Camm, A John

McComb, Janet M

PubMed

McComb JM

Camm AJ

Newcastle University E-Prints

Primary prevention of sudden cardiac death usingimplantable cardioverter defibrillatorsMore patients need to be screened and treatedThe National Institute for Clinical Excellence(NICE) has recommended that implantablecardioverter defibrillators should be routinelyconsidered for patients who have survived ventricularfibrillation or ventricular tachycardia with haemo-dynamic compromise for secondary prevention ofarrhythmic death. It also recommends it in certainpatients who have not yet had a serious arrhythmicevent but who are at high risk of sudden cardiac deathas primary prevention. This second group comprisesmainly patients who have survived a myocardial infarc-tion. Only a tiny minority of these patients is currentlybeing investigated and treated with implantabledefibrillators.After an infarction, impaired ventricular functionwith an ejection fraction of 35% or less, non-sustainedventricular tachycardia (three beats or more) on ambu-latory 24 hour monitoring, and inducible ventriculartachycardia at electrophysiological testing identify asubgroup of patients at high risk of sudden death.Paradoxically, antiarrhythmic drugs increase the risk ofdeath and should be avoided in patients withsignificantly impaired ventricular function.1 At best,amiodarone decreases the risk of sudden death slightlybut does not affect overall mortality, with a risk reduc-tion of 13%-15%.2Two prospective randomised controlled trials ofpreventive strategies have shown the benefit of theimplantable cardioverter defibrillator in this high riskgroup. The multicentre automatic defibrillator trial, orMADIT, compared the implantable cardioverterdefibrillator with best medical treatment, whichincluded amiodarone in 74% of the control group.3 Itwas a relatively small study, justified by its sequentialtrial design. The multicentre unsustained tachycardiatrial, or MUSTT, compared an electrophysiologicallyguided strategy with no antiarrhythmic therapy.4 Thestrategy involved serial drug testing—antiarrhythmicdrugs were given, and the electrophysiology studyrepeated to determine if ventricular tachycardia couldstill be induced. Suppression of induction of ventricu-lar tachycardia was deemed a success. If not,antiarrhythmic drugs were withdrawn and an implant-able cardioverter defibrillator implanted. Although thiswas not a trial of the implantable cardioverter defibril-lator itself, benefit was seen only in those patientstreated with defibrillators.Both these trials have shown that implantablecardioverter defibrillators confer a relative riskreduction of 54%-60% in all-cause mortality. Using thisevidence the American College of Cardiology, Ameri-can Heart Association,5 National Institute for ClinicalExcellence,6 and European Society of Cardiology7 haveall recommended using an implantable cardioverterdefibrillator as a primary prevention strategy in suchhigh risk patients. In addition, NICE recommends thatscreening programmes should be put in place so thatthese patients can be identified.Screening requires assessment of ventricularfunction, 24 hour ambulatory monitoring in those withan ejection fraction of less than 35%, and anelectrophysiological study in those with non-sustainedventricular tachycardia aimed at provoking sustainedventricular tachycardia. Despite the recommendationin September 2000 that screening programmes be putin place, there seems to be none in the UnitedKingdom. Screening should be undertaken as acascade as identification requires all three criteria.Assessment of ventricular function is already requiredby the national service framework for heart disease, forwhich extra resource should be available, but only aminority of post-infarction patients undergo ambula-tory monitoring and extremely few undergo electro-physiological studies.Best guesses suggest that after an infarction about1% of patients will fulfil all three criteria and thereforebe considered for cardioverter defibrillatorimplantation.8–11 These estimates are based on a varietyof assumptions—that 4%-16% of post-infarctionpatients will have an ejection fraction of 35% orless,8 10 11 of these 12%-16% will have non-sustainedventricular tachycardia on ambulatory monitoring,8 10and that sustained ventricular tachycardia will beinducible at electrophysiological study in 22%-35% ofthese.11 12 There are 300 000 myocardial infarctionseach year in