Cardiology: Earn 3 CPD mediCal and meChaniCal therapy Points onlinE HigHligHts frOm tHe 2016 m & m cardiOlOgy meeting: merging medical and mecHanical management fire and ice trials: atrial fibrillation ablation procedures Approximately 60% of patients with atrial to initial drug therapy in symptomatic fibrillation (AF) are symptomatic and will patients. Pulmonary vein isolation is the be considered for treatment. Although standard approach. antiarrhythmic drugs are generally used The most commonly used method of as first line therapy, AF will reoccur in catheter ablation has been radiofrequency Dr Razeen Gopal around 50% of patients within 6 to 12 ablation, which requires only limited use Interventional Cardiologist & Director months. Ablation is significantly more of fluoroscopy, because catheter guidance Electrophysiology effective than drug therapy and improves is achieved with the use of an electro-ana- Laboratory and Service quality of life. In the ThermoCool AF tomical mapping system. This approach Cape Town AF Centre trial approximately two thirds of patients is complex and requires extensive train- Cape Town with symptomatic AF who had not ing. In contrast, cryoablation uses cryo- South Africa improved with at least one drug remained genic energy applied with a balloon in a free from symptomatic paroxysmal AF at single-step mode, which leads to necrosis 9 months after ablation in comparison to of the pulmonary vein antra by freezing. 16% treated with alternative antiarrhyth- It is a faster and simpler procedure that mic drug therapy.1 Initial treatment with uses more extensive fluoroscopic guid- ablation therapy is also associated with ance to position the balloon catheter at significantly better outcomes than drug the pulmonary veins. therapy and early referral as soon as pos- The FIRE and ICE study was designed sible after diagnosis improves the clinical to compare radiofrequency ablation with This article was made outcome.2,3 cryoballoon ablation in a large population possible by an unrestricted Current guidelines recommend cath- of patients with paroxysmal AF.4 It was a educational grant from eter ablation of drug-refractory paroxys- multicenter, randomised, noninferiority, medtronic, boehringer ingelheim and ge mal atrial fibrillation or as an alternative parallel group, open-label trial including Healthcare, which had no control over content. OctOber 2016 1 SpecialiSt care and Medical ethicS – M&M Meeting 762 patients with symptomatic paroxysmal were most frequent in the radiofrequency AF that was refractory to class I or class group (4.3% vs. 1.9%), phrenic nerve III antiarrhythmic drugs or beta-blockers. injury occurred in 2.7% of the cryobal- The primary efficacy endpoint was the loon patients and in none of the patients first documented clinical failure occurring receiving radiofrequency ablation. Both more than 90 days after the ablation pro- the mean total procedure time (124 vs. cedure, defined as documented recurrence 141 minutes; P<0.001) and left atrial of atrial fibrillation (lasting more than 30 dwell times were shorter in the cryobal- seconds), documented occurrence of atrial loon group. Mean total fluoroscopy time flutter or atrial tachycardia, prescription was shorter in the radiofrequency abla- of antiarrhythmic drugs (class I or III), tion group (17 vs. 22 minutes; P<0.001). or repeat ablation. The primary safety end In the long-term follow-up analysis point was a composite of death from any (30 months), in comparison with radiof- cause, stroke or transient ischemic attack requency ablation, there were significant from any cause, and serious adverse events benefits associated with the cryoballoon considered to be related to the therapeutic procedure.5 Patients treated with cry- intervention. oballoon had significantly fewer repeat There were no significant differences in ablations (11.8% vs. 17.6%; P=0.03), either the primary efficacy or safety end- direct-current cardioversions (3.2% vs. points. One-year Kaplan-Meier event rate 6.4%; P=0.04), all-cause hospitalisations estimates for clinical failure were 34.6% (32.6% vs. 41.5%; P=0.01) and cardiovas- for cryoballoon and 35.9% for radioabla- cular rehospitalisations (23.8% vs. 35.9%; tion (hazard ratio, HR 0.96; 95%CI, 0.76 P<0.01). Quality of life scores were to 1.22; P<0.001 for noninferiority). The improved in both groups. safety endpoint occurred in 10.2% and In comparison with radiofrequency 12.8%, respectively (P=0.24). However, ablation, cryoballoon ablation is a simpler the sites of complications were differ- and more cost effective procedure with ent. Whereas groin-site complications better long-term clinical outcomes. innovation in anticoagulation care Traditional vitamin K antagonist (VKA) convenience, efficacy and safety com- anticoagulants may be reversed by admin- pared with warfarin, fears of bleeding istering vitamin K (oral or IV), fresh fro- risk and lack of a specific reversal agent zen plasma (FFP) and blood products, or has, for many prescribers, been a barrier more quickly by prothrombinase complex to the use of NOACs. Consequently, anti- concentrates (PCC) or recombinant acti- coagulation is still widely underused for Prof Joanne van Ryn vated factor VII (rFVIIa). stroke prevention in patients with atrial Senior Principle Scientist Treatment protocols for bleeding in fibrillation (AF). Cardiometabolic Disease patients receiving non-vitamin K antago- Idarucizumab is a NOAC reversal Research nist anticoagulants (NOAC) are similar agent, specific to dabigatran. It is a mon- Boehringer Ingelheim to those for VKA and include NOAC oclonal antibody fragment that binds Biberach discontinuation, supportive measures irreversibly to dabigatran with an affinity Germany (e.g., mechanical compression, surgical that is 350 times as high as that observed haemostasis and fluid/blood replace- with thrombin. After intravenous admin- ment), FFP, platelets, PCC or rFVIIa. istration, it produces immediate and com- However, in comparison with bleeding plete reversal of the anticoagulant effects on warfarin, a lower 30 day mortality was of dabigatran, with no intrinsic procoag- observed after bleeding in patients treated ulant or anticoagulant activity itself. The for venous thromboembolism (VTE) with efficacy of idarucizumab remains con- dabigatran, because it has a short half- stant in the presence of mild-moderate life and is rapidly cleared from the body. renal impairment, studies have revealed Even in the absence of a specific reversal no clinically relevant drug-related adverse Earn 3 CPD points at agent, major bleeding occurs no more events and local tolerability reactions are www.denovomedica.com frequently with dabigatran in patients comparable with placebo. requiring urgent surgery or invasive pro- The efficacy and safety of idarucizumab Click on ‘Accredited cedures than it does with warfarin. Up in dabigatran-treated patients who pre- CPD modules’. until recently, despite improvements in sent with serious bleeding or who require 2 OctOber 2016 SpecialiSt care and Medical ethicS – M&M Meeting urgent surgery or intervention is the subject In patients with a life-threatening bleed, of an ongoing study (RE-VERSE AD). coagulation tests may be of use to help It includes two groups of adults who are identify the contribution of dabigatran to taking dabigatran and who reflect clinical bleeding. Activated partial thromboplastin situations in which a reversal agent would time (aPTT) approximates dabigatran lev- be required. Patients in group A are those els in plasma and is a useful tool to quickly with overt uncontrollable or life-threaten- obtain anticoagulant status, whereas a ing bleeding that is judged by the treat- normal thrombin time (TT) essentially ing clinician to require a reversal agent. excludes a contribution of dabigatran to Patients in group B are those who require bleeding. Due to the possibility of coagu- surgery or an invasive procedure that can- lopathy in the absence of anticoagulant not be delayed for at least 8 hours and for treatment, abnormal coagulation tests in which normal haemostasis is be required. patients with liver disease or severe blood In an interim analysis including 90 loss must be interpreted with caution. patients (51 in group A and 39 in group Furthermore, consideration of the time B), dabigatran was completely reversed of the most recent dabigatran dose in a in all patients and laboratory results were bleeding patient is important. Dabigatran normalised within minutes in 88% to 98%. is unlikely to be the major contributor to Among the patients who could be bleeding where more than 48 hours (nor- assessed, haemostasis in group A (n=35) mal renal function) or 72 hours (impaired was restored at a median of 11.4 hours. renal function) has elapsed since the most Among patients in group B who under- recent dose was taken. went a procedure (n=36), normal intra- Where necessary, to avoid thrombosis operative haemostasis was reported in after anticoagulation reversal, the short 33 (92%). No new safety concerns were half-life of idarucizumab (terminal half- identified. life = 4.4-8.1 hours) allows dabigatran to be restarted within 24 hours of its Clinical implications of administration. In patients requiring emergency sur- idarucizumab gery or an invasive procedure, the rapid In patients receiving dabigatran, the onset of action of idarucizumab allows the management of bleeding complications procedure to be undertaken shortly after should be individualised on the basis of administration with reinitiation of antico- the location and severity of the haemor- agulant therapy once haemostasis has been rhage. When it is available, idarucizumab restored. Because idarucizumab is specific is the treatment of choice for dabigatran for dabigatran, it has no effect on the effi- reversal. However, clinicians should bear cacy of alternative anticoagulants, which in mind that coexisting medical conditions may need to be considered in patients with may have a greater influence on prognosis renal impairment requiring resumption of than the ability to rapidly neutralize the anticoagulation, and in whom the half-life anticoagulant effect of dabigatran. of idarucizumab is prolonged. controversies in treatment of cad Intravascular ultrasound-derived minimal Irrespective of lipid profile and other lumen area is frequently used as a surro- characteristics, treatment with statins can gate marker of significant left main