CME (July 2006)
Monthly Self-Study Series

Ischemic Heart Disease - A Guide to Clinical Practice
~ An update on the implication of recent clinical trials, with special focus on new medications, life-style management and exercise prescription.

Dr. WONG Bun Lap, Bernard
M.B.,B.S. (HK), M.R.C.P. (UK), F.H.K.C.P. (HK), F.H.K.A.M. (Medicine),
D.M.E. (Ireland), D.C.H. (London), Specialist in Cardiology

If I have seen further, it is by standing on the shoulders of
giants.
~ Sir Isaac Newton (1642-1727)

Introduction

Herrick J.B. presented his landmark paper "Modern Concept of Coronary Thrombosis and Myocardial Infarction" before the Association of American Physicians in 1912. He formulated the important modern concept of coronary thrombosis and myocardial infarction.¹ In the thereafter 93 years, our understanding and management of ischemic heart disease was advanced tremendously. In the 21st century, 75% morbidity and mortality reduction was achieved by life-style modification (stop smoking, diet and exercise), modern medications and cutting-edge revascularization techniques.²

In this article, we will go through the simple definition, patho-physiology, classification, the local and global impact of ischemic heart disease, a short history on the development of modern management, tips on daily clinical practice (interventional, medical and life-style management) according to the up-dated guidelines (ESC & AHA/ACC) and a glance on the recent booming advancement on new medications.

Again, like my previous articles on hypertension and hypercholesterolemia, I sincerely hope that this article is simple, clear and useful to daily clinical practice for all my dearest colleagues.

I am a great believer in luck, and I find the harder I work, the more I have of it.

~ Thomas Jefferson (1743-1826),
the third US President

What is Ischemic Heart Disease?

Definition

Coronary artery disease is most commonly caused by obstructive atherosclerosis of epicardial coronary arteries. This leads to an inadequate perfusion of the myocardium and causes an imbalance between myocardial tissue oxygen supply and demand (myocardial ischemia).

Atherosclerosis - A Life Long Progressive Process

Coronary atherosclerosis is a progressive process. As confirmed by postmortem examination on accident victims, it may start asymptomatically as early as before age 20.

In general, stenosis with <70% of the cross-sectional area is asymptomatic.

In coronary artery with stenosis 70-75% of the crosssectional area, the distal vessels dilate to reduce the vascular resistance and preserve the coronary blood flow. With stenosis more than 75% of the cross-sectional area, normal coronary blood flow cannot be maintained despite of the maximum dilatation of the distal vessels. Physiological changes that increase the oxygen demands such as emotion and physical exertion will result in ST level changes with or without (silent ischemia) angina.

>80% cross-sectional area stenosis, the coronary blood flow cannot meet the myocardial oxygen demand. Resting angina is the result. (Figure 1, Figure 2)

Figure 1

Figure 2

Classification:

Ischemic heart disease can be classified into

• Acute Coronary Syndrome (ACS) and
• Chronic Coronary Artery Disease.

Figure 3

Figure 4

Figure 5

What is Acute Coronary Syndrome (ACS)?
(Figure 1, Figure 2, Figure 3, Figure 4 and figure 5)

Acute coronary syndromes (ACS) included the following:

1. Unstable Angina (UA)
2. Non-ST segment elevating Myocardial Infarction (NSTEMI)
3. ST-Segment Elevating Myocardial Infarction (STEMI)

All of them are caused by a sudden severe imbalance between oxygen supply and demand. Important causes included:

1. Sudden atherosclerotic plaque rupture (caused by extreme emotion, physical exertion, smoking, hypertension, hyperlipidemia...) with superimposed thrombi formation causing severe (UA & NSTEMI) to total coronary obstruction (STEMI)
2. Coronary spasm e.g. Prinzemetal's variant angina
3. Sudden increase in oxygen demand (extreme exertion and emotion)

Usually, one or more the above happens together. (For example: our beloved Majong Games!)

