Increased risk of stroke and mortality following new-onset atrial fibrillation during hospitalization.

AIMS: The outcome of patients who develop new-onset atrial fibrillation (AF) during hospitalization is unknown, and the management of this patient population is not specifically addressed by current guidelines. We investigated the incidence of death and inhospital stroke among a large cohort of hospitalized inpatients who developed new-onset AF. METHODS AND RESULTS: All patients ≥50 years of age admitted to a tertiary academic medical centre (20 April 2005 to 31 December 2011; n = 84 919) were studied. Demographic variables were compared among patients categorized as having new-onset, pre-existing, or no AF. A propensity-matched analysis was employed to compare outcomes by generalized estimating equations. Primary endpoints were all-cause 30-day and 1-year mortality and inhospital stroke. New-onset AF occurred in 1749 (2.1%) hospitalized patients. Among patients with new-onset AF, mortality at 30 days and 1 year was higher compared with patients without AF (at 30 days: OR 2.28, 95% CI 1.72-3.02, P < 0.0001; at 1 year: RR 1.53, 95% CI 1.36-1.73, P < 0.0001), and compared with patients with pre-existing AF at 30 days (OR 1.52, 95% CI 1.06-2.17, P = 0.02) -an effect that persisted as non-significant trend at 1 year (RR 1.14, 95% CI 0.98-1.34, P = 0.09). Risk of inhospital stroke was higher in patients with new-onset AF compared with patients without AF (OR 4.53, 95% CI 1.36-15.11, P = 0.02). Among patients with new-onset AF, the CHA2DS2-Vasc score correlated with incidence of inhospital stroke. CONCLUSION: New-onset AF among hospitalized inpatients is independently associated with an increased incidence of stroke and mortality.

Exploring the Changes in Code Status During the COVID-19 Pandemic and the Implications for Future Pandemic Care.

Objective: We aim to explore patterns of inpatient code status during the COVID-19 pandemic compared with a similar timeframe the previous year, as well as utilization of palliative care services.Methods: This is a retrospective cohort study using data from the Montefiore Health system of all inpatient admissions between March 15-May 31, 2019 and March 15-May 31, 2020. Univariate logistic regression was performed with full code status as the outcome. All statistically significant variables were included in the multivariable logistic regression.Results: The total number of admissions declined during the pandemic (16844 vs 11637). A lower proportion of patients had full code status during the pandemic (85.1% vs 94%, P < .001) at the time of discharge/death. There was a 20% relative increase in the number of palliative care consultations during the pandemic (12.2% vs 10.5%, P < .001). Intubated patients were less often full code (66.5% vs 82.2%, P < .001) during the pandemic. Although a lower portion of COVID-19 positive patients had a full code status compared with non-COVID patients (77.6% vs 92.4%, P<.001), there was no statistically significant difference in code status at death (38.3% vs 38.3%, P = .96).Conclusions: The proportion of full code patients was significantly lower during the pandemic. Age and COVID status were the key determinants of code status during the pandemic. There was a higher demand for palliative care services during the pandemic.

Phase 1b randomized study of antidote-controlled modulation of factor IXa activity in patients with stable coronary artery disease.

