Addressing the Global Burden of Cardiovascular Disease in Women: JACC State-of-the-Art Review.

Cardiovascular diseases (CVDs) are responsible for approximately 35% of all deaths in women. In 2019, the global age-standardized CVD prevalence and mortality of women were 6,403 per 100,000 and 204 per 100,000, respectively. Although the age- and population-adjusted prevalence has decreased globally, opposite trends are evident in regions of socioeconomic deprivation. Cardiovascular health and outcomes are influenced by regional socioeconomic, environmental, and community factors, in addition to health care system and individual factors. Cardiovascular care in women is commonly plagued by delayed diagnoses, undertreatment, and knowledge gaps, particularly in women-specific or women-predominant conditions. In this paper, we describe the global epidemiology of CVD and highlight multilevel determinants of cardiometabolic health. We review knowledge and health care gaps that serve as barriers to improving CVD outcomes in women. Finally, we present national, community, health care system, and research strategies to comprehensively address cardiometabolic risk and improve outcomes in women.

Predictors of Atrial Fibrillation Development in Patients With Embolic Stroke of Undetermined Source: An Analysis of the RE-SPECT ESUS Trial.

BACKGROUND: A proportion of patients with embolic stroke of undetermined source have silent atrial fibrillation (AF) or develop AF after the initial evaluation. Better understanding of the risk for development of AF is critical to implement optimal monitoring strategies with the goal of preventing recurrent stroke attributable to underlying AF. The RE-SPECT ESUS trial (Randomized, Double-Blind Evaluation in Secondary Stroke Prevention Comparing the Efficacy and Safety of the Oral Thrombin Inhibitor Dabigatran Etexilate Versus Acetylsalicylic Acid in Patients With Embolic Stroke of Undetermined Source) provides an opportunity to assess predictors for developing AF and associated recurrent stroke. METHODS: RE-SPECT ESUS was a randomized, controlled trial (564 sites, 42 countries) assessing dabigatran versus aspirin for the prevention of recurrent stroke in patients with embolic stroke of undetermined source. Of 5390 patients enrolled and followed for a median of 19 months, 403 (7.5%) were found to develop AF reported as an adverse event or using cardiac monitoring per standard clinical care. Univariable and multivariable regression analyses were performed to define predictors of AF. RESULTS: In the multivariable model, older age (odds ratio for 10-year increase, 1.99 [95% CI, 1.78-2.23]; P<0.001), hypertension (odds ratio, 1.36 [95% CI, 1.03-1.79]; P=0.0304), diabetes (odds ratio, 0.74 [95% CI, 0.56-0.96]; P=0.022), and body mass index (odds ratio for 5-U increase, 1.29 [95% CI, 1.16-1.43]; P<0.001) were independent predictors of AF during the study. In a sensitivity analysis restricted to 1117 patients with baseline NT-proBNP (N-terminal prohormone of brain natriuretic peptide) measurements, only older age and higher NT-proBNP were significant independent predictors of AF. Performance of several published predictive models was assessed, including HAVOC (AF risk score based on hypertension, age ≥75 years, valvular heart disease, peripheral vascular disease, obesity, congestive heart failure, and coronary artery disease) and CHA2DS2-VASc (stroke risk score based on congestive heart failure, hypertension, age ≥75 years [doubled], diabetes, previous stroke, transient ischemic attack or thromboembolism [doubled], vascular disease, age 65 to 74 years, and sex category [female]) scores, and higher scores were associated with higher rates of developing AF. CONCLUSIONS: Besides age, the most important variable, several other factors, including hypertension, higher body mass index, and lack of diabetes, are independent predictors of AF after embolic stroke of undetermined source. When baseline NT-proBNP was available, only older age and elevation of this biomarker were predictive of subsequent AF. Understanding who is at higher risk of developing AF will assist in identifying patients who may benefit from more intense, long-term cardiac monitoring. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02239120.

Clinical outcomes in patients with atrial fibrillation according to sex during anticoagulation with apixaban or warfarin: a secondary analysis of a randomized controlled trial.