Please refer to Figures 3, 4 and 5 (P.2).

In case of obesity, smoking, exercise lacking, hypertensive, diabetic, hypercholestrolemic and hyperuricemic subjects, the whole process will be faster and cause symptoms or life in patient as young as the age of 14. One of my cases, a 14 year old boy suffered from acute myocardial infarct. Coronary angiogram revealed severe coronary artery disease involving left main, proximal left anterior descending and proximal circumflex coronary arteries. Coronary arterial bypass grafting was performed after medical stabilization. He is now a happy and active school boy again!

In Figures 4 & 5 (P.5), you can easily see that acute coronary syndrome is a continuum of diseases (UA, NSTEMI, STEMI). The degree of the coronary artery obstruction determines the clinical picture and prognosis.

• Mild non-total coronary artery obstruction → No heart muscle damage → No cardiac markers (CKMB, Troponins T/Troponins I) elevation → Unstable Angina (UA) → comparably better morbidity and mortality
• Severe non-total coronary artery obstruction → heart muscle damage → cardiac markers positive (CKMB, Troponins T/Troponins I) → Non-ST elevating myocardial infarction (NSTEMI) → Non-Q or Small Q wave myocardial infarction → morbidity and mortality higher than UA
• Total coronary artery obstruction → Massive heart muscle damage → cardiac markers strongly positive (CKMB, Troponins T/Troponins I) → ST elevating myocardial infarction (STEMI) → Q wave myocardial infarction → Highest morbidity and mortality.

What is Chronic Coronary Artery Disease (CAD)?

Chronic Coronary Artery Disease (CAD) is most commonly caused by chronic obstruction of coronary arteries by atheromatous plaque. The patients usually present with chronic stable angina, congestive heart failure, arrhythmias. With the progress of atherosclerosis, the patients may eventually suffer from Acute Coronary Syndrome (ACS) and Sudden Cardiac Death (SCD).

You can never have true freedom without financial freedom. Freedom may be free, but it has a price.

~ Robert T Kiyosaki in Rich Dad, Poor Dad

What is the Local and Global Impact of Ischemic Heart Disease?

Ischemic heart disease is one of the most common diseases on earth. There are over 13.2 million sufferers in the world. The number is increasing by 1.2 million per year.³

In Hong Kong, heart disease was the second killer since 1960s. In 2003, it killed ⁵,390 Hong Kong citizens.⁶

In a 1995-1996 community survey, the estimated Hong Kong ischemic heart disease prevalence was 2.4%, which were around 164,523 sufferers in our 6,855,125 population.⁷ Compared with the United States prevalence of 6.80%⁸, we should have 466,148 sufferers in projection instead of only 164,523. In my opinion, Hong Kong is a more urbanized eco-system than many parts of the United States. We are having bigger and fatter meals (Canton Style), weaker and lesser exercises (if not totally without) and also stressor and longer working hours (Post-1997-crossover phenomenon). We are probably only seeing the tip of the iceberg.

There were more than 60,000 hospital admissions per year for cardiac diseases (including all public and private hospitals).⁹ Only for admissions under the diagnosis of ischemic heart disease (excluding arrhythmia, congestive heart failure and myocardial infarction, most of them are also caused by ischemic heart disease) there were 17,523 admissions in 2003, that was approximately 48 admissions per day.⁶ Ischemic heart disease is really causing a very heavy economic impact on our society in terms of productivity and medical expenses.

Genius is one percent inspiration, and 99 percent perspiration.

~ Thomas Alva Edison (1847-1931)

The History of Coronary Artery Disease¹⁰

Anatomy of the Coronary Artery

Leonardo Da Vinci (1452-1519), one of the greatest multitalent geniuses in our history produced the earliest anatomical drawings of the heart (Figures 6 & 7).

Figure 6. Self Portrait of Leonardo da Vinci

Figure 7. Reproduction of Leonardo da Vinci's drawing of the heart

Quad.d'Anatomia, published by O.C.L.Vangensten, A Fonahn, and H. Hopstock. Christiana, 1911-1916, Vol. 11, Folio 4 Recto.