the United Kingdom; over half thepatients survive. Using these assumptions, over 1500patients each year should be considered for animplantable cardioverter defibrillator as a primary pre-vention strategy. If the recommendations made byNICE are adopted many patients should be screenedafter infarction. About 24 000 should undergoambulatory monitoring; 16%, or about 4000, shouldundergo electrophysiological study, and 1%, or about250, should have a cardioverter defibrillator implanted.Since the guidance from NICE was published, afurther primary prevention trial (MADIT 2) has showna relative reduction in mortality of 31% in post-infarction patients treated with an implantable cardio-verter defibrillator compared with the control groupreceiving usual treatment.13 This trial used a much sim-plified selection criterion—ejection fraction less than30% after myocardial infarction—obviating the needfor the screening cascade described by NICE. It doessuggest, however, that at least five times as manypatients as fulfil the current NICE criteria might benefitfrom an implanted defibrillator.Increasing the number of patients beinginvestigated and treated according to the guidancefrom NICE will need much additional resource. Tillthen few British patients will receive the carerecommended by NICE and widely available in theWestern world.Janet M McComb consultant cardiologistDepartment of Cardiology, Freeman Hospital, Newcastle upon TyneNE7 7DN (j.m.mccomb@ncl.ac.uk)EditorialsBMJ 2002;325:1050–11050 BMJ VOLUME 325 9 NOVEMBER 2002 bmj.comA John Camm professor of cardiologyRegional Cardiothoracic CentreJMM and AJC have received research grants and speaking feesfrom manufacturers of implantable cardioverter defibrillators.Both contributed advice to the health technology appraisalcommittee of NICE.1 Cardiac Arrhythmia Suppression Trial (CAST) Investigators. Preliminaryreport: effect of encainide and flecainide on mortality in a randomizedtrial of arrhythmia suppression after myocardial infarction. N Engl J Med1989;321:406-12.2 Connolly S. Evidence based analysis of amiodarone efficacy and safety.Circulation 1999;100:2025-34.3 Moss A, Hall W, Cannom D, Daubert J, Higgins S, Klein H, et al for themulticenter automatic defibrillator implantation trial investigators.Improved survival with an implantable defibrillator in patients with cor-onary disease at high risk for malignant ventricular arrhythmia. N Engl JMed 1996;335:1933-40.4 Buxton A, Lee K, Fisher J, Josephson M, Prystowsky E, Hafley M. A rand-omized study of the prevention of sudden cardiac death in patients withcornary artery disease. N Engl J Med 1999;341:1882-90.5 Gregatoros G, Cheitlin M, Connill A, al e. ACC/AHA guidelines forimplantation of cardiac pacemakers and antiarrhythmia devices. A reportof the ACC/AHA task force on practice guidelines (committee on pace-maker implantation). J Am Coll Cardiol 1998;31:1175-206.6 National Institute for Clinical Excellence. Guidance on the use ofimplantable cardioverter defibrillators for arrhythmias. London: NationalInstitute for Clinical Excellence, 2000.7 Hauer R, Aliot E, Block M, Capucci A, Luderitz B, Santini M, et al. Indica-tions for implantable cardioverter defibrillator (ICD) therapy Studygroup on guidelines on ICDs of the working group on arrhythmias andthe working group on cardiac pacing of the European Society of Cardi-ology. Eur Heart J 2001;22:1074-81.8 Maggioni A, Zuanetti G, Franzosi M, Rovelli F, Santoro E, Stazewsky L, etal. Prevalence and prognostic significance of ventricular arrhythmias afteracute myocardial infarction in the fibrinolytic era GISSI-2 results. Circula-tion 1993;87:312-22.9 Every N, Hlatky M, McDonald K, Weaver W, Hallstrom A. Estimating theproportion of post myocardial infarction patients who may benefit fromprophlactic implantable defibrillator placement from analysis of theCAST Registry. Am J Cardiol 1998;82:683-5.10 Hohnloser S, Klingenheben T, Zabel M, Shopperl M, Mauss O.Prevalence, characteristics and prognostic value during long term followup of nonsustained ventricular tachycardia after myocardial infarction inthe thrombolytic era. J Am Coll Cardiol 1999;33:1895-902.11 Schmitt C, Barthel P, Ndrepepa G, Schreieck J, Plewan A, Schomig A, etal. Value of programmed ventricular stimulation for prophylactic internalcardioverter-defibrillator implantation in postinfarction patients prese-lected by noninvasive risk stratifiers. J Am Coll Cardiol 2001;37:1901-7.12 