Position Statement on Vascular Access Safety for Percutaneous Devices in AMI Complicated by Cardiogenic Shock.

In the United States, the frequency of using percutaneous mechanical circulatory support devices for acute myocardial infarction complicated by cardiogenic shock is increasing. These devices require large-bore vascular access to provide left, right, or biventricular cardiac support, frequently under urgent/emergent circumstances. Significant technical and logistical variability exists in device insertion, care, and removal in the cardiac catheterization laboratory and in the cardiac intensive care unit. This variability in practice may contribute to adverse outcomes observed in centers that receive patients with cardiogenic shock, who are at higher risk for circulatory insufficiency, venous stasis, bleeding, and arterial hypoperfusion. In this position statement, we aim to: 1) describe the public health impact of bleeding and vascular complications in cardiogenic shock; 2) highlight knowledge gaps for vascular safety and provide a roadmap for a regulatory perspective necessary for advancing the field; 3) propose a minimum core set of process elements, or "vascular safety bundle"; and 4) develop a possible study design for a pragmatic trial platform to evaluate which structured approach to vascular access drives most benefit and prevents vascular and bleeding complications in practice.

Improving Enrollment of Underrepresented Racial and Ethnic Populations in Heart Failure Trials: A Call to Action From the Heart Failure Collaboratory.

Importance: Despite bearing a disproportionate burden of heart failure (HF), Black and Hispanic individuals have been poorly represented in HF clinical trials. Underrepresentation in clinical trials limits the generalizability of the findings to these populations and may even introduce uncertainties and hesitancy when translating trial data to the care of people from underrepresented groups. The Heart Failure Collaboratory, a consortium of stakeholders convened to enhance HF therapeutic development, has been dedicated to improving recruitment strategies for patients from diverse and historically underrepresented groups. Observations: Despite federal policies from the US Food and Drug Administration and National Institutes of Health aimed at improving trial representation, gaps in trial enrollment proportionate to the racial and ethnic composition of the HF population have persisted. Increasing trial globalization with limited US enrollment is a major driver of these patterns. Additional barriers to representative enrollment include inequities in care access, logistical issues in participation, restrictive enrollment criteria, and English language requirements. Conclusions and Relevance: Strategies for improving diverse trial enrollment include methodical study design and site selection, diversification of research leadership and staff, broadening of eligibility criteria, community and patient engagement, and broad stakeholder commitment. In contemporary HF trials, diverse trial enrollment is not only feasible but can be efficiently achieved to improve the generalizability and translation of trial knowledge to clinical practice.

Heart Failure Population with Therapeutic Response to Sacubitril/Valsartan, Spironolactone and Candesartan: FDA Perspective.

Sacubitril/valsartan was approved by the Food and Drug Administration in 2015 to reduce the risk of cardiovascular death and hospitalization for heart failure (HHF) in patients with chronic heart failure with reduced ejection fraction defined as left ventricular ejection fraction (LVEF) ≤ 40%. This approval was based on PARADIGM-HF trial. Subsequently, PARAGON-HF was conducted to support a claim for sacubitril/valsartan in patients with heart failure with preserved ejection fraction (HFpEF), defined as LVEF ≥ 45%. PARAGON-HF failed to meet the pre-defined threshold for statistical significance for the primary composite endpoint. However, analysis of the primary endpoint by LVEF as a continuous variable demonstrated that sacubitril/valsartan was efficacious in patients with mildly abnormal LVEF similar to patients with LVEF ≤ 40% evaluated in PARADIGM-HF. This led to a broader indication for sacubitril/valsartan-"to reduce the risk of cardiovascular death and hospitalization for heart failure in adult patients with chronic heart failure. Benefits are most clearly evident in patients with left ventricular ejection fraction (LVEF) below normal. LVEF is a variable measure, so use clinical judgment in deciding whom to treat." This article describes the rationale for a revised indication for sacubitril/valsartan, emphasizes the need to go beyond a dichotomous classification of HF based on a traditional LVEF cut-off and clarifies that the product label for sacubitril/valsartan does not refer to HFpEF.

Dysregulation of the renin-angiotensin system in septic shock: Mechanistic insights and application of angiotensin II in clinical management.

