(Circulation. 1998;97:2584-2586.)
© 1998 American Heart Association, Inc.
Testing the Efficacy of Lipid-Lowering Therapy Versus Revascularization: The Time Has Come, or Is It Past Due?
Enas A. Enas, MD, FACC
Medical Director,
CADI Research Foundation,
Woodridge, Ill
To the Editor:
Small, lipid-rich, vulnerable plaques that are angiographically
unimpressive and hemodynamically insignificant are
responsible for most cases of fatal and nonfatal myocardial
infarctions, whereas large, stable plaques that produce
angiographically severe stenoses generally result in stable
angina but rarely result in myocardial infarction. Accordingly,
lipid-optimizing therapy, which stabilizes the vulnerable plaques, may
have a major impact on prevention of myocardial infarction and death,
whereas revascularization procedures, which are
directed at severely stenotic lesions, may not. Therefore, I
was particularly struck by the fascinating conclusion by Forrester and
Shah1 in Circulation:
"Coronary angiography does not identify, and consequently
revascularization therapies do not treat, the
lesions that lead to myocardial infarction." Their conclusions, if
proven correct, will have enormous implications for the management of
coronary artery disease, since coronary angiography has
been the gold standard for its diagnosis and
revascularization its mainstay of treatment for
decades.
The United States is home to only 5% of the world's population but
performs almost 50% of the invasive coronary procedures
worldwide. Of a total of 900 000 coronary angioplasties
performed worldwide in 1994, 404 000 were done in the United States,
at an average cost of $21 700 each.2 Another
501 000 coronary bypass surgeries and 1.1 million
coronary angiograms were done on Americans the same year, each
at an average cost of $44 200 and $10 880, respectively.
Revascularization procedures are done in 58% of
all acute myocardial infarctions and account for about half the cost of
hospital admission for this condition.3
Ironically, examination of regional, national, and international
variations in the use of coronary
revascularization before or after a myocardial
infarction demonstrates no relation between these procedure rates and
subsequent death and reinfarction.4 During a
19-year follow-up of the National Health And Nutrition Examination
Survey (NHANES I), survival rates after the first myocardial infarction
among whites and blacks were similar, although whites had a 6-fold
higher rate of coronary
revascularization.5 Among the
participants of the Global Utilization of Streptokinase and TPA for
Occluded arteries (GUSTO-1)6 and the Survival And
Ventricular Enlargement (SAVE) studies, a 3-fold difference
in the rate of revascularization between Canadian
and American patients was observed with no significant difference in
mortality or reinfarction at 1 year.7 In the
largest comparison, involving 233 702 elderly patients with acute
myocardial infarction, the relative rate of coronary
revascularization was 4.6-fold higher in the United
States than in Canada.8 However, the 1-year
mortality rate was identical (34%). A similar observation was made in
a large international study9 involving 8000
patients in 6 countries who had acute myocardial infarction without ST
elevation. Although the United States and Brazil had a 3-fold higher
rate of in-hospital coronary angioplasties and a 7-fold higher
rate of bypass surgeries than Canada, Australia, Hungary, or Poland,
there was no difference in rate of death or recurrent myocardial
infarction in 6 months. An ominous finding in that
study9 was the 3-fold higher rate of stroke and
major bleeding requiring transfusion in Brazil and the United States,
perhaps due to the aggressive coronary intervention. In that
and many other studies, the use of invasive coronary procedures
was determined by the availability of these procedures and not the
severity or acuity of coronary artery
disease.4 7
The benefits of revascularization are
immediate but decrease steadily with time. After coronary
angioplasty, restenosis occurs in 40% to 60% of vessels,
usually within the first 6 months.10 During a
10-year follow-up of patients with successful coronary
angioplasty, 35% had repeat coronary angioplasty, 31% had
coronary bypass surgery, 14% suffered acute myocardial
infarction, and 19% died.11 Yet, 53% had severe
recurrent/persistent angina. In a 10-year follow-up of 1388
coronary bypass surgery patients, only 18% of the grafts were
patent and nondiseased.12 About half of the
bypass patients will require repeat
revascularization in 10
years.10 In large tertiary-care centers, up to
one third of coronary angioplasty volume and one fourth of the
surgical volume is performed on patients who had previously undergone
coronary bypass procedures. Coronary bypass reoperation
has a 5-fold higher perioperative mortality rate
(6.4%) and considerably lower 10-year survival rate (69%) and
event-free survival rate (41%).13
In sharp contrast to revascularization, the
benefits of lipid-optimizing therapy are slow but steadily increase
over time. Therefore, it may take 7 to 10 years to demonstrate
significant differences in cost and outcome between
revascularization procedures and lipid-lowering
therapy. Surprisingly, a doubling in the rate of death or myocardial
infarction (6.3% versus 3.3%) in 2.7 years was reported with
coronary angioplasty compared with medical therapy in the
second Randomized Intervention Treatment of Angina study
(RITA-2).14 More importantly, the combined risk
of death, myocardial infarction, or coronary bypass surgery was
significantly lower in those randomized to medical therapy (7.1%
versus 12.3%), even though only 12% of this group received
lipid-lowering therapy. The result of the RITA-2 study provided no
evidence to support the widely held belief that successful
coronary angioplasty of a severe coronary
stenosis reduces the risk of myocardial infarction.
