Molecular and temporal control of restimulation-induced cell death (RICD) in T lymphocytes.

For effective adaptive immunity, T lymphocytes must rapidly expand and contract in an antigen-specific manner to effectively control invading pathogens and preserve immunological memory, without sustaining excessive collateral damage to host tissues. Starting from initial antigen encounter, carefully calibrated programmed cell death pathways are critical for maintaining homeostasis over distinct phases of the T cell response. Restimulation-induced cell death (RICD), a self-regulatory apoptosis pathway triggered by re-engagement of the T cell receptor (TCR), is particularly important for constraining effector T cell expansion to preclude overt immunopathology; indeed, genetic disorders affecting key molecules involved in RICD execution can manifest in excessive lymphoproliferation, malignancy, and autoimmunity. Herein we review our current knowledge of how RICD sensitivity is ultimately regulated over the course of an immune response, including recent revelations on molecules that tune RICD by enforcing resistance or promoting susceptibility in expanding versus mature effector T cells, respectively. Detailed dissection of the molecular and temporal control of RICD also illuminates novel therapeutic strategies for correcting abnormal T cell responses noted in various immune disorders by ultimately tuning RICD sensitivity.

The evolution of pituitary cysts in growth hormone-treated children.

OBJECTIVES: We have previously shown that pituitary cysts may affect growth hormone secretion. This study sought to determine cyst evolution during growth hormone treatment in children. METHODS: Forty-nine patients with short stature, a pituitary cyst, and at least two brain MRI scans were included. The percent of the pituitary gland occupied by the cyst (POGO) was calculated, and a cyst with a POGO of ≤15% was considered small, while a POGO >15% was considered large. RESULTS: Thirty-five cysts were small, and 14 were large. Five of the 35 small cysts grew into large cysts, while 6 of the 14 large cysts shrunk into small cysts. Of 4 cysts that fluctuated between large and small, 3 presented as large and 1 as small. Small cysts experienced greater change in cyst volume (CV) (mean=61.5%) than large cysts (mean=-0.4%). However, large cysts had a greater net change in CV (mean=44.2 mm3) than small cysts (mean=21.0 mm3). Older patients had significantly larger mean pituitary volume than younger patients (435.4 mm3 vs. 317.9 mm3) and significantly larger mean CV than younger patients (77.4 mm3 vs. 45.2 mm3), but there was no significant difference in POGO between groups. CONCLUSIONS: Pituitary cyst size can vary greatly over time. Determination of POGO over time is a useful marker for determining the possibility of a pathologic effect on pituitary function since it factors both cyst and gland volume. Large cysts should be monitored closely, given their extreme, erratic behavior.

Frailty and spontaneous intracerebral hemorrhage: Does the modified frailty index predict mortality?

OBJECTIVE: This study aims to elucidate the impact of frailty on spontaneous intracranial hemorrhage (SICH) patient outcomes in the United States. PATIENTS AND METHODS: This is a single center retrospective chart review of all adult patients (≥18 years old) admitted with a primary diagnosis of SICH due to hypertension, amyloid angiopathy, and coagulopathy from 2014-2017. The studied variables included length of stay, age, sex, ICH score variables, medications, and frailty as measured by the modified Frailty Index (mFI). RESULTS: A total of 240 patients with 248 SICH were included in the analysis. In this study, mFI was not predictive of overall mortality (p = 0.12). To further investigate this issue, patients with ICH scores of 2 or 3 were separately analyzed to assess the impact of mFI on moderate ICH cases. However, mFI was also not associated with increased hospital mortality in moderate ICH cases (p = 0.812). In bivariate Spearman analysis, mFI significantly correlated with several outcome measures including modified Rankin Scale (MRS) at discharge (p = 0.01), but ICH score also correlated with these outcomes (p < 0.001). Although ICH & mFI scores were both predictive of MRS with linear regression, multivariate demonstrated that the ICH score was the only independent risk factor for MRS (p = 0.698, p < 0.001 respectively). CONCLUSION: Frailty, as measured by the mFI, was not an independent risk factor for increased mortality or worse outcomes in SICH patients. This study does not support incorporating the mFI score for SICH patients for prognostication.

Combining Engineered Nucleases with Adeno-associated Viral Vectors for Therapeutic Gene Editing.

