Management of complex cardiovascular problems 4e

Director of the Intervention Center at PekingUniversity People’s Hospital, President, Chinese College of Cardiovascular Physician CCCP, Beijing, China Professor of Cardiology Professor o

of Complex Cardiovascular Problems

Director of the Intervention Center at Peking

University People’s Hospital,

President, Chinese College of Cardiovascular

Physician (CCCP), Beijing, China

Professor of Cardiology

Professor of Internal Medicine

Deputy President, Nanjing First Hospital,

Nanjing Medical University

Director of Catheterization Laboratories,

Nanjing First Hospital

Chief of Cardiology Nanjing First Hospital

Busan, Korea

Vice President Academic and Clinical Affairs, Detroit Medical Center Heart Hospital Detroit, MI

A S S O C I A T E E D I T O R

Faisal Latif, MD

Associate Professor of Medicine, University of Oklahoma, OKC, OK

Registered office: John Wiley & Sons, Ltd, The Atrium, Southern Gate, Chichester, West

Sussex, PO19 8SQ, UK

Editorial offices: 9600 Garsington Road, Oxford, OX4 2DQ, UK

The Atrium, Southern Gate, Chichester, West Sussex, PO19 8SQ, UK

111 River Street, Hoboken, NJ 07030-5774, USA

For details of our global editorial offices, for customer services and for information about how to apply for permission to reuse the copyright material in this book please see our website at www.wiley.com/wiley-blackwell

The right of the author to be identified as the author of this work has been asserted in accordance with the UK Copyright, Designs and Patents Act 1988.

All rights reserved No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, except as permitted by the UK Copyright, Designs and Patents Act 1988, without the prior permission of the publisher.

Designations used by companies to distinguish their products are often claimed as trademarks All brand names and product names used in this book are trade names, service marks, trademarks or registered trademarks of their respective owners The publisher is not associated with any product

or vendor mentioned in this book It is sold on the understanding that the publisher is not engaged

in rendering professional services If professional advice or other expert assistance is required, the services of a competent professional should be sought.

The contents of this work are intended to further general scientific research, understanding, and discussion only and are not intended and should not be relied upon as recommending or promoting a specific method, diagnosis, or treatment by health science practitioners for any particular patient The publisher and the author make no representations or warranties with respect to the accuracy or completeness of the contents of this work and specifically disclaim all warranties, including without limitation any implied warranties of fitness for a particular purpose.

In view of ongoing research, equipment modifications, changes in governmental regulations, and the constant flow of information relating to the use of medicines, equipment, and devices, the reader is urged to review and evaluate the information provided in the package insert or instructions for each medicine, equipment, or device for, among other things, any changes in the instructions or indication of usage and for added warnings and precautions Readers should consult with a specialist where appropriate The fact that an organization or Website is referred to

in this work as a citation and/or a potential source of further information does not mean that the author or the publisher endorses the information the organization or Website may provide or recommendations it may make Further, readers should be aware that Internet Websites listed in this work may have changed or disappeared between when this work was written and when it is read No warranty may be created or extended by any promotional statements for this work Neither the publisher nor the author shall be liable for any damages arising herefrom.

Library of Congress Cataloging-in-Publication Data:

Names: Nguyen, Thach, editor | Hu, Dayi, editor | Chen, Shao Liang, editor.

| Kim, Moo-Hyun (Cardiologist), editor | Grines, Cindy, editor.

Title: Management of complex cardiovascular problems / edited by Thach Nguyen, Dayi Hu, Shao Liang Chen, Moo-Hyun Kim, Cindy Grines ; associate editor, Faisal Latiff.

Description: Fourth edition | Chichester, West Sussex, UK ; Hoboken, NJ : John Wiley & Sons Inc.,

2016 | Includes bibliographical references and index.

Identifiers: LCCN 2015035763 (print) | LCCN 2015036342 (ebook) | ISBN 9781118965030 (cloth)

| ISBN 9781118965047 (Adobe PDF) | ISBN 9781118965054 (ePub)

Subjects: | MESH: Cardiovascular Diseases–therapy | Evidence-Based Medicine.

Classification: LCC RC671 (print) | LCC RC671 (ebook) | NLM WG 120 | DDC 616.1/2–dc23

LC record available at http://lccn.loc.gov/2015035763

A catalogue record for this book is available from the British Library.

Wiley also publishes its books in a variety of electronic formats Some content that appears in print may not be available in electronic books.

Cover image: gettyimages.com © Janulla

Set in 8/10pt Frutiger Light by Aptara Inc., New Delhi, India

List of Contributors, vii

Foreword to the Third Edition, xvii

Udho Thadani and Nguyen Duc Cong

3 Stable Coronary Artery Disease, 50

Mohammed Haris Umer Usman, L ˆe Ho `ang D ´uc To `an, L ˆe,Thi Ngo.c Tr ˆam, Hu`ynh Thi Thu Tr ´uc, An Huynh andAman Amanullah

4 Acute Coronary Syndrome, 86

Udho Thadani, Quang Tuan Nguyen and Han Yaling

5 ST Segment Elevation Myocardial

Infarction, 113

Thach Nguyen, Xu Bo, Faisal Latif, Ho Thuong Dung,Duane Pinto, Pham Manh Hung, Michael Gibson andRunlin Gao

6 Heart Failure (Stages A, B and C), 141

Dan Le, Trong Ha Le, V ˜o Minh Vîe.t, Bao V Ho, Tuan D.

