disclosure statements of contemporary published articles to become aware of the entanglement of science and industry.

There is little question that both industry and science need to interact to focus direct resources to appropriate targets. No one is better able to do that than well informed scientists working in their disease fields. Industry needs scientific input and scientists need the financial resources of industry. I have been able to see that relationship play out to achieve major impacts on heart disease. But corporate decisions also can be driven by market forces and not altruism. Drug and device research has been redirected or stopped as a result of decisions made by sales forces. At other times, drugs that have great potential in the laboratory have been shelved because of a lack of scientific leadership.


So where is the moral and ethical balance? Published disclosures by authors is not much more than a catharsis in the process where action is required. Medical advisory boards are critical for successful drug and device development. That exchange is crucial to move medical science forward, but the large sums of money raise appropriate questions of what is driving the discussion.

At a more grass roots level, the financial role of investigators and hospitals in clinical trials has raised some concern. Traditionally, the institution and investigators have been reimbursed for their time and expense for recruiting and following patients. Patients, of course, are not reimbursed in clinical trials but are placed at considerable risk of an uncertain result. The reimbursements for marginal expenses seem to be appropriate. More recently, payments to physicians and hospitals have been made at current fee schedules for the implantation of a variety of new devices such as pacemakers and valves. In addition, both physicians and hospitals have invested in the financial success of these clinical trials clouding over their altruistic goals. It has been an incentive for recruiting patients for trials and has been a source of considerable revenue both for the physicians and the institution, without informing the patients of their financial relationship to industry. The image of the patient being placed at risk for the success of a clinical trial of a device by doctors and hospitals seeking financial gain is more than a little disturbing.

There is a lot of money sloshing around in the health care world that has the potential to lead to ethical uncertainty. It is the physician’s responsibility to build up ethical barriers to prevent us from slipping into that morass.

Dr. Goldstein is professor of medicine at Wayne State University and the division head emeritus of cardiovascular medicine at Henry Ford Hospital, both in Detroit.

The balance between medical research and the pharmaceutical world has always been unsettling. The recent spate of articles in the press reporting the large payments by industry to a number of highly paid medical staff of the Memorial Sloan Kettering Cancer Institute in New York has raised again the continuing issue around that relationship.

When large sums of money are paid to medical leaders for serving on advisory boards, it is reasonable to question whom are they representing: industry or medical science. These relationships are not limited to cancer hospitals and can be presumed to pertain to cardiology and other specialties. One need only look at the disclosure statements of contemporary published articles to become aware of the entanglement of science and industry.

There is little question that both industry and science need to interact to focus direct resources to appropriate targets. No one is better able to do that than well informed scientists working in their disease fields. Industry needs scientific input and scientists need the financial resources of industry. I have been able to see that relationship play out to achieve major impacts on heart disease. But corporate decisions also can be driven by market forces and not altruism. Drug and device research has been redirected or stopped as a result of decisions made by sales forces. At other times, drugs that have great potential in the laboratory have been shelved because of a lack of scientific leadership.


So where is the moral and ethical balance? Published disclosures by authors is not much more than a catharsis in the process where action is required. Medical advisory boards are critical for successful drug and device development. That exchange is crucial to move medical science forward, but the large sums of money raise appropriate questions of what is driving the discussion.

At a more grass roots level, the financial role of investigators and hospitals in clinical trials has raised some concern. Traditionally, the institution and investigators have been reimbursed for their time and expense for recruiting and following patients. Patients, of course, are not reimbursed in clinical trials but are placed at considerable risk of an uncertain result. The reimbursements for marginal expenses seem to be appropriate. More recently, payments to physicians and hospitals have been made at current fee schedules for the implantation of a variety of new devices such as pacemakers and valves. In addition, both physicians and hospitals have invested in the financial success of these clinical trials clouding over their altruistic goals. It has been an incentive for recruiting patients for trials and has been a source of considerable revenue both for the physicians and the institution, without informing the patients of their financial relationship to industry. The image of the patient being placed at risk for the success of a clinical trial of a device by doctors and hospitals seeking financial gain is more than a little disturbing.

There is a lot of money sloshing around in the health care world that has the potential to lead to ethical uncertainty. It is the physician’s responsibility to build up ethical barriers to prevent us from slipping into that morass.

Dr. Goldstein is professor of medicine at Wayne State University and the division head emeritus of cardiovascular medicine at Henry Ford Hospital, both in Detroit.

The first update to U.S. medical-society guidelines for managing atrial fibrillation since 2014 raised the threshold for starting anticoagulant therapy in women, pegged the direct-acting oral anticoagulants (DOACs) as preferred over warfarin, and introduced for the first time weight loss as an important intervention tool for treating patients with an atrial arrhythmia.

Mitchel L. Zoler/MDedge News

On January 28, the American College of Cardiology, American Heart Association, and Heart Rhythm Society posted online a 2019 focused update (Circulation. 2019 Jan 28. doi: 10.1161/CIR.0000000000000665) to the 2014 atrial fibrillation (AF) management guidelines that the groups had previously published (J Am Coll Cardiol. 2014 Dec 2;64[21]:2246-80).

Perhaps the two most important changes, as well as the two that lead off the new document, were a pair of class I recommendations on using oral anticoagulation in AF patients.

One of these updates reset the threshold for initiating oral anticoagulant therapy in women from 2 points on the CHA2DS2-VASc scale to 3 points, while leaving the threshold for men unchanged at 2 points. This brought U.S. guidelines in line with European guidelines, set by the European Society of Cardiology in 2016 (Eur Heart J. 2016 Oct 7;37[38]:2893-962). It will now also mean that, because of the way the CHA2DS2-VASc score is calculated, women with AF who are at least 65 years old will no longer automatically get flagged as needing oral anticoagulant therapy.

“This is a really important shift. It’s recognition that female sex is not as important a risk factor [for AF-associated stroke] as once was thought,” commented Hugh Calkins, MD, professor of medicine at Johns Hopkins Medicine in Baltimore and a member of the panel that wrote the update. “This will change the number of women with AF who go on anticoagulation,” predicted Dr. Calkins, who directs the cardiac arrhythmia service at his center. “We have been struggling with the notion that all women 65 or older with AF had to be on an anticoagulant. Now a clinician has more leeway. In general, patients with AF remain underanticoagulated, but this clarifies practice and brings us in line with the European guidelines.”

The second important change to the anticoagulation recommendations was to specify the DOACs as recommended over warfarin in AF patients eligible for oral anticoagulation and without moderate to severe mitral stenosis or a mechanical heart valve, which also matches the 2016 European guidelines and updates the prior, 2014, U.S. guidelines, which didn’t even mention DOACs.

Prescribing a DOAC preferentially to AF patients has already become routine among electrophysiologists, but possibly not as routine among primary care physicians, so this change has the potential to shift practice, said Dr. Calkins. But the higher price for DOACs, compared with warfarin, can pose problems. “The cost of DOACs remains an issue that can be a serious limitation to some patients,” said Craig T. January, MD, professor of medicine at the University of Wisconsin in Madison and chair of the guideline-writing panel. He also bemoaned the absence of head-to-head comparisons of individual DOACs that could inform selecting among apixaban, dabigatran, edoxaban, and rivaroxaban.

Another notable change in the 2019 update was inclusion for the first time of weight loss as a recommended intervention, along with other risk factor modification, an addition that Dr. Calkins called “long overdue.”

Mitchel L. Zoler/MDedge News

“This is a new recommendation, and it will potentially be important,” said Dr. January, although the guidelines do not spell out how aggressive clinicians should be about having patients achieve weight loss, how much loss patients should achieve, or how they should do it. “There are a lot of observational data and basic science data suggesting the importance of weight loss. Most electrophysiologists already address weight loss. The problem is how to get patients to do it,” commented Vivek Reddy, MD, professor of medicine and director of cardiac arrhythmia services at Mount Sinai Hospital in New York.

Dr. Reddy expressed surprise over two other features of the updated guidelines. For the first time, the guidelines now address percutaneous left atrial appendage (LAA) occlusion and say: “Percutaneous LAA occlusion may be considered in patients with AF at increased risk of stroke who have contraindications to long-term anticoagulation.” The guidelines’ text acknowledges that this runs counter to the Food and Drug Administration labeling for the Watchman LAA occlusion device, which restricts the device to patients “deemed suitable for long-term warfarin (mirroring the inclusion criteria for enrollment in the clinical trials) but had an appropriate rationale to seek a nonpharmacological alternative to warfarin.”