AIM: To assess clinical outcomes, efficacy, and safety according to sex during anticoagulation with apixaban compared with warfarin in patients with atrial fibrillation. METHODS AND RESULTS: Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) was a randomized, double-blind, placebo-controlled, multicentre trial that included 11 785 (64.7%) men and 6416 (35.3%) women with atrial fibrillation or flutter randomized to receive either warfarin or apixaban. The primary efficacy endpoint was stroke or systemic embolism; secondary efficacy endpoints were death from any cause and cardiovascular death. The primary safety endpoint was major bleeding; secondary safety endpoints were a composite of major bleeding and non-major clinically relevant bleeding. The risk of stroke or systemic embolism was similar in women vs. men [adjusted hazard ratio (adjHR): 0.91; 95% confidence interval (CI): 0.74-1.12; P = 0.38]. However, among patients with history of stroke or transient ischaemic attack, women had a lower risk of recurrent stroke compared with men (adjHR: 0.70; 95% CI: 0.50-0.97; P = 0.036). Women also had a lower risk of all-cause death (adjHR: 0.63; 95% CI: 0.55-0.73; P < 0.0001) and cardiovascular death (adjHR: 0.62; 95% CI: 0.51-0.75; P < 0.0001), and a trend towards less major bleeding (adjHR: 0.86; 95% CI: 0.74-1.01; P = 0.066) and major or non-major clinically relevant bleeding (adjHR: 0.89; 95% CI: 0.80-1.00; P = 0.049). The efficacy and safety benefits of apixaban compared with warfarin were consistent regardless of sex. CONCLUSION: In the ARISTOTLE trial, women had a similar rate of stroke or systemic embolism but a lower risk of mortality and less clinically relevant bleeding than men. The efficacy and safety benefits of apixaban compared with warfarin were consistent in men and women. TRIAL REGISTRATION: ARISTOTLE ClinicalTrials.gov number, NCT00412984.

Apixaban in patients with atrial fibrillation and prior coronary artery disease: insights from the ARISTOTLE trial.

BACKGROUND: A substantial portion of patients with atrial fibrillation (AF) also have coronary artery disease (CAD) and are at risk for coronary events. Warfarin is known to reduce these events, but increase the risk of bleeding. We assessed the effects of apixaban compared with warfarin in AF patients with and without prior CAD. METHODS AND RESULTS: In ARISTOTLE, 18,201 patients with AF were randomized to apixaban or warfarin. History of CAD was defined as documented CAD, prior myocardial infarction, and/or history of coronary revascularization. We analyzed baseline characteristics and clinical outcomes of patients with and without prior CAD and compared outcomes by randomized treatment using Cox models. A total of 6639 (36.5%) patients had prior CAD. These patients were more often male, more likely to have prior stroke, diabetes, and hypertension, and more often received aspirin at baseline (42.2% vs. 24.5%). The effects of apixaban were similar among patients with and without prior CAD on reducing stroke or systemic embolism and death from any cause (hazard ratio [HR] 0.95, 95% confidence interval [CI] 0.71-1.27, P for interaction=0.12; HR 0.96, 95% CI 0.81-1.13, P for interaction=0.28). Rates of myocardial infarction were numerically lower with apixaban than warfarin among patients with and without prior CAD. The effect of apixaban on reducing major bleeding and intracranial hemorrhage was consistent in patients with and without CAD. CONCLUSIONS: In patients with AF, apixaban more often prevented stroke or systemic embolism and death and caused less bleeding than warfarin, regardless of the presence of prior CAD. Given the common occurrence of AF and CAD and the higher rates of cardiovascular events and death, our results indicate that apixaban may be a better treatment option than warfarin for these high-risk patients.

Heart failure complicating non-ST-segment elevation acute coronary syndrome: timing, predictors, and clinical outcomes.