Although angioplasty was superior to medical therapy in relieving
angina, the benefit was confined to patients with severe angina or
baseline exercise time of 
9 minutes. The lack of survival benefit,
along with possible excess morbidity and definite excess cost,
associated with revascularization procedures
underscores the need to temper our enthusiasm to invade all
stenotic coronary lesions irrespective of the severity
of angina or exercise intolerance.
Lipid-lowering therapy with "statins" saves money while saving
lives. For example, the cost per year of life gained is $9200 for
coronary bypass surgery in left main disease and $91 500 for
coronary angioplasty for 1-vessel
disease15 compared with $7000 for
simvastatin in secondary prevention in middle-aged men with
average serum cholesterol levels (213 mg/dL). The cost per
year of life gained with simvastatin decreases to $2100
when the indirect cost of lost wages is also
included16 and becomes net cost savings in
younger patients.
It appears that the time for testing the efficacy of lipid-lowering
therapy versus revascularization has not only come
but is also past due.
References
1.
Forrester JS, Shah PK. Lipid-lowering versus
revascularization: an idea whose time (for testing)
has come. Circulation. 1997;96:1360–1362.[Abstract/Free Full Text]
2.
Heart and Stroke Facts. Dallas, Tex:
American Heart Association; 1997.
3.
Nelson EC, Greenfield S, Hays RD, Larson C, Leopold B,
Batalden PB. Comparing outcomes and charges of patients with acute
myocardial infarction in three community hospitals: an approach for
assessing "values." Int J Qual Health Care. 1995;7:95–108.[Abstract/Free Full Text]
4.
Pilot L, Califf RM, Sapp S, Miller DP, Mark DB,
Weaver WD, Gore JM, Armstrong PW, Ohman EM, Topol EJ. Regional
variation across the United States in the management of acute
myocardial infarction: GUSTO-1 Investigators: Global Utilization of
Streptokinase and Tissue Plasminogen Activator
for Occluded Coronary Arteries. N Engl J
Med. 1995;333:565–572.[Abstract/Free Full Text]
5.
Gillum RF, Mussolino ME, Madans JH. Coronary
heart disease incidence and survival in African-American women and men:
the NHANES I Epidemiologic Follow-up Study. Ann Intern Med. 1997;127:111–118.[Abstract/Free Full Text]
6.
Van de Werf F, Topol EJ, Lee KL, Woodlief LH,
Granger CB, Armstrong PW, Barbash GI, Hampton JR, Guerci A, Simes
RJ, Ross AM, Califf RM. Variations in patient management and outcomes
for acute myocardial infarction in the United States and other
countries: results from the GUSTO trial: Global Utilization of
Streptokinase and Tissue Plasminogen Activator
for Occluded Coronary Arteries. JAMA. 1995;273:1586–1591.[Abstract/Free Full Text]
7.
Reeder GS. Identification and management of the
low-risk patient after myocardial infarction. ACC Curr J
Review. May/June 1997:27–31.
8.
Tu JV, Pashos CL, Naylor CD, Chen E, Normand SL,
Newhouse JP, McNeil BJ. Use of cardiac procedures and outcomes in
elderly patients with myocardial infarction in the United States and
Canada. N Engl J Med. 1997;336:1500–1505.[Abstract/Free Full Text]
9.
