Integrated therapeutics II …Cardiovascular disorders

 Hypertension

 Heart failure

 Coronary heart disease

 Acute coronary syndromes

 Thrombosis

 Stroke

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 I. HYPERTENSION

• Definition: HTN is a persistent, nonphysiologic elevation of arterial BP;

• (1) Having an SBP of 140 mm Hg or greater
• (2) Having a DBP of 90 mm Hg or greater
• (3) Taking antihypertensive medication or
• (4) Having been told at least twice by a physician or other health
professional that one has HTN.

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 I. HYPERTENSION …

 TABLE 1. BP and HTN Classification based…..AHA, ACC, J Am Coll Cardiol 2021;71:e127-248.

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 I. HYPERTENSION … Etiology

 Prevalence  Etiology…Classification
 Most common chronic disease  A. Essential HTN:
 Affects 46% of the population  90% (no identifiable cause)
 Prevalence increases with age  Obesity is a contributor
Major modifiable risk factor for CV  Evaluate Na intake
disease and stroke

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 I. HYPERTENSION …Etiology

B. Secondary HTN- ~ (5%):- secondary to medical conditions or medication

Medical conditions
Primary aldosteronism
Renal disease….CKD…Fluid retention
Cushing syndrome… Increased Cortisol secretion
Thyroid or parathyroid disease…HR

Pheochromocytoma…. Increased E/NE secretion

 Medications (e.g., Cyclosporine, NSAIDs, Sympathomimetics, ESA, COC etc,.)

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 I. HYPERTENSION …Risk Factors

Modifiable risk factors Relatively fixed risk factors

a. Current cigarette smoking • a. CKD
b. Diabetes mellitus b. Family history
c. Dyslipidemia c. Increased age
d. Overweight/obesity d. socioeconomic status
e. Physical inactivity e. Age
f. Unhealthy diet f. Psychosocial stress
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 Pathophysiology
7

 Factors that control BP- contribute to the development of essential

hypertension
 Includes
 Malfunctions in RAAS
 Abnormal neuronal mechanisms

 Defects in peripheral autoregulation

 Defects in vascular endothelial mechanisms

 Nitric
oxide, prostacyclin and bradykinin vs. angiotensin II and
endothelin I
 Disturbances in sodium, calcium, and natriuretic hormone
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8

 The RAAS is the main controller of BP

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 Pathophysiology…
9

 Arterial BP is the pressure in the arterial wall

 SBP
 Represents the peak value
 Achieved during cardiac contraction
 DBP
 Represents the nadir value
 Achieved after contraction when the cardiac chambers are
filling

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 Pathophysiology…
10

 Pulse pressure
 Is the difference between SBP and DBP & a measure of arterial wall tension
 Mean arterial pressure (MAP)
 Theaverage pressure throughout the cardiac cycle of contraction
 Used clinically to represent overall arterial BP, especially in hypertensive
emergency
 MAP = (SBP x 1/3) + (DBP x 2/3) = (2DBP + SBP)/3
 BP = CO x TPR
 CO- major determinant of SBP
 TPR- largely determines DBP

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 Clinical presentation
11

 “silent killer”
 The patient may appear healthy or may have the presence of
additional CV risk factors
 The patient may complain of
 Headache
 Dizziness
 Nervousness
 Flushed face
 Lack of sleep

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 Goal of therapy
12

 To reduce associated morbidity and mortality

 To reduce hypertension-associated complications

 To reduce side effects of antihypertensive medications

 To reduce CV risk

 To maintain goal BP (<130/80 mm Hg)

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 BP Goals to Different Guidelines
13

BP Goal AHA/ACC JNC-7 JNC-8 ASH/ISH ESC/ESH CHEP

Age < 60 <130/80 <140/90 <140/90 <140/90 <140/90 <140/90

Age 60-79 <130/80 <140/90 <150/90 <140/90 <140/90 <140/90

Age 80+ <130/80 <140/90 <150/90 <150/90 <150/90 <150/90

Diabetes <130/80 <130/80 <140/90 <140/90 <140/85 <130/80

CKD <130/80 <130/80 <140/90 <140/90 <130/90 <140/90

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 I. HYPERTENSION …TREATMENT

 Table 2. Non-Pharmacologic -Recommended Lifestyle Modifications

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 Pharmacological therapy
• Drug therapy is indicated if BP is still excessive 3-6 months after
implementation of life style changes.
• Antihypertensive drugs
– Any one of the following classes of drugs could be used as first step
agents:
• Diuretics
• Calcium antagonists
• Angiotensin converting enzyme inhibitors
• Angiotensin II receptor blockers
– Alternative Agents
• Beta blockers
• Alpha blockers
• Centrally acting antihypertensives E.g. Methyl dopa
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• Arterial vasodilators e.g. hydralazine, minoxidil 15
 I. HYPERTENSION …TREATMENT

 Pharmacologic Treatment

 Initiating therapy with a single antihypertensive drug is reasonable in adults

with stage 1 HTN and a BP goal of less than 130/80 mm Hg
 Initiating antihypertensive drug therapy with two first-line agents of different
classes is recommended in adults with stage 2 HTN
First-line agents include:- Thiazide diuretics, CCBs, and ACEIs or ARBs

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 Drug therapy based on compelling indication
17

Compelling
indication

Heart failure Recurrent

with reduced Post MI CAD DM CKD stroke
EF prevention
Standard
drug Diuretic with
therapy BB then add BB then add Diuretic with
ACEI then add ACEI or ARB ACEI or ARB
ACEI or ARB ACEI or ARB ACEI
BB
Add on
drug Aldosterone CCB, Diuretic Diuretic
therapy antagonist or
ARB

CCB, BB

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 I. HYPERTENSION …TREATMENT

 A. Thiazides -(Chlorthalidone, Hydrochlorothiazide, Indapamide,

Metolazone)

 MoA – Act on the kidneys to reduce sodium reabsorption in the distal

convoluted tubule.
By impairing sodium transport in the distal convoluted tubule, natriuresis and
concomitant water loss are induced.

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 I. HYPERTENSION …TREATMENT

 Chlorothalidone …… 6.25–25 mg QD
 Hydrochlorothiazide…… 12.5–50 mg QD
  Na/water excretion…… extracellular fluid volume…  CO…  BP
 Most commonly used
 Proved to be effective in reducing HTN associated target organ damage
 Most useful in the elderly but not effective in patients with renal failure
(GFR of <30 mL/min/1.73 m2)
 In such case, use loop diuretics instead
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 I. HYPERTENSION …TREATMENT

 A. Thiazides… Important ADRs

 Electrolyte abnormalities (hypokalemia, hyponatremia, hypomagnesaemia)
Hyperuricemia…Worsen Gout

Dosing and monitoring

 Ineffective for patients with a GFR less than 30 mL/minute/1.73 m2
 Monitor SrCr, Na, K, and Mg 7–10 days after initiation or titration.
 Patients taking metolazone will need to be more closely monitored because of
the enhanced diuretic effect, particularly if used with loop diuretics
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 I. HYPERTENSION …TREATMENT

 A. Thiazides…
 Can worsen gout by increasing serum uric acid
 Not recommended for patients with a CrCl <30 mL/minute because of
reduced efficacy.
 Greater risk of developing DM than with ACE inhibitor, ARB, and CCB; use
caution in patients at high risk of DM (e.g., family history, obesity).
 Can assist in the management of osteoporosis by preventing urine calcium
loss.
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 I. HYPERTENSION …TREATMENT

 B. Loops (bumetanide, furosemide, torsemide)

MoA – Act by reversibly binding to the Na, K, Cl cotransport mechanism
on the ascending loop of Henle, thereby inhibiting the active
reabsorption of these ions
Clinical use: HTN management for patients with HF and CKD, using
scheduled twice-daily dosing
 Inhibit reabsorption of Na/cl/k cotransport…..20-25%

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 I. HYPERTENSION …TREATMENT
 B. Loops (bumetanide, furosemide, torsemide)…

Important ADRs
• Electrolyte abnormalities (hypokalemia, hyponatremia, hypomagnesemia)

• Dehydration/hypovolemia

 Dosing and monitoring: SCr, Na, K, and magnesium 7–10 days after initiation or titration.
Approximate dose equivalence (oral)
• Furosemide 40 mg

• Bumetanide 1 mg
• Torsemide 10–20 mg
• Ethacrynic acid 25–50 mg (may be useful for patients with allergic reactions to other loop
diuretics caused by sulfa moiety)
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 I. HYPERTENSION …TREATMENT

 C. K-sparking (amiloride, triamterene)

 MoA – Block the epithelial Na channel on the lumen side of the kidney collecting
tubule.
Na channel blockers directly inhibit Na entry into the Na channels.
Clinical use: Typically used in combination with thiazide-type diuretic for K balance
Contraindications
• Anuria
• Hyperkalemia
• Severe renal or hepatic disease

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 I. HYPERTENSION …TREATMENT

 C. K-sparking (amiloride, triamterene)…

 Important ADR – Hyperkalemia

Dosing and monitoring
• Avoid in patients with a CrCl of less than 10 mL/minute/1.73 m2.
• Monitor SCr and K for 7–10 days after initiation or titration.

