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Handbook of

Clinical Pharmacy

Edited by

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F. D. Fernndez-Gins, PharmD
P. Nieto-Guindo, PharmD

001

Handbook of Clinical Pharmacy


Chapter: Pharmacological Management of Stable Angina
Edited by: Fernndez-Gins FD and Nieto-Guindo P
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Pharmacological Management
of Stable Angina
Hctor Mateo-Carrasco1*, Emilio Molina-Cuadrado2, Miguel
Gmez Matarn3 and Russel Parsons1
Pharmacy Department, Northampton General Hospital NHS Trust,
Northampton, UK.
2
Pharmacy Department, Torrecardenas Hospital, Almera, Spain
3
Cardiology Department, Torrecrdenas Hospital, Almera, Spain
1

*Corresponding author: Hctor Mateo-Carrasco, Pharmacy


Department, Cliftonville NN1 5BD, Northampton, United Kingdom,
Tel: 01604 634700; E-mail: Hector.Mateo-Carrasco@ngh.nhs.uk

Abstract
Stable angina occurs when myocardial oxygen demand overwhelms supply, due to an atheroma plaque that occludes blood flow in
the coronary arteries. Prevalence is higher in males, and increases sharply with age. Tobacco, hypertension, hyperlipidemia, diabetes,
obesity, and age have been identified as risk factors for SA. Therapatic goals include: blood pressure <130/70 mm Hg, heart rate 5060 bpm, total cholesterol <200 mg/dL, and glycemic control (glucose <130 mg/dL or HbA1c levels <7%). In addition to lifestyle
modifications (smoking cessation, diet and exercise), the initial treatment for most patients should contain low-dose aspirin, plus a
-blocker, an ACE Inhibitor, and a statin. Non-dihydropyridine calcium channel blockers may have be indicated in COPD or asthma.
Nitroglycerin is a potent veno and vasodilator used for symptomatic relief of acute chest pain, while long-acting forms (transdermal)
and other nitrates can be used as second line treatment or added to -blockers or calcium antagonists. Other agents such as ranolazine,
ivabradine, and nicorandil are generally third-line drugs. Angiotensin-2 receptor blockers are recommended if patients develop ACE
Inhibitor-related dry cough. Other anti-hypertensives (thiazides, loop diuretics, aldosterone antagonists, 1-antagonists, or 2central
agonists) must be considered if high BP despite other anti-hypertensive agents.

Keywords: Stable angina; Angina pectoris; Pharmacotherapy


Pathophysiology
Angina pectoris (also know as stable angina, SA) is a chronic medical syndrome that occurs when cardiac oxygen needs overwhelms
oxygen supply, due to a restricted blood flow caused by atherosclerotic obstructive coronary artery disease. Myocardial ischemia
courses with a typical pattern of oppressive chest pain that may radiate to the left arm, neck, jaw and back, but atypical symptoms
such as gastrointestinal discomfort, breathlessness, or nausea may appear, particularly in older people, women and diabetic patients.
Pain is normally triggered by physical activity or emotional stress and usually subsides after rest or nitroglycerin administration.
Haemodynamically significant atherosclerosis occludes about 70% of the vessel lumen (or at least 50% of the left main coronary artery).
Epidemiologic data suggests that 8% of men and 3% of women aged between 55 and 64 years, and 14% and 8% of those aged 65 and
74, respectively, suffer from SA. Tobacco, diabetes, hypertension, hyperlipidemia, age, previous episodes of angina, sedentarism, obesity,
and stress, have been identified as independent risk factors for stable angina.
Class

Symptoms

I: No symptoms

Angina only develops during strenuous or prolonged physical activity

II: Slight limitation

Angina develops only during vigorous physical activity

III: Moderate limitation

Symptoms appear with everyday living activities

IV: Severe limitation (angina at rest)

Inability to perform any activity without symptoms

Table 1: Functional classification of SA by the Canadian Cardiovascular Society (CCS).

