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SECTION 2 Treatment ofcoronary artery disease
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98
Bloodpressure
Even moderate amount of aerobic physical activity signicantly
lowers systolic (−6.9 mmHg) and diastolic blood pressure (BP)
(−4.9mmHg), which is thought to be from reduction in systemic
vascular resistance (7.1%).
Effects ata cellularlevel
• Endothelial dysfunction is known to be an important component
in the development of atherosclerosis. Aseminal study demonstrated regular exercise results in improvement in coronary endothelial function and coronary ow reserve in patients with CAD.
• Nitric oxide activity causes dilation in coronary arteries, resulting
Cardiology Foundation (ACCF) secondary prevention guidelines, it
is a classIrecommendation that patients with acute coronary syndromes or whose status is immediately post coronary artery bypass
graing or percutaneous coronary intervention should be referred
for comprehensive outpatient cardiac rehabilitation either prior to
hospital discharge or at the time of the rst appointment.
Witt etal. showed that CAD patients who participated in structured cardiac rehabilitation programmes, which included supervised exercise as well as counselling and education sessions, had a
marked survival advantage over non- participants. Risk of recurrent myocardial infarction (MI) was also found to be reduced by
28% (relative risk 0.72, 95% CI 0.52– 0.99).
in improved ow haemodynamics through atherosclerotic vessels. Exercise training was found to increase expression and phosphorylation of endothelial nitric oxide synthase, which results in
increased vascular nitric oxide activity.
• Telomeres are chromatin structures that preserve genomic in-
tegrity and stability. Dysfunctional telomeres have been linked
to atherosclerosis in humans. Risk factors such as hypertension,
diabetes, smoking, and psychosocial stresses have been shown to
cause white cell telomere shortening. Studies suggest that physical activity may attenuate changes in endothelium that result
from telomere shortening.
• Endothelial precursor cells are a type of haematopoietic stem cell
that can dierentiate into endothelial cells. Atherosclerosis is associated with a decrease in the pool of circulating endothelial precursor cells. Exercise training in patients with CAD has been
shown to stimulate an increase in the number of circulating endothelial precursor cells.
• Inammation plays a pivotal role in the development and progres-
sion of atherosclerosis. High- sensitivity C- reactive protein has
been found to be an independent predictor of atherothrombotic
events. Milani etal. showed a signicant decrease in high- sensitivity C- reactive protein levels aer 3months of exercise training
as compared to controls.
Where do we stand?
Despite numerous studies supporting the benecial eects of
physical activity, this has not resulted in a more active population.
According to the US Centers for Disease Control and Prevention,
the prevalence of adults who engaged in moderate physical activity
ranged from 33% to 62%, and prevalence of vigorous physical activity ranged from 15% to 42%. Being able to do regular physical activity and having an active lifestyle is not only dependent on
patient participation and motivation but also requires strong recommendations from treating physicians. To increase adherence,
providers can refer to physical activity as an ‘exercise prescription’,
which underscores the fact that exercise is almost as important as
the medicine(s) that are being prescribed for secondary prevention.
Weightreduction
An estimated two- thirds of adults in the United States are overweight (body mass index (BMI) 25.0– 29.9kg/ m) or obese (BMI
30.0– 39.9kg/ m). It is projected that the prevalence of CAD by
2035 will increase by 5– 16%, with more than 100,000 excess cases of
CAD attributable to increased adolescent obesity. Obesity is associated with increased CAD mortality and also causes worsening of
CAD risk factors.
What is thetarget goal?
Recognizing the importance of weight reduction in secondary prevention, the AHA/ ACCF secondary prevention guidelines give a
classIrecommendation to check BMI and/ or waist circumference
at every visit. Based on the current evidence, they recommend
achieving/ maintaining a BMI of between 18.5 and 24.9 kg/ m.
e guidelines also set a target for waist circumference (measured
horizontally at the iliac crest) to be less than 89cm (35inches) for
women and less than 102cm (40inches) for men.
Centralobesity
It has been shown that central obesity poses a signicant risk for
CAD and that waist- to- hip ratio or any surrogate of central obesity
can be a better predictor of CAD than BMI, providing additional
prognostic information above and beyond traditional risk factors.
Ahigher level of risk for CV disease is associated with increase in
waist circumference. For a 1cm increase in waist circumference,
the relative risk of a CV disease event increased by 2%. Waist circumference has gained particular attention since its inclusion in the
diagnostic criteria for metabolic syndrome. It provides additional
prognostic information.