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 I. HYPERTENSION …TREATMENT

 D. Aldosterone antagonists (eplerenone, spironolactone)

 MoA – Inhibit the effect of aldosterone by competing for intracellular

aldosterone receptors in the cortical collecting duct.
This decreases Na and water reabsorption while decreasing K secretion.

Clinical use
Resistant HTN
Patients with HTN and HFrEF or HFpEF.
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 I. HYPERTENSION …TREATMENT

 D. Aldosterone antagonists (eplerenone, spironolactone)…

 Important ADRs
 Hyperkalemia
 Gynecomastia and mastodynia with spironolactone
Contraindications
 Anuria
 Acute renal insufficiency – Avoid if CrCl is 30 mL/min or less.
 Hyperkalemia – Avoid if K is 5.0 mEq/L or more.
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 I. HYPERTENSION …TREATMENT

 D. Aldosterone antagonists (eplerenone, spironolactone)

 Dosing and monitoring:

 Monitor SCr and K monthly for the first 2 months of therapy and
after dose titrations when used solely for HTN indication.
 When used with concomitant HFrEF, monitor SCr and K on day 3,
day 7, and monthly for the first 3 months after initiation or titration
and periodically thereafter.
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 I. HYPERTENSION …TREATMENT

 Used in combination with thiazide or loop diuretics

 Counteract the potassium depleting properties of other diuretic agents
 Includes
 Amloride …… 5-10 mg QD or BID
 Triamterine …… 50-100 mg QD
 Spironolactone …… 25-50 mg QD or BID
 Eplerenone …… 50 -100 mg QD or BID

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 I. HYPERTENSION …TREATMENT
 E. Calcium channel blockers
 Dihydropyridine CCBs ….Amlodipine, Felodipine, Nifedipine
Useful for isolated systolic hypertension or use in African American patients
 Nondihydropyridine CCBs….Diltiazem, verapamil
(a) hypertensive patients with comorbid conditions which would benefit from HR
reduction (e.g., atrial fibrillation, stable angina)
(b) Contraindicated in heart block
(c) Potential drug interactions due to CYP450 inhibition

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 Calcium Channel Blockers…Dosing
31

 Dihydropyridine CCBs
 Amlodipine …… 2.5- 10 mg QD
 Nifedipine …… 30 -90 mg QD
 Felodipine …… 5-20 mg QD
 Isradipine …… 5-10 mg BID
 Non-dihydropyridine CCBs
 Diltiazem (SR)…… 180-360 mg BID
 Verapamil (SR)…… 180-480 mg QD or BID
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 I. HYPERTENSION …TREATMENT

 E. Calcium channel blockers…Clinical use

• Option as first-line therapy for most patients with HTN

• Potent blood pressure lowering…..Africans

• Improve anginal symptoms

 Important ADRs

• Peripheral edema

• Orthostatic hypotension

• Reflex tachycardia….. (Nifedipine)

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 I. HYPERTENSION …TREATMENT

F. ACE inhibitors…Clinical use

(A) Indications to use ACEIs first line
• Non–African American patients

• Albuminuria – Reduce the progression of nephropathy and diabetic and nondiabetic

albuminuria
• HF or left ventricular dysfunction with a left ventricular EF of 40% or less
• CAD, post-MI
• Recurrent stroke prevention – when used in combination with thiazide-type diuretics

(B) Recommended as add-on therapy for African American patients

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 ACE Inhibitors….Dosing
34

 Benazepril …… 10-40 mg, QD or BID

 Captopril …… 12.5-150 mg, BID or TID
 Enalapril …… 5-40 mg, QD or BID
 Fosinopril …… 10-40 mg, QD
 Lisinopril …… 10-40 mg, QD
 Quinapril …… 10-80 mg, QD or BID
 Ramipril …… 2.5-10 mg, QD or BID

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 I. HYPERTENSION …TREATMENT
 F. ACE inhibitors…Monitoring
 Simultaneous use of an ACEI, ARB, and/or renin inhibitor is not
recommended to treat adults with HTN
 Consider avoiding in women during childbearing years.
 Lower-than-average dose if the patient is an older, is receiving concomitant
diuretic therapy, or has renal impairment.
 Reassess SrCr and K 1–2 weeks after initiation or dose titration.
 Monitor K closely, especially if renal impairment exists or another K-sparing
drug or K supplement is used.
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 I. HYPERTENSION …TREATMENT

 F. ACE inhibitors and ARBs… Important ADRs

Increasing SrCr – increase of as much as 30% above baseline is acceptable.

Hyperkalemia

Angioedema – Occurs 2–4 times more often in blacks and smokers

 Cough, dry (11% with 2.5% discontinuation)

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 I. HYPERTENSION …TREATMENT

 F. ACE inhibitors…..Contraindication
 Pregnancy…Cat D
 Bilateral renal artery stenosis
Angioedema
Concomitant aliskiren administration…S/E are additive

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 Angiotensin Receptor Antagonist…Dosing
38

 Candesartan…… 8-32 mg, QD or BID

 Irbesartan …… 150-300 mg QD
 Losartan …… 50-100 mg QD or BID
 Valsartan …… 80-320 mg QD
 Eprosartan …… 600-800 mg QD or BID
 Olmesartan …… 20-40 mg QD
 Telmisartan …… 20-80 mg QD

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 I. HYPERTENSION …TREATMENT

 G. ARBs…Clinical use
(A) Indications to use ARBs first line
• Non–African American patients
• Albuminuria – Reduce the progression of nephropathy and diabetic and nondiabetic
albuminuria
• HF or left ventricular dysfunction with left ventricular ejection fraction of 40% or less
• CAD
• Recurrent stroke prevention – when used in combination with thiazide-type diuretics

(B) Recommended as add-on therapy for African American patients

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 I. HYPERTENSION …TREATMENT

 G. ARBs …Contraindications
• Pregnancy
• Do not co-administer with aliskiren.
• Bilateral renal artery stenosis

 Extreme caution - angioedema associated with ACEI use.

 Must weigh risk-benefit of use; consider other agents, if possible
Important ADRs – Similar to those with ACEIs except for cough
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 I. HYPERTENSION …TREATMENT

 G. ARBs…Monitoring
 Simultaneous use of an ACEI, ARB, and/or renin inhibitor can be harmful
(i.e.)
Can worsen renal function and/or hyperkalemia) and
Is not recommended to treat adults with HTN
Consider avoiding in women during childbearing years.
 Monitor SCr and K values for 7–10 days after initiation or titration.
 Monitor K closely, especially if renal impairment exists or another K-sparing
drug or K supplement is used.
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 I. HYPERTENSION …TREATMENT

 H. β-Blockers…Dosing
 Atenolol …… 25-100 mg QD
 Metoprolol …… 50-200 mg QD
 Bisoprolol …… 5-10 mg QD
 Nadolol …… 40-120 mg QD
 Propranolol …… 40-320 mg QD

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 I. HYPERTENSION …TREATMENT

 H. β-Blockers…MOA
 MOA – Selective (β1) or nonselective (β1 and β2) blocker results in negative
inotropic and chronotropic actions.
 Some β-blockers (e.g., pindolol, acebutolol) have intrinsic sympathomimetic
activity, (i.e. can exert low-level agonist activity at the β-adrenergic receptor while
acting as a receptor site antagonist).
 Agents without intrinsic sympathomimetic activity are usually used for HTN.
 Carvedilol and labetalol also have α1-blocking activity, and
 Nebivolol also has nitric oxide–mediated vasodilating properties.
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 I. HYPERTENSION …TREATMENT

 H. β-Blockers:- Clinical Uses

 Not considered first line for essential HTN because of the lack of positive outcome
data; however, are adjunctive agents when patients with HTN have indications for β-
blockade.
 HF or left ventricular systolic dysfunction with LVEF (40% or less) – First line
(metoprolol succinate, carvedilol, bisoprolol) with ACEIs (or ARBs)
 Post-MI (within first 3 years) – First line
 β-Blockers with α1-blocking activity are likely more effective antihypertensive agents
than are β-blockers without this mechanism.
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 I. HYPERTENSION …TREATMENT

 H. β-Blockers:- ADRs
 Bradycardia – Adjust doses for symptomatic bradycardia only.
 Heart block – Adjust doses or discontinue therapy for greater than first-degree heart
block.
 Bronchospastic disease….Asthma, COPD
 Exercise intolerance
 Sexual dysfunction
 Fatigue
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 I. HYPERTENSION …TREATMENT

 H. β-Blockers…Contraindications
 Sinoatrial or AV node dysfunction
 Decompensated HF
 Severe bronchospastic disease

Monitoring
 Relative contraindications include hypotension and bronchospastic lung disease.
 Taper shorter-acting agents rather than abruptly discontinuing them to avoid rebound
anginal and hypertensive effects.
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 I. HYPERTENSION …TREATMENT

 I. Direct renin inhibitor (aliskiren)

MoA – decreasing plasma renin activity and inhibiting the conversion of
angiotensinogen to angiotensin I
Dosing and monitoring
 Dose: 150mg -300mg PO Daily
Consider avoiding in women during childbearing years.
 High-fat meals decrease absorption substantially.