Pharmacotherapy Overview

Lifestyle modifications are the first step and an essential component of the treatment and must comprise weight management,
increased physical activity, moderation of alcohol consumption and smoking cessation, limitation of dietary sodium and highsaturated fat, emphasis on consumption of fresh fruits, vegetables, and annual influenza vaccination. In addition to these measures,
first line pharmacological treatment should include one or two anti-anginal drugs as necessary plus drugs for secondary prevention
of cardiovascular disease. Drugs should be up-titrated to the maximum tolerated dose; treatment response should be reassessed every
2-4 weeks before considering increasing dose, changing or adding new agents. Percutaneous coronary intervention (PCI) and coronary
artery bypass graft (CABG) are normally reserved for poorly controlled patients. If necessary, PCI should be considered over CABG in
diabetic or over 65 patients.

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The initial approach in the management of SA include reducing premature cardiovascular death and nonfatal myocardial infarction,
while maintaining a satisfactory level of activity, functional capacity, and quality of life. The following are generally accepted therapeutic
goals for most patients: blood pressure below 130/70 mm Hg, heart rate between 50-60 bpm, LDL-Cholesterol (LDL-C) <70 mg/dL, and
glycosilated haemoglobin A1C (HBA1C) 53mmol/mol (7%).

03

Antianginal drugs
All patients should be on one of the following treatment options: (a) -blocker, (b) non-dihydropiridine calcium channel blockers,
(c) -blockers plus a dihydropiridine CCB, (d) -blockers plus a dihydropiridine CCB plus nitrates, ranolazine or nicorandil, or (e)
nitrates, ranolazine or nicorandil alone.
-blockers: Mechanism of action (MA): 1 cardiac adrenergic receptor blockade that reduces myocardial contractility, heart rate,
and blood pressure. The reduction of the myocardial demand of oxygen increases tolerance to physical activity. Although there are
no documented differences among the group in terms of efficacy, carvedilol and the long-acting cardio-selective agents (atenolol,
metoprolol and bisoprolol) are the drugs of choice in most cases.
Role in therapeutics (RT): Indicated in all patients with SA unless intolerance (first line). -blockers improve mortality by 20% and
the number of episodes of sudden death by 34%, with higher benefit in high-risk patients. In patients with left-ventricular dysfunction,
bisoprolol, carvedilol, nebivolol, and metoprolol require initiation at very low doses and further up-titration over a period of weeks or
months.
Side effects (SE) and contraindications (CI): Due to 1 action (bradycardia, hypotension, heart failure, fatigue, dizziness,
depression), and due to extra-cardiac 2 receptors (bronchospasm and dyspnea, nausea and diarrhea, cold extremity, and metabolic
disorders). Non-selective -blockers should be used cautiously in asthmatic or COPD with spasticity patients, and are contraindicated
in Prinzmetal angina, severe bradicardia (50 bpm), and pregnancy. Dose titration should be progressive (on a 2-days interval) to avoid
rebound effect.
Drug

Clearance

Selectivy

Dose

Dose adjustment

Atenolol

Renal

25 mg/12h to 200 mg/day

ClCr<35mL/min: 50 mg/day; ClCr<15mL/min: 25mg/day


ClCr<40mL/min: 20mg/day

Bisoprolol

Mixed

5-20 mg/day

Carvedilol

Hepatic

12.5-25 mg/12h (50mg/12h for patients>85kg)

Metoprolol

Hepatic

25-200 mg/12h

Oxprenolol

Hepatic

40-320 mg/day

Propranolol

Hepatic

40-480 mg/day

Table 2: Features of -blockers used in angina.

