Management of Hypertension

Management of Hypertension
Ghada A Bawazeer. MSc, Pharm.D., BCPS Ibrahim Sales, Pharm.D. Assistant Professors-Clinical Pharmacy Dept College of Pharmacy Sept. 2013

Background 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

Hypertension in Saudi Arabia
Elkhalifa et al (2011): prevalence of HTN 26% Alzahrani (2011): prehypertension 37%, hypertension 18% Alshehri (2008): 57.8% in diabetic patients

Data from National Health & Nutrition Examination Survey (NHNES)
BP Control Rate National Health and Nutrition Examination Survey (NHANES), United States, 2003–2010 Controlled % Uncontrolled % Unaware % Aware and not treated 15.8% Aware and treated % Data from National Health & Nutrition Examination Survey (NHNES)

What is the recommendation for BP screening?
JNC VII NICE 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 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 or Stage 1 HTN or Stage 2 HTN > 160 or > 100 Isolated Systolic HTN > 140 < 90

Blood Pressure Classification: 2007 European Societies of HTN and Cardiology
BP Classification SBP mmHg DBP mmHg Optimal BP < 120 < 80 Normal and /or High Normal and /or Grade 1 and / or Grade 2 and / or Grade 3 > 180 and / or > 110 Isolated Systolic HTN >140 < 90 ISH according to NICE: SBP >160 and DBP <90 mm Hg

Cardiovascular Risk and Blood Pressure
Strong correlation between BP and CV morbidity and mortality. Risk increases Patients with prehypertension SBP vs DBP

Etiology 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 A: Accuracy, Apnea, Aldosteronism ( ) 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. A: Accuracy, Apnea, Aldosteronism ( ) B: Bruits, Bad Kidneys: RAS / Renal Parenchyma/ Pheochromocytoma C: Cushings, Coarctation of Aorta, Catechol ( ) D: Drugs, Diet E: Erythropoietin ( ), Endocrinopathies/

Hypertension Pathophysiology
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

How much resistance to blood flow Total peripheral resistance (TRP)
How much blood flow How much resistance to blood flow BP Cardiac Output (CO) Total peripheral resistance (TRP) 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) Increase pre-load Increased fluid volume excess sodium intake renal sodium retention Venous constriction: Excess stimulation of RAAS Sympathetic

Neuro-Humoral Mechanisms
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

Diagnostic algorithm for hypertension
Hypertension Visit 1 BP Measurement, History and Physical examination Hypertensive Urgency / Emergency Hypertension Visit 2 Target Organ Damage or Diabetes or BP ≥ 180/110? Diagnosis of HTN Yes No BP: / Office BPM ABPM (If available) Home BPM (If available) 14

Criteria for the diagnosis of hypertension and recommendations for follow-up
BP: / Office BP Diagnosis of HTN Hypertension visit 3 >160 SBP or >100 DBP >140 SBP or >90 DBP < 140 / 90 Continue to follow-up <160 / 100 Hypertension visit 4-5 ABPM or HBPM or ABPM (If available) Diagnosis of HTN Awake BP >135 SBP or >85 DBP or 24-hour >130 SBP or >80 DBP <135/85 and <130/80 Continue to follow-up Home BPM >135/85 < 135/85 Diagnosis of HTN Continue to follow-up Repeat Home BPM If < 135/85 Patients with high normal blood pressure (office SBP and/or DBP 85-89) should be followed annually. 15

Diagnosis Blood pressure measurement
Based on average of > 2 accurate measurements taken during two or more clinical encounters

Patient Evaluation Routine Laboratory Tests : Urinalysis
Blood chemistry (potassium, sodium and creatinine) Fasting glucose Fasting total cholesterol and high density lipoprotein cholesterol (HDL), low density lipoprotein cholesterol (LDL), triglycerides Standard 12-leads ECG 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% of hypertensive patients have at least 1 additional risk factor  Risk factors =  Global CV risk Rantala A, et al. J Intern Med 1999;245; Wannamethee S, et al. J Hum Hypertens 1998;12;735-41 19

