Paul Burton

The Seattle Heart Failure Model: Prediction of Survival in Heart Failure

Background— Heart failure has an annual mortality rate ranging from 5% to 75%. The purpose of the study was to develop and validate a multivariate risk model to predict 1-, 2-, and 3-year survival in heart failure patients with the use of easily obtainable characteristics relating to clinical status, therapy (pharmacological as well as devices), and laboratory parameters. Methods and Results— The Seattle Heart Failure Model was derived in a cohort of 1125 heart failure patients with the use of a multivariate Cox model. For medications and devices not available in the derivation database, hazard ratios were estimated from published literature. The model was prospectively validated in 5 additional cohorts totaling 9942 heart failure patients and 17 307 person-years of follow-up. The accuracy of the model was excellent, with predicted versus actual 1-year survival rates of 73.4% versus 74.3% in the derivation cohort and 90.5% versus 88.5%, 86.5% versus 86.5%, 83.8% versus 83.3%, 90.9% versus 91.0%, and 89.6% versus 86.7% in the 5 validation cohorts. For the lowest score, the 2-year survival was 92.8% compared with 88.7%, 77.8%, 58.1%, 29.5%, and 10.8% for scores of 0, 1, 2, 3, and 4, respectively. The overall receiver operating characteristic area under the curve was 0.729 (95% CI, 0.714 to 0.744). The model also allowed estimation of the benefit of adding medications or devices to an individual patients therapeutic regimen. Conclusions— The Seattle Heart Failure Model provides an accurate estimate of 1-, 2-, and 3-year survival with the use of easily obtained clinical, pharmacological, device, and laboratory characteristics.

Rivaroxaban versus placebo in patients with acute coronary syndromes (ATLAS ACS-TIMI 46): a randomised, double-blind, phase II trial.

BACKGROUND Rivaroxaban is an oral direct factor Xa inhibitor that has been effective in prevention of venous thromboembolism in patients undergoing elective orthopaedic surgery. However, its use after acute coronary syndromes has not been investigated. In this setting, we assessed the safety and efficacy of rivaroxaban and aimed to select the most favourable dose and dosing regimen. METHODS In this double-blind, dose-escalation, phase II study, undertaken at 297 sites in 27 countries, 3491 patients stabilised after an acute coronary syndrome were stratified on the basis of investigator decision to use aspirin only (stratum 1, n=761) or aspirin plus a thienopyridine (stratum 2, n=2730). Participants were randomised within each strata and dose tier with a block randomisation method at 1:1:1 to receive either placebo or rivaroxaban (at doses 5-20 mg) given once daily or the same total daily dose given twice daily. The primary safety endpoint was clinically significant bleeding (TIMI major, TIMI minor, or requiring medical attention); the primary efficacy endpoint was death, myocardial infarction, stroke, or severe recurrent ischaemia requiring revascularisation during 6 months. Safety analyses included all participants who received at least one dose of study drug; efficacy analyses were by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00402597. FINDINGS Three patients in stratum 1 and 26 in stratum 2 never received the study drug. The risk of clinically significant bleeding with rivaroxaban versus placebo increased in a dose-dependent manner (hazard ratios [HRs] 2.21 [95% CI 1.25-3.91] for 5 mg, 3.35 [2.31-4.87] for 10 mg, 3.60 [2.32-5.58] for 15 mg, and 5.06 [3.45-7.42] for 20 mg doses; p<0.0001). Rates of the primary efficacy endpoint were 5.6% (126/2331) for rivaroxaban versus 7.0% (79/1160) for placebo (HR 0.79 [0.60-1.05], p=0.10). Rivaroxaban reduced the main secondary efficacy endpoint of death, myocardial infarction, or stroke compared with placebo (87/2331 [3.9%] vs 62/1160 [5.5%]; HR 0.69, [95% CI 0.50-0.96], p=0.0270). The most common adverse event in both groups was chest pain (248/2309 [10.7%] vs 118/1153 [10.2%]). INTERPRETATION The use of an oral factor Xa inhibitor in patients stabilised after an acute coronary syndrome increases bleeding in a dose-dependent manner and might reduce major ischaemic outcomes. On the basis of these observations, a phase III study of low-dose rivaroxaban as adjunctive therapy in these patients is underway. FUNDING Johnson & Johnson Pharmaceutical Research & Development and Bayer Healthcare AG.