Nguyen, Khalid Numan Al Azza, Hau Van Tran andGianluca Rigatelli

7 Acute Decompensated and Chronic Stage

D Heart Failure, 169

Patrick Campbell, Selim R Krim, Thach Nguyen, MarvinEng, Yidong Wei and Hau Van Tran and Hector Ventura

13 Cardiovascular Problems

in Elderly Patients, 364

Daniel E Forman and Nanette Wenger

14 Cardiovascular Problems in Women, 379

Kahroba Jahan, Ainol Shareha Sarar, Nisa Arshad, NguyenPhuc Nguyen, Amsa Arshad, Sajaj Agarwal, ThachNguyen and Kwan Lee

Index, 406

NABEEL ALI, MD

Xavier University School of Medicine, Aruba

HY TAT AN

MS Class of 2020 Tan Tao University School of Medicine

Tan Duc E-City, Duc Hoa – Long An Vietnam

KHALID NUMAN AL AZZA, MD

Jordan University of Science and Technology

Irbid, Jordan

AMAN M AMANULLAH, MD, PhD, FACC, FAHA

Clinical Professor of Medicine

Sidney Kimmel Medical College of Thomas Jefferson UniversitySection Chief, Noninvasive Cardiology, Albert Einstein Medical CenterPhiladelphia, PA 19141

Clinical Associate Professor, University of Chicago

Clinical Assistant Professor, University of Illinois at Chicago

Chicago, IL

PATRICK T CAMPBELL, MD

Advanced Heart Failure Fellow

Section of Cardiomyopathy & Heart Transplantation

Ochsner Heart and Vascular Center, New Orleans

MIHAIL G CHELU, MD, PHD, FHRS

Assistant Professor University of Utah School of Medicine

Electrophysiology Division Salt Lake City, UT

SHAO LIANG CHEN, MD, PhD, FACC

Professor of Cardiology

Professor of Internal Medicine

Deputy President, Nanjing First Hospital, Nanjing Medical UniversityDirector of Catheterization Laboratories, Nanjing First HospitalChief of Cardiology, Nanjing First Hospital

Nanjing, China

NGUYEN DUC CONG, MD, PhD

Professor of Medicine

Director of Thong Nhat Hospital

Director of Geriatric Department of Pham Ngoc Thach MedicalUniversity

Vice Director of Geriatric Department, The University of Medicine andPharmacy

Vice Director Department of Internal Medicine, School of Medicine, theNational University of Hochiminh City, Hochiminh City, Vietnam

VIJAY DAVE, MD

Director of Medical Education

St Mary Medical Center Hobart, IN

HO THUONG DUNG, MD, PhD, FSCAI

Vice Director of Thong Nhat Hospital, HCM City

Vice Chairman of Interventional Cardiology Association of HCM CityHochiminh City, Vietnam

MARVIN H ENG, MD

Structural Heart Disease Fellowship Director

Center for Structural Heart Disease, Division of Cardiology

Henry Ford Health System, Detroit, MI

DANIEL FORMAN, MD

Professor of Medicine, University of Pittsburgh

Chair, Geriatric Cardiology Section, University of Pittsburgh MedicalCenter

Director, Cardiac Rehabilitation, VA Pittsburgh Healthcare SystemPittsburgh, PA

RUNLIN GAO, MD, FACC, FESC, FSCAI

Professor of Medicine

Member, Chinese Academy of Medical Sciences

Chief Cardiologist, Fuwai Hospital Beijing, China

Assistant Professor of Medicine, Baylor College of Medicine

Ben Taub Hospital, Houston, Texas

NGUYEN LAN HIEU, MD, PhD

Vice director, Heart Center

Hanoi Medical University Hospital

Hanoi, Vietnam

BAO V HO, MD, MSC

New York Institute of Technology, College of Osteopathic MedicineOld Westbury, NY

DAYI HU, MD, FACC, FESC

Director of the Heart Center at Peking University People’s Hospital,Beijing China

President of the China Heart Federation Beijing China

PHAM MANH HUNG, PHD, MD, FACC, FESC

Associate Professor, Hanoi Medical University

Secretary General, Vietnam National Heart Association

Director, Cardiac Catheterization Laboratories Vietnam NationalHeart Institute

Hanoi, Vietnam

PHAM NHU HUNG, MD, PhD, FACC, FASCC

Consultant of Cardiology and Electrophysiology

Director of Electrophysiology Laboratories, Hanoi Heart HospitalHanoi, Vietnam

PHAN NAM HUNG, MD

General Secretary, the Internal Medicine Society of Vietnam

Vice Chief, Cardiovascular Medicine Department, Binh Dinh

General Hospital

Qui Nhon, Vietnam

AN HUYNH

MS Class of 2019, Tan Tao University School of Medicine

Tan Duc E-City, Duc Hoa – Long An Vietnam

HUNG D HUYNH

Senior Research Associate, Community Healthcare System, St Mary

Medical Center, Hobart, IN; and Webmaster, Riverside, CA

KIM N HUYNH

Honor Student, Miss Hall’s School

Vice President, International Student Alliance

Pittsfield, MA

KAHROBA JAHAN MD

Division of Cardiology, Sarver Heart Center

Banner University Medical Center South Campus

University of Arizona, Tucson, AZ

DEEPAK JOSHI, MD

Cardiology Fellow

The Brody School of Medicine at East Carolina University

Greenville, NC

MOO-HYUN KIM, MD, FACC, FSCAI

Director, Global Clinical Trial Center

Professor, Dept of Cardiology, Dong-A University HospitalBusan, Korea

NEAL KLEIMAN MD

Professor, Department of Medicine

Weill Cornell Medical College of Cornell University

Director, Applied Platelet Physiology Lab

Director, Cardiac Catheterization Laboratories

Houston Methodist DeBakey Heart & Vascular Center

Houston, TX

SELIM R KRIM, MD

Staff, Section of Cardiomyopathy & Heart TransplantationOchsner Heart and Vascular Center, New Orleans LA

FAISAL LATIF, MD, FACC, FSCAI

Associate Professor of Medicine

Associate Program Director, Cardiology Fellowship ProgramUniversity of Oklahoma Health Sciences Center

Director, Cardiac Catheterization Laboratories

VA Medical Center, Oklahoma City, OK

MS Class of 2019 Tan Tao University School of Medicine

Tan Duc E-City, Duc Hoa – Long An Vietnam

KWAN S LEE, MD FACC FSCAI

Medical Director of Cardiology

Director Cardiac Catheterization Laboratory

Banner University Medical Center South Campus

Sarver Heart Center, Banner University Medical Center South CampusUniversity of Arizona Tucson, AZ

XIAN KAI LI, MD, PhD

Cardiology Department

Shanghai Tenth People’s Hospital of Tongji University

Shanghai, China

TUNG DINH MAI, DO

Resident, Department of Internal Medicine

Detroit Medical Center – Sinai Grace Hospital

Wayne State University – School of Medicine, Detroit, MichiganClinical faculty, Department of Medicine

