Sex differences in the management of atherosclerotic cardiovascular disease.

Disparities between women and men persist in the diagnosis, treatment, and prognosis of atherosclerotic cardiovascular disease (ASCVD). Despite growing attention to sex-based differences in cardiovascular care, there are continued disparities in short- and long-term outcomes. Such disparities highlight the need to identify pathophysiologic differences in treatment patterns for stable ischemic heart disease, non-ST elevation myocardial infarction (NSTE-ACS), ST-elevation myocardial infarction (STEMI), and myocardial infarction with non-obstructive coronary arteries (MINOCA). The role of age as an effect modifier should also be considered given that young women diagnosed with ACS continue to experience increased rates of in-hospital mortality and major adverse cardiovascular events. Both patient-directed and systems-based approaches remain integral to improve outcomes in cardiovascular care. While inadequate representation of women in clinical trials remains a barrier to the implementation of evidence-based therapies, a growing body of data has established the efficacy and safety of medications in women across acute coronary syndromes. This review seeks to feature existing data on the differential treatment guidelines, care implementation, and cardiovascular outcomes between women and men, highlighting next directions for clinical investigation.

Underrepresentation of Women in Late-Breaking Cardiovascular Clinical Trials.

Background: Cardiovascular disease is the leading cause of mortality for women and men. Prior studies have demonstrated the underrepresentation of women in published clinical trials, but no study to date has assessed inclusion of women in late-breaking clinical trials (LBCTs) presented at national meetings. The objective is to characterize the inclusion of women participants in LBCT presented at the 2021 American College of Cardiology (ACC), American Heart Association (AHA), and European Society of Cardiology (ESC) annual meetings and identify trial characteristics associated with improved inclusion. Methods: LBCT presented at the 2021 ACC, AHA, and ESC meetings were identified and the inclusion of women as participants was assessed. The inclusion to prevalence ratio (IPR) was calculated by dividing the percentage of women participants by the percentage of women in the disease population. IPRs <1 indicate underenrollment of women. Of the 68 LBCT, 3 trials were excluded due to lack of subject matter relevance. Results: Inclusion of women ranged from 0% to 71%. Only 47.1% of trials reported sex-specific analyses. The average IPR was 0.76 for all trials and did not vary based on conference, trial center, geographic region, or funding source. The average IPR varied based on subspecialty, with a statistical difference between interventional cardiology and heart failure (0.65 vs. 0.88, p = 0.02). The average IPR was significantly lower for procedural studies compared with medication trials (0.61 vs. 0.78, p = 0.008), as well as for studies with mean age <65 and trial size <1500 participants. There was no difference in IPR based on female authorship. Conclusions: LBCT can impact novel drug and device approval, intervention indications, and patient management. Nonetheless, most LBCT underenroll women, particularly, procedural LBCT. In 2021, sex-based enrollment disparities persist, highlighting the need to engage key stakeholders, including funding organizations, national governing bodies, editorial board members, and medical societies, in the creation of a coordinated strategic initiative to advance gender parity. These findings warrant further investigation to increase inclusion of women in trials, including potential enrollment requirements for consideration as LBCT by meeting organizers.

Ischemia with No Obstructive Arteries (INOCA): A Review of the Prevalence, Diagnosis and Management.

Ischemia with no obstructive arteries (INOCA) is defined as patients with angiographic evidence of ischemia but no obstructive coronary artery disease (CAD) at coronary angiography. INOCA is estimated to be prevalent is 3-4 million individuals with a female predominance. INOCA is composed of different endotypes including: microvascular dysfunction, vasospasm and a combination of the 2. Diagnosis of INOCA requires either non-invasive or invasive techniques aimed at assessing coronary flow reserve (CFR), Index of Microcirculatory Resistance (IMR) and spasm secondary to acetylcholine injection. Although INOCA is associated with an increased risk of MACE and a decrease in quality of life, less than half of patients are appropriately treated. Treatment of INOCA remains elusive with current therapeutics tailored towards the specific endotype and ongoing clinical trials looking to assess the efficacy of traditional CAD medications.