Obesityparadox
Many studies have found an ‘obesity paradox’ in which overweight
and obese individuals with established CAD have a better prognosis
compared with patients who are not overweight or obese. On the
other hand, patients with normal BMI (18.5– 24.9kg/ m) and high
Cardiacrehabilitation
body fat are at high risk for CV disease. is begs the question of
what is being measured and the predictive capabilities of our weight
metrics. It has been established that BMI is an inadequate reec-
Cardiac rehabilitation programmes have been recognized as an
integral component of the comprehensive care of patients with
CAD, largely because it helps improve compliance and adherence
to physical activity. According to the AHA / American College of
tion of central obesity, which is a known risk factor for CV events,
and regardless of initial BMI, weight loss has been associated with
a reduced risk of fatal and non- fatal CV events (hazard ratio 0.62;
P=0.018).
10 Lifestyle management and secondary prevention ofcoronary arterydisease 99
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erefore, although the ‘obesity paradox’ exists, studies have
shown safety and potential long- term benets of weight loss in overweight and obese patients with CAD when taking baseline BMI or
fat percentage into account.
How toachieve thetarget?
According to AHA recommendations, the clinician should con-
motivated to change and smoking cessation advice at this point can
be most eective. e AHA/ ACCF secondary prevention guidelines give a classI recommendation that patients should be asked
about tobacco use at every oce visit and if they are still smoking,
their willingness to quit should be assessed. en the patient should
be assisted by development of a plan for quitting which may include
pharmacotherapy and/ or referral to a tobacco cessation programme.
sistently encourage weight maintenance/ reduction through an appropriate balance of lifestyle physical activity, structured exercise,
caloric intake, and formal behavioural programmes.
In the Look AHEAD trial, greater self- reported physical activity
was the strongest correlate of weight loss aer 1year.
Diet
A healthy diet can have benecial eects in patients with CAD by
multiple biological pathways, including the following: improve-
Smokingcessation
Smoking cessation has been shown to reduce all- cause mortality in
patients with established CAD. A Cochrane review showed that
patients who quit smoking aer MI or cardiac surgery reduced their
risk of death by at least one- third. In the INTERHEART study,
36% of risk for acute MI was accounted for by smoking. Patients who
continue to smoke aer having an MI had a 50% increased risk of
non- fatal or fatal MI.
Unfortunately, despite the known benets, rates of smoking cessation remain low. As shown by the EUROASPIRE III study, the prevalence of smoking in patients with diagnosed CAD was 51.9%.
How does smoking affect CAD?
• Long- term exposure to cigarette smoke results in altered nitric
oxide synthesis and impaired endothelial function, and cessa-
tion was found to be the most signicant factor for improving
endothelial function in patients who previously suered an MI.
• Cigarette smoking is associated with increased risk of vulnerable
plaque rupture.
• Cigarette smoking is the most important independent predictor
of reduced endothelial precursor cells.
• Cigarette smoking can result in dysfunctional thrombotic
mechanism(s) that may result in initiation and/ or propagation of
thrombus formation.
• Cigarette smokers were found to have increased circulating
markers of inammation.
Benefits ofsmokingcessation
Smoking cessation in CAD patients has been estimated to cause a
35% risk reduction in all- cause mortality. In a 30- year follow- up
study of post- coronary artery bypass gra patients, smoking cessation was associated with a 3- year gain in life expectancy, and
also showed a greater eect on reducing mortality than any other
intervention.
How totackle tobaccoabuse
ere are multiple approaches to help patients quit smoking.
Physicians are recommended to assess tobacco use at each visit and
provide counselling regarding smoking cessation. Counselling and
pharmacotherapy combined are more eective than either method
alone. e AHA task force on risk reduction notes that the patient who has been recently hospitalized for a coronary event is very
ment in serum lipids, reduced inammation and oxidative stress,
improved endothelial function, reduced BP, decreased insulin resistance, weight loss, and decreased thrombotic tendency. For
instance, the INTERHEART study showed a 34% reduction in MI
incidence simply with a diet rich in fruits and vegetables.
What constitutes a healthy diet?
Historically, dietary recommendations for secondary prevention
predominantly focused on the role of dietary components; however,
foods are typically consumed in combinations. erefore, in recent
years the focus has shied to provide guidance in terms of dietary
patterns. One exception is dietary sodium. It has been studied as a
single nutrient as little sodium is found naturally in foods and it is
added to foods either during preparation, for preservation, and/ or at
the time of consumption.
e latest AHA/ ACC lifestyle management guideline takes the
approach of suggesting diet patterns instead of focusing on certain
macronutrients. It gives a classIA recommendation to consume a
dietary pattern that:
• Emphasizes intake of vegetables, fruits, and whole grains.