Michigan State University – College of Osteopathic Medicine

East Lansing, Michigan

ARAVINDA NANJUNDAPPA, FACC, FSCAI, RVT

Professor of Medicine and Surgery

Director of TAVR Program

West Virginia University, Charleston, WV

CHISALU NCHEKWUBE, MD

Internal Medicine Residency Program

Department of Internal Medicine

University of Illinois Hospital and Health Sciences System

Chicago, IL

RAJASEKHAR NEKKANTI, MD FACC FASE CCDS

Associate Professor of Medicine

Program Director, Cardiology Fellowship Program

Director, Continuing Medical Education-Cardiovascular Series

East Carolina Heart Institute

The Brody School of Medicine at East Carolina University

Director, Echocardiography Laboratories

East Carolina Heart Institute at Vidant Medical Center

St Mary Medical Center, Hobart, IN

NGOC-QUANG NGUYEN, MD, PhD, FASCC, FSCAI

Department of Cardiology, Hanoi Medical University

Head of Coronary Care Unit (C7), Vietnam National

Heart Institute

Bach Mai Hospital, Hanoi, Vietnam

QUANG TUAN NGUYEN, MD, PHD, FACC, FSCAI

CEO, Hanoi Heart Hospital

Medical Director, Hanoi Heart Hospital

Associate professor, Hanoi Medical University

President, Vietnam Interventional Cardiology Society

President, Hanoi Heart Association, Hanoi, Vietnam

THACH NGUYEN, MD, FACC, FSCAI

Deputy Editor-in-chief, Interventional Cardiology Grand Rounds, NYC,

NY, and Associate-editor-in-chief, Journal of Geriatric Cardiology, Beijing, China; and Editorial Consultant, Journal of Interventional Cardiology; Hoboken, NJ, and Chinese Medical Journal, Beijing, China, and Honorary Professor of Medicine, Hanoi Medical University,

and Vietnam Heart Institute, Hanoi, Vietnam, and Capital University

of Medical Sciences, Beijing, China; and The Institute of Geriatric

Cardiology, 301 Hospital of the Chinese People’s Liberation Army,

Beijing, China; and Friendship Hospital, Beijing, and the Tenth

People’s Hospital, Shanghai, China, and Visiting Professor, Nanjing First Hospital, Nanjing Medical University, Nanjing, China; and Clinical

Assistant Professor of Medicine, Indiana University Northwest, IN,USA, Director of cardiovascular research Methodist hospital,

Merrillville, IN; and Director of Cardiology, Community Healthcare

System, St Mary Medical Center, Hobart, IN, USA

Chairman, Department of Cardiology,

MHG, Memorial Ankara Hospital

Ankara, Turkey

PHAN DINH PHONG, MD, PhD

Head of Training Center

Vietnam National Heart Institute

Bach Mai Hospital, Hanoi, Vietnam

DUANE PINTO, MD FACC FSCAI

Associate Professor of Medicine, Harvard Medical School

Director, General Cardiology Fellowship Program

Director, Cardiac Intensive Care Unit, Beth Israel Deaconess

Medical Center

Boston MA

GIANLUCA RIGATELLI, MD, PhD, EBIR, FACP, FACC, FESC, FSCAI

Cardiovascular Diagnosis and Endoluminal Interventions Unit

Rovigo, General Hospital, Rovigo, Italy

MICHAEL RINALDI, MD

Interventional Cardiology and Vascular Medicine

Director, Clinical Research, Sanger Heart and Vascular Institute

Professor of Medicine, Carolinas HealthCare System

Charlotte, NC

MADHUR ROBERTS, MD

Cardiovascular Fellow, PGY 6

University of Tennessee Medical Center

Knoxville, TN

AINOL SHAREHA SAHAR, MD FACC FSCAI FNHAM SCIM

Senior Consultant Cardiologist

Deputy Head, Department of Cardiology

Penang General Hospital

Penang Malaysia

SARA SHAH

Honor Student, Munster High School

National Society of High School Scholar

Delegate, the Congress of Future Medical Leaders

2015 Nominee, National Youth Leadership Forum in Medicine

EVGENY SHLYAKHTO, MD, PhD, FESC, FACC

President, Russian Society of Cardiology

Director, Federal Almazov Heart Blood Endocrinology Centre

St Petersburg, Russian Federation

UDHO THADANI, MD, MRCP, FRCPC, FACC, FAHA

Professor Emeritus of Medicine University of Oklahoma Health SciencesCenter

Consultant Cardiologist Oklahoma University Medical Center and VAMedical Center

Oklahoma City, OK

MS Class of 2019 Tan Tao University School of Medicine

Tan Duc E-City, Duc Hoa – Long An Vietnam

L ˆE THI NGO.C TR ˆAM

MS Class of 2019, Tan Tao University School of Medicine

Tan Duc E-City, Duc Hoa – Long An Vietnam

Mercy Medical Center – North IA

HU ´YNH THI THU TR ´UC

MS Class of 2019 Tan Tao University School of Medicine

Tan Duc E-City, Duc Hoa – Long An Vietnam

VIEN THANH TRUONG, MD

Resident in Internal Medicine

Junior Lecturer, Internal Medicine Department

Pham Ngoc Thach University of Medicine, Ho Chi Minh City, Vietnam

M HARIS U USMAN, MD, MS

Interventional Cardiology Fellow

Detroit Medical Center, Wayne State University

Detroit MI

HECTOR O VENTURA, MD, FACC, FACP

Director, Section of Cardiomyopathy & Heart Transplantation

Ochsner Heart and Vascular Center, New Orleans

New Orleans, LA

MS Class of 2019 Tan Tao University School of Medicine

Tan Duc E-City, Duc Hoa – Long An Vietnam

YIDONG WEI, MD, FACC

Professor, Chief, Department of Cardiology

Shanghai Tenth People’s Hospital of Tongji University

Shanghai, China

NANETTE K WENGER, MD, MACC, MACP, FAHA

Professor of Medicine (Cardiology) Emeritus

Emory University School of Medicine

Consultant, Emory Heart and Vascular Center

Atlanta, GA

BO XU, MBBS

Director, Catheterization Laboratory

Fu Wai Hospital, National Center for Cardiovascular Diseases

Beijing, China

HAN YALING, MD, FACC, FESC

Academician of Chinese Academy of Engineering

President, Institute of Cardiovascular Medicine of PLA

Director, Department of Cardiology

General Hospital of Shenyang Military Region

Shenyang, Liaoning China

The modern cardiologist is confronted with a bewildering amount of newinformation At last count there were more than one hundred cardiologyjournals Many cardiology textbooks, covering every aspect of the fieldand dozens of symposia are published each year The major cardiovascularcenters all have their ‘in house’ publications, which emphasize their localaccomplishments In addition, industry bombards cardiologists with manyreviews, each placing the sponsor’s project and trial in the best light.What the practicing cardiologist really needs is a text that emphasizesunbiased, up to date information and that places this information into

