ghada a bawazeer. msc, pharm.d., bcps ibrahim sales, pharm.d. assistant professors-clinical pharmacy...
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1
Management of Hypertension
Ghada A Bawazeer. MSc, Pharm.D., BCPSIbrahim Sales, Pharm.D.
Assistant Professors-Clinical Pharmacy DeptCollege of Pharmacy
Sept. 2013
Most diagnoses occurring between the third and fifth decades of life.
Hypertension accounts for significant morbidity and mortality
One billion individual suffer from hypertension worldwide ( 26%). WHO year 2000 estimation
Seven millions deaths/year are attributed to hypertension
Billions of dollars are spent annually in direct and indirect cost of hypertension
Background
2
Elkhalifa et al (2011): prevalence of HTN 26%
Alzahrani (2011): prehypertension 37%, hypertension 18%
Alshehri (2008): 57.8% in diabetic patients
Hypertension in Saudi Arabia
Data from National Health & Nutrition Examination Survey (NHNES)
National Health and Nutrition Examination Survey (NHANES), United States, 2003–2010◦Controlled 46.5%◦Uncontrolled 53.5%
Unaware 39.4% Aware and not treated 15.8% Aware and treated 44.8 %
4
BP Control Rate
What is the recommendation for BP screening?
JNC VII Age:> 18 yrs Every 2 yrs if normal Recheck in 1 yr if Pre–HTN Stage 1 - Confirm in 2
months Stage 2 - Confirm in 1
month If > 180 / 110, treat now
NICE Age: >40 yrs Recheck in 5 yrs if
normal Recheck freq if Pre–HTN If > 180 / 110, treat now
No National policy in KSA
Blood Pressure Classification:JNC VII
BP Classification
SBP mmHg DBP mmHg
Normal < 120 and < 80
Pre - HTN 120 - 139 or 80 - 89
Stage 1 HTN 140 - 159 or 90 - 99
Stage 2 HTN > 160 or > 100
Isolated Systolic HTN
> 140 < 90
Blood Pressure Classification:2007 European Societies of HTN and
CardiologyBP Classification SBP mmHg DBP mmHg
Optimal BP < 120 < 80
Normal 120 - 129 and /or 80 - 84
High Normal 130 - 139 and /or 85 - 89
Grade 1 140 - 159 and / or 90 - 99
Grade 2 160 - 179 and / or 100 - 109
Grade 3 > 180 and / or > 110
Isolated Systolic HTN >140 < 90
ISH according to NICE: SBP >160 and DBP <90 mm Hg
Strong correlation between BP and CV morbidity and mortality.
Risk increases Patients with prehypertension SBP vs DBP
Cardiovascular Risk and Blood Pressure
Essential HTN ◦ > 90% unknown causes
Genetics monogenic and polygenic forms of BP dysregulation
Genes affect sodium balance, urinary kallikrein excretion, nitric
oxide release, excretion of aldosterone, and angiotensinogen
Etiology
Secondary◦ <10% have identifiable causes
removing the offending agent (when feasible) or treating/correcting the underlying comorbid condition should be the first step in management.
Etiology
A: Accuracy, Apnea, Aldosteronism ( ) B: Bruits, Bad Kidneys: RAS / Renal Parenchyma/ Pheochromocytoma C: Cushings, Coarctation of Aorta, Catechol ( ) D: Drugs, Diet E: Erythropoietin ( ), Endocrinopathies/
Multiple factors that control BP are potential contributing components in the development of essential hypertension:◦ Genetics◦ Cardiac output◦ Sodium regulation◦ RAAS system◦ Sympathetic drive◦ Peripheral resistance◦ Vascular endothelium and smooth muscle ◦ Electrolyte
Hypertension Pathophysiology
How much blood flow
How much resistance to
blood flow
BP
Total peripheral resistance (TRP)
Cardiac Output(CO)
Increase pre-load Increased fluid volume
excess sodium intake renal sodium retention
Venous constriction: Excess stimulation of
RAAS Sympathetic
Functional vascular constriction and/or Structural vascular hypertrophy
Excess stimulation of the RAAS ↑ Sympathetic Genetic alterations of cell
membranes Endothelial-derived factors Hyperinsulinemia (metabolic
syndrome)
Renin-Angiotensin-Aldosterone System (RAAS)◦Very complex endogenous system ◦Controlled mainly by the kidney Influences vascular tone and sympathetic nervous
system activity Sympathetic nervous system
Neuro-Humoral Mechanisms
BP: 140-179 / 90-109BP: 140-179 / 90-109
ABPM (If available)
ABPM (If available)
Office BPM
Office BPM
Home BPM (If available)Home BPM
(If available)
Yes
Hypertension Visit 2Target Organ Damage
or Diabetesor BP ≥ 180/110?
Hypertension Visit 2Target Organ Damage
or Diabetesor BP ≥ 180/110?
