Potential impact of cardiology phone-consultation for patients risk-stratified by the HEART pathway.

Objective: Bedside consultation by cardiologists may facilitate safe discharge of selected patients from the emergency department (ED) even when admission is recommended by the History, Electrocardiogram, Age, Risk factors, Troponin (HEART) pathway. If bedside evaluation is unavailable, phone consultation between emergency physicians and cardiologists would be most impactful if the resultant disposition is discordant with the HEART pathway. We therefore evaluate discordance between actual disposition and that suggested by the HEART pathway in patients presenting to the ED with chest pain for whom cardiology consultation occurred exclusively by phone and to assess the impact of phone-consultation on disposition. Methods: We performed a single-center, retrospective study of adults presenting to the ED with chest pain whose emergency physician had a phone consultation with a cardiologist. Actual disposition was abstracted from the medical record. HEART pathway category (low-risk, discharge; high-risk, admit) was derived from ED documentation. For discharged patients, major adverse cardiac events were assessed at 30 days by chart review and phone follow-up. Results: For the 170 patients that had cardiologist phone consultation, discordance between actual disposition and the HEART pathway was 17%. The HEART pathway recommended admission for nearly 80% of discharged patients. Following cardiologist phone-consultation, 10% of high-risk patients were discharged, with the majority having undergone a functional study recommended by the cardiologist. At 30 days, discharged patients had experienced no episodes of major adverse cardiac events or rehospitalization for cardiac reasons. Conclusion: For patients presenting to the ED with chest pain, cardiology phone-consultation has the potential to safely impact disposition, primarily by facilitating functional testing in high-risk individuals.

Cardiomyopathic Toxicity From Chemotherapy: Is There an Opportunity for Preemptive Intervention?

OPINION STATEMENT: The fight against cancer has never appeared more optimistic with multiple ongoing advances in cancer therapeutics; however, the prevention of cardiotoxicity from these treatments, both old and new, is a major focus of recent research. We recommend conceptualizing the prevention of cardiotoxicity as binary whereby primary prevention involves a uniform application of preventative efforts to anyone receiving a potentially cardiotoxic drug and secondary prevention directed towards those with left ventricular dysfunction, whether symptomatic or not. Recent studies suggest that cardioprotective medications such as renin-angiotensin inhibitors and beta blockers, among others, may be beneficial in the primary prevention of cardiotoxicity. Importantly, the magnitude of this protective effect appears to be driven by baseline risk of cardiac disease. In terms of secondary prevention, we recommend that patients with symptomatic heart failure related to cancer treatment should be treated as aggressively as patients with heart failure from other causes, as indicated by the most recent guidelines. We identify a relative paucity of data to guide those with asymptomatic left ventricular dysfunction. We summarize the literature to date with an emphasis on recent investigation and outline the importance of a continued partnership between cardiologists, oncologists, and primary care providers.

Plasma hepatocyte growth factor is a novel marker of AL cardiac amyloidosis.

BACKGROUND: Cardiac amyloidosis is an infiltrative cardiomyopathy that is challenging to diagnose. We hypothesized that the novel biomarkers hepatocyte growth factor (HGF), galectin-3 (GAL-3), interleukin-6 (IL-6), and vascular endothelial growth factor (VEGF) would be elevated in cardiac amyloidosis and may be able to discriminate from non-cardiac systemic amyloidosis or other cardiomyopathies with similar clinical or morphologic characteristics. METHODS: Patients were selected from the Vanderbilt Main Heart Registry according to the following groups: (1) amyloid light-chain (AL) cardiac amyloidosis (n = 26); (2) transthyretin (ATTR) cardiac amyloidosis (n = 7); (3) left ventricular hypertrophy (LVH) (n = 45); (4) systolic heart failure (n = 42); and (5) non-cardiac systemic amyloidosis (n = 7). Biomarkers were measured in stored plasma samples. Biomarkers' discrimination performance in predicting AL cardiac amyloidosis (i.e., Concordance index) was reported. A survival analysis was used to explore the relationship between HGF levels and mortality among AL cardiac amyloidosis patients. RESULTS: HGF levels were markedly elevated in patients with AL cardiac amyloidosis (median = 622, interquartile range (IQR): 299-1228 pg/mL) compared with the other groups, including those with non-cardiac systemic amyloidosis (median = 134, IQR: 94-163 pg/mL, p < 0.001). HGF was not a specific marker for ATTR amyloidosis. Gal-3 was elevated in all groups with amyloidosis but could not differentiate between those with and without cardiac involvement. There was no difference in IL-6 or VEGF between those with AL cardiac amyloidosis compared to other groups (p = 0.13 and 0.057, respectively). CONCLUSIONS: HGF may be a specific marker that distinguishes AL cardiac amyloidosis from other cardiomyopathies with similar clinical or morphologic characteristics. Further studies are necessary to determine whether HGF levels predict the likelihood of survival.