“We do not take a position on the FDA’s” actions, Dr. January said in an interview.

“The ACC, AHA, and HRS guidelines should reflect what the FDA decided,” Dr. Reddy said in an interview. “I’m a little surprised the guidelines said that anticoagulation had to be contraindicated.

The 2019 update also added a class IIb, “may be reasonable” recommendation for catheter ablation of AF in patients with heart failure with reduced ejection fraction.

“I think a IIb recommendation is unfair; I think it should be a IIa recommendation because there have been positive results from two large, randomized, multicenter trials – CASTLE-AF [Catheter Ablation vs. Standard Conventional Treatment in Patients With LV Dysfunction and AF; N Engl J Med. 2018 Feb 1;378(5):417-27] and AATAC [Ablation vs Amiodarone for Treatment of AFib in Patients With CHF and an ICD; Circulation. 2016 Apr 26;133(7):1637-44], as well as positive results from several smaller randomized studies,” Dr. Reddy said. “I’m really surprised” that the recommendation was not stronger.

Dr. Calkins has been a consultant to Abbott, Altathera, AtriCare, Boehringer-Ingelheim, King, Medtronic, and St. Jude and has received research funding from Boehringer-Ingelheim, Boston Scientific, and St. Jude. Dr. January had no disclosures. Dr. Reddy has been a consultant to, received research funding from, or has an equity interest in more than three dozen companies.

mzoler@mdedge.com

The first update to U.S. medical-society guidelines for managing atrial fibrillation since 2014 raised the threshold for starting anticoagulant therapy in women, pegged the direct-acting oral anticoagulants (DOACs) as preferred over warfarin, and introduced for the first time weight loss as an important intervention tool for treating patients with an atrial arrhythmia.

Mitchel L. Zoler/MDedge News

On January 28, the American College of Cardiology, American Heart Association, and Heart Rhythm Society posted online a 2019 focused update (Circulation. 2019 Jan 28. doi: 10.1161/CIR.0000000000000665) to the 2014 atrial fibrillation (AF) management guidelines that the groups had previously published (J Am Coll Cardiol. 2014 Dec 2;64[21]:2246-80).

Perhaps the two most important changes, as well as the two that lead off the new document, were a pair of class I recommendations on using oral anticoagulation in AF patients.

One of these updates reset the threshold for initiating oral anticoagulant therapy in women from 2 points on the CHA2DS2-VASc scale to 3 points, while leaving the threshold for men unchanged at 2 points. This brought U.S. guidelines in line with European guidelines, set by the European Society of Cardiology in 2016 (Eur Heart J. 2016 Oct 7;37[38]:2893-962). It will now also mean that, because of the way the CHA2DS2-VASc score is calculated, women with AF who are at least 65 years old will no longer automatically get flagged as needing oral anticoagulant therapy.

“This is a really important shift. It’s recognition that female sex is not as important a risk factor [for AF-associated stroke] as once was thought,” commented Hugh Calkins, MD, professor of medicine at Johns Hopkins Medicine in Baltimore and a member of the panel that wrote the update. “This will change the number of women with AF who go on anticoagulation,” predicted Dr. Calkins, who directs the cardiac arrhythmia service at his center. “We have been struggling with the notion that all women 65 or older with AF had to be on an anticoagulant. Now a clinician has more leeway. In general, patients with AF remain underanticoagulated, but this clarifies practice and brings us in line with the European guidelines.”

The second important change to the anticoagulation recommendations was to specify the DOACs as recommended over warfarin in AF patients eligible for oral anticoagulation and without moderate to severe mitral stenosis or a mechanical heart valve, which also matches the 2016 European guidelines and updates the prior, 2014, U.S. guidelines, which didn’t even mention DOACs.

Prescribing a DOAC preferentially to AF patients has already become routine among electrophysiologists, but possibly not as routine among primary care physicians, so this change has the potential to shift practice, said Dr. Calkins. But the higher price for DOACs, compared with warfarin, can pose problems. “The cost of DOACs remains an issue that can be a serious limitation to some patients,” said Craig T. January, MD, professor of medicine at the University of Wisconsin in Madison and chair of the guideline-writing panel. He also bemoaned the absence of head-to-head comparisons of individual DOACs that could inform selecting among apixaban, dabigatran, edoxaban, and rivaroxaban.

Another notable change in the 2019 update was inclusion for the first time of weight loss as a recommended intervention, along with other risk factor modification, an addition that Dr. Calkins called “long overdue.”

Mitchel L. Zoler/MDedge News

“This is a new recommendation, and it will potentially be important,” said Dr. January, although the guidelines do not spell out how aggressive clinicians should be about having patients achieve weight loss, how much loss patients should achieve, or how they should do it. “There are a lot of observational data and basic science data suggesting the importance of weight loss. Most electrophysiologists already address weight loss. The problem is how to get patients to do it,” commented Vivek Reddy, MD, professor of medicine and director of cardiac arrhythmia services at Mount Sinai Hospital in New York.

Dr. Reddy expressed surprise over two other features of the updated guidelines. For the first time, the guidelines now address percutaneous left atrial appendage (LAA) occlusion and say: “Percutaneous LAA occlusion may be considered in patients with AF at increased risk of stroke who have contraindications to long-term anticoagulation.” The guidelines’ text acknowledges that this runs counter to the Food and Drug Administration labeling for the Watchman LAA occlusion device, which restricts the device to patients “deemed suitable for long-term warfarin (mirroring the inclusion criteria for enrollment in the clinical trials) but had an appropriate rationale to seek a nonpharmacological alternative to warfarin.”

“We do not take a position on the FDA’s” actions, Dr. January said in an interview.

“The ACC, AHA, and HRS guidelines should reflect what the FDA decided,” Dr. Reddy said in an interview. “I’m a little surprised the guidelines said that anticoagulation had to be contraindicated.

The 2019 update also added a class IIb, “may be reasonable” recommendation for catheter ablation of AF in patients with heart failure with reduced ejection fraction.

“I think a IIb recommendation is unfair; I think it should be a IIa recommendation because there have been positive results from two large, randomized, multicenter trials – CASTLE-AF [Catheter Ablation vs. Standard Conventional Treatment in Patients With LV Dysfunction and AF; N Engl J Med. 2018 Feb 1;378(5):417-27] and AATAC [Ablation vs Amiodarone for Treatment of AFib in Patients With CHF and an ICD; Circulation. 2016 Apr 26;133(7):1637-44], as well as positive results from several smaller randomized studies,” Dr. Reddy said. “I’m really surprised” that the recommendation was not stronger.

Dr. Calkins has been a consultant to Abbott, Altathera, AtriCare, Boehringer-Ingelheim, King, Medtronic, and St. Jude and has received research funding from Boehringer-Ingelheim, Boston Scientific, and St. Jude. Dr. January had no disclosures. Dr. Reddy has been a consultant to, received research funding from, or has an equity interest in more than three dozen companies.

mzoler@mdedge.com

The first update to U.S. medical-society guidelines for managing atrial fibrillation since 2014 raised the threshold for starting anticoagulant therapy in women, pegged the direct-acting oral anticoagulants (DOACs) as preferred over warfarin, and introduced for the first time weight loss as an important intervention tool for treating patients with an atrial arrhythmia.

Mitchel L. Zoler/MDedge News

On January 28, the American College of Cardiology, American Heart Association, and Heart Rhythm Society posted online a 2019 focused update (Circulation. 2019 Jan 28. doi: 10.1161/CIR.0000000000000665) to the 2014 atrial fibrillation (AF) management guidelines that the groups had previously published (J Am Coll Cardiol. 2014 Dec 2;64[21]:2246-80).

Perhaps the two most important changes, as well as the two that lead off the new document, were a pair of class I recommendations on using oral anticoagulation in AF patients.

One of these updates reset the threshold for initiating oral anticoagulant therapy in women from 2 points on the CHA2DS2-VASc scale to 3 points, while leaving the threshold for men unchanged at 2 points. This brought U.S. guidelines in line with European guidelines, set by the European Society of Cardiology in 2016 (Eur Heart J. 2016 Oct 7;37[38]:2893-962). It will now also mean that, because of the way the CHA2DS2-VASc score is calculated, women with AF who are at least 65 years old will no longer automatically get flagged as needing oral anticoagulant therapy.