Association of Hemoglobin Levels With Clinical Outcomes in Acute Coronary Syndromes

Background—In the setting of an acute coronary syndrome (ACS), anemia has the potential to worsen myocardial ischemia; however, data relating anemia to clinical outcomes in ACS remain limited. Methods and Results—We examined the association between baseline hemoglobin values and major adverse cardiovascular events through 30 days in 39 922 patients enrolled in clinical trials of ACS. After adjustment for differences in baseline characteristics and index hospitalization treatments, a reverse J-shaped relationship between baseline hemoglobin values and major adverse cardiovascular events was observed. In patients with ST-elevation myocardial infarction, when those with hemoglobin values between 14 and 15 g/dL were used as the reference, cardiovascular mortality increased as hemoglobin levels fell below 14 g/dL, with an adjusted OR of 1.21 (95% CI 1.12 to 1.30, P<0.001) for each 1-g/dL decrement in hemoglobin. At the other end of the range of hemoglobin, patients with hemoglobin values >17 g/dL also had excess mortality (OR 1.79, 95% CI 1.18 to 2.71, P=0.007). In patients with non–ST-elevation ACS, with those with hemoglobin 15 to 16 g/dL used as the reference, the likelihood of cardiovascular death, myocardial infarction, or recurrent ischemia increased as the hemoglobin fell below 11 g/dL, with an adjusted OR of 1.45 (95% CI 1.33 to 1.58, P<0.001) for each 1 g/dL decrement in hemoglobin. Patients with hemoglobin values >16 g/dL also had an increased rate of death or ischemic events (OR 1.31, 95% CI 1.03 to 1.66, P=0.027). Conclusions—Anemia is a powerful and independent predictor of major adverse cardiovascular events in patients across the spectrum of ACS.

Anemia and Its Relationship to Clinical Outcome in Heart Failure

Background—Anemia is often observed in patients with chronic heart failure (CHF), but its implications for patient outcomes are not well understood. The goal of this study was to investigate the relationship between anemia, severity of CHF, and clinical outcomes. Methods and Results—Hemoglobin concentration (Hb) was measured in 912 subjects with CHF enrolled in the Randomized Etanercept North American Strategy to Study Antagonism of Cytokines (RENAISSANCE) trial. In a subgroup of 69 subjects, cardiac MRI was performed at randomization and 24 weeks later. Anemia (Hb ≤12.0 g/dL) was present in 12% of subjects. Cox regression analysis indicated that for every 1-g/dL-higher baseline Hb, the risk of mortality was 15.8% lower (P =0.0009) and the risk of mortality or hospitalization for heart failure was 14.2% lower (P >0.0001). Greater CHF severity was associated with significantly lower Hb concentrations. An increase in Hb over time was associated with a decrease in left ventricular mass and lower mortality, whereas a decrease in Hb over time was associated with an increase in left ventricular mass and higher mortality. In multivariate analysis, anemia remained a significant, independent predictor of death or hospitalization for heart failure, with both outcomes being significantly higher in all NYHA classes. Conclusions—Anemia is frequently present in patients with CHF. Lower Hb is associated with greater disease severity, a greater left ventricular mass index, and higher hospitalization and mortality rates.

Tumor Necrosis Factor-α Is Expressed in Donor Heart and Predicts Right Ventricular Failure After Human Heart Transplantation

BACKGROUND-Myocardial failure is an important problem after heart transplantation. Right ventricular (RV) failure is most common, although its mechanisms remain poorly understood. Inflammatory cytokines play an important role in heart failure. We studied the expression of tumor necrosis factor (TNF)-alpha and other cytokines in donor myocardium and their relationship to the subsequent development of RV failure early after transplantation. METHODS AND RESULTS-Clinical details were obtained, and ventricular function was assessed by transesophageal echocardiography in 26 donors before heart retrieval. A donor RV biopsy was obtained immediately before transplantation, and each recipient was followed for the development of RV failure. Reverse transcriptase-polymerase chain reaction was performed to detect TNF-alpha, interleukin-2, interferon-gamma, and inducible nitric oxide synthase expression. Eight of 26 recipients (30.8%) developed RV failure. Seven of these 8 (87.5%) expressed TNF-alpha, but only 4 of the 18 (22.2%) who did not develop RV failure expressed TNF-alpha (P<0.005). As a predictor of RV failure, TNF-alpha mRNA had a sensitivity of 87.5%, a specificity of 83.3%, a positive predictive value of 70%, and a negative predictive value of 93.7%. Western blotting demonstrated more TNF-alpha protein in the myocardium of donor hearts that developed RV failure (658+/-60 versus 470+/-57 optical density units, P<0.05). Immunocytochemistry localized TNF-alpha expression to cardiac myocytes. Reverse transcriptase-polymerase chain reaction detected interferon-gamma in 2 (7.7%), interleukin-2 in 1 (3.8%), and inducible nitric oxide synthase mRNA in 1 (3.8%) of the 26 donor hearts, none of which developed RV failure. CONCLUSIONS-TNF-alpha expression in donor heart cardiac myocytes seems to predict the development of RV failure in patients early after heart transplantation.

