Whether the association between platelet count (PC) and thrombotic and bleeding risk is independent of or varies by residual platelet reactivity to antiplatelet therapies is unclear. We sought to ...investigate the independent and combined effects of PC and platelet reactivity on thrombotic and bleeding risk after coronary artery implantation of drug-eluting stents (DES). Patients enrolled in the prospective, multicenter Assessment of Dual AntiPlatelet Therapy with Drug-Eluting Stents study were stratified by PC tertiles. The study cohort comprised 8,402 patients. By linear regression analysis, lower PC was strongly and independently associated with higher platelet reactive units (PRUs) on clopidogrel. After multivariable adjustment (including PRU and aspirin reactive units), high, but not low, PC tertile was independently associated with higher risk of thrombotic complications, including spontaneous myocardial infarction and stent thrombosis. Although no independent association was observed between PC tertiles and hemorrhagic risk, both high and low PC tertiles were associated with increased risk for all-cause mortality. After stratification of PC tertiles by tertiles of PRUs, the crude risk of thrombotic complications was highest in patients in the high PC and high PRU tertiles. By multivariable adjustment, PRU increases were uniformly associated with higher risk of thrombotic events across PC tertiles, without evidence of interaction. In conclusion, higher PCs and higher PRUs act independently and synergistically in determining thrombotic risk. Alongside PRU, PCs could be a simple hematological parameter to consider for risk stratification and in tailoring duration and potency of pharmacologic platelet inhibition after DES implantation.
The National Institutes of Health National Heart, Lung, and Blood Institute convened a working group in March 2008 to discuss how therapies for heart failure (HF) might be best advanced using ...clinical trials involving left ventricular assist devices (LVAD). This group opined that the field was ready for a trial to assess the use of long-term ventricular assist device therapy in patients who are less ill than patients currently eligible for destination therapy, which resulted in the Randomized Evaluation of VAD InterVEntion before Inotropic Therapy (REVIVE-IT) pilot study. The specific objective of REVIVE-IT was to compare LVAD therapy with optimal medical management in patients with less advanced HF than current LVAD indications to determine if wider application of permanent LVAD use to less ill patients would be associated with improved survival, quality of life, or functional capacity. REVIVE-IT represented an extraordinary effort to provide data from a randomized clinical trial to inform clinicians, scientists, industry, and regulatory agencies about the efficacy and safety of LVAD therapy in a population with less advanced HF. Despite significant support from the medical community, industry, and governmental agencies, REVIVE-IT failed to accomplish its goal. The reasons for its failure are instructive, and the lessons learned from the REVIVE-IT experience are likely to be relevant to any future study of LVAD therapy in a population with less advanced HF.
Abstract Objectives The aim of this study was to compare the incidence and impact of cessation of dual-antiplatelet therapy (DAPT) in women and men treated with percutaneous coronary intervention. ...Background Nonadherence to cardiovascular medications and female sex are associated with worse outcomes. However, the patterns and impact of DAPT cessation in women compared with men following percutaneous coronary intervention have not been studied. Methods Baseline characteristics, patterns of DAPT cessation, and 2-year clinical outcomes were compared in 5,031 patients (1,279 women, 3,739 men) enrolled following successful percutaneous coronary intervention with stents in the PARIS (Patterns of Non-Adherence to Antiplatelet Regimens in Stented Patients) study. DAPT cessation was adjudicated as physician-guided discontinuation, interruption for surgery, or disruption due to bleeding or noncompliance. Clinical endpoints were major adverse cardiac events (a composite of cardiac death, definite or probable stent thrombosis, spontaneous myocardial infarction, or clinically indicated target lesion revascularization), a second restricted definition of major adverse cardiac events excluding target lesion revascularization, and bleeding. Results DAPT cessation was more common in women than men (59.1% vs. 55.9%, p = 0.007) and comprised increased rates of discontinuation, disruption for bleeding, and disruption due to noncompliance. The impact of DAPT cessation was similar regardless of sex and varied according the mode; in particular, disruption was associated with increased risk for both ischemic and bleeding events. After adjusting for differences in baseline and treatment characteristics as well as DAPT cessation events, female sex remained an independent predictor of bleeding but not of ischemic events. Conclusions DAPT cessation was more common in women, but its impact was similar in women and men. Female sex was an independent predictor of bleeding but not of ischemic events after adjustment for differences in DAPT cessation and baseline and treatment characteristics.