• Includes sh, low- fat dairy products, poultry, legumes, and non-
tropical vegetable oils and nuts.
• Limits intake of sweets, sugar- sweetened beverages, and intake of
red meat.
• Achieves 5– 6% of calories from saturated fatty acids (SFAs).
• In addition for patients with high BP, to lower their sodium intake
preferably to below 2400 g/ day.
ere are many dietary patterns with dierent components but most
of them follow the pattern listed here. Some of these are briey discussed in the following sections.
Mediterranean- stylediet
e Mediterranean diet is high in fruits, vegetables (emphasis on
green vegetables), whole grains (cereal, bread, rice, pasta), and fatty
sh (rich in omega- 3 fatty acid). It is low in red meat and substitutes higher- fat dairy foods with lower- fat or fat- free dairy products by using oils (olive and canola) or nuts (walnuts, almonds, or
hazelnuts).
e Lyon Diet Heart study was a randomized secondary prevention trial which tested if the Mediterranean style diet could reduce
recurrence of CV events aer rst MI. Aer a mean follow- up of
27months, it was found that the risk of cardiac death and non- fatal
MI was signicantly reduced with the intervention diet.
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SECTION 2 Treatment ofcoronary artery disease
Portfolio diet
e portfolio diet mainly focuses on four cholesterol- lowering strategies:viscous bre (8.2 g/ 1000 calories), plant sterols (1 g/ 1000 calories), almonds (1.4 g/ 1000 calories), and soy protein (22.7 g/ 1000
calories) within a reduced- fat diet (<30% of total calories). It is
mainly a vegetarian diet with SFAs comprising less than 7% of total
calories and cholesterol less than 200 mg/ day.
In a controlled 1- month dietary intervention, the portfolio diet
was found to lower LDL cholesterol by 29% in hyperlipidaemic patients compared with an 8% reduction with the step II diet (low SFA
(<7% of total calories) and cholesterol (<200 mg/ day)). However,
when this was studied in a free- living setting over 12months, the
eect on LDL cholesterol reduction was reduced to 12.8%. Less
have shown to be benecial in secondary prevention are reduction
in SFAs, transfatty acids, cholesterol, and total fat, with emphasis on
higher consumption of whole grains, fruits, and vegetables.
Depression
Depression was found to be three times more common in patients
aer having an MI than in the general population, and 15– 20% of
patients hospitalized with acute MI met the criteria for major depression. It has also been shown that depression is associated with
a higher risk of recurrent events 1– 2years aer an MI. erefore,
the AHA recommends screening for depression as a part of secondary prevention of CAD, and if diagnosed, beginning appropriate
treatment.
benet observed in a real- life setting was attributed to lack of dietary
compliance by the authors.
DASHdiet
e Dietary Approaches to Stop Hypertension (DASH) diet consists of a dietary pattern that is rich in fruits and vegetables (eight
to ten servings/ day) and low- fat dairy products (two to three servings/ day). e diet mainly includes whole grains, legumes, sh,
and poultry. It is high in dietary bre and limited in added sugars,
red meat, and fat. Total fat is 27% of total calories, SFA is less than
7% of total calories, and cholesterol is 150 mg/ day. e DASH trial
randomized 459 adults with mildly elevated BP to a Western diet, a
fruits and vegetables diet, or the DASH diet for 8 weeks. It was found
that as compared with the Western diet, the DASH diet lowered systolic BP and diastolic BP by −5.5mmHg and −3mmHg, respectively.
It also lowered total cholesterol (−9.5%), LDL cholesterol (−9.1%),
and HDL cholesterol (9.2%). It was found that in hypertensive patients, the eect was greater (−11.6mmHg SBP). Adding sodium
restriction to the DASH diet was shown to have additional hypotensive eects in the DASH- Sodium trial.
