1. Management of Hypertension: An Overview & Update
11/12/11
Marcus Weiser, DO
PGY3
Chief Resident
Via Christi Family Medicine

2. Outline Classification Causes History, PE, initial testing
Antihypertensive agents
Monotherapy & combination therapy
Background with classification & causes
Bulk of talk geared toward antihypertensive classes and evidence-based discussion of why specific agents are preferred

3. Hypertension Sustained elevation of arterial systemic blood pressure
Single most common diagnosis at US family physician office visits (coded at 11.1%)
Age usually affected
29% of US adults
Prevalence increases with age
US FM OV, htn coded in 11.1% of visits
Nextgen emr self-populates individualized list of each provider’s most commonly used assessments: mine htn #1
50% of age 60-69, about 75% of those > 70

4. Hypertension
Baseline high blood pressure at age 50 reduces life expectancy by about 5 years.1
Associations
Erectile dysfunction, ophthalmologic conditions, osteoporosis, anxiety, chronic kidney disease, obstructive sleep apnea, coronary artery disease, cerebrovascular disease, peripheral arterial disease, congestive heart failure, dementia
Framingham cohort study. Why do we care about htn
Many ways to scare patients into compliance (like mentioning ED or dementia may get the attention of some patients who don’t initially care). Little bit of education can go a long way, I like to simplify this education

5. In a residency clinic, I am in the habit of using terms patients understand, terms more likely to get attention

6. Types Prehypertension (SBP 120-139 or DBP 80-89)
Stage I (SBP or DBP 90-99)
Confirm within 2 months
Stage II (SBP > 159 or DBP > 99)
Evaluate within 1 month (within 1 week if > 180/110)
Type I (vasoconstriction, high renin, high SBP)
Treat with ACE, ARB, BB
Type II (Na dependent, low renin, high DBP)
Treat with diuretics, CCB
Ways to classify htn
Jnc7, Pre – no med tx indicated except in dm or ckd
I – monotherapy
II – combo therapy
Renin/Angiotensin system
Type I – high renin (inappropriately high, exaggerated renal elimination of sodium) Tx ace, arb, bb (often SBP higher)
Type II – low renin (kidney detects excessive Na reabsorption, renin suppressed) Tx diuretics, ccb (often DBP more elevated) (most african americans have low renin levels)

7. ICD-10 codes I10 essential (primary) hypertension
ICD-10-CA modification in Canada
I10.0 benign hypertension
I10.1 malignant hypertension
I11 hypertensive heart disease
I11.0 hypertensive heart disease with (congestive) heart failure
I11.9 hypertensive heart disease without (congestive) heart failure
ICD-10-CA modification in Canada - 4th character extensions were deleted to allow for use of dual classification for added specificity
I12 hypertensive renal disease
I12.0 hypertensive renal disease with renal failure
I12.9 hypertensive renal disease without renal failure
I13 hypertensive heart and renal disease
I13.0 hypertensive heart and renal disease with (congestive) heart failure
I13.1 hypertensive heart and renal disease with renal failure
I13.2 hypertensive heart and renal disease with both (congestive) heart failure and renal failure
I13.9 hypertensive heart and renal disease, unspecified
I15 secondary hypertension
I15.0 renovascular hypertension
I15.1 hypertension secondary to other renal disorders
I15.2 hypertension secondary to endocrine disorders
I15.8 other secondary hypertension
I15.9 secondary hypertension, unspecified
5th digits assigned to specify
0 benign or unspecified
1 malignant
R03.0 elevated blood-pressure reading, without diagnosis of hypertension
11.1% of OV use one of these codes

