Vice Chairman, Department of Internal Medicine

Texas Tech University Health Sciences Center

Professor of Medicine and the Michael and

Clinical Pharmacy Specialist—Cardiology

Residency Program Director—PGY2 Cardiology

San Mateo Multispecialty Physicians Group

Director of Cardiac Intermediate Care Unit

Philip J. and Harriet L. Goodhart Professor of

Director of Cardiovascular Imaging Program

Zena and Michael A. Wiener Cardiovascular

Associate Professor of Medicine (Cardiology)

Articles

Editorial Advisory Board

Cardiology Review Editorial Advisory Board

I hope everyone has had an enjoyable holiday season, and I want to wish everyone a wonderful New Year. With the holidays over, it is back to work for most of us, and 

 will help us get caught up with the latest news and advances in cardiology. This particular issue of CR discusses many important articles and viewpoints that I am sure you will find quite useful.

Dr. Eric Bates delves into the cost-effectiveness of percutaneous coronary intervention (PCI) in patients with stable coronary artery disease and abnormal fractional flow reserve (FFR), and opines that revascularization for ischemia is reasonable, but current data do not prove superiority of FFR-guided versus angiography-guided decision making. FFR appears to be most useful when the indications for PCI are ambiguous based on noninvasive testing and coronary angiography or when noninvasive testing is absent, equivocal, or does not provide objective evidence of ischemia in the myocardial territory perfused by the index artery.

Dr. Ragavendra Baliga discusses the role of implantable defibrillators (ICD) and survival in mildly symptomatic heart failure (HF), and states that given that sudden death is more likely to occur in milder forms of HF, ICDs are more likely to be the treatment of choice in these patients, whereas a biventricular pacemaker is more likely to be the device of choice in advanced forms of HF. Drs. Mohammad Dalabih and Michael Habib look at the value of nighttime intensivists and reflect that until there is evidence to the contrary, our priority should be to make sure that every critically ill patient is cared for in an ICU staffed by a daytime intensivist, and not to spend more money staffing a select few ICUs around the clock.

Drs. Niki Katsiki and Dimitri Mikhailidis discuss vitamin D and hypertension in older patients and report that that high-dose cholecalciferol supplementation every 3 months for a year was ineffective in reducing blood pressure in older (≥70 years) patients with isolated hypertension. They think that further randomized clinical trials are needed to clarify the role of vitamin D supplementation in daily practice. Dr. Michael Rich reviews the role of statins for the prevention of contrast-induced acute kidney injury (CI-AKI) and points out that that there is a growing body of literature that supports the use of statins for prevention of CI-AKI, at least in selected high-risk populations, and it seems very reasonable to prescribe statin therapy prior to coronary angiography or PCI in patients at moderate to high risk for CI-AKI.

Dr. Srikanth Seethala examines variation in surgical readmission rates and quality of hospital care, and reflects that performing elective procedures only at highly experienced centers might provide a better outcome, but the practicality of this approach should be carefully investigated, as low-volume centers might need to perform emergency procedures. Dr. Mushabbar A. Syed discusses echocardiographic screening and long-term survival in the general population and emphasizes that although there is general agreement that these tests can detect early cardiovascular disease, there is lack of agreement on which test is best, when/who to screen, and the overall appropriateness of this approach.

For our Clinical Forum section, Drs. Mehdi Shishehbor, Hitinder Gurm, and Timir Paul review the optimal duration of dual antiplatelet therapy (DAPT) after implantation of drug-eluting stents, and in general suggest an individualized approach by careful assessment of a balance between stent thrombosis and risk of bleeding, but overall favor 12 months of DAPT for most patients.

Finally, the insightful compilation of top stories and meeting highlights from the American Heart Association 2013 Scientific Sessions by our excellent managing editor, Ms. Jackie Syrop, should keep you updated on the latest happenings presented at the meeting. She discusses results of the CATIS trial, ENGAGE AF-TIMI 48, TOPCAT, CORAL, NIAMI, and the CTSN trial.

I hope that you will find these commentaries to be valuable and enjoyable. I encourage you to share your insights, thoughts, and personal experiences on the topics touched upon in this issue. On a broader level, I would love to hear feedback on how we can make this journal even better. My goal continues to be to make you look forward to every issue of 

Editor's Page

Editor-in-Chief Debabrata Mukherjee, MD, MS, FACC, welcomes our readers to a new year of Cardiology Review.

Enjoy the Holidays and New Year With Cardiology Review

The house call may soon be a video chat. In 15 states, a new app called Doctors on Demand is now available for iPhones and iPads and Android phones and tablets. According to the 

 website, at launch there is already a team of US-licensed physicians across the country who are ready to take your video call.

The app allows patients to enter symptoms or concerns, pay $40, and be connected via video to a doctor. The app is not to be used for emergencies but it is designed for noncritical problems such as colds/flu, rashes, pediatric questions, sports injuries, allergies, and many general health questions. It uses the picture-taking ability of the mobile phone or tablets to provide the physician with images the patient may want the doctor to see.

According to TechCrunch.com (December 10, 2013), Doctor on Demand uses a HIPAA-secure network and synchronous video chat to allow patients to communicate with doctors. Former Stanford physician and former White House Fellow Pat Basu, MD, is the app’s co-founder and Chief Medical Officer. He plans to put together a multidisciplinary team of doctors so that eventually patients can be routed to a specialist based on keywords input at the start of the log-in process.