With the recent advent of several generations of targeted DNA nucleases, most recently CRISPR/Cas9, genome editing has become broadly accessible across the biomedical community. Importantly, the capacity of these nucleases to modify specific genomic loci associated with human disease could render new classes of genetic disease, including autosomal dominant or even idiopathic disease, accessible to gene therapy. In parallel, the emergence of adeno-associated virus (AAV) as a clinically important vector raises the possibility of integrating these two technologies towards the development of gene editing therapies. Though clear challenges exist, numerous proof-of-concept studies in preclinical models offer exciting promise for the future of gene therapy.

Reliability of a Manual Procedure for Marking the EZ Endpoint Location in Patients with Retinitis Pigmentosa.

PURPOSE: We developed and evaluated a training procedure for marking the endpoints of the ellipsoid zone (EZ), also known as the inner segment/outer segment (IS/OS) border, on frequency domain optical coherence tomography (fdOCT) scans from patients with retinitis pigmentosa (RP). METHODS: A manual for marking EZ endpoints was developed and used to train 2 inexperienced graders. After training, an experienced grader and the 2 trained graders marked the endpoints on fdOCT horizontal line scans through the macula from 45 patients with RP. They marked the endpoints on these same scans again 1 month later. RESULTS: Intragrader agreement was excellent. The intraclass correlation coefficient (ICC) was 0.99, the average difference of endpoint locations (19.6 µm) was close to 0 µm, and the 95% limits were between -284 and 323 µm, approximately ±1.1°. Intergrader agreement also was excellent. The ICC values were 0.98 (time 1) and 0.97 (time 2), the average difference among graders was close to zero, and the 95% limits of these differences was less than 350 µm, approximately 1.2°, for both test times. CONCLUSIONS: While automated algorithms are becoming increasingly accurate, EZ endpoints still have to be verified manually and corrected when necessary. With training, the inter- and intragrader agreement of manually marked endpoints is excellent. TRANSLATIONAL RELEVANCE: For clinical studies, the EZ endpoints can be marked by hand if a training procedure, including a manual, is used. The endpoint confidence intervals, well under ±2.0°, are considerably smaller than the 6° spacing for the typically used static visual field.

Genome Engineering Using Adeno-associated Virus: Basic and Clinical Research Applications.

In addition to their broad potential for therapeutic gene delivery, adeno-associated virus (AAV) vectors possess the innate ability to stimulate homologous recombination in mammalian cells at high efficiencies. This process--referred to as AAV-mediated gene targeting--has enabled the introduction of a diverse array of genomic modifications both in vitro and in vivo. With the recent emergence of targeted nucleases, AAV-mediated genome engineering is poised for clinical translation. Here, we review key properties of AAV vectors that underscore its unique utility in genome editing. We highlight the broad range of genome engineering applications facilitated by this technology and discuss the strong potential for unifying AAV with targeted nucleases for next-generation gene therapy.

Confocal Adaptive Optics Imaging of Peripapillary Nerve Fiber Bundles: Implications for Glaucomatous Damage Seen on Circumpapillary OCT Scans.

PURPOSE: To improve our understanding of glaucomatous damage as seen on circumpapillary disc scans obtained with frequency-domain optical coherence tomography (fdOCT), fdOCT scans were compared to images of the peripapillary retinal nerve fiber (RNF) bundles obtained with an adaptive optics-scanning light ophthalmoscope (AO-SLO). METHODS: The AO-SLO images and fdOCT scans were obtained on 6 eyes of 6 patients with deep arcuate defects (5 points ≤-15 db) on 10-2 visual fields. The AO-SLO images were montaged and aligned with the fdOCT images to compare the RNF bundles seen with AO-SLO to the RNF layer thickness measured with fdOCT. RESULTS: All 6 eyes had an abnormally thin (1% confidence limit) RNF layer (RNFL) on fdOCT and abnormal (hyporeflective) regions of RNF bundles on AO-SLO in corresponding regions. However, regions of abnormal, but equal, RNFL thickness on fdOCT scans varied in appearance on AO-SLO images. These regions could be largely devoid of RNF bundles (5 eyes), have abnormal-appearing bundles of lower contrast (6 eyes), or have isolated areas with a few relatively normal-appearing bundles (2 eyes). There also were local variations in reflectivity of the fdOCT RNFL that corresponded to the variations in AO-SLO RNF bundle appearance. CONCLUSIONS: Relatively similar 10-2 defects with similar fdOCT RNFL thickness profiles can have very different degrees of RNF bundle damage as seen on fdOCT and AO-SLO. TRANSLATIONAL RELEVANCE: While the results point to limitations of fdOCT RNFL thickness as typically analyzed, they also illustrate the potential for improving fdOCT by attending to variations in local intensity.