Preclinical trials indicate that CD34+ cells represent an effective angiogenic stem cell component. Early-phase clinical trials suggest that intramyocardial administration of autologous CD34+ cells ...may improve functional capacity and symptoms of angina. RENEW is a pivotal phase 3 trial designed to determine the efficacy of granulocyte colony-stimulating factor (G-CSF)–mobilized CD34+ stem cells for the treatment for patients with refractory angina and chronic myocardial ischemia. Patients (n = 444) receiving maximally tolerated antianginal therapies and lacking conventional revascularization options with Canadian Cardiovascular Society class III or IV angina and ischemia on stress testing will be randomized 2:1:1 to cell therapy (G-CSF–mediated stem cell mobilization, apheresis, and intramyocardial injection of 1 × 105 autologous CD34+ cells/kg), active control (G-CSF–mediated stem cell mobilization, apheresis, and intramyocardial placebo injection), or open-label standard of care. The primary efficacy end point is change in exercise treadmill time in the treated vs active control patients, with 90% power to detect a 60-second difference in exercise time between cell-treated (n = 200) and active control (n = 100) patients. Key secondary end points include total number of anginal episodes per week and the incidence of independently adjudicated major adverse cardiac events and serious adverse events. RENEW will be the first adequately powered study aimed at definitively determining the efficacy of a cell therapy (intramyocardially delivered autologous CD34+ cells) for improvement of functional capacity in patients with refractory angina.
Background Persistent use of secondary prevention therapies after acute myocardial infarction (MI) is critical to optimizing long-term outcomes. Methods Medication persistence was assessed among ...7,955 MI patients in 216 hospitals participating in the Treatment with Adenosine Diphosphate Receptor Inhibitors: Longitudinal Assessment of Treatment Patterns and Events after Acute Coronary Syndrome study from 2010 to 2012. Persistence was defined as continuation of aspirin, adenosine diphosphate receptor inhibitors, β-blockers, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, and statins from discharge to 6 months post-MI. Multivariable logistic regression modeling was used to determine factors associated with nonpersistence, defined as <80% persistence with all medication classes. Results Overall, 31% of MI patients stopped taking a least 1 medication by 6 months. The most common reasons cited for medications discontinuation were side effects and physician instruction (57%), whereas financial concerns were cited in 8% overall. After multivariable modeling, black race (odds ratio 1.36, 95% CI 1.15-1.62), older age (odds ratio 1.07, 95% CI 1.02-1.12), atrial fibrillation (odds ratio 1.67, 95% CI 1.33-2.09), dialysis (odds ratio 1.79, 95% CI 1.15-2.78), and depression (odds ratio 1.22, 95% CI 1.02-1.45) were associated with lower likelihood of persistence. Private insurance (odds ratio 0.85, 95% 0.76-0.95), prescription cost assistance (odds ratio 0.63, 95% CI 0.54-0.75), and outpatient follow-up arranged before discharge (odds ratio 0.89, 95% CI 0.80-0.99) were associated with higher persistence. Conclusions Nearly one-third of MI patients are no longer persistent with their prescribed medications by 6 months. Patients at high risk for nonpersistence may be identified by clinical and sociodemographic features. These observations underscore key opportunities to optimize longitudinal use of secondary prevention therapies.
Background Autologous bone marrow mononuclear cell (ABMMNC) therapy has shown promise in patients with heart failure (HF). Cell function analysis may be important in interpreting trial results. ...Methods In this prospective study, we evaluated the safety and efficacy of the transendocardial delivery of ABMMNCs in no-option patients with chronic HF. Efficacy was assessed by maximal myocardial oxygen consumption, single photon emission computed tomography, 2-dimensional echocardiography, and quality-of-life assessment (Minnesota Living with Heart Failure and Short Form 36). We also characterized patients' bone marrow cells by flow cytometry, colony-forming unit, and proliferative assays. Results Cell-treated (n = 20) and control patients (n = 10) were similar at baseline. The procedure was safe; adverse events were similar in both groups. Canadian Cardiovascular Society angina score improved significantly ( P = .001) in cell-treated patients, but function was not affected. Quality-of-life scores improved significantly at 6 months ( P = .009 Minnesota Living with Heart Failure and P = .002 physical component of Short Form 36) over baseline in cell-treated but not control patients. Single photon emission computed tomography data suggested a trend toward improved perfusion in cell-treated patients. The proportion of fixed defects significantly increased in control ( P = .02) but not in treated patients ( P = .16). Function of patients' bone marrow mononuclear cells was severely impaired. Stratifying cell results by age showed that younger patients (≤60 years) had significantly more mesenchymal progenitor cells (colony-forming unit fibroblasts) than patients >60 years (20.16 ± 14.6 vs 10.92 ± 7.8, P = .04). Furthermore, cell-treated younger patients had significantly improved maximal myocardial oxygen consumption (15 ± 5.8, 18.6 ± 2.7, and 17 ± 3.7 mL/kg per minute at baseline, 3 months, and 6 months, respectively) compared with similarly aged control patients (14.3 ± 2.5, 13.7 ± 3.7, and 14.6 ± 4.7 mL/kg per minute, P = .04). Conclusions ABMMNC therapy is safe and improves symptoms, quality of life, and possibly perfusion in patients with chronic HF.