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 I. HYPERTENSION …TREATMENT

 I. Direct renin inhibitor (aliskiren)…Contraindications

 Pregnancy
 Patients with diabetes when used in combination with ACEIs or ARBs because of
increased risk of renal impairment, hyperkalemia, and hypotension
 Avoid use in combination with cyclosporine or itraconazole.
 Avoid concurrent use with ACEIs or ARBs in patients with (CrCl less than 60
mL/min).
Important ADRs
 Angioedema

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 Hyperkalemia if used concomitantly with ACEI 48
 I. HYPERTENSION …TREATMENT

 HTN with Comorbidities - Stable ischemic heart disease (SIHD)

 BP< 130/80 mm Hg is recommended.
 β-blockers, ACEIs, or ARBs as first-line therapy, with other drugs added as
needed to further control HTN.
In persistent uncontrolled HTN, adding dihydropyridine CCBs to β-
blockers is recommended.
 In adults who have had an MI or ACS, it is reasonable to continue β-blockers
beyond 3 years as long-term therapy for HTN.
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 I. HYPERTENSION …TREATMENT
 HTN with Comorbidities - HF

 Higher risk of developing HF than do normotensive men and women.

Long-term treatment of HTN reduces the risk of HF by around 50%.
 The optimal BP should be <130/80 mm Hg.
NDHP CCBs- not recommended in the treatment of HTN in adults with HFrEF.
In adults with HF with symptoms of volume overload, diuretics should be
prescribed to control HTN then, ACEIs or ARBs and βBs

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 I. HYPERTENSION …TREATMENT
 HTN with Comorbidities - Diabetes mellitus

 Because CVD is the No. 1 killer of, and main source of morbidity in patients with

DM, controlling CV risk factors such as HTN in patients with diabetes is of utmost
importance.
 Antihypertensives should be initiated at a BP ≥130/80 mm Hg with a treatment
goal of <130/80 mm Hg.
 All first-line classes of antihypertensive agents (diuretics, ACEIs, ARBs, and
CCBs) are useful and effective.
 In Pts with DM and HTN, ACEIs or ARBs is considered in the presence of
albuminuria.
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 I. HYPERTENSION …TREATMENT
 HTN with Comorbidities - Diabetes mellitus

 In pregnant patients with DM and preexisting HTN, a BP ≤ 135/85 mm Hg suggested

to reduce the risk of accelerated maternal HTN and to minimize impaired fetal growth.

For BP>120/80 mm Hg :- lifestyle intervention (weight loss, DASH-style eating pattern

and increased physical activity).

 BP ≥140/90 mm Hg :- Lifestyle therapy PLUS Pharmacologic therapy to achieve BP goals.

 BP ≥160/100 mm Hg:- in addition to lifestyle therapy, initiation and timely titration of two
drugs or a single-pill combination of drugs shown to reduce CV events.

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 I. HYPERTENSION …TREATMENT
 HTN with Comorbidities - CKD (GFR less than 60 mL/minute/1.73 m2)

 Adults with HTN and CKD should be treated to a BP goal of <130/80 mm Hg.

 In adults with HTN and CKD (≥ stage 3 or stage 1 or 2 with albuminuria [>300
mg/day)
oACEI is reasonable to slow kidney disease progression and
oARB may be reasonable if an ACEI is not tolerated.
 In patients without albuminuria (≤300 mg/d), usual first-line medications can be
used.
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 I. HYPERTENSION …TREATMENT
Black patients: β-Blockers and ACE inhibitors are generally less effective as monotherapy
than in non–black patients.

In black adults with HTN :- thiazide-type diuretic or CCB.

β-blockers and ACE inhibitors should still be used if comorbid conditions dictate.
Women
i. Oral estrogen-containing contraceptives can increase BP, and the risk can increase with the
duration of use.
ii. HTN increases the risk to mother and fetus in women who are pregnant.

Preferred medications include methyldopa, nifedipine and labetalol.

ACE inhibitors, ARBs, and aliskiren should not be used b/c of the potential for fetal defects
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 Recommendations for Combination Therapy…AHA
55

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 Complication of hypertension:
myocardial infarct (MI)
progressive high-pressure damage to the
renal capillaries, the glomeruli.
high-pressure damage to the retinal arteries
high-pressure hemorrhage in the brain (hemorrhagic
stroke) or from an embolus broken off a non-cerebral vessel
exposed to high pressure (ischemic stroke).

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II. CHRONIC HEART FAILURE (CHF)

HF is a complex clinical syndrome that results from any structural or

functional impairment of ventricular filling or ejection of blood.

Despite advances in pharmacotherapy, HF remains a leading cause of

morbidity and mortality worldwide.

Mortality is 50% at 5 years.

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II. CHRONIC HEART FAILURE (CHF) ….Classification
Table 2. Definitions of HFrEF and HFpEF

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New York Heart Association Functional Classification
ACC)/AHA guidelines of chronic HF utilize a staging system
II. CHF….. Clinical Presentation/Physical Examination
The clinical presentation of HF consists of symptoms of:-

SOB/dyspnea

Orthopnea/SOB on lying down

Paroxysmal nocturnal dyspnea (PND)

Fatigue/weakness:- (circulation-related abnormalities in skeletal muscles);

Edema; abdominal distention; (most likely because of right-sided HF).

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II. CHF….. Clinical Presentation/Physical Examination
Because of compensatory mechanisms, early stages of HF lack specific signs;
however, late stages of HF have the following signs:
Tachycardia
Pedal edema
Increased JVP (usually greater than 6 cm)
Abnormal lung sounds (crackles) and
S3 gallop

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II. CHF….. Diagnosis of HF
HF is evaluated using various parameters:
P/E:- to determine the presence of clinical symptoms and signs
Blood tests:- CBC
BUN, SCr, glucose, fasting lipid profile, liver function tests, and thyroid-
stimulating hormone
 Other HF-specific laboratory tests (especially in patients with a high
possibility of an HF diagnosis) include BNP and NT-proBNP.

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II. CHF….. Diagnosis of HF
Other diagnostic tests for HF include:
 Chest radiography:- heart size and pulmonary congestion and to detect
alternative cardiopulmonary diseases
ECHO with Doppler :- LVEF and filling patterns ( “gold-standard” test);
CT scans:- cardiac structure and function
MRI:- LV volume and LVEF measurements, which are more definitive than
ECHO, as well as myocardial perfusion, viability, and fibrosis..

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II. CHF….. Etiologies for HF
Ischemic heart disease (CAD,MI)
HTN

Toxic damage (Alcohol, cocaine, Medications, Radiation etc. )

Immune-mediated and inflammatory damage (Infection, Autoimmune)

Metabolic derangements: (Thyroid diseases, parathyroid disease, DM)

Valve and myocardium structural defects (Acquired, Congenital)
 High-output states (Severe anemia, sepsis, thyrotoxicosis, pregnancy)

9/13/2022 65
II. CHF….. Pathophysiology: Role of Neurohormones
With myocardial injury, filling pressures and blood pressure decreases,
stimulate baroreceptors in the internal carotid arteries and aortic arch and thus
activating the sympathetic nervous system (SNS) and vasopressin.
Increases occur in epinephrine and norepinephrine concentrations and
increased heart rate, contractility, and afterload occur by peripheral
vasoconstriction.
In turn, this leads to apoptosis and an increased potential for arrhythmias.

9/13/2022 66
II. CHF….. Pathophysiology: Role of Neurohormones

9/13/2022 67
II. CHF….. Pathophysiology: Role of RAAS

9/13/2022 68
Figure 3. Summary of the renin-angiotensin-aldosterone system
Beneficial and Detrimental Effects of the Compensatory
Responses in Heart Failure
II. CHF….. Treatment
The goals of therapy
 Relieve or reduce symptoms
 Prevent or minimize hospitalizations for exacerbations of HF
 Slow progression of the disease process
 Improve the patient’s quality of life
Prolong survival

9/13/2022 70
II. CHF….. Treatment….. Drugs for Routine Use
1. Diuretics
Indicated in patients with evidence of fluid retention
 Short-term benefits (days)
 Decreased JVP
 Decreased pulmonary congestion
Decreased peripheral edema
 Intermediate-term benefits (weeks to months)
 Decreased daily symptoms
 Increased exercise tolerance
 Long-term benefits (months to years): No benefit on mortality
9/13/2022 71
II. CHF….. Treatment….. Drugs for Routine Use
1. Diuretics
 Should be combined with an ACEI or ARB and a β-blocker
 Start with low initial dose; and titrate on the basis of the patient’s
weight and diuresis.
Note the difference in bioavailability of oral doses.
 Goal:- for a weight loss of 0.45–0.9 kg (1–2 lb) per day.
 Combine loop with a thiazide diuretic for dual-nephron blockade

9/13/2022 72
II. CHF….. Treatment….. Drugs for Routine Use
1. Diuretics
 Loop diuretics are preferred because of their:
Greater diuretic capabilities
 Retain efficacy with decreased renal function.
Thiazide diuretics may be adequate if only mild volume overload and HTN
Monitoring: K+ of ≥4.0 mEq/L and Mg++ of ≥2.0 mEq/L to minimize the
risk of arrhythmias.
Monitor every 1–2 weeks after start or dose increase.
9/13/2022 73
II. CHF….. Treatment….. Drugs for Routine Use
Table . Diuretics and Recommended Dosing

9/13/2022 74
II. CHF….. Treatment….. Drugs for Routine Use
2. ACE inhibitors
 Recommended in all patients with HFrEF, to reduce morbidity and mortality
 Benefits
 Decreased mortality
 Decreased hospitalizations
 Symptom improvement and improved clinical status
 Improved sense of well-being

9/13/2022 75
II. CHF….. Treatment….. Drugs for Routine Use
2. ACE inhibitors… Dosing and administration
Start low, and double the dose every 1–4 weeks to target dose.