coro- reduce the 5-year incidence of major nary artery stenosis. However, traditional coronary events, coronary revascularisa- cut-off values (4-6 mm2) may overestimate tion and stroke by about 20% per mmol/L the functional significance of stenosis and reduction in LDL-C. The size of the pro- Dr Iftikhar Ebrahim thereby increase the rate of unnecessary portional reduction in major vascular Cardiologist percutaneous coronary intervention. events is directly proportional to the abso- Netcare Unitas Hospital In patients where the indication for lute LDL-C reduction achieved and there Centurion intervention is uncertain, correction of is no evidence of any threshold beyond Gauteng dyslipidaemias, and in particular LDL- which these risk reductions are diminished. cholesterol (LDL-C) reduction, has Nevertheless, the ability of current statin been shown to improve cardiovascular therapy to reduce LDL-C is limited and outcomes. the residual cardiovascular risk remains OctOber 2016 3 SpecialiSt care and Medical ethicS – M&M Meeting high, even with the addition of ezetimibe. trials enrolling 4465 patients who had Pro-protein convertase subtilisin/kexin completed a phase 2 or 3 trial of the 9 (PCSK9) is a serine protease that is PCSK9 inhibitor evolocumab, after 1 year highly expressed in the liver and intes- of therapy LDL-C was reduced by 61%, tine and which regulates degradation of and cardiovascular events were reduced the LDL receptor. Expression of PCSK9 by 53%.6 Another study with a different reduces the clearance of LDL cholesterol, PCSK9 inhibitor, alirocumab, showed while inhibition increases activity of the similar results. In comparison with pla- LDL receptor, which in turn increases cebo in patients at high risk for cardio- clearance of LDL. Although statins vascular events and LDL cholesterol ≥1.8 upregulate the LDL receptor, they also mmol/l on maximum doses of statins with increase the activity of PSCK9, which may or without other lipid-lowering therapy, attenuate cholesterol clearance. Therefore, alirocumab reduced LDL-C by 62% and PSCK9 inhibition is an attractive target to major cardiovascular events by 48%.7 enhance the LDL-lowering efficacy of sta- Ongoing cardiovascular outcomes tri- tin treatment and various PCSK9 inhibi- als will evaluate the impact of PCSK9 tors are currently under development. inhibition on clinical outcomes in distinct In comparison to standard therapy populations throughout the cardiovascu- alone, in two open-label, randomised lar risk continuum. minimize right ventricular pacing to prevent af and Hf (minerVa study) The MINERVA study evaluated whether endpoint composed of death, cardiovas- atrial preventive pacing and atrial anti- cular hospitalizations, or permanent AF) tachycardia pacing (DDDRP) + managed (hazard ratio, HR = 0.74, 95% confidence ventricular pacing (MVP) reduces mor- interval 0.55-0.99, P = 0.04). DDDRP + Prof Giovanni Botto tality, morbidity, or permanent AF com- MVP was associated with a relative risk Director pared with standard dual chamber pacing reduction for permanent AF of 61% (HR EP-Lab (Control DDDR). It was a multicentre = 0.39, 95% CI 0.21-0.75, P = 0.004). Sant’Anna Hospital (63 centres), international, randomized, “Physiological pacing” demonstrated Como and Professor single blind study with 3 arms enroll- only a modest advantage, expressed by Insubria University ing 1,166 patients with class I or class II a reduction of AF, mostly limited to pts Varese indications for dual chamber pacing, a with sinus node disease (SND). Italy history of atrial tachyarrhythmias and no Most algorithms are strictly designed history of permanent AF or third-degree to eliminate ALL RV pacing, but VP 0% AV block. at ANY COST would be not beneficial, In comparison with Control DDDR, due to the concern about long AV delay. DDDRP + MVP was associated with Atrial antitachycardia pacing therapies reduced incidence of the primary end- may help in tailoring the proper program- point (the 2-year incidence of a combined ming in implanted patients. 4d echocardiography and monitoring percutaneous interventions Three-dimensional echocardiography is has become increasingly popular as a an innovative imaging technique allow- standard for noninvasive monitoring for ing unprecedented imaging of the heart cardiosurgical and cardiac catheter inter- and cardiac flow in real time using volu- ventional procedures. Three-dimensional Prof Jaroslaw Kasprzak metric datasets. Since 2007 it is also avail- probes are also soon to be tested for this Department of Cardiology able for transesophageal imaging, which purpose. The benefits include less manip- Medical University of Łódz´ allows using higher frequency trans- ulation of the probe to obtain any desired Poland ducers and provides cleaner, less noisy cross-section, availability of simultaneous signal of uniform quality resulting in cross-sectional imaging (biplane or tri- improved three-dimensional data qual- plane imaging), as well as display of data ity. Transesophageal echocardiography from a three-dimensional perspective. 