Schwartz, Ronald G.

Vorobiof, Gabriel

English

Via Medica Journals

217www.cardiologyjournal.orgHOT TOPICSCardiology Journal2007, Vol. 14, No. 3, pp. 217219Copyright ' 2007 Via MedicaISSN 18975593Address for correspondence: Ronald G. Schwartz, MD MSCardiology Unit, University of Rochester Medical Center601 Elmwood Avenue, Box 679N, Rochester, NY 14642, USATel: +1 585 275 0026e-mail: ronald_schwartz@urmc.rochester.eduEncouragement to optimize medical therapy forcoronary heart diseaseGabriel Vorobiof and Ronald G. SchwartzDepartments of Medicine, Cardiology Unit, and Imaging Sciences, Division of Nuclear Medicine,University of Rochester Medical Center, Rochester, NY, USATherapeutic goals in treating ischemic heartdisease include improving outcomes and reducingsymptoms. Medical therapy for coronary artery dis-ease (CAD) has been substantially improved in thelast three decades with the addition of HMG-coreductase inhibitors (statins), niacin, fibrates, an-giotensin converting enzyme inhibitors and recep-tor blockers, beta blockers, and novel anti-plateletagents to supplement aspirin. The incremental val-ue of each of these therapies has been demonstrat-ed by the gold standard of clinical science, the ran-domized controlled trial. Percutaneous coronaryintervention (PCI), first performed by Dr. AndreasGruentzig in September 1977 [1] also has the capac-ity in selected populations to relieve symptoms andenhance survival. Since its introduction, percutane-ous coronary revascularization has undergone manyrevisions and improvements and is currently per-formed ~1 million times annually in the UnitedStates alone [2]. The importance of identifying thepatient populations that benefit from these medicaland revascularization interventions is underscoredby the recently published COURAGE trial [3].Substantial clinical benefit of PCI has beendemonstrated in trials examining patients with STelevation myocardial infarction (STEMI) and highrisk patients with non-ST elevation myocardial in-farction (NSTEMI) [4]. Prior to the publication ofthe COURAGE Trial in April 2007, the evaluationof medical therapy and PCI in patients with stableCAD has been limited: Fewer than 3000 patientsin small randomized controlled trials and observa-tions thus far indicate faster and more durableanginal relief in patients receiving PCI when comparedto optimal medical therapy (OMT). A recent meta-analysis of 11 randomized trials comparing PCI toOMT in patients with stable CAD demonstrated nosuperiority of one strategy over the other for theendpoints of total mortality, cardiac death, non-fa-tal myocardial infarction or rates of coronary arterybypass surgery (CABG) or PCI [5]. What was sore-ly needed to settle the debate of the incrementalprognostic and symptomatic benefit in stable CADafforded by PCI was a large, multi-center rand-omized clinical trial in which all patients receiveaggressive, guideline driven medical therapy withupstream randomization of the use of PCI. Theseconsiderations provide the impetus for the designand execution of the Clinical Outcomes UtilizingRevascularization and Aggressive Guideline driv-en drug Evaluation (COURAGE) trial.COURAGE was funded by the Veteran AffairsAdministration and several pharmaceutical compa-nies (several coronary catheter companies refusedthe opportunity to support this trial). COURAGErandomized 2287 patients with stable obstructiveCAD and myocardial ischemia to either OMT orOMT with PCI.  Importantly, all patients in this tri-al were treated with aggressive, guideline drivenmedical and lifestyle therapy, and randomizationassignment in the trial occurred only after carefuleducation of patient and referring physicians andacceptance of an interventionalist to perform PCIif this randomization arm was selected. Quality oflife and angina metrics as well as hard event out-comes were carefully tracked. Patients with severeleft ventricular dysfunction (LVEF < 30%), thosewith left main CAD (> 50%) or those with a recentrevascularization were excluded. At a mean followup of 4.6 years, no significant differences betweenthe PCI group and the medical therapy group in thecomposite of death, MI and stroke were observed.Similarly, hospitalization for acute coronary218Cardiology Journal 2007, Vol. 14, No. 3www.cardiologyjournal.orgsyndrome (ACS) or MI was similar. The only signif-icant difference between the 2 groups was a mod-est improvement of anginal relief at during the first3 years in the PCI group, which was insignificant at5 years. Economic analyses, currently unpublished,were presented by Dr. William Weintraub at theAmerican College of Cardiologys 2007 Annual Sci-entific Session. The preliminary data indicate un-favorable cost effectiveness for patients randomizedto PCI with an average quality-adjusted life-year(QALY) gained by PCI compared to optimal medi-cal therapy of > $200,000. The QALY threshold ofcost effectiveness is widely considered to be under$50,000.The COURAGE investigators envisioneda decade ago in the trial design the therapeutic valueof aggressive, guideline driven