OBJECTIVES: This study sought to describe the occurrence and timing of heart failure (HF), associated clinical factors, and 30-day outcomes in patients with non-ST-segment elevation acute coronary syndromes (NSTE-ACS). BACKGROUND: Little is known about HF-complicating NSTE-ACS. METHODS: Using pooled patient-level data from 7 clinical trials from 1994 to 2008, we describe the occurrence and timing of HF, associated clinical factors, and 30-day outcomes in NSTE-ACS patients. HF at presentation was defined as Killip classes II to III; patients with Killip class IV or cardiogenic shock were excluded. New in-hospital cases of HF included new pulmonary edema. After adjusting for baseline variables, we created logistic regression models to identify clinical factors associated with HF at presentation and to determine the association between HF and 30-day mortality. RESULTS: Of 46,519 NSTE-ACS patients, 4,910 (10.6%) had HF at presentation. Of the 41,609 with no HF at presentation, 1,194 (2.9%) developed HF during hospitalization. A total of 40,415 (86.9%) had no HF at any time. Patients presenting with or developing HF during hospitalization were older, more often female, and had a higher risk of death at 30 days than patients without HF (adjusted odds ratio [OR]: 1.74; 95% confidence interval: 1.35 to 2.26). Older age, higher presenting heart rate, diabetes, prior myocardial infarction (MI), and enrolling MI were significantly associated with HF during hospitalization. CONCLUSIONS: In this large cohort of NSTE-ACS patients, presenting with or developing HF during hospitalization was associated with an increased risk of 30-day mortality. Research targeting new strategies to prevent and manage HF in this high-risk population is needed.

Risk of cardiovascular events associated with positive serology for Chagas: a systematic review.

BACKGROUND: Chagas disease affects mainly poor populations in Latin America. This review assesses the evidence on the independent risk of cardiovascular events associated with positive Chagas serology. METHODS: We searched for studies using the following outcomes: death, stroke, new onset heart failure, heart failure hospitalization or evidence of left ventricular dysfunction. Studies comparing patients with positive serology for Chagas with a control group with a follow-up longer than 1 year were selected. The Medline, Lilacs and Embase databases were searched on 21 January 2011 without restrictions. RESULTS: From 5236 potentially relevant studies, 25 fulfilled the inclusion criteria. Fourteen included patients with heart failure, six with severe symptoms and nine with mild symptoms or asymptomatic patients with low ejection fraction. In four studies of patients in functional class III or IV and in three studies of patients with mild symptoms, a higher risk of death was reported among those with positive serology for Chagas. Of the 11 studies of patients without symptoms or low ejection fraction, 3 showed a higher risk of mortality related to Chagas exposure. Two of these were based on the same cohort of people aged >60 years. Overall, 8 out of the 14 heart failure studies and 2 out of the 11 heart damage studies adjusted for confounding factors. CONCLUSION: Positive serology for Chagas is associated with a higher risk of death for patients with heart failure. However, there is little evidence to link positive serology for Chagas with cardiovascular events in asymptomatic subjects.

NT-probrain natriuretic peptide predicts complexity and severity of the coronary lesions in patients with non-ST-elevation acute coronary syndromes.

UNLABELLED: NT-probrain natriuretic peptide (NT-proBNP) has been associated with left ventricular (LV) dysfunction and adverse outcome in patients with non-ST-elevation acute coronary syndromes (NSTEACS). However, the underlying pathophysiological mechanisms responsible for this association have not been well established. We sought to explore the relation between NT-proBNP levels and extension of coronary artery disease (CAD) and the presence of more complex and severe coronary lesions. METHODS: This prospective, multicenter angiographic substudy included 585 patients admitted with NSTEACS. Blinded measurements of NT-proBNP and troponin T were performed at a median time of 3 hours after admission and analyzed centrally. Angiograms were read at a core laboratory by 2 independent readers blinded to patient data. Complex coronary lesion was defined as the presence of at least one of the following: thrombus (+), TIMI flow < 2, or ulcerated plaque. RESULTS: NT-probrain natriuretic peptide levels increased proportionally as LV function decreased. The levels of NT-proBNP were directly related to the extent of the CAD. This association was maintained when we analyzed patients with normal LV function (n = 257). Patients with complex coronary lesions or those with at least one of its individual component had higher levels of NT-proBNP compared with those without complex coronary lesions. After adjusting for clinical and electrocardiographic variables and other biomarkers, positive troponin (OR 2.20, 95% CI 1.50-3.22, P < .0001) and supramedian NT-proBNP levels (OR 1.72, 95% CI 1.19-2.47, P = .003) independently contributed to the prediction of complex coronary lesions. CONCLUSION: In this study of patients with NSTEACS, NT-proBNP levels progressively increase with the severity of CAD and degree of LV dysfunction. Increased levels of NT-proBNP independently predict the presence of more complex coronary lesions.