Buxton A, Lee K, DiCarlo L, Gold M, Greer G, Prystowsky E, et al. for themulticenter unsustained tachycardia trial investigators. Electrophysi-ologic testing to identify patients with coronary artery disease who are atrisk for sudden death. N Engl J Med 2000;342:1937-45.13 Moss AJ, Zareba W, Hall WJ, Klein H, Wilber DJ, Cannom DS, et al. Pro-phylactic implantation of a defibrillator in patients with myocardialinfarction and reduced ejection fraction. N Engl J Med 2002; 346:877-83.Bisphosphonates as adjuvant treatment for breastcancerTheir effects are unclear, and long term trials are neededBisphosphonates are potent inhibitors of theosteoclastic bone resorption that is associatedwith skeletal metastases, with proved efficacy inreducing skeletal complications in metastatic cancer.Randomised clinical trials investigating the adjuvantuse of bisphosphonates to prevent bone metastases inpatients with breast cancer have yielded intriguing yetconflicting results. Defining the potential role of theseagents in the treatment of breast cancer is of greatclinical relevance.The skeleton is the first site of recurrence in25-40% of patients with metastatic breast cancer. Thedevelopment of bone metastases entails complexinteractions between cancer cells and the microenvi-ronment of bones. In the early establishment of metas-tases, bone is destroyed by the osteoclast, which isactivated by a variety of cytokines produced directly orindirectly by the tumour cell. As bone matrix is brokendown, a rich supply of mitogenic factors is released,which in turn can lead to increased proliferation ofcancer cells.Bisphosphonates are effective in treating conditionsin which excessive bone resorption and osteoclast activ-ity prevail, including osteoporosis and Paget’s disease ofbone. Several randomised clinical trials in patients withbreast cancer with bone metastases have shown the abil-ity of bisphosphonates to reduce skeletal related eventsand symptoms, including pathological fractures, surgery,radiation, compression of the spinal cord, hypercalcae-mia, and pain, although they have not shown improvedsurvival.1–6 Clodronate and pamidronate have beenevaluated extensively in patients with metastatic cancerand are widely used in oncology.1–3 Zoledronic acid andibandronic acid represent highly potent, newer genera-tion bisphosphonates with recently shown benefit inreducing skeletal related events.4–6Preclinical studies show that bisphosphonatesmight also be capable of preventing the developmentof bone metastases. Laboratory data show thatbisphosphonates can inhibit adherence of breastcancer cells to the bone matrix, inhibit release ofgrowth factors stored in the bone matrix, and enhancethe sensitivity of osteoclasts, macrophages, and tumourcells to apoptosis.Three randomised clinical trials of the oralbisphosphonate clodronate as adjuvant treatment inbreast cancer have yielded conflicting results. AGerman trial of 302 patients with primary breast can-cer with immunocytochemical evidence of cancer cellsin a bone marrow aspirate randomised patients to twoyears of clodronate or control. At almost five years offollow up, a reduction in the recurrence of bone metas-tases, a trend towards reduction in visceral metastases,and an increase in overall survival were seen in theclodronate group.7 8 The effect of clodronate as anadjuvant seemed weakened with longer follow up.A Finnish trial including 299 women with lymphnode positive breast cancer randomised to three yearsof clodronate as an adjuvant showed virtually theopposite result, with no effect on the rate of bonemetastasis and a deleterious effect on relapse rates ofnon-bone metastasis as well as survival.9 After five yearsof follow up, bone metastases were detected equally inthe clodronate and placebo groups, and non-skeletalmetastases were significantly more common in theclodronate group. Overall survival was significantlyworse in the clodronate group.EditorialsBMJ 2002;325:1051–21051BMJ VOLUME 325 9 NOVEMBER 2002 bmj.com

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Primary prevention of sudden cardiac death using implantable cardioverter defibrillators: More patients need to be screened and treated

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Primary prevention of sudden cardiac death using implantable cardioverter defibrillators : More patients need to be screened and treated

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