targets for treatmentbeyond the popular recommendations of that era toachieve excellent results in terms of hypertensioncontrol, lipid reduction (average LDL reached was71 mg/dL) and lifestyle factors in all patients treat-ed in both arms of this trial. Except for a higherusage of calcium channel blockers and nitrates inthe medical-therapy arm, no differences betweentreatment arms were found in the eventual medi-cal regimens of patients enrolled in COURAGE.Importantly, no pre-specified subgroups revealedbenefit from either the PCI or medical-therapystrategies. By the play of chance, more patients withproximal LAD disease were assigned to the OMTarm. The significant annual and cumulative eventrates of the COURAGE trial indicate these patientswith stable CAD were at expected levels of signif-icant subsequent cardiac risk.Several factors were unique about this study.This was a North American trial with fifty U.S. andCanadian centers involved in this study making itthe largest randomized investigation of stable CADpatients to date. Secondly, an impressive total of2168 (95%) of patients had objective evidence ofischemia, the majority of which had multiple revers-ible defects determined by routine radionuclideperfusion imaging (SPECT). Thirdly, in the PCIgroup, 94% of patients received a contemporary PCIstrategy consisting of at least one stent. Drug-elut-ing stents were only available towards the latterstages of this trial which meant only 3% of patientsassigned to PCI received a coated stent. Lastly,OMT provided superior relief from angina than pre-viously thought possible, and symptom relief wasreliably obtained in both arms of the trial. Relieffrom angina at 1 year was 66% in the PCI group and58% in the medial-therapy group (a difference of8%) while at 3 years the difference declined withrates of 72% and 67%, respectively. Perhaps mostimportantly, the trial gives us the courage to rec-ognize in stable patients with CAD an initial strat-egy of optimal, aggressive, guideline driven medi-cal therapy did not put patients in harms way, andleaves the door open for later revascularization forthe one-third of patients who may require it foranginal relief.The COURAGE study presents an opportuni-ty for cardiologists and the general healthcare com-munity to pause and re-examine current practicetrends. In this modern age of spiraling healthcarecosts one wonders whether a more evidenced-based approach to the management of stable CADmight curtail some of the costs. Additionally, theseresults provide good news for patients and theirphysicians worldwide who are now able to choosemedical therapy with full confidence that it is notinferior to a strategy of PCI in terms of death, MI,stroke or ACS. It would be interesting if the COUR-AGE investigators revealed the data on the differ-ences in morbidity that patients in the PCI arm mayhave suffered due to complications from their inva-sive procedures. Many pre-specified analyses of theCOURAGE data will be forthcoming to evaluatecost-effectiveness, the role of SPECT perfusionimaging and PCI to identify high risk groups thatmay selectively benefit from the addition of up-stream PCI not reported in the initial paper.How generalizable are these results? One ofthe criticisms of the study was that 35,539 patientsunderwent screening assessments and only 3071met eligibility criteria (< 9%) prior to randomiza-tion. This may partly be explained by difficultiesencountered in randomizing patients with signifi-cant proximal coronary disease due to local physi-cian bias and misconception. If one is biased to be-lieve, on the basis of PCI studies in acute MI thatthe intervention applies to patients with stable CADas well, an ethical dilemma is posed for the physi-cian or patient considering randomization in COUR-AGE. While recruitment was problematic due toreferral biases, the final study group reportedlyreflected the initial screened cohort.Are the results of COURAGE surprising? De-spite a prevalent bias based on MI studies that themajority of patients with stable coronary disease canbe better treated successfully with focal treatment(balloon and stent angioplasty), consideration ofpathophysiology and other clinical trials argueagainst this supposition. The reality is that coronarydisease is a diffuse, widespread and systemic dis-ease of atherosclerosis affecting much of the cardi-ovascular tree, and patients presenting with ACS219Gabriel Vorobiof and Ronald G. Schwartz, Encouragement to optimize medical therapy for CADwww.cardiologyjournal.orgusually have more than one active, inflamed plaquein need of treatment [6]. Data from four angiograph-ic trials, summarized by the widely quoted meta-analysis of Ernst Falk [7], are remarkably consist-ent in demonstrating the vast majority of MIs oc-cur in areas of the coronary artery that are nothemodynamically significant.In the COURAGE trial, SPECT myocardialperfusion scintigraphy (MPS) may hold a key tounderstanding who benefits most from PCI, andwhen patients actually succeed or fail to respondto aggressive, guideline