Medical Marijuana, Recreational Cannabis, and Cardiovascular Health: A Scientific Statement From the American Heart Association.

Cannabis, or marijuana, has potential therapeutic and medicinal properties related to multiple compounds, particularly Δ-9-tetrahydrocannabinol and cannabidiol. Over the past 25 years, attitudes toward cannabis have evolved rapidly, with expanding legalization of medical and recreational use at the state level in the United States and recreational use nationally in Canada and Uruguay. As a result, the consumption of cannabis products is increasing considerably, particularly among youth. Our understanding of the safety and efficacy of cannabis has been limited by decades of worldwide illegality and continues to be limited in the United States by the ongoing classification of cannabis as a Schedule 1 controlled substance. These shifts in cannabis use require clinicians to understand conflicting laws, health implications, and therapeutic possibilities. Cannabis may have therapeutic benefits, but few are cardiovascular in nature. Conversely, many of the concerning health implications of cannabis include cardiovascular diseases, although they may be mediated by mechanisms of delivery. This statement critically reviews the use of medicinal and recreational cannabis from a clinical but also a policy and public health perspective by evaluating its safety and efficacy profile, particularly in relationship to cardiovascular health.

The American Heart Association 2030 Impact Goal: A Presidential Advisory From the American Heart Association.

Each decade, the American Heart Association (AHA) develops an Impact Goal to guide its overall strategic direction and investments in its research, quality improvement, advocacy, and public health programs. Guided by the AHA's new Mission Statement, to be a relentless force for a world of longer, healthier lives, the 2030 Impact Goal is anchored in an understanding that to achieve cardiovascular health for all, the AHA must include a broader vision of health and well-being and emphasize health equity. In the next decade, by 2030, the AHA will strive to equitably increase healthy life expectancy beyond current projections, with global and local collaborators, from 66 years of age to at least 68 years of age across the United States and from 64 years of age to at least 67 years of age worldwide. The AHA commits to developing additional targets for equity and well-being to accompany this overarching Impact Goal. To attain the 2030 Impact Goal, we recommend a thoughtful evaluation of interventions available to the public, patients, providers, healthcare delivery systems, communities, policy makers, and legislators. This presidential advisory summarizes the task force's main considerations in determining the 2030 Impact Goal and the metrics to monitor progress. It describes the aspiration that these goals will be achieved by working with a diverse community of volunteers, patients, scientists, healthcare professionals, and partner organizations needed to ensure success.

Non-eligibility for reperfusion therapy in patients presenting with ST-segment elevation myocardial infarction: Contemporary insights from the National Cardiovascular Data Registry (NCDR).

BACKGROUND: Reperfusion therapy is lifesaving in patients presenting with ST-segment elevation myocardial infarction (STEMI). Contemporary data describing the characteristics and outcomes of patients presenting with STEMI not receiving reperfusion therapy are lacking. METHODS: Using the ACTION Registry-GWTG database, we examined 219,726 STEMI patients (January 2007-December 2013) at 721 percutaneous coronary intervention (PCI)-capable hospitals in United States. Clinical characteristics and in-hospital outcomes were stratified by those who underwent reperfusion (n = 188,200; 86%), those who did not undergo reperfusion with a reason for ineligibility (n = 27,179; 12%), and those without reperfusion but had no reason for ineligibility (n = 4,347; 2%). RESULTS: Compared with STEMI patients receiving reperfusion therapy, the nonreperfusion groups were older, were more often female, and had higher rates of hypertension, diabetes, prior myocardial infarction, prior stroke, atrial fibrillation, and left bundle-branch block and heart failure on presentation. The major reason for reperfusion noneligibility was coronary anatomy not suitable for PCI (33%). Presence of 3-vessel coronary disease was more common in the nonreperfusion groups (with or without a documented reason) compared with reperfusion group (38% and 36% vs 26%, P < .001, respectively). In-hospital mortality was higher in patients not receiving reperfusion therapy with or without a documented reason compared with the reperfusion group (adjusted odds ratio [95% CI] 1.88 [1.78-1.99] and 1.37 [1.21-1.57], respectively). CONCLUSION: Most patients with STEMI not receiving reperfusion therapy had a documented reason. Coronary anatomy not suitable for PCI was the major contributor to ineligibility. In-hospital mortality was higher in patients not receiving reperfusion therapy.

Clinical characteristics and in hospital outcomes of heart transplant recipients with allograft vasculopathy undergoing percutaneous coronary intervention: Insights from the National Cardiovascular Data Registry.