8. Causes CKD (any cause) Renal Artery Stenosis Cushing Syndrome
Primary Hyperaldosteronism
Hyper/Hypothyroidism
Hyperparathyroidism
Pheochromocytoma
Obstructive Sleep Apnea
Coarctation of the Aorta
Black Licorice
Medications
BP Cuff too small
Arm position
Caffeine
Nicotine
Substance Abuse/Intoxication
Short sleep duration
Alcohol Use
Salt intake?
Impatience, hostility
Starting with secondary causes
licorice
Oral contraceptives, albuterol, NSAIDS, decongestants
arm position parallel to torso associated with mm Hg higher mean systolic and diastolic blood pressure readings than arm position perpendicular to torso
Habitual coffee not associated, soda use is
Etoh/opiate/benzo withdrawal, meth/cocaine use
each hour of reduction in sleep duration associated with 37% increase in odds of incident hypertension
In men, not shown in women
Inconsistent data, but little harm
But not high job stress – no association there, JAMA, no association with psych dx depression/anxiety, it pays to be chill

9. History Symptoms Medications Past Medical History Social History
Corticosteroids, OCPs, NSAIDs, venlafaxine, buspirone, carbamazepine, clozapine, bromocriptine, cyclosporin, tacrolimus, EPO
Past Medical History
DM, CAD, CHF, DSLD, Thyroid/Renal Dz
Social History
Dietary sodium, stress, smoking, alcohol intake, activity level, St. John’s wort, ergot-containing herbal preparations, cocaine, anabolic steroids, narcotic withdrawal, meth, PCP

10. Physical Exam Proper blood pressure measurement Carotid bruits
Seated in chair with back in calm, quiet, warm room for at least 5 minutes. Bare arm elevated so elbow is level with heart. No smoking or caffeine 1 hour prior
Cuff width > 2/3 arm diameter
Cuff length > 2/3 arm circumference
Average of 2 measurements
Carotid bruits
Cardiac auscultation
Abdomen
Extremities
chair back, supine, standing can falsely elevate readings
No significant difference between bare arm and one layer sleeve in normotensive, may be significant difference in hypertensive but do not roll up sleeve
Small cuff falsely elevates readings
Bruits may suggest carotid stenosis
Murmurs – valve dz, S3 – CHF, displaced PMI – LVH
Abd – AAA, abdominal bruits, striae
Ext – Femoral pulses (coarc), femoral bruits (PVD), edema (CHF)

11. Initial Testing Serum Potassium Serum Creatinine Fasting Blood Glucose
Fasting Lipid Panel
Urinalysis
Electrocardiogram
- Uniformly recommended by 4 expert panels (CHEP, ESH/ESC, ICSI, JNC7)
Hematocrit
Serum Calcium
Serum Sodium
Serum Uric Acid
Urine Albumin/Creatinine Ratio
- Recommended by some, not all 4 panels
Canadian Hypertension Education Program
European Society of Hypertension
European Society of Cardiology
Institute for clinical systems improvement
Joint National Committee 7
Easy to forget about EKG, but important to check for LVH
And QT interval – prolonged is associated with increased cv events and increased mortality in patients with htn

12. Additional Testing to Consider
PTH
TSH
24 hour urine metanephrine
Plasma Aldosterone
Plasma Renin
Dexamethasone supression test
Sleep study
RAS imaging
Secondary causes of htn is outside the scope of this lecture. Testing to consider for causes mentioned earlier

13. Agents Ace-inhibitors (ACEs) Angiotensin Receptor Blockers (ARBs)
Calcium Channel Blockers (CCBs)
Beta Blockers (BBs)
Thiazide Diuretics (TZD)
Loop Diuretics (Loops)
Aldosterone Antagonists
Alpha Blockers
Other agents
Preferred agent within each class has dosage listed
Doses are recommended for efficacy without adverse effects

14. ACEs & ARBs Special Indications ACE ARB CHF (SOLVD, AIRE, TRACE)
Post-MI (SAVE)
Diabetes (UKPDS, HOPE)
CKD (REIN, AASK, CAPTOPRIL)
Recurrent Stroke Prevention (PROGRESS)
High CAD Risk (ALLHAT, HOPE, ANBP2)
ARB
CHF (Val-HeFT)
Diabetes
CKD (RENAAL, IDNT, CAPTOPRIL)
Purposes of this lecture, ACE/ARB one class of agents.
DM with or without proteinuria