Hypertension Visit 1BP Measurement,
History and Physical examination
Hypertension Visit 1BP Measurement,
History and Physical examination
HypertensiveUrgency /
Emergency
HypertensiveUrgency /
Emergency
Diagnosisof HTN
Diagnosisof HTN
No
Diagnostic algorithm for hypertension
Criteria for the diagnosis of hypertension and recommendations for follow-up
BP: 140-179 / 90-109BP: 140-179 / 90-109
ABPM (If available)ABPM (If available)
Diagnosisof HTN
Awake BP>135 SBP or>85 DBP or
24-hour>130 SBP or
>80 DBP
Awake BP>135 SBP or>85 DBP or
24-hour>130 SBP or
>80 DBP
Awake BP<135/85
and24-hour<130/80
Awake BP<135/85
and24-hour<130/80
Continue to follow-up
Office BPOffice BP
Diagnosisof HTN
Hypertension visit 3 >160 SBP or >100 DBP
>140 SBP or>90 DBP
< 140 / 90
Diagnosisof HTN
Continue to follow-up
<160 / 100
Hypertension visit 4-5
ABPM or HBPM
or
Home BPMHome BPM
>135/85>135/85 < 135/85 < 135/85
Diagnosisof HTN
Continue to follow-up
Patients with high normal blood pressure (office SBP 130-139 and/or DBP 85-89) should be followed annually.
Repeat Home BPM
Repeat Home BPM
If< 135/85
If< 135/85
Blood pressure measurement◦Based on average of > 2 accurate
measurements taken during two or more clinical encounters
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Diagnosis
Patient Evaluation Routine Laboratory Tests :
1. Urinalysis2. Blood chemistry (potassium, sodium and creatinine)3. Fasting glucose4. Fasting total cholesterol and high density lipoprotein
cholesterol (HDL), low density lipoprotein cholesterol (LDL), triglycerides
5. Standard 12-leads ECG6. Microalbuminurea (if diabetic patient)
Patient Evaluation Optional Laboratory Tests
◦ Investigation in specific patient subgroups For those with diabetes or chronic kidney disease:
assess urinary albumin excretion, since therapeutic recommendations differ if proteinuria is present.
For those suspected of having an endocrine cause for the high blood pressure, or renovascular hypertension, see following slides.
Other secondary forms of hypertension require specific testing.
Assess global cardiovascular risk in all hypertensive patients
91%
Rantala A, et al. J Intern Med 1999;245;163-74. Wannamethee S, et al. J Hum Hypertens 1998;12;735-41
Risk factors = Global CV risk
91% of hypertensive patients have at least 1 additional risk factor
III. Assessment of the overall cardiovascular risk
Cardiovascular Risk Factors • Presence of Risk Factors
– Increasing age– Male gender– Smoking– Family history of premature cardiovascular disease (age< 55 in men and < 65 in women)– Dyslipidemia– Sedentary lifestyle– Unhealthy eating– Abdominal obesity– Dysglycemia (diabetes, impaired glucose tolerance, impaired fasting glucose)
• Presence of Target Organ Damage– Microalbuminuria or proteinuria– Left ventricular hypertrophy– Chronic kidney disease (glomerular filtration rate < 60 ml/min/1.73 m2)
• Presence of atherosclerotic vascular disease– Previous stroke or TIA– Coronary Heart Disease– Peripheral arterial disease
CV Risk Factors that may alter thresholds and targets in the treatment of HTN
Methods of Risk Assessment
• Clinical impression• Risk factor counting• Risk calculation or equation tools
• Framingham hard coronary heart disease (CHD)http://www.framinghamheartstudy.org/risk/hrdcoronary.html
• SCORE Canada – Systematic Cerebrovascular and Coronary Risk Evaluation www.score-canada.ca
• Cardiovascular Age™ www.myhealthcheckup.com • Others: see notes
Will be discussed in more details during PPL 3 and Dyslipidemia
lecture
Optimal goal of BP is still debatable J-curve phenomena: not conclusive
hypothesis Current evidences have many limitations to
conclusively support 140/90 or 130/80 in HTN without diabetes, or <130/80 in patients with diabetes, CKD
There is a trend towards better outcomes with the lower range
What is the optimal BP target in hypertensive patients?
22
JNC7 2003
AHA 2007
NICE 2011
CHEP 2013
ESC2009
No co-morbidConditions
<140/90 mm Hg
BP within 130-
139/80-85 mm Hg
Patients with
Diabetes <130/80 mm Hg
23
Blood pressure treatment goals among the different guidelines
24
Blood pressure treatment goals among the different guidelines
JNC7 2003
AHA 2007
NICE 2011
CHEP 2013
ESC2007
Patients with Known coronary artery disease
(MI, stable angina, unstable angina)
Noncoronary atherosclerotic
vascular disease (ischemic stroke, TIA, PAD, abdominal aortic
aneurysm) FRS > 10%
No specific recommendatio
n
<130/80 mm Hg
No specifi
c recommenda
tion
<140/90 mm Hg
Suggesting it is wise to lower to < 130/80
Patients with left ventricular dysfunction
(heart failure)
<120/80 mm Hg
25
Blood pressure treatment goals among the different guidelines
JNC7 2003
AHA 2007
NICE 2011
CHEP 2013
ESC2007
Patients with CKD <130/80
<130/80 <140/90 <140/90 Not
clear
Elderly population (>80 yr)
<140/90
<140/90 <150/90 <150/90
<140/90
Management of Hypertension
Patient-oriented outcome: ◦Reducing CV risk◦reduce HTN-associated morbidity and mortality. target-organ damage (e.g., CV events,
cerebrovascular events, heart failure, kidney disease).