His remark on the heart was amazingly accurate: "The heart... is a vessel made of thick muscle, kept alive and nourished by artery and vein as the other muscles are."

Da Vinci's work was then followed by the famous anatomist Andreas Vesalius (1514-1564) in much greater details (Figure 8).

Figure 8. The cardiovascular system

Vesalius, A. and Kalkar, J.S. (1538). Tabulae Anatomica, P.D. Bernardi, Venice.

First Description of Angina Pectoris
William Heberden (1710-1801) was the first doctor recognized and described angina pectoris in details. Actually, he had no idea of any relationship between angina and the heart.

The Invention of Stethoscope
Rene-Theophile-Hyacinthe Laennec (1781-1826) invented the first simple stethoscope in France with one wooden tube and one ear-piece. In 1851 Arthur Leared invented the first binaural stethoscope.

Electrocardiogram
The first commercial ECG model was sold in 1908 by the Cambridge Scientific Instrument Company of England.

The Modern Concept of Coronary Thrombosis and Myocardial Infarction
Herrick J.B. formulated the important modern concept of coronary thrombosis and myocardial infarction.1 He presented his landmark paper "Modern Concept of Coronary Thrombosis and Myocardial Infarction" before the Association of American Physicians in 1912. He was also the first one to employ the use of ECG ST segment changes in the diagnosis of myocardial infarction.

The History of Medicine Development

• Digitalis
  In the year 1785, Dr. William Withering in Birmingham, prepared standardized digitalis preparation from the plant foxglove and described the dose-response relationship and toxicity.
• Aspirin
  Aspirin was used for the treatment for rheumatic fever by Dr. J.J. Maclagen in 1876.
  Recently, her anti-platelet function was discovered and was widely indicated for ischemic heart disease since 1986.11
• Nitroglycerin
  In the year 1840, Constantin Hering, a German physician in Philadelphia, prepared an alcoholic solution of nitroglycerin embedded in a sugar pellet. The pellet dissolved rapidly on the tongue and relieved angina pectoris.
• Diuretics
  In 1952 Diamox (acetazolamide), the first oral diuretics was invented by Roblin and Clapp, from the Lederle Laboratory.
• Beta-blockers
  In the year 1962, Black and Stephenson invented the first beta-blocker, propranolol (Inderal).
• Angiotensin-Convertase Enzyme Inhibitor (ACEI)
  In the year 1977, Ondetti, MA & Cushman D.W. from the Squibb institute encouraged by the earlier findings of Dr. J.H.Laragh, invented the first oral ACEI-Captopril.

The History of Coronary Intervention
Werner Forssmann (1904-1979), a German physician performed the first human cardiac catheterization in 1929. He fed an urinary catheter into his own right heart through an incision into his left antecubital vein. After the catheterization, he walked to the X-ray department. The X-ray firm confirmed that the catheter was really in his heart. One lesson to learn is: after his successful experiment, he was marginalized by his colleagues and fired by his hospital. Anyway, Dr. Werner Forssmann received his Nobel Prize in Physiology or Medicine in 1956.

In 1959, Sones, a paediatric cardiologist, accidentally injected contrast into the coronary artery instead of the left ventricle at the Cleveland Clinic and performed the first coronary angiogram.

Once again, in Cleveland Clinic, Ohio, U.S., Rene Favaloro (1923-2000), an Argentinian surgeon, performed the first Coronary Artery Bypass Grafting (CABG) in the year 1967.

Andreas R. Gruntzig (1939-1985), a German radiologist, performed the first Percutaneous Transluminal Coronary Angioplasty (PTCA) to left anterior descending artery (LAD) in 1977 in Zurich, Switzerland.

First human coronary stent implantation (Self-expanding, wire mesh) was performed in 1986.

First Balloon-expandable stents was performed in 1994.