PCSK9 inhibitors and their role in high-risk patients in reducing LDL cholesterol levels: evolocumab.

Patients with familial hypercholesterolemia or statin intolerance are especially challenging to manage since LDL cholesterol levels often remain considerably elevated despite clinicians' best efforts. With statins regarded as first-line pharmacologic therapy by the current American College of Cardiology/American Heart Association guidelines to reduce LDL cholesterol and cardiovascular risk, there is now a critical need to determine when other agents will play a role beyond maximally tolerated statin therapy and lifestyle changes. In this review, we take a closer look at evolocumab (Repatha(®)), one of the new injectable human monoclonal antibodies to PCSK9 and its efficacy and safety properties from the results of various trials.

PCSK9 inhibitors and their role in high-risk patients in reducing LDL cholesterol levels: alirocumab.

In this review, we examine alirocumab (Praluent(®)), a monoclonal antibody to PCSK9 and its role in reducing LDL-C levels. By comparing the results of various studies and trials we discuss the efficacy and safety of alirocumab. We aim to guide clinicians of the role of alirocumab in clinical practice. Overall, PCSK9 inhibitors are promising new agents in further reducing LDL-C levels in addition to diet and maximally tolerated statin therapy. Long-term outcome studies are currently ongoing and will further delineate the role of PCSK9 inhibitors.

Lipid phenotypes at the extremes of high-density lipoprotein cholesterol: The very large database of lipids-9.

BACKGROUND: Low serum levels of high-density lipoprotein cholesterol (HDL-C) are an important risk factor for atherosclerotic disease. To date, therapeutically raising HDL-C has not been shown to impact risk for cardiovascular events. OBJECTIVE: We aim to characterize lipid parameters at the extremes of HDL-C. METHODS: We examined cholesterol profiles from 1,350,908 US adults and children from the Very Large Database of Lipids who were clinically referred for advanced lipoprotein testing from 2009 to 2011. We categorized patients into HDL-C percentile categories (<0.1th, 0.1th-<1st, 1st-5th, 25th-75th, 95th-99th, >99th-99.9th, and >99.9th). Within these groups, we examined HDL-C subclasses, low-density lipoprotein cholesterol (LDL-C), LDL and very-low density lipoprotein densities, non-HDL-C, triglycerides (TG), very-low density lipoprotein cholesterol, and remnant lipoprotein cholesterol (RLP-C), as well as prevalence of Fredrickson-Levy dyslipidemias. RESULTS: Extremely low HDL-C percentiles were associated with increased LDL density, TG, and especially RLP-C. Very high HDL-C levels (≥ 92 mg/dL) showed increasing HDL2-C/HDL3-C ratio and very low levels of RLP-C and triglyceride-rich lipoproteins. Type IV dyslipidemia had the highest prevalence among classical dyslipidemia and was the most frequent at extremely low HDL-C percentiles. CONCLUSIONS: These findings demonstrate a high prevalence of elevated triglyceride-rich lipoprotein levels and increased LDL density in patients with extremely low HDL-C levels. The relative contributions of these various changes in lipid profiles of patients with low HDL-C to cardiovascular risk need to be further scrutinized to more fully establish if low HDL-C is truly an independent risk factor for coronary heart disease or simply reflects detrimental shifts in the levels of atherogenic lipoproteins.