“This is a really important shift. It’s recognition that female sex is not as important a risk factor [for AF-associated stroke] as once was thought,” commented Hugh Calkins, MD, professor of medicine at Johns Hopkins Medicine in Baltimore and a member of the panel that wrote the update. “This will change the number of women with AF who go on anticoagulation,” predicted Dr. Calkins, who directs the cardiac arrhythmia service at his center. “We have been struggling with the notion that all women 65 or older with AF had to be on an anticoagulant. Now a clinician has more leeway. In general, patients with AF remain underanticoagulated, but this clarifies practice and brings us in line with the European guidelines.”

The second important change to the anticoagulation recommendations was to specify the DOACs as recommended over warfarin in AF patients eligible for oral anticoagulation and without moderate to severe mitral stenosis or a mechanical heart valve, which also matches the 2016 European guidelines and updates the prior, 2014, U.S. guidelines, which didn’t even mention DOACs.

Prescribing a DOAC preferentially to AF patients has already become routine among electrophysiologists, but possibly not as routine among primary care physicians, so this change has the potential to shift practice, said Dr. Calkins. But the higher price for DOACs, compared with warfarin, can pose problems. “The cost of DOACs remains an issue that can be a serious limitation to some patients,” said Craig T. January, MD, professor of medicine at the University of Wisconsin in Madison and chair of the guideline-writing panel. He also bemoaned the absence of head-to-head comparisons of individual DOACs that could inform selecting among apixaban, dabigatran, edoxaban, and rivaroxaban.

Another notable change in the 2019 update was inclusion for the first time of weight loss as a recommended intervention, along with other risk factor modification, an addition that Dr. Calkins called “long overdue.”

Mitchel L. Zoler/MDedge News

“This is a new recommendation, and it will potentially be important,” said Dr. January, although the guidelines do not spell out how aggressive clinicians should be about having patients achieve weight loss, how much loss patients should achieve, or how they should do it. “There are a lot of observational data and basic science data suggesting the importance of weight loss. Most electrophysiologists already address weight loss. The problem is how to get patients to do it,” commented Vivek Reddy, MD, professor of medicine and director of cardiac arrhythmia services at Mount Sinai Hospital in New York.

Dr. Reddy expressed surprise over two other features of the updated guidelines. For the first time, the guidelines now address percutaneous left atrial appendage (LAA) occlusion and say: “Percutaneous LAA occlusion may be considered in patients with AF at increased risk of stroke who have contraindications to long-term anticoagulation.” The guidelines’ text acknowledges that this runs counter to the Food and Drug Administration labeling for the Watchman LAA occlusion device, which restricts the device to patients “deemed suitable for long-term warfarin (mirroring the inclusion criteria for enrollment in the clinical trials) but had an appropriate rationale to seek a nonpharmacological alternative to warfarin.”

“We do not take a position on the FDA’s” actions, Dr. January said in an interview.

“The ACC, AHA, and HRS guidelines should reflect what the FDA decided,” Dr. Reddy said in an interview. “I’m a little surprised the guidelines said that anticoagulation had to be contraindicated.

The 2019 update also added a class IIb, “may be reasonable” recommendation for catheter ablation of AF in patients with heart failure with reduced ejection fraction.

“I think a IIb recommendation is unfair; I think it should be a IIa recommendation because there have been positive results from two large, randomized, multicenter trials – CASTLE-AF [Catheter Ablation vs. Standard Conventional Treatment in Patients With LV Dysfunction and AF; N Engl J Med. 2018 Feb 1;378(5):417-27] and AATAC [Ablation vs Amiodarone for Treatment of AFib in Patients With CHF and an ICD; Circulation. 2016 Apr 26;133(7):1637-44], as well as positive results from several smaller randomized studies,” Dr. Reddy said. “I’m really surprised” that the recommendation was not stronger.

Dr. Calkins has been a consultant to Abbott, Altathera, AtriCare, Boehringer-Ingelheim, King, Medtronic, and St. Jude and has received research funding from Boehringer-Ingelheim, Boston Scientific, and St. Jude. Dr. January had no disclosures. Dr. Reddy has been a consultant to, received research funding from, or has an equity interest in more than three dozen companies.

mzoler@mdedge.com

A new iteration of the SPRINT MIND hypertension trial will seek to prove conclusively the original study’s tantalizing suggestion: that intensive blood pressure control decreases the risk of developing mild cognitive impairment (MCI) and, eventually, dementia.

SPRINT MIND 2.0 will re-recruit SPRINT MIND subjects and enable another follow-up cognitive assessment and other clinical tests as they remain on their standard of care blood pressure regimen. It is largely funded by an $800,000 grant from the Alzheimer’s Association.

Initially released last July at the Alzheimer’s Association International Conference, the results of the SPRINT MIND have now appeared online in JAMA. Although it failed to meet its primary endpoint of reducing dementia incidence, the study did score on two secondary endpoints. Patients who reduced their systolic blood pressure to less than 120 mm Hg were 19% less likely to develop MCI and 17% less likely to be diagnosed with all-cause dementia than were those who achieved a hypertension target of less than 140 mm Hg.

The secondary results, and positive movement in the primary results, sparked excitement in the dementia research community last summer. They have suggested that the median 5-year follow-up just wasn’t long enough to show any significant effects on dementia, which can take years to fully manifest. Adding 2 more years with SPRINT MIND 2.0 should be long enough to discern those benefits, if indeed they exist.

“SPRINT MIND 2.0 and the work leading up to it offers genuine, concrete hope,” Maria C. Carrillo, PhD, chief science officer for the Alzheimer’s Association, said in a press statement. “MCI is a known risk factor for dementia, and everyone who experiences dementia passes through MCI. When you prevent new cases of MCI, you are preventing new cases of dementia. The Alzheimer’s Association finds these data to be compelling and is committed to getting clarity and certainty on the dementia outcome by following participants for a longer period of time.”

The study strengthens the new and energetic push to find ways to prevent dementia, which has proven itself intractable in every drug study to date.

“This study is in line with where the field of dementia research is going: preventing memory loss earlier,” said Laurie Ryan, PhD, chief of the dementias of aging branch in the National Institute on Aging. “Much like we have research-based interventions for heart health and cancer prevention, we hope to have guidance based on this and subsequent studies that will more definitively show how to slow or even stop dementia well before symptoms appear.”

NIA director Richard J. Hodes, MD, agreed.

“Dementia continues to be a large public health challenge, and based on the primary results of this study, we still have yet to find an intervention strategy proven to reduce the risk of dementia,” he said in a press statement. “Nevertheless, the secondary results showing that intensive lowering of blood pressure may reduce risk for MCI, a known risk factor for dementia, gives us additional avenues to explore on the path to prevention.”

SPRINT MIND was a substudy of the Systolic Blood Pressure Intervention Trial (SPRINT). It compared two strategies for managing hypertension in older adults. The intensive strategy had a target of less than 120 mm Hg, while standard care had a target of less than 140 mm Hg. SPRINT showed that more intensive blood pressure control produced a 25% reduction in the composite primary composite endpoint of cardiovascular events, stroke, and cardiovascular death. The intensive arm was so successful that SPRINT helped inform the 2017 high blood pressure clinical guidelines from the American Heart Association and American College of Cardiology.

Michelle Sullivan/MDedge News

The SPRINT MIND substudy, headed by Jeff D. Williamson, MD, of Wake Forest University, Winston-Salem, NC, asked whether intensive management had any effect on probable all-cause dementia or MCI, as well as imaging evidence of changes in white matter lesions and brain volume. It followed patients for up to 7 years and comprised 9,361 SPRINT subjects at least 50 years old (mean, 68 years) with at least one cardiovascular risk factor. Nearly a third (30%) were black, and 10% Hispanic. The primary outcome was incident probable dementia. Secondary outcomes were MCI and a composite of MCI and/or probable dementia. About a third had a SBP of 132 mm Hg or less, another third had a systolic pressure of 132-145 mm Hg, and the remainder had a systolic pressure greater than 145 mm Hg.

Physicians could use their choice of antihypertensive treatments. The study protocol encouraged, but did not mandate, thiazide-type diuretics as a first-line agent, followed by loop diuretics and beta-adrenergic blockers. Chlorthalidone was encouraged as the primary thiazide-type diuretic, and amlodipine as the preferred calcium-channel blocker.

The interventions did successfully control blood pressure, with a significant difference between the treatment groups. The mean SBP was 121.6 mm Hg in the intensive therapy group and 134.8 mm Hg in the standard group – a statistically significant difference of 13.3 mm Hg.