BACKGROUND: Cardiac allograft vasculopathy is a major cause of morbidity and mortality following heart transplantation. Large multicenter studies evaluating the clinical characteristics and inhospital outcomes of heart transplant recipients undergoing percutaneous coronary intervention (PCI) are lacking. OBJECTIVE: To evaluate the clinical characteristics, treatment patterns and inhospital outcomes of heart transplant recipients undergoing PCI compared to general population. METHODS: We analyzed 1,897,328 patients from the National Cardiovascular Data Registry CathPCI registry who underwent PCI of at least 1 native vessel between July 2009 and December 2013 from 1,477 centers, of which 542 patients (0.03%) were heart transplant recipients. Clinical characteristics were evaluated and, after 1:4 propensity matching, inhospital outcomes were compared between 538 heart transplant patients and 2,128 non-transplant patients. RESULTS: Transplant recipients undergoing PCI had a higher prevalence of diabetes, dyslipidemia and peripheral vascular disease; lower prevalence of angina, acute coronary syndrome, abnormal noninvasive functional study, and type C coronary lesions compared to the non-transplant PCI population. After propensity matching, all-cause inhospital mortality was similar between transplant and non-transplant groups (1.3% vs 1.0%; OR, 1.21; 95% CI, 0.54-2.67). CONCLUSION: This is the largest series to date outlining the characteristics of heart transplant recipients undergoing PCI. Similar inhospital outcomes were noted in heart transplant recipients compared to the general population. Further studies evaluating long-term outcomes are warranted.

Use and Outcomes of Triple Therapy Among Older Patients With Acute Myocardial Infarction and Atrial Fibrillation.

BACKGROUND: Antithrombotic therapy for acute myocardial infarction (MI) with atrial fibrillation (AF) among higher risk older patients treated with percutaneous coronary intervention (PCI) remains unclear. OBJECTIVES: This study sought to determine appropriate antithrombotic therapy for acute MI patients with AF treated with PCI. METHODS: We examined 4,959 patients ≥65 years of age with acute MI and AF who underwent coronary stenting (Acute Coronary Treatment and Intervention Outcomes Network Registry-Get With the Guidelines). The primary effectiveness outcome was 2-year major adverse cardiac events (MACE) comprising death, readmission for MI, or stroke; the primary safety outcome was bleeding readmission. Outcomes with dual antiplatelet therapy (DAPT) or triple therapy (DAPT plus warfarin) were compared using Cox proportional hazard modeling with inverse probability-weighted propensity adjustment. RESULTS: Among 4,959 patients, 27.6% (n = 1,370) were discharged on triple therapy. Relative to DAPT, patients on triple therapy had a similar risk of MACE (adjusted hazard ratio [HR]: 0.99 [95% confidence interval (CI): 0.86 to 1.16]) but significantly greater risk of bleeding requiring hospitalization (adjusted HR: 1.61 [95% CI: 1.31 to 1.97]) and greater risk of intracranial hemorrhage (adjusted HR: 2.04 [95% CI: 1.25 to 3.34]). Of 1,591 Medicare Part D patients, 90-day post-discharge warfarin persistence among patients discharged on warfarin was 93.2% (n = 412). Results of 90-day landmark analyses comparing triple therapy versus DAPT in patients persistently on warfarin versus those not discharged on warfarin who had not filled a warfarin prescription were similar to our primary findings. CONCLUSIONS: Approximately 1 in 4 older AF patients undergoing PCI for MI were discharged on triple therapy. Those receiving triple therapy versus DAPT had higher rates of major bleeding without a measurable difference in composite MI, death, or stroke.

Chronic vitamin K antagonist therapy and bleeding risk in ST elevation myocardial infarction patients.