Trends in utilization and spending on remote monitoring of pacemakers and implantable cardioverter-defibrillators among Medicare beneficiaries.

BACKGROUND: National trends and costs associated with remote and in-office interrogations of pacemakers and implantable cardioverter-defibrillators (ICDs) have not been previously described. OBJECTIVE: The purpose of this study was to evaluate utilization and Medicare spending for remote monitoring and in-office interrogations for pacemakers and ICDs. METHODS: We performed a retrospective cohort study of claims and spending for remote and in-office interrogations of pacemakers and ICDs for Medicare fee-for-service beneficiaries from 2012 to 2015. Aggregate and per-beneficiary claims and spending were calculated for each device type. RESULTS: Among all patients, 41.9% were female and the mean age was 78.3 years. From 2012 to 2015, remote monitoring utilization increased sharply. Aggregate professional remote monitoring claims for pacemakers increased by 61.3% and for ICDs by 5.6%, with an increase in technical claims (combined for pacemakers and ICDs) of 32.8%. Spending on all remote and in-office interrogations for these devices totaled $160 million per year, with remote costs increasing nearly 25% from $45.4 million in 2012 to $56.7 million in 2015. At the beneficiary level, remote interrogations increased for pacemakers from 0.6 to 0.9 per year, and for ICDs from 1.3 to 1.4 per year, whereas in-office interrogations decreased from 2.8 to 2.7 per year and from 3.0 to 2.9 per year, respectively. Beneficiary-level analysis revealed increased expenditures on remote interrogation offset by decreases in in-office expenditures, with total annual spending decreasing by $2 and $5 per beneficiary, respectively. CONCLUSION: Remote monitoring utilization increased substantially from 2012 to 2015, whereas annual costs per beneficiary decreased.

Value-Based Health Care in Undergraduate Medical Education.

PROBLEM: Value-based health care (VBHC) is an innovative framework for redesigning care delivery to achieve better outcomes for patients and reduce cost; however, providing students with the skills to understand and engage with these topics is a challenge to medical educators. APPROACH: Here, the authors present a novel, VBHC curriculum integrated into a required course for post-core clerkship students-launched in 2018 at Harvard Medical School and taught in conjunction with Harvard Business School faculty-that highlights key principles of VBHC most relevant to undergraduate medical education. The course integrates VBHC with related health disciplines, including health policy, ethics, epidemiology, and social medicine, using a case-based method. Students practice active decision making while learning key concepts to address value in clinical practice. OUTCOMES: Since the course's inception in March 2018, 95 students (87%) completed the standardized course evaluation; the majority said VBHC content and pedagogical style (i.e., case-based learning) enhanced their learning. Students' critiques focused on too little integration with other disciplines (e.g., social medicine, ethics), the physical space, and inadequate time for debates about potential tensions between VBHC and other course disciplines. NEXT STEPS: The authors believe that by exposing medical students to the principles of VBHC, students will fulfill the expectations of graduating physicians by excelling as critical thinkers, collaborative team members, and judicious care providers throughout their residency, clinical practice, and beyond. Future VBHC curricula expansions may include elective coursework, intensive seminar series, and formal dual degrees.

Health Care in the United States: Individual Right or Government Duty?

The authors discuss the notion of health care as a governmental duty rather than a right of individuals. The notion of individual rights was proposed by political philosophers of the 17th and 18th centuries, who posited that people existed in a state of nature before coming together to form communities. Members of communities relinquish certain freedoms in exchange for services provided by government, including protection of the natural rights of "life, liberty, and the pursuit of happiness." In this tradition, there are natural rights that exist before government and must be protected from government infringement. The U.S. Constitution almost exclusively enshrines negative rights, which protect natural rights from government interference. Rights belong to individuals, whereas the government has duties to provide services, such as basic education, that society deems to be important. The discussion of health care as a positive right, one requiring government to provide citizens with services, runs counter to this tradition of natural rights.The authors propose that reframing the discussion to see universal access to health care as an obligation of government, rather than a right of individuals, will center the discussion more accurately within U.S. political tradition. This may drain the emotional charge associated with claims to "rights" from public debate and allow for productive negotiations over the extent of health care appropriate for government to provide, within the context of the other obligations that form the social contract between the citizenry and its government.