Dementia developed in 149 in the aggressive control group and 176 in the standard group – a nonsignificant difference of 17% (hazard ratio, 0.83). MCI developed in 287 in the intensive group and 353 in the standard treatment group. This amounted to a statistically significant 19% reduction. There was also a significant 15% reduction in the composite outcome of MCI or probable dementia in favor of intensive treatment.

As evidenced by the Alzheimer’s Association grant, dementia researchers chose to focus on SPRINT MIND’s positive secondary endpoints. At the AAIC meeting, Dr. Williamson even suggested that antihypertensive medications could be seen as disease-modifying agents for cognitive decline. Data support his claim: No dementia intervention yet tested has approached this level of success.

“I think we can say this is the first disease-modifying strategy to reduce the risk of MCI,” Dr. Williamson said during a press briefing. And although the primary endpoint – the 17% relative risk reduction for probable all-cause dementia – didn’t meet statistical significance, “It’s comforting to see that the benefit went in the same direction and was of the same magnitude..”

msullivan@mdedge.com

SOURCE: Williamson JD et al. JAMA 2019 Jan 28. doi:10.1001/jama.2018.21442.

A new iteration of the SPRINT MIND hypertension trial will seek to prove conclusively the original study’s tantalizing suggestion: that intensive blood pressure control decreases the risk of developing mild cognitive impairment (MCI) and, eventually, dementia.

SPRINT MIND 2.0 will re-recruit SPRINT MIND subjects and enable another follow-up cognitive assessment and other clinical tests as they remain on their standard of care blood pressure regimen. It is largely funded by an $800,000 grant from the Alzheimer’s Association.

Initially released last July at the Alzheimer’s Association International Conference, the results of the SPRINT MIND have now appeared online in JAMA. Although it failed to meet its primary endpoint of reducing dementia incidence, the study did score on two secondary endpoints. Patients who reduced their systolic blood pressure to less than 120 mm Hg were 19% less likely to develop MCI and 17% less likely to be diagnosed with all-cause dementia than were those who achieved a hypertension target of less than 140 mm Hg.

The secondary results, and positive movement in the primary results, sparked excitement in the dementia research community last summer. They have suggested that the median 5-year follow-up just wasn’t long enough to show any significant effects on dementia, which can take years to fully manifest. Adding 2 more years with SPRINT MIND 2.0 should be long enough to discern those benefits, if indeed they exist.

“SPRINT MIND 2.0 and the work leading up to it offers genuine, concrete hope,” Maria C. Carrillo, PhD, chief science officer for the Alzheimer’s Association, said in a press statement. “MCI is a known risk factor for dementia, and everyone who experiences dementia passes through MCI. When you prevent new cases of MCI, you are preventing new cases of dementia. The Alzheimer’s Association finds these data to be compelling and is committed to getting clarity and certainty on the dementia outcome by following participants for a longer period of time.”

The study strengthens the new and energetic push to find ways to prevent dementia, which has proven itself intractable in every drug study to date.

“This study is in line with where the field of dementia research is going: preventing memory loss earlier,” said Laurie Ryan, PhD, chief of the dementias of aging branch in the National Institute on Aging. “Much like we have research-based interventions for heart health and cancer prevention, we hope to have guidance based on this and subsequent studies that will more definitively show how to slow or even stop dementia well before symptoms appear.”

NIA director Richard J. Hodes, MD, agreed.

“Dementia continues to be a large public health challenge, and based on the primary results of this study, we still have yet to find an intervention strategy proven to reduce the risk of dementia,” he said in a press statement. “Nevertheless, the secondary results showing that intensive lowering of blood pressure may reduce risk for MCI, a known risk factor for dementia, gives us additional avenues to explore on the path to prevention.”

SPRINT MIND was a substudy of the Systolic Blood Pressure Intervention Trial (SPRINT). It compared two strategies for managing hypertension in older adults. The intensive strategy had a target of less than 120 mm Hg, while standard care had a target of less than 140 mm Hg. SPRINT showed that more intensive blood pressure control produced a 25% reduction in the composite primary composite endpoint of cardiovascular events, stroke, and cardiovascular death. The intensive arm was so successful that SPRINT helped inform the 2017 high blood pressure clinical guidelines from the American Heart Association and American College of Cardiology.

Michelle Sullivan/MDedge News

The SPRINT MIND substudy, headed by Jeff D. Williamson, MD, of Wake Forest University, Winston-Salem, NC, asked whether intensive management had any effect on probable all-cause dementia or MCI, as well as imaging evidence of changes in white matter lesions and brain volume. It followed patients for up to 7 years and comprised 9,361 SPRINT subjects at least 50 years old (mean, 68 years) with at least one cardiovascular risk factor. Nearly a third (30%) were black, and 10% Hispanic. The primary outcome was incident probable dementia. Secondary outcomes were MCI and a composite of MCI and/or probable dementia. About a third had a SBP of 132 mm Hg or less, another third had a systolic pressure of 132-145 mm Hg, and the remainder had a systolic pressure greater than 145 mm Hg.

Physicians could use their choice of antihypertensive treatments. The study protocol encouraged, but did not mandate, thiazide-type diuretics as a first-line agent, followed by loop diuretics and beta-adrenergic blockers. Chlorthalidone was encouraged as the primary thiazide-type diuretic, and amlodipine as the preferred calcium-channel blocker.

The interventions did successfully control blood pressure, with a significant difference between the treatment groups. The mean SBP was 121.6 mm Hg in the intensive therapy group and 134.8 mm Hg in the standard group – a statistically significant difference of 13.3 mm Hg.

Dementia developed in 149 in the aggressive control group and 176 in the standard group – a nonsignificant difference of 17% (hazard ratio, 0.83). MCI developed in 287 in the intensive group and 353 in the standard treatment group. This amounted to a statistically significant 19% reduction. There was also a significant 15% reduction in the composite outcome of MCI or probable dementia in favor of intensive treatment.

As evidenced by the Alzheimer’s Association grant, dementia researchers chose to focus on SPRINT MIND’s positive secondary endpoints. At the AAIC meeting, Dr. Williamson even suggested that antihypertensive medications could be seen as disease-modifying agents for cognitive decline. Data support his claim: No dementia intervention yet tested has approached this level of success.

“I think we can say this is the first disease-modifying strategy to reduce the risk of MCI,” Dr. Williamson said during a press briefing. And although the primary endpoint – the 17% relative risk reduction for probable all-cause dementia – didn’t meet statistical significance, “It’s comforting to see that the benefit went in the same direction and was of the same magnitude..”

msullivan@mdedge.com

SOURCE: Williamson JD et al. JAMA 2019 Jan 28. doi:10.1001/jama.2018.21442.

A new iteration of the SPRINT MIND hypertension trial will seek to prove conclusively the original study’s tantalizing suggestion: that intensive blood pressure control decreases the risk of developing mild cognitive impairment (MCI) and, eventually, dementia.

SPRINT MIND 2.0 will re-recruit SPRINT MIND subjects and enable another follow-up cognitive assessment and other clinical tests as they remain on their standard of care blood pressure regimen. It is largely funded by an $800,000 grant from the Alzheimer’s Association.

Initially released last July at the Alzheimer’s Association International Conference, the results of the SPRINT MIND have now appeared online in JAMA. Although it failed to meet its primary endpoint of reducing dementia incidence, the study did score on two secondary endpoints. Patients who reduced their systolic blood pressure to less than 120 mm Hg were 19% less likely to develop MCI and 17% less likely to be diagnosed with all-cause dementia than were those who achieved a hypertension target of less than 140 mm Hg.

The secondary results, and positive movement in the primary results, sparked excitement in the dementia research community last summer. They have suggested that the median 5-year follow-up just wasn’t long enough to show any significant effects on dementia, which can take years to fully manifest. Adding 2 more years with SPRINT MIND 2.0 should be long enough to discern those benefits, if indeed they exist.

“SPRINT MIND 2.0 and the work leading up to it offers genuine, concrete hope,” Maria C. Carrillo, PhD, chief science officer for the Alzheimer’s Association, said in a press statement. “MCI is a known risk factor for dementia, and everyone who experiences dementia passes through MCI. When you prevent new cases of MCI, you are preventing new cases of dementia. The Alzheimer’s Association finds these data to be compelling and is committed to getting clarity and certainty on the dementia outcome by following participants for a longer period of time.”