4 OctOber 2016 SpecialiSt care and Medical ethicS – M&M Meeting Regarding the currently used percutane- as Mitraclip implantation in mitral regur- ous interventional procedures, some of gitation or implantation of occluders in them require more detailed preprocedural minute perivalvular leaks benefit mark- quantification and understanding of ana- edly from direct visualization of the inter- tomical relationships. Atrial septal defects vention sites, both in multiplane and in en can be thoroughly visualized to enhance face “anatomical perspective” volume ren- preprocedural planning with precise plan- dered images, which are useful for direct imetry. This allows for fully noninvasive topographic guidance of device catheters. device sizing, and 3D imaging can also Finally, in any case of unexpected intrap- provide otherwise unavailable real-time rocedural complications transesophageal views, which contribute to the success of three-dimensional probe is the ultimate the procedure, especially in complex sep- imaging tool to rapidly explain the prob- tal defects. Recently introduced advanced lem and guide corrections. A brief sum- percutaneous valvular interventions mary of possible therapeutic techniques require both complete preprocedural which might benefit from a three-dimen- understanding of abnormal anatomy and sional perspective and multidimensional unprecedented cooperation of interven- imaging for pre- or intra-procedural plan- tionist and imager during the procedure. ning are summarized in the table. Morphological corrective treatments such Procedure biplane 3d Septal puncture +++ + biplane preferred Atrial septal defect occl. +++ +++(pre) LAA occlusion ++ ++ (pre) PMBV ++ ++ directing catheter into MV TAVI + + MitraClip +++ +++ grasping guided only by 2D Perivalvar leak occluder ++ +++ critical role of 3D guidance 4d echocardiography: added value through technological progress Echocardiography has evolved for over 60 improved presentation of data, allowing years to become a versatile, every day-use understanding of complex spatial anatomy advanced imaging technique for cardiac of the heart (presentation of nonplanar anatomy and flow. In the recent decade, a structures that do not fit in cross-sectional major technological step has been made image planes) and improved quantification Prof Jaroslaw Kasprzak to convert routine echocardiography from of distances, areas and volumes, as well Department of Cardiology Medical University of Łódz´ two-dimensional cross-sectional into the as volume-based functional parameters, Poland first cardiological routine, bedside volumet- such as ejection fraction. Even the simplest ric imaging technique. The developments applications of matrix three-dimensional of more than 60 years delivered multiple transducers, such as multiplane modes, varieties of echocardiographic examina- improve the quality of assessment of tion and since 1974 efforts have been made chamber volumes or valve planimetry. For to provide three-dimensional representa- most measurements, three-dimensional tion of cardiac structure and physiology. echocardiography offers 2-3 fold improved Currently three-dimensional echocardio- reproducibility (comparable to resonance graphic probes are available as a clinically imaging) and some of the available param- applicable commercial device on high-end eters, such as right ventricular quantifica- Earn 3 CPD points at echocardiographic systems allowing real- tion were previously not available using www.denovomedica.com time volumetric scanning of the heart from other ultrasound methods. These improved precordial, transesophageal or intracar- qualitative and quantitative features are Click on ‘Accredited diac windows. The principal benefits of supported by the use of three-dimensional CPD modules’. three-dimensional echocardiography lie in color Doppler imaging. OctOber 2016 5 SpecialiSt care and Medical ethicS – M&M Meeting Clinical examples include any distance three-dimensional datasets and dedicated measurements in unrestricted planes, for specific clinically oriented pathways, robust, realistic planimetry for defects such as quantification of the left or right or stenotic sites or volumetry of cavities ventricular function, assessment of mitral of tissue volume utilizing actual spatial valve and automatic extraction quantifi- outline. As regards cardiac valve disease, cation of the left ventricular outflow tract the method offers precise quantification together with aortic valve functional com- of valvular orifices, detailed anatomical plex. Expected developments of the tech- description of segmental valve lesions and nique are expanding everyday feasibility approaches to quantify true three-dimen- of large, high resolution, uniform quality sional volume of proximal isovelocity datasets from single beat acquisitions, as convergence zones. Improved assessment well as improving quantification based of segmental leaflet disease is facilitated on artificial intelligence and automated by “anatomical perspective” of volume critical data extraction. Ongoing work rendered images, and transesophageal is exploring potential of fusion of three- window is often used to obtain ultimate dimensional ultrasound datasets with image resolution and quality. Importantly, other imaging modalities, such as com- current echocardiographic systems are puted tomography or real-time