NOVEL APPROACHES TO Topical Psoriasis Therapy.

Topical corticosteroids are the cornerstone of treatment for the majority of psoriasis patients. However, potential side effects of topical corticosteroids (i.e., cutaneous atrophy, telangiectasias, hypothalamic-pituitary axis suppression), coupled with the complex pathophysiology of psoriasis and the individual needs/preferences of psoriasis patients, represent a few of the limitations associated with topical corticosteroid monotherapy. While the combination of some agents with varying mechanisms of action has proven to be an effective strategy for improving efficacy and reducing concomitant drug application, others have displayed less efficacy, harm, and/or reduced cost-effectiveness. The purpose of this article is to review novel topical therapeutic combinations for the management of psoriasis and explore the role compounding pharmacies can have in providing healthcare providers and patients with effective and affordable alternative psoriasis therapies.

Baseline predictors of central aortic blood pressure: a PEAR substudy.

Elevated central systolic blood pressure (BP) increases the risk of cardiovascular events and appears superior to peripheral BP for long term risk prediction. The objective of this study was to identify demographic and clinical factors associated with central pressures in patients with uncomplicated hypertension. We prospectively examined peripheral BP, central aortic BP, and arterial wall properties and wave reflection in 57 subjects with uncomplicated essential hypertension in the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) Study. Significant predictors of central SBP included height, smoking status, heart rate (HR), and peripheral systolic BP (SBP), while central diastolic BP (DBP) was explained by peripheral DBP and HR. These variables accounted for nearly all of the variability in central SBP and central DBP (R(2) = 0.94 and R(2) = 0.98, respectively). Central pulse pressure variability was largely explained by gender, ex-smoking status, HR, peripheral SBP, and peripheral DBP (R(2) = 0.94). Central augmented pressure had a direct relationship with smoking status, peripheral SBP, and duration of hypertension, whereas it was indirectly related to height, HR, and peripheral DBP. Easily obtainable demographic and clinical factors are associated with central pressures in essential hypertensive persons. These relationships should be considered in future studies to improve assessment of BP to reduce cardiovascular risk and mortality.

SGLT-2 inhibitors and their potential in the treatment of diabetes.

Diabetes remains a burgeoning global problem, necessitating ongoing efforts on the part of pharmaceutical and device manufacturers, patients, and society to curb the frightening trends in morbidity and mortality attributable to the malady. Since 1835 when phlorizin was discovered, sodium glucose co-transporter 2 (SGLT-2) inhibitors have rested tantalizingly on the horizon, promising a more physiological approach to glucose control. These agents lower glucose by enhancing its excretion by blocking reabsorption in the renal tubules, thus eliminating glucose from the body along with the molecules' attendant effects on caloric balance, plasma osmolality, and lipids. Consequently, SGLT-2 inhibitors improve glucose control to an extent comparable to other hypoglycemic agents while simultaneously reducing body weight, blood pressure, and cholesterol - an admirable portfolio. One agent, canagliflozin, has recently been approved by the US Food and Drug Administration (FDA) and two other agents have progressed through Phase III trials, including dapagliflozin and empagliflozin. Collectively, when used as monotherapy, these agents have demonstrated reductions in hemoglobin A1c (HbA1c), body weight, and blood pressure of -0.34% to -1.03%, -2.0 to -3.4 kg, and -1.7 to -6.4 mmHg/-0.3 to -2.6 mmHg (systolic blood pressure/diastolic blood pressure), respectively. SGLT-2 inhibitors have been well tolerated, with hypoglycemia (0.9% to 4.3%) occurring infrequently in clinical trials. Safety signals related to breast and bladder cancer have arisen with dapagliflozin, though these are unsubstantiated and likely ascribed to the presence of preexisting cancer. As these agents emerge, clinicians should embrace the addition to the formulary for treating type 2 diabetes, but must also weight the risk-benefit of this new class in deciding which patient types are most likely to benefit from their novel mechanism of action.

Management of hypertension with fixed-dose triple-combination treatments.