Summary Background The international standard of care for women with suspected advanced ovarian cancer is surgical debulking followed by platinum-based chemotherapy. We aimed to establish whether use ...of platinum-based primary chemotherapy followed by delayed surgery was an effective and safe alternative treatment regimen. Methods In this phase 3, non-inferiority, randomised, controlled trial (CHORUS) undertaken in 87 hospitals in the UK and New Zealand, we enrolled women with suspected stage III or IV ovarian cancer. We randomly assigned women (1:1) either to undergo primary surgery followed by six cycles of chemotherapy, or to three cycles of primary chemotherapy, then surgery, followed by three more cycles of completion chemotherapy. Each 3-week cycle consisted of carboplatin AUC5 or AUC6 plus paclitaxel 175 mg/m2 , or an alternative carboplatin combination regimen, or carboplatin monotherapy. We did the random assignment by use of a minimisation method with a random element, and stratified participants according to the randomising centre, largest radiological tumour size, clinical stage, and prespecified chemotherapy regimen. Patients and investigators were not masked to group assignment. The primary outcome measure was overall survival. Primary analyses were done in the intention-to-treat population. To establish non-inferiority, the upper bound of a one-sided 90% CI for the hazard ratio (HR) had to be less than 1·18. This trial is registered, number ISRCTN74802813, and is closed to new participants. Findings Between March 1, 2004, and Aug 30, 2010, we randomly assigned 552 women to treatment. Of the 550 women who were eligible, 276 were assigned to primary surgery and 274 to primary chemotherapy. All were included in the intention-to-treat analysis; 251 assigned to primary surgery and 253 to primary chemotherapy were included in the per-protocol analysis. As of May 31, 2014, 451 deaths had occurred: 231 in the primary-surgery group versus 220 in the primary-chemotherapy group. Median overall survival was 22·6 months in the primary-surgery group versus 24·1 months in primary chemotherapy. The HR for death was 0·87 in favour of primary chemotherapy, with the upper bound of the one-sided 90% CI 0·98 (95% CI 0·72–1·05). Grade 3 or 4 postoperative adverse events and deaths within 28 days after surgery were more common in the primary-surgery group than in the primary-chemotherapy group (60 24% of 252 women vs 30 14% of 209, p=0·0007, and 14 women 6% vs 1 woman <1%, p=0·001). The most common grade 3 or 4 postoperative adverse event was haemorrhage in both groups (8 women 3% in the primary-surgery group vs 14 6% in the primary-chemotherapy group). 110 (49%) of 225 women receiving primary surgery and 102 (40%) of 253 receiving primary chemotherapy had a grade 3 or 4 chemotherapy related toxic effect (p=0·0654), mostly uncomplicated neutropenia (20% and 16%, respectively). One fatal toxic effect, neutropenic sepsis, occurred in the primary-chemotherapy group. Interpretation In women with stage III or IV ovarian cancer, survival with primary chemotherapy is non-inferior to primary surgery. In this study population, giving primary chemotherapy before surgery is an acceptable standard of care for women with advanced ovarian cancer. Funding Cancer Research UK and the Royal College of Obstetricians and Gynaecologists.