Surrogate ◦ to achieve a desired target BP
a tool that clinicians use to evaluate response to therapy
Not a guarantee of prevention of hypertension-associated TOD
27
Goals of Therapy
Lifestyle modification
AND
Pharmacological therapy
Approach to Treatment
28
Lifestyle Recommendations for Prevention and Treatment of Hypertension
To reduce the possibility of becoming hypertensive,Reduce sodium intake to less than 1500 mg/day • Healthy diet: high in fresh fruits, vegetables, low fat dairy products,
dietary and soluble fibre, whole grains and protein from plant sources, low in saturated fat, cholesterol and salt in accordance with Canada's Guide to Healthy Eating.
I. Regular physical activity: accumulation of 30-60 minutes of moderate intensity dynamic exercise 4-7 days per week in addition to daily activities; For non-hypertensive or stage 1 hypertensive individuals, the use of resistance or weight training exercise (such as free weight lifting, fixed-weight lifting, or handgrip exercise) does not adversely influence blood pressure.
• Low risk alcohol consumption: (≤2 standard drinks/day and less than 14/week for men and less than 9/week for women)
• Attaining and maintaining ideal body weight (BMI 18.5-24.9 kg/m2)• Waist Circumference: Men <102 cm Women <88 cm• Tobacco free environment
Impact of Lifestyle Therapies on Blood Pressure in Hypertensive Adults
Intervention Intervention SBP/DBP
Reduce sodium intake-1800 mg/day sodium
Hypertensive-5.1 / -2.7
Weight loss per kg lost -1.1 / -0.9
Alcohol intake -3.6 drinks/day -3.9 / -2.4
Aerobic exercise 120-150 min/week -4.9 / -3.7
Dietary patternsDASH diet
Hypertensive -11.4 / -5.5
Padwal R et al. CMAJ 2005;173;(7);749-751
Lifestyle Therapies in Adults with Hypertension: Summary
Intervention Target
Reduce foods with added sodium < 2300 mg /day
Weight loss BMI <25 kg/m2
Alcohol restriction < 2 drinks/day
Physical activity 30-60 minutes 4-7 days/week
Dietary patterns DASH diet
Smoking cessation Smoke free environment
Waist circumference Men <102 cm Women <88 cm
Drug Therapy for Hypertension
Use first line classes◦ACE, ARB, CCB, Diuretics, BB◦All classes demonstrated CV risk reduction benefits Major determinant in reduction of Cardiovascular
Risk is BLOOD PRESSURE REDUCTION recommend treatment with drugs taken only once a
day. recommend generic where appropriate and minimize
cost.
General Principles
Population SBP DBP
High risk (TOD or CV risk factors) 140 90
Low risk (no TOD or CV risk factors) 160 100
Diabetes 130 80
Lifestyle modification is recommended for all regardless of BP
II. Indications for PharmacotherapyUsual blood pressure threshold values for initiation of pharmacological treatment for hypertension
TOD=target organ damage
Target Organ Damage (TOD) Cerebrovascular disease
◦ transient ischemic attacks◦ ischemic or hemorrhagic
stroke◦ vascular dementia
Hypertensive retinopathy Left ventricular
dysfunction Left ventricular
hypertrophy
Coronary artery disease◦ myocardial infarction◦ angina pectoris◦ congestive heart failure
Chronic kidney disease◦ hypertensive nephropathy
(GFR < 60 ml/min/1.73 m2)◦ albuminuria
Peripheral artery disease◦ intermittent claudication◦ ankle brachial index < 0.9
Stage 1 HTN◦ No TOD, low CV risk
Life style modification (LS)◦ TOD, moderate-high risk
LS + drug therapy Stage 2 HTN
◦ LS + drug therapy JNC 7 recommend 2 combination therapy as initial
therapy Isolated Systolic HTN
◦ When BP >140/90 mm Hg
When to initiate drug therapy?
Algorithm for treatment of HTN
degree of BP
elevation
presence of compelling Indications
38
III. Treatment of Adults with Systolic/Diastolic Hypertension WITHOUT Other Compelling Indications
TARGET <140/90 mmHg
INITIAL TREATMENT AND MONOTHERAPY
*BBs are not indicated as first line therapy for age 60 and above
Beta-blocker*
Long-actingCCB
Thiazide ACEI ARB
Lifestyle modificationtherapy
ACEI, ARB and direct renin inhibitors are contraindicated in pregnancy and caution is required in prescribing to women of child bearing potential
A combination of 2 first line drugs may be considered as initial therapy if the blood pressure is >20 mmHg systolic or >10 mmHg diastolic above target
III. Considerations Regarding the Choice of First-Line Therapy
• ACEI, renin inhibitors and ARBs are contraindicated in pregnancy and caution is required in prescribing to women of child bearing potential.
• BBs are not recommended as first line therapy for patients age 60 and over without another compelling indication.
• Diuretic-induced hypokalemia should be avoided through the use of potassium sparing agents if required.
• The use of dual therapy with an ACEI and an ARB should only be considered in selected and closely monitored people with advanced heart failure or proteinuric nephropathy.
• ACEI are not recommended (as monotherapy) for black patients without another compelling indication.
Chlorthalidone is the diuretic that was use in most of the influential trials
It is 2X more potent in lowering BP on a mg-per-mg basis than HCTZ
HCTZ has not been as extensively studied in major long term hypertension clinical trials.
