David A. Vorchheimer

Persistent depression affects adherence to secondary prevention behaviors after acute coronary syndromes.

AbstractBACKGROUND: The persistence of depressive symptoms after hospitalization is a strong risk factor for mortality after acute coronary syndromes (ACS). Poor adherence to secondary prevention behaviors may be a mediator of the relationship between depression and increased mortality. OBJECTIVE: To determine whether rates of adherence to risk reducing behaviors were affected by depressive status during hospitalization and 3 months later. DESIGN: Prospective observational cohort study. SETTING: Three university hospitals. PARTICIPANTS: Five hundred and sixty patients were enrolled within 7 days after ACS. Of these, 492 (88%) patients completed 3-month follow-up. MEASUREMENTS: We used the Beck Depression Inventory (BDI) to assess depressive symptoms in the hospital and 3 months after discharge. We assessed adherence to 5 risk-reducing behaviors by patient self-report at 3 months. We used χ2 analysis to compare differences in adherence among 3 groups: persistently nondepressed (BDI<10 at hospitalization and 3 months); remittent depressed (BDI ≥10 at hospitalization; <10 at 3 months); and persistently depressed patients (BDI ≥10 at hospitalization and 3 months). RESULTS: Compared with persistently nondepressed, persistently depressed patients reported lower rates of adherence to quitting smoking (adjusted odds ratio [OR] 0.23, 95% confidence interval [95% CI] 0.05 to 0.97), taking medications (adjusted OR 0.50, 95% CI 0.27 to 0.95), exercising (adjusted OR 0.57, 95% CI 0.34 to 0.95), and attending cardiac rehabilitation (adjusted OR 0.5, 95% CI 0.27 to 0.91). There were no significant differences between remittent depressed and persistently nondepressed patients. CONCLUSIONS: Persistently depressed patients were less likely to adhere to behaviors that reduce the risk of recurrent ACS. Differences in adherence to these behaviors may explain in part why depression predicts mortality after ACS.

Normalization of platelet reactivity in clopidogrel-treated subjects.

Summary.  Background: Aspirin (ASA) + clopidogrel are commonly used in acute coronary syndrome (ACS), but persistent antiplatelet effects may complicate surgery.Methods and Results: To study the possibility of normalizing platelet reactivity after ASA + clopidogrel treatment, 11 healthy subjects received a 325‐mg ASA + clopidogrel loading dose (300 or 600 mg dependent on study arm), followed by 81 mg of ASA + 75 mg of clopidogrel daily for 2 days. Platelet reactivity was assessed by light transmittance aggregometry (LTA) [challenged by adenosine diphosphate (ADP), arachidonic acid (AA), collagen, and thrombin receptor activating peptide (TRAP)] and flow cytometry for platelet activation by GPIIb/IIIa receptor exposure pretreatment, 4 and 72 h postload. To normalize platelet reactivity, increasing amounts of pooled platelets from five untreated volunteers [volunteers (V)‐platelet‐rich plasma (PRP)] were added ex vivo to the subjects PRP (S‐PRP). At both 4 and 72 h, 40% and 50% V‐PRP were needed to overcome platelet disaggregation in the 300 or 600 mg arms, respectively, after ADP challenge; an additional 10% V‐PRP fully normalized aggregation. Recovery of function was linear with each incremental increase of V‐PRP. ADP‐induced GPIIb/IIIa activation showed the same pattern as LTA (r = 0.74). Forty percent V‐PRP was required to normalize platelet function to AA, collagen, and TRAP.Conclusion: Our results suggest that the pre‐operative transfusion of 10 platelet concentrate units (the equivalent of 40% V‐PRP) after a 300‐mg clopidogrel loading or 12.5 units (50% V‐PRP) after a 600 mg loading may adequately reverse clopidogrel‐induced platelet disaggregation to facilitate postoperative hemostasis. An additional 2.5 units fully normalized platelet function. The potential clinical implications of our observations could include shorter hospitalizations and reduced bleeding complications. But these observations should be fully explored in an in vivo clinical setting with clopidogrel‐treated patients before and after surgery.

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.

Association of Anhedonia With Recurrent Major Adverse Cardiac Events and Mortality 1 Year After Acute Coronary Syndrome