Doctor on Demand has raised $3 million in seed funding from Google Ventures, Andreesen Horowitz, Venrock, and Athena Health CEO Jonathan Bush, among others, and advisory assistance from a variety of physicians and entrepreneurs, even a former Senator. 

What Your Patients Are Reading

Video calls to doctors and more news that your patients are reading.

TACC Names Hospitals Taking Part in Patient Navigator Program

The American College of Cardiology (ACC) is launching a program that applies a team approach to keeping patients at home and healthy after discharge from the hospital. The ACC Patient Navigator Program was started in response to the increased penalties in effect beginning October 1, 2013, for hospitals with excessive readmission rates within 30 days of discharge for heart attack and heart failure.

The program supports a team of caregivers at selected hospitals to help patients overcome challenges during their hospital stay and in the weeks following discharge, when they are most a risk for readmission.

The ACC Patient Navigator Program will serve as a test for innovative patient-centered solutions to address issues that affect patient health and readmissions, said ACC President John G. Harold, MD, MACC. “These hospitals will serve as pioneers in a new approach to heart disease treatment and care that puts emphasis on meeting patients’ ongoing needs and helping patients make a seamless transition from the hospital to the home.”

Nearly 1 in 5 patients hospitalized with heart attack and 1 in 4 hospitalized with heart failure are readmitted within 30 days of discharge, often for conditions that seem to be unrelated to the original diagnosis, according to the ACC.

The first 11 hospitals participating in the ACC Patient Navigator Program, chosen because of their commitment to quality demonstrated by participation in the National Cardiovascular Data Registry and Hospital to Home program, include:

		Christiana Care Health Services, Wilmington, DC

		Einstein Medical Center, Philadelphia, PA

		Indiana University Health Methodist Hospital, Indianapolis, IN

		MedStar Washington Hospital Center, Washington, DC

		Providence St. Vincent Medical Center, Portland, OR

		Ronald Reagan UCLA Medical Center, Los Angeles, CA

		Vanderbilt Heart and Vascular Institute, Nashville, TN

		WakeMed Health and Hospital, Raleigh, NC

AstraZeneca is the founding sponsor of the ACC Patient Navigator Program. 

Guidance on Transcatheter Txs for Mitral Regurgitation

Anew overview issued by the American College of Cardiology (ACC), the American Association for Thoracic Surgery (AATS), the Society of Thoracic Surgeons (STS), and the Society for Cardiovascular Angiography and Interventions (SCAI) Foundation states that it is imperative that professional societies, industry, taxpayers, and regulatory agencies collaborate to promote needed research and ensure appropriate integration of transcatheter therapies for the treatment of patients with severe mitral regurgitation (MR).

The societies say that a number of transcatheter therapies for MR are expected to be available for clinical use in the coming years. Therefore, a thoughtful process is needed to ensure that such innovative treatments are introduced into medical practice in the United States with appropriate safeguards.

The overview contains several recommendations for appropriate integration, including the following:

		Further research involving a wider spectrum of patients and devices;

		Continued development of regional heart valve referral centers of excellence that consist of a dedicated, multidisciplinary heart team and dedicated care pathways;

		Required participation of all centers in the ongoing TVT Registry, with limitation of new devices and reimbursement for their application to those centers that meet national criteria;

		Establishment of operator training and credentialing criteria for mitral valve procedures; and

		Creation of guidelines, performance measures, and appropriate use criteria for transcatheter MR interventions.

www.cardiosource.org/en/News-Media/Publications/Cardiology-Magazine/2013/11/New-Societal-Overview-Aims-to-Provide-Guidance-on-Transcatheter-Therapies-for-Mitral-Regurgitation.aspx?print=1

Aworking group of the Kidney Disease: Improving Global Outcomes (KDIGO) recommends wider statin use among patients with chronic kidney disease (CKD) and published a synopsis of the key recommendations on lipid management and monitoring in adults with CKD in the December 9, 2013, issue of the 

Specific LDL cholesterol treatment targets were removed from the guidelines on managing lipids in patients with CKD, instead basing the decision to start cholesterol-lowering treatment on the absolute risk of coronary events, and evidence that a therapy will help lower that risk.

Marcello Tonelli, MD, of the University of Alberta, Canada, and colleagues present a synopsis of 8 key recommendations in KDIGO’s 2013 practice guidelines.

The key recommendations for statin treatment in patients with CKD include:

		Adults at least 50 years of age who have an estimated glomerular filtration rate (eGFR) less than 60 mL/min/1.73 m2 and who are not treated with chronic dialysis or kidney transplantation should be treated with a statin or a statin with ezetimibe (Level 1A recommendation).

		Adults with dialysis-dependent CKD should not begin treatment with statins or statin/ezetimibe (Level 2A recommendation).

		Patients already taking a statin at the time of dialysis should continue to do so (Level 2C recommendation).

		Kidney transplant patients should receive statin treatment because their risk for coronary events is dramatically increased (Level 2B recommendation).

		Adults age 18 to 49 years who have an eGFR <60 mL/min/1.73 m2 but who are not treated with dialysis or kidney transplantation should be treated with statins if they are known to have coronary disease, diabetes, prior ischemic stroke, or an estimated 10-year incidence of coronary death or nonfatal MI exceeding 10% (Level 2A recommendation).

		Among people with CKD, low-density lipoprotein (LDL) cholesterol is an insufficient test for cardiovascular risk. Adults with newly diagnosed CKD should therefore undergo lipid profile testing (Level 1C recommendation).

		Adults 50 years or older who have CKD and an eGFR 60 mL/min/1.73 m2 or higher should be treated with a statin (Level 1B recommendation).