Other populardiets
e majority of other popular diets focus on extreme fat or carbohydrate restriction to achieve weight loss. Among them are the Atkins
diet (very low carbohydrate), Zone diet (macronutrient balance),
and the Ornish diet (very low fat). e ATO Z (Atkins, Traditional,
Ornish, Zone) weight loss study compared the eect of these
three diets and a conventional low- fat (<10% of energy from SFAs),
high- carbohydrate diet on weight loss in 311 postmenopausal
women. Women on the Atkins diet had greater short- term weight
loss (2months, 4.4kg; 6months, 5.6kg) than the women following
other diets. However, aer 12months signicant dierence was only
noted in the Atkins (4.7kg) and Zone diets (1.6kg). At the end of
12months, the Atkins diet showed greater changes in triglyceride
levels (−29.3 mg/ dL, signicantly dierent from Zone), HDL cholesterol (+4.9 mg/ dL, signicantly dierent from the Ornish diet),
systolic BP (−7.7mmHg, signicantly dierent from all other diets),
and diastolic BP (−4.4 mmHg, signicantly dierent from the
Ornish diet).
e major conclusion that we draw from these studies is that for
weight loss, calorie restriction is more important than macronutrient distribution in diet. However, in regard to targeting CV risk
factors (such as elevated BP, lipids, and lipoprotein), modication
of macronutrient intake may be instrumental. Dietary patterns that
Conclusion
Achieving lifestyle modication remains the hardest component of
secondary prevention of CAD. e EUROASPIRE survey showed
that the prevalence of persistent smoking in patients aer having
an MI was 51.9%, moderate physical activity was only reported
by 30.2%, and only half of the patients followed dietary recommendations to lose weight. Studies such as EUROACTION and
GOSPEL have shown that a sustained, professional, comprehensive, and multidisciplinary support between physician and patient
led to better compliance with lifestyle modication and resulted
in signicantly improved control of risk factors and decreased
event rates.
In conclusion, lifestyle modication has similar favourable effect size estimates compared to cardiopreventive drugs. However, it
remains the biggest challenge in secondary prevention as the gap
between current recommendations on lifestyle changes, risk factor
control, and clinical practice still persists.
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11
Optimal medical therapy
for coronary arterydisease
David R. Holmes and Valentin Fuster
Introduction
Cardiovascular disease remains the leading cause of death in the
United States and the developed world and is becoming increasingly more prevalent globally. Indeed, in less developed nations,
cardiovascular disease is now a relatively greater burden than in
more developed economies. It is currently the number one cause of
death worldwide, as a result of two phenomena, namely increased
life expectancy due to successful treatment/ prevention of infectious
disease as well as increased exposure to known risk factors such as
tobacco use, obesity and a sedentary lifestyle.– Cardiovascular disease is typically the result of atherosclerosis which can present as
coronary heart disease, cerebrovascular disease, peripheral arterial
disease, or aortic atherosclerosis. Given the generalized disease process, many individuals develop and present with more than one clinical manifestation. is has important implications for screening;
for example, in patients presenting with clinically evident peripheral
arterial disease, consideration should be given for screening to detect the presence of asymptomatic coronary artery disease.
Revascularization strategies have been the focus of substantial
study and interest from cardiologists and cardiovascular surgeons
alike as well as the patient populations involved. ese strategies
have been shown to improve quality of life, improving symptoms by
decreasing angina, and in selected angiographic and clinical subsets
of patients, to prevent myocardial infarction and improve survival.
ese strategies are recommended and carried out in multiple
subsets of patients with both acute and chronic presentations such
as acute myocardial infarction/ unstable angina or chronic stable angina. Against this background it is essential to remain focused on the
bedrock foundational principle of optimal medical therapy for patients at increased risk for cardiovascular disease, for patient status
post either percutaneous coronary intervention (PCI) or coronary
artery bypass gra (CABG) surgery, as well as for those being treated
conservatively.
Optimal medical therapy consists of lifestyle modication strategies as well as pharmaceutical management.– Emphasis must
be persistently maintained on implementation of these strategies,
through patient education and eorts to optimize compliance.
ere are a number of issues to be addressed including societal
factors such as individual/ family situations, national and regional
economic conditions, as well as political policy. Strategies for prevention of coronary artery disease on a global scale have been promulgated by a number of dierent organizations including both the
World Health Organization and the World Heart Foundation and
include individual as well as societal approaches. Depending on the
clinical setting, approaches can be dened as primary or secondary.
