Effectiveness and Safety of Enteric-Coated vs Uncoated Aspirin in Patients With Cardiovascular Disease: A Secondary Analysis of the ADAPTABLE Randomized Clinical Trial.

Importance: Clinicians recommend enteric-coated aspirin to decrease gastrointestinal bleeding in secondary prevention of coronary artery disease even though studies suggest platelet inhibition is decreased with enteric-coated vs uncoated aspirin formulations. Objective: To assess whether receipt of enteric-coated vs uncoated aspirin is associated with effectiveness or safety outcomes. Design, Setting, and Participants: This is a post hoc secondary analysis of ADAPTABLE (Aspirin Dosing: A Patient-Centric Trial Assessing Benefits and Long-term Effectiveness), a pragmatic study of 15 076 patients with atherosclerotic cardiovascular disease having data in the National Patient-Centered Clinical Research Network. Patients were enrolled from April 19, 2016, through June 30, 2020, and randomly assigned to receive high (325 mg) vs low (81 mg) doses of daily aspirin. The present analysis assessed the effectiveness and safety of enteric-coated vs uncoated aspirin among those participants who reported aspirin formulation at baseline. Data were analyzed from November 11, 2019, to July 3, 2023. Intervention: ADAPTABLE participants were regrouped according to aspirin formulation self-reported at baseline, with a median (IQR) follow-up of 26.2 (19.8-35.4) months. Main Outcomes and Measures: The primary effectiveness end point was the cumulative incidence of the composite of myocardial infarction, stroke, or death from any cause, and the primary safety end point was major bleeding events (hospitalization for a bleeding event with use of a blood product or intracranial hemorrhage). Cumulative incidence at median follow-up for primary effectiveness and primary safety end points was compared between participants taking enteric-coated or uncoated aspirin using unadjusted and multivariable Cox proportional hazards models. All analyses were conducted for the intention-to-treat population. Results: Baseline aspirin formulation used in ADAPTABLE was self-reported for 10 678 participants (median [IQR] age, 68.0 [61.3-73.7] years; 7285 men [68.2%]), of whom 7366 (69.0%) took enteric-coated aspirin and 3312 (31.0%) took uncoated aspirin. No significant difference in effectiveness (adjusted hazard ratio [AHR], 0.94; 95% CI, 0.80-1.09; P = .40) or safety (AHR, 0.82; 95% CI, 0.49-1.37; P = .46) outcomes between the enteric-coated aspirin and uncoated aspirin cohorts was found. Within enteric-coated aspirin and uncoated aspirin, aspirin dose had no association with effectiveness (enteric-coated aspirin AHR, 1.13; 95% CI, 0.88-1.45 and uncoated aspirin AHR, 0.99; 95% CI, 0.83-1.18; interaction P = .41) or safety (enteric-coated aspirin AHR, 2.37; 95% CI, 1.02-5.50 and uncoated aspirin AHR, 0.89; 95% CI, 0.49-1.64; interaction P = .07). Conclusions and Relevance: In this post hoc secondary analysis of the ADAPTABLE randomized clinical trial, enteric-coated aspirin was not associated with significantly higher risk of myocardial infarction, stroke, or death or with lower bleeding risk compared with uncoated aspirin, regardless of dose, although a reduction in bleeding with enteric-coated aspirin cannot be excluded. More research is needed to confirm whether enteric-coated aspirin formulations or newer formulations will improve outcomes in this population. Trial Registration: ClinicalTrials.gov Identifier: NCT02697916.

Comparative Effectiveness of Aspirin Dosing in Cardiovascular Disease.