The objective of this review is to evaluate the role of fixed-dose triple-combination therapy for the management of hypertension. An assessment of clinical trials showed that half the patients with hypertension have uncontrolled blood pressure (BP), with underlying factors including therapeutic inertia and poor patient adherence. Many patients will require three antihypertensive agents to achieve BP goals, and current guidelines recommend combining drugs with complementary mechanisms of action. Three single-pill triple-combination treatments are available and each includes an agent affecting the renin-angiotensin-aldosterone pathway (either a direct renin inhibitor or an angiotensin II receptor blocker) in combination with a calcium channel blocker and diuretic. These triple-combination therapies consistently demonstrated significantly greater BP reduction relative to the component dual combinations, with BP reductions documented across a range of patient populations. Triple-combination treatments were well tolerated in all clinical trials reviewed. The use of single-pill, triple-combination antihypertensive therapy has been shown to be an effective, well-tolerated, and convenient treatment strategy that can help patients achieve BP control.

The evolving landscape of RAAS inhibition: from ACE inhibitors to ARBs, to DRIs and beyond.

Chronic renin-angiotensin-aldosterone system (RAAS) activation has far-reaching effects on cardiometabolic risk and is a substantial contributor to cardiovascular (CV) disease and renal dysfunction. The vascular effects of sustained RAAS activation are associated with hemodynamic imbalances, as well as inflammatory stimulation and prothrombotic processes that lead to fibrosis, endothelial dysfunction and cellular remodeling. RAAS inhibition therapies, which include the use of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers and more recently, direct renin inhibitors, have been used in clinical practice for more than 30 years. Our understanding of how these drugs work, alone and in combination, has contributed to an expanding landscape of treatment options and established RAAS inhibition as essential for reducing the risk of CV and renal disease. This perspective provides a historical overview of how RAAS inhibitors have evolved to their present-day status and will discuss recently discovered functions for components of this complicated and powerful regulatory system.

Dapagliflozin: a novel sodium-glucose cotransporter type 2 inhibitor for the treatment of type 2 diabetes mellitus.

The prevalence of diabetes mellitus has grown to staggering numbers, and its incidence is expected to rise in the next 2 decades. The need for novel approaches to treat hyperglycemia cannot be ignored. Current agents have been shown to modestly improve glycemia and in some cases prevent complications of diabetes, but they become less effective over time and are often accompanied by undesirable adverse effects. Dapagliflozin is the lead agent in a new class of oral antidiabetic agents known as sodium-glucose cotransporter type 2 (SGLT2) inhibitors, which represent a novel approach to the management of type 2 diabetes mellitus. By selectively and reversibly blocking the SGLT2 receptor, dapagliflozin prevents the reabsorption of glucose at the renal proximal tubule. Phase II and III clinical trials have demonstrated that dapagliflozin is a safe and effective method for treating type 2 diabetes. Dapagliflozin produces a sustained, dose-dependent reduction in plasma glucose levels while simultaneously improving insulin secretion and sensitivity. Over 12-24 weeks, reductions in hemoglobin A(1c) ranged from 0.54-0.89% when dapagliflozin was administered once/day (either as monotherapy or add-on therapy to oral antidiabetic drugs with or without insulin) to patients with type 2 diabetes. Therapy with dapagliflozin also results in a mild osmotic-diuretic effect that may account for decreases in total body weight (~2-3 kg) and blood pressure (systolic 2-5 mm Hg, diastolic 1.5-3 mm Hg), and increases in hematocrit (1-2%). Dapagliflozin has a favorable safety profile, with the rates of hypoglycemia similar to those of placebo. Genital and urinary tract infections were more commonly reported in patients taking dapagliflozin (2-13%) than those taking placebo (0-8%). Dapagliflozin does not appear to cause electrolyte disturbances, hepatotoxicity, or nephrotoxicity. Results from clinical trials have been promising, and well-designed clinical programs that address the long-term safety and efficacy of dapagliflozin are under way.

Carvedilol reduces aortic wave reflection and improves left ventricular/vascular coupling: a comparison with atenolol (CENTRAL Study).

Blood pressure (BP) characteristics, such as central aortic pressure and arterial stiffness, independently predict cardiovascular events. The effects of pharmacologically dissimilar ß-blockers on these properties have not been fully elucidated. Patients with essential hypertension and without significant concomitant cardiovascular disease were randomly assigned to controlled-release carvedilol, force-titrated to 80 mg (n=22), or atenolol, force-titrated to 100 mg (n=19); each was given once daily for 4 weeks. Baseline characteristics were similar. At the end of week 4, atenolol and carvedilol reduced central and brachial systolic and diastolic BP to a similar extent. Central augmentation index was increased in atenolol-treated patients but not carvedilol-treated patients (atenolol 4.47% vs carvedilol -0.68%; P=.04). Mean augmented central aortic pressure increased slightly during atenolol treatment (+1.1 mm Hg) but decreased slightly during carvedilol treatment (-1.1 mm Hg), although the difference in these changes was not statistically significant (P=.23). Pulse pressure amplification was reduced more with atenolol at week 4 (atenolol -10.7% vs carvedilol -1.8%; P=.02). Therefore, we conclude that carvedilol results in more favorable pulse pressure amplification and augmentation index by increasing arterial compliance and reducing the magnitude of wave reflection, respectively, compared with atenolol.