Cognitive and Physical Function by Statin Exposure in Elderly Individuals Following Acute Myocardial Infarction.

Despite beneficial effects on morbidity and mortality after acute myocardial infarction (AMI), concerns remain about the safety of statin therapy, particularly their potential effects on cognitive and physical function, in elderly individuals. Among statin-naive AMI patients age ≥ 65 years in a multicenter US registry, we examined the association between statin prescription at discharge and change in cognition (via Modified Telephone Interview for Cognitive Status [TICS-M]) assessed at 1 and 6 months after AMI. Short Form-12 Physical Component score, hand grip, walk time, and chair-rise tests were used to assess physical function. We conducted noninferiority testing to evaluate the hypothesis that the mean change in cognitive function was no worse among patients recently started on statins compared with those who were not. Among 317 elderly AMI patients, 262 patients (83%) were prescribed a statin at discharge and 55 were not. After matching for propensity to be discharged on statin after AMI, the effect of statin treatment on change in TICS-M from 1 to 6 months (estimated difference, 0.11 points; 95% confidence interval: -2.11 to 2.32, P = 0.92) showed noninferiority (inferiority threshold 3 points). There were no significant differences in any physical function measure. Among statin-naive elderly individuals recovering from AMI, initiation of statin therapy was not associated with detectable changes in short-term cognitive or physical function. These findings support the general safety of statin therapy for secondary prevention in this population.

PCSK9 inhibitors and neurocognitive adverse events: exploring the FDA directive and a proposal for N-of-1 trials.

Proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors are a novel class of medications that greatly lower low-density lipoprotein cholesterol (LDL-C) by upregulating LDL receptor availability. In early 2014, the US Food and Drug Administration (FDA) directed developers of PCSK9 inhibitors to monitor neurocognitive adverse effects and consider neurocognitive testing in at least a subset of participants in ongoing late-stage trials. Available trial evidence indicates that neurocognitive adverse events may occur more commonly in individuals receiving an antibody to PCSK9, but these events are uncommon and have not been associated with on-treatment LDL-C levels. Moreover, it is unclear to what extent closer monitoring of trial participants allocated to PCSK9 inhibitors has led to an ascertainment bias. Regardless, further trial data are needed, and long-term outcomes trials are ongoing, with at least one including a neurocognitive substudy. Considering lessons learned from the statin experience, high-quality prospective cohort studies and randomized trials may not be enough to allay concerns or settle debate since the focus of effect in these studies is the group average. Therefore, we suggest that n-of-1 trials could be considered to bring the focus to the individual while retaining the benefits of blinding and randomization in evidence generation. Ultimately, any neurocognitive adverse effects that might exist with PCSK9 inhibition and lipid lowering must be weighed against potential benefits of therapy, including avoidance of myocardial infarction and stroke, and a reduced risk of dementia due to neurovascular benefits from long-term lipid lowering.

Cholesterol, statins, and dementia: what the cardiologist should know.

Alzheimer dementia (AD) is an important clinical problem that appears to be closely tied to comorbid cardiovascular disease, making it a relevant topic for the clinical cardiologist. Determinants of cardiovascular health, especially midlife dyslipidemia, are associated with an increased risk of dementia based on molecular and epidemiologic data. Given the potential role of dyslipidemia in the development of dementia, statins have been investigated as potential therapeutic options to slow or prevent disease. This review discusses the role of dyslipidemia and other cardiovascular risk factors in the pathogenesis of AD, with a focus on the existing evidence for the use of statin medications in the treatment and prevention of AD from observational studies and randomized clinical trials. Clinical questions for the practicing cardiologist are addressed.