BACKGROUND: The appropriate dose of aspirin to lower the risk of death, myocardial infarction, and stroke and to minimize major bleeding in patients with established atherosclerotic cardiovascular disease is a subject of controversy. METHODS: Using an open-label, pragmatic design, we randomly assigned patients with established atherosclerotic cardiovascular disease to a strategy of 81 mg or 325 mg of aspirin per day. The primary effectiveness outcome was a composite of death from any cause, hospitalization for myocardial infarction, or hospitalization for stroke, assessed in a time-to-event analysis. The primary safety outcome was hospitalization for major bleeding, also assessed in a time-to-event analysis. RESULTS: A total of 15,076 patients were followed for a median of 26.2 months (interquartile range [IQR], 19.0 to 34.9). Before randomization, 13,537 (96.0% of those with available information on previous aspirin use) were already taking aspirin, and 85.3% of these patients were previously taking 81 mg of daily aspirin. Death, hospitalization for myocardial infarction, or hospitalization for stroke occurred in 590 patients (estimated percentage, 7.28%) in the 81-mg group and 569 patients (estimated percentage, 7.51%) in the 325-mg group (hazard ratio, 1.02; 95% confidence interval [CI], 0.91 to 1.14). Hospitalization for major bleeding occurred in 53 patients (estimated percentage, 0.63%) in the 81-mg group and 44 patients (estimated percentage, 0.60%) in the 325-mg group (hazard ratio, 1.18; 95% CI, 0.79 to 1.77). Patients assigned to 325 mg had a higher incidence of dose switching than those assigned to 81 mg (41.6% vs. 7.1%) and fewer median days of exposure to the assigned dose (434 days [IQR, 139 to 737] vs. 650 days [IQR, 415 to 922]). CONCLUSIONS: In this pragmatic trial involving patients with established cardiovascular disease, there was substantial dose switching to 81 mg of daily aspirin and no significant differences in cardiovascular events or major bleeding between patients assigned to 81 mg and those assigned to 325 mg of aspirin daily. (Funded by the Patient-Centered Outcomes Research Institute; ADAPTABLE ClinicalTrials.gov number, NCT02697916.).

Rationale and Design of the Aspirin Dosing-A Patient-Centric Trial Assessing Benefits and Long-term Effectiveness (ADAPTABLE) Trial.

Importance: Determining the right dosage of aspirin for the secondary prevention treatment of atherosclerotic cardiovascular disease (ASCVD) remains an unanswered and critical question. Objective: To report the rationale and design for a randomized clinical trial to determine the optimal dosage of aspirin to be used for secondary prevention of ASCVD, using an innovative research method. Design, Setting, and Participants: This pragmatic, open-label, patient-centered, randomized clinical trial is being conducted in 15 000 patients within the National Patient-Centered Clinical Research Network (PCORnet), a distributed research network of partners including clinical research networks, health plan research networks, and patient-powered research networks across the United States. Patients with established ASCVD treated in routine clinical practice within the network are eligible. Patient recruitment began in April 2016. Enrollment was completed in June 2019. Final follow-up is expected to be completed by June 2020. Interventions: Participants are randomized on a web platform in a 1:1 fashion to either 81 mg or 325 mg of aspirin daily. Main Outcomes and Measures: The primary efficacy end point is the composite of all-cause mortality, hospitalization for nonfatal myocardial infarction, or hospitalization for a nonfatal stroke. The primary safety end point is hospitalization for major bleeding associated with a blood-product transfusion. End points are captured through regular queries of the health systems' common data model within the structure of PCORnet's distributed data environment. Conclusions and Relevance: As a pragmatic study and the first interventional trial conducted within the PCORnet electronic data infrastructure, this trial is testing several unique and innovative operational approaches that have the potential to disrupt and transform the conduct of future patient-centered randomized clinical trials by evaluating treatments integrated in clinical practice while at the same time determining the optimal dosage of aspirin for secondary prevention of ASCVD. Trial Registration: ClinicalTrials.gov Identifier: NCT02697916.

Association of Post-Traumatic Stress Disorder Symptoms Following Hurricane Katrina With Incident Cardiovascular Disease Events Among Older Adults With Hypertension.