Functional role of kallikrein 6 in regulating immune cell survival.

BACKGROUND: Kallikrein 6 (KLK6) is a newly identified member of the kallikrein family of secreted serine proteases that prior studies indicate is elevated at sites of central nervous system (CNS) inflammation and which shows regulated expression with T cell activation. Notably, KLK6 is also elevated in the serum of multiple sclerosis (MS) patients however its potential roles in immune function are unknown. Herein we specifically examine whether KLK6 alters immune cell survival and the possible mechanism by which this may occur. METHODOLOGY/PRINCIPAL FINDINGS: Using murine whole splenocyte preparations and the human Jurkat T cell line we demonstrate that KLK6 robustly supports cell survival across a range of cell death paradigms. Recombinant KLK6 was shown to significantly reduce cell death under resting conditions and in response to camptothecin, dexamethasone, staurosporine and Fas-ligand. Moreover, KLK6-over expression in Jurkat T cells was shown to generate parallel pro-survival effects. In mixed splenocyte populations the vigorous immune cell survival promoting effects of KLK6 were shown to include both T and B lymphocytes, to occur with as little as 5 minutes of treatment, and to involve up regulation of the pro-survival protein B-cell lymphoma-extra large (Bcl-XL), and inhibition of the pro-apoptotic protein Bcl-2-interacting mediator of cell death (Bim). The ability of KLK6 to promote survival of splenic T cells was also shown to be absent in cell preparations derived from PAR1 deficient mice. CONCLUSION/SIGNIFICANCE: KLK6 promotes lymphocyte survival by a mechanism that depends in part on activation of PAR1. These findings point to a novel molecular mechanism regulating lymphocyte survival that is likely to have relevance to a range of immunological responses that depend on apoptosis for immune clearance and maintenance of homeostasis.

Aliskiren and valsartan combination therapy for the management of hypertension.

Combination therapy is necessary for most patients with hypertension, and agents that inhibit the renin-angiotensin-aldosterone system (RAAS) are mainstays in hypertension management, especially for patients at high cardiovascular and renal risk. Single blockade of the RAAS with an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) confers some cardiorenal protection; however, these agents do not extinguish the RAAS as evidenced by a reactive increase in plasma renin activity (PRA), a cardiovascular risk marker, and incomplete cardiorenal protection. Dual blockade with an ACE inhibitor and an ARB offers no additional benefit in patients with hypertension and normal renal and left ventricular function. Indeed, PRA increases synergistically with dual blockade. Aliskiren, the first direct renin inhibitor (DRI) to become available has provided an opportunity to study the merit of DRI/ARB combination treatment. By blocking the first and rate-limiting step in the RAAS, aliskiren reduces PRA by at least 70% and buffers the compensatory increase in PRA observed with ACE inhibitors and ARBs. The combination of a DRI and an ARB or an ACE inhibitor is an effective approach for lowering blood pressure; available data indicate that such combinations favorably affect proteinuria, left ventricular mass index, and brain natriuretic peptide in patients with albuminuria, left ventricular hypertrophy, and heart failure, respectively. Ongoing outcome studies will clarify the role of aliskiren and aliskiren-based combination RAAS blockade in patients with hypertension and those at high cardiorenal risk.

Improving blood pressure control rates by optimizing combination antihypertensive therapy.