Calcium channel blockers (CCB): MA: blockade of voltage-dependent Ca2+ channels located in the cardiac muscle and blood
vessels, thus depressing formation and propagation of electric impulses in the myocardium and decreasing coronary vascular resistance.
RT: non-dihydropyridines (verapamil and diltiazem) can be an alternative to -blockers (if the latter are contraindicated). Avoid
CCB in patients with left ventricular dysfunction (they might precipitate or worsen heart failure). Dihydropyridines are indicated in
combination to -blockers when therapeutic goals are not achieved at full doses (bear in mind the risk of hypotension). Not to be used
in monotherapy (particularly rapid-release nifedipine) due to the increased risk of myocardial infarction. CCB have not shown to reduce
long-term mortality; besides, they are first-choice drugs in Prinzmetal angina because of their capability to stabilize vasospasm, and as
antihypertensives.
SE & CI: rebound bradycardia, hypotension and conduction disturbancies, especially when administered in association with
-blockers (caution advised). Non-dihydropyridines are contraindicated in heart failure as well as in patients with impaired ventricular
ejection fraction. Other adverse events may include: headache, ankle edema, ecchymosis, constipation, erectile dysfunction, and gastroesophageal reflux. Verapamil is a strong CYP3A4 inducer.
Verapamil
Diltiazem

No

80/8h

120/8h

60/8h (geriatric patients 60/12h)

360/day

Amlodipine

5/day

10/day

Nifedipine

30/day

120/day

Nicardipine

20/8h

30/8h

Felodipine

Yes

5/day

10/day

Nisoldipine

5/12h

40/day

Table 3: Dose ranges for CCB in stable angina.

Nitroglycerin and other nitrates


MA: They behave as potent smooth muscle relaxing agents, with a predominant venous action that lowers preload and myocardial
demand, while vasodilation increases oxygen supply.

SE and interactions (I): Flushing, headache, and orthostatic hypotension that may be limiting in hypersensitive or severe patients.
Phosphodiesterase V inhibitors are generally contraindicated due to the risk of severe hypotension. The concomitant intake of nitrates
should be avoided after 24 hours of sildenafil and vardenafil intake, and up to 48h after tadalafil.
Nicorandil
MA: Potassium channel activator with a nitrate component that exerts a vasodilation mixed venous/arterial territories.
RT: sSimilar efficacy to other antianginal agents, but it may present some advantages in addition to them (non-approved indication).
In monotherapy, it is considered second or third line after failure of other combinations. Starting dose is 10 mg/12h (5 mg/12h in

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RT: Sublingual or aerosolized administration of nitroglycerin is indicated for the relief of acute chest pain. Moreover, transdermal
nitroglycerin and other nitrates may play a role in the long-term control of chronic symptoms (either as monotherapy or added to
-blockers and/or CCB). They improve exercise tolerance, time until ischemic event, and ST depression during exercise. Transdermal
long-acting formulations can increase duration of effects, but tolerance may develop (leaving a drug-free period of 8h is recommended).
Isosorbide mono and dinitrate possess longer duration of action and may be administered once daily. Nitrates they are not indicated in
monotherapy.

04

migraine-prone patients) and increment up to 30 mg/12h if needed.


SE: Excessive vasodilation (headache, flushing, dizziness). Not indicated in patients with history of myocardial infarction with acute
ventricular failure and low load pressure due to the risk of cardiogenic shock.
Ivabradine
MA: Reduces heart rate through specific action on the sinus node. It lacks effect over conductivity, blood pressure, or contractility.
RT: Its use is limited to poorly or uncontrolled patients with normal sinus rhythm on other combinations. Starting dose is 5 mg/12h
(2.5 mg/12h in the elderly), and further up-titration after 3-4 weeks (maximum dose 7.5 mg/12h). Use with caution in severe renal
impairment.
SE & I: Bradycardia, first degree heart block, ventricular extrasystole, headache, visual disturbancies (phosphenes and blurred
vision), and dizziness. Monitor potassium levels regularly. Potential for interactions due to its hepatic metabolism (avoid concomitant
use with non-diydropyridines, amiodarone, and other CYP450-metabolized drugs).
Ranolazine
MA: Blockade of slow Na+ channels that activates the Na+-Ca2+ transporter, creating a gradient of Ca2+ inside the cell that delays its
relaxation and decreases the distensibility of the ventricle during diastole, which eventually leads to an augment of cardiac activity (does
not affect rate or BP).
RT: Its prolonged use lowers the number of angina episodes and nitroglycerin needs, but has not been demonstrated to affect
mortality. As a result, it is limited to patients with persistent pain yet in one of the other combinations.
SE & I: Hepatically cleared (risk of interactions, in particular when associated to non-dihydropyridines, fluconazole, and
erythromycin). Doses in these cases must not exceed 500 mg/12h, given the potential for nausea and dizziness. Caution is advised when
administered concomitantly with other drugs that may prolong the QT interval, such as quinolones, macrolides, and ondansetron.