Rivaroxaban in Patients Stabilized After a ST-Segment Elevation Myocardial Infarction: Results From the ATLAS ACS-2–TIMI-51 Trial (Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary Syndrome–Thrombolysis In Myocardial Infarction-51)

OBJECTIVES The present analysis reports on the pre-specified subgroup of ST-elevation myocardial infarction (STEMI) patients, in whom anticoagulant therapy has been of particular interest. BACKGROUND In ATLAS ACS-2-TIMI-51 (Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary Syndrome-Thrombolysis In Myocardial Infarction-51), rivaroxaban reduced cardiovascular events across the spectrum of acute coronary syndrome (ACS). METHODS Seven thousand eight hundred seventeen patients in ATLAS ACS-2-TIMI 51 presented with a STEMI. After being stabilized (1 to 7 days), they underwent randomization to twice daily rivaroxaban 2.5 mg, rivaroxaban 5 mg, or placebo. Data are presented as 2-year Kaplan-Meier rates, and for intention-to-treat (ITT) and modified ITT (mITT) analyses. RESULTS Among STEMI patients, rivaroxaban reduced the primary efficacy endpoint of cardiovascular death, myocardial infarction, or stroke, compared with placebo (ITT: 8.4% vs. 10.6%, hazards ratio [HR]: 0.81, 95% confidence interval [CI]: 0.67 to 0.97, p = 0.019; mITT: 8.3% vs. 9.7%, HR: 0.85, 95% CI: 0.70 to 1.03, p = 0.09). This reduction emerged by 30 days (ITT and mITT: 1.7% vs. 2.3%, p = 0.042) and was evident in analyses that included events while patients received background dual antiplatelet therapies (ITT: 7.9% vs. 11.9%, p = 0.010; mITT: 7.7% vs. 10.1%, p = 0.061). In terms of the individual doses, rivaroxaban 2.5 mg reduced cardiovascular death (ITT: 2.5% vs. 4.2%, p = 0.006; mITT: 2.2% vs. 3.9%, p = 0.006), which was not seen with 5 mg of rivaroxaban. Rivaroxaban versus placebo increased non-coronary artery bypass grafting Thrombolysis In Myocardial Infarction major bleeding (2.2% vs. 0.6%, p < 0.001) and intracranial hemorrhage (0.6% vs. 0.1%, p = 0.015) without a significant increase in fatal bleeding (0.2% vs. 0.1%, p = 0.51). CONCLUSIONS In patients with a recent STEMI, rivaroxaban reduced cardiovascular events. This benefit emerged early and persisted during continued treatment with background antiplatelet therapies. Rivaroxaban compared with placebo increased the rate of major bleeding, but there was no significant increase in fatal bleeding. (An Efficacy and Safety Study for Rivaroxaban in Patients With Acute Coronary Syndrome; NCT00809965).

Myocardial Dysfunction in Donor Hearts A Possible Etiology

BACKGROUND Potential cardiac donors show various degrees of myocardial dysfunction, and the most severely affected hearts are unsuitable for transplantation. The cause of this acute heart failure is poorly understood. We investigated whether alterations in calcium-handling proteins, beta-adrenoceptor density, or the inhibitory G protein Gialpha could account for this phenomenon in unused donor hearts (n=4 to 8). We compared these with end-stage failing hearts (n=14 to 16) and nonfailing hearts (n=3 to 12). METHODS AND RESULTS Myocardial samples were obtained from unused donor hearts displaying ejection fractions <30%. Both trabeculae and isolated myocytes responded as poorly as those from the group of failing hearts to increasing stimulation frequency with regard to inotropic function in vitro. Immunodetectable abundance of sarcoplasmic reticulum calcium-ATPase and sodium calcium exchanger were greater (177%; P<0.01) and smaller (29%; P<0.01), respectively, in the unused donor hearts relative to the failing group, which suggests that alterations of these proteins are not a common cause of contractile dysfunction in the 2 groups. Myocytes from the unused donor group were desensitized to isoprenaline to a similar degree as those from the failing heart group. However, beta-adrenoceptor density was reduced in the failing (P<0.001) but not in the unused donor heart group (P=0.37) relative to the nonfailing heart group (n=5). Gialpha activity was increased in samples from unused donor and failing hearts relative to nonfailing hearts (P<0.05). CONCLUSIONS Increased activity of the inhibitory G protein Gialpha is a significant contributory factor for impaired contractility in these acutely failing donor hearts.