intrapro- equipped with advanced dedicated quan- cedural fluoroscopy, to guide and enhance tification suites supporting the analysis of performance during cardiac procedures. deep vein thrombosis and pulmonary embolism: acute treatment and prevention of recurrence Venous thromboembolism (VTE) is a Furthermore, it has potential for a num- common chronic disease, being the third ber of serious drug-drug interactions. In most common cardiovascular disorder contrast, the newer non-vitamin K oral after myocardial infarction and stroke. anticoagulants (NOACs), dabigatran, Professor Menno Huisman After the initial event, there is a high rate edoxaban, rivaroxaban and apixaban pro- MD PhD FESC of recurrence - 11% within one year and vide efficient anticoagulation, are simpler Department of Thrombosis up to 40% within 10 years. Complications to use and are associated with a similar and Hemostasis are also common. After pulmonary or lower risk of bleeding complications. Leiden University Medical embolism (PE), the cumulative incidence They have a rapid onset and short offset Center Leiden of chronic thromboembolic pulmonary of action, fixed dosing, no known food The Netherlands hypertension is approximately 4% at 2 effects, fewer drug interactions and do not years, and post-thrombotic syndrome require routine monitoring. occurs in nearly one third of patients Unlike warfarin, heparin bridging is within 5 years of an initial deep vein not recommended when using rivaroxa- thrombosis (DVT). Consequently, to help ban or apixaban. However, the necessity prevent recurrent events and complica- for initial parenteral anticoagulation with tions, management requires prophylactic the other NOACs has also been ques- anticoagulation, which must be balanced tioned, and it is uncertain which patients with the risk of bleeding complications. might benefit from this. In patients at low Clinical guidelines for the treatment risk of complications, withholding par- of VTE have recommended initial paren- enteral anticoagulation allows earlier dis- teral anticoagulation with subcutaneous charge from hospital. low molecular weight heparin (LMWH) All of the NOACs have shown superi- or fondaparinux, followed by oral antico- ority versus placebo in long-term preven- agulation, both of which carry a risk of tion of DVT/PE recurrence, but there are serious (and potentially fatal) bleeding. no direct comparative studies of different Until recently, warfarin has been the NOACs in this setting. standard oral agent for prophylactic anti- In the RECOVER and RECOVER Earn 3 CPD points at coagulation. However, it has limitations in II studies, dabigatran 150 mg BID was www.denovomedica.com that its anticoagulation activity is unpre- compared to warfarin over 6 months dictable, with considerable inter- and in patients with confirmed acute symp- Click on ‘Accredited intra-individual variation, necessitating tomatic DVT of the leg and/or PE and CPD modules’. regular monitoring and dose adjustments. who had received initial parenteral 6 OctOber 2016 SpecialiSt care and Medical ethicS – M&M Meeting anticoagulation. Dabigatran was non- haemodynamically stable patients con- inferior to warfarin for prevention of sidered to be at risk of early mortality. recurrent symptomatic VTE or fatal VTE The Pulmonary Embolism Thrombolysis (hazard ratio, HR 1.09 (95%CI 0.77-1.54). (PEITHO) trial compared thrombolysis However, major bleeding events and clin- with tenecteplase to placebo in normo- ically-relevant non-major bleeding events tensive patients with confirmed PE, an occurred significantly less frequently abnormal right ventricle on echocardi- among patients treated with dabigatran ography or computed tomography, and (HR 0.56; 95%CI 0.45-0.71). a positive troponin I or T test result. Dabigatran is the only NOAC to have Thrombolysis reduced the occurrence long-term data versus warfarin in this of haemodynamic decompensation and setting. In the RE-MEDY study, over death within the first 7 days, but was also a treatment period of up to 36 months, associated with a significant increase in dabigatran 150 mg BID was as effective extracranial bleeding and stroke (primar- as warfarin for prevention of recurrent or ily haemorrhagic), suggesting that throm- fatal VTE, but was associated with a 46% bolysis should not be administered to lower risk of major bleeding and clini- high-risk stable patients. cally relevant non-major bleeds (HR 0.54; However, meta-analyses suggest that 95%CI 0.41-0.71). In the RE-SONATE results may differ depending on patient study, 6 months continuation of dabi- age and absence of right ventricular dys- gatran in patients who had received up to function. Trials are ongoing to determine 18 months initial anticoagulant therapy whether it is possible to improve the effi- was associated with a 92% reduction in cacy/risk ratio of fibrinolysis by selecting the risk of recurrent VTE versus pla- patients with a lower bleeding risk, using cebo. Recurrent VTE/VTE-related death a safer (lower dose) thrombolytic regimen occurred in 0.4% of dabigatran patients or, in the small group of patients who are vs. 5.6% in the placebo group (HR 0.08; suitable, using a catheter-based regimen. 