Michael D. Miedema

Implications of Coronary Artery Calcium Testing Among Statin Candidates According to American College of Cardiology/American Heart Association Cholesterol Management Guidelines: MESA (Multi-Ethnic Study of Atherosclerosis)

BACKGROUND The American College of Cardiology (ACC)/American Heart Association (AHA) cholesterol management guidelines have significantly broadened the scope of candidates eligible for statin therapy. OBJECTIVES This study evaluated the implications of the absence of coronary artery calcium (CAC) in reclassifying patients from a risk stratum in which statins are recommended to one in which they are not. METHODS MESA (Multi-Ethnic Study of Atherosclerosis) is a longitudinal study of 6,814 men and women 45 to 84 years of age without clinical atherosclerotic cardiovascular disease (ASCVD) risk at enrollment. We excluded 1,100 participants (16%) on lipid-lowering medication, 87 (1.3%) without low-density lipoprotein levels, 26 (0.4%) with missing risk factors for calculation of 10-year risk of ASCVD, 633 (9%) >75 years of age, and 209 (3%) with low-density lipoprotein <70 mg/dl from the analysis. RESULTS The study population consisted of 4,758 participants (age 59 ± 9 years; 47% males). A total of 247 (5.2%) ASCVD and 155 (3.3%) hard coronary heart disease events occurred over a median (interquartile range) follow-up of 10.3 (9.7 to 10.8) years. The new ACC/AHA guidelines recommended 2,377 (50%) MESA participants for moderate- to high-intensity statins; the majority (77%) was eligible because of a 10-year estimated ASCVD risk ≥7.5%. Of those recommended statins, 41% had CAC = 0 and had 5.2 ASCVD events/1,000 person-years. Among 589 participants (12%) considered for moderate-intensity statin, 338 (57%) had a CAC = 0, with an ASCVD event rate of 1.5 per 1,000 person-years. Of participants eligible (recommended or considered) for statins, 44% (1,316 of 2,966) had CAC = 0 at baseline and an observed 10-year ASCVD event rate of 4.2 per 1,000 person-years. CONCLUSIONS Significant ASCVD risk heterogeneity exists among those eligible for statins according to the new guidelines. The absence of CAC reclassifies approximately one-half of candidates as not eligible for statin therapy.

Causes of Delay and Associated Mortality in Patients Transferred With ST-Segment–Elevation Myocardial Infarction

Background— Regional ST-segment–elevation myocardial infarction systems are being developed to improve timely access to primary percutaneous coronary intervention (PCI). System delays may diminish the mortality benefit achieved with primary PCI in ST-segment–elevation myocardial infarction patients, but the specific reasons for and clinical impact of delays in patients transferred for PCI are unknown. Methods and Results— This was a prospective, observational study of 2034 patients transferred for primary PCI at a single center as part of a regional ST-segment–elevation myocardial infarction system from March 2003 to December 2009. Despite long-distance transfers, 30.4% of patients (n=613) were treated in ⩽90 minutes and 65.7% (n=1324) were treated in ⩽120 minutes. Delays occurred most frequently at the referral hospital (64.0%, n=1298), followed by the PCI center (15.7%, n=317) and transport (12.6%, n=255). For the referral hospital, the most common reasons for delay were awaiting transport (26.4%, n=535) and emergency department delays (14.3%, n=289). Diagnostic dilemmas (median, 95.5 minutes; 25th and 75th percentiles, 72–127 minutes) and nondiagnostic initial ECGs (81 minutes; 64–110.5 minutes) led to delays of the greatest magnitude. Delays caused by cardiac arrest and/or cardiogenic shock had the highest in-hospital mortality (30.6%), in contrast with nondiagnostic initial ECGs, which, despite long treatment delays, did not affect mortality (0%). Significant variation in both the magnitude and clinical impact of delays also occurred during the transport and PCI center segments. Conclusions— Treatment delays occur even in efficient systems for ST-segment–elevation myocardial infarction care. The clinical impact of specific delays in interhospital transfer for PCI varies according to the cause of the delay.