Some experts are critical of the new recommendations, however, pointing out that except for a single 1A recommendation, they are mostly graded 2B and 2C, and number needed to treat and number needed to harm are not provided.

News & Trends

American Heart Association 2013 Scientific Sessions

The American Heart Association Scientific Sessions is the leading cardiovascular meeting for basic, translational, clinical, and population science in the United States. More than 18,000 cardiovascular experts from more than 105 countries attended this years Sessions. More than 5000 presentations were made at the meeting, with 1000 invited faculty and 4000 abstract presentations from leaders in cardiovascular disease.

, we review 6 important studies presented during the Sessions: CATIS, ENGAGE AF-TIMI 48, TOPCAT, CORAL, NIAMI, and the CTSN trial.

CATIS: No Benefit Seen in BP Reduction in Acute Phases of Stroke

Researchers presenting data from the China Antihypertensive Trial in Acute Ischemic Stroke (CATIS) study found that compared with no antihypertensive treatment, treating patients to achieve a target blood pressure (BP) with antihypertensive medications did not reduce the risk for major disability at 14 days or hospital discharge. Jiang He, MD, PhD, and colleagues from Tulane University School of Public Health and Tropical Medicine in New Orleans, LA, said that unless a patient’s systolic blood pressure (SBP) is 220 mm Hg or more, or their diastolic pressure is 120 mm Hg or more, the decision to lower blood pressure with antihypertensive treatments in patients with ischemic stroke does not improve or worsen outcome.

The study was published online in the Journal of the American Medical Association on November 17.

CATIS was a randomized, controlled, multicenter, single-blind study with blinded end points that examined whether moderate BP reduction within 48 hours of stroke onset would reduce death and major disability. It also assessed the effect of antihypertensive treatment in the acute phase on 3-month mortality, major disability, and vascular events at a post treatment follow-up. The study included 4071 Chinese patients.

Patients were randomized to receive antihypertensive therapy (n = 2038) with the aim of lowering systolic BP by 10% to 25% within 24 hours of randomization or to discontinue all hypertension medications taken prior to the stroke during their hospitalization (n = 2033). At discharge all patients were prescribed antihypertensive medica- tions according to clinical guidelines.

SBP reduction was achieved in both groups at both 24 hours/d and day 7 but was significantly lower in the treated group. At 7 days the SBP was even lower and still significantly lower between groups. The significant difference between SBP levels did not affect outcomes, however, either on the primary or secondary composite end point. The results of the CATIS trial indicate that antihypertensive treatment within 48 hours is not superior to routine management in patients with an acute ischemic stroke in reducing mortality and morbidity.

http://jama.jamanetwork.com/article.aspx?articleid=1778674

. The study was supported by Tulane University and Collins C. Diboll Private Foundation; Soochow University; and the National Science Foundation of China.

ENGAGE AF-TIMI 48: Once-Daily Edoxaban Noninferior to Warfarin in AF

The investigational oral factor Xa inhibitor edoxaban (Lixiana) taken once daily at dosages of either 60 mg or 30 mg was noninferior to warfarin for preventing stroke or systemic embolism in a randomized atrial fibrillation (AF) trial of more than 20,000 patients in 46 countries. Follow-up was a mean of 2.8 years.

Both doses of edoxaban were associated with significantly less major bleeding than warfarin in the trial (ENGAGE AF-TIMI 48 [Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation—Thrombosis in Myocardial Infarction 48]).

Lead author Robert P Giugliano, MD, of Brigham and Women’s Hospital, Boston, MA, said the high-dose edoxaban regimen tended to be more effective than warfarin. The rate of ischemic stroke was similar with high-dose edoxaban and warfarin, but was higher with the low-dose edoxaban regimen. ENGAGE AF-TIMI 48 was published online in the 

Hemorrhagic strokes and cardiovascular mortality were both significantly lower on both factor Xa inhibitor regimens than on warfarin.

The risk of hemorrhagic stroke went down 46% for high-dose edoxaban and 53% for low-dose edoxaban compared with warfarin (P <.01 for both differences). For ischemic stroke, high-dose edoxaban versus warfarin was the same (P = .97) and the risk went up 41% with low-dose edoxaban versus warfarin (P <.001). The results of the ENGAGE AF-TIMI 48 study indicate that both edoxaban 60 mg daily and 30 mg daily are noninferior for stroke prophylaxis in patients with AF compared with warfarin.

. The trial was funded by Daiichi Sankyo. Dr Guigliano discloses receiving consulting fees from Daiichi Sankyo, Janssen, and Merck; lecture fees from Bristol-Myers Squibb, Daiichi Sankyo, Merck, and Sanofi; and grant support through his center from Daiichi Sankyo, Merck, J&J, Sanofi, and AstraZeneca.

NIAMI Trial: Nitrites Don’t Protect Myocardium

Results of the Nitrites in Acute Myocardial Infarction (NIAMI) trial presented at the AHA 2013 Scientific Sessions show that a 5-minute infusion of sodium nitrite just prior to opening the culprit artery in patients with ST-segment-elevation MI (STEMI) had no effect on infarct size as measured by coronary magnetic resonance (CMR) imaging 6 to 8 days later. After 6 months, there was also no effect on measures of myocardial remodeling.

Lead author Nishat Siddiqui, MD, of the University of Aberdeen, Scotland, said that the current study is conclusive in stating that at this dose, and by this route, and at this point in ischemia, nitrite does not do anything to reduce infarct size. She noted that perhaps a different dose or longer infusion duration would be a possible point for future studies.