 Avoid use in angioedema as the result of previous ACE inhibitor use or

pregnant or plan to become pregnant.

Use caution if SBP < 80 mm Hg, SCr > 3 mg/dL, or K >5.0 mEq/L

9/13/2022 76
III. CHF….. Treatment….. Drugs for Routine Use
2. ACE inhibitors …Monitoring
 SrCr and k every 1–2 weeks after initiating therapy or with increasing the

dose, especially in high-risk patients (DM,K+ supplements, azotemia, MRA).

SrCr: (up to 30% increase is acceptable) because of renal efferent artery dilation

Rarely, acute renal failure occurs, especially if the patient is intravascularly

depleted (be careful to avoid overdiuresis).

9/13/2022 77
II. CHF….. Treatment….. Drugs for Routine Use
2. ACE inhibitors ….Adverse effects
 Angioedema (less than 1%): May (ARB) (cross reactivity is 5-10%) or
hydralazine combined with isosorbide dinitrate
 Cough (20%): May change to ARBs (less than 1%)
 Hyperkalemia

9/13/2022 78
II. CHF….. Treatment….. Drugs for Routine Use
Table. Dosing of ACE Inhibitors

9/13/2022 79
II. CHF….. Treatment….. Drugs for Routine Use
2. ARBs
 Recommended in patients with HFrEF with current or prior symptoms who
cannot take an ACE inhibitor because of cough or angioedema

Benefits:
Have not been proven superior to ACE inhibitors at target HF dosages
Decrease HF-related hospitalization and CV death
Considered if the patient has had ACE inhibitor–induced angioedema (cross-
reactivity 5-10%)
9/13/2022 80
II. CHF….. Treatment….. Drugs for Routine Use
2. ARBs
Dosing and administration
Same as ACE inhibitors for monitoring and titration
Monitoring
Same as for ACE inhibitors
Expect no cough and rare angioedema.

9/13/2022 81
II. CHF….. Treatment….. Drugs for Routine Use
2. ARBs
Table . Dosing of ARBs

9/13/2022 82
II. CHF….. Treatment….. Drugs for Routine Use
3. β-Blockers
Recommended in all patients with HFrEF, even stage B, with current or prior symptoms of
HF unless contraindicated.
Benefits (when added to an ACE inhibitor)
Decreased mortality
Decreased hospitalizations
Symptom improvement and Improved clinical status – Increases LVEF

9/13/2022 83
II. CHF….. Treatment….. Drugs for Routine Use
3. β-Blockers
MOA:- Blocks the effect of norepinephrine and other sympathetic
neurotransmitters on the heart and vascular system
 Decreases ventricular arrhythmias (sudden cardiac death)
 Decreases cardiac hypertrophy and cardiac cell death
 Decreases vasoconstriction and heart rate
Decreases cardiac remodeling

9/13/2022 84
II. CHF….. Treatment….. Drugs for Routine Use
3. β-Blockers
Carvedilol also provides α1-blockade.
(a) Further decreases SVR (afterload)- greater reduction in BP than metoprolol succinate

Of the GDMT β-blockers, bisoprolol is the most cardioselective for the β1-receptor;
Of the β-blockers, nebivolol is the most cardioselective.
 Nebivolol increases nitric oxide and endothelial nitric oxide synthase; however, nebivolol is
not a GDMT because it does not have the same extent of mortality reduction as other GDMT
β-blockers.
9/13/2022 85
II. CHF….. Treatment….. Drugs for Routine Use
3. β-Blockers…Dosing and administration
 Only Bisoprolol, Carvedilol, and Metoprolol succinate are recommended in HFrEF.

 Add to existing ACE inhibitor or ARB therapy after trying to reach target ACE

inhibitor dosing when HF symptoms are stable and patients are euvolemic.

 Should not be prescribed without diuretics in patients with a current or recent history

of fluid retention

9/13/2022 86
II. CHF….. Treatment….. Drugs for Routine Use
3. β-Blockers…Dosing and administration
 Start low, and increase (double) the dose every 2 weeks (or slower, if
needed) to the target dose, achieve the target dose in 8–12 weeks.
 Avoid abrupt discontinuation; can precipitate clinical deterioration
 May not notice improvement in symptoms for several months

 Higher doses of β-blockers are suggestive of a greater reduction in

mortality and improvement in LVEF

9/13/2022 87
II. CHF….. Treatment….. Drugs for Routine Use
3. β-Blockers …Monitoring
 BP, HR, and symptoms of hypotension (monitor 1–2 weeks)
 Higher β-blocker doses are associated with greater mortality reduction.
Therefore, if hypotension alone is the problem, try reducing the ACE inhibitor (or
another antihypertensive) first.
 Increased edema or fluid retention (monitor 1–2 weeks= Responds to diuretic
increase
 Fatigue or weakness
Usually resolves spontaneously in several weeks
 May require dosage decrease or discontinuation

9/13/2022 88
II. CHF….. Treatment….. Drugs for Routine Use
3. β-Blockers …Dosing of β-Blockers

9/13/2022 89
II. CHF….. Treatment….. Drugs for Routine Use
4. Aldosterone antagonists … Recommendation
In patients with NYHA class II–IV HF with an LVEF of 35% or less to reduce
morbidity and mortality unless a contraindication exists.
In patients after an acute MI who have an LVEF of 35% or less with symptoms of
HF or history of DM, unless contraindicated
Routine combined use of an ACE inhibitor, ARB, and aldosterone antagonist is
potentially harmful because of the risk of hyperkalemia.

9/13/2022 90
II. CHF….. Treatment….. Drugs for Routine Use
4. Aldosterone antagonists … MOA
Blocks the effects of aldosterone in the kidneys, heart, and vasculature
Decreases potassium and magnesium loss; decreases ventricular arrhythmias and
sudden death

 Decreases sodium and fluid retention

 Blocks direct fibrotic actions on the myocardium
 Compared with spironolactone, eplerenone is more selective for aldosterone
receptors in the vasculature, kidney, myocardium, and brain.
9/13/2022 91
II. CHF….. Treatment….. Drugs for Routine Use
4. Aldosterone antagonists
Benefits
 Decreasedmortality
Decreased hospitalizations for HF
 Improved symptoms
Dosing and administration
 Should be added to ACEI (or ARB) and β-blocker therapy
 Avoid use if SCr > 2.5 mg/dL, eGFR < 30 mL/min, or K >5.0 mEq/L.
In the absence of hypokalemia (K < 4.0 mEq/L), supplemental potassium is
not recommended when taking an aldosterone antagonist.
9/13/2022 92
II. CHF….. Treatment….. Drugs for Routine Use
4. Aldosterone antagonists … Dosing

9/13/2022 93
II. CHF….. Treatment….. Drugs for Use in Selected Patients
1. Digoxin
Benefits
 Improved symptoms
 Improved exercise tolerance
 Decreased hospitalizations
 No effect on mortality
 Greater effects with low LVEF (less than 25%) or NYHA classes III and IV

9/13/2022 94
II. CHF….. Treatment….. Drugs for Use in Selected Patients
1. Digoxin …Dosing and administration
 For most patients, 0.125 mg/day is adequate
 Consider dosing 0.125 mg every other day in patients older than 70 years,
those with impaired renal function, or those with low lean body mass.
 No indication to load patients with digoxin in the setting of HF
 Drug interactions: Clarithromycin, Amiodarone, Itraconazole,
Cyclosporine, tacrolimus ,Verapamil ,Quinidine, etc.

95
II. CHF….. Treatment….. Drugs for Use in Selected Patients
2. Hydralazine combined with Isosorbide dinitrate
Recommendations

 In addition to ACEIs and β-blockers to reduce morbidity and mortality

for African with NYHA functional class III or IV HFrEF

May be useful in patients who cannot tolerate an ACEI or an ARB because of

hyperkalemia and/or renal dysfunction or if the patient is pregnant

 Benefits – Decreased mortality.