Use of coronary artery calcium testing to guide aspirin utilization for primary prevention: estimates from the multi-ethnic study of atherosclerosis

Background—Aspirin for the primary prevention of coronary heart disease (CHD) is only recommended for individuals at high risk for CHD although the majority of CHD events occur in individuals who are at low to intermediate risk. Methods and Results—To estimate the potential of coronary artery calcium (CAC) scoring to guide aspirin use for primary prevention of CHD, we studied 4229 participants from the Multi-Ethnic Study of Atherosclerosis who were not on aspirin at baseline and were free of diabetes mellitus. Using data from median 7.6-year follow-up, 5-year number-needed-to-treat estimations were calculated by applying an 18% relative CHD reduction to the observed event rates. This was contrasted to 5-year number-needed-to-harm estimations based on the risk of major bleeding reported in an aspirin meta-analysis. Results were stratified by a 10% 10-year CHD Framingham Risk Score (FRS). Individuals with CAC≥100 had an estimated net benefit with aspirin regardless of their traditional risk status (estimated 5-year number needed to treat of 173 for individuals <10% FRS and 92 for individuals ≥10% FRS, estimated 5-year number needed to harm of 442 for a major bleed). Conversely, individuals with zero CAC had unfavorable estimations (estimated 5-year number needed to treat of 2036 for individuals <10% FRS and 808 for individuals ≥10% FRS, estimated 5-year number needed to harm of 442 for a major bleed). Sex-specific and age-stratified analyses showed similar results. Conclusions—For the primary prevention of CHD, Multi-Ethnic Study of Atherosclerosis participants with CAC≥100 had favorable risk/benefit estimations for aspirin use while participants with zero CAC were estimated to receive net harm from aspirin.

Utility of Nontraditional Risk Markers in Individuals Ineligible for Statin Therapy According to the 2013 American College of Cardiology/American Heart Association Cholesterol Guidelines

Background— In the general population, the majority of cardiovascular events occur in people at the low to moderate end of population risk distribution. The 2013 American College of Cardiology/American Heart Association guideline on the treatment of blood cholesterol recommends consideration of statin therapy for adults with an estimated 10-year atherosclerotic cardiovascular disease (ASCVD) risk ≥7.5% based on traditional risk factors. Whether use of nontraditional risk markers can improve risk assessment in those below this threshold for statin therapy is unclear. Methods and Results— Using data from the Multi-Ethnic Study of Atherosclerosis (MESA), a population sample free of clinical CVD at baseline, we calibrated the Pooled Cohort Equations (cPCE). ASCVD was defined as myocardial infarction, coronary heart disease death, or fatal or nonfatal stroke. Adults with an initial cPCE <7.5% and elevated levels of additional risk markers (abnormal test) whose new calculated risk was ≥7.5% were considered statin eligible: low-density lipoprotein cholesterol ≥160 mg/dL; family history of ASCVD; high-sensitivity C-reactive protein ≥2 mg/dL; coronary artery calcium score ≥300 Agatston units or ≥75th percentile for age, sex, and ethnicity; and ankle-brachial index <0.9. We compared the absolute and relative ASCVD risks among those with versus without elevated posttest estimated risk. We calculated the number needed to screen to identify 1 person with abnormal test for each risk marker, defined as the number of participants with baseline cPCE risk <7.5% divided by the number with an abnormal test reclassified as statin eligible. Of 5185 participants not taking statins with complete data (age, 45–84 years), 4185 had a cPCE risk <7.5%. During 10 years of follow-up, 57% of the ASCVD events (183 of 320) occurred among adults with a cPCE risk <7.5%. When people with diabetes mellitus were excluded, the coronary artery calcium criterion reclassified 6.8% upward, with an event rate of 13.3%, absolute risk of 10%, relative risk of 4.0 (95% confidence interval [CI], 2.8–5.7), and number needed to screen of 14.7. The corresponding numbers for family history of ASCVD were 4.6%, 15.1%, 12%, 4.3 (95% CI, 3.0–6.4), and 21.8; for high-sensitivity C-reactive protein criteria, 2.6%, 10%, 6%, 2.6 (95% CI, 1.4–4.8), and 39.2; for ankle-brachial index criteria, 0.6%, 9%, 5%, 2.3 (95% CI, 0.6–8.6), and 176.5; and for low-density lipoprotein cholesterol criteria, 0.5%, 5%, 1%, 1.2 (95% CI, 0.2–8.4), and 193.3, respectively. Of the 3882 with <7.5% cPCE risk, 431 (11.1%) were reclassified to ≥7.5% (statin eligible) by at least 1 of the additional risk marker criteria. Conclusions— In this generally low-risk population sample, a large proportion of ASCVD events occurred among adults with a 10-year cPCE risk <7.5%. We found that the coronary artery calcium score, high-sensitivity C-reactive protein, family history of ASCVD, and ankle-brachial index recommendations by the American College of Cardiology/American Heart Association cholesterol guidelines (Class IIB) identify small subgroups of asymptomatic population with a 10-year cPCE risk <7.5% but with observed ASCVD event rates >7.5% who may warrant statin therapy considerations.