95%CI 0.02-0.25). Any bleeding events In 2016, treatment guidelines for VTE occurred in 10.5% versus 5.9% of patients, were updated to include the following respectively (HR 1.82; 95%CI 1.23-2.68). recommendations:8 In patients with PE, guidelines recom- • For proximal DVT or PE, long-term mend risk stratification when deciding anticoagulation (3 months, or at least on course of therapy. Anticoagulation 3 months for unprovoked DVT) is rec- alone is recommended for patients at low ommended over no therapy. or intermediate risk of early mortality • For VTE and no cancer, as long-term (defined as in hospital or 30-day mortal- anticoagulant therapy, dabigatran, ity), whereas reperfusion is recommended rivaroxaban, apixaban or edoxaban for those who are high risk (defined as are recommended over vitamin K suspected or confirmed presence of shock antagonist (VKA) therapy and VKA or persistent arterial hypotension). therapy is recommended over LMWH. Currently it is uncertain whether • For VTE with cancer, LMWH is rec- thrombolysis would be of benefit in ommended over VKA and NOACs. advancing anticoagulation care in your region: selected topics in antithrombotic treatment for af patients Cardioembolic disease is the most impor- a thrombin inhibitor, and rivaroxaban, tant cause of stroke in patients over the apixaban and edoxaban, which are FXa age of 65 years. Consequently, providing inhibitors. However, this is a relatively new Professor Menno Huisman effective and safe anticoagulation for peo- class of drugs and questions still remain MD PhD FESC ple with atrial fibrillation (AF) is essential. about the practicalities and safety of use, Department of Thrombosis In this regard, the non-vitamin K antag- especially in patients with renal insuffi- and Hemostasis onist anticoagulants (NOACs) represent ciency and in those who require urgent Leiden University Medical a significant advance in therapy. Four surgical intervention or procedures where Center Leiden NOACs are approved for use and are avail- the risk of bleeding may be problem- The Netherlands able worldwide. They include dabigatran, atic. Furthermore, dabigatran is the only OctOber 2016 7 SpecialiSt care and Medical ethicS – M&M Meeting NOAC for which a reversal agent is now essential to support periprocedural deci- available and protocols are required to sion-making. If possible, surgery or pro- guide efficient and appropriate use of that. cedures may need to be delayed in patients NOACs are not recommended in with renal insufficiency or in those where patients with creatinine clearance (CrCl) use of another anticoagulant complicates <30 ml/min. However, phase III trials the bleeding risk. A prolonged activated have included patients with mild and partial thromboplastin time (aPTT) indi- moderate renal insufficiency and indicate cates an anticoagulant effect of dabi- that all 4 NOACs effectively reduce the gatran, and a prolonged prothrombin time incidence of stroke and systemic embo- (PT) indicates an anticoagulant effect of lism in comparison with warfarin, with- the FXa inhibitors. However, because nor- out an increase in major bleeding events mal values with either test do not exclude in patients with CrCl ≥30 ml/min. clinically relevant NOAC plasma levels, In patients with a CrCl <50 ml/min and the clinical utility of these tests is limited. where the risk of bleeding is high, the dose For patients on dabigatran, there is now of NOAC may be reduced according to the a specific reversal agent that provides the manufacturer’s prescribing information. option of immediate reversal when sur- The BRIDGE study demonstrated that gery is required. Administration of idaru- in patients with AF requiring interrup- cizumab allows the patient to proceed to tion of warfarin for an elective invasive or surgery without delay and with NOAC surgical procedure, bridging with paren- anticoagulation immediately reversed. teral anticoagulation with low molecular Following idarucizumab administration, weight heparin (LMWH) is unnecessary. dabigatran can be restarted after 24 hours In comparison with bridging, no bridg- when it is clinically appropriate. If earlier ing was non-inferior for the prevention of anticoagulation is required, LMWH may arterial thromboembolism, but decreased also be initiated at any time after idaru- the risk of major bleeding. cizumab, allowing for minimal time with- The short half-lives and rapid onset of out anticoagulation. action of NOACs allow for short inter- Idarucizumab is provided ready to use ruption of therapy without heparin bridg- and is administered in a fixed dose regard- ing. In line with this, the European Heart less of the clinical situation. It has no Rhythm Association (EHRA) practical known contraindications. guide on the use of NOACs in patients The Global Registry on Long-Term with nonvalvular AF does not recom- Oral Antithrombotic Treatment in Patients mend heparin bridging when interrupting with Atrial Fibrillation (GLORIA-AF) is a NOAC therapy. large, international, observational registry In the RE-LY trial, which compared designed to investigate patient character- dabigatran with warfarin for stroke preven- istics influencing choice of antithrombotic tion in AF, with dabigatran interruption, treatment of stroke