BACKGROUND: Whether selective factor IXa inhibition produces an appropriate anticoagulant effect when combined with platelet-directed therapy in patients with stable coronary artery disease is unknown. REG1 consists of RB006 (drug), an injectable RNA aptamer that specifically binds and inhibits factor IXa, and RB007 (antidote), the complementary oligonucleotide that neutralizes its anti-IXa activity. METHODS AND RESULTS: We evaluated the safety, tolerability, and pharmacodynamic profile of REG1 in a randomized, double-blind, placebo-controlled study, assigning 50 subjects with coronary artery disease taking aspirin and/or clopidogrel to 4 dose levels of RB006 (15, 30, 50, and 75 mg) and RB007 (30, 60, 100, and 150 mg). The median age was 61 years (25th and 75th percentiles, 56 and 68 years), and 80% of patients were male. RB006 increased the activated partial thromboplastin time dose dependently; the median activated partial thromboplastin time at 10 minutes after a single intravenous bolus of 15, 30, 50, and 75 mg RB006 was 29.2 seconds (25th and 75th percentiles, 28.1 and 29.8 seconds), 34.6 seconds (25th and 75th percentiles, 30.9 and 40.0 seconds), 46.9 seconds (25th and 75th percentiles, 40.3 and 51.1 seconds), and 52.2 seconds (25th and 75th percentiles, 46.3 and 58.6) (P<0.0001; normal 25th and 75th percentiles, 27 and 40 seconds). RB007 reversed the activated partial thromboplastin time to baseline levels within a median of 1 minute (25th and 75th percentiles, 1 and 2 minutes) with no rebound increase through 7 days. No major bleeding or other serious adverse events occurred. CONCLUSIONS: This is the first experience of an RNA aptamer drug-antidote pair achieving inhibition and active restoration of factor IXa activity in combination with platelet-directed therapy in stable coronary artery disease. The preliminary clinical safety and predictable pharmacodynamic effects form the basis for ongoing studies in patients undergoing elective revascularization procedures.

The primary and secondary prevention of coronary artery disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition).

The following chapter devoted to antithrombotic therapy for chronic coronary artery disease (CAD) is part of the Antithrombotic and Thrombolytic Therapy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Grade 1 recommendations are strong and indicate that the benefits do or do not outweigh risks, burden, and costs. Grade 2 suggests that individual patient values may lead to different choices (for a full understanding of the grading see the "Grades of Recommendation" chapter by Guyatt et al in this supplement, CHEST 2008; 133[suppl]:123S-131S). Among the key recommendations in this chapter are the following: for patients with non-ST-segment elevation (NSTE)-acute coronary syndrome (ACS) we recommend daily oral aspirin (75-100 mg) [Grade 1A]. For patients with an aspirin allergy, we recommend clopidogrel, 75 mg/d (Grade 1A). For patients who have received clopidogrel and are scheduled for coronary bypass surgery, we suggest discontinuing clopidogrel for 5 days prior to the scheduled surgery (Grade 2A). For patients after myocardial infarction, after ACS, and those with stable CAD and patients after percutaneous coronary intervention (PCI), we recommend daily aspirin (75-100 mg) as indefinite therapy (Grade 1A). We recommend clopidogrel in combination with aspirin for patients experiencing ST-segment elevation (STE) and NSTE-ACS (Grade 1A). For patients with contraindications to aspirin, we recommend clopidogrel as monotherapy (Grade 1A). For long-term treatment after PCI in patients who receive antithrombotic agents such as clopidogrel or warfarin, we recommend aspirin (75 to 100 mg/d) [Grade 1B]. For patients who undergo bare metal stent placement, we recommend the combination of aspirin and clopidogrel for at least 4 weeks (Grade 1A). We recommend that patients receiving drug-eluting stents (DES) receive aspirin (325 mg/d for 3 months followed by 75-100 mg/d) and clopidogrel 75 mg/d for a minimum of 12 months (Grade 2B). For primary prevention in patients with moderate risk for a coronary event, we recommend aspirin, 75-100 mg/d, over either no antithrombotic therapy or vitamin K antagonist (Grade 1A).

Antithrombotic effects of factor Xa inhibition with DU-176b: Phase-I study of an oral, direct factor Xa inhibitor using an ex-vivo flow chamber.

