Drug Treatment for Cardiovascular Disease

Outline the cardiovascular disease continuum

Risk factors (High LDL, smoking, obesity, diabetes, male gender, age, FH), endothelial dysfunction, hypertension, stroke atherosclerosis, angina, thrombosis, acute coronary syndromes, heart failure, arrhythmias and sudden cardiac death

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Which medicines are used to treat hypertension? (1)

ACE inhibitors (ramipril), ang II receptor blockers (losartan/candasartan), Ca 2+ channel blockers (amlodipine). Thiazide diuretics (indapamide). Aldosterone antagonists (spironolactone). Renin antagonist (aliskiren). Beta blockers (bisoprolol)

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Which medicines are used to treat hypertension? (2)

Alpha blockers (doxazosin), other vasodilators (sodium nitroprusside, minoxidil)

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Which medicines are used for stable angina?

Beta blockers (bisprolol). Ca 2+ channel blockers (amlodipine). Organic nitrates (glyceral trinitrate). Ivabradine. Ranolazine. ACE inhibitors (ramipril). Statins (atorvastatin). Aspirin

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Which medicines are used to treat unstable angina/MI?

ADP antagonists (ticagrelor). Anti-thrombins (low mwt heparins, fondaprinux). Aspirin. Platelet glycoprotein IIb/IIIa antagonists (tirofiban). Fibrinolytics (alteplase). Statins (atorvastatin). Beta blockers (bisoprolol). ACE inhibitors (ramipril)

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Which medicines are used to treat chronic heart failure? (1)

ACE inhibitors (ramipril). Ang II receptor blockers (losartan/candasartan). Beta blockers (carvedilol). Aldosterone antagonists (spironolactone). Loop diuretics (furosemide). Ivabradine. Cardiac glycoside (digoxin)

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Which medicines are used to treat chronic heart failure? (2)

Ang II receptor blocker/neprilysin inhibitor (sacubitril)

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Which medicines are used for arrhythmias?

Class I (Na + channel blockers). Class II (beta blockers). Class III (K+ channel blockers). Class IV (Ca 2+ channel blockers). Digoxin. Adenosine

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What is the mechanism of action for statins?

Statins block HMG-CoA reductase enzyme to prevent the formation of mevalonic acid and then cholesterol. Prevents the oxidation of LSL. Drives hepatic cells to express HDL. Reduces risk of atherosclerosis and CHD

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Describe features of atorvastatin (1)

Rapid absorption, high first pass metabolism (CYP450), some metabolites active against HMG-CoA reductase. Reaches peak plasma concentration in 1-2 hrs, almost entirely bound to proteins in blood

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Describe features of atorvastatin (2)

T 1/2 of 14 hrs, activity against HMG-CoA reductase lasts 20-30 hrs due to active metabolites. Excreted mainly into bile. Geriatric patients have slower metabolism/greater response/need lower doses

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What are the common side effects of atorvastatin?

GI symptoms non-allergic rhinitis, nose bleeds, muscle pain (could be placebo effects)

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What are the serious side effects of atorvastatin?

Heptotoxicity, rhabdomyolysis (serious muscle damage, dose-dependent) - rare

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Statin use increases the risk of developing what?

Type-2 diabetes (even in these individuals statins reduce the incidence of cardiac events)

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What is hypertension?

An elevation of systolic and/or diastolic pressure to the point where it increases the risk of CVD (~ 140/90 mmHg, guidelines - stages)

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An elevation in systolic pressure is common in which patients?

Elderly patients. Prevalence - ~30% population, ~65% over 60 years of age

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What are the major risks with hypertension?

Stroke, coronary artery disease, congestive heart failure. Causes damage to target organs (heart, retina, kidneys) and the vascular endothelium

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What does the WHO say about hypertension?

Hypertension is the most important preventable cause of premature death in the developed world and thought to be responsible for ~62% of strokes and ~49% of ischaemic heart disease worldwide

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What is the general trend between mean systolic/diastolic BP and age?

For males and females, systolic BP increases gradually with age. Diastolic BP increases then decreases with age (variations within race/ethnicity)

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What do early studies suggest about pharmacological anti-hypertensive treatments?