OBJECTIVES: Acute management of ST elevation myocardial infarction (STEMI) patients on chronic vitamin K antagonist (VKA) therapy is uncertain. This study aims to estimate in-hospital major bleeding risk among STEMI patients on chronic VKA treated with primary percutaneous coronary intervention (PCI); and determine the relationship between bleeding and acute treatments stratified by international normalised ratio (INR) values. METHODS: We retrospectively examined 120,270 STEMI patients treated with primary PCI at 586 national registry hospitals (2007-2012). RESULTS: Overall, 3101 patients (2.6%) were on VKA which was associated with increased in-hospital major bleeding risk when compared with patients not on VKA (17.0%, vs 10.1%; adjusted OR 1.26, 95% CI 1.13 to 1.40). In patients on VKA, admission INR ≥2.0 was not associated with an increase in bleeding risk compared to INR <2.0. Patients on VKA were more likely to receive clopidogrel or bivalirudin within 24 h of presentation (acute), but less likely to receive prasugrel, heparin, or glycoprotein IIb/IIIa inhibitors (GPI). In those patients, acute GPI was associated with increased bleeding risk (adjusted OR 1.92, 95% CI 1.54 to 2.40) while bivalirudin was associated with decreased risk (adjusted OR 0.69, 95% CI 0.55 to 0.86); bleeding risk associated with heparin, bivalirudin, ADP-receptor blockers, or GPI was similar between INR ≥2.0 and <2.0. CONCLUSIONS: In STEMI patients treated with primary PCI, chronic VKA therapy was associated with a significant increase in in-hospital major bleeding risk compared to no VKA therapy, irrespective of whether admission INR was ≥2.0 or not. In patients on VKA, GPI was associated with increased bleeding risk while bivalirudin was associated with decreased risk.

Transcatheter coiling of saphenous vein graft to coronary sinus after coronary artery bypass surgery: a case report.

Unintended graft anastamosis to coronary veins after coronary artery bypass surgery is an extraordinarily rare complication. The following case report involves the unintended grafting of a saphenous vein to the coronary sinus rather than the intended arterial target during coronary artery bypass surgery, and the subsequent physiologic consequences and clinical management.

Clot strength is negatively associated with ambulatory function in patients with peripheral artery disease and intermittent claudication.

Peripheral artery disease (PAD) is associated with exercise impairment and greater thrombotic risk. We investigated whether clot formation and platelet aggregation assessed by thromboelastography and light-transmission aggregometry correlate with the severity of symptomatic PAD assessed by ambulatory function measures. We studied 40 symptomatic patients with PAD in whom severity of disease was assessed using ankle-brachial index, peak walking time (PWT), claudication onset time, peak oxygen uptake, daily ambulatory activity, and walking impairment questionnaire (WIQ) scores. Clot strength correlated negatively with peak oxygen uptake, PWT, WIQ distance, and stair-climbing scores. Time to clot formation did not correlate with exercise parameters. Platelet aggregation was negatively correlated with WIQ distance score and was positively correlated with PWT and peak oxygen uptake. In conclusion, clot strength and platelet aggregation correlated with objective and self-perceived ambulatory measures. Patients with PAD having more severe walking impairment may be likely to form stronger clots.

Effect of exercise training on clot strength in patients with peripheral artery disease and intermittent claudication: An ancillary study.

OBJECTIVES: Patients with peripheral artery disease have walking impairment, greater thrombotic risk, and are often treated with exercise training. We sought to determine the effect of a 3-month-long exercise program on clot strength among patients with peripheral artery disease and intermittent claudication. METHODS: Twenty-three symptomatic peripheral artery disease patients were randomly assigned to a walking exercise program or to an attention control group who performed light resistance exercise. We investigated the effect of exercise training on clot strength and time to clot formation was assessed by thromboelastography. RESULTS: After 3 months of exercise, clot strength (maximal amplitude) and time to clot formation (R) did not change significantly from baseline, even after improvements in claudication onset time (p < 0.01) and peak walking time (p < 0.05). Furthermore, changes in clot formation parameters were not significantly different between groups. Among the 10 individuals demonstrating a reduction in clot strength (reduced maximal amplitude), one was a smoker (10%) compared to 9 of 13 non-responders (69%) whose maximal amplitude was unchanged or increased (p = 0.0097). CONCLUSION: In this ancillary study, a 12-week walking program improved ambulatory function in peripheral artery disease patients with claudication, but does not modify clot strength or time to clot formation. Larger studies are needed to confirm these hypothesis generating findings and to determine whether a different amount or type of exercise may induce a change in clotting in this patient population.

Impact of diabetes mellitus on clinical characteristics, management, and in-hospital outcomes in patients with acute myocardial infarction (from the NCDR).