It is not definitively known if the clinical benefits of reducing CV morbidity and mortality that have been proven with chlorthalidone can be extrapolated to HCTZ.
In clinical practice, however, CV benefits in hypertension apply to all thiazide-type diuretics, and benefits are considered a class effect.
Does the CV benefits seen in ALLHAT for Chlortahlidone extend to hydrochlorothiazide?
41
Add-on Therapy for Systolic/Diastolic Hypertension without Other Compelling
Indications
IF BLOOD PRESSURE IS NOT CONTROLLED CONSIDER
• Nonadherence• Secondary HTN• Interfering drugs or lifestyle• White coat effect
If blood pressure is still not controlled, or there are adverse effects, other classes of antihypertensive drugs may be combined (such as
alpha blockers or centrally acting agents).
2. Triple or Quadruple Therapy
1. Add-on Therapy
If partial response to monotherapy
III. Summary: Treatment of Isolated Systolic Hypertension without Other Compelling Indications
CONSIDER
• Nonadherence• Secondary HTN• Interfering drugs or
lifestyle• White coat effect
Thiazide diuretic
Long-actingDHP CCB
Dual therapy
Triple therapy
Lifestyle modificationtherapy
ARB
TARGET <140 mmHg, < 150 mmHg for age > 80 years
*If blood pressure is still not controlled, or there are adverse effects, other classes of antihypertensive drugs may be combined (such as ACE inhibitors, alpha blockers, centrally acting agents, or nondihydropyridine calcium channel blocker).
Option 1: Increase the dose of the first agent, remember:◦ Dose response curves for efficacy are relatively flat
◦ 80% of the BP lowering efficacy is achieved at half-standard dose
Option 2: Add another drug from the 1st line classes◦ Combinations of standard doses have additive blood
pressure lowering effects.
Partial response
Most patients will require 2 or more agents to achieve BP control
Consider combination from among the first line drugs Different possible combinations, consider patient factors
and cost. CHEP GL:
◦DHP-CCB + Diuretic ◦DHP-CCB + ACEI or ARB ◦DHP-CCB + BB
Combination therapy
Use combination from first line classes Many fixed-dose combination products are
commercially available, consider patient factors and cost◦some are generic
Most products contain a thiazide-type diuretic and have multiple dose strengths available.
Individual dose titration is more complicated with fixed-dose combination
Considerations when Selecting a Combination Therapy
ACEI + ARB, not recommended (Grade A) If a diuretic is not used as first or second line
therapy, triple dose therapy should include a diuretic, when not contraindicated
If a BB was used initially, a CCB is preferred over thiazide-type diuretic, to reduce the person’s risk of developing diabetes.
Caution should be exercised in combining anon-DHP CCB and a BB to reduce the risk of bradycardia or heart block
Considerations when Selecting a Combination Therapy
Use caution in initiating therapy with 2 drugs in whom adverse events are more likely (e.g. frail elderly, those with postural hypotension or who are dehydrated).
Considerations when Selecting a Combination Therapy
Choice of antihypertensive agentHTN with compelling indications:
Choice of Pharmacological Treatment for Hypertension
Individualized treatment• Compelling indications:
– Ischemic Heart Disease– Recent ST Segment Elevation-MI or non-ST Segment Elevation-MI– Left Ventricular Systolic Dysfunction– Cerebrovascular Disease– Left Ventricular Hypertrophy– Non Diabetic Chronic Kidney Disease– Renovascular Disease– Smoking
• Diabetes Mellitus– With Nephropathy– Without Nephropathy
• Global Vascular Protection for Hypertensive Patients– Statins if 3 or more additional cardiovascular risks– Aspirin once blood pressure is controlled
2013 Canadian Hypertension Education Program (CHEP)
Important messages from past recommendations
• Patients with diabetes are at high cardiovascular risk
• Most patients with diabetes have hypertension
• Treatment of hypertension in patients with diabetes reduces total mortality, myocardial infarction, stroke, retinopathy and progressive renal failure rates.
• Treating hypertension in patients with diabetes reduces death and disability and reduces health care system costs
• In diabetes, TARGET <130 systolic and <80 mmHg diastolic
• If a patient has both diabetes and CKD, TARGET <130 systolic and <80 mmHg diastolic
• The use of the combination of ACE inhibitor with an ARB should only be considered in selected and closely monitored people with advanced heart failure or proteinuric nephropathy.
XII. Treatment of Hypertension in association with Diabetes Mellitus: Summary
More than 3 drugs may be needed to reach target values for diabetic patients
If Creatinine over 150 µmol/L or creatinine clearance below 30 ml/min ( 0.5 ml/sec), a loop diuretic should be substituted for a thiazide diuretic if control of volume is desired
Threshold equal or over 130/80 mmHg and TARGET below 130/80 mmHg
Diabetes
withNephropathy
> 2-drug combinations
ACE Inhibitoror ARB
withoutNephropathy
1. ACE Inhibitor or ARB
or2. DHP-CCB or
Thiazide diuretic
Monitor serum potassium and creatinine carefully in patients with CKD prescribed an ACEI or ARB
Combinations of an ACEI with an ARB are specifically not recommended in the absence of proteinuria
A combination of 2 first line drugs may be considered as initial therapy if the blood pressure is >20 mmHg systolic or >10 mmHg diastolic above target. Combining an ACEi and a DHP-CCB is recommended.