Drugs for secondary prevention of cardiovascular disease


Angiotensin Converter Enzyme Inhibitors (ACEI) and Angiotensin-2 Receptor Antagonists (ARB)
MA: Blockade of either the angiotensin-converter enzyme (ACE Inhibitors) or the angiotensin-II receptor (ARB), reducing the
deleterious vasopressor action of the renin-angiotensin-aldosterone system, leading to a reduction of blood pressure. ventricular
remodeling and ventricular hypertrophy of the heart.
RT: ACE inhibitors (or ARB) should be prescribed in all patients with SA who also have hypertension, diabetes, LV systolic
dysfunction (ejection fraction <40%), and/or chronic kidney disease, unless contraindicated.
SE & I: Renal failure, hypotension, hyperkalemia, angioedema, dry cough (main limiting adverse reaction of ACE Inhibitors).
Contraindicated in pregnancy. A clinically relevant interaction with Lithium may precipitate toxicity of the latter.
Captopril

25100

Candesartan

832

Enalapril

540

Eprosartan

400800

Fosinopril

1040

Irbesartan

150300

Lisinopril

1040

Losartan

25100

Perindopril

48

Olmesartan

2040

Quinapril

1080

Telmisartan

2080

Ramipril

2.520

Valsartan

80320

Trandolapril

14
Table 4: Usual dosage range for ACEI and ARB.

Anticoagulant and antiplatelet agents


Antiplatelets are considered disease-modifiers of Angina pectoris and used for primary and for secondary prophylaxis, as well as for
other ischemic events, as in revascularization procedures.
MA: Low-dose ASA (75-162 mg) reduces platelet aggregation via thromboxane A2 inhibition. Thienopyridines (clopidogrel and
prasugrel) and ticagrelor block different sites of the P2Y12 adenosin phosphate receptor in cell membranes.
RT: ASA has demonstrated to cut down the incidence of ischemic events by 33%; hence they are indicated in all the patients with SA.
Thienopyridines are reserved for ASA-related allergy or intolerance. Ticagrelor is a newly introduced irreversible P2Y12 antagonist used
in combination with aspirin for the prevention of thrombotic events in patients with acute coronary syndrome or myocardial infarction
with ST elevation that was associated to lower mortality rates but also a greater rate of non-lethal bleeding compared to clopidogrel.

Immediately prior to PCI, patients should be administered ASA 150-300 mg (or clopidogrel 300-600 mg), plus 75-100 mg thereafter
(or clopidogrel 75 mg). Glycoprotein IIB-IIIA receptor antagonists role (abciximab, eptifibatida and tirofiban) is limited to the course
of a PCI. After stent placement, at least one (if bare metal stent), three (if sirolimus-releasing stent), or six months (if paclitaxel-coated
stent) of dual antiplatelet therapy is recommended, though dual antiplatelet therapy should continue ideally for up to twelve months,
unless hemorrhagic events.
Anticoagulants in Angina pectoris are exclusively used for coronary angioplasty. Current guidelines recommend unfractioned

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SE & I: Aspirin may cause gastric irritation, ulcer, renal impairment, anemia, tinnitus, and hypercalcaemia. Caution advised in
patients on chronic ibuprofen and naproxen, as they may interfere with the antiplatelet activity of aspirin. The risk of bleeding is the
main adverse effect associated to the P2Y12 antagonists. In addition, they may cause gastrointestinal disturbancies, and, less commonly,
headache, dizziness, paraesthesia, and leucopenia.