In NIAMI, 229 patients at 4 centers undergoing primary stenting for their first MI were randomized in a double-blind set-up to be infused right before stent expansion, with either 70 μmol of sodium nitrite in 5-mL saline or a placebo.

At CMR imaging on days 6 to 8, 118 patients who received the nitrite infusion showed minimal reduction of less than 1% (P = .34) in infarct size as a proportion of myocardial area at risk, compared with the 111 who received placebo. There were no significant differences in the secondary end points of plasma troponin or creatinine kinase at 72 hours.

After 6 months there were no significant differences in final infarct size, left ventricular ejection fraction, or left ventricular end-systolic or end-diastolic volumes.

There was a 4.5% improvement in infarct size among diabetics who received nitrites (n = 14), compared with those assigned to placebo (n = 19), but the difference was not significant.

This study was funded by the Medical Research Council of the United Kingdom.

Surgery and Repair Do Equally Well in Ischemic Mitral Regurgitation

A study sponsored by the National Institutes of Health and Canadian Institutes of Health Research found that both mitral-valve repair and chordal-sparing mitral valve replacement surgery did equally well with respect to left-ventricular (LV) reverse remodeling or major adverse cardiac or cerebrovascular events (MACCEs) at 12 months. The rates of death at 30 days and 12 months were similar in the 2 treatment arms of the Cardiac Surgery Clinical Research Network (CTSN). Results were published online in The New England Journal of Medicine.

Lead author Michael Acker, MD, of the University of Pennsylvania Perelman School of Medicine in Philadelphia, explained that mitral valve replacement provides a more durable correction of severe ischemic mitral regurgitation (MR). “Mitral valve recurrent MR might have an important effect on long-term outcomes,” he said, “but additional follow-up and subset analysis may provide some insight into predictors and the clinical impact of mitral insufficiency recurrence, allowing the optimization of therapeutic decisions for individual patients.”

Dr. Acker said that ischemic mitral insufficiency is not primary mitral valve disease but rather is the result of myocardial infarction (MI). The guidelines are not completely clear on what to do about this problem, he noted, as they are unclear on whether to repair or replace. In the United States the preference is for mitral valve repair over replacement.

In CTSN, 126 patients were randomized to mitral valve repair and 125 to mitral valve replacement. Mean LV end-systolic volume index (LVESVI) among patients who underwent repair was 54.6 mL/m2 of body surface area at 12 months; in the replacement group, mean LVESVI was 60.7 mL/m2 of body surface area. The mean change from baseline was -6.6 and -6.8 mL/m2, respectively.

There were no significant between-group differences in the risk of death at 30 days or 12 months, and no significant difference in the rate of a composite of major adverse cardiac or cerebrovascular events, function, or quality of life at 12 months. Valve replacement did allow for a more durable improvement in MR, however. The rate of moderate or severe MR at 12 months was 32.6% in the repair arm and just 2.3% in the replacement arm, a statistically significant difference.

www.nejm.org/doi/full/10.1056/NEJMoa1312808

Stents Do Not Benefit Renal Artery Stenosis

No advantages are conferred by renal artery stenting in patients with renal artery stenosis over best medical therapy, according to the Cardiovascular Outcomes in Renal Atherosclerotic Lesions (CORAL) study, funded by the National Heart, Lung, and Blood Institute. The study, which enrolled 947 patients with renal artery atherosclerosis (stenosis greater or equal to 60%), was launched in 2005.

CORAL patients had either systolic hypertension and were taking 2 or more blood pressure— lowering drugs, or chronic kidney disease. They were randomized to medical therapy alone or medical therapy plus renal artery stenting. Crossovers were strictly controlled.

The study showed that patients who have hypertension and renal artery disease do just as well with medical therapy versus interventional therapy. At a median follow-up of 43 months, the rate of primary composite end point was no different between the 2 groups. In both groups, the primary end point (death from cardiovascular or renal causes, MI, stroke, hospitalization for congestive heart failure, progressive renal insufficiency, or need for kidney replacement) occurred in 35% of patients. The investigators concluded that medical therapy without stenting is the preferred management strategy for the majority of people with atherosclerotic renal artery stenosis.

Study coauthors Michael Jaff, MD, of Massachusetts General Vascular Center, Boston, MA, said the bottom line is to make sure these patients are given “a really good try at intensive medical therapy long before you consider renal artery stents.”

www.nejm.org/doi/full/10.1056/NEJMoa1310753

Aldosterone Inhibitor Shows Promise for Heart Failure With Preserved EF

Fesults of the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial suggest that spironolactone may improve clinical outcome in patients with heart failure with preserved ejection fraction (HFPEF). The study found that while patients who took spironolactone failed to show benefit for the clinical primary end point, they did have significantly fewer heart failure hospitalizations, a part of the primary end point, over the 3-plus years of follow-up.

TOPCAT randomized 3445 HF patients with an LVEF less than or equal to 45% to receive the aldosterone antagonist or placebo. Spirinolactone was titrated up to 30 mg/d to 45 mg/d. There were no significant differences in adverse events, except more hyperkalemia with spironolactone and more hypokalemia with placebo.

Although the primary end point wasn’t met for the overall population, the researchers were confident that hospitalizations for heart failure had been reduced by the medication. Margaret Redfield of the Mayo Clinic in Rochester, MN, said the trial showed a signal of benefit even though findings were not statistically significant. She noted that all-cause hospitalizations and mortality did not appear to be meaningfully affected by spironolactone, and cautioned that in clinical practice without the careful monitoring of creatinine and serum potassium in the trial, the prevalence of worsening renal function and hyperkalemia would be more common.