ACCORD Study: Results and rationale for lack of impact on BP recommendations
• Overall BP study was neutral with no benefit of systolic target < 120 mmHg vs < 140 mmHg for primary outcome, yet:
• Power issue: Annual rate of primary outcome 1.87% in the intensive arm versus 2.09% in the standard arm vs 4%/year event rate projected during sample size calculations
• Significant interaction between BP and glycaemia control studies such that those in usual care glycaemia group (A1c 7%+) had a significant improvement in primary outcome with lower BP target
• Secondary outcome for stroke reduction showed a benefit for lower BP target (41% RRR)
• Therefore no clear evidence supporting a change in BP targets for people with diabetes at this point
ACCORD study NEJM 2010
Not first line therapy in uncomplicated HTN by almost all guidelines
Doesn’t reduce CV risk as does ACEI/ARB, CCB, diuretics in patients with only HTN.
Consider to use if compelling indication present (MI, CAD, HF)
those with an intolerance or contraindication to ACEI or ARBs, CCB
women of child-bearing potential people with evidence of increased sympathetic drive.
When would you consider BB?
54
Alternative Antihypertensive agents
55
56
Hypertension management in Selected
Populations
Isolated systolic hypertension is common in the elderly◦Treat similar to previous discussion
What about the very elderly? Studies showed HTN in the very elderly (>80 yrs)
should be treated◦HYVET trial: reduced mortality at BP <150/90
What is the goal of BP in the very elderly?◦Not clear
Elderly
57
Use diuretics with caution: susceptible to volume depletion Elderly patients are more sensitive to :
◦ volume depletion and sympathetic inhibition than younger patients orthostatic hypotension >> dizziness >> increase risk of
falls Use caution with diuretics, ACEI, and ARBs provide significant
benefits and can safely be used in the elderly,◦ Start at low initial doses
Avoid centrally acting agents and alpha-blockers
Elderly
Orthostatic Hypotension◦SBP decrease of ↓ more than 20 mm Hg or DBP
↓more than 10 mm Hg when changing from supine to standing.
Risk factors: elderly, DM, severe volume depletion, baroreflex dysfunction, autonomic insufficiency, and use of venodilators
Start with low doses of the antihypertensive agent
Patients susceptible to orthostatic Hypotension
59
HTN in pregnancy major cause of maternal and neonatal morbidity and mortality.
Preeclampsia:◦Elevated BP > 140/90 that appears after 20 weeks
gestation accompanied by new-onset proteinuria (> 300 mg/24 hours). life-threatening complications for mother and fetus.
◦Definitive treatment of preeclampsia is Delivery
HTN & Pregnancy
60
Eclampsia:◦onset of convulsions in preeclampsia. ◦A medical emergency. ◦Treatment: Delivery restricting activity, bed rest, and close monitoring. Antihypertensives prior to induction of labor if DBP is
> 105 mm Hg with a target DBP of 95 to 105 mm Hg. IV hydralazine (common), IV labetalol Immediate-release oral nifedipine should not be used
HTN & Pregnancy
61
Gestational hypertension:◦ New onset hypertension after mid-pregnancy, no
proteinuria chronic hypertension
◦ elevated BP that is noted before the pregnancy began◦ Treatment:
consensus about most appropriate therapy in pregnancy is lacking
Methyldopa is still considered the drug of choice Other agents are listed in table 19-7
HTN & Pregnancy
62
Treatment of HTN in Pregnancy
63
Cardioselective BB can be safely used in patients with Asthma or COPD and HTN (with compelling indication)
HTN & Reactive airway diseases
64
noncoronary form of atherosclerotic vascular disease
Use ACEI BB can be problematic in PAD, but not
contraindicated in this group Use BB with α and β and blcoking activity
(carvedilol)
HTN in Patients with PAD
IV. Vascular Protection for Hypertensive Patients: Statins
In addition to current Canadian recommendations on management of dyslipidemia, statins are recommended in high-risk
hypertensive patients with established atherosclerotic disease or with at least 3 of the following criteria:
• Male
• Age 55 or older
• Smoking
• Total-C/HDL-C ratio of 6 mmol/L or higher
• Family History of Premature CV disease
• LVH
• ECG abnormalities
• Microalbuminuria or Proteinuria
ASCOT-LLA Lancet 2003;361:1149-58
IV. Vascular Protection for Hypertensive Patients: ASA
Consider low dose ASA
Caution should be exercised if BP is not controlled.
Secondary Prevention
Use of Aspirin in patients with HTN
Daily low dose aspirin is established in the secondary prevention of cardiovascular
disease
Aspirin in Patients with Diabetes and HTN
Low dose aspirin (75-162 mg) in Diabetic patients at increased CVD risk (10 year risk of CVD events over 10%) and not at increased risk for bleeding
(ACCF/AHA Class IIa, Level of Evidence: B) (ADA Level of Evidence: C)Low dose ASA maybe considered in diabetics at
intermediate CV risk
(ACCF/AHA Class IIb, Level of Evidence: C) (ADA Level of Evidence: E)
(ACCF/AHA Class III, Level of Evidence: C) (ADA Level of Evidence: C)
Do Not recommend low dose aspirin in patients at low risk. Potential Harm offset potential benefit
Circulation. 2010;121:2694-2701
High risk of bleeding
i. history of previous GI bleeding or
ii. PUD iii. concurrent use of
medications that increase bleeding risk, such as NSAIDS or warfarin
High CV riskAge M >50 , W >60+ one or more of:SmokingHypertensionDyslipidemiaFamHx of premature CVDalbuminuria
Moderate CV riskYounger patients+ one or more RFOlder patients with 10-year risk of 5-10%
Low CV riskAge M <50 yr , W <60 yr. With no major additionalCVD risk factors; 10-year CVD risk under 5%
Circulation. 2010;121:2694-2701
patients who are uncontrolled (failure to achieve goal BP of <140/90 mm Hg, or lower when indicated) with the use of three or more drugs.