Patients with diabetes mellitus (DM) presenting with acute myocardial infarction (AMI) have worse outcomes versus those without DM. Comparative contemporary data in patients presenting with AMI with insulin-requiring diabetes mellitus (IRDM), noninsulin-requiring diabetes mellitus (NIRDM), and newly identified DM (hemoglobin A1C level >6.5%) versus patients without DM are limited. This observational study from the National Cardiovascular Data Registry (NCDR) Acute Coronary Treatment and Intervention Outcomes Network-Get with the Guidelines (ACTION Registry-GWTG consisted of 243,861 patients with AMI from 462 US sites identified from January 2007 to March 2011 entered into the registry. Clinical characteristics, management, and in-hospital outcomes were analyzed. Patients with DM with non-ST-segment elevation myocardial infarction (NSTEMI; n = 53,094, 35%) were less likely to undergo diagnostic angiography or revascularization, whereas those with ST-segment elevation myocardial infarction (STEMI) (n = 21,507, 23%) were less likely to undergo reperfusion therapy compared with patients without DM. There was an increased adjusted risk of in-hospital mortality in the DM group in both the NSTEMI (odds ratio [OR] 1.14, 95% confidence interval [CI] 1.06 to 1.22) and STEMI (OR 1.17, 95% CI 1.07 to 1.27) population. In patients with DM, the risk-adjusted in-hospital mortality was higher in patients with IRDM than those with NIRDM in the NSTEMI group (OR 1.12, 95% CI 1.01 to 1.24) but not in the STEMI group (OR 1.12, 95% CI 0.95 to 1.32). Newly diagnosed patients with DM presenting with AMI had similar unadjusted in-hospital outcomes compared with patients without DM. In conclusion, patients with DM presenting with AMI have a higher mortality risk than patients without DM. In patients with DM, those with IRDM presenting with NSTEMI had an increased mortality than those with NIRDM.

In-hospital switching between clopidogrel and prasugrel among patients with acute myocardial infarction treated with percutaneous coronary intervention: insights into contemporary practice from the national cardiovascular data registry.

BACKGROUND: Although randomized clinical trials have compared clopidogrel with higher potency ADP receptor inhibitors (ADPris) among patients with myocardial infarction, little is known about the frequency and factors associated with switching between ADPris in clinical practice. METHODS AND RESULTS: We studied 47 040 patients with myocardial infarction treated with percutaneous coronary intervention, who received either clopidogrel or prasugrel within 24 hours of admission at 361 US hospitals from July 2009 to June 2011 using the merged Acute Coronary Treatment and Intervention Outcomes Network Registry-Get With the Guidelines and CathPCI Registry database. Hierarchical logistic regression modeling was used to determine factors independently associated with in-hospital ADPri switching. Among 40 531 patients treated initially in-hospital with clopidogrel, 2125 (5.2%) were discharged on prasugrel; this frequency steadily increased from 0% to 7% during the study period. Among 6509 patients treated initially in-hospital with prasugrel, 751 (11.5%) were discharged on clopidogrel. The frequency of this switch increased from 6% to 18% during the first 2 quarters of the study period and decreased to 9% by the end. Switching clopidogrel to prasugrel was associated with high-risk angiographic characteristics (thrombotic, long, and bifurcating lesions), reinfarction in-hospital, and private health insurance coverage. Older age, previous cerebrovascular event, in-hospital coronary artery bypass grafting, in-hospital bleeding, and warfarin use at discharge were associated with switching prasugrel to clopidogrel. CONCLUSIONS: Clopidogrel and prasugrel are not uncommonly switched in-hospital in patients with myocardial infarction undergoing percutaneous coronary intervention. In contemporary US practice, in addition to risk for bleeding and recurrent ischemic events, medical drug coverage is a major determinant of ADPri selection.

Impact of time of presentation on process performance and outcomes in ST-segment-elevation myocardial infarction: a report from the American Heart Association: Mission Lifeline program.