Direct comparison of characteristics, treatment, and outcomes of patients enrolled versus patients not enrolled in a clinical trial at centers participating in the TIMI 9 Trial and TIMI 9 Registry.

BACKGROUND: Questions about the generalizability of randomized trial results to clinical practice have arisen because the overall mortality rate is generally lower in trials, potentially because patients who are at lower risk are enrolled. However, little is known about the characteristics of patients included in clinical trials versus those who are not included. METHODS: The Thrombolysis In Myocardial Infarction (TIMI) 9 Registry prospectively evaluated patients with ST-elevation myocardial infarction at 20 hospitals during the TIMI 9 trial, which compared hirudin versus heparin with fibrinolysis. We compared the characteristics, treatment, and outcomes of patients enrolled in TIMI 9B (n = 3002) with other fibrinolytic-eligible patients not enrolled in TIMI 9B (n = 296) and with those not eligible for fibrinolysis by American College of Cardiology/American Heart Association criteria, at the same centers (n = 282), with the latter groups divided by use of reperfusion therapy. RESULTS: Across the groups, ranging from those in the TIMI 9 trial to those ineligible for fibrinolysis, we observed a gradient of higher-risk baseline characteristics, lower use of reperfusion therapy, and higher mortality rates (P <.001). In addition, comparing fibrinolytic-eligible patients in TIMI 9B versus those not enrolled in the trial, the use of aspirin, beta-blockers, and angiotensin-converting enzyme inhibitors was significantly higher in the TIMI 9B trial. Ineligible patients not treated with reperfusion therapy had much lower rates of use of these medications and the highest inhospital mortality rate (24%, adjusted odds ratio 2.8, P <.0001) CONCLUSIONS: In this prospective registry, patients not enrolled in a clinical trial had higher risk characteristics and worse outcomes; however, they also were treated less frequently with guideline-recommended medications, which may have contributed to their higher mortality rates.

Thresholds for the electrocardiographic change range of biochemical markers of acute myocardial infarction (GUSTO-IIa data).

The definition of acute myocardial infarction (AMI) is increasingly dependent on levels of biochemical markers, including troponin. We aimed to determine the levels of biochemical markers associated with definite evolutionary electrocardiographic (ECG) changes in patients with ST-segment elevation myocardial infarction. By examining the database of 855 patients from the troponin substudy of GUSTO-IIa, we selected patients with ST-segment elevation at baseline, evidence of evolution of the QRS, T, and ST-segment waveforms on the predischarge electrocardiogram, and 3 measurements of > or =1 of the following: creatine kinase (CK)-MB, troponin T, or troponin I. We identified 222 patients with evolutionary ECG changes. The median QRS score for this population was 5 points; the fifth percentile was 1. For patients with 3 CK-MB measurements, the fifth percentile as a multiple of the upper limit of normal was 2.1 (upper limit of normal 7.0 ng/ml). For patients with troponin T measurements, the fifth percentile as a multiple of the upper limit of normal was 11.0 (upper limit of normal 0.1 ng/ml). For patients with troponin I measurements, the fifth percentile as a multiple of the upper limit of normal was 3.8 (upper limit of normal 1.5 ng/ml). This study revealed that 95% of the patients with definite ECG evidence of AMI had a more than twofold increase in CK-MB and more than a 3- to 11-fold increase in troponin.

Persistence of the prothrombotic state after acute coronary syndromes: implications for treatment.

BACKGROUND AND RESULTS: Acute coronary syndromes (unstable angina and acute myocardial infarction) are generally caused by thrombosis over a disrupted atherosclerotic plaque. During the acute phase, antithrombotic therapy (including aspirin and heparin) has been shown to reduce the risk of death or myocardial infarction (MI). The purpose of this review is to examine the high-risk period for clinical thrombotic events that extends for several weeks after presentation and to review the treatments aimed at reducing these events. RESULTS: More than half of clinical events reported during the first month occur after the first 3 to 5 days that comprise the standard in-hospital treatment period. Several different antithrombotic approaches have been tested, including longer duration of antiplatelet therapy, anticoagulant treatment, and oral glycoprotein (GP) IIb/IIIa inhibitors. Aspirin is effective at reducing risk, and clopidogrel provides additional benefit, as does dalteparin for at least the first month. Warfarin in addition to aspirin, while generally disappointing, has not been adequately tested at higher doses. Oral GP IIb/IIIa inhibitors cause a paradoxic increased risk of death for unclear reasons. CONCLUSION: Further reduction of risk during the weeks after presentation with acute coronary syndromes remains an important therapeutic goal.