96
II. CHF….. Treatment….. Drugs for Use in Selected Patients
2. Hydralazine combined with Isosorbide dinitrate
Mechanism of action
 Hydralazine
 Arterial vasodilator (reduces afterload)
 Increases effect of nitrates through antioxidant mechanisms
 Isosorbide dinitrate
 Stimulates nitric oxide signaling in the endothelium
Venous vasodilator (reduces preload).
97
II. CHF….. Treatment….. Drugs for Use in Selected Patients
2. Hydralazine combined with Isosorbide dinitrate
Table . Dosing of Hydralazine Combined with Isosorbide Dinitrate

98
II. CHF….. Treatment….. Drugs for Use in Selected Patients
2. Hydralazine combined with Isosorbide dinitrate
Monitoring
 Headache
Hypotension
 Drug-induced lupus with hydralazine
 Risk factors:- high dose, female sex, family history of autoimmune disease,
therapy duration exceeding 3–6 months, & slow acetylator
 A baseline antinuclear antibody (ANA) should be determined before initiating hydralazine
therapy. 99
II. CHF….. Treatment….. Drugs for Use in Selected Patients
2. Hydralazine combined with Isosorbide dinitrate
Monitoring
 Drug-induced lupus with hydralazine
 Routine follow-up ANA tests are not recommended because a positive test often does not
indicate drug-induced lupus;-50% of patients receiving hydralazine therapy have a positive
ANA yet do not have lupus.
 Patients who report lupus-like symptoms while receiving hydralazine should discontinue
hydralazine and receive close monitoring
Typical symptoms: fever, weight loss, and musculoskeletal symptoms (arthritis).
100
II. CHF….. Treatment….. Drugs for Use in Selected Patients
3. Angiotensin receptor-neprilysin inhibitor (ARNI)
Mechanism of action
 Sacubitril – Prodrug metabolized to an active metabolite that inhibits
neprilysin, increasing natriuretic peptide concentrations
 Valsartan – ARB; selectively blocks the AT II type 1 receptor and inhibits AT II–
dependent aldosterone release.
The bioavailability of valsartan in sacubitril/valsartan is 40% greater than
that of valsartan alone

101
II. CHF….. Treatment….. Drugs for Use in Selected Patients
3. Angiotensin receptor-neprilysin inhibitor (ARNI)
Recommendation (AHA/ACC/HFSA guidelines)
 ACEI or ARBs or ARNIs in conjunction with GDMT β-blockers and aldosterone
antagonists in selected patients are recommended for patients with chronic HFrEF to
reduce morbidity and mortality.
 In patients with chronic symptomatic HFrEF NYHA class II or III who tolerate an
ACE inhibitor or ARB, replacement by an ARNI is recommended to further reduce
morbidity and mortality.

102
II. CHF….. Treatment….. Drugs for Use in Selected Patients
Table. Dosing of Sacubitril/Valsartan

103
II. CHF….. Treatment….. Drugs for Use in Selected Patients
3. Angiotensin receptor-neprilysin inhibitor (ARNI)
Monitoring – S/E
Hypotension and hyperkalemia were the most common adverse effects
Cough (11.3%) and elevated SCr (3.3%), but less commonly than enalapril.
Because sacubitril inhibit neprilysin and BNP degradation, therefore BNP will be
needed for evaluation of HF management and severity.
Angioedema - African American patients appear to be at high risk.
Avoid in pregnancy
104
II. CHF….. Treatment….. Drugs for Use in Selected Patients
4. Other Drugs
Anticoagulation
Recommended in HF with AF with an additional risk factor for stroke
Reasonable in patients with HF who have AF with no additional risk factor for
stroke
 Not recommended in the absence of AF, prior stroke, or a cardioembolic source
 Warfarin was associated with fewer nonfatal strokes than aspirin or
clopidogrel.
105
II. CHF….. Treatment….. Drugs for Use in Selected Patients
4. Other Drugs
Statins

 Not recommended solely on the basis of HF diagnosis

 In all patients with a recent or remote history of MI or ACS, statins

should be used to prevent symptomatic HF and CV events.

 Associated with a reduction in hospitalization – a secondary end point

106
II. CHF….. Treatment….. HFpEF
Overall Management
 Clinical evidence for efficacious agents for HFpEF has generally been
disappointing.
Therapies for symptoms, comorbidities, and risk factors that may worsen
CV disease are recommended.
Blood pressure should be controlled in patients with HFpEF to prevent
morbidity.
Diuretics should be used for relief of symptoms due to volume overload
in patients with HFpEF. 107
II. CHF….. Treatment….. HFpEF
Overall Management
 Use of β-blocking agents, ACE inhibitors, and ARBs in patients with HTN
is reasonable to control blood pressure.
 In appropriately selected patients with HFpEF (with LVEF of 45% or
more, elevated BNP conc or HF admission within 1 year, eGFR greater than
30 mL/minute, SCr < 2.5 mg/dL, K <5.0 mEq/L), aldosterone receptor
antagonists may be considered to decrease hospitalizations.

108
II. CHF….. Treatment….. HFpEF
Specifc Drugs Studied in HFpEF
 ACEIs:- not reduce mortality in HFpEF but Improve exercise tolerance and reduce
hospitalizations

ARBs:- not reduce mortality in HFpEF, May reduce HF hospitalizations

Aldosterone antagonists:-considered to decrease hospitalizations

Digoxin:-can be considered for rate control in AF and HFpEF, but NDHP CCBs may
be more effective.

Nitrates:- Routine use in patients with HFpEF is not recommended but provide
symptomatic relief for patients with HFpEF and symptomatic CAD
109
 ischemic HEART DISEASES (IHD):
CORONARY ARTERY DISEASES (CAD)

Acute Coronary Syndromes (ACS)

9/13/2022 110
 Introduction
• Ischemic heart disease fall into two large
groups:
• Chronic coronary artery disease (CAD)
which most commonly present with stable
angina
• Acute coronary syndromes (ACS):-ST-
segment myocardial infarction (STEMI),
non-ST-segment elevation MI (NSTEMI)
and unstable angina (UA).
111
 Acute Coronary Syndromes (ACS):-Introduction
 ACSs are a form of CHD that comprises the most
common cause of CVD death.

 In contrast to CAD, an ACS results primarily from

diminished myocardial blood flow secondary to an
occlusive or partially occlusive coronary artery
thrombus

 STEMI are considered medical emergencies and

warrant immediate intervention
9/13/2022 112
 Clinical presentation and Diagnosis

113 9/13/2022
9/13/2022 114
 Etiology
 More than 90% of patients is atheromatous plaque
rupture, fissuring, or erosion of an unstable
atherosclerotic plaque
 Stable stenoses are characteristic of stable angina

9/13/2022 115
 Pathogenesis of ACSs
 Plaque Rupture and Clot Formation

 Plaques that rupture are generally characterized by a soft

lipid rich necrotic core, a thin fibrous cap, intra-plaque
hemorrhage and expansive vascular remodeling.

 Following plaque rupture, a clot (a partially or

completely occlusive thrombus) forms on top of the
ruptured plaque.

 The thrombogenic contents of the plaque are exposed to

blood elements.
9/13/2022 116
 Pathogenesis of ACSs…
 Exposure of collagen and tissue factor induce platelet
adhesion and activation
promote the release of platelet-derived vasoactive substances,
including ADP and TXA2.

 These produce vasoconstriction and potentiate platelet activation.

 During platelet activation, a change in the conformation in the GP

IIb/IIIa surface receptors of platelets occurs that cross-links
platelets to each other through fibrinogen bridges.

 This is considered the final common pathway of platelet

aggregation.
9/13/2022 117
 Clinical Presentations

9/13/2022 118
 Clinical Presentations…

9/13/2022 119
 Clinical Presentations…

9/13/2022 120
 Treatment: Desired Outcomes
Short-term desired outcomes are:
Early restoration of blood flow to the infarct-related artery

 To prevent infarct expansion (in the case of MI) or

 To prevent complete occlusion and MI (in UA);

Prevention of coronary artery reocclusion

Relief of ischemic chest discomfort

Prevention of death and other MI complications;

9/13/2022 121
 General Approach to Treatment

9/13/2022 122
 Initial Anti-ischemic and Analgesic Therapies for ACS

9/13/2022 123
 General Approach to Treatment…

9/13/2022 124
 Reperfusion Strategies for STEMIs…

Advantages of PCI over Fibrinolytics

 Lower mortality rate with primary PCI.

 Greater opening of occluded artery (90%Vs 60%)

 Less risk of bleeding (ICH % major bleedings).

 Provide diagnostic modality for coronary anatomy

 Provides prognostic data related to mortality

9/13/2022 125
 Fibrinolytic Therapy for STEMI
 Fibrinolytic agent is indicated in patients with STEMI:-
Who present to the hospital within 12 hours of the
onset of chest discomfort
Who are initially seen at a non-PCI capable
hospital
Who have an anticipated time from first medical
contact-to-device greater than 120 minutes if
transferred to a PCI capable hospital
9/13/2022 126
 Fibrinolytic Therapy for STEMI…

 Guidelines recommend that:-

Time to balloon:- within 90 min

Time to needle:- within 30 minutes of arrival

 All hospitals should have protocols addressing

Fibrinolysis eligibility

Dosing, and

Monitoring
9/13/2022 127
 Fibrinolytic Therapy for STEMI…
 Fibrin-specific:- alteplase, reteplase, or tenecteplase is
preferred over a non-fibrin-specific ( streptokinase).
 Fibrin-specific fibrinolytics open a greater percentage of
infarcted arteries.
 ICH and major bleeding are the most serious side effects
of fibrinolytic agents.
 The risk of ICH is higher with fibrin-specific agents than
with streptokinase.
 However, the risk of systemic bleeding other than ICH is
higher with streptokinase than more fibrin-specific agents
9/13/2022 128
 Fibrinolytic Therapy for STEMI…

9/13/2022 129
 Therapy for NSTE-ACS

 The goal:-prevent total occlusion of the related

artery and to control chest pain and associated

symptoms.