05

heparin at doses of 60-100 U/kg plus additional boluses if needed. Low molecular weight heparins do not have any safety advantages.
Lipid lowering agents
MA: Statins inhibit the main endogenous cholesterol synthesis pathway, achieving significant reductions of low-density proteins
(LDL) levels and triglycerides (7-40%), and an increase of HDL. They prevent the growth of the atheroma plaque and promote its
regression.
RT: On average, they have shown to reduce mortality about 25% and hence they are indicated in patients with SA whose LDL
cholesterol levels are above 70 mg/dL, as well as in every patient submitted to PCI irrespectively of their cholesterol levels.
SE & I: They are commonly associated to headache, gastrointestinal discomfort, and elevated liver function tests. However, the most
serious adverse event, though relatively infrequent, is the risk for irreversible myositis and rabdomyolysis. They are contraindicated
in severe liver disease and in pregnancy. Due to the increased risk of myopathy associated to simvastatin, its use is contraindicated
in combination with other potent CYP34A inhibitors, such as macrolides (particularly clarithromycin), azol antifungals, protease
inhibitors (ritonavir), fusidic acid, and grapefruit. Additionally, the dose of simvastatin should not exceed 20 mg/day when administered
concomitantly with amlodipine, verapamil, diltiazem, and amiodarone.
Ezetimibe reduces LDL levels by 15 to 20% and is normally used as second choice drug, or added to statins for optimal cholesterol
reduction. Its main side effect is headache. Other agents, such as the anionic interchange resins (colestiramine and colestipol) are
less efficacious and hence reserved to those patients with persistently high cholesterol levels despite full doses of the previous agents.
Fibrates decrease triglycerides blood levels and, to a minor extent, also cholesterol, but they are considered second-line agents. They are
contraindicated in renal failure and are associated to dyspepsia and myopathy.
%LDL Reduction

Ator

Fluva

Lova

Pita

Prava

Rosu

10-20

20 mg

10 mg

10 mg

Simva
5 mg

20-30

40 mg

20 mg

20 mg

10 mg

30-40

10 mg

80 mg

40 mg

2 mg

40 mg

5 mg

20 mg

40-45

20 mg

80 mg

4 mg

80 mg

510 mg

40 mg

46-50

40 mg

1020 mg

50-55

80 mg

20 mg

56-60

40 mg

Table 5: Dose range and equivalence of statins.

Anti-hypertensive drugs
Hypertension is the most important risk factor associated to the onset of cardiovascular diseases. Target BP for most patients should
be established below 130/70 mm Hg. For patients over 55, current guidelines recommend dihydropyridine CCB as first-line agents,
while ACE Inhibitors or ARB (first choice in patients under 55) are considered second-line drugs. Thiazide diuretics, -1 antagonists,
and -2 central agonists must be added to the previous agents if BP target is not achieved despite full doses. Please seek expert advice or
refer to specific hypertension guidelines for detailed guidance on the management of hypertension.

Thiazides: Inhibit distal reabsorption of Na+/Cl-

Loop diuretics: inhibit Na+, K+, Cl-, Ca++ and Mg++


reabsorption in the ascending loop of Henle.
Potassium sparing: Inhibit transport of Na y Cl
+

Aldosterone antagonists: Block aldosterone


receptors

Drug

Dose mg/day

Chlorothiazide

125500

Chlortalidone

12.525

Hydrochlorothiazide

12.550

Indapamide

1.252.5

Furosemide
Torsemide
Bumetanide

Eplerenone

50100

Gynecomastia (lower degree with eplerenone),


hyperkalemia, gastrointestinal disturbances,
somnolence.

