Saul Benedict Freedman

Telehealth interventions for the secondary prevention of coronary heart disease: a systematic review

Coronary heart disease (CHD) is a leading cause of death globally. Despite proven health benefits and international recommendations, attendance at cardiac rehabilitation programs is poor. Telehealth (phone, Internet, and videoconference communication between patient and health-care provider) has emerged as an innovative way of delivering health interventions. This review aimed to determine telehealth effectiveness in CHD management. Study design includes systematic review with meta-analysis. Randomized controlled trials evaluating telehealth interventions in patients with CHD were identified by searching multiple electronic databases, reference lists, relevant conference lists, gray literature, and key-word searching of the Internet. Studies were selected if they evaluated a telephone, videoconference, or web-based intervention, provided objective measurements of mortality, changes in multiple risk factor levels or quality of life. In total, 11 trials were identified (3145 patients). Telehealth interventions were associated with nonsignificant lower all-cause mortality than controls [relative risk = 0.70, 95% confidence interval (CI) = 0.45-1.1; P = 0.12]. These interventions showed a significantly lower weighted mean difference (WMD) at medium long-term follow-up than controls for total cholesterol (WMD = 0.37mmol/l, 95% CI = 0.19-0.56, P < 0.001), systolic blood pressure (WMD = 4.69 mmHg, 95% CI = 2.91-6.47, P < 0.001), and fewer smokers (relative risk = 0.84, 95% CI = 0.65-0.98, P = 0.04). Significant favorable changes at follow-up were also found in high-density lipoprotien and low-density lipoprotein. In conclusion, telehealth interventions provide effective risk factor reduction and secondary prevention. Provision of telehealth models could help increase uptake of a formal secondary prevention by those who do not access cardiac rehabilitation and narrow the current evidence-practice gap.

Antithrombotic therapy in patients treated with oral anticoagulation undergoing coronary artery stenting. An expert consensus document with focus on atrial fibrillation

Dual antiplatelet treatment with aspirin and clopidogrel is recommended after coronary stenting (PCI-S). There is scant evidence defining optimal post-PCI-S antithrombotic therapy in patients with atrial fibrillation (AF) in whom oral anticoagulation (OAC) is mandated. To evaluate the safety and efficacy of the antithrombotic strategies for this population, we conducted a systematic review of the available evidence in patients treated with OAC undergoing PCI-S. AF was the most frequent indication for OAC. Post-PCI-S management was highly variable, and triple therapy with warfarin, aspirin, and clopidogrel was the most frequent and effective combination. Warfarin plus aspirin alone was not sufficiently effective in the early period after PCI-S and should not be prescribed. While acknowledging that the optimal antithrombotic treatment for patients with AF at medium or high thromboembolic risk undergoing PCI-S is currently undefined, triple therapy of warfarin, aspirin, and clopidogrel is currently recommended, although associated with an increased risk of major bleeding. Restrictive use of drug-eluting stent is also recommended, due to the need for prolonged multiple-drug antithrombotic therapy which may increase the bleeding risk. Whether the combination of warfarin and clopidogrel (without aspirin) will preserve efficacy and produce less bleeding is an important issue still needing to be addressed.

Therapy persistence in newly diagnosed non-valvular atrial fibrillation treated with warfarin or NOAC. A cohort study.

Efforts to reduce stroke in atrial fibrillation (AF) have focused on increasing physician adherence to oral anticoagulant (OAC) guidelines, but high early vitamin K antagonist (VKA) discontinuation is a limitation. We compared persistence of non-VKA OAC (NOAC) with VKA treatment in the first year after OAC inception for incident AF in real-world practice. We studied 27,514 anticoagulant-naïve patients with incident non-valvular AF between January 2011 and May 2014 in the UK primary care Clinical Practice Research Datalink, with full medication use linkage: mean age 74.2 ± 12.4, 45.7% female, mean follow-up 1.9 ± 1.1 years. After treatment initiation and follow-up until 1/2015, the proportion remaining on OAC at one year (persistence) was estimated using competing risk survival analyses. OAC was commenced ≤ 90 days after incident AF in 13,221 patients (48.1%): 12,307 VKA and 914 NOAC (apixaban, dabigatran, rivaroxaban). Amongst those treated with OAC, the proportion commencing NOAC increased from zero in 1/2011 to 27.0% in 5/2014, and OAC prescriptions for CHA2DS2VASc score ≥ 2 (guideline adherence) increased from 41.2% to 65.5%. Persistence with OAC declined over 12 months to 63.6% for VKA and 79.2% for NOAC (p< 0.0001). Persistence for those with CHA2DS2VASc ≥ 2 was significantly greater for NOAC (83.0%) than VKA (65.3%, p< 0.0001) at one year and all earlier time points. Comparison of VKA and NOAC cohorts matched on individual CHA2DS2VASc components showed consistent results. In conclusion, persistence was significantly higher with NOAC than VKA, and could alone lead to fewer cardioembolic strokes. Increased guideline adherence following NOAC introduction could further decrease AF stroke burden.