15. ACEs & ARBs Contraindications Monitor Agents
Pregnancy, Angioedema, Renovascular Disease, Hyperkalemia, Acute Renal Failure
Monitor
Creatinine, Potassium
Agents
Benazepril or Lisinopril (20mg to 40mg PO daily)
Enalapril, Ramipril
Losartan, Olmesartan, Valsartan
Purposes of this lecture, ACE/ARB one class of agents. Treating htn, only one arb generic losartan, $60/month
Lisinopril & Benazepril are $4 and once daily, other 2 shorter acting – often bid
Lisinopril is more widely used, we will go over ACCOMPLISH trial later on
No true max until hyperkalemia or increasing cr, variable bp improvement

16. Calcium Channel Blockers
Special Indications
High CAD risk (ALLHAT, CONVINCE)
Migraines
Raynaud’s
Angina (non-dihydropyridine)
Atrial Fibrillation (non-dihydropyridine)
Atrial Flutter (non-dihydropyridine)
No absolute indications
Verapamil, diltiazem – similar to bb

17. Calcium Channel Blockers
Contraindications
2nd or 3rd degree heart block
Agents
Amlodipine (5mg to 10mg PO daily)
Nifedipine, Nicardipine, Felodipine
Amlodipine is $8 per month, ONCE DAILY

18. Beta Blockers Special Indications Contraindications
CHF (MERIT-HF, COPERNICUS, CIBIS)
Post-MI (BHAT, CAPRICORN)
Angina, Atrial Fibrillation, Atrial Flutter, Tremor, Migraine
Contraindications
Asthma, COPD, 2nd or 3rd degree heart block, Depression, Acute CHF
Avoid abrupt cessation
Agents
Metoprolol (50mg to 200mg PO BID)
Carvedilol (3.125mg to 25mg PO BID)
Atenolol, Nebivolol, Labetalol, Esmolol, Propranolol, Timolol
May have an adverse effect on depression
Taper gradually over 2 weeks to d/c to avoid angina exacerbation, MI, ventricular arrythmias
Immediate-release form $4, metoprolol preferred for htn, coreg $4 preferred for chf

19. Beta Blockers Inappropriate first-line treatment
JNC8
Worse BP control (LIFE)
Worse CV outcome prevention (LIFE)
Increased mortality (ASCOT)
Higher risk of stroke 2
More side effects 2
Increased risk of type II diabetes 3
Increasing concern over the last 8 years
1st 3 with atenolol, ASCOT 2005 stopped early
16% higher stroke risk with any BB than any other antihypertensive, huge cochrane meta-analysis
ED, fatigue

20. Thiazide Diuretics Special Indications High CAD risk (ALLHAT)
Recurrent stroke prevention (PROGRESS)
DM without proteinuria (ALLHAT)
Edema
Osteoporosis

21. Thiazide Diuretics Contraindications Monitor Agents
Stage IV CKD, Gout, Hyponatremia, Acute Renal Failure
Monitor
Creatinine, Potassium, Sodium
Agents
Chlorthalidone (12.5mg to 25mg PO daily)
Hydrochlorothiazide, Indapamide, Metolazone
GFR < 30 switch to loop (torsemide)
Chlorthalidone is preferred, hctz much more widely used

22. Thiazide equivalence? Chlorthalidone vs HCTZ
Chlorthalidone use has sharply declined over the last 20 years for reasons unknown 4
Unclear why hctz use increasing and chlorthalidone use decreasing, evidence shows opposite should be occurring
Although the 2 medications never been compared head to head for cv benefits, they have each been individually compared to other agents in many large trials

23. ACCOMPLISH
Major reduction in cv events with amlodipine compared to hctz (when used in combo with benazepril)

24. Chlorthalidone vs HCTZ
Amlodipine appears superior to HCTZ
Amlodipine has major benefits compared to hctz

25. ALLHAT
Secondary Outcome

26. Chlorthalidone vs HCTZ
Amlodipine appears superior to HCTZ
Chlorthalidone appears superior to Amlodipine
Chlorthalidone had decreased rates of chf compared to amlodipine

