Cardiovascular Disease: Concepts in Management

From Advances in Internal Medicine 2009, sponsored by the University of Utah School of Medicine, Salt Lake City

Educational Objectives

The goal of this program is to improve management of coronary artery disease and atrial fibrillation (AF). After hear­ing and assimilating this program, the clinician will be better able to:

1.   Discuss findings of the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial and the COURAGE nuclear substudy.

2.   Identify candidates for revascularization therapy.

3.   Select rhythm control or rate control strategies for patients with AF, based on clinical findings and guidelines.

4.   Explain detrimental effects of AF on cardiovascular health.

5.   Select appropriate drug therapy for restoring rhythm.

Faculty Disclosure

In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the planning committee to disclose relevant financial relationships within the past 12 months that might create any per­sonal conflicts of interest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business or commercial interest. For this program, Drs. Michaels and Hamdan and the planning committee reported nothing to disclose.

Acknowledgements

Drs. Michaels and Hamdan were recorded in Park City, UT, at Advances in Internal Medicine 2009, presented Febru­ary 1-6, 2009, by the University of Utah School of Medicine. The Audio-Digest Foundation thanks the speakers and the University of Utah School of Medicine for their cooperation in the production of this program.

Stable Coronary Artery Disease: Who Needs Massive Intervention?

Andrew D. Michaels, MD, Associate Professor of Medicine and Director, Cardiac Catheterization Laboratory and Interventional Cardiology, University of Utah School of Medicine, Salt Lake City

Percutaneous coronary intervention (PCI): acute coronary syndromes (ACS)  —  clear benefit in patients with ST-el­evation myocardial infarction (STEMI) and non-STEMI (NSTEMI); shown superior to thrombolytics in decreasing mortality, reinfarction, heart failure (HF), and stroke in patients with STEMI; compared to conservative approach, early invasive approach recommended in most patients with unstable angina or NSTEMI (except low-risk patients where both approaches equivocal); stable angina  —  earlier studies showed PCI can reduce angina and improve quality of life; previous studies did not show improvement in hard outcomes with PCI, compared to maximal med­ical therapy

Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial: tested whether PCI would decrease death and MI; enrolled symptomatic patients with stable angina, ³70% proximal ves­sel stenosis on coronary angiography, and positive stress test, or patients with ³80% proximal vessel stenosis with­out known ischemia on stress testing; patients randomized to optimal medical therapy or optimal medical therapy and PCI; primary end point, death and nonfatal MI; results and conclusions  —  no difference in death, MI, stroke, hospitalizations for acute coronary syndrome, or all-cause mortality; fewer patients in PCI group required repeat PCI; in patients with chronic stable coronary artery disease (CAD), PCI and optimal medical therapy does not de­crease death, MI, or stroke, compared to optimal medical therapy alone; freedom from angina  —  modestly im­proved with PCI; at 1 yr, number needed to treat (NNT) with PCI over optimal medical therapy, 12 (decreased over 5 yr of follow-up); trend toward more patients in PCI group having no angina; statistically significant (but modest) difference in quality of life with PCI

Issues to consider about COURAGE trial: enrollment exclusion  —  of 35,000 patients screened for enrollment, 91% excluded due to lack of demonstrable ischemia, unsuitable anatomy (eg, type A lesion in proximal left anterior de­scending [LAD] coronary artery), low ejection fraction (EF), revascularization within last 6 mo, contraindication to PCI, serious comorbidities, severe angina (New York Heart Association [NYHA] class IV), failure to respond to medical therapy, left main disease, post-MI complications, disapproval from physician, or refusal by patient; medi­cation compliance  —  in patients with ACS, data show 71% compliant with aspirin at 3 mo, 46% with b-blockers, 40% with statin, and 20% with triple therapy; patients in COURAGE trial highly supervised and followed weekly (compliance >85%); institutions  —  in COURAGE trial, medical therapy tended to be better in Canadian and US Veterans’ Affairs (VA) hospitals; PCI tended to be better in US non-VA hospitals; important to consider whether type of PCI and medical therapy differs by institution; other issues  —  42% of patients enrolled in COURAGE had minimal angina; procedural success rates  —  low (89%) for PCI; plain old balloon angioplasty (POBA) performed in 14% of patients with PCI (indicates procedural failure); actual success rate may be extremely low (»75%); sig­nificant difference in success rates between Canadian hospitals and US non-VA hospitals in PCI; 32% assigned to medical therapy crossed over and underwent PCI within first year; incomplete revascularization  —  present in many patients assigned to PCI; 70% had multivessel disease, but only 40% received >1 stent