CONTEXT Depression consistently predicts recurrent events and mortality in patients with acute coronary syndrome (ACS), but it has 2 core diagnostic criteria with distinct biological correlates-depressed mood and anhedonia (loss of pleasure or interest). OBJECTIVE To determine if depressed mood and/or anhedonia predict 1-year medical outcomes for patients with ACS. DESIGN Observational cohort study of post-ACS patients hospitalized between May 2003 and June 2005. Within 1 week of admission, patients underwent a structured psychiatric interview assessing clinically impairing depressed mood, anhedonia, and major depressive episode (MDE). Also assessed were the Global Registry of Acute Coronary Events risk score, Charlson comorbidity index, left ventricular ejection fraction, antidepressant use, and depressive symptom severity using the Beck Depression Inventory. SETTING Cardiac units of 3 university hospitals in New York and Connecticut. PARTICIPANTS Consecutive sample of 453 patients with ACS (age, 25-93 years; 42% women). MAIN OUTCOMES MEASURES All-cause mortality (ACM) and documented major adverse cardiac events (MACEs)-myocardial infarction, hospitalization for unstable angina, or urgent/emergency coronary revascularization)-actively surveyed for 1 year after admission. RESULTS There were 67 events (16 deaths and 51 MACEs; 14.8%): 108 (24%) and 77 (17%) patients had anhedonia and depressed mood, respectively. Controlling for sex, age, and medical covariates, anhedonia (adjusted hazard ratio, 1.58; 95% confidence interval, 1.16-2.14; P < .01) was a significant predictor of combined MACE and ACM, but depressed mood was not. Anhedonia continued to significantly predict outcomes (P < .05) when additionally controlling for MDE diagnosis or depressive symptom severity. Findings were confirmed using depressed mood and anhedonia subscores from the Beck Depression Inventory in place of clinician interview ratings. CONCLUSIONS Anhedonia identifies risk of MACE and ACM beyond that of established medical prognostic indicators, including MDE and depressive symptom severity. Correlates of anhedonia may add to the understanding of the link between depression and heart disease.

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.

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.

Oral Platelet Glycoprotein IIb/IIIa Receptor Antagonists: The Present Challenge Is Safety

An indisputable body of angiographic,1 2 angioscopic,3 pathological,4 and biochemical5 evidence supports the role of thrombus in the pathogenesis of acute myocardial infarction, unstable angina, and percutaneous coronary intervention.6 Compelling data from large-scale trials and analyses have established the role of platelet inhibitors in reducing coronary events in patients with the acute coronary syndromes and in maintaining patency of vascular grafts in the long term.7 8 Persistent reports of high clinical event rates in the modern era of acute coronary syndromes despite aggressive medical therapy have spurred the development of more effective antiplatelet agents. Despite its efficacy, aspirin is a relatively weak antiplatelet agent, inhibiting only thromboxane A2–mediated platelet aggregation. The final common pathway of platelet aggregation involves activation of the platelet glycoprotein IIb/IIIa (GP IIb/IIIa) receptor to allow fibrinogen binding.9 Studies involving a number of intravenous inhibitors of GP IIb/IIIa receptors have demonstrated efficacy in reducing ischemic complications after percutaneous angioplasty10 11 12 and in the acute coronary syndromes.13 14 15 16 In patients who have survived an episode of unstable angina or myocardial infarction, activation of the hemostatic system may persist for several months after the acute event.5 Studies with GP IIb/IIIa inhibitors12 16 and with specific antithrombins17 have demonstrated efficacy of these agents during the short-term period coinciding with intravenous administration, with subsequent decay in clinical benefit after cessation of parenteral treatment so that no demonstrable clinical benefit is evident at late (1 month) follow-up. Hence, there exists a compelling rationale for long-term antiplatelet treatment, including …

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

Decreased Reendothelialization and Increased Neointima Formation With Endostatin Overexpression in a Mouse Model of Arterial Injury

329.2 billion 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.

Platelet function normalization after a prasugrel loading‐dose: time‐dependent effect of platelet supplementation

Background—Impaired endothelial regeneration contributes to arterial lesion formation. Endostatin is a specific inhibitor of endothelial cell growth and induces endothelial cell apoptosis. We examined the effect of endostatin overexpression on reendothelialization and neointima formation in a mouse model of arterial injury. Methods and Results—Mice underwent femoral arterial denudation and received recombinant adenovirus, expressing either murine endostatin (n=19) or control adenoviral vector (n=12), by jugular vein injection. Endostatin gene transfer resulted in high serum levels of endostatin. Strong adenoviral gene expression of &bgr;-galactosidase–expressing control vector was detected in liver tissue and was absent in the injured arterial wall at 1 week. Deposits of endostatin protein were detected along the denuded arterial wall and were not seen in the noninjured contralateral artery at 1 week. Endostatin deposits were also absent in the injured artery of control vector–treated animals. Overexpression of endostatin led to decreased reendothelialization and increased apoptosis of luminal endothelial cells 2 and 4 weeks after arterial injury (P <0.05). In addition, endostatin overexpression resulted in increased neointima formation (P <0.05). Endothelial apoptosis and neointima area correlated positively with endostatin serum levels, whereas the degree of reendothelialization correlated negatively with endostatin serum levels (P <0.05). Furthermore, poor reendothelialization correlated with increased neointima formation (P <0.05). Conclusions—In summary, decreased reendothelialization and enhanced endothelial apoptosis, in response to endostatin overexpression, were associated with increased neointima formation. These findings demonstrate that high serum levels of endostatin are capable of inhibiting endothelial regeneration and promoting arterial lesion growth in conditions of endothelial injury.