27. ALLHAT Secondary Outcome
Lower rate of combined CVD with Chlorthalidone

28. Chlorthalidone vs HCTZ
Amlodipine appears superior to HCTZ
Chlorthalidone appears superior to Amlodipine
Chlorthalidone appears superior to Lisinopril
Lower rates of combined cv dz with chlorthalidone than lisinopril

29. ACE-I Beats Diuretic (ANBP2)
Rate of events per year

30. Chlorthalidone vs HCTZ
Amlodipine appears superior to HCTZ
Chlorthalidone appears superior to Amlodipine
Chlorthalidone appears superior to Lisinopril
Enalapril appears superior to HCTZ
Less cv events with enalapril than hctz.
So we have both the ace-i & amlodipine appearing superior than hctz, yet allhat shows chlorthalidone more beneficial than an both ace-I & amlodipine

31. Thiazide equivalence? Chlorthalidone vs HCTZ
Chlorthalidone use has sharply declined over the last 20 years for reasons unknown 4
No evidence that HCTZ improves cardiovascular outcomes
Large body of evidence in major trials (ALLHAT) showing cardiovascular event reduction and outcome benefit with chlorthalidone
Chlorthalidone has much longer half-life, is times more potent, and has slightly more hypokalemia (7-8% patients require treatment 5,6)
Stress that no head to head trial comparing outcomes chlorthalidone & hctz, but no evidence . . .
Longer half life provides for better hs bp control
Because it is more potent, lower dose required.

32. Thiazide Diuretics
Chlorthalidone superior reduction of nighttime BP, compared to HCTZ 7
13.5 mmHg vs 6.4 mmHg
Chlorthalidone ( mg) vs HCTZ (25-50mg)
Agents
Chlorthalidone (12.5mg to 25mg PO daily)
Hydrochlorothiazide, Indapamide, Metolazone
Chlorthalidone is preferred. Lower dose, 12.5 cut in half, $4 list recent
Unclear if increasing to 25mg provides for much additional bp reduction in patient that is not hypervolemic

33. Loop Diuretics Special Indications Contraindications Monitor Agents
CHF, Edema
Contraindications
Gout, Acute Renal Failure
Monitor
Creatinine, Electrolytes
Agents
Torsemide (5mg to 10mg PO daily)
Furosemide, Bumetanide
Torsemide (or Torrosemide) around $20/month, once daily, 5-10 for htn, up to 200 for edema
Torsemide is longer acting than both lasix and bumex and absorbed better than lasix
Furosemide is $4, but you have neph & cardio fighting over whether it should be q day or bid, best advantage

34. Aldosterone Antagonists
Special Indications
CHF (RALES)
Post-MI (EPHESUS)
Contraindications
Gout, Hyperkalemia, Acute Renal Failure
Monitor
Creatinine, Potassium
Agents (ASCOT)
Spironolactone (25mg to 50mg once daily)
Amiloride, Triamterene
Spironolactone $4, may go up to 200 for edema, but for htn.
ASCOT

35. ASCOT
Patients with uncontrolled hypertension on 3 antihypertensive agents
Spironolactone 25mg once daily added as 4th agent
Mean BP drop of 22/10 at one year follow-up

36. Alpha Blockers Special Indications Contraindications Agents BPH
High CV risk (ALLHAT)
Agents
Doxazosin, Prazosin, Terazosin
doubled risk of CHF, increased number of cv events
Don’t use just for htn

37. Other Agents Clonidine Methyldopa Hydralazine Tekturna Minoxidil
Isosorbide dinitrate/mononitrate
Centrally acting, stimulates alpha 2 adrenergic receptor
Peripheral vasodilator
Direct renin inhibitor
Vasodilator – I could use some of this
nitrates

38. Low . . . but how low is too low?
Treatment goal < 140/90
< 130/80 in diabetics per JNC7 recommendation
ACCORD, INVEST
BP targets below 140/90 overall do not improve morbidity or mortality
DBP < 70 increases risk of death, MI, stroke
According to JNC7, but some criticize the lack of convincing data behind this recommendation
Action to Control Cardiovascular Risk in Diabetes in 2008 revealed
no cardiovascular benefit (no reduced rate of fatal & nonfatal cv events) for the primary endpoint with more aggressive lowering of blood pressure (to less than 120 systolic versus less than 140 systolic) in high risk hypertensive diabetic patients
Invest 22k, 27% diabetics, showed M&M improvement upon bp reduction to SBP goal between But increased mortality upon reducing sbp to < 130.
JNC8?
Watch out for elderly ISH