Primary approaches aim at either preventing disease or delaying
the onset of disease and are most benecial when applied early. In
this sphere, there is increased interest in implementing strategies in
childhood, hoping to inculcate lifestyle habits that prevent cardiovascular disease. Secondary prevention is aimed at people who have
clinically apparent disease of any vascular bed— cardiac, peripheral,
cerebrovascular, or aortic. Secondary prevention should also be applied in patients felt to be at high risk for developing coronary artery
disease by virtue of their individual baseline risk factors. Treatment
strategy should be individualized based in part on baseline clinical
characteristics of the patient; for example, the presence of comorbid
conditions such as diabetes or chronic kidney disease, as well as
the presentation during an index event, the time duration from the
index event to presentation, and current symptoms. Patients who
have not had a prior cardiovascular event are considered at high risk
if their predicted risk of such an event is greater than 10% at 10years;
these individuals should also be considered for multiple risk intervention strategies. Primary and secondary prevention share the
common elements of risk factor modication while pharmaceutical
therapeutic regimens may vary between the two groups. In either
case, the intervention should be tailored to the specic clinical setting with emphasis on patient education and enhancing long- term
compliance.
Given the tremendous societal and individual burden of cardiovascular disease, there has been great interest in identication of
the major modiable risk factors and subsequent formulation and
implementation of specic preventive strategies. Substantial global
variability in the incidence of cardiovascular disease has been identied.– Some important clues as to the most important risk factors
involved may shed light on the potential for prevention.
104
16
Numbers smoked per day
Odds ratio (95% CI)
≥41
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SECTION 2 Treatment ofcoronary artery disease
Box 11.1 Potentially modifiable risk factors forretarding or
avoiding cardiovasculardisease
• Smoking
• Dyslipidaemia
• Hypertension
• Diabetes
• Abdominal obesity
• Psychosocial factors
• Daily consumption of fruits and vegetables
• Regular alcohol consumption
• Regular physical activity.
Source data from Yusuf S, Rangarajan K, Teo S, etal. Cardiovascular risk and events in
17 low- , middle- , and high- income countries. N Engl J Med 2014;371:818– 27.
approach in 15,152 cases and 14,820 controls worldwide. ey found
that there were nine risk factors which accounted for the population attributable risk in 90% of men and 94% of women. ree of
these factors were associated with less risk— moderate or strenuous
physical activity dened as at least 4 hours/ week, daily consumption
of fruits or vegetables, and consumption of alcohol three or more
times/ week. e latter factor needs to be interpreted in terms of the
risk:benet ratio of alcohol:moderate consumption is associated
with benet while larger consumption is associated with a marked
increase in risk. Of the adverse factors, there was a striking linear
increase in myocardial infarction depending upon the number of
cigarettes smoked/ day (Fig. 11.1). e authors identied that there
is no safe level of smoking. However, the benet from smoking cessation occurs relatively early.
Yusuf et al. evaluated cardiovascular risk events in 17 low-,
middle- , and high- income countries. In this study, the authors enrolled 146,424 people and assessed their risk using the
INTERHEART risk score. is score includes data on clinical
demographics— age, gender, smoking history, diabetes, hypertension, and a positive family history of heart disease. In addition,
waist- to- hip ratio, psychosocial factors, diet, and physical activity
are also assessed. ey identied that rates of major cardiovascular
events and case fatality rates were lowest in high- income countries
and highest in low- income countries. Such observations underscore the fact that modiable risk factors may be targeted. is is
particularly important for developing strategies to improve outcome in the lower- income countries which predominate globally in
which the incidence of cardiovascular disease is rising signicantly.
A fundamental operating tenant in this space is that the earlier
in life modiable strategies can be instituted, the more eective
they will be in either preventing disease or delaying its onset. In
the INTERHEART study, nine potentially modiable factors were
identied (Box 11.1). e authors found that these risk factors accounted for over 90% of the population attributable risk of a rst
myocardial infarction.
Yusuf etal. also studied the eect of potentially modiable risk
factors associated with myocardial infarction using a case– control
Specific riskfactors
Tobaccocessation
Given the importance of smoking, there has been intense interest
in strategies for prevention of its eects.– Professional societal
guidelines for primary prevention recommend complete abstinence.
e impact of regional initiatives on outcome can be illustrated by
several community programmes. In Olmsted County, Minnesota,
United States, smoke- free ordinances were initiated in all workplaces beginning initially in 2002 (Fig. 11.2). e authors analysed
the outcome of this regional public health policy on cardiovascular
morbidity and mortality. During this time, the incidence of diabetes
mellitus as well as obesity (body mass index (BMI) ≥30kg/ m) increased signicantly, conferring increased potential risk to the entire
population. However, there was a 33% reduction in the incidence
of myocardial infarction (P <0.001) and a 17% reduction in the incidence of sudden cardiac death (P=0.13). e authors concluded
that smoking is a health hazard not only for the individual smoker
but also for people exposed to second- hand smoke and that ‘secondhand smoke exposure should be considered a modiable risk factor
for myocardial infarction’. Primary prevention involves counselling on abstinence including the use of family, school, and healthcare
Fig.11.1 Relationship between numbers of cigarettes smoked per day and odds of myocardial infarction.