prevention in patients in comparison to those who did not receive with newly diagnosed nonvalvular AF and bridging, bridged patients had more major to collect data on outcomes of antithrom- bleeding (6.5% vs. 1.8%, P<0.001) with- botic therapy in clinical practice across dif- out a benefit in terms of thromboembolic ferent regions of the world. It will enrol up events (1.2% vs. 0.6%, p=0.16). to 56 000 patients across nearly 50 coun- Depending on the clinical situation and tries. The study consists of three phases. providing that adequate haemostasis has Phase I includes patients before approval been established, dabigatran should be of NOACs. Phase II, beginning early after restarted as soon as possible after the pro- approval of dabigatran, monitors dabi- cedure or surgery requiring interruption gatran safety and addresses potential chan- of anticoagulation. Guidelines recom- nelling across treatment options based on mend waiting ≥24 hours for patients with propensity scoring to assess comparabil- a low bleeding risk and 48-72 hours for ity of baseline characteristics of patients those with high bleeding risk. treated with dabigatran or VKA. Phase III Earn 3 CPD points at Because renal impairment may slow entails analysis of large treatment groups, www.denovomedica.com down elimination of NOACs and recent adjusting for differences in propensity use of other oral anticoagulants may con- score, to provide information about the Click on ‘Accredited tribute to bleeding risk, assessment of relative effectiveness and safety of NOACs CPD modules’. renal function and coagulation tests are and VKA in routine clinical care. 8 OctOber 2016 SpecialiSt care and Medical ethicS – M&M Meeting In early analyses of patients in phase re-initiation of NOACs is straightfor- II, overall the data show a clear shift away ward for patients requiring an invasive from prescription of warfarin to a prefer- procedure or surgery. The availability of ence for NOACs after the introduction of idarucizumab, a specific reversal agent these anticoagulants (64% vs. 0% in Phase for dabigatran, further simplifies man- I and 38% vs. 52% in Phase II). During agement of these patients and signifi- the same period, the use of aspirin has cantly reduces bleeding risk when there decreased from 25% to 5%. is no time to wait for dabigatran plasma levels to decline before surgery. Bridging Conclusions is not required when restarting NOAC anticoagulation. NOACs can be used in safely patients Accordingly, real-world registries dem- with renal insufficiency. onstrate a worldwide move away from Because of their short half-life and warfarin in preference for NOACs in quick time to onset, discontinuation and patients with AF. arrhythmia treatment in africa Fifteen percent of the world’s population, centers, trained cardiologists and electro- some one billion people, live in the 54 coun- physiologists. Training is also required for tries on the African continent. Nevertheless, physicians in other medical specialities Africa remains the world’s poorest and most (e.g., obstetrics), and non-physician tech- underdeveloped continent, with a gross nicians who will be able to use hand-held domestic product (GDP) per capita in many echocardiography for early detection of Dr Ashley Chin countries being less than USD 2000. With cardiac disease, to facilitate early referral Cardiologist/ the exception of North Africa and South to a cardiologist or cardiothoracic surgeon. Electrophysiologist Africa, African countries have few working The high cost of PMs is one of the Groote Schuur Hospital doctors and even fewer specialist cardiolo- most important barriers to the establish- University of Cape Town gists. Although pacing remains one of the ment of an effective cardiac pacing ser- Cape Town most cost effective treatments for relieving vice in SubSaharan Africa. This may be symptoms prolonging life, it is unavailable overcome by re-use of PMs, which is safe to most Africans. In the 2009 11th Survey and cost-effective. of Cardiac Pacing, only 2 African countries The Pan African Society of Cardiology submitted any data at all – South Africa, 60 (PASCAR) Task Force on PM re-use has pacemaker (PM) units per million popula- been convened to address the unmet needs tion and Sudan 5 per million. By compari- of PM/ICD in SubSaharan Africa. The son, 2011 data indicated 938 PM units per objectives of the task force are as follows: million in Europe. 1. Prevent and treat cardiovascular dis- The 2014 PASCAR survey on pacing ease (CVD) in Africa (treat heart and electrophysiology in Africa surveyed 14 block and prevent sudden death): at African countries and found a severe short- least one pacing and ICD unit per age of PM centers and doctors with appro- African country. priate skills in all. In South Africa, there has 2. Educate and train African healthcare been a steady increase in PM implants over professionals about CVD: PASCAR time, but rates are still very low in compari- Fellowship in Clinical Cardiology and son with Europe – 173 PM doctors at 54 Cardiac Pacing. centers, distributed over 5 provinces, with 3. Educate laypersons about CVD: no centers in 4 provinces. In contrast, with Procurement, supply and regulatory the exception