Impact on cognitive function-are all statins the same?

Dementia is a major public health concern, affecting an estimated 7% of the population over 65 and 30% over 80 years of age. There is mounting evidence in the literature from meta-analyses of high-quality prospective cohort studies that statins may have a positive impact in reducing the incidence of dementia. Little is known, however, on whether certain types of statins are more impactful than others. This narrative review specifically explores the various properties of different statin types and whether these differences lead to a clinically significant differential impact on cognitive function. We critically evaluate the literature, emphasizing interesting and important new findings, and overall aim to bring the reader up-to-date on evidence-based recommendations.

Statins, mood, sleep, and physical function: a systematic review.

PURPOSE: We aimed to evaluate the effects of statins on mood, sleep, and physical function. METHODS: We performed a systematic computer-aided search of MEDLINE/PubMed, EMBASE, and the Cochrane Central Register and augmented this search by scrutinizing reference lists and making inquiries among colleagues and experts in the field. All patient populations and study types were considered. We selected studies of statin therapy compared with no statin or placebo. Outcome measures included mood, sleep, and physical function. RESULTS: Thirty-four studies were included in qualitative synthesis. Seven of eight (88 %) observational studies, 4/6 (66 %) randomized trials with mood as a primary endpoint (487 total participants; exposure 4 weeks to 1 year), and 3/3 (100 %) randomized trials with mood as a secondary endpoint (2,851 total participants; exposure 1-4 years) were not compatible with a negative mood effect of statins. Comparatively, fewer studies examined statin effects on sleep and physical function. Studies reporting negative effects contained potential sources of bias, including multiple testing or lack of adjustment for confounders in observational studies, and failure to prespecify outcomes or report blinding in trials. CONCLUSIONS: A limited body of available evidence is most compatible with no adverse effect of statins on quality of life measures, namely, mood, sleep, and physical function. Studies suggesting such effects suffer from an increased risk of bias. High-quality, prospective, and adequately powered studies are needed, especially in the domains of sleep and physical function, with careful attention to patients who may be most vulnerable to adverse effects.

Narrowing sex differences in lipoprotein cholesterol subclasses following mid-life: the very large database of lipids (VLDL-10B).

BACKGROUND: Women have less risk of atherosclerotic cardiovascular disease compared with men up until midlife (ages 50 to 60), after which the gap begins to narrow post menopause. We hypothesized that the average lipid profile of women undergoes unfavorable changes compared with men after midlife. METHODS AND RESULTS: We examined lipids by sex and age in the Very Large Database of Lipids 10B (VLDL 10B) study. The analysis included 1 350 908 unique consecutive patients clinically referred for lipoprotein testing by density gradient ultracentrifugation from 2009 to 2011. Ratio variables were created for density subclasses of LDL-C, HDL-C, and VLDL-C (LLDR, LHDR, LVDR, respectively). Men showed higher median LDL-C values than women for ages 20 to 59, with the greatest difference in their 30s: 146 mg/dL in men versus 130 mg/dL in women. In contrast, women consistently had higher values after midlife (age 60), for example ages 70 to 79: 129 mg/dL in women versus 112 mg/dL in men. After age 50, women had higher LDL-C each decade, for example 14% higher from their 30s to 50s, while HDL-C concentrations did not differ. Women had more buoyant LDL-C and HDL-C (lower LLDR and LHDR) than men at all ages but the gap closed in higher age groups. In contrast, women had a generally denser VLDL-C (higher LVDR) leading into midlife, with the gap progressively closing in higher age groups, approximating that of men in their 60s and 70s. CONCLUSION: The narrowing sex differential in cardiovascular disease risk after midlife is mirrored by a higher total atherogenic lipoprotein cholesterol burden in women and a closer approximation of the less favorable density phenotype characteristic of men.

Very large database of lipids: rationale and design.