COURAGE nuclear substudy: »300 patients underwent nuclear stress testing before and »1 yr after randomization; patients randomized to PCI tended to have more significant drop (from 8.0% to 5.5%) in ischemic burden, com­pared to medical therapy group (“where it was pretty flat”); hard outcomes (ie, death or MI)  —  more events seen in patients who did not have significant drop in ischemia, compared to those with significant reduction in ischemia; summary  —  correlation between residual ischemic burden and hard outcomes; very few patients with significant amount of ischemic myocardium enrolled in COURAGE; patients with  significant amount of ischemic myocar­dium, proximal LAD CAD, left main disease, or 3-vessel disease should be revascularized

American Heart Association/American College of Cardiology revascularization guidelines (2007): stable an­gina class I recommendations  —  nondiabetic patients with multivessel disease or single-vessel disease with signifi­cant ischemic myocardium; patients with CAD without previous attempt at antianginal therapy who are good PCI candidates with low risk; asymptomatic patients  —  small percentage of patients with abnormal computed tomogra­phy angiography (CTA) should undergo invasive angiography and revascularization; class I recommendation for asymptomatic diabetic patients with normal EF and significant amount of ischemic myocardium; class IIa recommendation  —  patients with proximal LAD CAD; consider in patients with severe disease, based on noninva­sive testing

Key points: PCI not overutilized in United States (7% of CAD patients); COURAGE enrolled homogeneous popula­tion (eg, 85% men with mild ischemic burden and mild angina symptoms); patients significantly more compliant, compared to general practice; angiography before randomization excluded patients with high-risk disease; speaker suggests PCI should be considered in symptomatic patients with significant ischemic burden, based on coronary CT or stress testing

Drug-eluting stents (DES): Swedish Coronary Angiography and Angioplasty Registry reported patients who re­ceived DES had higher risk for death than those who received bare-metal stents (BMS); when data reanalyzed 1 yr later, BMS and DES curves superimposed; in 2003, generally, high-risk patients given DES, and low-risk patients given BMS; by 2005, event rate with BMS substantially increased; data from randomized trials showed no differ­ence in death or MI between BMS and DES, and risk for repeat procedure for restenosis lower with DES; recent meta-analysis showed no increased risk for stent thrombosis, MI, or death, if patient with DES can remain on dual antiplatelet therapy (aspirin and clopidogrel) for 1 yr

SYNergy between percutaneous coronary intervention with TAXus and cardiac surgery (SYNTAX) study: pa­tients with complex CAD randomized to DES or coronary artery bypass grafting (CABG); patients had 3-vessel disease, or left main disease with 1-, 2-, or 3-vessel disease; no difference in all-cause mortality; stroke signifi­cantly lower with PCI, compared to CABG; no difference in composite of death, stroke, and MI; higher need for re­peat revascularization over 1 yr with DES, compared to CABG

Summary: invasive angiography and revascularization recommended for patients with high-risk, based on stress test­ing (eg, significant ischemic myocardium, poor exercise tolerance); low threshold for revascularization for diabetic patients with silent ischemia; patients with severe disabling or refractory anginal symptoms despite medical ther­apy

Are DES better than BMS? DES clearly reduce risk for in-stent restenosis; DES associated with delayed re-endo­thelialization (requires prolonged course of dual antiplatelet therapy); if patient has no upcoming surgeries and can remain on clopidogrel for 6 to 12 mo, DES recommended; in patients scheduled for surgery or at high risk for bleeding on clopidogrel, BMS recommended (1-mo course of clopidogrel required to prevent stent thrombosis)

Atrial Fibrillation

Mohamed H. Hamdan, MD, Professor of Internal Medicine, and Associate Chief, Division of Cardiology, Uni­versity of Utah School of Medicine, Salt Lake City

Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) trial: patients randomized to rhythm control or rate control; in rate control arm, any combination of atrioventricular (AV) nodal blocking agents allowed, and AV junction ablation and pacing allowed in rare cases; in rhythm control arm, combination of drugs used; prevalence of sinus rhythm 65% in rhythm control arm (40% in rate control arm); no difference in primary end point (all-cause mortality) between arms; risk for stroke  —  patients in rhythm control arm had higher incidence of stroke; almost all patients presented with subtherapeutic international normalized ratio (INR; patients random­ized to rhythm control who presented during follow-up visits in normal sinus rhythm (NSR) less likely to continue taking warfarin [Coumadin]); less warfarin used in rhythm control arm than in rate control arm (explains higher in­cidence of stroke); conclusions  —  1) rate control acceptable strategy in some patients with atrial fibrillation (AF), but rate control not superior to rhythm control; 2) even when restoring rhythm, patients must be maintained on war­farin; limitations of trial  —  1) 40% to 50% of patients excluded from trial (presumably symptomatic); AFFIRM re­sults do not apply to all patients with AF; 2) 75% of patients had normal EF; 9% to 10% in New York Heart Association (NYHA) class II or higher; not applicable to patients with left ventricular (LV) dysfunction or HF symptoms; 3) restoring NSR with drugs results in 50% to 60% maintenance of normal sinus rhythm

Atrial Fibrillation and Congestive Heart Failure (AF-CHF) trial: looked at effect of maintenance of NSR on mor­tality in patients who have AF and LV dysfunction; no difference found between arms; prevalence of AF during fol­low-up, »30% in rhythm control arm (»60% in rate control arm); conclusion  —  rhythm control strategy not always warranted or needed in patients with HF and AF (reasonable to do rate control); limitations of trial  —  1) nearly 40% of patients randomized to rate control were in NSR; 2) »30% still in AF during follow-up; looking at higher per­centage of patients with persistent AF may have resulted in higher success rate of maintenance of NSR, and in dif­ference between arms

Detrimental effects of AF: higher risk for LV dysfunction, hypertension, and other cardiovascular conditions; when coexisting variables controlled for, patients with AF still have higher mortality; AF increases sympathetic activity (even in absence of significant change in blood pressure [BP]); high sympathetic tone detrimental to heart; greater irregular response results in greater sympathetic excitation; AF alters ventricular repolarization; study found QT in­tervals shorten during follow-up after cardioversion, and dispersion significantly higher at day 1, compared to day 30; effects on myocytes  —  when cells randomized to regular pacing or irregular pacing, significant decrease in frac­tional shortening in irregular arm; restoring rhythm improves pump function (EF improves and chamber dimen­sions decrease) independent of rate; AF reversible cause of myopathy

Approaches to management: symptomatic patient  —  start with rate control; asymptomatic patients  —  if baseline un­certain, restore rhythm and ask patient how he or she feels; if patient feels no difference, and AF normal, acceptable to do rate control and anticoagulation; do not assume patient asymptomatic unless certain about baseline; asymp­tomatic patients with LV dysfunction  —  attempt to restore rhythm; ensure adequate rate control with Holter moni­toring (average heart rate [HR] of 85-90 beats per min [bpm] acceptable); restore rhythm in patients with adequate rate control and check for improved pump function

Restoring rhythm: if drug therapy fails, catheter ablation acceptable second-line therapy; propafenone or flecainide  —class 1C agents; use if echocardiography normal; can be used as outpatient medications; rule out CAD with baseline stress testing before starting; repeat stress testing while patient on drug to rule out proarrhythmia; if echocardiography (ECG) abnormal, and patient has history of hypertension and significant hypertrophy, do not use class 1C agents (reasonable to use class 1C agents if hypertrophy not significant); CAD  —  sotalol and dofetilide (Tikosyn) drugs of choice; HF  —  amiodarone or Tikosyn drugs of choice; if no or minimal heart disease, use class 1C agent; if heart disease significant, consider amiodarone or catheter ablation; amiodarone can be started as outpa­tient medication, but has many side effects; patients on dofetilide must be admitted (measure creatinine clearance and follow QT intervals); dronedarone  —  similar to amiodarone but no iodine so no side effects of thyroid and lung toxicity; trial found drug decreased risk for cardiovascular hospitalization or death from any cause by 24%; likely to be applied to patients without LV dysfunction