BACKGROUND: Prior studies demonstrated that patients with ST-segment-elevation myocardial infarction presenting during off-hours (weeknights, weekends, and holidays) have slower reperfusion times. Recent nationwide initiatives have emphasized 24/7 quality care in ST-segment-elevation myocardial infarction. It remains unclear whether patients presenting off-hours versus on-hours receive similar quality care in contemporary practice. METHODS AND RESULTS: Using Acute Coronary Treatment and Intervention Outcomes Network-Get With The Guidelines (ACTION-GWTG) database, we examined ST-segment-elevation myocardial infarction performance measures in patients presenting off-hours (n=27 270) versus on-hours (n=15 972; January 2007 to September 2010) at 447 US centers. Key quality measures assessed were aspirin use within first 24 hours, door-to-balloon time, door-to-ECG time, and door-to-needle time. In-hospital risk-adjusted all-cause mortality was calculated. Baseline demographic and clinical characteristics were similar. Aspirin use within 24 hours approached 99% in both groups. Among patients undergoing primary percutaneous coronary intervention (n=41 979; 97.1%), median door-to-balloon times were 56 versus 72 minutes (P<0.0001) for on-hours versus off-hours. The proportion of patients achieving door-to-balloon time ≤90 minutes was 87.8% versus 79.2% (P<0.0001), respectively. There were no differences attaining door-to-ECG time ≤10 minutes (73.4% versus 74.3%, P=0.09) and door-to-needle time ≤30 minutes (62.3% versus 58.7%; P=0.44) between on-hours versus off-hours. Although in-hospital all-cause mortality was similar (4.2%) in both groups, the risk-adjusted all-cause mortality was higher for patients presenting off-hours (odds ratio, 1.13; 95% confidence interval, 1.02-1.26). CONCLUSIONS: In contemporary community practice, achievement of quality performance measures in patients presenting with ST-segment-elevation myocardial infarction was high, regardless of time of presentation. Door-to-balloon time was, however, slightly delayed (by an average of 16 minutes), and risk-adjusted in-hospital mortality was 13% higher in patients presenting off-hours.

Statin therapy in patients with chronic kidney disease undergoing percutaneous coronary intervention (from the Evaluation of Drug Eluting Stents and Ischemic Events Registry).

Secondary prevention trials have demonstrated the efficacy of statins in reducing cardiovascular morbidity and mortality in patients with coronary artery disease and events after percutaneous coronary intervention (PCI). However, there are few data describing the clinical value of statins in patients with coronary artery disease and chronic kidney disease (CKD) undergoing PCI. Of 10,148 patients who entered into Evaluation of Drug Eluting Stents and Ischemic Events, a multicenter registry of unselected patients undergoing PCI from July 2004 to December 2007, we studied 2,306 patients with CKD (estimated glomerular filtration rate ≤60 ml/min based on the Modified Diet in Renal Disease calculation). Patients were stratified into those receiving statins at discharge (n = 1,833, 79%) or not (n = 473, 21%). Patients in the statin group had a greater prevalence of hypertension, recent myocardial infarction (MI), and use of ß blockers and angiotensin-converting enzyme inhibitors. Outcomes were assessed from discharge through 1-year follow-up. One-year all-cause mortality was 5.7% in statin group versus 8.7% in the no statin group (adjusted hazard ratio 0.55, 95% confidence interval 0.34 to 0.88). The composite of death, MI, and repeat revascularization was lower in statin group (adjusted hazard ratio 0.71, 95% confidence interval 0.51 to 0.99). In conclusion, among patients with CKD undergoing PCI, the prescription of statins at hospital discharge was associated with a significant improvement in subsequent outcomes including mortality and composite end point of death, MI, and repeat revascularization.

Influence of presenting electrocardiographic findings on the treatment and outcomes of patients with non-ST-segment elevation myocardial infarction.

The influence of the presenting electrocardiographic (ECG) findings on the treatment and outcomes of patients with non-ST-segment elevation myocardial infarction (NSTEMI) has not been studied in contemporary practice. We analyzed the clinical characteristics, in-hospital management, and in-hospital outcomes of patients with NSTEMI in the Acute Coronary Treatment and Intervention Outcomes Network Registry-Get With The Guidelines (ACTION Registry-GWTG) according to the presenting ECG findings. A total of 175,556 patients from 485 sites from January 2007 to September 2011 were stratified by the ECG findings on presentation: ST depression (n = 40,146, 22.9%), T-wave inversions (n = 24,627, 14%), transient ST-segment elevation (n = 5,050, 2.9%), and no ischemic changes (n = 105,733, 60.2%). Patients presenting with ST-segment depression were the oldest and had the greatest prevalence of major cardiac risk factors. Coronary angiography was performed most frequently in the transient ST-segment elevation group, followed by the T-wave inversion, ST-segment depression, and no ischemic changes groups. The angiogram revealed that patients with ST-segment depression had more left main, proximal left anterior descending, and 3-vessel coronary artery disease and underwent coronary artery bypass grafting most often. In contrast, patients with transient ST-segment elevation had 1-vessel CAD and underwent percutaneous coronary intervention the most. The unadjusted mortality was highest in the ST-segment depression group, followed by the no ischemic changes, transient ST-segment elevation, and T-wave inversion group. Adjusted mortality using the ACTION Registry-GWTG in-hospital mortality model with the no ischemic changes group as the reference showed that in-hospital mortality was similar in the transient ST-segment elevation (odds ratio 1.15, 95% confidence interval 0.97 to 1.37; p = 0.10), higher in the ST-segment depression group (odds ratio 1.46, 95% confidence interval 1.37 to 1.54; p <0.0001), and lower in the T-wave inversion group (odds ratio 0.91, 95% confidence interval 0.83 to 0.99; p = 0.026). In conclusion, the clinical and angiographic characteristics and treatment and outcomes of patients with NSTEMI differed substantially according to the presenting ECG findings. Patients with ST-segment depression have a greater burden of co-morbidities and coronary atherosclerosis and have a greater risk of adjusted in-hospital mortality compared with the other groups. These findings highlight the importance of integrating the presenting ECG findings into the risk stratification algorithm for patients with NSTEMI.