Yusuf S, Hawken S, Ounpuu S, etal. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study):case- control study.
Lancet 2004;364:937– 52 with permission from Elsevier.
8
4
2
1
Never
1–5 6–10 11–15 16–20
21–25 26–30 31–40
11 Optimal medical therapy for coronary arterydisease 105
Incidence rate/100,000
MI
SCD
2009
blood pressure (mmHg)
blood pressure (mmHg)
Systolic blood pressure Diastolic blood pressure
Age at risk
IHD mortality, floating
absolute risk, and 95% CI
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200
150
100
50
0
1995
1997 1999 2001 2003
2005 2007 2009 1995 1997 1999 2001 2003
Year
Incidence Smoothing spline
2005 2007
Year
Fig.11.2 Incidence of acute myocardial infarction (MI) and sudden cardiac death (SCD) during implementation of smoke- free environment
ordinances implemented from 2002 onwards.
Source data from Hurt R, Weston S, Ebbert JO, etal. Myocardial infarction and sudden cardiac death in Olmsted county Minnesota, before and after smoke- free workplace
laws. Archives of Internal Medicine 2012; 172:1635– 41 and Centers for Disease Control and Prevention (CDC). Behavioral Risk Factor Surveillance System Survey Data. Atlanta,
GA:Centers for Disease Control and Prevention, US Dept of Health and Human Services; 1999– 2010. http:// www.cdc.gov/ brfss/ technical_ infodata/ surveydata.htm
resources as well as the application of nicotine replacement therapy
as needed. For younger individuals still living at home, eorts also
need to be addressed at parental behaviour to discontinue smoking
in that group of role models.
Smoking cessation is a key element for secondary prevention as
smoking is an independent major risk factor for cardiovascular,
cerebrovascular, and peripheral arterial disease. In multiple studies,
patients who continue to smoke aer coronary revascularization
have increased rates of cardiovascular events including death, myocardial infarction, and need for repeat revascularization., In the
longer- term 5- year follow- up data of the SYNTAX trial which randomized patients with de novo three- vessel or le main coronary
artery disease to either CABG surgery or PCI, continued smoking
had a marked independent deleterious eect; the hazard ratio (HR)
256
64
16
4
of continued smoking on death, myocardial infarction, or stroke was
1.8 (95% condence interval (CI) 1.3– 2.5).
Critchley etal., evaluated the eect of discontinuing smoking
in a meta- analysis of 12,603 patients with established cardiovascular
disease. In this group of patients, which included those with either
prior myocardial infarction or prior revascularization, mortality
was markedly decreased in those patients who had discontinued
smoking (HR 0.64, 95% CI 0.58– 0.71).
Hypertension
A second key modiable risk factor has been hypertension, which
is the focus of increasing attention (Fig. 11.3).– Earlier studies
used 140/ 90mmHg or greater as a target. However, denitions of
‘hypertension’ continue to evolve depending upon whether oce
Age at risk
(year)
80–89
70–79
60–69
50–59
40–49
(year)
80–89
70–79
60–69
50–59
40–49
Fig.11.3 The interrelationships between blood pressure, age, and coronary heart disease. IHD, ischaemic heart disease.
Source data from Hennekens CH, Lopez- Sendon J.Prevention of cardiovascular disease events in those with established disease or at high risk. http:// www.uptodate.com 2017.
Accessed 4 April 2017.
1
120
Usual systolic
160 70 90
Usual diastolic
110
106
4.0
BMI
Relative risk
45
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SECTION 2 Treatment ofcoronary artery disease
visit recordings are used or whether ambulatory or home blood
pressure measurements are used as a standard. Using ambulatory or home blood pressure measures, a 24- hour average of at
least 130/ 80mmHg, a daytime average of at least 135/ 85mmHg,
or a night time average of at least 120/ 70mmHg would be considered hypertensive. Hypertension is extremely common— in the
NHANES survey in the United States, estimates are that approximately 30% of people are hypertensive and in 8– 10% of the population, hypertension is undiagnosed; an even larger percentage
of patients are not treated to goal. Hypertension is oen associated with obesity; as this increases, the rate of hypertension will
also increase. Evaluation of the eect of a specic target has been
controversial, with the description of a J- curve showing improved
cardiovascular events down to specic levels of blood pressure
but then increasing event rates if lower blood pressure levels (e.g.