Direct and specific inhibition of factor Xa is an emerging therapeutic strategy for atherothrombotic disease. Parenteral factor Xa inhibitors promise efficacy comparable to standard therapies, which could be extended to ambulatory patients with oral agents. We evaluated the antithrombotic effect of the oral, direct factor Xa inhibitor DU-176b in a phase-I study. Healthy subjects (n = 12) received a single, 60 mg dose of DU-176b. Antithrombotic effects were assessed by comparing ex-vivo thrombus formation at 1.5, 5, and 12 hours post-dose versus baseline, along with factor Xa activity, thrombin generation and clotting parameters. Under venous flow after 1.5 and 5 hours, the thrombus was 28% and 21% smaller versus baseline, respectively (p < 0.05). Under arterial condition, the reduction was 26% and 17% (p < 0.05). Thrombin generation decreased by 28% at 1.5 hours and 10% at 5 hours. Changes in PT and INR correlated well with plasma drug concentrations (R2 = 0.79 and 0.78). Direct and specific inhibition of factor Xa by DU-176b significantly reduced ex-vivo thrombus formation at both venous and arterial rheologies, up to 5 hours post-dose. The effects mirrored changes in clotting parameters, suggesting their potential usefulness for monitoring in a clinical setting.

Platelets in atherothrombosis.

Atherosclerosis is a diffuse, systemic disease that affects the coronary, cerebral, and peripheral arterial trees. Disruption of atherosclerotic plaques leads to thrombus formation and arterial occlusion. This unpredictable and potentially life-threatening atherothrombotic sequence underlies clinical events such as angina, myocardial infarction, transient ischemic attacks, and stroke. One of the key components of a clot is the platelet. Although it was previously thought that platelets were relatively inactive cells that merely provided a framework for the attachment of other cells and proteins to mechanically stop bleeding due to injury, it is now known that this is not the case. Platelets secrete and express a large number of substances that are crucial mediators of both coagulation and inflammation. This article reviews the centrality of the platelet in atherothrombosis and briefly looks at the efficacy of antiplatelet agents in preventing and treating cardiovascular disease.

What is QT interval prolongation?

QT interval prolongation is an irregularity of the electrical activity of the heart that places patients at risk for ventricular arrhythmias. Serious complications of drug-induced QT interval prolongation are rare; the identification of patients at risk may help to prevent these events.

Antithrombotic therapy for coronary artery disease: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy.

This chapter about antithrombotic therapy for coronary artery disease (CAD) is part of the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy: Evidence Based Guidelines. Grade 1 recommendations are strong and indicate that the benefits do, or do not, outweigh risks, burden, and costs. Grade 2 suggests that individual patients' values may lead to different choices (for a full understanding of the grading see Guyatt et al, CHEST 2004; 126:179S-187S). Among the key recommendations in this chapter are the following: For patients presenting with non-ST-segment elevation (NSTE) acute coronary syndrome (ACS), we recommend immediate and then daily oral aspirin (Grade 1A). For patients with an aspirin allergy, we recommend immediate treatment with clopidogrel, 300-mg bolus po, followed by 75 mg/d indefinitely (Grade 1A). In all NSTE ACS patients in whom diagnostic catheterization will be delayed or when coronary bypass surgery will not occur until > 5 days, we recommend clopidogrel as bolus therapy (300 mg), followed by 75 mg/d for 9 to 12 months in addition to aspirin (Grade 1A). In NSTE ACS patients in whom angiography will take place within 24 h, we suggest beginning clopidogrel after the coronary anatomy has been determined (Grade 2A). For patients who have received clopidogrel and are scheduled for coronary bypass surgery, we recommend discontinuing clopidogrel for 5 days prior to the scheduled surgery (Grade 2A). In moderate- to high-risk patients presenting with NSTE ACS, we recommend either eptifibatide or tirofiban for initial (early) treatment in addition to treatment with aspirin and heparin (Grade 1A). For the acute treatment of NSTE ACS, we recommend low molecular weight heparins over unfractionated heparin (UFH) [Grade 1B] and UFH over no heparin therapy use with antiplatelet therapies (Grade 1A). We recommend against the direct thrombin inhibitors as routine initial antithrombin therapy (Grade 1B). For patients after myocardial infarction, after ACS, and with stable CAD, we recommend aspirin in doses from 75 to 325 mg as initial therapy and in doses of 75 to 162 mg as indefinite therapy (Grade 1A). For patients with contraindications to aspirin, we recommend long-term clopidogrel (Grade 1A). For primary prevention in patients with at least moderate risk for a coronary event, we recommend aspirin, 75 to 162 mg/d, over either no antithrombotic therapy or vitamin K antagonist (VKA) [Grade 2A]; for patients at particularly high risk of events in whom the international normalized ratio (INR) can be monitored without difficulty, we suggest low-dose VKA (target INR, 1.5) [Grade 2A].