The study strengthens the new and energetic push to find ways to prevent dementia, which has proven itself intractable in every drug study to date.

“This study is in line with where the field of dementia research is going: preventing memory loss earlier,” said Laurie Ryan, PhD, chief of the dementias of aging branch in the National Institute on Aging. “Much like we have research-based interventions for heart health and cancer prevention, we hope to have guidance based on this and subsequent studies that will more definitively show how to slow or even stop dementia well before symptoms appear.”

NIA director Richard J. Hodes, MD, agreed.

“Dementia continues to be a large public health challenge, and based on the primary results of this study, we still have yet to find an intervention strategy proven to reduce the risk of dementia,” he said in a press statement. “Nevertheless, the secondary results showing that intensive lowering of blood pressure may reduce risk for MCI, a known risk factor for dementia, gives us additional avenues to explore on the path to prevention.”

SPRINT MIND was a substudy of the Systolic Blood Pressure Intervention Trial (SPRINT). It compared two strategies for managing hypertension in older adults. The intensive strategy had a target of less than 120 mm Hg, while standard care had a target of less than 140 mm Hg. SPRINT showed that more intensive blood pressure control produced a 25% reduction in the composite primary composite endpoint of cardiovascular events, stroke, and cardiovascular death. The intensive arm was so successful that SPRINT helped inform the 2017 high blood pressure clinical guidelines from the American Heart Association and American College of Cardiology.

Michelle Sullivan/MDedge News

The SPRINT MIND substudy, headed by Jeff D. Williamson, MD, of Wake Forest University, Winston-Salem, NC, asked whether intensive management had any effect on probable all-cause dementia or MCI, as well as imaging evidence of changes in white matter lesions and brain volume. It followed patients for up to 7 years and comprised 9,361 SPRINT subjects at least 50 years old (mean, 68 years) with at least one cardiovascular risk factor. Nearly a third (30%) were black, and 10% Hispanic. The primary outcome was incident probable dementia. Secondary outcomes were MCI and a composite of MCI and/or probable dementia. About a third had a SBP of 132 mm Hg or less, another third had a systolic pressure of 132-145 mm Hg, and the remainder had a systolic pressure greater than 145 mm Hg.

Physicians could use their choice of antihypertensive treatments. The study protocol encouraged, but did not mandate, thiazide-type diuretics as a first-line agent, followed by loop diuretics and beta-adrenergic blockers. Chlorthalidone was encouraged as the primary thiazide-type diuretic, and amlodipine as the preferred calcium-channel blocker.

The interventions did successfully control blood pressure, with a significant difference between the treatment groups. The mean SBP was 121.6 mm Hg in the intensive therapy group and 134.8 mm Hg in the standard group – a statistically significant difference of 13.3 mm Hg.

Dementia developed in 149 in the aggressive control group and 176 in the standard group – a nonsignificant difference of 17% (hazard ratio, 0.83). MCI developed in 287 in the intensive group and 353 in the standard treatment group. This amounted to a statistically significant 19% reduction. There was also a significant 15% reduction in the composite outcome of MCI or probable dementia in favor of intensive treatment.

As evidenced by the Alzheimer’s Association grant, dementia researchers chose to focus on SPRINT MIND’s positive secondary endpoints. At the AAIC meeting, Dr. Williamson even suggested that antihypertensive medications could be seen as disease-modifying agents for cognitive decline. Data support his claim: No dementia intervention yet tested has approached this level of success.

“I think we can say this is the first disease-modifying strategy to reduce the risk of MCI,” Dr. Williamson said during a press briefing. And although the primary endpoint – the 17% relative risk reduction for probable all-cause dementia – didn’t meet statistical significance, “It’s comforting to see that the benefit went in the same direction and was of the same magnitude..”

msullivan@mdedge.com

SOURCE: Williamson JD et al. JAMA 2019 Jan 28. doi:10.1001/jama.2018.21442.

SNOWMASS, COLO. – Appropriate counseling before making a referral for atrial fibrillation ablation entails helping the patient understand what can realistically be expected in the way of benefit, along with instilling awareness of the warning signals heralding serious late complications, Samuel J. Asirvatham, MD, said at the annual Cardiovascular Conference at Snowmass sponsored by the American College of Cardiology.

“Who to steer toward ablation? You have to have a symptomatic patient – that’s a given. For the ones who are paroxysmal, the ones with a relatively normal heart, there’s a much better chance that you’ll help manage their symptoms with ablation than if they have persistent or permanent A-fib. Notice I do not use the word ‘cure’ for A-fib. We talk about controlling symptoms and decreasing frequency, because the longer follow-up you have with intensive monitoring, the more you realize that patients still tend to have some A-fib,” explained Dr. Asirvatham, an electrophysiologist who is professor of medicine and pediatrics at the Mayo Clinic in Rochester, Minn.

The rationale for early atrial fibrillation (AF) ablation in younger patients with troublesome symptoms of paroxysmal AF despite pharmacologic attempts at rate or rhythm control is that it will arrest the progression from an atrial arrhythmia that has just a few triggers readily neutralized by pulmonary vein isolation to persistent AF with a diseased heart and a multitude of arrhythmia trigger points coming from many directions.


A solid candidate for ablation of paroxysmal AF has about a 75% likelihood of having a successful first ablation procedure, with substantial improvement in symptoms and no need for medication. Another 9%-10% will achieve marked reduction in symptom burden upon addition of antiarrhythmic agents that weren’t effective before ablation.

Late complications can be deceptive

Periprocedural stroke/transient ischemic attack, tamponade, or bleeding on the table are infrequent complications readily recognized by the interventionalist. More problematic are several late complications which are often misinterpreted, with the resultant delay causing major harm.

• Pulmonary vein stenosis. This complication of inadvertent ablation inside the pulmonary vein manifests as shortness of breath, typically beginning about 4 weeks post ablation.

“This is very different from the shortness of breath they had with atrial fibrillation. They almost always have a cough that they didn’t have before, and they may have hemoptysis. It’s very important to recognize this promptly, because before it closes completely we can do an angioplasty and stent the vein with good results. But once it closes completely, it becomes an extremely complicated procedure to try to reopen that vein,” according to Dr. Asirvatham.

Very often the patient’s general cardiologist, chest physician, or primary care physician fails to recognize what’s happening. He cited an example: He recently had a patient with a cough who was first referred to an infectious disease specialist, who ordered a bronchoalveolar lavage. The specimen grew atypical actinomycetes. That prompted a referral to thoracic surgery for an open-lung biopsy. But that procedure required cardiac clearance beforehand. It was a cardiologist who said, ‘Wait – all this started after you had an ablation?’

“That patient had pulmonary vein stenosis. And, unfortunately, that complication has not gone away. Being a referral center for pulmonary vein isolation, we see just as many cases of pulmonary vein stenosis today as we did a few years ago,” he said.

• Atrial esophageal fistula. The hallmark of this complication is onset of a plethora of what Dr. Asirvatham called “funny symptoms” more than a month post ablation. These include fever, transient ischemic attacks (TIAs), sepsislike symptoms, discomfort in swallowing, and in some cases hemoptysis.

“The predominant picture is endocarditis/TIA/stroke. If you see this, and the patient has had ablation, immediately refer to surgery to have the fistula between the esophagus and heart fixed. This is not a patient where you say, ‘Nothing by mouth, give some antibiotics, and see what happens.’ I can tell you what will happen: The patient will die,” the cardiologist said.

• Atrial stiffness. This typically occurs about a month after a second or third ablation procedure, when the patient develops shortness of breath that keeps worsening.

“You think ‘pulmonary vein stenosis,’ but the CT scan shows the veins are wide open. Many of these patients will get misdiagnosed as having heart failure with preserved ejection fraction even though they never had it before. The problem here is the atrium has become too stiff from the ablation, and this stiff atrium causes increased pressure, resulting in the shortness of breath. Sometimes patients feel better over time, but sometimes it’s very difficult to treat. But it’s important to recognize atrial stiffness and exclude other causes like pulmonary vein stenosis,” Dr. Asirvatham continued.

• Gastroparesis. This occurs because of injury to the vagus nerve branches located at the top of the esophagus, with resultant delayed gastric emptying.

“It’s an uncomfortable feeling of fullness all the time. The patient will say, ‘It seems like I just ate, even though I ate 8 hours ago,” the electrophysiologist said. “Most of these patients will recover in about 6 months. They may feel better on a gastric motility agent, like a macrolide antibiotic. I personally have not seen a patient who did not feel better within 6-8 months.”
 