Pharmacological anti-hypertensive treatments in severe hypertension showed that lowering BP prolonged survival. Therapy accepted by patients. Fall in diastolic BP of 5-6 mmHg reduces risk of stroke by ~ 40% and of CHD by ~29%

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Outline the diagnosis and assessment of hypertension using the NICE guidelines

Measure BP by using sphygmomanometer. If BP < 140/90, not hypertensive, review within 5 years. If BP > 140/90, use ABPM/HBPM (if BP <135/80 - not hypertensive, if BP > 135/80 initiate treatment). If BP > 180/110 refer to specialised/treatment

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Describe features of primary or 'essential' hypertension

No identifiable cause in the patient (majority of cases). Possible causes - polygenetic predisposition (genes unknown) and environmental/lifestyle influences (e.g. high salt diet, stress)

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Give examples of hypertensinogenic factors

Obesity, insulin resistance (primary/secondary)

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Describe features of secondary hypertension

Cause can be identified in the patient (minority of cases) e.g. renal (renal stenosis), endocrine (e.g. primary aldosteronism, contraceptive pill). Identified monogenetic syndromes

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Describe features of hypertension younger people

Hypertension is an abnormality (mechanisms which regulate mean arterial BP fail to work properly). Mean systolic/diastolic BP rise - due to defect in Na+ excretion by kidneys, due to neuro-hormonal dysfunction (midlife HT - more readily treatable)

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Describe features of hypertension in older people

Hypertension is a consequence of ageing - age related arterial stiffening leads to isolated systolic HT. Diastolic BP typically falls so there's only a small increase in mean BP (major cause of HT in aged - less readily treatable)

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How do you calculate BP?

BP = CO x TPR

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Which tool is used to determine the risk of having a stroke or MI within the next 10 years?

QRISK score

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Outline the pathophysiology of primary hypertension (1)

Stimulation of the sympathetic and renin/angiotensin/aldosterone systems leads to increase vascular tone in arteries and increase in TPR. Also, there is an increase in Na/H2O retention which increases blood volume

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Outline the pathophysiology of primary hypertension (2)

Increase in blood volume and increase in vascular tone of veins leads to increase in central venous pressure, increase in cardiac stretch and increased CO2

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Outline the normal feedback control of arterial BP - renal component

Increase in mean BP. Regulatory systems (decrease autonomic NS/RAAS), decrease pressure natriuresis, decrease renal Na+ excretion, decrease blood volume and CO - reverse high mean BP

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Outline the normal feedback control of arterial BP - vascular component

Increase in mean BP. Regulatory systems (decrease autonomic NS/RAAS), blood vessels dilate, decrease arterial resistance and/or increase venous capacitance, decrease TPR and CO, reverse high mean BP

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Drugs used to treat hypertension have mostly which three main effects?

Natriuretic, vasodilating and direct cardiac effect (not all medicines have direct cardiac effect, mainly Ca 2+ channel blockers and beta 1 receptor blockers). Patients use several medicines (combination), no single type works

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Outline the renin-angiotensin-aldosterone system (1)

Low blood volume/Na+/pressure initiates renin release (stimulate SNS) to convert angiotensinogen to ang I. ACE converts ang I to ang II. Ang II causes vasoconstriction, increased ADH release, increase renal H2O reabsorption

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Outline the renin-angiotensin-aldosterone system (2)

Increased aldosterone release and increased renal Na+ reabsorption. These effects results in increased blood volume/Na+/pressure

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Angiotensin II causes what type of dysfunction?

Endothelial dysfunction

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Describe features of ACE inhibitors such as ramipril

Mechanism - block production of ang II and inhibit bradykinin breakdown. Can be combined with Ca 2+ channel blockers. Increase survival post MI and in congestive heart failure

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What are the adverse effects of ACE inhibitors/ramipril (generally well tolerated)?

Chronic dry cough in 5-10% of patients. Hypotension especially on first dose (dizziness). Deterioration of renal function. Hyperkalemia

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What are the important contraindications when using ACE inhibitors?

Pregnancy, renal failure, bilateral renal stenosis, angioedema (swelling of skin, subdermis, mucosa) due to bradykinin

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Describe features of angiotensin receptor blockers/losartan

Mechanism - block ang II receptors. Adverse effects (very well tolerated) - similar to ACE inhibitors but no cough. Similar indications/CI to ACE inhibitors

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What are the side effects of ARBs?