an appropriate context The third edition of Management of Complex

Cardiovascular Problems, carefully edited by Dr Nguyen, does precisely

this

Particularly new, reader friendly, features are the boxes of ‘Take HomeMessages’ [Action Points in the Fourth Edition] which give succinct sum-

maries of each chapter, together with Critical Thinking (new concepts);

Evidence-Based Medicine (the key results of important clinical trials); and Clinical Pearls (advice from master clinicians).

This unique format provides busy cardiologists with an approach to dealwith information overload and will thereby enhance the quality of caredelivered to the cardiac patient Thus, Dr Thach Nguyen and his talentedauthors have again provided us with important ammunition for the waragainst heart disease This fine book describes clearly some of the mostdifficult problems that cardiovascular specialists face, and it provides enor-mously helpful directions in dealing with them This eminently readablebook should be equally valuable to practicing cardiologists in the frontlines of the battle against the global scourge of cardiovascular diseaseand to trainees in the field

Eugene Braunwald, M.D.Boston, Massachusetts

PRACTICING CARDIOLOGY IS LIKE CAR RACING AT

THE INDY 500

When driving to work, do you drive in the fast lane? When using theinternet, do you use a shortcut to open a new window? For short andquick communication, do you text or pick up the phone? In 2016, docardiologists still work with 20th century mentality or do they see andwork through a 21st century lens or Google Glass? In this fourth edition

of Management of Complex Cardiovascular Problems, the authors and

editors offer new strategic views and tactical maps similar to the onesused in car racing; they are presented, however, with the wit of a youngbroker in the middle of the New York Stock Exchange pit

When confronting a cardiac problem, the first strategy is to identifythe challenges How long is the race? Where are there dangerous turns?Which slippery slope could dump the best and most promising rider? Ifthis vital information is available ahead of the game, the practicing car-diologists could program their brain, rewire the shortcuts, and reserveenough adrenaline needed for the run

The second strategy when examining a patient is to risk profile thepatient thereby discriminating the sickest from the less sick By doing so,more resources, time, and manpower could be allocated for the smallnumber of patients who need it the most without compromising quality

of care for the entire group

Then the authors and editors would offer a strategic map which tizes the process of investigation and management Which is the straightline to the target (direct tests to confirm a clinical diagnosis)? How doesone rule out the most important differential diagnoses? Which optionoffers the best cost and time effective (most fuel efficient) treatment?

priori-At the same time, signposts warning of imminent risks or end of dangerzones are positioned in strategic locations dotting the horizons Signs pre-dicting the near future (or prognostic factors) are also prominently posted.Metrics which monitor the progress (follow-up) and evaluate the perfor-mance of the operators (practicing cardiologists) are positioned on largebillboards or LED screens along the track All of these signs are trans-parently posted for the practicing cardiologists without a paternalisticovertone

Instead of arguing for a preferred solution to a particular problem, theauthors and editors provide raw data in the form of abstracts detailingimportant randomized clinical trials; this enables the practicing cardiol-ogist readers to scrutinize the main results and understand their differ-ences By so doing, they are able to intelligently select the best betweenmultiple options There is no need to spoonfeed readers with digestedand regurgitated data The numbers speak for themselves However, theeditors and authors do give practical pearls (which are shortcuts in reallife) in order to cut time and cost.

Information is provided by the writers and editors utilizing short graphs so that readers will be able to store them in their short-term mem-ory and analyze them before storing them in different compartments oftheir long-term memories The strategy is to tailor these messages fortoday’s cardiologists who may be overbooked, impatient, and/or hyper-active

para-To all of our readers: The authors and editors of this book have sharedmany of your trials and tribulations We have experienced the many sleep-less nights We labor every day in the hospital, at the patient’s bedside,like yourself We too have felt the need for the practical advices found

in this book; indeed, that is why we have written them We are, like all

of you, our colleagues, both experienced and beginners, young and old,men and women; there are no divisions of class, age, sex, or race here.This book is not written from an ivory tower perspective – we aim topractice what we preach Although much practical information and sug-gestions are given, we have also written from our subjective experienceand from our hearts After all, there is much drama and many ups anddowns occurring daily on every cardiac floor in every healthcare facilityacross the globe Hopefully, the outcome of our care and treatment willalways be a happy and beneficial one for the patients The bottom line

is that we practice cardiology to the best of our ability in a responsiblemanner that is both cost-effective and time-effective and provides excel-lent patient-centered care We are all equal in our quest of striving for thebest management and clinical success

That is the goal of this handbook To give you, the cardiologist ing car driver), the tools, the data, and the resources that you need tosuccessfully navigate the race to the finishing line

(rac-For the completion of this book, we owe much to our teachers, friends,colleagues, families, staff and patients I (TNN) am indebted to Dr EugeneBraunwald, who wrote the foreword of the first to the third editions, forhis invaluable encouragement, very kind words and advices My deepestappreciation goes to my fellow editors and contributors and to my fam-ily, with the dedicated support of Huang Weitao, NNG CN; my parentsSau N Nguyen (+ 2012) and Hanh T.H Tran, and my family in Irvine CAand La Porte IN, especially Robert Luscomb Jr, Le Cong Dinh JD, L ˆe GiaLong and L ˆe Trung Hung, SGN, VN; Dr Huynh Duong Hung, Webmaster,Riverside CA; Professor Bui Duy Tam, SFO, L ˆe Ho `ang D ´uc To `an, V ˜o Minh,