A new oral antiplatelet agent with potent antithrombotic properties: comparison of DZ-697b with clopidogrel a randomised phase I study.

DZ-697b is a new orally active antiplatelet agent that inhibits collagen and ristocetin-mediated platelet activation. It does not require metabolisation to generate its active compound and has a safer profile than clopidogrel in pre-clinical studies. We compared the antithrombotic effects and bleeding time prolongations of three DZ-697b doses with clopidogrel 300 mg. In a four-treatment, three-period, crossover-design, 20 healthy subjects (31 + or - 7 years, 85% males) were randomised to single oral doses of DZ-697b (60, 120 and 360 mg), and clopidogrel (300 mg) (n=15 in each treatment with crossing-over). Antithrombotic effects were assessed by measuring six-hour post-dose changes from baseline in thrombus size in the Badimon chamber and platelet adhesion using Diamed Impact-R platelet function assay. Bleeding times were also measured pre-dose and at six hours post-dose. DZ-697b caused dose-dependent reductions in thrombus size at both high- and low-shear rates (mean reductions at 60, 120 and 360 mg doses of: 13.0%, 18.7%, 26.4% and 11.4%, 12.7%, 22.1% respectively, p<0.05 for all). Effect of clopidogrel (reductions of 18.7% and 11.0% respectively, p<0.05 for both) was closest to DZ-697b 120 mg. Reductions in platelet adhesion were also dose-dependent. Bleeding time ratio from baseline were shorter with DZ-697b versus clopidogrel (1.3, 1.4 and 1.5 versus 1.9, p<0.05 for all). The oral agent DZ-697b shows potent, dose-dependent, antithrombotic effects that are comparable to 300 mg clopidogrel at the 120 mg dose. Despite having equal or greater antiplatelet potency than 300 mg clopidogrel, bleeding time prolongations are significantly shorter with DZ-697b.

Sirolimus-eluting stent placement for refractory renal artery in-stent restenosis: sustained patency and clinical benefit at 24 months.

Renal artery stenosis may cause or exacerbate hypertension and renal failure. Percutaneous transluminal renal artery stent placement, increasingly the first-line therapy for ostial atherosclerotic renal artery stenosis, can be complicated by in-stent restenosis weeks to months after the procedure. There is currently no consensus for the treatment of in-stent restenosis. Sirolimus-eluting stents have been shown to be effective to treat in-stent restenosis in the coronary circulation. We report a case of sustained 24-month patency after repair of recurrent renal artery in-stent restenosis with use of a sirolimus-eluting stent.

Multi-bed vascular disease and atherothrombosis: scope of the problem.

While atherosclerosis has traditionally been divided into three types of disease, coronary artery or coronary heart disease (CHD), cerebrovascular disease, and peripheral vascular or peripheral arterial disease (PAD), it is now clear that atherosclerosis is a systemic disease caused by the same pathologic processes regardless of the vascular bed involved. The burden of disease is enormous both in the US and around the world with 61,800,000 Americans affected with one or more types of CVD, responsible for 958,775 deaths annually at a cost of approximately US 329.2 billion dollars annually. Despite trends of decreasing cardiovascular mortality, the global burden of cardiovascular disease is expected to rise, with CHD and stroke becoming the first and fourth most common causes of mortality and morbidity globally. Atherosclerosis is a multibed process with a substantial portion of patients afflicted with disease in more than one bed, although often assymptomatic. Now that there are multiple therapies available to modify and treat atherosclerosis and atherosclerotic risk factors, identification and treatment of these patients are important since their leading cause of death is from co-existing cardiovascular disease.