Blood Pressure Time in Target Range and its Impact on Clinical Outcomes.

PURPOSE OF REVIEW: To examine the concept of time in target range for blood pressure (BP) management, exploring its calculation methods, implications for patient outcomes, and potential use in patient care. RECENT FINDINGS: Recent post-hoc analyses of clinical trials and observational studies highlight the importance of BP time in target range in predicting cardiovascular outcomes. Higher time in target range correlates with reduced risks of major adverse cardiovascular events including heart failure, stroke, myocardial infarction and all-cause mortality. Additionally, longer time in target range decreases the risk of incident atrial fibrillation and risk of developing dementia. BP time in target range is a novel metric offering valuable insights into BP control and its impact on clinical outcomes. Higher time in target range is consistently associated with better cardiovascular outcomes across various patient populations. However, the clinical application of BP time in target range requires further investigation through prospective clinical trials and real-world studies. Integrating wearable devices for continuous BP monitoring could enhance the practical utility of BP time in target range in hypertension management.

Obicetrapib-the Rebirth of CETP Inhibitors?

PURPOSE OF REVIEW: To provide perspective on the current development status, and potential future role, of obicetrapib, a third-generation cholesterylester transfer protein (CETP) inhibitor. Obicetrapib has received recent attention following positive Phase II clinical trial data and initiation of Phase III trials for the treatment of dyslipidemia and atherosclerotic cardiovascular disease (ASCVD). RECENT FINDINGS: The ROSE and ROSE2 trials are Phase II studies that examined the lipid lowering effects of obicetrapib in patients on pre-existing high-intensity statin therapy. Obicetrapib significantly reduced key dyslipidemia biomarkers including low density lipoprotein cholesterol (LDL-C), Apolipoprotein B (Apo B), and non-high-density lipoprotein cholesterol (non-HDL-C) while increasing high-density lipoprotein cholesterol (HDL-C). Four phase III clinical trials, including a cardiovascular outcomes trial, are ongoing. Preliminary data for obicetrapib shows favorable effects on dyslipidemia, which could theoretically lead to a decrease in ASCVD clinical events. Short-term safety data in preliminary studies shows no significant safety signals.

Impact of the COVID-19 Pandemic on Conduct and Results of CLEAR Outcomes Trial.

INTRODUCTION: The COVID-19 pandemic disrupted clinical research. CLEAR Outcomes investigated the effect of bempedoic acid (BA) versus placebo in 13 970 patients with statin intolerance and high cardiovascular (CV) risk. BA reduced the risk of the primary endpoint (composite of CV death, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization) by 13%. CLEAR Outcomes began before and continued for 2.7 years after the start of the pandemic. METHODS: The impact of the COVID-19 pandemic on patient disposition, adverse events, and major adverse CV events (MACE) in CLEAR Outcomes was assessed. RESULTS: Rates of severe infection, hospitalization, or first MACE associated with a positive COVID-19 test were low and balanced between treatment groups. Rates of all-cause death, non-CV death, and undetermined death increased in the pandemic period compared with the pre-pandemic period, while rates of CV death with a known etiology remained stable. A sensitivity analysis excluding undetermined deaths occurring after the onset of the pandemic from the CV death designation yielded hazard ratios of 0.84 (95% CI, 0.76-0.93) for the primary endpoint and 0.94 (95% CI, 0.76-1.16) for the secondary endpoint of CV death, compared with 0.87 (95% CI, 0.79-0.96) and 1.04 (95% CI, 0.88-1.24), respectively, in the original analysis. CONCLUSION: The CLEAR Outcomes trial continued uninterrupted throughout the COVID-19 pandemic. Certain trial endpoints may have been impacted by the pandemic. Specifically, the classification of undetermined deaths as CV deaths may have attenuated the effect of BA on key efficacy endpoints.

A Technology-Assisted Web Application for Consumer Access to a Nonprescription Statin Medication.