Differences in the profile, treatment, and prognosis of patients with cardiogenic shock by myocardial infarction classification: A report from NCDR.

BACKGROUND: Cardiogenic shock is a deadly complication of an acute myocardial infarction (MI). We sought to characterize differences in patient features, treatments, and outcomes of cardiogenic shock by MI classification: ST-segment-elevation MI (STEMI) versus non-ST-segment elevation MI (NSTEMI). METHODS AND RESULTS: We compared differences in care by the shock status of 235 541 patients with STEMI and NSTEMI treated at 392 US hospitals from 2007 to 2011. Cardiogenic shock occurred in 12.2% of patients with STEMI versus 4.3% of patients with NSTEMI. Compared with STEMI shock, NSTEMI shock was more likely in patients who were older and predominantly women; had diabetes mellitus, hypertension, previous heart failure, MI, or peripheral arterial disease; and who received coronary artery bypass grafting (11.6% versus 21.2%; P<0.0001) but less likely to have received percutaneous coronary intervention (84.2% versus 35.3%; P<0.0001). Compared with patients with STEMI presenting with shock at admission, patients with NSTEMI presenting with shock had longer delays to percutaneous coronary intervention (1.2 versus 3.2 hours) and coronary artery bypass grafting (7.9 versus 55.9 hours). Cardiogenic shock in patients with STEMI was associated with a lower mortality risk (33.1% shock versus 2.0% no shock; adjusted odds ratio, 14.1; 95% confidence interval, 13.0-15.4; interaction P value <0.0001) compared with patients with NSTEMI (40.8% shock versus 2.3% no shock, odds ratio, 19.0; 95% confidence interval, 17.1-21.2). CONCLUSIONS: Cardiogenic shock is associated with high mortality in patients with STEMI and NSTEMI. However, urgent revascularization is more commonly pursued in patients with STEMI presenting with shock than in patients with NSTEMI. More research is needed to improve the outcomes for patients with MI presenting with shock, particularly those presenting with NSTEMI.

Effect on platelet reactivity from a prasugrel loading dose after a clopidogrel loading dose compared with a prasugrel loading dose alone: Transferring From Clopidogrel Loading Dose to Prasugrel Loading Dose in Acute Coronary Syndrome Patients (TRIPLET): a randomized controlled trial.

BACKGROUND: Adding a prasugrel loading dose (LD) to a clopidogrel LD could be desirable because clopidogrel may fail to provide adequate levels of platelet inhibition in patients with acute coronary syndrome undergoing percutaneous coronary intervention. METHODS AND RESULTS: The pharmacodynamic response of prasugrel 60 mg ld alone was compared with prasugrel 60 mg or 30 mg added 24 hours to clopidogrel 600 mg in Transferring From Clopidogrel Loading Dose To Prasugrel Loading Dose In Acute Coronary Syndrome Patients study: a multicenter, randomized, double-blind, double-dummy, 3-arm, parallel, active-comparator controlled study. Two hundred eighty-two patients were randomized to 3 LD strategies: placebo plus prasugrel 60 mg, clopidogrel 600 mg plus prasugrel 60 mg, or clopidogrel 600 mg plus prasugrel 30 mg. Platelet function was assessed using VerifyNow P2Y12 Reaction Units (PRU) immediately before prasugrel LD, and 2, 6, 24, and 72 hours after prasugrel LD in 149 patients with evaluable platelet function studies. At 6 hours after the prasugrel 60 mg LD, the least squares mean (95% confidence interval) difference between placebo/prasugrel 60 mg and clopidogrel 600 mg/prasugrel 60 mg (primary outcome) was 22.2 (-11.0 to 55.5; P=0.19; least squares mean PRU 57.9 versus 35.6, respectively). For clopidogrel 600 mg/prasugrel 30 mg (least squares mean PRU, 53.9), the difference was 3.9 (-28.2 to 36.1; P=0.81) versus placebo/prasugrel 60 mg. No significant differences in PRU were observed at any time point across the 3 groups. There were few bleeding events observed regardless of treatment. CONCLUSIONS: Platelet reactivity with prasugrel 60 mg LD added to clopidogrel 600 mg LD was not significantly different compared with prasugrel 60 mg LD alone in acute coronary syndrome patients undergoing percutaneous coronary intervention. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01115738.