IMPORTANCE OF THE FIELD: Hypertension is the most common preventable cause of cardiovascular morbidity and mortality. Despite the availability of a multitude of antihypertensive drugs, blood pressure (BP) control rates remain poor in the majority of patients with hypertension due to both patient- and clinician-related factors. The purpose of this review is to describe how healthcare professionals can best utilize combination therapy to optimize patient antihypertensive treatment and achieve BP goals. AREAS COVERED IN THIS REVIEW: Data are discussed describing the common need for multiple antihypertensive agents for achieving BP control, importance of the time required for BP control on patient outcomes, and key clinical trial experiences for guiding decisions in antihypertensive regimen selection, with particular attention to the efficacy and tolerability of triple-therapy combinations and the benefits and disadvantages of single-pill formulations for combination regimens. Literature searches of these various topics were conducted in July 2009 (using no time period limits), with the paper later updated with published literature available as of May 2010 (including abstracts from the 2010 annual meeting of the American Society of Hypertension). WHAT THE READER WILL GAIN: The reader will derive an appreciation for general need for the use of two, and often three or more, antihypertensive agents for achieving BP goals, supporting the importance of thorough patient assessment in determining the appropriateness of combination therapy early in the course of treatment. They will also be updated as to the clinical trial data available for triple-therapy combinations, including both published and recently presented data. TAKE HOME MESSAGE: By optimizing efficacy, decreasing side effects, and increasing adherence, combination therapy using single-pill combinations can improve outcomes in patients with mild to moderate hypertension.

How to obtain appropriate type 2 diabetes control in the first 180 days of treatment initiation.

Good control of diabetes provides meaningful microvascular risk reduction; yet, patients with type 2 diabetes mellitus commonly languish at unsatisfactory levels of glycated hemoglobin (HbA1c) for protracted periods. A variety of factors contribute to this clinical inertia, as clinicians tend to be too conservative in their treatment of patients who are not achieving glycemic control. Available clinical data suggest the near-maximal blood glucose reduction achievable with use of most antidiabetic agents typically occurs within several weeks of treatment initiation. Based on this time course of action, we propose that optimal glycemic control can be attained within 180 days of treatment initiation by advancing antihyperglycemic therapy more rapidly than typical current practice. Our approach builds on current recommendations, though it seeks to redefine standard management of type 2 diabetes by placing greater emphasis on the timing of treatment intensification. We recommend the total period patients spend with uncontrolled hyperglycemia be minimized by shortening the number of steps along the treatment intensification ladder. This can be achieved by establishing combination therapy early in cases where baseline HbA1c levels are markedly elevated, including the prompt addition of basal insulin therapy when it becomes apparent that oral agents alone are unlikely to attain glycemic goals.

Efficacy and safety of ticagrelor: a reversible P2Y12 receptor antagonist.

OBJECTIVE: To summarize the pharmacokinetic and pharmacodynamic properties of ticagrelor, a selective P2Y12 receptor antagonist, and evaluate its role in the treatment of patients with acute coronary syndromes (ACS). DATA SOURCES: A literature search was conducted in MEDLINE (1966-November 2009), International Pharmaceutical Abstracts (1970-November 2009), and EMBASE (1990-November 2009) using the MeSH terms and key words AZD6140, ticagrelor, P2Y12 receptor antagonist, cardiovascular disease, ACS, atherothrombosis, and platelets. STUDY SELECTION AND DATA EXTRACTION: Selected studies evaluated the pharmacology, pharmacokinetics, pharmacodynamics, safety, and efficacy of ticagrelor for the treatment of ACS. DATA SYNTHESIS: Ticagrelor selectively and reversibly blocks the P2Y12 receptor, inhibiting platelet aggregation and preventing amplification of platelet activation. Optimal dosing strategy as determined by ticagrelor's pharmacokinetic and pharmacodynamic profile is a loading dose of 180 mg followed by 90 mg by mouth twice daily. At these doses, greater platelet inhibition is observed with ticagrelor as compared to clopidogrel 75 mg once daily in both clopidogrel-experienced and -naïve patients. Studies in patients experiencing ACS concluded that ticagrelor reduced the rate of cardiovascular death, nonfatal myocardial infarction, stent thrombosis, and overall mortality compared to clopidogrel without increasing major bleeding when administered with standard therapy for ACS. There was no significant difference in the risk of stroke with ticagrelor compared to clopidogrel; however, intracranial bleeding was more common with ticagrelor. Ticagrelor is well tolerated; however, minor bleeding, dyspnea, hypotension, nausea, and ventricular pauses were reported more frequently than with clopidogrel. Reversible inhibition with ticagrelor may allow for more rapid surgical intervention after discontinuation, suggesting greater flexibility in treatment of ACS. CONCLUSIONS: Ticagrelor's improved pharmacokinetic and pharmacodynamic profile builds upon the limitations of currently available P2Y12 receptor antagonists. Ticagrelor represents a promising approach for the prevention of cardiovascular events in patients with ACS.