2550
Table 3

ACEIs and ARB

Table 4

-2 central agonists: diminish vascular


resilience, renal vascular resilience, and heart
rate.

Hepatic failure, ketoacidosis (diabetic patients),


hyperkalemia

510
50100

-blockers

-1 blockers: Selectively block -1 receptors,


leading to peripheral vasodilation.

Electrolytic alterations, hypovolemia. Associated to


potassium sparing diuretics

Amiloride

CCB

Arrhythmias, sudden death and digitalis intoxication (.


Normally associated to ARA-2, ACEI, -blockers, and
potassium sparing diuretics

2080
2.510

Triamterene

Spironolactone

SE, Interactions & frequent combinations

Associated to thiazides

Table 5
Doxazosin

116

Prazosin

220

Terazosin

120

Clonidine

0.10.8

Methyldopa

2501000

Reserpine

Orthostatic hypotension, hepatic failure, UTIs,


respiratory tract infections

Hypotension, severe renal and hepatic failure, sleep


disorders, coronary disease, myocardial infarction

0.10.25

Table 6: Main features of antihypertensives.

Oral antidiabetic agents


Maintained glucose levels above 130 mg/dL have been associated to a higher risk of cardiovascular events, as well as renal and
ocular impairment. The introduction of oral antidiabetic agents in angina therapy is recommended if glycosilated hemoglobin HbA1c
levels remain over 7% despite lifestyle modifications. Insulinization is necessary in poorly-controlled diabetic individuals with oral
antidiabetics.

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Group & MA

06

Biguanides, second-generation sulfonylureas, repaglinide, and glitazones have similar efficacy, whereas nateglinide and alphaglycosidase inhibitors are less efficacious. Metformin promotes weight loss and must be first line in obese patients. It is contraindicated
in individuals suffering from renal failure. Sulfonylureas should be considered first-line agents if intolerance or contraindication to
metformin exists. Combination of metformin and sulfonylureas or glitazones is preferred over metformin in monotherapy due to the
occurrence of a beneficial gastrointestinal safety profile.
Drug

Mechanism of action

Glybenclamide

Dose

Observations

1.25-20 mg/day
Sulfonylureas: Stimulate insulin secretion

5-40 mg/day
1-8 mg/day

Contraindicated in renal and hepatic impairment.


Risk of hypoglycemia, signs of adrenergic
downregulation, hematologic disorders

Metformin

Biguanides: Inhibit gluconeogenesis and


glucogenolysis, increase insulin muscle uptake.
Delays intestinal absorption.

500 mg/12h to

Caution in hepatic and renal impairment

Pioglitazone

Thiazolidindiones: PPAR receptor activator,


increasing sensitivity to insulin by liver, fat tissue
and skeletal muscle.

Glipizide
Glimepiride

Nateglinide
Repaglinide
Acarbose
Miglitol

Meglitinides: K+ ATP channels in cells,


leading to an increase to Ca2+ that stimulates
insulin secretion.
-glycosidase inhibitors: Delay intestinal
disaccharides digestion

2,550 mg/day

Gastrointestinal disturbances

15-45 mg/day

Contraindicated in bladder cancer. Delayed onset


of action, risk of hypoglycemia. Caution in heart
failure, renal and hepatic impairment.

60-120 mg/8h
0.5-4 mg/8h to 16 mg/day

Contraindicated in severe hepatic failure and


combined to gemfibrozil. Gastrointestinal side
effects, hypoglycemia.

25-100 mg/8h

Hepatic and renal impairment. Gastrointestinal


discomfort.

25-100 mg/8h

Caution in pregnancy, breastfeeding, and renal


impairment, Gastrointestinal alterations.

Table 7: Compared features of oral antidiabetics.