Effect of multiple doses of omeprazole on the pharmacokinetics, pharmacodynamics, and safety of a single dose of rivaroxaban.

Abstract Many patients with acute coronary syndrome receive chronic dual antiplatelet therapy (acetylsalicylic acid and clopidogrel) for secondary event prophylaxis, and new oral anticoagulants are being investigated as adjunctive therapy in this indication. Gastrointestinal side effects such as bleeding are commonly associated with antiplatelet use; accordingly, many patients receive proton pump inhibitors (PPIs) to mitigate this. PPIs can reduce the antiplatelet activity of clopidogrel through cytochrome P450 2C19 inhibition, and pantoprazole reduces the bioavailability of dabigatran, a direct thrombin inhibitor that acts via cytochrome P450 2C19-independent mechanisms. These observations support the investigation of potential pharmacokinetic and pharmacodynamic interactions between PPIs and anticoagulants. We evaluated the influence of administering once-daily omeprazole 40 mg for 5 days on the pharmacokinetics and pharmacodynamics of a single 20-mg dose of the oral direct factor Xa inhibitor, rivaroxaban, in a randomized, open-label, 2-way, crossover, drug–drug interaction study in healthy subjects. No clinically meaningful interactions were observed; geometric mean ratios were 101%, 101%, and 93.5% for rivaroxaban area under the plasma concentration–time curve from time 0 to the time of the last quantifiable concentration (AUClast), or until infinity (AUC∞), and maximum plasma concentration (Cmax), respectively. Prothrombin time increased similarly in both treatment groups, with maximal values observed approximately 4 hours post rivaroxaban administration. A single 20-mg rivaroxaban dose appears well tolerated when administered alone or after 5 days of once-daily omeprazole 40 mg administration.

Is thrombosis a contributor to heart failure pathophysiology? Possible mechanisms, therapeutic opportunities, and clinical investigation challenges

Thrombotic events (coronary thrombosis, venous thromboembolism, intraventricular thrombosis, intracranial and systemic thromboembolism) occur frequently in patients with heart failure. These events may be precipitated by several mechanisms including hypercoagulability through enhancement of procoagulant reactions, impairment of the protein C pathway, protease activated receptor (PAR) activation, adenosine-mediated thrombosis, or neurohormonal activation; stasis secondary to low cardiac output; and endothelial dysfunction from neurohormonal activation or systemic inflammation. Pathophysiologic evidence and analyses of retrospective data support the hypothesis that antithrombotic agents may improve outcomes in patients with heart failure. Warfarin has not been shown to reduce clinical events in patients with heart failure, although several of the completed randomized trials were underpowered, and the most recent was not placebo-controlled. Many unanswered questions remain that justify continued research in this area. This paper examines the conceptual framework, opportunities, and challenges of clinical investigative approaches with the newer anti-thrombotic agents in patients with heart failure. Critical questions are raised with regard to clinical trial designs that warrant consideration as the field progresses.

Pharmacokinetics and pharmacodynamics of rivaroxaban and its effect on biomarkers of hypercoagulability in patients with chronic heart failure

BACKGROUND Heart failure (HF) is associated with a hypercoagulable state that predisposes to thromboembolism and anti-coagulation may improve clinical outcomes. The oral, direct Factor Xa inhibitor, rivaroxaban, has not been studied in patients with HF. We hypothesized that rivaroxaban would also reduce biomarkers of hypercoagulability in patients with HF. METHODS This study consisted of two cohorts: Cohort 1, open-label, actively controlled with enoxaparin 40 mg once daily, included 8 patients with acute decompensated HF; Cohort 2, double-blind and placebo-controlled, included 18 patients with stable, severe New York Heart Association Class III/IV HF. RESULTS The pharmacokinetics (PK) and pharmacodynamics (PD) of rivaroxaban were similar across both cohorts. Biomarker assessments were performed in Cohort 2; prothrombin fragment 1.2 (F1.2) mean concentration decreased by 2.7 ng/ml over 7 days with rivaroxaban, and increased by 11.6 ng/ml with placebo, an absolute difference of 14.3 ng/ml (p = 0.0009). A non-significant reduction in rate of increase of D-dimer (DD) and thrombin-anti-thrombin complex (TAT) levels with rivaroxaban was observed over 7 days (p = 0.31 and p = 0.77, respectively). CONCLUSION Rivaroxaban has similar PK/PD in patients with either acute or chronic HF. In vivo, hypercoagulability biomarkers appear to increase over time. Rivaroxaban reversed this trend for F1.2, and may reduce the rate of increase of DD and TAT in patients with stable, severe HF.