Causes: Treatment
◦assure adequate diuretic therapy◦appropriate use of combination therapies◦use alternative antihypertensive agents when
needed
71
Resistant HTN
Resistant HTN
72
presence of very elevated BP, typically greater than 180/120 mm Hg.
HTN Urgencies are not associated with acute or immediately progressing target-organ injury
HTN emergencies are associated with acute or immediately progressing target-organ injury◦ encephalopathy, intracranial hemorrhage, acute left
ventricular failure with pulmonary edema, dissecting aortic aneurysm, unstable angina, and eclampsia or severe hypertension during pregnancy.
Hypertensive Crisis
73
Don’t correct rapidly Goal:
◦ gradual reduction in BP to prevent cerebrovascular accidents, MI, and acute kidney failure.
adjusting maintenance therapy, ◦ Add a new agent ◦ and/or by increasing the dose of a present medication.◦ Use oral agents over a period of several hours to several
days.◦ Reevaluate patient within and no later than 7 days
(preferably after 1 to 3 days)
74
Hypertensive Urgency
Require hospitalization and administration of parenteral therapy
See table 19-11 Goal:
◦ a reduction in MAP of up to 25% within minutes to hours. ◦ If the patient is then stable, BP can be reduced toward
160/100 to 160/110 mm Hg within the next 2 to 6 hours. Rapid drops in BP may lead to end-organ ischemia or
infarction. ◦ If patients tolerate this reduction well, additional gradual
reductions toward goal BP values can be attempted after 24 to 48 hours.
75
Hypertensive Emergency
Parenteral Antihypertensive Agents for Hypertensive Emergency
76
Parenteral Antihypertensive Agents for Hypertensive Emergency
77
50% of patients with newly diagnosed hypertension are continuing treatment at 1 year
Identify potential barriers to adherence◦ Misunderstanding of Condition◦ Denial of illness / Asymptomatic◦ Lack of patient involvement in care plan◦ Unexpected adverse effects of medicine◦ Too many f/u visits, lab requests◦ Emphasis on PCMH Goals / Objectives
HTN & Non-Adherence
• Assess adherence to pharmacological and non-pharmacological therapy at every visit
• Teach patients to take their pills on a regular schedule associated with a routine daily activity e.g. brushing teeth.
• Simplify medication regimens using long-acting once-daily dosing
• Utilize fixed-dose combination pills • Utilize unit-of-use packaging e.g. blister packaging
HTN & Non-Adherence
Replacing multiple pill antihypertensive combinations with single pill combinations!
Encourage greater patient responsibility/autonomy in regular monitoring of their blood pressure
Educate patients and patients' families about their disease/treatment regimens verbally and in writing
Use an interdisciplinary care approach coordinating with work-site health care givers and pharmacists if available
HTN & Non-Adherence
Efficacy◦BP: 2-4 weeks after initiation and each dose change◦Once BP goal is reached: monitor BP q 3-6 months◦Adherence at every visit, annual review of meds
Disease progression◦Periodically ,◦S&S of progressive hypertension-associated TOD
Toxicity:◦See Table 19-8
Monitoring Therapeutic Plan for patient with HTN
81
82
Within 3 days of start of therapy and again at 1 week
Patient Education on:◦ Home BP measurement:
educate patient to measure during the early morning hours for most days and then at different times of the day on alternative days of the week
◦ Use of automated ambulatory BP monitoring Currently used in situations such as suspected white coat
hypertension.
83
Monitoring Therapeutic Plan for patient with HTN
84
Review on the Individual
Antihypertensive agents
Subclass Drug (Brand Name) Usual Dose Range, mg/day Daily Frequency
Diuretics Thiazides
Chlorthalidone (Hygroton)
Hydrochlorothiazide (Esidrix, HydroDiuril,
Microzide, Oretic)Indapamide (Lozol)
Metolazone (Mykrox)Metolazone (Zaroxolyn)
6.25–25
12.5–25
1.25–2.50.5–1
2.5–10
1
1
111
LoopsBumetanide (Bumex)
Furosemide (Lasix)Torsemide (Demadex)
0.5–420–805–10
221
Diuretics
85
Subclass Drug (Brand Name) Usual Dose Range, mg/day Daily Frequency
Potassium sparing
Amiloride (Midamor)Amiloride/
hydrochlorothiazide (Moduretic)Triamterene (Dyrenium)
Triamterene/ hydrochlorothiazide
(Dyazide)
5–105–10/50–100
50–100
37.5–75/25–50
1 or 21
1 or 2
1
Diuretics
Aldosterone Antagonists
Eplerenone (Inspra)Spironolactone
(Aldactone)Spironolactone/
hydrochlorothiazide (Aldactazide)
50–10025–50
25–50/25–50
1 or 21 or 2
1
Diuretics
86
Thiazides are more effective antihypertensives than loop diuretics in most patients
Loops are preferred in chronic kidney disease High dietary sodium intake can blunt their effect very effective in lowering BP when used in
combination with most other antihypertensives◦Additive/synergistic effect◦Counteract a compensatory increase in sodium and
fluid retention may be seen with antihypertensive agents.