Vîe.t, Hu`ynh Tro.ng ˆAn, Lˆe Tro.ng H`a, Hu`ynh Thi Thu Tr ´uc, Lˆe Thi Ngo.c

Tr ˆam, Hy Tat An, Ho `ang Qu ́ ̂oc B ao, Truỷ ̂e.n Thîe.n T́̂an Tr´ı T`ai of Tan Tao

University School of Medicine, Long An, Vietnam; special assistance wasgiven by Cindy Macko at the Library of St Mary Medical Center, Hobart,

IN and Yin Rong-Xiu at the Institute of Cardiovascular Disease, CapitalUniversity of Medical Sciences, Beijing, China Above all, we are indebted

to our patients – the purpose of our care, the source of our quests, theinspiration of our daily work To them we give our heartfelt thanks

Evidence-based medicine: The ASCVD risk estimator 4

Critical thinking: Why treat patients with a risk of 7.5%? 5

Additional high-risk markers 5

Intriguing observations: Validation of the new risk calculator for US patients – The REGARDS study 6

High-risk predictors 6

Investigations 7

Symptoms to look for 7

Signs to look for 7

Smart testing 7

Laboratory 8

Intriguing observations: Lipid level changes with season 8

Looking forward: A new biomarker – HDL-C efflux capacity

in the Dallas Heart Study 8

Evidence-based medicine: Statin and ezetimibe

combination – The IMPROVE-IT trial 13

Critical thinking: Lower is better 13

Patients intolerant of statins 14

Evidence-based medicine: The PCSK9 ODYSSEY

ALTERNATIVE trial 14

Adverse effects of statins 15

Management of Complex Cardiovascular Problems, Fourth Edition Edited by

Thach N Nguyen, Dayi Hu, Shao Liang Chen, Moo Hyun Kim and Cindy L Grines

Clinical pearls: Tactics when encountering possible

side-effects with statins 16

Risk of development of diabetes with statin 16

Evidence-based medicine: The MESA study 17

Strong warning: Interactions between clarithromycin and statins 17

Evidence-based medicine: Statin toxicity from macrolide antibiotics 18

Management of patients not on the recommendation list

of the ACC/AHA guidelines 18

Evidence-based medicine: The SHARP trial 19

Clinical pearls: Why did CKD patients respond less with statins? 20

Patients with diabetes 21

Patients with heart failure 21

Patients younger than 40 years 21

Fibrates and statin 23

Statin and niacin 23

Hyperlipidemia – in particular, elevated low-density lipoprotein cholesterol(LDL-C) – is a major risk factor for various forms of cardiovascular (CV)diseases (CVDs) Hyperlipidemia occurs secondary to diet, genetic factors,and/or the presence of other diseases

CHALLENGES

In the treatment of hyperlipidemia, there are four groups of patients whobenefit from statin therapy [1], as listed in Table 1.1 Clinical atheroscle-rotic CVD (ASCVD) includes acute coronary syndromes (ACS) or a history

of myocardial infarction (MI), stable or unstable angina, coronary or otherarterial revascularization, stroke, transient ischemic attack (TIA), or periph-eral arterial disease (PAD) presumed to be of atherosclerotic origin [1]

The first challenge is for all patients who need to be treated to be

iden-tified and treated accordingly No patient should be left behind withouttreatment

The second issue is that up to 20% of patients are intolerant to statintherapy due to side-effects [2] In addition, 5% of patients are resistant to

statins [3] How to treat these patients optimally is the second challenge The third challenge is to optimize the treatment for the patients not

addressed in the American College of Cardiology/American Heart

Associ-ation (ACC/AHA) guidelines The fourth challenge is to select the

effec-tive management for high triglyceride (TG) or low high-density lipoproteincholesterol (HDL-C) levels

1 Patients with clinical atherosclerotic cardiovascular disease.

2 Patients with an LDL-C level of 190 mg/dL or higher without secondary

cause

3 Primary prevention: patients with diabetes, aged 40 to 75 years, or with an

LDL-C level of 70 to 189 mg/dL

4 Primary prevention: patients aged 40 to 75 years with an LDL-C level of

70 to 189 mg/dL and atherosclerotic cardiovascular disease risk estimate of7.5% or higher

STRATEGIC MAPPING

The 2013 ACC/AHA guidelines heralded a radical change in the agement of hyperlipidemia, which was a shift in focus from achievingcertain numerical targets (LDL-C in particular) to ensuring application ofevidence-based dosage of statins shown to improve CV outcomes Thestrategy is to identify the patients with hyperlipidemia through a compre-hensive history and physical examination For any adults aged 20 years

man-or older, questions concerning a high-cholesterol diet, obesity in the ily, and dietary habits should be asked Then, a history of atherosclerosis

fam-of any major vascular bed should be documented, because this tion is very important in classifying patients into a high- or low-risk group.Other medical conditions or the use of drugs causing high cholesterol lev-els should also be investigated After these investigations, blood tests areordered to confirm the diagnosis of hyperlipidemia and its possible etiolo-gies Once the diagnosis is confirmed, education and treatment may bestarted, and follow-up results monitored In the new management strat-egy, the patients should be involved deeply in the discussion of risks andthe decision to start statin therapy This strategy is to keep treatment notonly ‘evidence-based’ but also ‘patient-centered’

informa-HIGH-RISK MARKERS

According the 2013 ACC/AHA guidelines, ASCVD risks can be calculated

by using the new Pooled Cohort Equations for ASCVD risk prediction,developed by the Risk Assessment Work Group [1] It is a tool to helpformulate clinical judgment when there is uncertainty about a patient’srisk

RCT

E V I D E N C E - B A S E D M E D I C I N E

The ASCVD risk estimator This new risk calculator

was derived from four community-based populationstudies that directly measured risk factors in black andwhite people free of known CVD at entry, and then recorded heartattack and stroke rates over at least 10 years Being based on actualobservations from contemporary US community cohorts, this newrisk estimator reflects the high long-term risk of CVD among blackand white Americans [4] This risk calculator may overestimate thescore in Hispanics and East Asians On the other hand, it does notestimate the risk of angioplasty or hospitalization for unstable

angina or TIA, so it underestimates global CV risks The majorcomponents in the risk calculator are listed in Table 1.2 (link for app:www.cardiosource.org/Science-And-Quality/Practice-Guidelines-and-Quality-Standards/2013-Prevention-Guideline-Tools.aspx).