Landscape of Cardiovascular Device Registries in the United States.

Background Regulators increasingly rely on registries for decision making related to high-risk medical devices in the United States. However, the limited uniform standards for registries may create substantial variability in registry implementation and utility to regulators. We surveyed the current landscape of US cardiovascular device registries and chart the extent of inconsistency in goals, administration, enrollment procedures, and approach to data access. Methods and Results A systematic review using Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines identified studies (1995-2017) referencing cardiovascular device registries with a US-based institution. Registries were then evaluated by reviewing associated articles and websites. Extracted data included device type, primary scientific aim(s), funding, stewardship (eg, administration of registry procedures), enrollment procedures, informed consent process, and mechanisms to access data for research. The 138 cardiovascular device registries in the cohort covered devices addressing interventional cardiology (65.9%), arrhythmias (15.2%), heart failure (10.1%), and valvular disease (10.1%). While the majority (55.8%) were industry-funded, stewardship was predominantly overseen by academic centers (74.0%). Most registry participation was voluntary (77.5%), but a substantial minority (19.7%) were required as a condition of device implantation. Informed consent requirements varied widely, with written consent required in only 55.1% of registries. Registry data were primarily accessible only to stewards (84.1%), with 13.8% providing pathways for external applications. Conclusions The majority of cardiovascular device registries were funded privately under the auspices of academic institutions, which set the rules for data access. The substantial variation between cardiovascular device registries suggests a role for regulators to further strengthen guidelines to improve quality, consistency, and ethical standards.

Current irritability robustly related to current and prior anxiety in bipolar disorder.

BACKGROUND: Although current irritability and current/prior anxiety have been associated in unipolar depression, these relationships are less well understood in bipolar disorder (BD). We investigated relationships between current irritability and current/prior anxiety as well as other current emotions and BD illness characteristics. METHODS: Outpatients referred to the Stanford Bipolar Disorders Clinic during 2000-2011 were assessed with the Systematic Treatment Enhancement Program for BD (STEP-BD) Affective Disorders Evaluation. Prevalence and clinical correlates of current irritability and current/prior anxiety and other illness characteristics were examined. RESULTS: Among 497 BD outpatients (239 Type I, 258 Type II; 58.1% female; mean ± SD age 35.6 ± 13.1 years), 301 (60.6%) had baseline current irritability. Patients with versus without current irritability had significantly higher rates of current anxiety (77.1% versus 42.9%, p < 0.0001) and history of anxiety disorder (73.1% versus 52.6%, p < 0.0001). Current irritability was more robustly related to current anxiety than to current anhedonia, sadness, or euphoria (all p < 0.001), and current irritability-current anxiety associations persisted across current predominant mood states. Current irritability was more robustly related to past anxiety than to all other assessed illness characteristics, including 1° family history of mood disorder, history of alcohol/substance use disorder, bipolar subtype, and current syndromal/subsyndromal depression (all p < 0.05). LIMITATIONS: Limited generalizability beyond our predominately white, female, educated, insured American BD specialty clinic sample. CONCLUSIONS: In BD, current irritability was robustly related to current/prior anxiety. Further studies are warranted to assess longitudinal clinical implications of relationships between irritability and anxiety in BD.

Neuropsychological performance and affective temperaments in Euthymic patients with bipolar disorder type II.

Affective temperament has been suggested as a potential mediator of the effect between genetic predisposition and neurocognitive functioning. As such, this report seeks to assess the extent of the correlation between affective temperament and cognitive function in a group of bipolar II subjects. 46 bipolar II outpatients [mean age 41.4 years (SD 18.2); female 58.9%] and 46 healthy controls [mean age 35.1 years (SD 18); female 56.5%] were evaluated with regard to their demographic and clinical characteristics, affective temperament, and neurocognitive performance. Crude bivariate correlation analyses and multiple linear regression models were constructed between five affective temperament subscales and eight neurocognitive domains. Significant correlations were identified in bipolar patients between hyperthymic temperament and verbal memory and premorbid IQ; cyclothymic temperament and attention; and irritable temperament, attention, and verbal fluency. In adjusting for potential confounders of the relationship between temperament and cognitive function, the strongest mediating factors among the euthymic bipolar patients were found to be residual manic and depressive symptoms. It is therefore concluded that affective temperaments may partially influence the neurocognitive performance of both healthy controls and euthymic patients with bipolar disorder type II in several specific domains.