BACKGROUND: Although statins reduce adverse cardiovascular outcomes, less than one-half of eligible patients receive treatment. A nonprescription statin has the potential to improve access to statins. OBJECTIVES: This study sought to assess concordance between clinician and consumer assessment of eligibility for nonprescription statin treatment using a technology assisted self-selection Web application (Web App) and evaluate effect on low-density lipoprotein cholesterol (LDL-C) levels. METHODS: This study was a prospective actual use 6-month study to evaluate use of a Web App to qualify participants without a medical background for a moderate-intensity statin based on current guidelines. Participants entered demographic information, cholesterol values, blood pressure, and concomitant medications into the Web App, resulting in 3 possible outcomes: "do not use," "ask a doctor," and "OK to use." RESULTS: The study included 1,196 participants, with a median age of 63 years (Q1-Q3: 57-68 years); 39.6% were women, 79.3% were White, 11.7% were Black, and 4.1% had limited literacy. Mean LDL-C was 139.6 ± 28.3 mg/dL and the median calculated 10-year risk of atherosclerotic cardiovascular disease was 10.1% (Q1-Q3: 7.3%-14.0%). Initial Web App self-selection resulted in an outcome concordant with clinician assessment in 90.7% (95% CI: 88.9%-92.3%) of participants, and 98.1% (95% CI: 97.1%-98.8%) had a concordant final use outcome during treatment. Mean percent change in LDL-C was -35.5% (95% CI: -36.6% to -34.3%). Serious adverse events occurred in 27 (2.3%) participants, none related to the study drug. CONCLUSIONS: In this actual use study, a technology-assisted Web App allowed >90% of consumers to correctly self-select for statin use and achieve clinically important LDL-C reductions. (Technology-Assisted Cholesterol Trial in Consumers [TACTiC]; NCT04964544).

Predicting hypertension control using machine learning.

Hypertension is a widely prevalent disease and uncontrolled hypertension predisposes affected individuals to severe adverse effects. Though the importance of controlling hypertension is clear, the multitude of therapeutic regimens and patient factors that affect the success of blood pressure control makes it difficult to predict the likelihood to predict whether a patient's blood pressure will be controlled. This project endeavors to investigate whether machine learning can accurately predict the control of a patient's hypertension within 12 months of a clinical encounter. To build the machine learning model, a retrospective review of the electronic medical records of 350,008 patients 18 years of age and older between January 1, 2015 and June 1, 2022 was performed to form model training and testing cohorts. The data included in the model included medication combinations, patient laboratory values, vital sign measurements, comorbidities, healthcare encounters, and demographic information. The mean age of the patient population was 65.6 years with 161,283 (46.1%) men and 275,001 (78.6%) white. A sliding time window of data was used to both prohibit data leakage from training sets to test sets and to maximize model performance. This sliding window resulted in using the study data to create 287 predictive models each using 2 years of training data and one week of testing data for a total study duration of five and a half years. Model performance was combined across all models. The primary outcome, prediction of blood pressure control within 12 months demonstrated an area under the curve of 0.76 (95% confidence interval; 0.75-0.76), sensitivity of 61.52% (61.0-62.03%), specificity of 75.69% (75.25-76.13%), positive predictive value of 67.75% (67.51-67.99%), and negative predictive value of 70.49% (70.32-70.66%). An AUC of 0.756 is considered to be moderately good for machine learning models. While the accuracy of this model is promising, it is impossible to state with certainty the clinical relevancy of any clinical support ML model without deploying it in a clinical setting and studying its impact on health outcomes. By also incorporating uncertainty analysis for every prediction, the authors believe that this approach offers the best-known solution to predicting hypertension control and that machine learning may be able to improve the accuracy of hypertension control predictions using patient information already available in the electronic health record. This method can serve as a foundation with further research to strengthen the model accuracy and to help determine clinical relevance.

Lp(a) - an overlooked risk factor.