<120mmHg) are achieved. In general, however, lower achieved
blood pressure control is associated with improved outcomes with
a target of 120– 130/ less than 90mmHg. e control of hypertension is particularly important in those patient groups at highest
risk for cardiovascular disease including those with diabetes and
chronic kidney disease.
Given the worldwide nature of these risk factors and the variability required for implementation of regional programmes,
targeted approaches have been developed. e Global Alliance
for Chronic Diseases (GACD) has focused on the global issues
of hypertension in six dierent countries— Tanzania, Kenya,
Columbia, Malaysia, India, and Canada. e GACD has emphasized the importance of optimizing the appropriateness and
alignment of healthcare in relation to cultural, socioeconomic,
and environmental issues. Tailored programmes for hypertension
begin with recognition of blood pressure as a medical problem, and
include the essential elements of salt reduction or salt substitution,
exercise, and medications when appropriate. e introduction of
a poly pill containing several drugs such as a beta blocker, acetylsalicylic acid (ASA), and a statin can improve patient compliance
and achieve better blood pressure control. Such multifaceted programmes may have a signicant impact on this very important risk
factor for cardiovascular disease.,,
Blood pressure reduction is an essential goal of secondary prevention. ere are a number of approaches that should be initiated early including increased physical activity, weight loss, and
restriction of sodium intake. Maintaining compliance with these
measures is important but dicult. Continued follow- up care and
encouragement as well as enrolment in peer groups such as longerterm cardiac rehabilitation programmes can be very helpful.
e goal of therapy for blood pressure should be 120/ 80 to 130/
80mmHg. is is particularly important in patients with diabetes
mellitus and those with chronic kidney disease. Astepped care
approach for medical therapy is usually required in patients who
have signicant hypertension. In patients with known cardiovascular disease, particularly prior myocardial infarction, guideline
therapy typically includes a beta blocker and either an angiotensinconverting enzyme or angiotensin receptor blocker to reach the
goal of therapy. In addition, depending on le ventricular function, a diuretic may be needed to optimize control. Continued
maintenance of medications for blood pressure control is an important goal of follow- up care in these patients with either known
cardiovascular disease or at high risk for developing it.
Obesity
e relationship between obesity and cardiovascular disease has
been the subject of numerous studies (Fig. 11.4)., is relationship is complex because obesity is associated with hypertension,
sleep apnoea, diabetes mellitus, sedentary lifestyle, and hyperlipidaemia, all of which are independent risk factors for cardiovascular
disease. Aune etal. performed a systemic review and meta- analysis
of BMI and all- cause mortality in 230 cohort studies in 30.3million
participants with 3.74million deaths. ey found that for each 5unit increment in BMI above 25, the relative risk of all- cause mortality was 1.18 (95% CI 1.15– 1.21). Interestingly, low body weight
was also a risk factor for mortality.
Whitlock etal. evaluated case- specic mortality in 57 prospective
studies involving 900,000 patients. BMI was found to be a strong
predictor of overall mortality. On the whole, ischaemic heart disease
accounted for 25% of all deaths of known aetiology. Above an apparent optimal range of 22.5– 25kg/ m, the excess mortality was progressive with increasing BMI and was mainly due to vascular disease.
Strategies for ameliorating obesity are dicult to implement.,,,, ese include dietary approaches which call for increased consumption of vegetables, fruits, and whole grains with
decreased consumption of sweets, sugar- sweetened beverages, and
replacement of red meat with sh, poultry, and legumes. e importance of the comorbidity of physical inactivity has been emphasized.
Hyperlipidaemia
A focus on lipid management is important for both primary and secondary prevention.– Initial emphasis as described includes weight
loss and dietary recommendations as well as exercise. ese should
be instituted and attempts to optimize compliance with them emphasized. For primary prevention, it is important to intervene with lifestyle modications as early as possible, preferably in childhood.
Statins have been the mainstay of therapy and have been documented in multiple large- scale randomized clinical trials and registries to not only reduce composite cardiac events but also mortality.
ey should be used, if tolerated, in all patients with known cardiovascular disease. Seven agents are currently available, two of which—
atorvastatin and rosuvastatin— are considered high intensity. e
3.6
3.2
2.8
2.4
2.0
1.6
1.2
0.8
15
Fig.11.4 BMI and all- cause mortality.