Enhanced active metabolite generation and platelet inhibition with prasugrel compared to clopidogrel regardless of genotype in thienopyridine metabolic pathways.

Clopidogrel response varies according to the presence of genetic polymorphisms. The CYP2C19*2 allele has been associated with impaired response; conflicting results have been reported for CYP2C19*17, ABCB1, and PON1 genotypes. We assessed the impact of CYP2C19, PON1, and ABCB1 polymorphisms on clopidogrel and prasugrel pharmacodynamic (PD) and pharmacokinetic (PK) parameters. Aspirin-treated patients (N=194) with coronary artery disease from two independent, prospective, randomised, multi-centre studies comparing clopidogrel (75 mg) and prasugrel (10 mg) were genotyped and classified by predicted CYP2C19 metaboliser phenotype (ultra metabolisers [UM] = *17 carriers; extensive metabolisers [EM] = *1/1 homozygotes; reduced metabolisers [RM] = *2 carriers). ABCB1 T/T and C/T polymorphisms and PON1 A/A, A/G and G/G polymorphisms were also genotyped. PD parameters were assessed using VerifyNow® P2Y12 and vasodilator stimulated phosphoprotein (VASP) expressed as platelet reactivity index (PRI) after 14 days of maintenance dosing. Clopidogrel and prasugrel active metabolite (AM) exposure was calculated in a cohort of 96 patients. For clopidogrel, genetic variants in CYP2C19, but not ABCB1 or PON1, affected PK and PD. For prasugrel, none of the measured genetic variants affected PK or PD. Compared with clopidogrel, platelet inhibition with prasugrel was greater even in the CYP2C19 UM phenotype. Prasugrel generated more AM and achieved greater platelet inhibition than clopidogrel irrespective of CYP2C19, ABCB1, and PON1 polymorphisms. The lack of effect from genetic variants on prasugrel AM generation or antiplatelet activity is consistent with previous studies in healthy volunteers and is consistent with improved efficacy in acute coronary syndrome patients managed with percutaneous coronary intervention.

Systematic review of effectiveness of oral sirolimus after bare-metal stenting of coronary arteries for prevention of in-stent restenosis.

Neointimal hyperplasia after percutaneous coronary intervention is a major determinant of in-stent restenosis (ISR). Drug-eluting stents (DES) mitigate neointimal hyperplasia and thereby lead to a lower rate of ISR compared with bare-metal stents (BMS). Recent studies have demonstrated that short-term use of oral sirolimus after BMS leads to a significant reduction in ISR. We therefore sought to do a systematic review of studies to determine the angiographic and clinical benefits of early short-term use of oral sirolimus after BMS of native coronary arteries. We conducted PubMed, Embase, Cochrane database review, and Web of Science search of studies comparing oral sirolimus after BMS to BMS alone or DES. Outcomes analyzed were ISR and target lesion revascularization (TLR) as well as major adverse cardiovascular events. A total of 488 patients from 4 studies were included in the review (2006 to 2010). Three studies, comparing BMS alone versus BMS plus oral sirolimus, demonstrated significant reduction in ISR in the oral sirolimus group. Two of these studies also demonstrated significant reduction in TLR at 6-12 month follow-up. The fourth study comparing BMS plus oral sirolimus versus DES showed a lower but nonsignificant reduction in TLR in addition to significant cost saving in the group treated with oral sirolimus. In conclusion, our systematic review demonstrates that early short-term systemic use of sirolimus after BMS resulted in a significant reduction in ISR and TLR. In addition, ISR rates were comparable to DES with the added benefit of cost saving.