Lipoprotein(a) (Lp(a)) is an increasingly discussed and studied risk factor for atherosclerotic cardiovascular disease and aortic valve stenosis. Many genetic and epidemiological studies support the important causal role that Lp(a) plays in the incidence of cardiovascular disease. Although dependent upon the threshold and unit of measurement of Lp(a), most estimates suggest between 20 and 30% of the world's population have elevated serum levels of Lp(a). Lp(a) levels are predominantly mediated by genetics and are not significantly modified by lifestyle interventions. Efforts are ongoing to develop effective pharmacotherapies to lower Lp(a) and to determine if lowering Lp(a) with these medications ultimately decreases the incidence of adverse cardiovascular events. In this review, the genetics and pathophysiological properties of Lp(a) will be discussed as well as the epidemiological data demonstrating its impact on the incidence of cardiovascular disease. Recommendations for screening and how to currently approach patients with elevated Lp(a) are also noted. Finally, the spectrum of pharmacotherapies under development for Lp(a) lowering is detailed.

Association of pulse pressure with death, myocardial infarction, and stroke among cardiovascular outcome trial participants.

Background: Prior evidence demonstrates that pulse pressure (PP), a surrogate marker of arterial stiffness, is an independent risk factor for mortality and major adverse cardiovascular (CV) events. Objectives: The study aimed to identify the association of PP with death, myocardial infarction, and stroke among participants enrolled in large CV outcome clinical trials and determine if this association was impacted by pre-existing CV disease, or specific CV risk factors. Methods: A total of 65,382 individuals, ages 19 to 98 years, that were enrolled in one of five CV outcome trials were analyzed. Baseline demographics, history, blood pressures, and medications were collected. Univariate and multivariable analyses were conducted to explore temporal patterns, risks, and adjusted survival rates. Results: Mean baseline PP was 52 ± 12 mmHg. For every 10 mmHg increase in PP, there was an increased risk of death, stroke, or myocardial infarction (hazard ratio (HR) 1.11, 95 % CI 1.08 to 1.14, p < 0.001). Similarly, a PP ≥ 60 mmHg demonstrated an HR of 1.27 (95 % CI 1.19 to 1.36, p < 0.001) compared with PP < 60 mmHg. A similar association existed for all subgroups analyzed except for participants with a history of stroke where increasing PP did not increase risk (HR 1.02, 95 % CI 0.95 to 1.10, p = 0.53). PP was a better predictor of adverse outcomes when compared to both systolic and diastolic blood pressures using the AIC and C-index. Conclusions: Among participants enrolled in CV outcome trials, baseline PP is associated with increased risk of death, myocardial infarction, and stroke for those with pre-existing CV disease and risk factors with the exception of a prior history of stroke.

Aldosterone Synthase Inhibition With Lorundrostat for Uncontrolled Hypertension: The Target-HTN Randomized Clinical Trial.

Importance: Excess aldosterone production contributes to hypertension in both classical hyperaldosteronism and obesity-associated hypertension. Therapies that reduce aldosterone synthesis may lower blood pressure. Objective: To compare the safety and efficacy of lorundrostat, an aldosterone synthase inhibitor, with placebo, and characterize dose-dependent safety and efficacy to inform dose selection in future trials. Design, Setting, and Participants: Randomized, placebo-controlled, dose-ranging trial among adults with uncontrolled hypertension taking 2 or more antihypertensive medications. An initial cohort of 163 participants with suppressed plasma renin (plasma renin activity [PRA] ≤1.0 ng/mL/h) and elevated plasma aldosterone (≥1.0 ng/dL) were enrolled, with subsequent enrollment of 37 participants with PRA greater than 1.0 ng/mL/h. Interventions: Participants were randomized to placebo or 1 of 5 dosages of lorundrostat in the initial cohort (12.5 mg, 50 mg, or 100 mg once daily or 12.5 mg or 25 mg twice daily). In the second cohort, participants were randomized in a 1:6 ratio to placebo or lorundrostat, 100 mg once daily. Main Outcomes and Measures: The primary end point was change in automated office systolic blood pressure from baseline to study week 8. Results: Between July 2021 and June 2022, 200 participants were randomized, with final follow-up in September 2022. Following 8 weeks of treatment in participants with suppressed PRA, changes in office systolic blood pressure of -14.1, -13.2, -6.9, and -4.1 mm Hg were observed with 100 mg, 50 mg, and 12.5 mg once daily of lorundrostat and placebo, respectively. Observed reductions in systolic blood pressure in individuals receiving twice-daily doses of 25 mg and 12.5 mg of lorundrostat were -10.1 and -13.8 mm Hg, respectively. The least-squares mean difference between placebo and treatment in systolic blood pressure was -9.6 mm Hg (90% CI, -15.8 to -3.4 mm Hg; P = .01) for the 50-mg once-daily dose and -7.8 mm Hg (90% CI, -14.1 to -1.5 mm Hg; P = .04) for 100 mg daily. Among participants without suppressed PRA, 100 mg once daily of lorundrostat decreased systolic blood pressure by 11.4 mm Hg (SD, 2.5 mm Hg), which was similar to blood pressure reduction among participants with suppressed PRA receiving the same dose. Six participants had increases in serum potassium above 6.0 mmol/L that corrected with dose reduction or drug discontinuation. No instances of cortisol insufficiency occurred. Conclusions and Relevance: Among individuals with uncontrolled hypertension, use of lorundrostat was effective at lowering blood pressure compared with placebo, which will require further confirmatory studies. Trial Registration: ClinicalTrials.gov Identifier: NCT05001945.