References
1. Foreman RD (1999) Mechanisms of cardiac pain. Annu Rev Physiol 61: 143-167.
2. Benson CJ, Eckert SP, McCleskey EW (1999) Acid-evoked currents in cardiac sensory neurons: A possible mediator of myocardial ischemic
sensation. Circ Res 84: 921-928.
3. Longhurst JC, Tjen-A-Looi SC, Fu LW (2001) Cardiac sympathetic afferent activation provoked by myocardial ischemia and reperfusion. Mechanisms
and reflexes. Ann N Y Acad Sci 940: 74-95.
4. Salpeter SR, Ormiston TM, Salpeter EE (2008) Cardioselective beta-blockers for chronic obstructive pulmonary disease. The Cochrane Library. John
Wiley & Sons, Ltd, Hoboken, NJ, USA.
5. Fu LW, Guo ZL, Longhurst JC (2008) Undiscovered role of endogenous thromboxane A2 in activation of cardiac sympathetic afferents during
ischaemia. J Physiol 586: 3287-3300.
6. Morrow DA, Scirica BM, Karwatowska-Prokopczuk E, Murphy SA, Budaj A, et al. (2007) Effects of ranolazine on recurrent cardiovascular events in
patients with non-ST-elevation acute coronary syndromes: the MERLIN-TIMI 36 randomized trial. JAMA 297: 1775-1783.
7. Wallentin L, Becker RC, Budaj A, Cannon CP, Emanuelsson H, et al. (2009) Ticagrelor versus clopidogrel in patients with acute coronary syndromes.
N Engl J Med 361: 1045-1057.
8. Tonelli M, Lloyd A, Clement F, Conly J, Husereau D, et al. (2011) Efficacy of statins for primary prevention in people at low cardiovascular risk: a
meta-analysis. CMAJ 2011 183: 11891202.
9. Bolen S, Feldman L, Vassy J, Wilson L, Yeh HC, et al. (2007) Systematic review: comparative effectiveness and safety of oral medications for type
2 diabetes mellitus. Ann Intern Med 147: 386-399.
10. [No authors listed] (1998) Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes
(UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group. Lancet 352: 854-865.
11. Salpeter S, Greyber E, Pasternak G, Salpeter E (2006) Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus.
Cochrane Database Syst Rev. 25: 002967.
12. U.S. Department of Health and Human Services, National Institutes of Health, National Heart, Lung, and Blood Institute (2004) The seventh report
of the joint national committee on prevention, detection, evaluation, and treatment of high blood pressure. NIH 04: 5230.
13. Raymond J. Gibbons, Jonathan Abrams, Kanu Chatterjee, Jennifer Daley, Prakash C Deedwania, et al. (2003) ACC/AHA 2002 guideline update for
the management of patients with chronic stable angina. Circulation 107: 149-158.
14. Kushner FG, Hand M, Smith SC Jr, King SB 3rd, Anderson JL, et al. (2009) 2009 focused updates: ACC/AHA guidelines for the management
of patients with ST-elevation myocardial infarction (updating the 2004 guideline and 2007 focused update) and ACC/AHA/SCAI guidelines on
percutaneous coronary intervention (updating the 2005 guideline and 2007 focused update) a report of the American College of Cardiology
Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 54: 2205-2241.
15. O' Flynn N, Timmis A, Henderson R, Rajesh S, Fenu E; Guideline Development Group (2011) Management of stable angina: summary of NICE
guidance. BMJ 343: d4147.
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Task Force on the Management of Stable Angina pectoris of the European Society of Cardiology. Eur Heart J 11: 1341-1381.
17. Budinski D, Arneson V, Hounslow N, Gratsiansky N (2009) Pitavastatin compared with atorvastatin in primary hypercholesterolemia or combined
dyslipemia. Clin Lipidol 4: 3.

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18. Bakhai A, Rigney U, Hollis S, Emmas C (2012) Co-administration of statins with cytochrome P450 3A4 inhibitors in a UK primary care population.
Pharmacoepidemiol Drug Saf 21: 485-493.

07

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