Gender by onset age interaction may characterize distinct phenotypic subgroups in bipolar patients.

OBJECTIVE: Although bipolar disorder (BD) is a common recurrent condition with highly heterogeneous illness course, data are limited regarding clinical implications of interactions between gender and onset age. We assessed relationships between onset age and demographic/illness characteristics among BD patients stratified by gender. METHODS: Demographic and unfavorable illness characteristics, descriptive traits, and clinical correlates were compared in 502 patients from Stanford University BD Clinic patients enrolled in the Systematic Treatment Enhancement Program for BD between 2000 and 2011, stratified by gender, across pre-, peri-, and post-pubertal (<12, 13-16, and >17 years, respectively) onset-age subgroups. RESULTS: Among 502 BD patients, 58.2% were female, of whom 21.9% had pre-pubertal, 30.7% peri-pubertal, and 47.4% post-pubertal onset. Between genders, although demographics, descriptive characteristics, and most clinical correlates were statistically similar, there were distinctive onset-age related patterns of unfavorable illness characteristics. Among females, rates of 6/8 primary unfavorable illness characteristics were significantly higher in pre-pubertal and peri-pubertal compared to post-pubertal onset patients. However, among males, rates of only 3/8 unfavorable illness characteristics were significantly higher in only pre-pubertal versus post-pubertal onset patients, and none between peri-pubertal versus post-pubertal onset patients. LIMITATIONS: Caucasian, insured, suburban, American specialty clinic-referred sample limits generalizability, onset age based on retrospective recall. DISCUSSION: We describe different phenotypic presentations across age at illness onset groups according to gender. Among females and males, peri-pubertal and post-pubertal onset age groups were more different and more similar, respectively. Further investigation is warranted to assess implications of gender-by-onset-age interactions to more accurately delineate distinctive BD phenotypes.

Different characteristics associated with suicide attempts among bipolar I versus bipolar II disorder patients.

BACKGROUND: Suicide attempts are common in patients with bipolar disorder (BD), and consistently associated with female gender and certain unfavorable BD illness characteristics. Findings vary, however, regarding effects of BD illness subtype and yet other illness characteristics upon prior suicide attempt rates. We explored the effects of demographics and BD illness characteristics upon prior suicide attempt rates in patients stratified by BD illness subtype (i.e., with bipolar I disorder (BDI) versus bipolar II disorder (BDII)). METHODS: Outpatients referred to the Stanford BD Clinic during 2000-2011 were assessed with the Systematic Treatment Enhancement Program for BD Affective Disorders Evaluation. Rates of prior suicide attempt were compared in patients with and without diverse demographic and BD illness characteristics stratified by BD subtype. RESULTS: Among 494 BD outpatients (mean ± SD age 35.6 ± 13.1 years; 58.3% female; 48.6% BDI, 51.4% BDII), overall prior suicide attempt rates in were similar in BDI versus BDII patients, but approximately twice as high in BDI (but not BDII) patients with compared to without lifetime eating disorder, and in BDII (but not BDI) patients with compared to without childhood BD onset. In contrast, current threshold-level suicidal ideation and lifetime alcohol use disorder robustly but less asymmetrically increased prior suicide attempt risk across BD subtypes. LIMITATIONS: American tertiary bipolar disorder clinic referral sample, cross-sectional design. CONCLUSIONS: Further studies are needed to assess the extent to which varying clinical characteristics of samples of patients with BDI and BDII could yield varying prior suicide attempt rates in patients with BDI versus BDII.

Differential prevalence and demographic and clinical correlates of second-generation antipsychotic use in bipolar I versus bipolar II disorder.