OBJECTIVE: To determine the association of post-traumatic stress disorder (PTSD) symptoms following Hurricane Katrina with incident cardiovascular disease (CVD) events in older, hypertensive, community-dwelling adults both overall and stratified by age, sex, and race. METHODS: This was a prospective cohort study performed in Southeastern Louisiana 12-24 months following Hurricane Katrina through February 2011. Participants were community-dwelling older adults (n = 2,073) enrolled in the Cohort Study of Medication Adherence Among Older Adults with no known history of CVD events. PTSD symptoms were assessed via telephone interview 12-24 months following Hurricane Katrina using the PTSD CheckList-Specific Version. The presence of PTSD symptoms was defined by scores greater than or equal to 37. Incident CVD events (stroke, myocardial infarction, hospitalization for congestive heart failure, or CVD death) were identified and adjudicated over a median 3.8-year follow-up period. RESULTS: Overall, 8.6% of participants screened positive for PTSD symptoms, and 11.6% had an incident CVD event during follow-up. PTSD symptoms were associated with an adjusted hazard ratio (aHR) for CVD events of 1.7 (95% confidence interval [CI], 1.1, 2.6). The association was present among blacks (aHR, 3.3, 95% CI, 1.7, 6.3) but not whites (aHR, 0.9, 95% CI, 0.4, 1.9); the interaction of PTSD symptoms and race on CVD events was statistically significant. CONCLUSION: PTSD symptoms following Hurricane Katrina were associated with a higher risk of incident CVD in older adults with hypertension, with a stronger association in blacks compared with whites.

A proposed mechanism for the Berecek phenomenon with implications for cardiovascular reprogramming.

Berecek et al reported in the 1990s that when spontaneously hypertensive rat (SHR) mating pairs were treated with captopril and the resulting pups were continued on the drug for 2 months followed by drug discontinuation, the pups did not develop full blown hypertension, and the cardiovascular structural changes associated with hypertension in SHR were mitigated. The offspring of the pups also displayed diminished hypertension and structural changes, suggesting that the drug therapy produced a heritable amelioration of the SHR phenotype. This observation is reviewed. The link between cellular renin angiotensin systems and epigenetic histone modification is explored, and a mechanism responsible for the observation is proposed. In any case, the observations of Berecek are sufficiently intriguing and biologically important to merit re-exploration and definitive explanation. Equally important is determining the role of renin angiotensin systems in epigenetic modification.

Role of intracellular angiotensin II.

It has become clear that the vasoactive peptide angiotensin II, like other so-called intracrines, can act in the intracellular space. Evidence has accumulated indicating that such angiotensin II activity can be upregulated in disease states and cause pathology. Indeed, other intracrines appear to be involved in disease pathogenesis as well. At the same time, nitric oxide, potentially a cell protective factor, has been shown to be upregulated by intracellular angiotensin II. Recently data have been developed indicating that other potentially protective factors are directly upregulated at neuronal nuclei by angiotensin II. This led to the suggestion that intracellular angiotensin II is cell protective and not pathological. Here, the data on both sides of this issue and a possible resolution are discussed. In summary, there is evidence for both protective and pathological actions of intracellular angiotensin, just as there is abundant evidence derived from whole animal physiology to indicate that angiotensin-driven signaling cascades, including angiotensin II type 2 receptor- and Mas receptor-mediated events, can mitigate the effects of the angiotensin II/angiotensin II type 1 receptor axis (25). This mitigation does not negate the physiological and pathological importance of angiotensin II/angiotensin II type 1 receptor action but does expand our understanding of the workings of both intracellular and extracellular angiotensin II.

A Pathogenic Mechanism Potentially Operative in Multiple Progressive Diseases and Its Therapeutic Implications.

A variety of peptide signaling moieties that we have termed intracrines can act in the interiors of their cells of synthesis or of target cells after internalization. These intracrine factors are known to be upregulated in such disorders as diabetic nephropathy, systolic heart failure, and age-related macular degeneration. Indeed, a similar set of intracrines is upregulated in each of these disorders, suggesting a commonality of mechanism. In addition, several chronic neurodegenerative disorders such as Alzheimer disease and Parkinson disease involve intercellular trafficking of intracellular disease-causing proteins. These disorders can be considered intracrine-like. Here the mechanistic and therapeutic implications of these observations, and of the relevant modes of intracrine action, are discussed, including the possibility that similar therapeutic approaches could be effective in multiple progressive disorders and the implications of these observations for intracrine pharmacology in general.