The best thing about future is that it only comes one day at a time.

~ Abraham Lincoln (1809-1865)

The Current Status of Coronary Revascularization

Coronary revascularization is the operational, invasive technique for the restoration of blood flow to ischemic myocardium. Which included Percutaneous Transluminal Coronary Angioplasty/Stenting (PTCA/S) and Coronary Artery Bypass Grafting (CABG). Coronary revascularization can provide a widely-opened and sustained coronary artery re-opening promptly. With the recent major breakthrough of Drug Eluting Stents (DES), Glycoprotein IIb/IIIa inhibitor, new stenting techniques and distal protective devices, PTCA/S becoming safer, faster and more and more beneficial in terms of morbidity and mortality. A detailed discussion on coronary revascularization is beyond the scope of this article. I will try to say a few words on the recent recommendations and guidelines.

Unstable Angina (UA) & Non-ST-Elevating Myocardial Infarction (NSTEMI) ¹²

With the improvement in both medical and invasive management, the worldwide trend is shifting toward a more invasive approach. Recent clinical trials, including FRagmin, FRISC II, TACTICS-TIMI 18 and RITA^13,14,15 shown a significant benefit of "routine cardiac catheterization with revascularization if feasible" over contemporary medical therapy. Base on those recent positive findings, early invasive strategy (Coronary Angiogram + PTCA/S) is strongly recommended for high risk UA/NSTEMI patients (AHA/ACC 2002 updated).¹²

High Risk Patients:

• ST segment changes
• Positive Troponin
• Recurrent ischemia
• Congestive heart failure
• Cardiogenic shock
• Patients within 6 months of prior PTCA/S or CABG

ST-Elevating Myocardial Infarction (STEMI)
Earlier studies by the last century (PCAT meta-analysis 1989-1996)16 already proved the superiority of Primary angioplasty over thombolytic therapy:

• 30-day mortality 4.4 vs 6.5%, p = 0.02
• 30-day mortality + reinfarction 7.2% vs 11.9%, p<0.001
• 26 more lives were saved per 1,000 patients treated with angioplasty¹⁷

In the last few years of the 20th century and our new millennium, with the

• Recent breakthrough advancement of glycoprotein IIb IIIa inhibitor
• Newer coronary stents technology and
• Increasing institutional experience.

The results of primary angioplasty were amazing. Despite the patient has to be transferred to an invasive centre (where catheterization lab available), death, re-infarction, stroke and hemorrhagic stroke were persistently better than thrombolysis. (PRAGUE-1¹⁸, PRAGUE-2¹⁹, Air-PAMI²⁰, DANAMI-2²¹)

Based on the above findings, the ACC/AHA guidelines for percutaneous coronary intervention 2001 support the use of PCI (Percutaneous Coronary Intervention) for STEMI:

"As an alternative to thrombolytic therapy in patients with AMI and ST segment elevation or new or presumed new left bundle branch block who can undergo angioplasty of the infarct artery <12 hr from the onset of ischemic symptoms or >12 hrsa if symptoms persist, if performed in a timely fashion, by individuals skilled in the procedure and supported by experienced personnel in an appropriate laboratory environment.

In patients who are within 36 hr of an acute ST elevation/ Q wave or new left bundle branch block MI who develop cardiogenic shock, are younger than 75 yr, and revascularization can be performed within 18 hr of the onset of shock by individuals skilled in the procedure and supported by experienced personnel in an appropriate laboratory environment."²²

Chronic Coronary Artery Disease (CAD)
In the arena of chronic stable angina patients, not much randomized data was available. A recent meta-analysis was published in the year 2000, including predominantly patients with single vessel disease, before the era of routine stenting and state-of-the-art adjuvant medical therapy. This meta-analysis shown that patients with angioplasty had better angina control and quality of life compared with medical treatment alone.²³

RITA-2 study, on the other hand including patients with multi-vessels disease revealed no significant difference on morbidity and mortality for the single or two-vessel group. For patients with 3 vessels diseases, an elevated mortality and peri-procedural myocardial infarction over the medical treatment group was observed.²⁴