Underutilization of evidence-based medications in acute ST elevation myocardial infarction: results of the Thrombolysis in Myocardial Infarction (TIMI) 9 Registry.

The TIMI 9 Registry set out to assess the management strategies and outcomes of an unselected group of patients with acute myocardial infarction presenting with ST segment elevation (STEMI). Demographic, procedural, and outcome data were collected from 840 consecutive patients with STEMI at 20 hospitals in United States and Canada between February and September 1994. Of them, 60% were treated with thrombolytic therapy, 9% with primary angioplasty, and 31% did not receive reperfusion therapy. Patients who did not receive reperfusion therapy were older, more likely female, and had a higher prevalence of prior myocardial infarction, congestive heart failure, higher Killip class on admission, and longer time from onset of symptoms to presentation. In evaluating the standard contraindications for fibrinolysis, approximately 10% in the thrombolytic group, 40% in the primary percutaneous coronary intervention (PCI), and 34% of those not receiving reperfusion therapy had at least one of these characteristics. Of those patients treated with fibrinolysis, only 20% met the National Heart Attack Alert Program goal of door-to-drug time < or =30 minutes. Likewise, of those treated with primary PCI, only 30% had PCI performed within < or =90 minutes. In-hospital mortality was significantly higher for patients not treated with reperfusion therapy (18.9%), compared with patients treated with fibrinolysis (7.6%) and those treated with primary PCI (10.5%) (P < 0.001). Thus, we found that reperfusion therapy was underused, with only 69% of patients with STEMI receiving this proven treatment, and of those only 25% treated within the recommended timeline. These data suggest that there is room for improvement in the management of these patients.

Critical pathway for acute ST-segment elevation myocardial infarction: estimating its potential impact in the TIMI 9 Registry.

BACKGROUND: Physicians are under increasing pressure to reduce costs and maintain high quality of care. Critical pathways may help accomplish this goal. METHODS: We assessed the potential impact of implementation of a critical pathway in the Thrombolysis in Myocardial Infarction (TIMI 9) Registry, in which 840 consecutive patients with ST-elevation myocardial infarction (STEMI) were enrolled at 20 hospitals in the United States and Canada. The proposed critical pathway targets 100% use of fibrinolysis in fibrinolytic-eligible patients, 95% use of aspirin, and 90% use of beta-blockers and angiotensin-converting enzyme inhibitors (ACE-I) and incorporates a strategy of early hospital discharge for low-risk patients. Risk reduction for each intervention was estimated based on the benefits seen in large randomized controlled clinical trials or meta-analysis. RESULTS: In the TIMI 9 Registry, fibrinolysis was used in 60% of the patients; primary percutaneous coronary intervention, in 9%; and no reperfusion therapy, in 31%. Only 87% of the registry patients took aspirin during hospitalization. Of those with documented left ventricular dysfunction or congestive heart failure, 32% were discharged on ACE-I; and of those with normal ejection fraction and no evidence of congestive heat failure, only 58% were treated with beta-blockers at discharge. For early benefit and by increasing the use of reperfusion therapy and aspirin to 95% and improving the time to treatment, one could potentially save 13 lives per 1,000 patients treated per year. Similarly, if beta-blocker and ACE-I use increased up to 90% for the long term, almost 2 lives per 1,000 patients treated per year could potentially be saved. In summary, by expanding the use of a critical pathway for thrombolysis in STEMI, 15 lives per 1,000 patients treated per year could be saved. To evaluate the potential economic impact of this critical pathway on low-risk patients, 358 of 505 thrombolysis patients had no recurrent ischemia, MI, shock, or congestive heart failure through day 5. Their median length of stay was 6.7 days (25-75th percentiles, range, 4.8-10.3 days), with 73% staying in-hospital more than the target of 5 days, with similar findings for patients treated with primary angioplasty. CONCLUSIONS: These findings demonstrate that significant opportunities exist for improving medical management of patients with acute MI. Critical pathways may help reduce costs while improving quality of care.