Should Antihypertensive Medications Be Routinely Administered in the Nighttime Instead of Daytime?

The optimal timing for administering antihypertensive medications remains a topic of debate. This review examines the effectiveness of nighttime vs daytime administration of antihypertensive medications in controlling blood pressure (BP). The MAPEC and Hygia trials suggest that nighttime dosing achieves better BP control and significantly lowers cardiovascular events. However, concerns about methodology and generalizability have been raised. In contrast, the HARMONY and TIME trials found no significant difference in BP control nor cardiovascular outcomes between daytime and nighttime dosing. Current research suggests that the timing of antihypertensive medication administration may not be a crucial factor. Therefore, the decision about the timing of antihypertensive medications administration should be individualized, taking into account patient preference and clinical context, in order to promote consistent compliance.

Bempedoic Acid for Primary Prevention of Cardiovascular Events in Statin-Intolerant Patients.

Importance: The effects of bempedoic acid on cardiovascular outcomes in statin-intolerant patients without a prior cardiovascular event (primary prevention) have not been fully described. Objective: To determine the effects of bempedoic acid on cardiovascular outcomes in primary prevention patients. Design, Setting, and Participants: This masked, randomized clinical trial enrolled 13 970 statin-intolerant patients (enrollment December 2016 to August 2019 at 1250 centers in 32 countries), including 4206 primary prevention patients. Interventions: Participants were randomized to oral bempedoic acid, 180 mg daily (n = 2100), or matching placebo (n = 2106). Main Outcome Measures: The primary efficacy measure was the time from randomization to the first occurrence of any component of a composite of cardiovascular death, nonfatal myocardial infarction (MI), nonfatal stroke, or coronary revascularization. Results: Mean participant age was 68 years, 59% were female, and 66% had diabetes. From a mean baseline of 142.2 mg/dL, compared with placebo, bempedoic acid reduced low-density lipoprotein cholesterol levels by 30.2 mg/dL (21.3%) and high-sensitivity C-reactive protein levels by 0.56 mg/L (21.5%), from a median baseline of 2.4 mg/L. Follow-up for a median of 39.9 months was associated with a significant risk reduction for the primary end point (111 events [5.3%] vs 161 events [7.6%]; adjusted hazard ratio [HR], 0.70 [95% CI, 0.55-0.89]; P = .002) and key secondary end points, including the composite of cardiovascular death, MI, or stroke (83 events [4.0%] vs 134 events [6.4%]; HR, 0.64 [95% CI, 0.48-0.84]; P < .001); MI (29 events [1.4%] vs 47 events [2.2%]; HR, 0.61 [95% CI, 0.39-0.98]); cardiovascular death (37 events [1.8%] vs 65 events [3.1%]; HR, 0.61 [95% CI, 0.41-0.92]); and all-cause mortality (75 events [3.6%] vs 109 events [5.2%]; HR, 0.73 [95% CI, 0.54-0.98]). There was no significant effect on stroke or coronary revascularization. Adverse effects with bempedoic acid included a higher incidence of gout (2.6% vs 2.0%), cholelithiasis (2.5% vs 1.1%), and increases in serum creatinine, uric acid, and hepatic enzyme levels. Conclusions: In a subgroup of high-risk primary prevention patients, bempedoic acid treatment was associated with reduced major cardiovascular events. Trial Registration: ClinicalTrials.gov Identifier: NCT02993406.