A Reassessment of the Pathophysiology of Progressive Cardiorenal Disorders.

Heart failure and chronic renal diseases are usually progressive and only partially amenable to therapy. These disorders can be the sequelae of hypertension or worsened by hypertension. They are associated with the tissue up-regulation of multiple peptides, many of which are capable of acting within the cell interior. This article proposes that these peptides, intracrines, can form self-sustaining regulatory loops that can spread through heart or kidney, producing progressive disease. Moreover, mineralocorticoid activation seems capable of amplifying some of these peptide networks. This view suggests an expanded explanation of the pathogenesis of progressive cardiorenal disease and suggests new approaches to treatment.

Age-Related Macular Degeneration and Intracrine Biology: An Hypothesis.

This laboratory has studied the intracellular actions of angiotensin II and other signaling proteins that can act in the intracellular space-peptides/proteins we have called intracrines. Moreover, we have suggested that general principles of intracrine action exist and can help explain the progression of some chronic degenerative diseases such as diabetic nephropathy and congestive heart failure. Here, a similar analysis is carried out in the case of age-related macular degeneration. We propose that intracrine mechanisms are operative in this disorder. In particular, we hypothesize that intracrine loops involving renin, angiotensin II, transforming growth factor-beta, vascular endothelial growth factor, bone morphogenetic protein-4, and p53, among other factors, are involved. If this analysis is correct, it suggests a commonality of mechanism linking chronic progressive renal diseases, congestive heart failure, and macular degeneration.

An Expanded View of Progressive Cardiorenal Disorders.

Chronic renal diseases and congestive heart failure are progressive disorders, which cannot be completely controlled by established therapies. It has been argued that intracrine biology involving the formation of self-sustaining intracrine regulatory loops accounts for the progression of these disorders and for the inability of standard therapies to stop disease spread. The renin-angiotensin system is a prime candidate to be involved in any such process, and an amplifying role for mineralocorticoid activation is also consistent with this view. Here, the notion of intracrine participation in congestive heart failure and chronic renal disease is expanded to include consideration of the participation of other intracrines including transforming growth factor beta 1, parathyroid hormone-related protein and vascular endothelial growth factor among others. The possibility that intracrine expression patterns account for disease phenotypes is explored. The therapeutic implications of this view are discussed.

A mechanism for mineralocortcoid participation in renal disease and heart failure.

Various forms of chronic renal disease as well as congestive heart failure progress irrespective of currently available supportive care. Clinical evidence indicates that blockade of the renin-angiotensin system and/or mineralocorticoid inhibition are partially effective. Recently, it was suggested that the initiation of feed-forward intracrine loops such as renin-angiotensin system up-regulation can explain the progression of disease in the face of the control of initiating factors such as high glucose or hypertension. Here, these notions are expanded to include a potential interaction of mineralocorticoid activity with intracrine renin-angiotensin system up-regulation. In addition to suggesting therapeutic interventions, these observations lead to an expanded view of intracrine physiology.

Studies of intracellular angiotensin II.

Many extracellular signaling proteins act within their cells of synthesis and/or in target cells after internalization. This type of action is called intracrine and it plays a role in diverse biological processes. The mechanisms of intracrine intracellular action are becoming clear thanks to the application of modern techniques of molecular biology. Here, progress in this area is reviewed. In particular the intracrine biology of angiotensin II is discussed.

Differences in cardiovascular disease risk when antihypertensive medication adherence is assessed by pharmacy fill versus self-report: the Cohort Study of Medication Adherence among Older Adults (CoSMO).