If safety issues are addressed, spironolactone is an option for patients with HFPEF, the researchers concluded.

Meeting Report

A review of the CATIS, ENGAGE AF-TIMI 48, TOPCAT, CORAL, NIAMI, and CTSN trials presented at the American Heart Association 2013 Scientific Sessions.

Meeting Report: American Heart Association 2013 Scientific Sessions

Fearon WF, Shilane D, Pijls NHJ, et al. Cost-effectiveness of percutaneous coronary intervention in patients with stable coronary artery disease and abnormal fractional flow reserve. 

The Fractional Flow Reserve versus Angiography for Multivessel Evaluation 2 (FAME-2) trial was a prospective, multicenter, open-label randomized trial in patients with single or multivessel stable ischemic heart disease (SIHD) and a fractional flow reserve (FFR) ≤0.08 across 1 or more stenosis.

 Patients were randomized to percutaneous coronary intervention (PCI) with second-generation drug-eluting stents plus best medical therapy or best medical therapy alone. The primary composite end point was death from any cause, nonfatal myocardial infarction (MI), or unplanned hospitalization leading to urgent revascularization during the first 2 years.

The trial was powered at 84% to include 1632 patients by estimating that the primary end point at 24 months would occur in 12.6% in the PCI group and 18.0% in the medical therapy group. No formal rules concerning halting the trial were specified in the protocol. Nevertheless, only 888 patients were randomized before the study was prematurely terminated, and follow-up was only a mean of 213 days. The primary outcome occurred in 4.3% of the 447 patients randomized to PCI and in 12.7% of the 441 patients randomized to medical therapy (

 <.001). It is important to note that there were no differences in death (0.2% vs 0.7%) or MI (3.4% vs 3.2%); the difference was in the rate of urgent revascularization (1.6% vs 11.1%; 

 <.001). Only 75 patients experienced an end point event: death, 1 (PCI) versus 3 (medical therapy); MI, 15 (PCI) versus 14 (medical therapy); and urgent revascularization, 7 (PCI) versus 49 (medical therapy).

It is not clear why the Data Safety Monitoring Board (DSMB) was concerned about the study results or why the Steering Committee accepted the DSMB recommendation to halt the trial prematurely when there were no differences in death or MI rates. Premature termination and incomplete follow-up in a randomized trial usually results in overestimation of the treatment effect and limits the value of the trial to the study volunteers, the investigators, and the scientific community. The “urgent” need for revascularization in the FAME-2 trial, not seen in other trials of SIHD, suggests that patients who perhaps should have undergone initial PCI for more significant symptoms or more severe stenoses were randomized to an inferior treatment with initial medical therapy because of participation in the trial and then crossed over to PCI because of uncontrolled symptoms. Equipoise in treatment options is supposed to be present before randomization. In fact, more than 50% of the lesions were >70% diameter stenosis and 14% were >90% diameter stenosis, and almost 25% of the patients had Canadian Cardiovascular Society (CCS) Class III/IV angina. The open-label design and investigator awareness of lesion percentage diameter stenosis may also have influenced the decision to cross over to PCI after initial medical therapy.

In the FAME-2 cost-effectiveness report, 12-month medical costs were calculated.

 Angina, number and doses of cardiac medications, employment status, and patient utility assessed by the European Quality of Life-5 Dimensions (EQ-5D) instrument were also determined. Patients undergoing PCI, not surprisingly, experienced less angina at 30 days (11.1% vs 28.9%), but there was no effect on employment status. The initial ($6027) and 1-year follow-up ($2883) cost differences were greater with the initial PCI strategy. The incremental costeffectiveness ratio (ICER) was $36,000 per quality-adjusted life-year (QALY), below the willingness-to-pay threshold of $50,000/QALY. However, the ICER was $102,000/QALY for CCS class 0/1 angina compared with $26,000/QALY with class 2-4 angina.

Because only 11% of patients provided 12-month EQ-5D scores, baseline and 1-month scores were used to determine QALY. Similarly, extrapolations were necessary to compute 12-month costs because the median follow-up was only 7 months. 

To Vascularize or Not to Revascularize SIHD Patients

There is a long-standing debate about whether or not to revascularize patients with SIHD. The traditional cardiology paradigm that myocardial ischemia predicts major adverse cardiac events has been used to promote a diagnostic strategy of exercise testing and cardiac catheterization, and a therapeutic strategy of revascularization with PCI or coronary artery bypass graft surgery (CABG) to improve prognosis. Unfortunately, this excellent theory has yet to be proved in randomized clinical trials.

Most recently, the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE)

 and Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI-2D)

 trials have again suggested that patients with SIHD can start with medical treatment and then undergo elective revascularization only if they or their physicians are not satisfied with symptom control, with no increased risk of death or MI expected from delaying the decision on revascularization until an initial trial of best medical therapy has been tried, and low risk for urgent revascularization. Evidence-based guidelines, based on these and other studies, continue to recommend this strategy.

PCI has become a very effective, relatively simple, low-risk procedure for treating myocardial ischemia due to focal coronary artery stenoses when revascularization is indicated. Recent criticism about the overuse of PCI in patients with SIHD has emphasized that ischemia is not documented in the majority of patients and that intermediate stenoses that might not cause ischemia are being stented because of the “oculo-stenotic reflex.” FFR is a pressure wire—based index that measures the physiologic significance of a coronary stenosis during cardiac catheterization. When the ratio between distal pressure and aortic pressure during maximal coronary vasodilation becomes ≤0.8, downstream perfusion is limited and may become inadequate when myocardial oxygen demand increases, resulting in myocardial ischemia.