 Early invasive strategy (interventional approach) or

 Ischemia-guided strategy ( medications)

9/13/2022 130
 Early Invasive Therapy for NSTE-ACS…
Indicated in those with NSTE-ACS who have refractory
angina or hemodynamic or electrical instability

 Superior to an ischemia-guided strategy in patients with

one or more of the following risk features:

Advanced age (older than 70)

Previous MI or revascularization

ST deviation

HF (i.e., LVEF less than 40%)

Markedly elevated troponins, and diabetes

9/12/2022 131
 Early Invasive Therapy for NSTE-ACS
 All pts undergoing PCI should receive ASA therapy
indefinitely.

 A P2Y12 inhibitor antiplatelet (clopidogrel, prasugrel, or

ticagrelor) should be administered concomitantly with
ASA for at least 12 months following PCI for a patient
with ACS

 A longer duration of P2Y12 inhibitor therapy may be

considered for selected patients with a low-bleeding risk
receiving a DES because the risk of stent thrombosis is

9/13/2022
greater upon cessation of DAPT. 132
 Antiplatelet recommendations
A. Aspirin
 Blocking the formation of TXA2– and TXA 2–
mediated platelet activation

 1st -line therapy in ACS; reduces the incidence of

recurrent MI and death

 LD for aspirin-naive pts; 162–325 mg at initial

presentation

 Avoid enteric coated initially because of delayed and

reduced absorption.
9/13/2022 133
 Antiplatelet recommendations…
B. P2Y12 inhibitors

 Choice of oral P2Y12 inhibitor depends on an

ischemia-guided therapy or early invasive approach
and PK differences .

 Prasugrel should not be administered to pts with a

history of stroke or TIA .

 The efficacy of ticagrelor is decreased in pts treated

with higher doses of aspirin (>300 mg daily)
compared with lower doses (<100 mg daily)
9/13/2022 134
 Comparison of Oral P2Y12 Receptor Inhibitors

9/13/2022 135
 Comparison of Oral P2Y12 Receptor Inhibitors

9/13/2022 136
 Long-term Management After ACS
DAPT
 Given at least 12 months after ACS
 Reduces mortality after ACS, regardless of whether
the patient received stenting.
 Aspirin should be continued indefinitely at a MD of
81 mg daily in all pts after ACS .
 In pts who were treated with an ischemia-guided
therapy, aspirin plus either clopidogrel 75 mg daily or
ticagrelor 90 mg BID should be continued for up to 12
months.
 After PCI (BMS or DES), aspirin plus clopidogrel 75
mg daily, prasugrel 10 mg daily, or ticagrelor 90 mg
twice daily should be continued for at least 12
months.
9/13/2022 137
 Duration of DAPT after PCI:
1. PCI after Acute Coronary Syndrome (STEMI and non-STEMI): The
minimum duration is 1 year irrespective of stent type.
2. In patients with stable ischemic heart disease, who required PCI,
DAPT should be continued for at least
 1 month in patients who required BMS
 6 months in those who required DES.

Interruption of DAPT:
High bleeding risk:
 Reasonable to stop after 6 months in patients with ACS who had PCI
 Reasonable to stop after 3 months in patients with SIHD who had PCI
with DES
 Reasonable to stop after 1 month in patients with SIHD who had PCI
9/13/2022 with BMS 138
 Anticoagulant agents
UFH

 Exerts its effects as an indirect thrombin inhibitor on

fibrin-bound clots

 Continued for 48 hours or until PCI

IV UFH: Initial bolus of 60 units/kg (maximum
4000 units)
Initial infusion of 12 units/kg/hour (maximum
1000 units/hour)
9/13/2022 139
 Anticoagulant agents…
a. UFH….

 S/E:- bleeding, thrombocytopenia, and HIT with or

without thrombosis.

 Monitoring includes aPTT or ACT, Hgb/Hct, and Plt.

 UFH is not renally cleared and can be used safely in

those with renal impairment

9/13/2022 140
 Anticoagulant agents…

Enoxaparin

 MWt is one-third of UFH with balanced anti-factor

Xa (anti-Xa) and anti-IIa activity.

 Dosing varies depending on the reperfusion strategy

and the time from the last dose to the procedure

 30-mg IV bolus given in STEMI (if age younger than

75) and in select pts with NSTE-ACS

9/13/2022 141
 Anticoagulant agents…
Fondaparinux

 Selective inhibitor of activated factor X (Xa)

 Longest half-life of anticoagulants (17 hours)

 Dosing NSTE-ACS: 2.5 mg SC daily, continued for

the duration of hospitalization or until PCI

9/13/2022 142
 Anticoagulant agents…
Fondaparinux…
 Not to be used as the sole anticoagulant during PCI

 Contraindicated if CrCl < 30 mL/minute/1.73 m2

 Does not require routine anti-Xa monitoring

 Risks:- bleeding, thrombocytopenia, and spinal or

epidural hematomas.

 No increased risk of HIT

9/13/2022 143
 Long-term Management After ACS…

β-Blockers
 Indicated for all pts unless contraindicated

 If not initiated orally within the first 24 hours,

reevaluate for possible initiation before discharge.

 Continue for at least 3 years (when EF is greater than

40%).

 Continue indefinitely in patients with an EF less

than 40%.
9/13/2022 144
 Long-term Management After ACS…
ACEIs
 Should be initiated and continued indefinitely for all
patients if
LVEF of 40% or less
HTN
DM, or
stable CKD, unless contraindicated.

 ARBs are indicated if the pt has contraindications to or is

intolerant of ACEIs.
9/13/2022 145
 Long-term Management After ACS…
Aldosterone receptor blockers
 Indicated in pts who are already receiving an ACEI
and β-blocker after MI and who have an LVEF of 40%
or less and either symptomatic HF or DM, unless
contraindicated.

 Contraindications:- K+ ≥ 5 mEq/L, CrCl<30 mL/ min,

and SCr > 2.5 mg/dL in men and >2.0 mg/dL in
women

9/13/2022 146
 Long-term Management After ACS…
Lipid-lowering therapies

 High-intensity statins are indicated in all pts after ACS

without contraindication and initiated as soon as possible
within the first 24 hours.

 Depending on the additional desired LDL percentage

reduction, either ezetimibe or a PCSK9 inhibitor can be
considered in combination with statin therapy in very
high-risk patients.

 An LDL goal of < 70 mg/dL is reasonable in patients

9/13/2022
post-ACS. 147
 Pain control
 NSAIDs and selective cox-2 inhibitors should be
discontinued at the time of presentation
they have been associated with an ↑sed risk of major
adverse cardiac events.
 Treat with acetaminophen, non-acetylated salicylates,
tramadol, or narcotics at the lowest dose to control
symptoms.
 It is reasonable to use nonselective NSAIDs, such as
naproxen, if initial therapy is insufficient.
 Monitor regularly for sustained HTN, edema,
worsening renal function, or GI bleeding.
 If these occur, consider dose reduction or
discontinuation.
9/13/2022 148
 Complications
 Cardiogenic shock:- Mortality rate is ~ 60%

 HF

 valvular dysfunction

 Stroke:- left ventricular thrombus embolization,

 VTE

 ventricular and atrial tachyarrhythmias

9/13/2022 149
 Venous Thromboembolism (VTE)

9/13/2022 150
 Introduction
 VTE is one of the most common CVDs.

 It is manifested as
DVT (thrombus causing obstruction of a deep vein
in the leg, pelvis, or abdomen) and
PE (thrombus causing obstruction of a pulmonary
artery or one of its branches and resulting in
pulmonary infarction)

9/13/2022 151
 Introduction
 A thrombus is a blood clot attached to the vessel wall
composed of platelets, fibrin, and clotting factors
partially or completely occlude the lumen of a blood
vessel →compromise blood flow and oxygen delivery
to distal tissue.

 It is often provoked by prolonged immobility and

vascular injury and most frequently seen in pts
hospitalized for a serious medical illness, trauma,

9/13/2022
or major surgery. 152
 Etiology and Risk Factors
 Unprovoked DVT ……no clear precipitating risk factor

 Provoked DVT:- clear risk factors

Cancer,
Acute medical illness
Surgery/ trauma
Immobility (often in hospital and lasting at least 3 days)
Obesity
Hormone therapy (estrogen containing)
Pregnancy (particularly the postpartum period

9/13/2022 153
 Etiology and Risk Factors…

 VTE risk factors can be categorized into one of the

three elements of Virchow triad:
 Stasis in blood flow
 Vascular endothelial injury
 Hypercoagulation states:- (inherited or
acquired changes in blood constituents)
 Not all risk factors carry equal risk

9/13/2022 154
 Risk stratification
a. Low risk (DVT, <10% without thromboprophylaxis)

Minor surgery in pts younger than 40 with no additional

risk factors

Medically ill pts who are fully mobile

b. Moderate risk (DVT, 10%–40% without prophylaxis)

Most general, pts undergoing open gynecologic or

urologic surgery

Medically ill pts, bed rest or sick

9/13/2022 155
 Risk stratification…
c. High risk (DVT , 40%–80% without prophylaxis)
Major surgery in pts older than 40 plus a prior VTE
Cancer
Hypercoagulable state
Hip or knee arthroplasty, hip fracture surgery
Major trauma
Spinal cord injury

9/13/2022 156
 Pathophysiology
 Hemostasis:- the arrest of bleeding following vascular
injury

 When a vessel is injured, a dynamic interplay between

thrombogenic and antithrombotic forces → local formation
of a hemostatic plug that seals the vessel wall and prevents
further blood loss.