Stroke Risk and Antithrombotic Strategies in Atrial Fibrillation

Background and Purpose— Although the stroke rate associated with atrial fibrillation has declined over the last 10 years, the emerging atrial fibrillation epidemic threatens to increase the incidence of cardioembolic stroke. Summary of Review— Oral anticoagulants are superior antithrombotic agents but are underused due to fear of bleeding and uncertainty about which patients will benefit. Individualized decisions on antithrombotic therapy require balancing the competing risks of thromboembolism and bleeding. The CHADS2 (Congestive heart failure, Hypertension, Age >75 years, and Diabetes mellitus, and 2 points for prior Stroke/transient ischemic attack) score and other schemes provide an estimate of thromboembolic risk; however, the external validity of these estimates in the context of well-controlled risk factors, or a hypercoagulable state, is uncertain. Moreover, it is very difficult to estimate bleeding risk. Recent studies highlight the need for meticulous international normalized ratio control to achieve optimal outcomes hampered by the high bleeding risk during oral anticoagulant inception and other limitations of warfarin. Dabigatran is at least as efficacious as warfarin in preventing stroke and systemic embolism for patients in whom the risk of thromboembolism outweighs bleeding risk. In addition, the results of ongoing trials evaluating alternative anticoagulants such as oral anti-Xa agents are awaited. In this review, we discuss emerging therapies including available and completed trials of direct antithrombins and anti-Xa agents, including ximelagatran, idraparinaux, and dabigatran; and new device therapies including left atrial appendage occlusion devices. Conclusions— In light of these promising new therapies, it is likely that atrial fibrillation thromboembolism guidelines will need to be rewritten and frequently updated.

Adverse prognosis of incidentally detected ambulatory atrial fibrillation

It was the aim of this study to determine prognosis of incidentally detected ambulatory atrial fibrillation (IA-AF) and its response to antithrombotic therapy. We performed a cohort study of 5,555 patients with IA-AF (mean age 70.9 ± 10.1, 38.4% female) and 24,705 age- and gender-matched controls without AF followed three years using UK Clinical Practice Research Datalink. We measured incidence rates of stroke, all-cause mortality, myocardial infarction, major bleeding, and effect of antithrombotic therapy. Patients with IA-AF had mean CHA2DS2VASc score 2.5 ± 1.5, 73% with score ≥2. The stroke incidence rate (IR) was 19.4 (95% confidence interval 17.1 - 21.9)/1,000 person-years vs 8.4 (7.7 - 9.1) in controls (p<0.001), mortality 40.1 (36.8 - 43.6)/1,000 person-years vs 20.9 (19.8 - 22.0) in controls (p<0.001), and myocardial infarction 9.0 (7.5 - 10.8)/1,000 person-years vs 6.5 (5.9 - 7.2) in controls (p<0.001). IRs of all endpoints increased with age. Oral anticoagulant ± antiplatelet therapy received by 51.0% in year following IA-AF was associated with adjusted hazard ratio (HR) of 0.35 (0.17 - 0.71) for stroke, and 0.56 (0.36 - 0.85) for death compared to no therapy, while antiplatelet treatment was associated with a non-significant reduction of HR: 0.81 (0.51 - 1.29) for stroke, and 0.80 (0.55 - 1.15) for death, though both carried a similar small non-significant adjusted excess IR of major bleeding. In conclusion, asymptomatic AF detected incidentally is associated with a significant adverse effect on stroke and death, with reduction in both associated with oral anticoagulant but not antiplatelet treatment. This provides justification to assess cost-effectiveness of community screening to detect unknown AF.