Blood lipids have major cardiovascular and public health implications. Lipid-lowering drugs are prescribed based in part on categorization of patients into normal or abnormal lipid metabolism, yet relatively little emphasis has been placed on: (1) the accuracy of current lipid measures used in clinical practice, (2) the reliability of current categorizations of dyslipidemia states, and (3) the relationship of advanced lipid characterization to other cardiovascular disease biomarkers. To these ends, we developed the Very Large Database of Lipids (NCT01698489), an ongoing database protocol that harnesses deidentified data from the daily operations of a commercial lipid laboratory. The database includes individuals who were referred for clinical purposes for a Vertical Auto Profile (Atherotech Inc., Birmingham, AL), which directly measures cholesterol concentrations of low-density lipoprotein, very low-density lipoprotein, intermediate-density lipoprotein, high-density lipoprotein, their subclasses, and lipoprotein(a). Individual Very Large Database of Lipids studies, ranging from studies of measurement accuracy, to dyslipidemia categorization, to biomarker associations, to characterization of rare lipid disorders, are investigator-initiated and utilize peer-reviewed statistical analysis plans to address a priori hypotheses/aims. In the first database harvest (Very Large Database of Lipids 1.0) from 2009 to 2011, there were 1 340 614 adult and 10 294 pediatric patients; the adult sample had a median age of 59 years (interquartile range, 49-70 years) with even representation by sex. Lipid distributions closely matched those from the population-representative National Health and Nutrition Examination Survey. The second harvest of the database (Very Large Database of Lipids 2.0) is underway. Overall, the Very Large Database of Lipids database provides an opportunity for collaboration and new knowledge generation through careful examination of granular lipid data on a large scale.

Statins and cognition: a systematic review and meta-analysis of short- and long-term cognitive effects.

OBJECTIVE: To evaluate the effect of statins on short-term cognitive function and the long-term incidence of dementia. PATIENTS AND METHODS: A systematic search was performed of MEDLINE, EMBASE, and the Cochrane Central Register from their inception to April 25, 2013. Adults with no history of cognitive dysfunction treated with statins were included from high-quality randomized controlled trials and prospective cohort studies after formal bias assessment. RESULTS: Sixteen studies were included in qualitative synthesis and 11 in quantitative synthesis. Short-term trials did not show a consistent effect of statin therapy on cognitive end points. Digit Symbol Substitution Testing (a well-validated measure of cognitive function) was the most common short-term end point, with no significant differences in the mean change from baseline to follow-up between the statin and placebo groups (mean change, 1.65; 95% CI, -0.03 to 3.32; 296 total exposures in 3 trials). Long-term cognition studies included 23,443 patients with a mean exposure duration of 3 to 24.9 years. Three studies found no association between statin use and incident dementia, and 5 found a favorable effect. Pooled results revealed a 29% reduction in incident dementia in statin-treated patients (hazard ratio, 0.71; 95% CI, 0.61-0.82). CONCLUSION: In patients without baseline cognitive dysfunction, short-term data are most compatible with no adverse effect of statins on cognition, and long-term data may support a beneficial role for statins in the prevention of dementia.

Cigarette smoking and clopidogrel interaction.

Dual antiplatelet therapy (DAPT) with aspirin and an adenosine diphosphate receptor antagonist is central to the modern management of acute coronary syndromes and percutaneous revascularization. The most widely used adenosine diphosphate receptor antagonist, clopidogrel therapy is limited by inter-individual variability in platelet inhibition. Recent data suggest a potential role of smoking in the metabolism of clopidogrel and high on-treatment platelet reactivity. Pharmacodynamic studies and post-hoc analyses of large clinical trials support a link between smoking status and the efficacy of clopidogrel therapy. The mechanism of the interaction between smoking status and clopidogrel efficacy remains unclear but may be mediated by cytochrome P450 (CYP)1A2. There is less evidence available on the influence of smoking status on platelet reactivity and clinical outcomes during prasugrel and ticagrelor therapy.