AIMS: To assess second-generation antipsychotic (SGA) use, demographics, and clinical correlates in patients with bipolar I disorder (BDI) versus bipolar II disorder (BDII). METHODS: Stanford Bipolar Disorder (BD) Clinic outpatients enrolled during 2000-2011 were assessed with the Systematic Treatment Enhancement Program for BD (STEP-BD) Affective Disorders Evaluation. Current SGA use, demographics, and clinical correlates were assessed for BDI versus BDII. RESULTS: Among 503 BD outpatients, in BDI versus BDII, SGA use was more than twice as common (44.0% versus 21.2%), and doses were approximately twice as high. BDI patients taking (N = 107) versus not taking (N = 136) SGAs less often had current full time employment and college degree; and more often had lifetime psychiatric hospitalization, current depression, and current complex pharmacotherapy, and had a higher mean current Clinical Global Impression for Bipolar Version Overall Severity score, and these persisted significantly after covarying for employment and education. Prior psychiatric hospitalization was the most robust correlate of SGA use in BDI patients. In contrast, these demographic and clinical correlates of SGA use were not statistically significant among patients with BDII, although BDII (but not BDI) patients taking (N = 55) versus not taking (N = 205) SGAs were more likely to have current mood stabilizer use (67.3% versus 51.7%). LIMITATIONS: American tertiary bipolar disorder clinic referral sample, cross-sectional design. CONCLUSIONS: Current SGA use was robustly associated with prior psychiatric hospitalization in BDI and to a more limited extent with current mood stabilizer use in BDII. SGA use associations with other unfavorable illness characteristics in BDI were less robust.

[Neuroprogression and cognition in Bipolar Disorders: A systematic review of cognitive performance in euthymic patients]. / Neuroprogresión y cognición en los trastornos bipolares: una revisión sistemática del rendimiento cognitivo en pacientes eutímicos.

In recent years, investigators have begun to consider the possibility of explaining the physiopathology of bipolar disorder from a neuroprogressive perspective. The evidence that supports the feasibility of such an approach is varied, and arises from neuroimaging studies, batteries of neurocognitive evaluations, and tests to identify the specific biomarkers of the disorder. The present article seeks to perform a review of the research that investigates the cognitive deficits in bipolar disorder. A bibliographic revision was performed of articles published between 1990 and 2015. Levels of cognitive performance were explored in both cross-sectional and longitudinal studies. The compiled studies signal the presence of altered cognitive function, even during periods of euthymia. However, there are contradictory results as to whether bipolar disorder presents a degenerative course. New lines of investigation suggest that only a percentage of individuals with bipolar disorder are affected in a progressive manner. It is of paramount importance to perform new longitudinal studies in high-risk populations, so as to validate or refute a neuroprogressive model of cognitive deficits in patients with bipolar disorder.

American tertiary clinic-referred bipolar II disorder compared to bipolar I disorder: More severe in multiple ways, but less severe in a few other ways.

BACKGROUND: Prevalence and relative severity of bipolar II disorder (BDII) vs. bipolar I disorder (BDI) are controversial. METHODS: Prevalence, demographics, and illness characteristics were compared among 260 BDII and 243 BDI outpatients referred to the Stanford University BD Clinic and assessed with the Systematic Treatment Enhancement Program for Bipolar Disorder Affective Disorders Evaluation. RESULTS: BDII vs. BDI outpatients had statistically similar prevalence (51.7% vs. 48.3%), and in multiple ways had more severe illness, having significantly more often: lifetime comorbid anxiety (70.8% vs. 58.4%) and personality (15.4% vs. 7.4%) disorders, first-degree relative with mood disorder (62.3% vs. 52.3%), at least 10 prior mood episodes (80.0% vs. 50.9%), current syndromal/subsyndromal depression (52.3% vs. 38.4%), current antidepressant use (47.3% vs. 31.3%), prior year rapid cycling (33.6% vs. 13.4%), childhood onset (26.2% vs. 16.0%), as well as earlier onset age (17.0±8.6 vs. 18.9±8.1 years), longer illness duration (19.0±13.0 vs. 16.1±13.0), and higher current Clinical Global Impression for Bipolar Disorder-Overall Severity (4.1±1.4 vs. 3.7±1.5). However, BDII vs. BDI patients significantly less often had prior psychosis (14.2% vs. 64.2%), psychiatric hospitalization (10.0% vs. 67.9%), and current prescription psychotropic use, (81.5% vs. 93.0%), and had a statistically similar rate of prior suicide attempt (29.5% vs. 32.1%). LIMITATIONS: American tertiary bipolar disorder clinic referral sample, cross-sectional design. CONCLUSIONS: Further studies are warranted to determine the extent to which BDII, compared to BDI, can be more severe in multiple ways but less severe in a few other ways, and contributors to occurrence of more severe forms of BDII.