of Tunisia, the other African issues of used PMs and ICDs to par- countries surveyed had 6 or fewer centers ticipating sites. and fewer than 20 PM doctors. Two coun- 4. Invest in cardiovascular research: tries have no PM doctors at all. The avail- PASCAR Registry on Pacemaker and ability of skills and centers for implantable ICD Re-Use in Africa, randomised Earn 3 CPD points at cardioversion devices (ICD) are even more clinical trial on new versus used pace- www.denovomedica.com scarce and with the exceptions of South makers, and the Arrhythmogenic Right Africa and Senegal, there are no electro- Ventricular Cardiomyopathy (ARVC) Click on ‘Accredited physiologists in SubSaharan Africa. Registry of South Africa (established CPD modules’. There is a desperate need for training in 2004). OctOber 2016 9 SpecialiSt care and Medical ethicS – M&M Meeting cryptogenic stroke and atrial fibrillation - what is the link? Stroke is a leading cause of mortality and endpoint was time to first detection of serious long-term disability. Patients with AF at 6 months. Secondary endpoints atrial fibrillation (AF) are at especially included time to first detection of AF at high risk. In the presence of AF the risk 12 months, recurrent stroke or transient of ischaemic stroke increases five-fold ischaemic attack (TIA) and change in use Dr Mike Alison and in comparison to non-AF-related of oral anticoagulant drugs. Cardiologist Sunninghill Hospital strokes, the risk of mortality doubles. In By 6 months, AF had been detected Johannesburg contrast, anticoagulation in patients with in 19 patients (8.9%) in the ICM group AF reduces the risk of stroke by 67%. and 3 patients (1.4%) in the control group Cryptogenic stroke is defined as brain (hazard ratio, HR 6.4; CI95% 1.9-21.7; infarction not clearly attributable to a def- P<0.001). Rates of detection at 12 and 36 inite cardioembolism, large artery athero- months were 12.4% vs. 2.0% and 30.0% sclerosis or small artery disease, despite vs. 3.0% in the ICM and control groups, extensive investigation. respectively. In the USA, approximately 200  000 In the ICM group, the median time cryptogenic strokes occur annually, from randomisation to detection of AF accounting for approximately 30% of all was 41 days (interquartile range 14-84 ischaemic strokes. Most occur in patients days) at 6 months and 84 days (inter- who are receiving antiplatelet therapy for quartile range 18-265 days) at 12 months. secondary prevention. Seventy nine percent of first episodes Long-term monitoring reveals atrial were asymptomatic during the first year. fibrillation (AF) in approximately 30% of By 12 months, 97% of patients in patients with cryptogenic stroke - patients whom AF was detected were receiving who would have benefitted from antico- oral anticoagulants. Ischaemic stroke or agulant therapy. In these individuals, the TIA occurred in 15 patients (7.1%) in the risk of recurrent stroke is high, where up ICM group as compared with 19 patients to 20% will have a second stroke within 4 (9.1%) in the control group. years of the initial event. Of 208 ICMs that were inserted, 5 Diagnosis of cryptogenic stroke is one (2.4%) were removed due to infection of exclusion. Investigations include brain of the insertion site or pocket erosion. CT/MR, 12-lead ECG, precordial elec- The device remained inserted in 98% trogram, extra- and intravascular imag- of patients at 6 months and 97% at 12 ing and cardiac monitoring for at least 24 months. hours. Nevertheless, unless the patient has Numerous additional studies of ICM an episode of AF during the assessment, mirror these observations from the that diagnosis is likely to be missed. CRYSTAL AF study, with AF detection Conventional monitoring strategies yields of up to 33% and median times to may not be sensitive enough to detect AF, detection ranging from 48 to 161 days. especially since up to 80% of AF episodes Similar observations have also been are asymptomatic. Patient compliance documented in real-world clinical prac- with holter monitors and event recorders tice. Using data from the de-identified is poor and, although it may be improved Medtronic DiscoveryLink™ database, with mobile cardiac telemetry, given the AF detection rates (episodes ≥2 minutes) paroxysmal nature of AF, a duration of were quantified using Kaplan-Meier monitoring limited to 30 days may not be survival estimates at 1 and 6 months for sufficient. patients who received an ICM (Reveal Long-term monitoring with insertable LINQ™) for the purpose of AF detec- cardiac monitors (ICM) may increase tion following a cryptogenic stroke.10 the detection of AF. The CRYSTAL AF Eighty five patients were monitored for study randomised 441 patients with a a mean of 569 days and paroxysmal AF Earn 3 CPD points at diagnosis of cryptogenic stroke and no was detected by ICM in 16% at a mean of www.denovomedica.com evidence of AF during at least 24 hours 109 days after stroke onset. In all cases, of ECG monitoring to either an insert- AF was asymptomatic and occurred in Click on ‘Accredited able (REVEALTM) cardiac monitor or episodes lasting predominantly between CPD modules’. conventional follow up.9 The primary 1 and 4 hours. Four patients suffered 10 OctOber 2016