 A disruption of this checks and balances → inappropriate clot

formation within the blood vessel → obstruct blood flow or
embolize to a distant vascular bed

9/13/2022 157
 Pathophysiology…

9/13/2022 158
 Clinical Presentation and Diagnosis

9/13/2022 159
 Prevention Strategies
a. Mechanical prophylaxis
 Includes Graduated compression stocking (GSC)- limited
efficacy and Intermittent Pneumonic compression (IPC)

 IPC has to be on the patient for at least 18 hours/day to

show efficacy.

 Both types of mechanical prophylaxis are poorly tolerated

by pts.

 Preferred for pts at high risk of bleeding, such as

immediately post-surgery

9/13/2022 160
 Prevention…
b. Pharmacologic prophylaxis
 LMWH – SC enoxaparin or dalteparin
 UFH – SC twice daily or three times daily
 Fondaparinux ….SC 2.5 mg daily
 Adjusted-dose warfarin – Only in orthopedic surgery
 Direct Oral Anticoagulants (DOACs) – Dabigatran,
rivaroxaban, and apixaban – in orthopedic surgery

9/13/2022 161
 Prevention…

9/13/2022 162
 VTE Prophylaxis in Non-orthopedic Surgery

9/13/2022 163
 VTE Prophylaxis in… Medically ill pts…

 UFH 5000 units Q 8 hrs and enoxaparin 40 mg

daily, the regimens have had similar efficacy,
except for in higher-risk medically ill pts (HF and
ischemic stroke), in which enoxaparin confer
greater protection against VTE.

 Enoxaparin has caused significantly less hematoma

(greater than 5 cm) than UFH.

9/13/2022 164
 Duration of VTE Prophylaxis

9/13/2022 165
 Treatment of DVT: anticoagulation

 Anticoagulation treatment for DVT may be divided into 3

distinct phases;

i. Initial phase (up to 10 days) …… to prevent propagation of

DVT and PE

ii. Principal phase (first 3 months) ….. reduce the risk of early
recurrent VTE

iii. Extended phase (beyond 3 months, with no scheduled

stop date)..reducing the long term risk of recurrent VTE

9/13/2022 166
 Anticoagulant properties and dosing for the treatment of VTE.

a. Unfractionated heparin.

 Preferred in special clinical situations:- severe renal

insufficiency, hemodialysis, or for critically ill pts.

 Body weight should be assessed and aPTT evaluation is

necessary for accurate and safe administration

 An APTT ratio of 1.5 to 2.5 should be reached within 24 hrs of

starting treatment.

 A lower aPTT in the first 24 hrs is associated with a higher

incidence of recurrent DVT
9/13/2022 167
 Weight-Baseda UFH Dosing for Continuous IV Infusion

9/13/2022 168
 UFH: Therapeutic Monitoring
 Close monitoring required: unpredictable pt
response

 aPTT is still used at some institutions

o Therapeutic range is institution specific

o Sometimes difficult to interpret

 Antifactor Xa level has replaced aPPT at some facilities

o Target concentration: 0.3 to 0.7 U/ml

9/13/2022 169
 UFH: Adverse Effects
 Primary adverse effect: bleeding

o More closely related to underlying risk factors than high

aPTT

 Thrombocytopenia

 Use of other antithrombotic therapy

 Preexisting source of bleeding

 Risk of bleeding increases with age, recent surgery,

hemostatic defects, heavy alcohol consumption, renal failure,
PUD, neoplasm

9/13/2022 170
 UFH: Adverse Effects…
 Thrombocytopenia (platelet count < 150,000)

o up to 30% of pts have appreciable decline in platelet count

 Heparin-Associated Thrombocytopenia (HAT)

 Benign, transient, mild

 Generally within the 1st few days of treatment in heparin-

naive pts

 Heparin-Induced Thrombocytopenia (HIT)

 Serious

 Requires immediate intervention

9/13/2022 171
 UFH: Adverse Effects…
 Long-term UFH – S/E

o Alopecia

o Priapism

o Suppressed aldosterone synthesis _ Hyperkalemia

o Osteoporosis:- UFH doses 20,000 units/day for > 6

months associated with significant bone loss, especially
during pregnancy

9/13/2022 172
 Anticoagulant ….for the treatment of VTE.

b. Low molecular weight heparins (LMWT).

LMWHs are given SC, with the dose adjusted for pt.
body weight.

LMWHs may be administered once or twice daily

o Enoxaparin

o Dalteparin

o Tinzaparin

9/13/2022 173
 Anticoagulant… for the treatment of VTE.

 Advantages of LMWT over UFH:

 Predictable anticoagulation dose response

 Improved SC bioavailability

 Dose-independent clearance

 Longer biologic t½ (given once or twice daily)

 Lower incidence of thrombocytopenia

 Reduced need for laboratory monitoring

9/13/2022 174
 LMWH…Adverse effects and Mgt
 Adverse effects:

o Bleeding:- most common

o Epidural & spinal hematomas possible in pts with epidural

catheters

o Thrombocytopenia, avoid with HIT history/diagnosis

 No proven reversal method

 May give IV protamine sulfate

 Not recommended if LMWH administered > 12 hrs

earlier

9/13/2022
Safe in pregnancy, does not cross placenta 175
 DOSING

9/13/2022 176
 Anticoagulant… for the treatment of VTE.

c. Fondaparinux
 Selectively inhibits factor Xa activity

 Prevents thrombus generation & clot formation

 No direct effect on thrombin activity at therapeutic

plasma concentrations

 No effect on platelet function…..recommended in pts

with Hx of HIT

9/13/2022 177
 Dosing & Administration
 Fondaparinux FDA-approved indications

o VTE prophylaxis following orthopedic surgery

o DVT/PE treatment

 VTE prevention: 2.5 mg SC daily 6 to 8 hr after surgery

 DVT or PE treatment:

o > 100 kg: 10 mg once daily

o 50_100kg : 7.5 mg SC once daily

o < 50 kg: 5 mg daily

9/13/2022 178
 Fondaparinux: Monitoring
 No routine coagulation testing required
 Evaluate baseline CBC then periodically
 Baseline kidney function in pts at risk of developing renal
failure
o discontinue if CrCl < 30 mL/min
 Safe in elderly pts
o however, major bleeding risk increases with age
 Pregnancy category B
 Not studied in pediatric populations
 Most common adverse effect: bleeding
o risk related to weight
o use caution with epidurals
9/13/2022 179
 Anticoagulant… for the treatment of VTE.

d. Warfarin:
 Anticoagulant of choice for long-term/extended
anticoagulation.

 FDA-approved indications

 VTE prevention & treatment

 prevention of thromboembolic complications associated with AF,

heart valve replacement, MI

 Requires continuous monitoring & patient education

o Narrow therapeutic index

9/13/2022
o Many food & drug interactions 180
 Warfarin…
 Inhibits vitamin K dependent clotting factors (II, VII,
IX, X)

 No direct effect on previously circulating clotting

factors or previously formed thrombi

 Time to pharmacologic effect dependent on the

elimination t½’s of coagulation proteins

o antithrombotic effect achieved 5 to 7 days after

initiation of therapy
9/13/2022 181
 Warfarin…Dosing & Administration

 Initiate warfarin at 5-10 mg po qd.

 Consider lower doses in the elderly, patents with

impaired nutrition, liver failure, CHF or with a high

risk of bleeding.

 Acute VTE: UFH, LMWH, or fondaparinux should be

overlapped with warfarin for > 5 days

o INR checked every 3 to 5 days until stable

9/13/2022 182
 Warfarin: Adverse Effects
 Bleeding/hemorrhagic complications
 INR (3.5 to 5.0): reduce dose or hold 1 or 2 doses
 INR (5 to 9): hold warfarin ± low dose vitamin K
 INR > 10 - Serious/life-threatening bleeding
o IV vitamin K
o Fresh frozen plasma
o recombinant factor VII
 Warfarin-induced skin necrosis
 Purple-toe syndrome

9/13/2022 183
 Warfarin: Interactions
 Vitamin K-containing foods

o stress dietary consistency, moderation

 Drugs that inhibit or induce CYP2C9, 1A2, 3A4

 Protein-binding displacement interactions

o transient changes

 Drugs that alter hemostasis, platelet function, or

clotting factor clearance

9/13/2022 184
 Warfarin: Special Populations

 Pregnancy category X

 Fetal hemorrhage

 Teratogenic complications

 CNS abnormalities

 Safe to use while breast-feeding

9/13/2022 185
186
 Introduction
187

Stroke is also called cerebrovascular accident.