Novel treatment approaches: “A-fib may be an autonomic epilepsy of the heart”

“Patients sometimes will ask you, ‘What is this ablation? What does that mean?’ You have to be truthful and tell them that it’s just a fancy word for burning,” the electrophysiologist said.

Achievement of AF ablation without radiofrequency or cryoablation, instead utilizing nonthermal direct-current pulsed electrical fields, is “the hottest topic in the field of electrophysiology,” according to Dr. Asirvatham.

These electrical fields result in irreversible electroporation of targeted myocardial cell membranes, leading to cell death. It is a tissue-specific intervention, so it’s much less likely than conventional ablation to cause collateral damage to the esophagus and other structures.

“Direct current electroporation has transitioned from proof-of-concept studies to three relatively large patient trials. This is potentially an important breakthrough because if we don’t heat, a lot of the complications of A-fib ablation will probably decrease,” he explained.

Two other promising outside-the-box approaches to the treatment of AF are autonomic nervous system modulation at sites distant from the heart and particle beam ablation without need for cardiac catheters.

“If you put electrodes everywhere in the body to see where A-fib starts, it’s not in the atrium, not in the pulmonary veins, it’s in the nerves behind the pulmonary veins, and before those nerves it’s in some other area of the autonomic nervous system. This has given rise to the notion that A-fib may be an autonomic epilepsy of the heart,” according to the electrophysiologist.

This concept has given rise to a completely different approach to treatment of AF through neurostimulation. That’s how acupuncture works. Also, headphones have been used successfully to terminate and prevent AF by stimulating autonomic nerve centers near the ears. Low-level electrical stimulation of the vagus nerve in order to reduce stellate ganglion activity is under study. So is the application of botulinum toxin at key points in the autonomic nervous system.

“Catheters, drugs, and devices that target these areas, maybe without any ablation in the heart itself, is an exciting area of future management of A-fib,” he said.

Another promising approach is borrowed from radiation oncology: particulate ablation using beams of carbon atoms, protons, or photons.

“The first patients have now been treated for ventricular tachycardia and A-fib. It really is quite amazing how precise the lesion formation is. And with no catheters in the heart, clot can’t form on catheters,” he observed.

Dr. Asirvatham reported having no financial conflicts regarding his presentation, although he serves as a consultant to a handful of medical startup companies and holds patents on intellectual property, the royalties for which go directly to the Mayo Clinic.

bjancin@mdedge.com

SNOWMASS, COLO. – Appropriate counseling before making a referral for atrial fibrillation ablation entails helping the patient understand what can realistically be expected in the way of benefit, along with instilling awareness of the warning signals heralding serious late complications, Samuel J. Asirvatham, MD, said at the annual Cardiovascular Conference at Snowmass sponsored by the American College of Cardiology.

“Who to steer toward ablation? You have to have a symptomatic patient – that’s a given. For the ones who are paroxysmal, the ones with a relatively normal heart, there’s a much better chance that you’ll help manage their symptoms with ablation than if they have persistent or permanent A-fib. Notice I do not use the word ‘cure’ for A-fib. We talk about controlling symptoms and decreasing frequency, because the longer follow-up you have with intensive monitoring, the more you realize that patients still tend to have some A-fib,” explained Dr. Asirvatham, an electrophysiologist who is professor of medicine and pediatrics at the Mayo Clinic in Rochester, Minn.

The rationale for early atrial fibrillation (AF) ablation in younger patients with troublesome symptoms of paroxysmal AF despite pharmacologic attempts at rate or rhythm control is that it will arrest the progression from an atrial arrhythmia that has just a few triggers readily neutralized by pulmonary vein isolation to persistent AF with a diseased heart and a multitude of arrhythmia trigger points coming from many directions.


A solid candidate for ablation of paroxysmal AF has about a 75% likelihood of having a successful first ablation procedure, with substantial improvement in symptoms and no need for medication. Another 9%-10% will achieve marked reduction in symptom burden upon addition of antiarrhythmic agents that weren’t effective before ablation.

Late complications can be deceptive

Periprocedural stroke/transient ischemic attack, tamponade, or bleeding on the table are infrequent complications readily recognized by the interventionalist. More problematic are several late complications which are often misinterpreted, with the resultant delay causing major harm.

• Pulmonary vein stenosis. This complication of inadvertent ablation inside the pulmonary vein manifests as shortness of breath, typically beginning about 4 weeks post ablation.

“This is very different from the shortness of breath they had with atrial fibrillation. They almost always have a cough that they didn’t have before, and they may have hemoptysis. It’s very important to recognize this promptly, because before it closes completely we can do an angioplasty and stent the vein with good results. But once it closes completely, it becomes an extremely complicated procedure to try to reopen that vein,” according to Dr. Asirvatham.

Very often the patient’s general cardiologist, chest physician, or primary care physician fails to recognize what’s happening. He cited an example: He recently had a patient with a cough who was first referred to an infectious disease specialist, who ordered a bronchoalveolar lavage. The specimen grew atypical actinomycetes. That prompted a referral to thoracic surgery for an open-lung biopsy. But that procedure required cardiac clearance beforehand. It was a cardiologist who said, ‘Wait – all this started after you had an ablation?’

“That patient had pulmonary vein stenosis. And, unfortunately, that complication has not gone away. Being a referral center for pulmonary vein isolation, we see just as many cases of pulmonary vein stenosis today as we did a few years ago,” he said.

• Atrial esophageal fistula. The hallmark of this complication is onset of a plethora of what Dr. Asirvatham called “funny symptoms” more than a month post ablation. These include fever, transient ischemic attacks (TIAs), sepsislike symptoms, discomfort in swallowing, and in some cases hemoptysis.

“The predominant picture is endocarditis/TIA/stroke. If you see this, and the patient has had ablation, immediately refer to surgery to have the fistula between the esophagus and heart fixed. This is not a patient where you say, ‘Nothing by mouth, give some antibiotics, and see what happens.’ I can tell you what will happen: The patient will die,” the cardiologist said.

• Atrial stiffness. This typically occurs about a month after a second or third ablation procedure, when the patient develops shortness of breath that keeps worsening.

“You think ‘pulmonary vein stenosis,’ but the CT scan shows the veins are wide open. Many of these patients will get misdiagnosed as having heart failure with preserved ejection fraction even though they never had it before. The problem here is the atrium has become too stiff from the ablation, and this stiff atrium causes increased pressure, resulting in the shortness of breath. Sometimes patients feel better over time, but sometimes it’s very difficult to treat. But it’s important to recognize atrial stiffness and exclude other causes like pulmonary vein stenosis,” Dr. Asirvatham continued.

• Gastroparesis. This occurs because of injury to the vagus nerve branches located at the top of the esophagus, with resultant delayed gastric emptying.

“It’s an uncomfortable feeling of fullness all the time. The patient will say, ‘It seems like I just ate, even though I ate 8 hours ago,” the electrophysiologist said. “Most of these patients will recover in about 6 months. They may feel better on a gastric motility agent, like a macrolide antibiotic. I personally have not seen a patient who did not feel better within 6-8 months.”
 

Novel treatment approaches: “A-fib may be an autonomic epilepsy of the heart”

“Patients sometimes will ask you, ‘What is this ablation? What does that mean?’ You have to be truthful and tell them that it’s just a fancy word for burning,” the electrophysiologist said.

Achievement of AF ablation without radiofrequency or cryoablation, instead utilizing nonthermal direct-current pulsed electrical fields, is “the hottest topic in the field of electrophysiology,” according to Dr. Asirvatham.

These electrical fields result in irreversible electroporation of targeted myocardial cell membranes, leading to cell death. It is a tissue-specific intervention, so it’s much less likely than conventional ablation to cause collateral damage to the esophagus and other structures.

“Direct current electroporation has transitioned from proof-of-concept studies to three relatively large patient trials. This is potentially an important breakthrough because if we don’t heat, a lot of the complications of A-fib ablation will probably decrease,” he explained.

Two other promising outside-the-box approaches to the treatment of AF are autonomic nervous system modulation at sites distant from the heart and particle beam ablation without need for cardiac catheters.

“If you put electrodes everywhere in the body to see where A-fib starts, it’s not in the atrium, not in the pulmonary veins, it’s in the nerves behind the pulmonary veins, and before those nerves it’s in some other area of the autonomic nervous system. This has given rise to the notion that A-fib may be an autonomic epilepsy of the heart,” according to the electrophysiologist.