39. Lifestyle Modifications First-Line Treatment
Sodium Restriction (2-8 mmHg)
DASH (8-14 mmHg)
Fruits, vegetables, low-fat dairy, reduced fat
Aerobic physical activity (4-9 mmHg)
Weight Reduction
(5-20 mmHg per 10 kg lost)
Moderate alcohol (2-4 mmHg)
Smoking Cessation
*From JNC7 Express Report, 2003
1 month trial, need to recheck anyways for dx
Na – no proven effect on cv M&M
Increased adherence, direct correlation with decreased cv mortality, mi, stroke
Moderate etoh consumption (1 or 2 drinks per day), decreased mortality and MI
So, its not that lifestyle modifications are not effective. It’s the getting patients to modify their life that’s usually what’s not effective.

40. Monotherapy vs Multi-Drug Therapy
Sequential treatment
Avoid excessive dosing
First-line agents
Avoid similar agents
Avoid excessive dosing
Other agents
Sequential means switch instead of add

41. Monotherapy – 1st line agents
1. Thiazide
Chlorthalidone 12.5mg daily, titrate to 25mg?
2. ACE/ARB
Benazepril or Lisinopril 20mg daily
Titrate up to 40mg, possibly beyond
3. Calcium Channel Blocker (dihydropyridine)
Amlodipine 5mg daily
Titrate up to 10mg once daily
Recommended agents are evidence-based (cost, compliance, efficacy)
In ABSENCE of any compelling indication
Doses are recommended for efficacy without adverse effects
Rare titration
ALLHAT showed Chlorthalidone to have fewer CV events than Lisinopril and Norvasc
Do not use benazepril/lisinopril or amlodipine bid
Again in absence of compelling indication

42. Specific indications change preferred first-line agent
Already mentioned special indications for each class

43. Monotherapy Sequential treatment
Try one agent, titrate up
If inadequate control, switch instead of add
Each first-line agent will normalize BP in 30-50% of patients 8,9
49.1% chance a different agent will control Stage I Hypertension following failure of initial agent 10
May prevent unnecessary multi-drug treatment
JNC7 recommendation for uncontrolled stage I hypertension on monotherapy is to optimize dose or add 2nd medication
Addition of a second drug from a different class should be initiated when use of a single drug in adequate doses fails to achieve the BP goal
Monotherapy treatment – new concept
Stage I only
if chance 1 drug will work, its worth the hassle/time
Consider first line agents
Clarify Not jnc7 recommendation.
Follow-up & compliance are additional considerations

44. Combination Therapy Consider combination for Stage 2
Add if sequential monotherapy fails
Drugs for each compelling indication
ACCOMPLISH
Include a diuretic
Consider Spironolactone as 4th agent (ASCOT)
First-line agents
In absence of compelling indication, jnc7 requires tzd diuretic
Consider benazepril amlodipine – accomplish trial

45. ACCOMPLISH
Avoiding Cardiovascular events through early COMbination therapy in Patients Living with Isolated Systolic Hypertension
11,506 patients, doses
Primary endpoint not bp, primary endpoint death from CV cause, stroke, MI, hosp angina, coronary revascularization, resuscitation after sudden cardiac death

46. ACCOMPLISH
Subset of patients with ambulatory BP monitoring had slightly lower average BP in Benazepril + HCTZ group.
Despite overall similar BP control, Benazepril + Amlodipine decreased CV morbidity & mortality by 20% compared to Benazepril + HCTZ. Terminated early by data safety monitoring board