It is a condition that reduces blood flow to the

brain.

It is sudden, focal interruption of cerebral blood flow

that causes neurologic deficit.

Stroke is a medical emergency

188
 Cont’d …
189

Ischemic stroke (IS):- artery supplying the brain is

occluded, leading to decreased blood flow to the
affected area
Thrombotic stroke :- a clot forms in a vessel and
reduces blood flow to the brain from the location
where the clot originates.
In embolic stroke, the clot forms in an area apart
from the brain, and travels until it reaches a blood
vessel that is too narrow to allow it to pass.
This occlusion impedes the flow of blood to the
brain.
 Cont’d …
190

Transient ischemic attack

is transient episode of neurologic dysfunction lasting less
than 24 hours.
It can actually lead to brain injury and increased risk of
recurrent stroke.
Hemorrhagic stroke
A result of bleeding into the brain and other spaces
within the CNS
Subarachnoid hemorrhage (SAH), Intracerebral
hemorrhage (ICH), and Subdural hematomas.
 Epidemiology
191

The second most common cause of death worldwide.

It is the fourth leading cause of death in the US.
In Ethiopia,
 Addis Ababa:- (53.8% IS & 46.2% HS)
 Bahir Dar:- (56.7% IS & 43.3% HS)
 Hawassa:- (50.3% IS & 49.7% HS)
 Jimma:- ( 51.7% IS & 48.3% HS)
 Etiology
192

SAH :- owing to trauma, rupture of an

intracranial aneurysm, or rupture of an
arteriovenous malformation

ICH :- blood vessel ruptures within the brain

parenchyma itself.

associated with uncontrolled high BP and

sometimes thrombolytic therapy
 Cont’d …
193

Causes of ischemic stroke

Atherosclerosis (cerebral vasculature)

30% are cryptogenic- Unknown origin

20% are Cardiogenic embolism

 Risk Factors for Ischemic Stroke
194

Nonmodifiable risk factors

Age (> 55 years)

Gender (males more than females)

Race and ethnicity (e.g. African American)

Genetic predisposition

Low birth weight

 Cont’d …
195

Modifiable Risk Factors

Cigarette smoking
Hypertension
Diabetes
Dyslipidemia
Atrial fibrillation
Obesity
Physical inactivity
Other cardiac diseases (e.g coronary heart disease)
 Pathophysiology
196

Pathophysiology of ischemic stroke.

o Three major mechanisms

Occlusion of an intracranial vessel by an embolus

In situ thrombosis of an intracranial vessel,

 typically affecting the small penetrating arteries

Hypoperfusion caused by flow-limiting stenosis of a

major extracranial artery.
197
 Cont’d …
198

Pathophysiology of hemorrhagic stroke

 not as well studied

the presence of blood in the brain parenchyma

causes damage to the surrounding tissue through
 Mechanical effect it produces (mass effect) and

 Neurotoxicity of the blood components and their

degradation products
 Clinical features
199

Trouble with speaking and understanding.

Paralysis or numbness of the face, arm or leg.
 This often happens just on one side of body.
 Also, one side of mouth may droop when you try to
smile.
Trouble with seeing in one or both eyes.
Headache- which may be accompanied by vomiting,
dizziness or altered consciousness
Trouble with walking.
 Cont’d …
200

Think "FAST" and do the following:

Face. Ask the person to smile.
Does one side of the face droop?
Arms. Ask the person to raise both arms.
Does one arm drift downward? Or is one arm unable to
rise up?
Speech. Ask the person to repeat a simple phrase.
Is his or her speech slurred or strange?
Time. If you observe any of these signs, visit ED
immediately
 Cont’d …
201

A sudden severe headache, nausea, vomiting, and photophobia may

be the first signs and symptoms of Hemorrhagic Stroke

May complain the headache is “the worst headache of my life,”

especially if the cause is a SAH.

Neck pain and nuchal rigidity may also be experienced at the time of

the hemorrhage.
 Diagnosis
202

CT scan of the head (24 hrs.)

Reveal an area of hyperintensity (white) identifying
that a hemorrhage has occurred or hypointense (dark)
in an area where an infarction has occurred.

MRI of the head

Reveal areas of ischemia earlier and with better
resolution than a CT scan.
 Cont’d …
203

Carotid Doppler studies

Degree of stenosis in the carotid arteries

Electrocardiogram (ECG)

AF, a major risk factor for cardioembolic stroke.

Transthoracic echocardiogram

Heart valve abnormalities

 Treatment of ischemic stroke
204

Goals of therapy
Reduce the ongoing neurologic injury

Decrease mortality

Decrease long-term disability

Prevent complications

Prevent stroke recurrence

 TreatmentCont’d
of ischemic
…. stroke
205

Acute Phase treatment of ischemic stroke

Alteplase
0.9 mg/kg IV (max 90 mg):-10% bolus over 1 minute
and 90% given over 60 minutes
ASA
160-325 mg daily started within 24 to 48 hours of
onset
Should be delayed 24-hour post t-PA
 TreatmentCont’d
of ischemic
… stroke
206

Inclusion and Exclusion Criteria for tPA Use in Acute IS

Inclusion criteria
Age 18 years or older

Clinical diagnosis of ischemic stroke causing a measurable

neurologic deficit

Time of symptom onset well established to be <4.5 hours

before treatment would begin
 Cont’d ….
207

Exclusion criteria
History of previous intracranial hemorrhage

Symptoms suggestive of SAH

Active internal bleeding

Acute bleeding diathesis

Patient has received heparin within 48 hours, resulting in an

elevated APTT

Recent anticoagulant use and elevated INR

TREATMENT:- Supportive measures
208

Supplemental oxygen therapy

If sao2 drops below 95%.
Management of body temperature
Temp. should be monitored every 4 hours for at least
first 48 hours and preferably as long as the patient is in
the ward.
Fever (>37.5°C) should be treated with paracetamol.
Hypothermia (<34°C) should be avoided
as it can lead to coagulopathies, electrolyte imbalance,
infection and cardiac arrhythmias.
 Cont’d …
209

Management of blood glucose

Should maintained between 140 and 180 mg/dl.

Hyperglycemia :- Insulin administration using

the sliding scale in the first week of stroke onset.

Hypoglycemia :- 20% glucose (50 ml bolus)

should be administered.
 Cont’d …
210

Increased intracranial pressure

An IV bolus of 40 mg furosemide may be used
Mannitol (0.5 gm/kg IV given over 20 minutes) can
be given every 6-8 hours.
If clinically indicated, dose frequency may be increased
to every 4 hours
This may be continued for 3-5 days.
 Cont’d …
211

Management of blood pressure

Anti-hypertensives should be started if:-
BP >185/110 and patient being considered for
thrombolysis
Hypertensive encephalopathy / nephropathy
Concomitant heart failure or myocardial infarction
Aortic dissection
Pre-eclampsia/eclampsia
 Cont’d …
212

Statin therapy
Patients with IS should be prescribed a statin
irrespective of cholesterol level.
The treatment of choice is atorvastatin 80mg (or
atorvastatin 40mg if <50kg)
Treatment with statin therapy should be avoided
or used with caution in patients with history
of hemorrhagic stroke.
 Cont’d …
213

Seizure management
Patients with seizure, even single should be
treated
with loading dose of phenytoin (15-20 mg/kg)
followed by maintenance dose 5 mg/kg per day for
a period of at least 3 months.
If needed, carbamazepine or sodium valproate
may be added.
 Cont’d …
214

DVT Prophylaxis
If patients are mobile:- do not require prophylaxis.
Patients with paralyzed legs (due to IS):-
standard heparin (5000u sc bid.) or LMWH).
For those who cannot tolerate heparin, aspirin
given for treatment is of some prophylactic value.
In patients with paralyzed legs (due to ICH),
 Routinephysiotherapy and early mobilization
should be carried out to prevent leg vein thrombosis.
 Treatment of hemorrhagic stroke
215

There is no proven treatment for ICH.

Management is based on neurointensive care treatment and

prevention of complications.

Treatment includes:
 Management of increased ICP, seizures, infections, hypertension and
prevention of rebleeding and delayed cerebral ischemia.
Cont’d …
216
 Cont’d …
217

Primary Prevention Stroke

Controlling hypertension
Lowering the amount of cholesterol and saturated fat
Quitting tobacco use
Controlling diabetes
Maintaining a healthy weight.
ASA or anticoagulant (warfarin) for patients with AF
based on CHAD2S2 VASc score
 Cont’d …
218

Secondary prevention of stroke

Noncardioembolic:-Antiplatelet therapy

Aspirin 50-325 mg daily (81 mg) or

Aspirin 25 mg + extended-release dipyridamole

200 mg twice daily or

Clopidogrel 75 mg daily
 Cont’d …
219

Cardioembolic (especially atrial fibrillation)

VKA (INR = 2.5)
Apixaban 5 mg twice daily
Dabigatran 150 mg twice daily
Rivaroxaban 20 mg daily
Atherosclerosis + LDL > 100 mg/dL
High intensity statin therapy
Hypertension
Blood pressure reduction
Questions or Comments?
220