estimator

1 Age (range from 20 to 59 years)

2 Race/ethnicity (white or other or African American)

3 Total cholesterol (mg/dL)

4 HDL-C (mg/dL)

5 LDL-C (mg/dL)

6 Systolic blood pressure (mmHg)

7 Blood pressure treated (yes or no)

8 Smoker (yes or no)

9 Diabetes (yes or no)

10 Has ASCVD (yes or no)

Why treat patients with a risk of 7.5%? According

to the 2013 ACC/AHA guidelines, a risk of 7.5% orhigher is the threshold to be considered for lifestyle andstatin therapy because meta-analyses of clinical trials showed statinsreduced CV events and strokes in individuals with a risk as low as5% to less than 10% While a 7.5% or greater chance of a heartattack or stroke in 10 years does not seem high enough to warrantdrug treatment, it is important to recognize that this translates into

a cumulative risk of fatal or non-fatal heart attack or stroke of about22% over 30 years (7.5% for each of three decades) [1]

Additional high-risk markers

For patients who are not included in the four statin benefit groups givenearlier, if the patients and their physicians believe that their lifetime riskmay be higher than the 10-year calculator estimates, a positive familyhistory or abnormal results of the tests listed in Table 1.3 could guide thepatient to the decision to start statin therapy [1]

Table 1.3 High-risk markers for decision to start statin therapy

1 Family history of premature atherosclerotic cardiovascular disease.

2 Elevated lifetime risk of atherosclerotic cardiovascular disease.

3 LDL-C of 160 mg/dL or greater.

4 High-sensitivity C-reactive protein (hs-CRP) of 2.0 mg/L or greater.

5 Subclinical atherosclerosis: coronary artery calcium (CAC) score of 300 or

greater or ankle brachial index (ABI) of less than 0.9

to 2007 and followed until 2010) were studied with a follow-up of

5 years for atherosclerotic CV events (non-fatal MI, cardiac death,stroke) [5] In total, there were 338 CV events (192 coronary arterydisease [CAD] events, 146 strokes) The observed and predicted5-year CVD incidence per 1000 person-years for participants with a10-year predicted ASCVD risk of less than 5% was 1.9 and 1.9; risk

of 5% to 7.5% was 4.8 and 4.8; risk of 7.5% to 10% was 6.1 and6.9; and risk of 10% or greater was 12.0 and 15.1, respectively(Hosmer–Lemeshow χ2= 19.9, P = 01) [5].

According to this study, among adults for whom statin therapywas initiated based on the ACC/AHA Cohort risk equations, theobserved and predicted 5-year ASCVD (non-fatal MI, cardiac death,stroke) risks were similar, indicating that these risk equations werewell-calibrated in the US population for whom they were designed

to be used and demonstrated moderate to good discrimination [5]

Table 1.4 Predictors determining the poor prognosis

1 Older than 75 years.

2 Multiple major risk factors (especially diabetes).

3 Severe and poorly controlled risk factors (especially continued cigarette

smoking)

4 Chronic kidney disease (CKD) based on proteinuria or reduced glomerular

filtration rate (GFR)

5 Statin intolerance or muscle disorders.

6 Hepatic or renal impairment.

7 Frailty or small body size.

8 South Asian ancestry.

9 History of hemorrhagic stroke.

liver metabolism South Asian patients originating from the Indian continent had higher CV risk

sub-INVESTIGATIONS

Symptoms to look for

Hyperlipidemia does not cause symptoms by itself The symptoms ited are the symptoms of the organ or system affected by atherosclerosis

exhib-Signs to look for

Long-standing hyperlipidemia can lead to corneal arcus, corneal cation, xanthelasma, or tendon xanthomas A clinician should look forclinical manifestations of atherosclerosis, such as decreased peripheralpulses, ischemic ulcers, vascular bruits, and abdominal aortic aneurysm,

opacifi-as well opacifi-as sequelae of a previous cerebrovopacifi-ascular or CV event

Smart testing

The selection of a diagnostic test depends on the level of certainty ofevidence regarding risks and benefits, how these risks and benefits com-pare with potential alternatives, and what the comparative cost or cost-effectiveness of the diagnostic test would be An informed patient shouldask his or her physician this question: Could you tell me the purpose andthe diagnostic accuracy of this test?

Laboratory Fasting lipid profile, fasting glucose, liver enzyme, and roid function tests should be ordered if indicated Calculation of LDL-Clevel using the Friedewald equation is highly robust and reproducible withrespect to accuracy in laboratories that participate in standardization pro-grams It is useful only when TG levels are lower than 400 mg/dL andwhen the calculated LDL level is greater than 70 mg/dL Baseline mea-surement of creatine kinase is reasonable for individuals believed to be

thy-at increased risk for adverse muscle events because of a personal or ily history of statin intolerance or muscle disease, clinical presentation, orconcomitant drug therapy that might increase the risk of myopathy [1]

fam-I N T R fam-I G U fam-I N G O B S E R V A T fam-I O N S : L fam-I P fam-I D L E V E L

C H A N G E S W I T H S E A S O N

In a study of 2.8 million adults that evaluated seasonal lipid trends, itwas found that lipid profiles were unfavorable in the colder monthscompared with the warmer months, closely following the trendsknown about patterns in acute MI and related mortality Totalcholesterol, LDL-C, and non-HDL-C levels were higher in the winterthan in the summer months During the winter months, LDL-C andnon–HDL-C levels were 3.5% and 1.7% higher among women,while TG levels were 2.5% higher in men [6]

Looking forward: A new biomarker – HDL-C efflux capacity in the Dallas Heart Study

It is unclear whether HDL-C concentration plays a causal role inatherosclerosis A more important factor may be the HDL-C efflux capac-ity, the ability of HDL to accept cholesterol from macrophages, which is

a key step in reverse cholesterol transport In a large, multi-ethnic ulation cohort, the HDL-C level, HDL particle concentration, and choles-terol efflux capacity were measured at baseline in 2924 adults free fromCVD The primary endpoint was ASCVD, defined as a first non-fatal MI,non-fatal stroke, or coronary revascularization or death from CV causes.The results showed that baseline HDL-C level was not associated with

pop-CV events in an adjusted analysis (hazard ratio [HR] 1.08, 95% dence interval [CI] 0.59 to 1.99) On the other hand, there was a 67%reduction in CV risk in the highest quartile of cholesterol efflux capac-ity versus the lowest quartile (HR 0.33, 95% CI 0.19 to 0.55) Therefore,cholesterol efflux capacity may become a better biomarker identifying ahigh-risk patient with CVD [7]