Upper respiratory tract infections, dizziness, back pain

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Describe features of aliskiren (renin inhibitor) (1)

Overcome problem of ACE inhibitors/ARBs (cause increased synthesis of renin which undermines their effectiveness).

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Describe features of aliskiren (renin inhibitor) (2)

ACE inhibitors leads to increase in renin – leads to increased concentrations of ang I/II (ACE enzyme not blocked for long)

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Describe features of aliskiren (renin inhibitor) (3)

Prevent overactivity of system – angiotensin II interaction with receptors inhibits production of renin

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What are the adverse effects of aliskiren?

Angioedema, hyperkalaemia (suppresses aldosterone synthesis), cough and GI symptoms. Adverse effects relatively uncommon, most frequent is headache

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What are the contraindications for aliskiren?

Should not be used in patients with renal impairment or diabetes who are taking ACE-I or ARB

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Describe features of losartan (1)

Rapid/complete absorption, 33% bioavailability due to metabolism. 15% of oral dose converted by first pass metabolism (CYP450) to produce metabolite EXP3174. Competitive ACE-I, peak effect at 1 hr, t1/2 of 2 hrs

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Describe features of losartan (2)

Plasma conc of drug/metabolite raised in cirrhosis but not affect by chronic renal impairment

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Describe features of ramipril (1)

Rapid absorption, mostly converted to ramiprilat in liver, higher activity against ACE compared to ramipril/pro-drug. Competitive ACE-I. Peak effect at 3-6 hrs. T1/2 13-17 hrs. 60% excreted by kidneys

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Describe features of ramipril (2)

Concentration increased in impaired renal function, controls BP for 24 hrs. Ramiprilat 60% protein bound in blood

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All drugs which block renin-angiotensin systems are contraindicated during what?

Pregnancy and breast feeding

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Why are ACE inhibitors and ARBs contraindicated in renal stenosis?

Results in lower glomerular pressure. Ang II constricts efferent > afferent arterioles, restores glomerular capillary pressure and GFR (ACE inhibitor /angiotensin receptor blockers decrease the concentration of Ang II)

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Describe features of aldosterone antagonists (1)

Diuretic effect by inhibiting the effect of aldosterone, reduces Na+ reabsorption in the collecting tubule. CI in patients with hyperkalaemia or renal impairment

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Describe features of aldosterone antagonists (2)

Lower blood volume – need more Na+ excretion/drives H2O excretion, use of diuretic drugs

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Describe features of aldosterone antagonists (3)

Block collecting tubule, more Na+ excreted, more water excreted, fall in blood volume/CO/BP (e.g. spironolactone, eplerenone)

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Describe features of spironolactone (1)

Oral bioavailability 80-90%, improved when taken with food. Rapidly/almost completely metabolised in liver to several active metabolites (e.g. 17 alpha-thiomethylspironolactone), t1/2 14-16 hrs

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Describe features of spironolactone (2)

Main elimination route is kidneys. Onset diuretic action is several days - acts by inhibiting synthesis of proteins/effect delayed until existing proteins are depleted from cells

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What are the side effects of spironolactone? (1)

Relates to effect of aldosterone receptor, includes increased urinary frequency, hyperkalaemia, hyponatraemia

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What are the side effects of spironolactone? (2)

Also blocks androgen (e.g. testosterone) receptor and androgen production. Anti-androgenic side effects include breast tenderness/enlargement and menstrual disturbances in women and gynecomastia (development of woman-like breasts) in men

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Spironolactone is contraindicated during what?

Pregnancy - possibility of reproductive tract abnormalities in the baby

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Outline the mechanism for vascular smooth muscle contraction (1)

NA/ang II binds to receptor. Activation of rho kinase (Ca 2+ sensitisation). Activation of phospholipase C (convert PIP2 to IP3 which activates SR to release Ca 2+). IP3 + DAG activates receptor gated channel (Na influx, membrane depolarisation)

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Outline the mechanism for vascular smooth muscle contraction (2)

(activate voltage gated Ca 2+ channel to cause Ca 2+ influx). Blocking mechanism leads to vasodilation)

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Describe features of calcium channel antagonists - CCBs

Inhibit constriction of arterioles by agonists (e.g. NA, Ang II) by blocking voltage gated Ca 2+ channels, decrease TPR. Reduce arterial stiffness, have diuretic effect

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Give an example of a vascular selective CCB

Amlodipine

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Give examples of non-selective CCBs

Act on vasculature and heart e.g. verapamil and diltiazem

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What are the adverse effects of selective CCBs/amlodipine?