47. ACCOMPLISH
Conclusions: Benazepril/Amlodipine superior to Benazepril/HCTZ at reducing CV events

48. Combination Therapy Drugs for each compelling indication ACCOMPLISH
Include a diuretic
First-line agents
Consider Spironolactone as 4th agent (ASCOT)
Interesting sidenote: accomplish trial authors mention increased compliance with combo pill, chlorthalidone only has atenolol or clonidine combos
JNC8 release date post-poned
predictions: different analyses - less stringent on diuretic included in 2 med combo vs stressing chlorthalidone vs hctz
Amlodipine is longer acting than hctz (like chlorthalidone), so 24 hour bp reduction may not be picked up without nighttime bp monitoring, which may explain results showing amlodipine benefit when bp control was so similar. Still, specific benefits other than bp reduction are possible
Remember 1st line agents
Remember ascot, spironolactone under-utilized, doesn’t have to be 4th but that’s the study, take home not to jump to other agents

49. Resistant Hypertension
Uncontrolled on 3 medications
Controlled on 4 or more medications
Must include a diuretic
3 meds must include a diuretic (must address both vasoconstriction and volume issue), otherwise not resistant just improperly treated.
May be inadequately diuresed

50. Causes CKD (any cause) Renal Artery Stenosis Cushing Syndrome
Primary Hyperaldosteronism
Hyper/Hypothyroidism
Hyperparathyroidism
Pheochromocytoma
Obstructive Sleep Apnea
Coarctation of the Aorta
Licorice
Medications
BP Cuff too small
Arm position
Caffeine
Nicotine
Substance Abuse/Intoxication
Short sleep duration
Alcohol Use
Salt intake?
Impatience, hostility
Same slide – causes of htn can cause resistant htn – good time to step back & reevaluate H&P
Oral contraceptives, albuterol, NSAIDS, decongestants
arm position parallel to torso associated with mm Hg higher mean systolic and diastolic blood pressure readings than arm position perpendicular to torso
Habitual coffee not associated, soda use is
Etoh/opiate/benzo withdrawal, meth/cocaine use
Last 4 more risk factors than causes
each hour of reduction in sleep duration associated with 37% increase in odds of incident hypertension
In men, not shown in women
Inconsistent data
But not high job stress – no association there, JAMA, no association with psych dx depression/anxiety, Chill out

51. Who do I screen for secondary causes of hypertension?
Resistant Hypertension
Early or Late onset
History & Physical Exam
Abnormal initial labs
Low potassium
High calcium
Abnormal subsequent monitoring
Increase Cr > 20% after starting ACE/ARB
< 10% of hypertensives
<25, >55
Labile, headaches, sweaty, energy / feel pulses / listen when they tell you symptoms of thyroid d/o / look like quasimoto hunchback of nd with abdominal striae, check cortisol

52. Additional Testing to Consider
PTH
TSH
24 hour urine metanephrine
Plasma Aldosterone
Plasma Renin
Dexamethasone supression test
Sleep study
RAS imaging
Secondary causes of htn is outside the scope of this lecture. Testing to consider for causes mentioned earlier

53. Cases 31 yo healthy AAM, BMI 31, BP 132/99 Benazepril Chlorthalidone
Losartan
Metoprolol
Chlorthalidone – high DBP = diuretic, no ccb/ace/arb in AA

54. Cases 77 yo 100 lb WF with hyperlipidemia BP 159/82 Benazepril
Metoprolol
HCTZ
Spironolactone
Benazepril – old stiff arteries with vasoconstriction and ISH, BB not first line

55. Cases 58 yo M, GFR 48, proteinuria, BP 150/95 Lisinopril HCTZ
Torsemide
Amlodipine
Lisinopril – ACE for CKD with proteinuria

56. Cases 47 yo M with depression/gout, BP 162/96 Chlorthalidone
Benazepril
Amlodipine
Metoprolol
Benazepril & Amlodipine (ACCOMPLISH), no diuretic in gout, bb may worsen depression

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Ernst ME, Carter BC, Goerdt CJ, Steffensmeier JJG, Bryles Phillips B, Zimmerman MB, Bergus GR. Comparative antihypertensive effects of hydrochlorothiazide and chlorthalidone on ambulatory and office blood pressure. Hypertension. 2006; 47: 352–358.
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