Diuretics
87
use usual doses to avoid adverse metabolic effects
Ideally, dose in the morning if given once daily and in the morning and late afternoon when dosed twice daily to minimize risk of nocturnal diuresis
chlorthalidone is approximately 1.5 times as potent as HCTZ; have additional benefits in osteoporosis; may require additional monitoring in patients with a history of gout or hyponatremia
Diuretics
88
Diuretics SE Profile: Electrolyte imbalance:
◦Hypokalemia (more pronounced with loops)◦Hypomagnesemia◦Monitor closely especially in patients with
LVH, coronary disease, on digoxin therapy >> serious cardiac arrhythmias
Hypercalcemia (loops: hypocalcemia) sexual dysfunction
Diuretics
89
Metabolic disturbances: ◦Hyperuricemia If gout occur in a patient who requires
diuretic therapy, allopurinol can be given to prevent gout and will not compromise the antihypertensive effects of the diuretic
Diuretics
90
Hyperglycemia and dyslipidemia (more with TH-like)◦usually are transient and often inconsequential.
Potassium-sparing diuretics can cause hyperkalemia◦Avoid use with ACEI, ARB, direct renin inhibitor, K
supplements◦Eplerenone selective ARA, more hyperkalemia than
spironolactone
Diuretics
91
Can be used safely with most agents concurrent administration with lithium may result in
increased lithium serum concentrations and can predispose patients to lithium toxicity.
Diuretics Interactions
92
Patients on thiazide-type diuretic therapy have a higher incidence of developing type 2 diabetes
Rational: ◦ insulin utilization is linked to intracellular potassium.
Hypokalemia predispose to largest increases in glucose concentrations. The potassium cut point at which this relationship appears is when serum potassium is less than 4.0 mEq/L.
Thiazide induced Hyperglycemia
93
thiazide-type diuretics are NOT contraindicated in patients with diabetes, however , linicans should minimize hyperglycemia by:◦ use the lowest effective dose (e.g., hydrochlorothiazide
12.5 or 25 mg daily)◦ maintain serum potassium values between 4.0 and 5.0
mEq/L ◦ Encourage lifestyle modification.
Thiazide induced Hyperglycemia
Angiotensin Converting Enzyme Inhibitors (ACEI)
95
Has many evidence-based uses in patients with HTN and any compelling indications
Most ACEI can be dosed once daily in hypertension◦Sometime, twice daily dosing is needed to maintain
24-hour effects with enalapril, benazepril, moexipril, quinapril and ramipril.
well tolerated
Angiotensin Converting Enzyme Inhibitors
96
ACEI Side Effects Profile Hypotension:
starting dose should be reduced (almost by 50%) in patients at risk of hypotension (who are sodium or volume depleted, in heart failure exacerbation, very elderly, or on concurrent vasodilators or diuretics)
◦Start low and go slow
Angiotensin Converting Enzyme Inhibitors
97
Hyperkalemia◦Risk factors: CKD, concomitant K-sparing
diuretic, ARA, ARB, direct renin inhibitor and or K-supplements
◦Monitor K, creatinine values within 4 week, when starting or increasing the dose
Angiotensin Converting Enzyme Inhibitors
98
Acute kidney failure: ◦ Risk factors: pre-existing kidney disease severe bilateral
renal artery stenosis or severe stenosis in artery to solitary kidney
◦ Slowly titrate the dose and monitor kidney function◦ Anticipate small increase in serum creatinine (MOA of the
drug) If more than 35% increase in Cr from baseline (< 3mg/dl)
or absolute increase of >1 mg/dL yo may need to stop ACEI or reduce dose
Angiotensin Converting Enzyme Inhibitors
99
Angioedema include lip and tongue swelling and possibly
difficulty breathing. Serious cases, laryngeal edema and/or pulmonary symptoms
D/C ACEI and avoid future use May use ARB
TRANSCEND study
Angiotensin Converting Enzyme Inhibitors
100
Persistent cough◦In 20% of patients◦Inhibition of bradykinin
Pregnancy: major congenital malformations do not use in pregnancy or in patients with a
history of angioedema
Angiotensin Converting Enzyme Inhibitors
101
Angiotensin Receptor Blockers
102
Studies established that the CV event lowering benefits of ARB therapy are similar to ACE inhibitor therapy in hypertension. ◦ON-TARGET study ACEI-based vs. ARB-based therapy vs. ACEI+ARB No difference in 1 end point: CV death or
hospitalization for heart failure Combo regimen: no additional benefit and more
SE Comparable CV benefit as CCB-based therapy
Angiotensin Receptor Blockers
103
Lowest incidence of SE renal insufficiencyHyperkalemiaOrthostatic hypotension. Apply same precautions as with ACE
inhibitors should not be used in pregnancy
Angiotensin Receptor Blockers
104
Calcium Channel Blockers
105
Calcium Channel Blockers
106
Two subclasses of CCBs:◦DHP and non-DHP pharmacologically very different Antihypertensive effectiveness is similar Different pharmacodynamic effects.