Future treatments in hypertension: Can we meet the unmet needs of patients?

The prevalence of arterial hypertension is approximately 47% in the United States and 55% in Europe. Multiple different medical therapies are used to treat hypertension including diuretics, beta blockers, calcium channel blockers, angiotensin receptor blockers, angiotensin converting enzyme inhibitors, alpha blockers, central acting alpha receptor agonists, neprilysin inhibitors and vasodilators. However, despite the numerous number of medications, the prevalence of hypertension is on the rise, a considerable proportion of the hypertensive population is resistant to these therapeutic modalities and a definitive cure is not possible with the current treatment approaches. Therefore, there is a need for novel therapeutic strategies to provide better treatment and control of hypertension. In this review, our aim is to describe the latest developments in the treatment of hypertension including novel medication classes, gene therapies and RNA-based modalities.

Supplements for Lipid Lowering: What Does the Evidence Show?

PURPOSE: In this review, the regulation, proposed hypolipidemic mechanism, and efficacy of common dietary supplements (DSs) marketed for cardiovascular health are discussed. RECENT FINDINGS: Data demonstrate modest but inconsistent lipid-lowering effects with common DSs such as probiotics, soluble fibers, plant sterols, green tea, berberine, guggul, niacin, and garlic. Furthermore, data is limited regarding turmeric, hawthorn, and cinnamon. Red yeast rice has shown to be a beneficial DS, but its safety and efficacy are dependent upon its production quality and monacolin K content, respectively. Finally, soy proteins and omega-3 fatty acid-rich foods can have significant health benefits if used to displace other animal products as part of a healthier diet. Despite the rising use of DSs, data demonstrate unpredictable results. Patients should be educated on the difference between these DSs and evidence-based lipid-lowering medications proven to improve cardiovascular outcomes.

Appropriateness of Cardiovascular Disease Prevention Recommendations Obtained From a Popular Online Chat-Based Artificial Intelligence Model.

This study examines the appropriateness of artificial intelligence model responses to fundamental cardiovascular disease prevention questions.

Newer alternatives for resistant hypertension: Beyond 2022 paradigms.

Given the increased incidence of resistant hypertension and no novel agents to manage hypertension for more than 15 years, there has been an increase in the development of newer agents with unique mechanisms that will hopefully aid in getting this subset of patients under control. More recent classes of agents include nonsteroidal mineralocorticoid receptor blockers, aminopeptidase A inhibitors, dual endothelin A and B antagonists and aldosterone synthetase inhibitors, and novel agents affecting angiotensinogen mRNA in the liver. All these agents are under different levels of development and, if all goes well, should be available to the public within the next 2-5 years. In addition to these agents, renal denervation is anticipated to be approved in the United States within the next 6-9 months, whereas it has already been authorized in certain European countries. Thus, by 2025 and later, we will have a more extensive armamentarium to help quell the rise in resistant hypertension. From early actuarial data associating elevated blood pressure with mortality to the first trials of blood pressure-lowering medications to contemporary American and European hypertension guidelines, the beneficial impact of blood pressure lowering in individuals with hypertension is well established1,2-4. Population-level decreases in incident cardiovascular disease and mortality over the past 50 years reflect this well-established impact. Yet, the year-over-year decline in the incidence of cardiovascular disease has now plateaued, and concomitantly rates of uncontrolled hypertension have increased5,6. Additionally, how the global COVID-19 pandemic impacts cardiovascular disease and hypertension-related outcomes is yet to be determined, but early data suggests population-level increases in blood pressure7.