This concept has given rise to a completely different approach to treatment of AF through neurostimulation. That’s how acupuncture works. Also, headphones have been used successfully to terminate and prevent AF by stimulating autonomic nerve centers near the ears. Low-level electrical stimulation of the vagus nerve in order to reduce stellate ganglion activity is under study. So is the application of botulinum toxin at key points in the autonomic nervous system.

“Catheters, drugs, and devices that target these areas, maybe without any ablation in the heart itself, is an exciting area of future management of A-fib,” he said.

Another promising approach is borrowed from radiation oncology: particulate ablation using beams of carbon atoms, protons, or photons.

“The first patients have now been treated for ventricular tachycardia and A-fib. It really is quite amazing how precise the lesion formation is. And with no catheters in the heart, clot can’t form on catheters,” he observed.

Dr. Asirvatham reported having no financial conflicts regarding his presentation, although he serves as a consultant to a handful of medical startup companies and holds patents on intellectual property, the royalties for which go directly to the Mayo Clinic.

bjancin@mdedge.com

SNOWMASS, COLO. – Appropriate counseling before making a referral for atrial fibrillation ablation entails helping the patient understand what can realistically be expected in the way of benefit, along with instilling awareness of the warning signals heralding serious late complications, Samuel J. Asirvatham, MD, said at the annual Cardiovascular Conference at Snowmass sponsored by the American College of Cardiology.

“Who to steer toward ablation? You have to have a symptomatic patient – that’s a given. For the ones who are paroxysmal, the ones with a relatively normal heart, there’s a much better chance that you’ll help manage their symptoms with ablation than if they have persistent or permanent A-fib. Notice I do not use the word ‘cure’ for A-fib. We talk about controlling symptoms and decreasing frequency, because the longer follow-up you have with intensive monitoring, the more you realize that patients still tend to have some A-fib,” explained Dr. Asirvatham, an electrophysiologist who is professor of medicine and pediatrics at the Mayo Clinic in Rochester, Minn.

The rationale for early atrial fibrillation (AF) ablation in younger patients with troublesome symptoms of paroxysmal AF despite pharmacologic attempts at rate or rhythm control is that it will arrest the progression from an atrial arrhythmia that has just a few triggers readily neutralized by pulmonary vein isolation to persistent AF with a diseased heart and a multitude of arrhythmia trigger points coming from many directions.


A solid candidate for ablation of paroxysmal AF has about a 75% likelihood of having a successful first ablation procedure, with substantial improvement in symptoms and no need for medication. Another 9%-10% will achieve marked reduction in symptom burden upon addition of antiarrhythmic agents that weren’t effective before ablation.

Late complications can be deceptive

Periprocedural stroke/transient ischemic attack, tamponade, or bleeding on the table are infrequent complications readily recognized by the interventionalist. More problematic are several late complications which are often misinterpreted, with the resultant delay causing major harm.

• Pulmonary vein stenosis. This complication of inadvertent ablation inside the pulmonary vein manifests as shortness of breath, typically beginning about 4 weeks post ablation.

“This is very different from the shortness of breath they had with atrial fibrillation. They almost always have a cough that they didn’t have before, and they may have hemoptysis. It’s very important to recognize this promptly, because before it closes completely we can do an angioplasty and stent the vein with good results. But once it closes completely, it becomes an extremely complicated procedure to try to reopen that vein,” according to Dr. Asirvatham.

Very often the patient’s general cardiologist, chest physician, or primary care physician fails to recognize what’s happening. He cited an example: He recently had a patient with a cough who was first referred to an infectious disease specialist, who ordered a bronchoalveolar lavage. The specimen grew atypical actinomycetes. That prompted a referral to thoracic surgery for an open-lung biopsy. But that procedure required cardiac clearance beforehand. It was a cardiologist who said, ‘Wait – all this started after you had an ablation?’

“That patient had pulmonary vein stenosis. And, unfortunately, that complication has not gone away. Being a referral center for pulmonary vein isolation, we see just as many cases of pulmonary vein stenosis today as we did a few years ago,” he said.

• Atrial esophageal fistula. The hallmark of this complication is onset of a plethora of what Dr. Asirvatham called “funny symptoms” more than a month post ablation. These include fever, transient ischemic attacks (TIAs), sepsislike symptoms, discomfort in swallowing, and in some cases hemoptysis.

“The predominant picture is endocarditis/TIA/stroke. If you see this, and the patient has had ablation, immediately refer to surgery to have the fistula between the esophagus and heart fixed. This is not a patient where you say, ‘Nothing by mouth, give some antibiotics, and see what happens.’ I can tell you what will happen: The patient will die,” the cardiologist said.

• Atrial stiffness. This typically occurs about a month after a second or third ablation procedure, when the patient develops shortness of breath that keeps worsening.

“You think ‘pulmonary vein stenosis,’ but the CT scan shows the veins are wide open. Many of these patients will get misdiagnosed as having heart failure with preserved ejection fraction even though they never had it before. The problem here is the atrium has become too stiff from the ablation, and this stiff atrium causes increased pressure, resulting in the shortness of breath. Sometimes patients feel better over time, but sometimes it’s very difficult to treat. But it’s important to recognize atrial stiffness and exclude other causes like pulmonary vein stenosis,” Dr. Asirvatham continued.

• Gastroparesis. This occurs because of injury to the vagus nerve branches located at the top of the esophagus, with resultant delayed gastric emptying.

“It’s an uncomfortable feeling of fullness all the time. The patient will say, ‘It seems like I just ate, even though I ate 8 hours ago,” the electrophysiologist said. “Most of these patients will recover in about 6 months. They may feel better on a gastric motility agent, like a macrolide antibiotic. I personally have not seen a patient who did not feel better within 6-8 months.”
 

Novel treatment approaches: “A-fib may be an autonomic epilepsy of the heart”

“Patients sometimes will ask you, ‘What is this ablation? What does that mean?’ You have to be truthful and tell them that it’s just a fancy word for burning,” the electrophysiologist said.

Achievement of AF ablation without radiofrequency or cryoablation, instead utilizing nonthermal direct-current pulsed electrical fields, is “the hottest topic in the field of electrophysiology,” according to Dr. Asirvatham.

These electrical fields result in irreversible electroporation of targeted myocardial cell membranes, leading to cell death. It is a tissue-specific intervention, so it’s much less likely than conventional ablation to cause collateral damage to the esophagus and other structures.

“Direct current electroporation has transitioned from proof-of-concept studies to three relatively large patient trials. This is potentially an important breakthrough because if we don’t heat, a lot of the complications of A-fib ablation will probably decrease,” he explained.

Two other promising outside-the-box approaches to the treatment of AF are autonomic nervous system modulation at sites distant from the heart and particle beam ablation without need for cardiac catheters.

“If you put electrodes everywhere in the body to see where A-fib starts, it’s not in the atrium, not in the pulmonary veins, it’s in the nerves behind the pulmonary veins, and before those nerves it’s in some other area of the autonomic nervous system. This has given rise to the notion that A-fib may be an autonomic epilepsy of the heart,” according to the electrophysiologist.

This concept has given rise to a completely different approach to treatment of AF through neurostimulation. That’s how acupuncture works. Also, headphones have been used successfully to terminate and prevent AF by stimulating autonomic nerve centers near the ears. Low-level electrical stimulation of the vagus nerve in order to reduce stellate ganglion activity is under study. So is the application of botulinum toxin at key points in the autonomic nervous system.

“Catheters, drugs, and devices that target these areas, maybe without any ablation in the heart itself, is an exciting area of future management of A-fib,” he said.

Another promising approach is borrowed from radiation oncology: particulate ablation using beams of carbon atoms, protons, or photons.

“The first patients have now been treated for ventricular tachycardia and A-fib. It really is quite amazing how precise the lesion formation is. And with no catheters in the heart, clot can’t form on catheters,” he observed.

Dr. Asirvatham reported having no financial conflicts regarding his presentation, although he serves as a consultant to a handful of medical startup companies and holds patents on intellectual property, the royalties for which go directly to the Mayo Clinic.

bjancin@mdedge.com

EVIDENCE SUMMARY

A 2017 network meta-analysis included 19 RCTs and 87,831 patients receiving anticoagulation, antiplatelet therapy, or LAAC for NVAF.¹ LAAC was superior to antiplatelet therapy (hazard ratio [HR]=0.44; 95% confidence interval [CI], 0.23-0.86; P<.05) and similar to NOACs (HR=1.01; 95% CI, 0.53-1.92; P=.969) for reducing risk of stroke.