In view of the above, the ACC/AHA 2002 Guidelines for Revascularization in patients with Stable Angina clearly support percutaneous coronary intervention for:

• "Patients who have not been successfully treated by medical therapy and can undergo revascularization with acceptable risk.
• Patients with single or double vessel disease without significant proximal Left Anterior Decending artery Coronary Artery Disease (LAD CAD) but with a large area of viable myocardium and high risk criteria on non-invasive testing.
• Patients with single or double vessel disease with significant proximal Left Anterior Decending artery Coronary Artery Disease (LAD CAD), who have anatomy suitable for catheter-based therapy and normal LV function and who do not have treated diabetes."²⁵

In simple words, medical therapy is the main therapy for chronic stable coronary artery disease. Percutaneous coronary intervention was preserved for medically refractory patients and patients with diseased vessels supplying large territory of myocardium.

Coronary Arterial By-Pass Grafting (CABG) Vs Percutaneous Coronary Intervention (PCI)
With the recent global rapid advancement in PCI technology, more and more PCI were performed. In Hong Kong, around 10,000 PCI vs 1,000 CABG are carrying out every year.

According to the landmark studies: New York State PTCA Registry²⁶, BARI²⁷ and ARTS²⁸, the followings are still traditionally belonging to our cardiothoracic colleagues:

• Proximal LAD stenosis (>70%)
• 3 vessels disease
• Left ventricular dysfunction.

In the recent 2-3 years, interventional cardiologists are already embarking on all the above three areas and even left main coronary diseases on a day-to-day bases. We are still waiting for more double-blinded control trials on head to head comparisons between CABG & PCI. In the mean time, we are treating patient on an individual basis. Good collaboration between family doctors, cardiologists, cardiothoracic surgeons, patients and family members is the key to success.

Team players are the leaders of tomorrow.

~ Dale Carnegie (1888-1955)

* * * * *

This marked the end of the first part of this Coronary Artery Disease CME article.

In this part I, we have discussed the definitions, the pathophysiology, the classifications, the local & global impact of the disease, the history of cardiology development, and the current indications of percutaneous coronary intervention (PCI) and coronary arterial by-pass grafting (CABG).

In part II (HKMA CME issue August 2006), we will concentrate our discussion on the current, updated medical treatment of coronary artery disease. Thank you very much for your precious time and please kindly keep up with your own healthy diet and exercise regime.

References:

1. Herrick, J.B. Certain clinical features of sudden obstruction of the coronary arteries. Trans. Asso. Am. Phys. 27, 100, 1912.

2. Yusef Salem, ESC Scientific Congress, 2005.

3. Braunwald E, Antman EM, Beasley JW, et al. ACC/AHA guidelines for the management of patients with unstable angina. J Am Coll Cardiol 36:970, 2000.

4. Cannon CP. J Thromb Thrombolysis 1995; 2: 205-218.

5. Link N, Tanner M. Coronary Artery Disease: Part I, Epidemiology and diagnosis. West J. Med 2001; 174:257-6.

6. Statistical Report 2003/2004, Hospital Authority.

7. Janus et al. 1997. Hong Kong cardiovascular risk factor prevalence study 1995-1996. US Census Bureau 2004.

8. US Census Bureau 2004.

9. Census & Statistic Department, Department of Health.

10. The History of Cardiology Louis J. Acierno, 1994, The Parthenon Publishing Group.

11. Hirsh, J., Fuster, V. and Salzman, E. (1986) Antiplatelet agents: the relationship among dose, side effects, and antithrombotic effectiveness. Chest 89 (Suppl.), 4S-10S.

12. Braunwald E, Antman EM, Beasley JW, et al. ACC/AHA guideline update for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction-2002: Summary Artilce: A report of the American College of Cardiology/American Heart Association Task Force on Practical Guidelines (Committee on the Management of Patients with Unstable Angina). Circulation 106: 1893, 2002.