Clinical case: man 55 yr of age presents for routine follow-up; asymptomatic; not highly physically active; AF on ECG; HR, 95 bpm; ECG unremarkable; management  —  check baseline; attempt to restore NSR and address antico­agulation; guidelines  —  if patient in AF >2 days, 3 wk of anticoagulation with INR of 2 to 3, or transesophageal echocardiography (TEE)-guided approach acceptable (patient must be therapeutic at time of cardioversion); if du­ration of AF <48 hr, 3 wk of anticoagulation not needed (consider heparin and proceed with cardioversion); man started on warfarin and low-dose b-blocker; postcardioversion, man “felt great” (indicates patient should be kept in NSR in event of recurrence); 3 wk later, AF recurs and patient given propafenone; aspirin acceptable for long-term anticoagulation since patient has no risk factors; consider long-term yearly risk and risk associated with cardiover­sion (3 wk of anticoagulation required before and 4 wk after cardioversion, or use TEE-guided approach)

Clinical trials: Catheter Ablation versus Standard conventional Treatment in patients with LEft ventricular dysfunc­tion and Atrial Fibrillation (CASTLE-AF) study  —  looking at effect of catheter ablation on mortality in patients with AF; hypothesis that pulmonary vein isolation improves mortality and hospitalization rates in patients with LV dysfunction; many electrophysiologic changes in AF and myopathic processes related to irregular sequence; restor­ing regular sequence by AV junction ablation and pacing may improve pump function (right ventricular pacing det­rimentally affects function); Atrioventricular Junction Ablation Followed by Resynchronization Therapy in Patients with Congestive Heart Failure and Atrial Fibrillation (AVERT-AF) trial  —  looks at AV junction ablation and biven­tricular pacing, compared to rate control; goal to show despite adequate rate control, restoring regular sequence with ablation and biventricular pacing improves pump function; Restoring Normal Sinus Rhythm on Blood Pres­sure Control in Patients with Atrial Fibrillation and Hypertension (RESTOR-BP) study  —  AF may lead to BP eleva­tion by increasing sympathetic activity, activation of renin-angiotensin system, and endothelial dysfunction; study tests hypothesis that rhythm control strategy in patients with persistent AF and hypertension associated with reduc­tion in mean BP and/or reduction in antihypertensive drug therapy

Suggested Reading

Curtis AB et al: Clinical factors that influence response to treatment strategies in atrial fibrillation: the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) study. Am Heart J 149:645, 2005; Freudenberger RS et al: Comparison of rate versus rhythm control for atrial fibrillation in patients with left ventricular dysfunction (from the AF­FIRM Study). Am J Cardiol 100:247, 2007; Hamdan MH et al: Atrioventricular junction ablation followed by resynchroni­zation therapy in patients with congestive heart failure and atrial fibrillation (AVERT-AF) study design. Pacing Clin Electrophysiol 29:1081, 2006; Lee TH et al: CABG vs. stenting--clinical implications of the SYNTAX trial. N Engl J Med 360:e10, 2009; Maron DJ et al: Impact of an initial strategy of medical therapy without percutaneous coronary intervention in high-risk patients from the Clinical Outcomes Utilizing Revascularization and Aggressive DruG Evaluation (COURAGE) trial. Am J Cardiol 104:1055, 2009; Marrouche NF et al: Catheter ablation versus standard conventional treatment in pa­tients with left ventricular dysfunction and atrial fibrillation (CASTLE-AF) - study design. Pacing Clin Electrophysiol 32:987, 2009; Shaw LJ et al: Optimal medical therapy with or without percutaneous coronary intervention to reduce isch­emic burden: results from the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial nuclear substudy. Circulation 117:1283, 2008; Teo KK et al: Optimal medical therapy with or without percutaneous coronary intervention in older patients with stable coronary disease: a pre-specified subset analysis of the COURAGE (Clini­cal Outcomes Utilizing Revascularization and Aggressive druG Evaluation) trial. J Am Coll Cardiol 54:1303, 2009.