◦DHP studied in the ALLHAT study◦Non-DHP◦have additional benefits in patients with atrial
tachyarrhythmia. Avoid in HF
Calcium Channel Blockers
107
CCB side effects profile DHP:
◦ Dizziness, flushing, headache, gingival hyperplasia, peripheral edema
◦ mood changes◦ various gastrointestinal complaints. ◦ Immediate release: reflex sympathetic stimulation
Non-DHP CCB:◦ anorexia, nausea, peripheral edema, and hypotension.
Verapamil causes constipation in about 7% of patients., less with diltiazem
Calcium Channel Blockers
108
drug interactions ◦CYP450 A3A4 (diltiazem, verapamil)◦Caution with: cyclosporine, digoxin,
lovastatin, simvastatin, tacrolimus, theophylline
Caution with non-DHP & BB: risk of heart block
CCB Hepatic metabolism inhibited by grape fruit juice (~ 1 qt/d= 4cups)
Calcium Channel Blockers
109
DHP:◦ Extended-release products are preferred for HTN◦ Immediate release DHP associated with an increased
incidence of adverse CV effects Not to be used in HTN
Non-DHP◦ SR formulation not AB rated by the FDA as interchangeable
on mg-per-mg basis Calan SR and Verelan
Different biopharmaceutical release mechanisms Clinical significant: none
CCB Formaulations
110
Rational: ◦ designed to target the circadian BP rhythm◦ blunting the early morning BP surge may result in greater
reductions in CV events than conventional products in the morning.
◦ Verapamil: Covera HS and Verelan PM, both dosed pm◦ Diltiazem: Cardizem LA, dosed am or pm
CONVINCE trial◦ Controlled ONset Verapamil Investigation of Cardiovascular
End-points No difference in CV events compared to a thiazide-type
diuretic–BB regimen
Chronotherapeutic formulations
111
Beta Blockers
112
Beta Blockers
113
Not a first line without compelling indications Compelling indications :
◦Post-MI, coronary artery disease◦left ventricular dysfunction and diabetes◦BB based therapy is not associated with lower CV
events Possible explanation: Most studies used atenolol atenolol was used as once daily instead of
twice daily (t1/2 is 6-7 hrs)
Beta Blockers
114
All BB provide a similar degree of BP lowering Different Pharmacodynamic properties:
◦Cardioselectivity◦ISA◦membrane-stabilizing effects
Cardioselective BB are preferred when treating HTN than nonselective BB◦cardioselectivity is a dose-dependent phenomenon
Beta Blockers
115
BB with ISA◦ do not appear to reduce CV events◦ resting heart rate, CO, and peripheral blood flow are not
reduced◦ may increase risk post-MI or in those with coronary artery
disease. ◦ rarely used
All -blockers exert a membrane-stabilizing action on cardiac cells when large doses are given◦ Of value when BB are used as an antiarrhythmic agent.
Beta Blockers
116
BB Pharmacokinetic differences ◦first-pass metabolism◦route of elimination (renal vs. hepatic)◦ lipophilicity (more CNS SE)◦serum half-lives.
Beta Blockers
117
BB Side Effect Profile◦Bradycardia◦2nd , 3rd heart block◦Acute HF: if initial dose is high◦Avoid abrupt cessation abrupt discontinuation may present as
tachycardia, sweating, and generalized malaise in addition to increased BP.
Taper gradually over 1 to 2 weeks
Beta Blockers
118
Metabolic SE of BB◦May increase serum cholesterol and glucose
values◦Transient , little clinical significance.
erectile dysfunction Cold extremities aggravate intermittent claudication or
Raynaud phenomenon
Beta Blockers
119
The first oral direct renin inhibitor Block RAAS at point of activation
Aliskiren (Tekturna ®)
120Nature Reviews Drug Discovery 7, 399-410 (May 2008)
Approved in 2007 as mono and combination therapy no long-term studies evaluating CV event reduction and
significant drug cost compared to older generic agents with outcome data
Available products: single drug or combination with:◦ amlodipine◦ HCTZ◦ Valsartan: no longer marketed◦ triple combination tab with HCTZ and amlodipine
Aliskiren (Tekturna ®)
Dose: 150-300 mg once daily◦ High fat meal decrease absorption
Side effects: ◦Similar to ACEI and ARB
Consider avoiding in women during childbearing years◦Can cause diarrhea◦Monitor K and serum Cr after initiation or titration of
dose◦Caution: angioedema
Aliskiren (Tekturna ®)
ALTITUDE trial:◦ Trial was terminated early◦ Aliskiren added to ACEI or ARB therapy in patients with type 2
diabetes mellitus and renal impairment compared with a placebo add-on
◦ An increase in nonfatal stroke, renal complications,◦ hyperkalemia, and hypotension and no apparent benefits among
patients randomized to aliskiren group FDA Black Box Warning:
◦Use in combination with ACEI or ARB in patients with diabetes or renal impairment (GFR<60 ml/min) should be avoided.
Aliskiren (Tekturna ®)
(Curr Drug Saf. 2012 Feb;7(1):76-85)
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