Three randomized clinical trials have evaluated the clinical utility of FFR. To determine the safety of deferring PCI on a stenosis with a normal FFR, the Deferral of Percutaneous Coronary Intervention (DEFER) trial randomized 181 patients with SIHD and FFR ≥0.75 across an intermediate stenosis to PCI or medical treatment.

 At 5-year follow-up, the deferred group had a lower rate of death or MI than the PCI group (3.3% vs 7.9%), supporting the safety of medical therapy for SIHD in the absence of documented myocardial ischemia.

To evaluate the utility of FFR in selecting patients for PCI, the Fractional Flow Reserve versus Angiography for Multivessel Evaluation (FAME) trial randomized 1005 patients with multivessel disease (including SIHD, unstable angina, and non-ST elevation MI [NSTEMI]) to either FFR-guided or angiography-guided PCI.

 The primary composite end point of death, MI, or repeat revascularization at 1 year was significantly lower (13.2% vs 18.3%) in patients who received FFR-guided PCI. An economic evaluation demonstrated that FFR-guided PCI was a cost-saving strategy ($2300 per patient) at 1 year, with fewer stents deployed.

To compare outcomes in FFR-guided PCI with medical therapy, the Fractional Flow Reserve versus Angiography for Multivessel Evaluation 2 (FAME 2) trial randomized 888 patients with single or multivessel SIHD to FFR-guided PCI with best medical therapy or best medical therapy alone.1 All stenoses were assessed by FFR; patients had to have at least 1 lesion with FFR ≤0.80. FFR-guided therapy decreased the need for urgent revascularization and was cost-effective.

The FAME-2 study showed reduced angina burden and good value for PCI ($36,000/QALY) in patients with documented ischemia. 2 In contrast, the COURAGE economic analysis suggested lack of cost-effectiveness for PCI (≥$168,000/QALY).

 An important difference between trials is that the primary end point in COURAGE was death/MI, whereas the primary end point in FAME-2 was death/MI/urgent revascularization. Patients in FAME-2 had higher rates of angina and a higher rate of hospitalization for acute coronary syndromes and for revascularization than the patients in COURAGE.

Both studies agree that there is no difference in death or MI rates whether one uses physiologic or angiographic criteria to select patients for PCI. The difference with medical therapy as an initial strategy is that there will be more subsequent PCI procedures, but fewer total PCI procedures—an attractive option for the future, when accountable care organizations (ACOs) will have a fixed budget for treating SIHD. For instance, in FAME-2, subsequent revascularization was required in 14 patients in the initial PCI group versus 86 patients in the best medical therapy group, an advantage the authors claim in favor of an initial PCI strategy. However, the total number of revascularization procedures was 461 in the PCI group and 86 in the medical therapy group.

FAME and FAME-2 support the concept that revascularization for ischemia is reasonable, but do not prove superiority of FFRguided versus angiography-guided decision making. FFR is most useful when the indications for PCI are ambiguous based on noninvasive testing and coronary angiography or when noninvasive testing is absent, equivocal, or does not provide objective evidence of ischemia in the myocardial territory perfused by the index artery.

 The PCI practice guidelines already give a class I indication for PCI in patients with ≥70% diameter stenosis and unacceptable angina on guideline-directed medical therapy.

 It is PCI in the 50% to 70% diameter stenosis that requires demonstration of ischemia by stress testing or FFR to meet appropriate use criteria.

 It is important to note that FFR is another piece of information for decision making, not a mandate to perform PCI. It still is unclear whether myocardial ischemia is a strong predictor of subsequent cardiac events. This hypothesis is being further evaluated in the International Study of Comparative Health Effectiveness with Medical and Invasive Approaches (ISCHEMIA) trial (ClinicalTrials. gov, NCT01471522).

1. De Bruyne B, Pijls NH, Kalesan B, et al. Fractional flow reserve-guided PCI versus medical therapy in stable coronary disease. 

2. Fearon WF, Shilane D, Pijls NH, et al. Cost-effectiveness of percutaneous coronary intervention in patients with stable coronary artery disease and abnormal fractional flow reserve. 

3. Pursnani S, Korley F, Gopaul R, et al. Percutaneous coronary intervention versus optimal medical therapy in stable coronary artery disease: a systematic review and meta-analysis of randomized clinical trials. 

4. Boden WE, O’Rourke RA, Teo KK, et al. Optimal medical therapy with or without PCI for stable coronary disease. 

5. The BARI 2D Study Group. A randomized trial of therapies for type 2 diabetes and coronary artery disease. 

6. Fihn SD, Gardin JM, Abrams J, et al. 2012 ACCF/AHA/ACP/AATS/ PCNA/SCAI/STS Guideline for the diagnosis and management of patients with stable ischemic heart disease. 

7. Montalescot G, Sechtem U, Achenbach S, et al. 2013 ESC guidelines on the management of stable coronary artery disease. 

8. Pijls NH, van Schaardenburgh P, Manoharan G, et al. Percutaneous coronary intervention of functionally nonsignificant stenosis: 5-year followup of the DEFER Study. 

9. Tonino PA, De Bruyne B, Pijls NH, et al. Fractional flow reserve versus angiography for guiding percutaneous coronary intervention. 