treated therapy prior to theonset of clinical events. Studies comparing the pre-diction of subsequent hard coronary events in menand women demonstrate the perfusion and function-al variables of radionuclide myocardial perfusionimaging consistently out-perform clinical, ECG, andarteriographic data [810]. A nuclear substudy ofCOURAGE has been undertaken from the begin-ning of the trial, and pre-specified analysis of theserial SPECT MPS data in the COURAGE trial areplanned to assess the hypothesis that ischemic per-fusion defect size and functional data (LV volumeindices and EF) can identify those patients withstable CAD who benefit most from PCI. Identifica-tion and correlation of scintigraphic and clinical re-sponses to treatment is also planned, to assess thequestion as to whether further broadening or inten-sification of treatment following SPECT MPS wasassociated with changed outcome. We should re-member that even patient groups fortunate to havebeen randomized to active arms of medical therapytrials still suffered substantial rates of coronaryevents. Beyond the framework of existing guidelineswhich in practice become artificial surrogates of suc-cess in treatment, much work remains to be done tooptimize care and minimize morbidity and mortalityin patients with stable ischemic heart disease [11].Thus, optimizing therapy and risk for patientswith stable CAD in 2007 should ideally be accom-plished by treating systemically to target diffuseplaque instability and rendering it unlikely to rup-ture and precipitate acute infarction or death. Im-proving coronary specific endothelial function andenhancing regional myocardial blood flow can beaccomplished by the combination of lifestyle andmedical therapeutic interventions as has been dem-onstrated for over a decade by multiple studies em-ploying PET and SPECT radionuclide MPS. Angi-na will improve substantially on medical therapy,and no increase in death or MI is associated withan initial strategy of aggressive, guideline drivenmedical therapy. If additional anginal relief is re-quired and the patient cannot afford to wait for thefull anti-anginal benefit of medical therapy, PCI re-mains a safe and viable option.The COURAGE trial has encouraged us all togive our patients with CAD aggressive, guidelinedriven lifestyle and medical therapy. The challengeof the COURAGE study now is to educate physiciansand patients to place these results in the appropri-ate context of the stable CAD patient population towhich the study applies, and to give patients timeand opportunity to sample the fruits of this contem-porary approach to high quality, cost effective care.References1. Gruentzig A. Transluminal dilation of coronary ar-tery stenosis. Lancet 1978; 1: 263263.2. Rosamond W, Flegal K, Friday G et al. Heart diseaseand stroke statistics, 2007 update: a report from theAmerican Heart Association Statistics Committeeand Stroke Statistics Subcommittee. Circulation,2007; 115: e69e171.3. Boden WE, ORourke RA, Teo KK et al. Optimalmedical therapy with or without PCI for stable coro-nary disease. N Engl J Med, 2007; 356: 15031516.4. Antman EM, Anbe DT, Armstrong PW et al. ACC//AHA guidelines for the management of patients withST-elevation myocardial infarction: executive summa-ry: a report of the American College of Cardiology//American Heart Association Task Force on PracticeGuidelines (Writing Committee to Revise the 1999Guidelines for the Management of Patients with AcuteMyocardial Infarction). Circulation, 2004; 110: 588636.5. Katritsis DG, Ioannidis JP. Percutaneous coronaryintervention versus conservative therapy in nona-cute coronary artery disease: A meta-analysis. Cir-culation, 2005; 111: 29062912.6. Rioufol G, Finet G, Ginon I et al. Multiple athero-sclerotic plaque rupture in acute coronary syndrome:a three-vessel intravascular ultrasound study. Circu-lation, 2002; 106: 804808.7. Falk E, Shah PK, Fuster V. Coronary plaque disrup-tion. Circulation, 1995; 92: 657671.8. Iskandrian AS, Chae SC, Heo J, Stanberry CD,Wasserleben V, Cave V. Independent and incrementalprognostic value of exercise single-photon emissioncomputed tomographic (SPECT) thallium imagingin coronary artery disease. J Am Coll Cardiol, 1993;22: 665670.9. Pancholy SB, Fattah AA, Kamal AM, Ghods M, Heo J.Incremental value of thallium SPECT imaging inwomen. J Nucl Cardiol, 1995; 2: 110116.10. Sharir T, Kang X, Germano G et al. Prognostic valueof poststress left ventricular volume and ejection frac-tion by gated myocardial perfusion SPECT in womenand men: gender-related differences in normal limitsand outcomes. J Nucl Cardiol 2006; 13: 495506.11. Schwartz RG, Kudes M. Monitoring effectiveness ofmedical therapy in 2006 (J Nucl Cardiol, 2006).Editorial. J Nucl Cardiol, 2006; 13: 184190.

Encouragement to optimize medical therapy for coronary heart disease

https://journals.viamedica.pl/cardiology_journal/article/download/21714/17318

Encouragement to optimize medical therapy for coronary heart disease

Abstract

Similar works

Full text

Available Versions

Via Medica Journals