C-reactive protein contributes to the hypercoagulable state in coronary artery disease

Summary.  Objectives: Elevated plasma C‐reactive protein (CRP) levels predict coronary events, but it is unclear whether CRP plays a role in thrombosis associated with these events. We investigated tissue factor (TF) induction by CRP on peripheral blood mononuclear cells (PBMC) from patients with coronary disease. Patients and Methods: PBMC from 35 patients with stable angina (SA) in study 1, 10 male patients with SA, 10 with unstable angina (UA) and 10 matched controls in study 2, and 25 patients with inflammatory disorders (ID) and 24 normal controls in study 3 were stimulated with CRP, interferon‐γ (IFN) or lipopolysaccharide (LPS), or their combination. PBMC from additional normal donors were also stimulated with CRP in adherent and non‐adherent conditions, and TF activity, antigen and mRNA expression detected. Results: CRP (5–25 μg mL−1) dose dependently induced more TF on PBMC from SA patients than 42 contemporary controls (P = 0.001, study 1). Compared with controls, patients with SA or UA had higher basal, and much higher CRP‐ or CRP/LPS‐induced monocyte TF activity although serum CRP levels were similar (study 2). IFN induced monocyte TF activity in patients with angina, but not in controls. Basal or CRP‐induced TF levels did not differ between controls and ID, even though ID patients had much higher serum CRP levels (study 3). CRP‐induced monocyte TF activity correlated with serum CRP levels in controls (P = 0.005) and ID (P = 0.007) in study 3, but not in patients with angina (P =0.84) in study 2. CRP induced more TF activity, protein and mRNA under adherent than non‐adherent conditions implying that it may mainly target macrophages in lymphocyte‐rich lesions. Conclusions: Our results indicate that monocytes from patients with angina are preactivated and express TF but CRP is unlikely to be a major priming factor in vivo. IFN and CRP further increase TF levels that may contribute to the hypercoagulable state in coronary disease.

Regional thallium uptake in irreversible defects.

BackgroundThallium reinjection immediately after stress-redistribution imaging identifies ischemic but viable myocardium in as many as 50% of the regions characterized by conventional redistribution imaging as irreversibly injured. However, we have previously shown that some regions in which irreversible defects persist despite reinjection are metabolically active, and hence viable, by positron emission tomography. In the current study, we determined whether the severity of reduction in thallium activity within irreversible defects on redistribution images and the magnitude of change in regional thallium activity after reinjection can further discriminate viable from nonviable myocardium in such defects. Methods and ResultsWe studied 150 patients with coronary artery disease by exercise thallium tomography using the rest-reinjection protocol. The three sets of images (stress, redistribution, and reinjection) were then analyzed quantitatively. The increase in regional thallium activity from redistribution to reinjection was computed, normalized to the increase observed in a normal region, and termed “differential uptake.” Of the 175 myocardial regions designated to have irreversible thallium defects on conventional 3-4-hour redistribution images, 132 had only mild-to-moderate reduction in thallium activity (51–85% of normal activity), and 43 had severe reduction in thallium activity (≤50% of normal activity). Thallium reinjection resulted in enhanced relative activity in 60 of 132 (45%) of the mild-to-moderate irreversible defects and 22 of 43 (51%) of the severe irreversible defects, leaving roughly half of these defects remaining irreversible after reinjection. However, in regions that appeared to remain irreversible despite reinjection, the magnitude of differential uptake differed between mild-to-moderate (74±14%) and severe (35Conclusions.16%) irreversible defects (p <0.001). All regions with mild-to-moderate defects demonstrated >50% differential uptake after reinjection. In contrast, all except two of the regions with severe irreversible defects demonstrated differential uptake of <50%. Fifteen patients also underwent positron emission tomography at rest with 18F-fluorodeoxyglucose (FDG) and 15O-water. FDG uptake was present in 91% of regions with mild-to-moderate reduction in thallium activity, and the results of differential uptake and FDG data were concordant in 81% of these regions. ConclusionsThese data indicate that the magnitude of thallium uptake after reinjection differs between mild-to-moderate and severe irreversible defects on standard 3-4-hour redistribution images. The substantial differential uptake of thallium (>50%) after reinjection in mild-to-moderate defects, even when relative thallium activity does not increase appreciably (and the defect appears to remain irreversible), coupled with preserved metabolic activity by positron emission tomography, supports the concept that such mild-to-moderate irreversible defects represent viable myocardium.

Incidence and determinants of myocardial infarction following percutaneous coronary interventions according to the revised Joint Task Force definition of troponin T elevation.