Yusuf S. Organization to Assess Strategies for
Ischemic Syndromes (OASIS Registry). Presented at the 46th
Annual Scientific Sessions of the American College of
Cardiology; March 16–19, 1997; Anaheim, Calif.
10.
Pearson T, Rapaport E, Criqui M, Furberg C, Fuster V,
Hiratzka L, Little W, Ockene I, Williams G. Optimal risk factor
management in the patient after coronary
revascularization: a statement for
healthcare professionals from an American Heart Association Writing
Group. Circulation. 1994;90:3125–3133.[Free Full Text]
11.
Hasdai D, Bell MR, Grill DE, Berger PB, Garratt KN,
Rihal CS, Hammes LN, Holmes DR Jr. Outcome 
10 years after
successful percutaneous transluminal coronary
angioplasty. Am J Cardiol. 1997;79:1005–1011.[Medline]
[Order article via Infotrieve]
12.
Fitzgibbon GM, Kafka HP, Leach AJ, Keon WJ, Hooper GD,
Burton JR. Coronary bypass graft fate and patient outcome:
angiographic follow-up of 5,065 grafts related to survival and
reoperation in 1,388 patients during 25 years. J Am Coll
Cardiol. 1996;28:616–626.[Abstract]
13.
Brener SJ, Ellis SG. Repeat
revascularization in patients with prior CABG:
angioplasty or surgery? ACC Curr J Review. January/February
1997:42–44.
14.
RITA-2 Trial Participants. Coronary angioplasty
versus medical therapy for angina: the second Randomized Intervention
Treatment of Angina (RITA-2) trial. Lancet. 1997;350:461–468.[Medline]
[Order article via Infotrieve]
15.
Goldman L, Garber AM, Grover SA, Hlatky MA. Cost
effectiveness analysis of assessment and management of risk
factors. J Am Coll Cardiol. 1996;27:1020–1030.[Medline]
[Order article via Infotrieve]
16.
Johannesson M, Jonsson B, Kjekshus J, Olsson AG,
Pedersen TR, Wedel H. Cost-effectiveness of simvastatin
treatment to lower cholesterol levels in patients with
coronary heart disease: Scandinavian Simvastatin
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Response
James S. Forrester, MD, FACC
George Burns and Gracie Allen Professor of
Cardiovascular Research Cedars-Sinai Medical
Center,
Professor of Medicine, UCLA
P. K. Shah, MD, FACC
Director, Division of Cardiology and
Atherosclerosis Research Center Shapell and Webb
Chair in Cardiology,
Cedars-Sinai Medical Center,
Professor of Medicine, UCLA,
Los Angeles, Calif
Angioplasty is superior to medical therapy in 2 respects: it
causes immediate reduction in angina, and it markedly improves the
angiographic image of the coronary artery. Against these
established positive effects are the data in our article and those
assembled by Dr Enas. Of particular importance since the publication of
our manuscript are the just-reported RITA II data, the first large
randomized trial of PTCA versus medical therapy. RITA II is a 2.7-year
follow-up of 1018 coronary disease patients randomized to
either PTCA or medical therapy. As Dr Enas notes, the results favor
medical therapy. On the basis of their results, the investigators
conclude that in patients with stable angina, "greater
symptomatic improvement must be balanced against the small
excess hazard of PTCA."
These data point to what seems to be a paradox: although
more-significant stenoses are more likely to
occlude,1 dilating them does not reduce the rate
of myocardial infarction. In RITA II, the rather striking differences
in outcomes were primarily due to procedure-related complications
during PTCA. Ironically, reduction of PTCA-related complications will
not resolve the paradox, because the unstable lesions that cause
myocardial infarction are not necessarily flow limiting before
occlusion. These less-stenotic lesions outnumber severe
stenoses by 
7:1.
The clinical relevance of this insight is that cardiologists often
perform angioplasty with the belief that by so doing, they will reduce
cardiac events. This belief, although logical, clearly is open to both
hypothetical and data-based skepticism. It now seems likely that the
issue will be joined by initiation of large randomized trials in the
near future.
References
1.
Mock ME, Ringqvist I, Fisher LD, Davis KB,
Chaitman BR, Kouchoukos NT, Kaiser GC, Alderman E, Ryan TJ,
Russell RO Jr, Mullin S, Fray D, Killip T III. Survival of medically
treated patients in the Coronary Artery Surgery Study [CASS]
Registry. Circulation. 1982;66:562–568.[Abstract/Free Full Text]