Coronary Artery Calcium to Guide a Personalized Risk-Based Approach to Initiation and Intensification of Antihypertensive Therapy

Background: The use of atherosclerotic cardiovascular disease (ASCVD) risk to personalize systolic blood pressure (SBP) treatment goals is a topic of increasing interest. Therefore, we studied whether coronary artery calcium (CAC) can further guide the allocation of anti-hypertensive treatment intensity. Methods: We included 3733 participants from the Multi-Ethnic Study of Atherosclerosis (MESA) with SBP between 120 and 179 mm Hg. Within subgroups categorized by both SBP (120–139 mm Hg, 140–159 mm Hg, and 160–179 mm Hg) and estimated 10-year ASCVD risk (using the American College of Cardiology/American Heart Assocation pooled-cohort equations), we compared multivariable-adjusted hazard ratios for the composite outcome of incident ASCVD or heart failure after further stratifying by CAC (0, 1–100, or >100). We estimated 10-year number-needed-to-treat for an intensive SBP goal of 120 mm Hg by applying the treatment benefit recorded in meta-analyses to event rates within CAC strata. Results: The mean age was 65 years, and 642 composite events took place over a median of 10.2 years. In persons with SBP <160 mm Hg, CAC stratified risk for events. For example, among those with an ASCVD risk of <15% and who had an SBP of either 120 to 139 mm Hg or 140 to 159 mm Hg, respectively, we found increasing hazard ratios for events with CAC 1 to 100 (1.7 [95% confidence interval, 1.0–2.6] or 2.0 [1.1–3.8]) and CAC >100 (3.0 [1.8–5.0] or 5.7 [2.9–11.0]), all relative to CAC=0. There appeared to be no statistical association between CAC and events when SBP was 160 to 179 mm Hg, irrespective of ASCVD risk level. Estimated 10-year number-needed-to-treat for a SBP goal of 120mmHg varied substantially according to CAC levels when predicted ASCVD risk <15% and SBP <160mmHg (eg, 10-year number-needed-to-treat of 99 for CAC=0 and 24 for CAC>100, when SBP 120-139mm Hg). However, few participants with ASCVD risk <5% had elevated CAC. Furthermore, 10-year number-needed-to-treat estimates were consistently low and varied less among CAC strata when SBP was 160 to 179 mm Hg or when ASCVD risk was ≥15% at any SBP level. Conclusions: Combined CAC imaging and assessment of global ASCVD risk has the potential to guide personalized SBP goals (eg, choosing a traditional goal of 140 or a more intensive goal of 120 mm Hg), particularly among adults with an estimated ASCVD risk of 5% to 15% and prehypertension or mild hypertension.

Effect of PCSK9 inhibitors on clinical outcomes in patients with hypercholesterolemia: A meta-analysis of 35 randomized controlled trials