BACKGROUND: Pharmacy refill adherence assesses the medication-filling behaviors, whereas self-report adherence assesses the medication-taking behaviors. We contrasted the association of pharmacy refill and self-reported antihypertensive medication adherence with blood pressure (BP) control and cardiovascular disease (CVD) incidence. METHODS AND RESULTS: Adults (n = 2075) from the prospective Cohort Study of Medication Adherence among Older Adults recruited between August 2006 and September 2007 were included. Antihypertensive medication adherence was determined using a pharmacy refill measure, medication possession ratio (MPR; low, medium, and high MPR: <0.5, 0.5 to <0.8, and ≥0.8, respectively) and a self-reported measure, eight-item Morisky Medication Adherence Scale (MMAS-8; low, medium, and high MMAS-8: <6, 6 to <8, and 8, respectively). Incident CVD events (stroke, myocardial infarction, congestive heart failure, or CVD death) through February 2011 were identified and adjudicated. The prevalence of low, medium, and high adherence was 4.5, 23.7, and 71.8% for MPR and 14.0, 34.3, and 51.8% for MMAS-8, respectively. During a median of 3.8 years' follow-up, 240 (11.5%) people had a CVD event. Low MPR and low MMAS-8 were associated with uncontrolled BP at baseline and during follow up. After multivariable adjustment and compared to those with high MPR, the hazard ratios for CVD associated with medium and low MPR were 1.17 [95% confidence interval (CI) 0.87-1.56)] and 1.87 (95% CI: 1.06-3.30), respectively. Compared to those with high MMAS-8, the hazard ratios (95% CI) for MMAS-8 for medium and low MMAS-8 were 1.04 (0.79-1.38) and 0.89 (0.58-1.35), respectively. CONCLUSION: While both adherence measures were associated with BP control, pharmacy refill but not self-report antihypertensive medication adherence was associated with incident CVD. The differences in these associations may be because of the distinctions in what each adherence measure assesses.

A possible mechanism for the progression of chronic renal disease and congestive heart failure.

Chronic neurologic diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, as well as various forms of chronic renal disease and systolic congestive heart failure, are among the most common progressive degenerative disorders encountered in medicine. Each disease follows a nearly relentless course, albeit at varying rates, driven by progressive cell dysfunction and drop-out. The neurologic diseases are characterized by the progressive spread of disease-causing proteins (prion-like proteins) from cell to cell. Recent evidence indicates that cell autonomous renin angiotensin systems operate in heart and kidney, and it is known that functional intracrine proteins can also spread between cells. This then suggests that certain progressive degenerative cardiovascular disorders such as forms of chronic renal insufficiency and systolic congestive heart failure result from dysfunctional renin angiotensin system intracrine action spreading in kidney or myocardium.

Could intracrine biology play a role in the pathogenesis of transmissable spongiform encephalopathies, Alzheimer's disease and other neurodegenerative diseases?

Transmissible spongiform encephalopathies have been shown to result from the misfolding of normal cellular prion proteins in neurons caused by a transmissible abnormal form of the protein. In recent years, similar transmission of abnormal proteins capable of inducing abnormal folding of their normal homologues has been reported in other neurological disorders including Alzheimer's disease, Parkinson's disease and the so-called tauopathies. Thus, a new paradigm--the notion that some neurodegenerative disorders are protein "foldopathies"--has gained wide support. In addition, over recent years, the notion that some intercellular signaling proteins/peptides are intracrines--that is, they can in some instances act within their cells of synthesis or within target cells--has also gained currency. Tenets of this intracrine physiology/action have been developed. Here, it is argued that the protein functionalities demonstrated by foldopathy-related proteins are similar to intracrine actions and that these disorders could be intracrine in nature. If correct, this proposal would have therapeutic implications.

Thirty years of intracrinology.

BACKGROUND: Intracrinology is the study of the intracellular actions, regulation, trafficking, and interactions of extracellular signaling peptides/proteins. METHODS: We describe the development of intracrine biology since the term was defined in 1984. RESULTS: Intracrine biology plays a role in many normal and pathological processes and represents a fertile field for the development of novel therapeutics. CONCLUSION: Although 30 years old, the field of intracrinology is only now becoming widely accepted. Intracrine principles can be applied to the investigation of physiological processes and to the development of new therapies.