10. Fearon WF, Bornschein B, Tonino PA, et al. Economic evaluation of fractional flow reserve-guided percutaneous coronary intervention in patients with multivessel disease. 

11. Weintraub WS, Spertus JA, Kolm P, et al. Effect of PCI on quality of life in patients with stable coronary disease. 

12. Weintraub WS, Boden WE, Zhang Z, et al. Cost-effectiveness of percutaneous coronary intervention in optimally treated stable coronary patients. 

13. Lotfi A, Jeremias A, Fearon WF, et al. Expert consensus statement on the use of fractional flow reserve, intravascular ultrasound, and optical coherence tomography: a consensus statement of the society of cardiovascular angiography and interventions [published online ahead of print October 6, 2013]. 

14. Patel MR, Dehmer GJ, Hirshfeld JW, Smith PK, Spertus JA. ACCF/ SCAI/STS/AATS/AHA/ASNC 2009 Appropriateness Criteria for Coronary Revascularization. 

Eric R. Bates, MD, is Professor of Internal Medicine at the University of Michigan. Dr. Bates graduated from the University of Michigan Medical School, where he trained in internal medicine and cardiology. His research efforts have focused on fibrinolytic and catheter-based reperfusion therapy for acute MI and cardiogenic shock, antiplatelet and anticoagulant therapy for coronary thrombosis, and coronary artery revascularization. He was vice-chair for the 2011 ACCF/AHA Guidelines for Percutaneous Coronary Intervention Writing Committee. He is also Chair of the Mission: Lifeline Science Task Force. 

CME Reviews

Cost-Effectiveness of PCI in Patients With Stable CAD, Abnormal FFR

Ragavendra Baliga, MD, MBA, FACP, FRCP (Edin), FACC

Gold MR, Daubert JC, Abraham WT, et al. Implantable defibrillators improve survival in mildly symptomatic heart failure patients receiving cardiac resynchronization therapy: analysis of the long-term follow-up of REVERSE. 

Cardiac resynchronization therapy (CRT) has been shown to improve functional status and reduce heart failure (HF) hospitalizations and mortality among HF patients with left ventricular (LV) systolic dysfunction and QRS prolongation. The benefits of CRT have been shown with both CRT pacemakers (CRT-P) and CRT with implantable defibrillators (CRT-D), but there are few studies comparing outcomes between CRT-P and CRT-D devices. The COMPANION study compared optimal medical therapy, CRT-P, or CRT-D, in advanced HF patients and was designed to compare outcomes between medical therapy and the groups receiving the devices. Other studies compared CRT-D versus implantable cardioverter defibrillators (ICDs). This study (REVERSE), by Gold et al, was designed to compare clinical outcomes and long-term survival among CRT patients with and without ICD.

REVERSE (REsynchronization reVErses Remodeling in Systolic left vEntricular dysfunction) was a multicenter trial that compared CRT-P in patients with 

 Patients enrolled were NYHA class I or II HF with QRS duration ≥120 msec on EKG; left ventricular ejection fracture (LVEF) ≤0.40, and left ventricular end-diastolic dimension (LVEDD) ≥55 mm on transthoracic echocardiography (TTE). Gold et al2 report the findings of a preplanned 5-year follow-up of the patients enrolled in REVERSE. The study cohort comprised 419 patients randomized to CRT-ON (active CRT), 74 of whom received CRT-P devices, while the remaining 345 patients received defibrillator back-up (CRT-D). Patients in the CRT-OFF group (controls) were programmed ON after the randomization period and therefore were not included in this study. Long-term follow-up of the study cohort was preplanned for 5 years so that sustained benefit and cost-effectiveness of treatment could be analyzed.

All-cause mortality was low (<3% annually). The investigators found that CRT-P patients were less likely to have ischemic cardiomyopathy and more likely to have left bundle branch block morphology on their upaced ECG. Patients who received CRT-D had larger baseline LV end-systolic left ventricular size, a lower mean LVEF, and were more likely to have had right bundle branch block and intraventricular conduction disturbance.

Over a period of 2 years, inappropriate shock for non-VT/VF (ventricular tachycardia/ventricular fibrillation) episodes occurred in 8% of patients. Over the same period, 18.7% of the CRT-D patients had an appropriate shock. These shocks terminated 17.6% (n = 54) of the 307 VT/VF episodes whereas anti-tachycardia pacing terminated the remaining 253 episodes. Complications related to the device and/or device implantation occurred in 28% of 74 CRT-P (n = 25 complications) and 34% of the 345 CRT-D group patients (n = 191 complications). During the 5-year follow-up period, complications related to the RV lead were higher in the CRT-D group (18.3%; 76 complications in 63 of 355 patients) compared with the CRT group (6.8%; 5 complications in 5 of 74 patients). In the CRT-D group a majority of these complications were related to the Fidelis lead, which has since been withdrawn from the market.

The authors report that there was improved survival in the CRTD group (65% reduction in mortality; hazard ratio [HR], 0.35; 

 = .003), whereas there was only a 24% risk reduction in the CRT-P arm (

 = .59; borderline significant). Other indices such as quality of life, 6-minute walk duration, clinical composite scores, and LV end-systolic volume index were similar in both groups. The mortality benefit with CRT was more likely in younger patients, women, increased unpaced QRS duration, and smaller LV volumes. Although the multivariate analysis demonstrated that CRT-D is more likely to improve survival given the study design and sample size, it did not reach statistical significance. 