Recurrence rates in bipolar disorder: Systematic comparison of long-term prospective, naturalistic studies versus randomized controlled trials.

Bipolar disorder (BD) is a recurrent, lifelong illness with high risks of disability and excess mortality. Despite many treatment options with demonstrated short-term efficacy, evidence concerning long-term treatment effectiveness in BD remains limited and the relative value of naturalistic studies versus randomized, controlled trials (RCTs) in its assessment, uncertain. Systematic computer-searching yielded 10 naturalistic studies and 15 RCTs suitable for analysis of recurrence rates and their association with treatments and selected clinical factors. In naturalistic studies (3904 BD subjects, 53.3% women, 85.8% BD-I, mean onset age 29.1, followed up to 2.1 years), the pooled recurrence rate was 55.2% (26.3%/year). In RCTs (4828 subjects, 50.9% women, 96.0% BD-I, mean onset age 23.1, followed up to 1.9 years), the pooled recurrence rate was 39.3% (21.9%/year) with mood-stabilizing drug-treatment versus 60.6% (31.3%/year) with placebo; drug-versus-placebo outcomes favored antipsychotics over lithium, and disfavor an approved anticonvulsant. Depressive episode-polarity increased from 27.7% at intake to 52.0% at first-recurrence (p<0.0001). Recurrence rate (%/year) did not differ by study-type, was greater with younger onset and rapid-cycling, and paradoxically declined with longer observation. In short, recurrences of major affective episodes up to two years during putative mood-stabilizing treatment of BD patients in prospective, naturalistic studies and RCTs were substantial and similar (26.3 vs. 21.9%/year). Episode-polarity shifted strongly toward depressive first-recurrences. These findings support the value of naturalistic studies to complement long-term RCTs, and add to indications that control of depression in BD remains particularly unsatisfactory.

Efficacy and tolerability of treatments for bipolar depression.

BACKGROUND: Depression in bipolar disorder is a major therapeutic challenge associated with disability and excess mortality. METHODS: We reviewed findings from randomized placebo-controlled trials concerning efficacy and adverse effects of treatments for acute bipolar depression, including anticonvulsants, antidepressants, lithium, and modern antipsychotics, to compare numbers-needed-to-treat (NNT) versus -to-harm (NNH). RESULTS: Included were data from 22 reports involving 33 drug-placebo pairs. Antidepressants (especially modern drugs) had the most favorable (highest) risk/benefit ratio (pooled NNH/NNT=18.1). Anticonvulsants were effective agents (pooled NNT=5.06), but carbamazepine and valproate were not as well tolerated (NNH<10) as lamotrigine, and they had an unfavorable pooled NNH/NNT (3.75). Some antipsychotics (lurasidone, olanzapine+fluoxetine, and quetiapine (NNT all < 10) were effective though aripiprazole and ziprasidone were not (NNT≥45); olanzapine alone was weakly effective (NNT=11.3), and all but lurasidone (NNH=20.2) were not well tolerated (NNH≤4.18). Lithium appeared to be poorly effective but well tolerated in only one trial. CONCLUSIONS: Some anticonvulsants and antipsychotics seemed effective for acute bipolar depression, but most antipsychotics were not well tolerated. Antidepressants were effective and well-tolerated; lithium remains inadequately tested. LIMITATIONS: There are remarkably few short-term treatment trials (2.75/12 treatments), and fewer long-term trials for bipolar depression, possibly arising from exaggerated concerns about inducing mania.