Synergistic physiologic mechanisms involving the renin-angiotensin system (RAS), the sympathetic nervous system, and the arginine-vasopressin system play an integral role in blood pressure homeostasis. A subset of patients with sepsis experience septic shock with attendant circulatory, cellular, and metabolic abnormalities. Septic shock is associated with increased mortality because of an inadequacy to maintain mean arterial blood pressure (MAP) despite volume resuscitation and the use of vasopressors. Vasodilatory shock raises the dose of vasopressors required to maintain a MAP of > 65 mm Hg. The diminished response to endogenous angiotensin II in sepsis-induced vasoplegia may be related to the aberrant RAS activation that stimulates a proinflammatory beneficial antibacterial response, increasing the secretion of proinflammatory cytokines that downregulate AT-1 receptors expression. Moreover, excessive systemic upregulation of nitric oxide synthase, stimulation of prostaglandin synthesis, and activation of ATP-sensitive potassium channels followed by reduced vascular entry of calcium ions are putative mechanisms in the reduced responsiveness to vasopressors. However, intravenous angiotensin II in catecholamine-resistant septic shock patients showed substantial evidence of raising the MAP to target hemodynamic levels, thus allowing time to treat underlying conditions. Nevertheless, evidence of catecholamine-sparing effect by adding angiotensin II, aimed at increasing the therapeutic index of vasopressor therapy, does not show an attenuation of end-organ damage. The use of angiotensin II in septic shock has not been evaluated in patients who are not catecholamine resistant. This, in conjunction with an evolving definition of catecholamine resistance, provides an opportunity for further evaluation of exogenous angiotensin II in septic shock.

Correction to: FDA Approval of Angiotensin II for the Treatment of Hypotension in Adults with Distributive Shock.

The author name that previously read.

FDA Approval of Angiotensin II for the Treatment of Hypotension in Adults with Distributive Shock.

Distributive shock is a subset of shock marked by decreased systemic vascular resistance, organ hypoperfusion and altered oxygen extraction. Despite the use of intravenous fluids and either higher dose of catecholamines or other additional exogenous vasopressors to maintain blood pressure in the target range, the rate of mortality remains higher in patients with septic shock. Therefore, there is clearly an unmet need for additional safe and effective treatments. The use of angiotensin II to raise the mean arterial pressure (MAP) could provide additional therapy and the opportunity to evaluate a catecholamine-sparing effect by decreasing the dose of concomitant catecholamines while maintaining a target MAP. ATHOS-3 (Angiotensin II for the Treatment of High-Output Shock phase 3; ClinicalTrials.gov number, NCT02338843) was an adequate and well-controlled trial. The primary endpoint was the rate of MAP response at hour 3 of treatment with study drug, defined as either a 10-mmHg increase from baseline in MAP or a MAP of at least 75 mmHg. The secondary endpoints were changes from baseline in Sequential Organ Failure Assessment (SOFA) scores (total and cardiovascular). Mortality was an exploratory endpoint. The trial provided substantial evidence of the effectiveness of angiotensin II in raising blood pressure over placebo in patients with distributive shock, while keeping catecholamine levels constant. There was no change in the secondary endpoint of total SOFA scores relative to placebo when catecholamine use was reduced in lieu of angiotensin II treatment. There was a slight decrease in the secondary endpoint of cardiovascular SOFA score relative to placebo during the catecholamine-sparing phase, reflecting the catecholamine-sparing effect. There was a consistent trend in decreased mortality relative to placebo over the 28-day study period. Based on the agreements emanating from the special protocol assessment to assess blood pressure effects, the data from this single study supported approval of angiotensin II by the Food and Drug Administration for marketing in the USA.

Disparities in hypertension and cardiovascular disease in blacks: The critical role of medication adherence.

Blacks are two to three times as likely as whites to die of preventable heart disease and stroke. Declines in mortality from heart disease have not eliminated racial disparities. Control and effective treatment of hypertension, a leading cause of cardiovascular disease, among blacks is less than in whites and remains a challenge. One of the driving forces behind this racial/ethnic disparity is medication nonadherence whose cause is embedded in social determinants. Eight practical approaches to addressing medication adherence with the potential to attenuate disparities were identified and include: (1) patient engagement strategies, (2) consumer-directed health care, (3) patient portals, (4) smart apps and text messages, (5) digital pillboxes, (6) pharmacist-led engagement, (7) cardiac rehabilitation, and (8) cognitive-based behavior. However, while data suggest that these strategies may improve medication adherence, the effect on ameliorating racial/ethnic disparities is not certain. This review describes the relationship between disparities and medication adherence, which likely plays a role in persistent disparities in cardiovascular morbidity and mortality.

Improving Medication Adherence in Cardiometabolic Disease: Practical and Regulatory Implications.

Medication nonadherence, a major problem in cardiovascular disease (CVD), contributes yearly to approximately 125,000 preventable deaths, which is partly attributable to only about one-half of CVD patients consistently taking prescribed life-saving medications. Current interest has focused on how labeling and education influence adherence. This paper summarizes the scope of CVD nonadherence, describes key U.S. Food and Drug Administration initiatives, and identifies potential targets for improvement. We describe key adherence factors, methods, and technological applications for simplifying regimens and enhancing adherence, and 4 areas where additional collaborative research and implementation involving the regulatory system and clinical community could substantially reduce nonadherence: 1) identifying monitoring methods; 2) improving the evidence base to better understand adherence; 3) developing patient/health provider team-based engagement strategies; and 4) alleviating health disparities. Alignment of U.S. Food and Drug Administration approaches to dissemination of information about appropriate use with clinical practice could improve adherence, and thereby reduce CVD death and disability.