The treatment goal of hyperlipidemia is to achieve the maximum tion of the long-term total risk of CV events from atherosclerotic diseases.The patients who were found to benefit most from statin are listed inTable 1.1 [5] Once the patients are risk stratified, they will be assigned

reduc-to receive high- or moderate-intensity statin therapy The high-intensitystatin therapy is expected to decrease the LDL-C level 50% from base-line, while the moderate-intensity statin therapy is expected to decreasethe LDL-C level 30% to 50% from baseline The schema for selection ofpatient and indication for statin therapy is shown in Figure 1.1 [1]

Strategic mapping for therapy

Drug therapy with statins is often considered simultaneously with thedecision to initiate therapeutic lifestyle changes (TLC) including diet andexercise After initiation of statin therapy, a follow-up lipid profile should

be obtained every 3 to 12 months to assess response and medicationcompliance The AHA/ACC guideline provides a weak recommendationthat the statin dose may be decreased if there are two consecutive LDLlevels below 40 mg/dL Once the patient has achieved these treatmentgoal(s), follow-up intervals may be reduced to every 4 to 6 months Theprimary focus of these visits is encouragement of long-term compliancewith therapy and check for side-effects [1]

When discussing the strategy for treatment, a well-informed patientshould ask about treatment options and question the success and com-plications of the proposed treatment The detailed investigative questionsfrom a patient’s perspective are listed below

1 What are the level of certainty of evidence regarding risk and

benefits?

2 How do these risks and benefits compare with potential alternatives?

3 What are the treatment options available?

4 What are the rates of success or failure of these treatment options?

5 What kind of side-effects or complications are to be expected with

these treatment options?

6 What would be the comparative cost or cost-effectiveness of the

treat-ment?

7 What happens if this treatment approach does not work for me?

8 How will you help me balance my treatment with the demand of active

life?

ASCVD Statin Benefit Groups

Clinical ASCVD

Definitions of High- and

Moderate-Intensity Statin Therapy

High

LDL–C ≥190 mg/dL

High-intensity statin

Moderate-intensity statin

Moderate-intensity statin High-intensity statin

High-intensity statin

Heart healthy lifestyle habits are the foundation of ASCVD prevention.

In individuals not receiving cholesterol-lowering durg therapy, recalculate estimated

10-y ASCVD risk every 4-6 y in individuals aged 40-75 y without clinical ASCVD or

diabetes and with LDL–C 70-189 mg/dL

Estimate 10-y ASCVD Risk

Moderate-to-high intensity statin

ASCVD prevention benefit of statin

therapy may be less clear in other groups

≥7.5% estimated 10-y ASCVD risk

and age 40-75 y

Type 1 or 2 Age 40-75 y

with Pooled Cohort Equations*

In selected individuals, consider additional factors

influencing ASCVD risk and potential ASCVD risk

benefits and adverse effects, drug-drug interactions,

and patient preferences for statin treatment

Lifestyle modification Lifestyle changes are the first requisites of thetreatment plan, including adherence to a Heart Healthy Diet, regular exer-cise habits, avoidance of tobacco products, and maintenance of a healthyweight.

The AHA/ACC guideline is promoting a Heart Healthy Diet based ontheir evidence review of different diet/lifestyle-focused studies The HeartHealthy Diet is defined as a diet rich in vegetables, fruits, low-fat dairyproducts, whole grains, poultry, fish, legumes, nuts, and vegetable oil It

limits intake of red meat, sweets, sugar-containing beverages, trans-fat,

and sodium, and it restricts intake of saturated fat to 5% to 6% of totaldaily calories The Heart Healthy Diet emphasizes caloric intake levels con-sistent with achieving and maintaining a healthy weight and has shown

a benefit with respect to lipid profiles and blood [1] Weight reduction

by at least 5% to 10% and weight maintenance are best achieved by acombination of caloric reduction and increased physical activity Lifestylechanges are the most cost-effective means to reduce risk for CAD One

of common questions is about the benefits and risks of diet drinks (DDs)

7 DDs/week and 7.2% who consumed 0 to 3 DDs/month Afteradjustment for CV risk factors, women who consumed 2 DDs/day ormore had a higher risk of CV events (HR 1.3, 95% CI 1.1 to 1.5),CVD mortality (HR 1.5, 95% CI 1.03 to 2.3), and overall mortality(HR 1.3, 95% CI 1.04 to 1.5) compared with the 0 to 3 DDs/monthgroup [8]

Statin therapy

Once the patient is risk stratified, the patient is assigned to receive

high-or intermediate-intensity statin therapy Table 1.5 shows the prihigh-ority rankscomparing one statin with another and their dosages In a meta-analysisincluding five randomized controlled trials comparing rosuvastatin withatorvastatin for the treatment of coronary atherosclerotic plaques,rosuvastatin was shown to reduce total atheroma volume further and

Table 1.5 Priority ranks comparing high-, intermediate-, and low-intensity statins

1 Failure of statin monotherapy to achieve treatment goals.

2 Intolerance, adverse drug interactions with higher-dose statin

monotherapy

3 Complementary benefits toward further reduction in CAD risk.

E V I D E N C E - B A S E D M E D I C I N E

Statin and ezetimibe combination – The

IMPROVE-IT Trial [10] The study included more than

18,000 patients who were stable after ACS (10 days

or less) who had a mean age of 64 years; 25% were female, 36%were receiving prior lipid treatment, and the median LDL-C at ACSevent was 95 mg/dL Patients were randomized to simvastatin

40 mg alone or simvastatin 40 mg plus ezetimibe 10 mg Over aperiod of 7 years, the addition of ezetimibe to simvastatin 40 mgreduced the primary endpoint – a composite of CV death, MI,unstable angina requiring rehospitalization, coronary

revascularization, or stroke The absolute reduction in risk over 7years was 2.0%, with 32.7% in the ezetimibe/simvastatin armexperiencing a primary endpoint compared with 34.7% in the

simvastatin arm (P < 016) The detailed results of IMPROVE-IT are

Lower is better The IMROVE-IT trial supported

the ‘lower is better’ cholesterol hypothesis In this study,the mean LDL-C level among the ACS patients was