Abstract Background Out-of-hospital cardiac arrest (OHCA) associated with acute myocardial infarction (MI) confers high in-hospital mortality; however, among those patients who survive, little is ...known regarding their post-discharge mortality and health care use rates. Objectives The purpose of this study was to determine 1-year survival and readmission rates after hospital discharge of older MI survivors with and without OHCA. Methods Using linked Acute Coronary Treatment and Intervention Outcomes Network Registry-Get With the Guidelines and Medicare data, this study analyzed 54,860 patients with MI who were older than 65 years of age and who had been discharged alive from 545 U.S. hospitals between April 2011 and December 2012. Multivariable models examined the associations between MI-associated OHCA and 1-year post-discharge mortality or all-cause readmission rates. Patients discharged to hospice were excluded, given their known poor prognosis. Results Following hospital discharge, compared with older MI survivors without OHCA (n = 54,219), those with OHCA (n = 641, 1.2%) were more likely to be younger, male, and smokers, but less likely to have diabetes, heart failure, or prior revascularization. OHCA patients presented more often with ST-segment elevation myocardial infarction (63.2% vs. 29.6%) and cardiogenic shock (29.0% vs. 2.2%); however, among in-hospital MI survivors, OHCA was not associated with 1-year post-discharge mortality (unadjusted 13.8% vs. 15.8%, p = 0.17, adjusted hazard ratio HR: 0.89; 95% confidence interval CI: 0.68 to 1.15). In contrast, MI survivors with OHCA actually had lower unadjusted and adjusted risk of the composite outcome of 1-year mortality or all-cause readmission than patients without OHCA (44.0% vs. 50.0%, p = 0.03, adjusted HR: 0.84; 95% CI: 0.72 to 0.97). Conclusions Among older patients with MI who survived to hospital discharge and were not discharged to hospice, those presenting with OHCA did not have higher 1-year mortality or health care use rates compared with those MI survivors without OHCA. These findings show that the early risk of adverse events in patients with OHCA does not persist after hospital discharge, and they support efforts to improve initial survival rates of older patients with MI and OHCA.
The For Angioedema Subcutaneous Treatment (FAST)-3 study was a phase III, randomized, double-blind, placebo-controlled study of icatibant (bradykinin B(2) receptor antagonist) in subjects with ...hereditary angioedema (HAE) resulting from C1-INH deficiency or dysfunction (type I/II).
To investigate icatibant efficacy and safety in subjects with acute HAE attacks.
Subjects with moderate to very severe cutaneous or abdominal symptoms received icatibant (n = 43) or placebo (n = 45). Five subjects with laryngeal (mild-to-moderate) first attacks received icatibant (n = 3) or placebo (n = 2), and 5 subjects with severe laryngeal first attacks received open-label icatibant.
Cutaneous or abdominal attacks: icatibant significantly reduced median times (vs placebo) to 50% or more reduction in symptom severity (2.0 vs 19.8 hours; P < .001, primary endpoint), onset of primary symptom relief (1.5 vs 18.5 hours; P < .001, key secondary endpoint), or almost complete symptom relief (8.0 vs 36.0 hours; P = .012) and provided a shorter time to initial symptom relief (0.8 vs 3.5 hours; P < .001). For laryngeal attacks, median time to 50% or more reduction in symptom severity was 2.5 hours (icatibant) and 3.2 hours (placebo). No icatibant-treated subject required rescue medication before symptom relief occurred. The incidence of adverse events (AEs) was similar in icatibant- and placebo-treated subjects (41% and 52%, respectively). All icatibant-treated subjects experienced injection site reactions, but none reported clinically relevant changes in safety parameters or serious AEs.
FAST-3 demonstrated that icatibant was effective and generally well tolerated in subjects with acute HAE attacks.
Clinicaltrials.gov Identifier: NCT00912093.
Background The reasons for postdischarge adenosine diphosphate receptor inhibitor (ADPri) switching among patients with myocardial infarction (MI) are unclear. We sought to describe the incidence and ...patterns of postdischarge ADPri switching among patients with acute MI treated with percutaneous coronary intervention. Methods We used TRANSLATE-ACS (2010-2012) data to assess postdischarge ADPri switching among 8,672 MI patients discharged after percutaneous coronary intervention who remained on ADPri therapy 1 year post-MI. We examined patient-reported reasons for switching, GUSTO moderate or severe bleeding, major adverse cardiovascular events (MACEs), and definite stent thrombosis events around the time of the switch. Results Among patients still on ADPri therapy 1 year post-MI, 663 (7.6%) switched ADPri during that year. Switching occurred at a median of 50 days postdischarge and most frequently in patients discharged on ticagrelor (64/226; 28.3%), followed by prasugrel (383/2,489; 15.4%) and clopidogrel (216/5,957; 3.6%) ( P < .001). Among patients discharged on prasugrel, 97.3% of switches were to clopidogrel and 87.5% of ticagrelor switches were to clopidogrel; both of these groups most often cited cost as a reason for switching (43.6% and 39.1%, respectively), whereas 60.7% who switched from clopidogrel cited physician decision as a reason. In the 7 days preceding the switch from clopidogrel, 40 (18.5%) had a MACE and 12 (5.6%) had a definite stent thrombosis event, whereas that from prasugrel or ticagrelor, a GUSTO moderate or severe bleeding event occurred in 1 (0.3%) and 0 patients, respectively. Conclusions Postdischarge ADPri switching occurred infrequently within the first year post-MI and uncommonly was associated with MACEs or bleeding events.
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