Source data from Aune D, Sen A, Prasad M, etal. BMI and all- cause
mortality:systematic review and non- linear dose- response meta- analysis of 230
cohort studies with 3.74million deaths among 30.3million participants. BMJ 2016;
doi:10.1136/ bmj.i2156
20 25 30
35 40
11 Optimal medical therapy for coronary arterydisease 107
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specic goals of therapy with statin treatment have varied. Some
of these goals have focused on target levels of low- density lipoprotein cholesterol (LDL- C) to achieve lower than 70 mg/ dL. More recent professional societal guidelines have been statin- dose based.
ese latter guidelines have recommended that secondary prevention in high- risk patients be the highest dose of statin; for example,
atorvastatin up to 80 mg/ day or rosuvastatin up to 40 mg/ day as tolerated. Given the pleotropic eects of statins, using a dose goal rather than an arbitrary goal of LDL- C of less than 70 mg/ dL has been
the rationale for this latter approach. In high- risk patients with an
acute coronary syndrome, intensive therapy reduces both all- cause
as well as cardiovascular mortality. In patients with stable angina,
high- intensity statins also signicantly reduce cardiovascular events
but there is heterogeneity in the all- cause mortality.
Statins (Table 11.1) are the mainstay of hypercholesterolaemia
management; as such, the issues of compliance are important. In
general, these drugs are well tolerated. e most common side effects are myalgias which may be clinically signicant and result in
Table11.1 Treatment ofhyperlipidaemia:statins are themainstay oftherapy. Newer combined approaches including PCSK9 inhibitors are
valuable adjuncts
Drug class Dose Major side effects and drug interactions
Statins
Atorvastatin 10– 80 mg/ day Headache; nausea; sleep disturbance; elevations in hepatocellular enzymes and alkaline
Fluvastatin IR:20– 80 mg/ day
XR:80 mg/ day
Lovastatin IR:20– 80 mg/ day
XR:20– 60 mg/ day
Pitavastatin 1– 4 mg/ day
Pravastatin 10– 80 mg/ day
Rosuvastatin 5– 40 mg/ day
Simvastatin 5– 40 mg/ day
PCSK9 inhibitors
Alirocumab 75– 150 mg every 2 weeks Injection site reactions
Evolocumab 140 mg every 2 weeks or 420 mg
Fibric acid derivatives
Fenofibrate Nanocrystal 145 mg/ day
Gemfibrozil 600 mg twice/ day Potentiates warfarin action. Absorption of gemfibrozil diminished by bile acid sequestrants
Nicotinic acid (niacin) IR:1– 6 g/ day Prostaglandin- mediated cutaneous flushing, headache, warm sensation, and pruritus;
Bile acid sequestrants
Cholestyramine 4– 24 g/ day Nausea, bloating, cramping, and constipation; elevations in hepatic transaminases and alkaline
Colestipol 5– 30 g/ day
Colesevelam 3.75 g/ day Similar
Cholesterol absorption inhibitors
Ezetimibe 10 mg/ day Increased transaminases in combination with statins
Neomycin 1 g twice/ day Ototoxicity; nephrotoxicity
Probucol (not available
in USA)
every month; homozygous familial
hypercholesterolaemia: 420 mg every
month to 420 mg every 2 weeks
Micronized 160– 200 mg/ day
XR (Niaspan®):0.5– 2 g/ day
500 mg twice/ day Loose stools; eosinophilia; QT prolongation; angioneurotic oedema
phosphatase. Myositis and rhabdomyolysis, primarily when given with gemfibrozil or cyclosporin;
myositis is also seen with severe renal insufficiency (CrCl <30 mL/ min). Lovastatin, atorvastatin,
rosuvastatin, and simvastatin potentiate effect of warfarin; this interaction is not seen with
pravastatin, fluvastatin, or pitavastatin. Most statins can also affect digoxin metabolism and levels
Skin rash, gastrointestinal (nausea, bloating, cramping) myalgia; lowers blood cyclosporin levels;
potentially nephrotoxic in cyclosporin treated patients. Avoid in patients with CrCl <30 mL/ min
hyperpigmentation (particularly in intertriginous regions); acanthosis nigricans; dry skin; nausea;
vomiting; diarrhoea; and myositis
phosphatase. Impaired absorption of fat- soluble vitamins and co- administered medications
including amiodarone, digoxin, warfarin, thiazides, beta blockers, levothyroxine, others;
interaction can be minimized by taking other medications at least 1 hour before or 4 hours after
bile and sequestrant
CrCl, creatinine clearance; IR, immediate release; XR, extended release.
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