The results of this study, suggesting CRT-P is more effective in improving survival than CRT-D, support the thesis that mortality in NYHA class I or II systolic HF is more likely to be due to sudden death. An earlier trial

 comparing CRT-D with ICD reported that mild systolic HF patients (LVEF ≤30% and NYHA class I or II symptoms) and wide QRS intervals (≥130 msec) benefited with CRT-D compared with an ICD alone; however, there was no mortality benefit. These patients had improved ventricular function and reduced the risk of worsening HF; these effects were most pronounced when the QRS interval was ≥150 msec. CRT did not reduce death in this population with a relatively low mortality, which could be explained by the findings of MERIT-HF3, that in milder forms of HF there was less pump dysfunction and consequently less dyssynchrony, making CRT less effective.

Ventricular arrhythmias are responsible for about half the mortality that occurs in systolic HF; this proportion is higher in those with mild symptoms, whereas the more likely cause is pump failure

 study sudden death was the cause of mortality in 64%, 59%, and 33% of NYHA class II, III, and IV patients, respectively, whereas poor pump function was the cause of mortality in 12%, 26%, and 56% in NYHA class II, III, and IV, respectively). An ICD improves survival in systolic dysfunction

 with very little adverse effect on the quality of life,

 although the benefit is apparent only a year or more after implantation of the ICD.

 The SCDHeFT trial reported that ICD therapy improved survival in NYHA class II but not class III patients. ICDs are utilized for secondary prevention in those patients who survive an unprovoked episode of VF or sustained VT, and in primary prevention in patients with systolic HF, NYHA functional class II or III, despite optimal medical therapy, and who are expected to survive at least a year with reasonable quality of life. One study has suggested that ICD implantation is likely to be futile when HF is simply too advanced.

 In fact, in their critique of the ICD literature, Tung et al

 disputed the effectiveness of ICDs compared with anti-arrhythmic drugs. In their opinion, there was (a) inadequate beta-blocker utilization in the control arm of most studies, (b) underestimation of the effects on morbidity, quality of life, and potential for proarrhythmia because appropriate ICD shocks are not necessarily equal to life-saving shocks, (c) a propensity for device and lead malfunction, and (d) incomplete analyses of the cost-effectiveness of device therapy because hospitalizations, recurrent shocks, and lead replacement are not factored in adequately.

About one-third of the patients with severe systolic HF have a QRS duration ≥120 msec, a marker of impaired ventricular emptying and, occasionally, mitral regurgitation due to dyssynchronous contraction of the left ventricle. CRT with atrial-synchronized pacing usually improves cardiac performance by increasing stroke volume and reducing mitral regurgitation. CRT was first reported in 1994,

 and the MIRACL study was the first to report clinical benefit in moderate to severe HF,

 which included improvements in distance walked in 6 minutes, NYHA functional class, quality of life, time on the treadmill during exercise testing, and ejection fraction. Subsequently, mortality benefit was also reported in moderate to severe HF.

 The benefit of resynchronization therapy has been reported in mild to moderate systolic HF.

 Consequently, current white papers and guidelines

 recommend that CRT be considered in systolic HF patients in sinus rhythm and a wide QRS complex (>120 msec) with symptoms that persist despite optimal medical therapy. Clinical benefit appears to be greatest in those with the most prolonged QRS duration and left bundle-branch block.

There are limitations associated with implanting devices in mild HF, including (a) the difficulty of implanting the LV lead successfully because of varying coronary venous anatomy, (b) discomfort due to diaphragmatic stimulation because of proximity to the left phrenic nerve, (c) lead dislodgement, which can occur in as many as 10% of patients in whom the implantation is initially successful,

 (d) coronary sinus dissection, (e) cardiac perforation, (f) LV dysfunction worsened by inadvertent right ventricular pacing, and (g) inappropriate ICD shocks.

 These limitations must be kept in mind before considering device therapy in mild HF.

As Gold et al discuss, this study was not designed to evaluate the role of ICD therapy in NYHA class I therapy. However, this study supports the findings that ICD therapy should be considered in patients with mild HF.

 Proof of cost-effectiveness is urgently required before CRT-D is offered to all patients with mild HF. The routine utilization of device therapy in HF has also been questioned,

 prompting calls for studies to better predict mortality in systolic heart failure.

 Given that sudden death is more likely to occur in milder forms of HF, ICDs are more likely to be the treatment of choice in these patients, whereas CRT-D is more likely to be the device of choice in advanced forms of HF. However, pharmacologic therapy continues to change in the natural history of HF, and therefore ongoing studies of the natural history of HF are important in our efforts to provide appropriate therapy.

1. Linde C, Abraham WT, Gold MR, St John Sutton M, Ghio S, Daubert C. Randomized trial of cardiac resynchronization in mildly symptomatic heart failure patients and in asymptomatic patients with left ventricular dysfunction and previous heart failure symptoms. 

2. Gold MR, Daubert JC, Abraham WT, et al. Implantable defibrillators improve survival in mildly symptomatic heart failure patients receiving cardiac resynchronization therapy: Analysis of the long-term follow-up of reverse. 

. Arrhythmia and electrophysiology. 2013.

3. Moss AJ, Hall WJ, Cannom DS, et al. Cardiac-resynchronization therapy for the prevention of heart-failure events. 

4. Effect of metoprolol cr/xl in chronic heart failure: Metoprolol cr/xl randomised intervention trial in congestive heart failure (merit-hf). 

5. Bardy GH, Lee KL, Mark DB, et al. Amiodarone or an implantable cardioverter- defibrillator for congestive heart failure. 

December 2013

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