Background We sought to examine the efficacy and safety of 2 PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors: alirocumab and evolocumab. Methods and Results We performed a systematic review and meta‐analysis of randomized controlled trials comparing treatment with and without PCSK9 inhibitors; 35 randomized controlled trials comprising 45 539 patients (mean follow‐up: 85.5 weeks) were included. Mean age was 61.0±2.8 years, and mean baseline low‐density lipoprotein cholesterol was 106±22 mg/dL. Compared with no PCSK9 inhibitor therapy, treatment with a PCSK9 inhibitor was associated with a lower rate of myocardial infarction (2.3% versus 3.6%; odds ratio [OR]: 0.72 [95% confidence interval (CI), 0.64–0.81]; P<0.001), stroke (1.0% versus 1.4%; OR: 0.80 [95% CI, 0.67–0.96]; P=0.02), and coronary revascularization (4.2% versus 5.8%; OR: 0.78 [95% CI, 0.71–0.86]; P<0.001). Overall, no significant change was observed in all‐cause mortality (OR: 0.71 [95% CI, 0.47–1.09]; P=0.12) or cardiovascular mortality (OR: 1.01 [95% CI, 0.85–1.19]; P=0.95). A significant association was observed between higher baseline low‐density lipoprotein cholesterol and benefit in all‐cause mortality (P=0.038). No significant change was observed in neurocognitive adverse events (OR: 1.12 [95% CI, 0.88–1.42]; P=0.37), myalgia (OR: 0.95 [95% CI, 0.75–1.20]; P=0.65), new onset or worsening of preexisting diabetes mellitus (OR: 1.05 [95% CI, 0.95–1.17]; P=0.32), and increase in levels of creatine kinase (OR: 0.84 [95% CI, 0.70–1.01]; P=0.06) or alanine or aspartate aminotransferase (OR: 0.96 [95% CI, 0.82–1.12]; P=0.61). Conclusions Treatment with a PCSK9 inhibitor is well tolerated and improves cardiovascular outcomes. Although no overall benefit was noted in all‐cause or cardiovascular mortality, such benefit may be achievable in patients with higher baseline low‐density lipoprotein cholesterol.

Association of Fruit and Vegetable Consumption During Early Adulthood With the Prevalence of Coronary Artery Calcium After 20 Years of Follow-Up: The Coronary Artery Risk Development in Young Adults (CARDIA) Study.

Background— The relationship between intake of fruits and vegetables (F/V) during young adulthood and coronary atherosclerosis later in life is unclear. Methods and Results— We studied participants of the Coronary Artery Risk Development in Young Adults (CARDIA) study, a cohort of young, healthy black and white individuals at baseline (1985–1986). Intake of F/V at baseline was assessed using a semiquantitative interview administered diet history, and coronary artery calcium was measured at year 20 (2005–2006) using computed tomography. We used logistic regression to adjust for relevant variables and estimate the adjusted odds ratios and 95% confidence intervals across energy-adjusted, sex-specific tertiles of total servings of F/V per day. Among our sample (n=2506), the mean (SD) age at baseline was 25.3 (3.5) years, and 62.7% were female. After adjustment for demographics and lifestyle variables, higher intake of F/V was associated with a lower prevalence of coronary artery calcium: odds ratio (95% confidence interval) =1.00 (reference), 0.78 (0.59–1.02), and 0.74 (0.56–0.99), from the lowest to the highest tertile of F/V, P value for trend <0.001. There was attenuation of the association between F/V and coronary artery calcium after adjustment for other dietary variables, but the trend remained significant: odds ratio (95% confidence interval): 1.00 (reference), 0.84 (0.63–1.11), and 0.92 (0.67–1.26), P value for trend <0.002]. Conclusions— In this longitudinal cohort study, higher intake of F/V during young adulthood was associated with lower odds of prevalent coronary artery calcium after 20 years of follow-up. Our results reinforce the importance of establishing a high intake of F/V as part of a healthy dietary pattern early in life.

Underuse of cardiovascular preventive pharmacotherapy in patients presenting with ST-elevation myocardial infarction

BACKGROUND Multiple medications have proven efficacy for the primary prevention of coronary heart disease (CHD), but the appropriate patient population remains controversial. Even in the presence of multiple cardiovascular risk factors, many patients are not considered high risk and are not offered preventive medications despite proven efficacy. METHODS We analyzed a prospective cohort of 1,710 consecutive ST-elevation myocardial infarction (STEMI) patients treated in a regional STEMI system from May 2007 to July 2010 and enrolled in a comprehensive database that includes preadmission medications. RESULTS Of the 1,707 patients analyzed, 1,180 (69.1%) did not have known CHD before their event; and 482 (41.7%) of those patients had premature events (men <55 years old, women <65 years old). In patients without known CHD, cardiovascular risk factors were abundant (52.1% had hypertension, 43.6% had dyslipidemia, 41.4% had a family history of CHD, 58.5% were current or former smokers, and 14.9% were diabetic). Despite the high prevalence of risk factors, only 24.1% were on aspirin, 16.1% were on a statin, and only 7.8% were taking an aspirin and statin. Use of preventive medications was even less common in patients with premature events, including aspirin (15.2% vs 30.2%, P value < .001), statins (11.1% vs 19.5%, P value < .001), and the combination (5.6% vs 9.4%, P value < .001). CONCLUSIONS Approximately 70% of a contemporary STEMI population did not have known CHD before their event, and >40% of those events would be considered premature. Despite the significant burden of cardiovascular risk factors, use of preventive therapy was alarmingly low in patients presenting with STEMI.