BACKGROUND Elevations in troponin T (TnT) occur frequently following percutaneous coronary intervention (PCI) and are associated with an adverse prognosis. The Joint ESC/ACC/AHA/WHF Task Force have released a proposal for a universal definition of myocardial infarction (MI), including diagnostic criteria for PCI associated MI. This is based on a TnT cut-point of more than three times the 99th percentile (0.03 ng/ml), which better reflects the precision of the assay. Our study investigated the incidence and predictive factors of a PCI associated MI, using the revised definition. METHODS 325 patients were studied following PCI with stenting. TnT was collected at both 8 and 18 h following PCI in patients with either stable or unstable angina and normal baseline TnT levels. Comparison was made of both clinical and procedural characteristics of patients with and without a rise in TnT following intervention, using cut points of 0.01 and 0.03 ng/ml. RESULTS TnT was elevated > or = 0.03 ng/ml in 27% and > or = 0.01 ng/ml in 39% of patients following PCI. Troponin elevation was significantly more likely in those patients who experienced peri-procedural ischemic symptoms or EKG changes, or in whom abciximab was used. The variables associated with a troponin rise showed a greater difference between TnT positive and negative patients when using 0.03 ng/ml compared to 0.01 ng/ml, suggesting that this may be a better definition of PCI-related MI. CONCLUSIONS Approximately one-quarter of low risk patients experience a procedural MI according to the revised definition. Rises in troponin were significantly associated with peri-procedural ischemic symptoms and EKG changes, and abciximab use, consistent with this level of TnT reflecting true myocardial necrosis.

The acute-phase protein serum amyloid A induces endothelial dysfunction that is inhibited by high-density lipoprotein.

The acute-phase protein serum amyloid A (SAA) is elevated during inflammation and may be deposited in atheroma where it promotes atherosclerosis. We investigated the proatherogenic effects of SAA on the vascular endothelium and their regulation by high-density lipoprotein (HDL). Exposure of human aortic endothelial cells (HAEC) to SAA (0.25-25μg/ml) decreased nitric oxide ((•)NO) synthesis/bioavailability, although the endothelial NO synthase monomer-to-dimer ratio was unaffected. SAA (10μg/ml) stimulated a Ca(2+) influx linked to apocynin-sensitive superoxide radical anion (O(2)(•-)) production. Gene expression for arginase-1, nuclear factor κB (NF-κB), interleukin-8, and tissue factor (TF) increased within 4h of SAA stimulation. Enzymatically active Arg-1/2 was detected in HAEC cultured with SAA for 24h. Therefore, in addition to modulating (•)NO bioavailability by stimulating O(2)(•-) production in the endothelium, SAA modulated vascular l-Arg bioavailability. SAA also diminished relaxation of preconstricted aortic rings induced by acetylcholine, and added superoxide dismutase restored the vascular response. Preincubation of HAEC with HDL (100 or 200, but not 50, μg/ml) before (not after) SAA treatment ameliorated the Ca(2+) influx and O(2)(•-) production; decreased TF, NF-κB, and Arg-1 gene expression; and preserved overall vascular function. Thus, SAA may promote endothelial dysfunction by modulating (•)NO and l-Arg bioavailability, and HDL pretreatment may be protective. The relative HDL to SAA concentrations may regulate the proatherogenic properties of SAA on the vascular endothelium.

Screening Education And Recognition in Community pHarmacies of Atrial Fibrillation to prevent stroke in an ambulant population aged >=65 years (SEARCH-AF stroke prevention study): a cross-sectional study protocol.

Background Atrial fibrillation (AF) is associated with a high risk of stroke and may often be asymptomatic. AF is commonly undiagnosed until patients present with sequelae, such as heart failure and stroke. Stroke secondary to AF is highly preventable with the use of appropriate thromboprophylaxis. Therefore, early identification and appropriate evidence-based management of AF could lead to subsequent stroke prevention. This study aims to determine the feasibility and impact of a community pharmacy-based screening programme focused on identifying undiagnosed AF in people aged 65 years and older. Methods and analysis This cross-sectional study of community-based screening to identify undiagnosed AF will evaluate the feasibility of screening for AF using a pulse palpation and handheld single-lead electrocardiograph (ECG) device. 10 community pharmacies will be recruited and trained to implement the screening protocol, targeting a total of 1000 participants. The primary outcome is the proportion of people newly identified with AF at the completion of the screening programme. Secondary outcomes include level of agreement between the pharmacists and the cardiologists interpretation of the single-lead ECG; level of agreement between irregular rhythm identified with pulse palpation and with the single-lead ECG. Process outcomes related to sustainability of the screening programme beyond the trial setting, pharmacist knowledge of AF and rate of uptake of referral to full ECG evaluation and cardiology review will also be collected. Ethics and dissemination Primary ethics approval was received on 26 March 2012 from Sydney Local Health District Human Research Ethics Committee—Concord Repatriation General Hospital zone. Results will be disseminated via forums including, but not limited to, peer-reviewed publication and presentation at national and international conferences. Clinical trials registration number ACTRN12612000406808.