LAAC and NOACs found “most effective”

A network meta-analysis of 21 RCTs, which included data from 96,017 patients, examined the effectiveness of 7 interventions to prevent stroke in patients with NVAF: 4 NOACs, VKA, aspirin, and LAAC; the analysis compared VKA with the other interventions.² The 2 trials that investigated LAAC accounted for only 1114 patients.

When the 7 interventions were ranked simultaneously on 2 efficacy outcomes (stroke/systemic embolism and all-cause mortality), all 4 NOACs and LAAC clustered together as “the most effective and lifesaving.”

Fewer hemorrhagic strokes with LAAC than VKA

A 2016 meta-analysis of 6 RCTs compared risk of stroke for adults with NVAF who received LAAC, VKA, or NOACs.³ No significant differences were found between NOACs and VKA or LAAC and VKA. The LAAC group had a significantly smaller number of patients.

A 2015 meta-analysis of 2406 patients with NVAF found that patients who received LAAC had significantly fewer hemorrhagic strokes (HR=0.22; P<.05) than patients who received VKA.⁴ No differences in all-cause stroke were found between the 2 groups during an average follow-up of 2.69 years.

LAAC found superior to warfarin for stroke prevention in one trial

A 2014 multicenter, randomized study (PROTECT-AF) of 707 patients with NVAF plus 1 additional stroke risk factor compared LAAC with VKA (warfarin).⁵ LAAC met criteria at 3.8 years for both noninferiority and superiority in preventing stroke, based on 2.3 events per 100 patient-years compared with 3.8 events per 100 patient-years for VKA. The number needed to treat with LAAC was 67 to result in 1 less event per patient-year.

A 2014 RCT (PREVAIL) evaluated patients with NVAF plus 1 additional stroke risk factor. LAAC was noninferior to warfarin for ischemic stroke prevention.⁶

Continue to: RECOMMENDATIONS

The American College of Cardiology (ACC) recommends LAAC for patients with NVAF who are not candidates for long-term anticoagulation.⁷ Similarly, the 2016 European Society of Cardiology guidelines issued a Class IIb recommendation for LAAC for stroke prevention in those with contraindications for long-term anticoagulation.⁸ Lastly, in a 2014 guideline, the American Heart Association, ACC, and the Heart Rhythm Society issued a Class IIb recommendation for surgical excision of the left atrial appendage in patients with atrial fibrillation undergoing cardiac surgery, but did not provide recommendations regarding LAAC.⁹

EVIDENCE SUMMARY

A 2017 network meta-analysis included 19 RCTs and 87,831 patients receiving anticoagulation, antiplatelet therapy, or LAAC for NVAF.¹ LAAC was superior to antiplatelet therapy (hazard ratio [HR]=0.44; 95% confidence interval [CI], 0.23-0.86; P<.05) and similar to NOACs (HR=1.01; 95% CI, 0.53-1.92; P=.969) for reducing risk of stroke.

LAAC and NOACs found “most effective”

A network meta-analysis of 21 RCTs, which included data from 96,017 patients, examined the effectiveness of 7 interventions to prevent stroke in patients with NVAF: 4 NOACs, VKA, aspirin, and LAAC; the analysis compared VKA with the other interventions.² The 2 trials that investigated LAAC accounted for only 1114 patients.

When the 7 interventions were ranked simultaneously on 2 efficacy outcomes (stroke/systemic embolism and all-cause mortality), all 4 NOACs and LAAC clustered together as “the most effective and lifesaving.”

Fewer hemorrhagic strokes with LAAC than VKA

A 2016 meta-analysis of 6 RCTs compared risk of stroke for adults with NVAF who received LAAC, VKA, or NOACs.³ No significant differences were found between NOACs and VKA or LAAC and VKA. The LAAC group had a significantly smaller number of patients.

A 2015 meta-analysis of 2406 patients with NVAF found that patients who received LAAC had significantly fewer hemorrhagic strokes (HR=0.22; P<.05) than patients who received VKA.⁴ No differences in all-cause stroke were found between the 2 groups during an average follow-up of 2.69 years.

LAAC found superior to warfarin for stroke prevention in one trial

A 2014 multicenter, randomized study (PROTECT-AF) of 707 patients with NVAF plus 1 additional stroke risk factor compared LAAC with VKA (warfarin).⁵ LAAC met criteria at 3.8 years for both noninferiority and superiority in preventing stroke, based on 2.3 events per 100 patient-years compared with 3.8 events per 100 patient-years for VKA. The number needed to treat with LAAC was 67 to result in 1 less event per patient-year.

A 2014 RCT (PREVAIL) evaluated patients with NVAF plus 1 additional stroke risk factor. LAAC was noninferior to warfarin for ischemic stroke prevention.⁶

Continue to: RECOMMENDATIONS

The American College of Cardiology (ACC) recommends LAAC for patients with NVAF who are not candidates for long-term anticoagulation.⁷ Similarly, the 2016 European Society of Cardiology guidelines issued a Class IIb recommendation for LAAC for stroke prevention in those with contraindications for long-term anticoagulation.⁸ Lastly, in a 2014 guideline, the American Heart Association, ACC, and the Heart Rhythm Society issued a Class IIb recommendation for surgical excision of the left atrial appendage in patients with atrial fibrillation undergoing cardiac surgery, but did not provide recommendations regarding LAAC.⁹

EVIDENCE SUMMARY

A 2017 network meta-analysis included 19 RCTs and 87,831 patients receiving anticoagulation, antiplatelet therapy, or LAAC for NVAF.¹ LAAC was superior to antiplatelet therapy (hazard ratio [HR]=0.44; 95% confidence interval [CI], 0.23-0.86; P<.05) and similar to NOACs (HR=1.01; 95% CI, 0.53-1.92; P=.969) for reducing risk of stroke.

LAAC and NOACs found “most effective”

A network meta-analysis of 21 RCTs, which included data from 96,017 patients, examined the effectiveness of 7 interventions to prevent stroke in patients with NVAF: 4 NOACs, VKA, aspirin, and LAAC; the analysis compared VKA with the other interventions.² The 2 trials that investigated LAAC accounted for only 1114 patients.

When the 7 interventions were ranked simultaneously on 2 efficacy outcomes (stroke/systemic embolism and all-cause mortality), all 4 NOACs and LAAC clustered together as “the most effective and lifesaving.”

Fewer hemorrhagic strokes with LAAC than VKA

A 2016 meta-analysis of 6 RCTs compared risk of stroke for adults with NVAF who received LAAC, VKA, or NOACs.³ No significant differences were found between NOACs and VKA or LAAC and VKA. The LAAC group had a significantly smaller number of patients.

A 2015 meta-analysis of 2406 patients with NVAF found that patients who received LAAC had significantly fewer hemorrhagic strokes (HR=0.22; P<.05) than patients who received VKA.⁴ No differences in all-cause stroke were found between the 2 groups during an average follow-up of 2.69 years.

LAAC found superior to warfarin for stroke prevention in one trial

A 2014 multicenter, randomized study (PROTECT-AF) of 707 patients with NVAF plus 1 additional stroke risk factor compared LAAC with VKA (warfarin).⁵ LAAC met criteria at 3.8 years for both noninferiority and superiority in preventing stroke, based on 2.3 events per 100 patient-years compared with 3.8 events per 100 patient-years for VKA. The number needed to treat with LAAC was 67 to result in 1 less event per patient-year.

A 2014 RCT (PREVAIL) evaluated patients with NVAF plus 1 additional stroke risk factor. LAAC was noninferior to warfarin for ischemic stroke prevention.⁶

Continue to: RECOMMENDATIONS

The American College of Cardiology (ACC) recommends LAAC for patients with NVAF who are not candidates for long-term anticoagulation.⁷ Similarly, the 2016 European Society of Cardiology guidelines issued a Class IIb recommendation for LAAC for stroke prevention in those with contraindications for long-term anticoagulation.⁸ Lastly, in a 2014 guideline, the American Heart Association, ACC, and the Heart Rhythm Society issued a Class IIb recommendation for surgical excision of the left atrial appendage in patients with atrial fibrillation undergoing cardiac surgery, but did not provide recommendations regarding LAAC.⁹