95 mg/dL in both treatment arms at baseline LDL-C levels werereduced to 69.9 mg/dL at 1 year with simvastatin 40 mg The

addition of ezetimibe 10 mg to simvastatin further lowered LDL-Clevels to 53.2 mg/dL at 1 year Over 7 years, there remained asignificant difference between the two treatments in the achievedLDL-C levels The incremental benefit was achieved in patientstreated well below the previously recommended threshold of

70 mg/dL These great benefits were driven mainly by a significant

reduction in MI (P < 002) and ischemic stroke (P < 008) in the

simvastatin/ezetimibe group [11]

The results of the IMPROVE-IT trial give room to use other

non-statins to lower LDL-C if a patient is unable to tolerate a statin

or unable to achieve the recommended 50% reduction by theACC/AHA guidelines [1]

Patients intolerant of statins

From 10% to 25% of patients in clinical practice report statin ance How to treat these patients is very difficult, as large, well-controlledRCTs of cholesterol-lowering drugs in statin-intolerant patients are lack-ing The results of the ODYSSEY ALTERNATIVE trial for patients intoler-ant to statin using a proprotein convertase subtilisin/kexin type 9 (PCSK9)inhibitor were presented at the 2014 annual scientific meeting of theAHA, and are shown next

intoler-RCT

E V I D E N C E - B A S E D M E D I C I N E

The PCSK9 ODYSSEY ALTERNATIVE Trial [12] The

ODYSSEY ALTERNATIVE trial enrolled 361 patients withstatin intolerance and an LDL-C level of 70 mg/dL orhigher at very high CV risk or LDL-C level of 100 mg/dL or higherand at high or moderate CV risk Mean baseline LDL was

190 mg/dL The primary endpoint was the percentage change frombaseline in LDL-C at week 24 After a placebo run-in phase for

4 weeks, the patients were randomized to alirocumab 75 or 150 mg

subcutaneously every 2 weeks (n = 126), ezetimibe 10 mg once daily (n = 125), or atorvastatin 20 mg once daily (n = 63) At week 24,

the alirocumab group had shown a much greater reduction in LDLthan the ezetimibe group Mean LDL level was reduced to

154 mg/dL with ezetimibe vs 96 mg/dL in the alirocumab group.The results of LDL reduction of the patients based on intention totreat or based on treatment received are listed in Table 1.8

Table 1.8 Percentage of LDL-C decrease in the ODYSSEY

ALTERNATIVE Trial

Adverse effects of statins

In clinical practice, because the statins are very effective in lowering

LDL-C, the main focus of clinicians in the first few months of follow-up is

to check the side-effects of statin They are rare, but they are real andthey can be controlled or reversed if detected early In the approach

to the patient with possible statin intolerance, readers can follow thealgorithm suggested by the American College of Cardiology and down-load the free apps (https://itunes.apple.com/en/app/statin-intolerance/id985805274)

Data from both primary and secondary prevention RCTs indicate that

no clinically significant liver problems are associated with statin therapy.Elevated hepatic transaminase levels (aspartate aminotransferase [AST]and/or alanine aminotransferase [ALT]) associated with high-intensitystatin therapy occurred in fewer than 1.5% of individuals over 5 years,and elevations associated with low- or moderate-intensity statin ther-apy occurred at rates similar to those seen with placebo or no statintreatment controls [3] Therefore, the US Food and Drug Administration(FDA) no longer requires routine monitoring of liver function tests.However, it is reasonable to measure hepatic function if symptoms sug-gesting hepatotoxicity arise (e.g., unusual fatigue or weakness, loss ofappetite, abdominal pain, dark-colored urine, or yellowing of the skin orsclera) [1]

The risk of a statin causing a life-threatening effect on muscles is lessthan 2:100,000 It is reasonable to measure creatine kinase (CK) levels inindividuals with muscle symptoms, including pain, tenderness, stiffness,cramping, weakness, or generalized fatigue [1]

Finally, the risk of cognitive impairment from statins is based primarily

on individual reports to the FDA [1] A recently published meta-analysisshowed no short-term effects of statins on cognition and a possible long-term protective effect against dementia [1]

C L I N I C A L P E A R L S

Tactics when encountering possible side-effects with statins [1] The AHA/ACC expert opinion

suggests as follows:

1 Obtain a history of prior or current muscle symptoms to establish

a baseline before initiating statin therapy

2 If the ALT or AST level increases above three times the upper limit of

normal, in case of a normal baseline, statin should be discontinuedand a repeat value in 2 weeks to 1 month obtained to ascertain if

it was due to the statin

3 If mild to moderate muscle symptoms develop during statin

ther-apy: Discontinue the statin therapy until the problem can be ated Evaluate the patient for other conditions that might increasethe risk for muscle symptoms (e.g., hypothyroidism, reduced renal

evalu-or hepatic function, rheumatic disevalu-orders such as polymyalgiarheumatica, steroid myopathy, vitamin D deficiency, or primarymuscle diseases, many medications which can interfere with themetabolism of statin)

4 If muscle symptoms resolve, and if no contraindication exists, give

the patient the original or a lower dose of the same statin toestablish a causal relationship between the muscle symptoms andstatin therapy If a causal relationship exists, discontinue the orig-inal statin Once muscle symptoms resolve, use a low dose of adifferent statin Once a low dose of a statin is tolerated, graduallyincrease the dose as tolerated

5 If unexplained severe muscle symptoms or fatigue develop,

promptly discontinue the statin and address the possibility of domyolysis by evaluating CK and creatinine and a urinalysis formyoglobinuria

rhab-6 If, after 2 months without statin treatment, muscle symptoms or

elevated CK levels do not resolve completely, consider other causes

of muscle symptoms If persistent muscle symptoms are mined to arise from a condition unrelated to statin therapy or ifthe predisposing condition has been treated, resume statin ther-apy at the original dose [1]

evidence that statin therapy is associated with an excess risk for dent diabetes (number needed to harm = 100 in primary prevention and

inci-500 to 1000 in secondary prevention) The risk of diabetes occurs almost