Plasma-Free Fatty Acids, Fatty Acid–Binding Protein 4, and Mortality in Older Adults (from the Cardiovascular Health Study)

Plasma-free fatty acids (FFAs) are largely derived from adipose tissue. Elevated levels of FFA and fatty acid-binding protein 4 (FABP4), a key cytoplasmic chaperone of fatty acids, have been associated with adverse cardiovascular outcomes, but limited data are available on the relation of these biomarkers with cardiovascular and total mortality. We studied 4,707 participants with a mean age of 75 years who had plasma FFA and FABP4 measured in 1992 to 1993 as part of the Cardiovascular Health Study, an observational cohort of community-dwelling older adults. Over a median follow-up of 11.8 years, 3,555 participants died. Cox proportional hazard regression was used to determine the association between FFA, FABP4, and mortality. In fully adjusted models, FFA were associated with dose-dependent significantly higher total mortality (hazard ratio [HR] per SD: 1.14, 95% confidence interval [CI] 1.09 to 1.18), but FABP4 levels were not (HR 1.04, 95% CI 0.98 to 1.09). In a cause-specific mortality analysis, higher concentrations of FFA were associated with significantly higher risk of death because of cardiovascular disease, dementia, infection, and respiratory causes but not cancer or trauma. We did not find evidence of an interaction between FFA and FABP4 (p = 0.45), but FABP4 appeared to be associated with total mortality differentially in men and women (HR 1.17, 95% CI 1.08 to 1.26 for men; HR 1.02, 95% CI 0.96 to 1.07 for women, interaction p value <0.001). In conclusion, in a cohort of community-dwelling older subjects, elevated plasma concentrations of FFA, but not FABP4, were associated with cardiovascular and noncardiovascular mortality.

Familial hypercholesterolemia in a large ambulatory population: Statin use, optimal treatment, and identification for advanced medical therapies

BACKGROUND Familial hypercholesterolemia (FH) is an autosomal dominant genetic disease resulting in elevated serum low-density lipoprotein cholesterol (LDL-C) levels. Patients with FH have a very high lifetime risk of cardiovascular disease, but FH often goes unrecognized in clinical care. New treatments including PCSK9 inhibitors are now available for this population, and the use of the electronic record may be able to help identify potential patients for therapy. OBJECTIVES The goal of this study was to determine the period prevalence of FH in a large ambulatory care population, including the homozygous form. In addition, use of cholesterol lowering therapy in individuals with FH was characterized. METHODS A retrospective analysis was carried out among patients seen in an upper Midwest health care system between 2009 and 2012. In a search of electronic health records (EHR) and using the current National Lipid Association guidelines, FH patients (including homozygous cases) were identified based on age and highest LDL-C. Statin therapy was characterized according to current FH treatment guidelines. RESULTS There were 391,166 individuals with available measures during the study timeframe. Of these, 841 were identified as having probable HeFH, representing a prevalence of 0.21% (about 1 in 470 patients) in this population. HoFH was identified as probable in 6 patients. For the total group, two-thirds of FH patients were on a statin, but only half were treated adequately. The remaining one-third of FH patients were not on statin therapy, with only 27% of those not on statin therapy having a documented statin intolerance. CONCLUSIONS FH is often underdiagnosed and suboptimally treated in clinical practice. Statin therapy in this population rarely went beyond low-moderate doses. These findings support EHR-based population health efforts to initiate an FH cascade-screening model and ensure higher quality care for this high-risk population and identify those who may benefit from advanced therapy.