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 20

Methods of Risk Assessment
Clinical impression Risk factor counting Risk calculation or equation tools Framingham hard coronary heart disease (CHD) SCORE Canada – Systematic Cerebrovascular and Coronary Risk Evaluation Cardiovascular Age™ Others: see notes Will be discussed in more details during PPL 3 and Dyslipidemia lecture Also see the AHA’s High Blood Pressure Health Risk Calculator at : 21

What is the optimal BP target in hypertensive patients?
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

Blood pressure treatment goals among the different guidelines
JNC7 2003 AHA 2007 NICE 2011 CHEP 2013 ESC 2009 No co-morbid Conditions <140/90 mm Hg BP within /80-85 mm Hg Patients with Diabetes <130/80 mm Hg

JNC7 2003 AHA 2007 NICE 2011 CHEP 2013 ESC 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 recommendation <130/80 mm Hg <140/90 mm Hg Suggesting it is wise to lower to < 130/80 Patients with left ventricular dysfunction (heart failure) <120/80 mm Hg

JNC7 2003 AHA 2007 NICE 2011 CHEP 2013 ESC Patients with CKD <130/80 <140/90 Not clear Elderly population (>80 yr) <150/90

Management of Hypertension

Goals of Therapy 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

Approach to Treatment Lifestyle modification AND
Pharmacological therapy

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. Regular physical activity: accumulation of 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 kg/m2) Waist Circumference: Men <102 cm Women <88 cm Tobacco free environment 29

Impact of Lifestyle Therapies on Blood Pressure in Hypertensive Adults
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 min/week -4.9 / -3.7 Dietary patterns DASH diet -11.4 / -5.5 Padwal R et al. CMAJ 2005;173;(7); 30

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 31

Drug Therapy for Hypertension

General Principles 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.

High risk (TOD or CV risk factors) 140 90
II. Indications for Pharmacotherapy Usual blood pressure threshold values for initiation of pharmacological treatment for hypertension Lifestyle modification is recommended for all regardless of BP 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 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

II. Indications for Pharmacotherapy Recommended Treatment Targets
Treatment consists of non-pharmacological ± pharmacological management Population SBP DBP Diabetes <130 <80 Very elderly (≥ 80 years) <150* <90 All others (including CKD) <140 *This higher treatment threshold for the very elderly reflects current evidence and heightened concerns of precipitating adverse effects, particularly in frail patients. Decisions regarding initiating and intensifying pharmacotherapy in the very elderly should be based upon an individualized risk-benefit analysis.

When to initiate drug therapy?
Stage 1 HTN No TOD, low CV risk Life style modification (LS) TOD, moderate-high risk LS + drug therapy Stage 2 HTN JNC 7 recommend 2 combination therapy as initial therapy Isolated Systolic HTN When BP >140/90 mm Hg

Algorithm for treatment of HTN
presence of compelling Indications degree of BP elevation

INITIAL TREATMENT AND MONOTHERAPY Lifestyle modification
III. Treatment of Adults with Systolic/Diastolic Hypertension WITHOUT Other Compelling Indications TARGET <140/90 mmHg INITIAL TREATMENT AND MONOTHERAPY Lifestyle modification therapy Thiazide ACEI ARB Long-acting CCB Beta- blocker* 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 *BBs are not indicated as first line therapy for age 60 and above ACEI, ARB and direct renin inhibitors are contraindicated in pregnancy and caution is required in prescribing to women of child bearing potential 39

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. 40

Does the CV benefits seen in ALLHAT for Chlortahlidone extend to hydrochlorothiazide?
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.

IF BLOOD PRESSURE IS NOT CONTROLLED CONSIDER
Add-on Therapy for Systolic/Diastolic Hypertension without Other Compelling Indications If partial response to monotherapy 2. Triple or Quadruple Therapy 1. Add-on Therapy 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). 42

III. Summary: Treatment of Isolated Systolic Hypertension without Other Compelling Indications
TARGET <140 mmHg, < 150 mmHg for age > 80 years Lifestyle modification therapy Thiazide diuretic ARB Long-acting DHP CCB *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). CONSIDER Nonadherence Secondary HTN Interfering drugs or lifestyle White coat effect Dual therapy Triple therapy 43

Partial response 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.