13. Cannon CP, Weintraub WS, Demopoulos LA, et al. Comparison of early invasive and conservative strategies in patients with unstable coronary syndromes treated with the glycoprotein IIb/IIIa inhibitor tirofibran. N Engl J Med 344: 1879, 2001.

14. FRagmin and Fast Revascularisation during Instability in Coronary artery disease Investigators: Invasive compared with non-invasive treatment in unstable coronary artery disease: FRISC II prospective randomized multicentre study. Lancet 354: 708, 1999.

15. Fox KA, Goodman SG, Klein W, et al. Management of Acute coronary syndromes. Variations in practice and outcomes; findings from the Global registry of Acute Coronary Events (GRACE). Eur Heart J 23: 1177, 2002.

16. Weaver WD, Simes RJ, Betriu A et al. Comparison of primary coronary angioplasty and intravenous thrombolytic therapy for acute myocardial infarction: A quantitative review. JAMA 278: 2093, 1997.

17. Grines C. Patel A, Zijlstra F, et al. Primary coronary angioplasty compared with intravenous thrombolytic therapy for acute myocardial infarction: six months follow-up and analysis of individual patient data from randomized trials. Am Heart J 145: 47, 2003.

18. Widimsky P, Groch L, Zelizko M, et al. Multcentre randomized trial comparing transport to primary angioplasty vs immediate thrombolysis vs combined strategy for patients with acute myocardial infarction presenting to a community hospital without a catheterization laboratory. The PRAGUE study. Eur Heart J 21: 823, 2000.

19. Widimsky P, Budesinsky T, Vorac D, et al. Long distance transport for primary angioplasty vs immediate thrombolysis in acute myocardial infarction. Final results of the randomized national multicentre trial-PRAGUE-2. Eur Heart J 24: 94, 2003.

20. Grines CL, Westerhausen DR Jr, Grines LL et al. A randomized trial of transfer for primary angioplasty versus on-site thrombolysis in patients with high-risk myocardial infarction: The Air Primary Angioplasty in Myocardial Infarction study. J Am Coll Cardiol 39: 1713, 2002.

21. Moon JC, Kalra PR, Coats AJ: DANAMI-2: Is primary angioplasty superior to thrombolysis in acute MI when the patient has to be transferred to an invasive centre? Int J Cardiol 85: 199, 2002.

22. Smith SC Jr, Dove JT, Jacobs AK, et al. ACC/AHA guidelines for percutaneous coronary intervention: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to revise the 1993 Guidelines For Percutaneous Transluminal Coronary Angioplasty). J Am Coll Cardiol 37: 2239i, 2001.

23. Bucher HC, Hengstler P, Schindler C, et al. Percutaneous transluminal coronary angioplasty versus medical therapy for treatment of non-acute coronary heart disease: A meta-analysis of randomized control trials. BMJ 321: 73-77, 2000.

24. Henderson RA, Pocock SJ, Clayton TC, et al. Seven-year outcome in the RITA-2 trial: coronary angioplasty vs medical therapy. J Am Coll Cardiol 2003; 42: 1161-1170.

25. Gibbons RJ, Abrams L, Chatterjee K, et al. ACC/AHA 2002 guideline update for the management of patients with chronic stable angina: A report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines.

26. Hannan EL, Racz MJ, MaCallister BD, et al. A comparison of three-year survival after coronary artery by-pass graft surgery and percutaneous transluminal coronary angioplasty. J Am Coll. Cardiol 33: 63-72.

27. The BARI Investigators, 7-Year outcome in the bypass angioplasty revascularization investigation (BARI) by treatment and diabetic status. N Engl J Med 1996; 335: 217-225.

28. van den Brand MJ, Rensing BJ, Morel MA, et al. The effect of completeness of revascularization on event-free survival at 1 year in the ARTS trial. J Am Coll Cardiol 2002; 39: 559-564.