Tachycardia, headache, peripheral oedema, vasodilator effects

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What are the adverse effects of non-selective CCBs?

Bradycardia and negative inotropy

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Calcium channel blockers are contraindicated in what?

Heart failure and pregnancy

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Describe features of amlodipine

Well absorbed orally, bioavailability of 60%, metabolised in liver by CYP450. Elimination t1/2 of 30-50 hrs. 60% eliminated by kidneys (renal impairment does not affect this). Interacts with simvastatin (causes higher plasma conc of simvastatin

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What are the common side effects of amlodipine?

Peripheral oedema, dizziness, palpitations due to effect on BP, fatigue and nausea (CI in pregnancy and breastfeeding)

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What is the mechanism of action for thiazide-like diuretics/indapamide?

Increase salt and water excretion by kidneys to reduce blood volume and CO. TPR also falls via an unknown mechanism

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What are the adverse effects of indapamide?

Hypokalaemia (low plasma K+), increased plasma cholesterol (monitoring). CI in gout

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What was the name of the first thiazide-like diuretic to be tested?

Hydrochlorothiazide (graphs/results)

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Describe features of indapamide

Rapid/complete absorption orally, peak plasma conc after 2 hrs. Extensive hepatic metabolism, heavily protein bound. Biphasic elimination, t1/2 of second component 20hrs. Common side effects - hypokalaemia, weakness, fatigue, numbness of extremities

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What are the drug interactions with indapamide?

Increases the effect of digitalis glycosides, may alter insulin requirements in diabetics, increases lithium toxicity as it decreases renal clearance of lithium

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Give examples of a: non-selective beta blocker, b1 selective blocker, partial agonist (blocks b1 but stimulates b2), b1 and a1 blocker

Propranolol, bisprolol, pindolol and carvedilol

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What is the mechanism of action for beta-adrenergic receptor blockers?

Reduce renin and plasma levels of ang II, leads to diuresis. Block sympathetic stimulation of heart, reduce CO

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What are the adverse effects of beta-adrenergic receptor blockers?

Bronchospasm (used with care in asthma due to b2 receptor block), cardiac depression (useful in heart failure but start with low dose), fatigue

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Describe the clinical use of beta-adrenergic receptor blockers

Proven to reduce mortality after MI and in chronic heart failure. Once 1st line drugs but fallen out of favour as antihypertensive due to results from trial (amlodipine + perindopril improved survival more than atenolol + bendroflumethiazide)

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Describe features of bisoprolol (1)

Bioavailability 80% orally, 20% subject to first pass metabolism. Peak conc after 2-4 hrs, t1/2 elimination 10 hrs. 50% metabolised, drug/metabolites eliminated in kidneys. Plasma t1/2 sensitive to renal impairment (longer in liver cirrhosis)

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Describe features of bisoprolol (2)

Abrupt cessation of treatment can exacerbate coronary artery disease - patients should taper therapy over a week even if they have no symptoms of CHD

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Describe features of bisoprolol (3)

Not completely b1 selective, should not be used in people with bronchospastic conditions (asthma). Can be used with caution if nothing else works

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Describe features of bisoprolol (4)

Should be used cautiously with other drugs that depress myocardial contractibility or AV nodal conduction (e.g. verapamil, digitalis glycosides)

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Describe features of a1 adrenergic blockers/prazosin (1)

Block sympathetically-mediated constriction of arterioles and decrease TPR. ADRs - postural hypotension (first dosing), ankle oedema, drowsiness

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Describe features of a1 adrenergic blockers/prazosin (2)

Indicated in mild heart failure and benign prostatic hyperplasia orthostatic). CI in hypotension and hyperlipidaemia

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Describe features of K channel agonists/minoxidil (1)

Mechanism - opens K+ channels in vascular smooth muscle cells, results in hyperpolarisation, reverse vasoconstrictor-mediated depolarisation and contraction (powerful). Causes tachycardia/oedema (so it's combined with diuretic/beta blocker)

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Describe features of K channel agonists/minoxidil (2)

Used for hypertensive emergency (malignant hypertension) - large/rapid rise in BP associated with target organ (kidneys/heart/eyes) damage and symptoms

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Drug Treatment for Cardiovascular Disease

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