Combination therapy 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

Considerations when Selecting a 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

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

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).

Choice of antihypertensive agent
HTN 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 50

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. 51

XII. Treatment of Hypertension in association with Diabetes Mellitus: Summary
Threshold equal or over 130/80 mmHg and TARGET below 130/80 mmHg with Nephropathy 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. ACE Inhibitor or ARB Diabetes 1. ACE Inhibitor or ARB or 2. DHP-CCB or Thiazide diuretic without Nephropathy > 2-drug combinations 1. Persons with diabetes mellitus should be treated to attain systolic blood pressure of lower than130 mmHg (Grade C) and diastolic blood pressure of less than 80 mmHg (Grade A). (These target blood pressure levels are the same as the blood pressure treatment thresholds.) Combination therapy using two first-line agents may also be considered as initial treatment of hypertension (Grade B) if the SBP is 20 mmHg above the target or if DBP is 10 mmHg above the target. However caution should be exercised in patients in whom a substantial fall in blood pressure is more likely or poorly tolerated (e.g. elderly patients, patients with autonomic neuropathy). 2. For persons with cardiovascular or kidney disease, including microalbuminuria or with cardiovascular risk factors in addition to diabetes and hypertension, an ACE inhibitor or an ARB is recommended as initial therapy (Grade A). 3. For persons with diabetes and hypertension not included in the above recommendation, appropriate choices include (in alphabetical order): ACE inhibitors (Grade A), angiotensin receptor blockers (Grade B), dihydropyridine CCBs (Grade A) and thiazide/thiazide-like diuretics (Grade A). 4. If target blood pressures are not achieved with standard-dose monotherapy, additional antihypertensive therapy should be used. For persons in whom combination therapy with an ACE inhibitor is being considered, a dihydropyridine CCB is preferable to hydrochlorothiazide (Grade A). 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 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 52

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 While the ACCORD blood pressure study was designed to determine if targeting systolic blood pressure < 120 mmHg in people with type 2 diabetes and high risk of cardiovascular events was superior to targeting < 140 mmHg systolic for the composite outcome f fatal and nonfatal major cardiovascular events. NEJM, March 2010. Action to Control Cardiovascular Risk in Diabetes ACCORD study NEJM 2010 53

When would you consider BB?
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.

Alternative Antihypertensive agents

Hypertension management in Selected Populations

Elderly 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 The Hypertension in the Very Elderly Trial

Elderly 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

Patients susceptible to 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

HTN & Pregnancy 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 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 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

Treatment of HTN in Pregnancy

HTN & Reactive airway diseases
Cardioselective BB can be safely used in patients with Asthma or COPD and HTN (with compelling indication)

HTN in Patients with PAD
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)

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: 66

IV. Vascular Protection for Hypertensive Patients: ASA
Consider low dose ASA Caution should be exercised if BP is not controlled. 67

Use of Aspirin in patients with HTN
Secondary Prevention Daily low dose aspirin is established in the secondary prevention of cardiovascular disease

Aspirin in Patients with Diabetes and HTN
Low dose aspirin ( 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) Do Not recommend low dose aspirin in patients at low risk. Potential Harm offset potential benefit (ACCF/AHA Class III, Level of Evidence: C) (ADA Level of Evidence: C) Circulation. 2010;121:

history of previous GI bleeding or PUD
High CV risk Age M >50 , W >60 + one or more of: Smoking Hypertension Dyslipidemia FamHx of premature CVD albuminuria High risk of bleeding history of previous GI bleeding or PUD concurrent use of medications that increase bleeding risk, such as NSAIDS or warfarin Moderate CV risk Younger patients + one or more RF Older patients with 10-year risk of 5-10% Low CV risk Age M <50 yr , W <60 yr. With no major additional CVD risk factors; 10-year CVD risk under 5% Circulation. 2010;121:

Resistant HTN 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

Resistant HTN

Hypertensive Crisis 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 Urgency 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)

Hypertensive Emergency
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.

Parenteral Antihypertensive Agents for Hypertensive Emergency

HTN & Non-Adherence Identify potential barriers to adherence
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 IT IS ESTIMATED THAT 50-80% OF PATIENTS WITH HTN DO NO TAKE ALL OF THEIR PRESCRIBED MEDICATION. ATRIAL OF 46 STUDIES SHOWE THAT THE FOLLOWING MAY HELP: BEHAVIORAL SKILL TRAINING, SELF MONITORING; TELEPHONE/MAIL CONTACT; SELF-EFFICACY ENHANCEMENT AND EXTERNAL COGNITIVE AIDS. Must work together to influence and reinforce instructions to improve patient’s lifestyles and BP Control. PCMH: Patient Centered Medical Home. NICE: 1.7 Patient education and adherence to treatment 1.7.1 Provide appropriate guidance and materials about the benefits of drugs and the unwanted side effects sometimes experienced in order to help people make informed choices. [2004] 1.7.2 People vary in their attitudes to their hypertension and their experience of treatment. It may be helpful to provide details of patient organisations that provide useful forums to share views and information. [2004] 1.7.3 Provide an annual review of care to monitor blood pressure, provide people with support and discuss their lifestyle, symptoms and medication. [2004] 1.7.4 Because evidence supporting interventions to increase adherence is inconclusive, only use interventions to overcome practical problems associated with non-adherence if a specific need is identified. Target the intervention to the need. Interventions might include: suggesting that patients record their medicine-taking encouraging patients to monitor their condition simplifying the dosing regimen using alternative packaging for the medicine using a multi-compartment medicines system.

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

Monitoring Therapeutic Plan for patient with HTN
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

Within 3 days of start of therapy and again at 1 week

Monitoring Therapeutic Plan for patient with HTN
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.

Review on the Individual Antihypertensive agents

Diuretics 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 1.25–2.5 0.5–1 2.5–10 1 Loops Bumetanide (Bumex) Furosemide (Lasix) Torsemide (Demadex) 0.5–4 20–80 5–10 2

Diuretics Subclass Drug (Brand Name) Usual Dose Range, mg/day
Daily Frequency Potassium sparing Amiloride (Midamor) Amiloride/hydrochlorothiazide (Moduretic) Triamterene (Dyrenium) Triamterene/ hydrochlorothiazide (Dyazide) 5–10 5–10/50–100 50–100 37.5–75/25–50 1 or 2 1 Diuretics Aldosterone Antagonists Eplerenone (Inspra) Spironolactone (Aldactone) Spironolactone/hydrochlorothiazide (Aldactazide) 25–50 25–50/25–50

Diuretics 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 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 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 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 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 Interactions
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.

Thiazide induced Hyperglycemia
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
thiazide-type diuretics are NOT contraindicated in patients with diabetes, however , linicans should minimize hyperglycemia by: use the lowest effective dose (e.g., hydrochlorothiazide or 25 mg daily) maintain serum potassium values between 4.0 and 5.0 mEq/L Encourage lifestyle modification.

Angiotensin Converting Enzyme Inhibitors (ACEI)

Angiotensin Converting Enzyme Inhibitors
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

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

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

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

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

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 Receptor Blockers

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

Lowest incidence of SE renal insufficiency Hyperkalemia Orthostatic hypotension. Apply same precautions as with ACE inhibitors should not be used in pregnancy

Calcium Channel Blockers

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

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

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)

CCB Formaulations 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

Chronotherapeutic formulations
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

Beta Blockers

Beta Blockers Not a first line without 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 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 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 BB Pharmacokinetic differences first-pass metabolism
route of elimination (renal vs. hepatic) lipophilicity (more CNS SE) serum half-lives.

Beta Blockers 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 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

Aliskiren (Tekturna ®)
The first oral direct renin inhibitor Block RAAS at point of activation Nature Reviews Drug Discovery 7, (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

Dose: 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

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. (Curr Drug Saf Feb;7(1):76-85)

Management of Hypertension

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