New Advances in the Management of Hypertension
A) Introduction

1) Hypertension is a chronic disease, accounting for the largest number of physician office visits.

2) 25-30% of the U.S. adult population

3) More prevalent in men than women.

4) African-Americans:

• Higher overall prevalence of HTN.

• Higher HTN associated morbidity.

• More likely to develop HTN at younger age.

• Higher proportion of hypertensives with Stage III-IV HTN (12% vs 6% in white hypertensives)

B) Morbidity of Hypertension

1) End stage renal disease

2) CAD/MI

3) Stroke

4) Relative risk of stroke and CAD at various diastolic bp levels in untreated patients:

Usual Diastolic Blood Pressure Relative Risk of CAD Relative Risk of Stroke
Lancet * MRFIT** Lancet MRFIT
76 0.5 0.67 0.3 0.51
84 0.7 0.80 0.5 0.74
91 1.0 1.00 1.0 1.00
98 1.5 1.16 1.8 1.46
99-105 2.0 1.68 3.5 2.25

* Lancet: 10 year follow up in summary of 9 studies of untreated patients (Lancet 1990;335:765).

* * MRFIT: Multiple Risk Factor Intervention Trial (Arch Int Med 1993; 153:598-615).

C) Diagnosis of Hypertension

1) Three separate readings over time of >140/90 in office setting.

2) No cigarettes or caffeine for 30 minutes prior to readings.

3) Measured after 5 minutes of rest.

4) A single diastolic bp of 110 usually proves to be tree HTN in follow up.

D) Classification of Hypertension

1) From the Sixth Report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure (JNC-VI), Arch Int Med 2006;157:2413.]

Category Systolic BP Diastolic BP Follow-up Interval
Optimal <120 <80
Normal <130 <85 2 years
High normal 130-139 85-89 1 year
Stage I (mild) 140-159 90-99 2 months
Stage II (moderate) 160-179 100-109 1 month
Stage III (severe) 180 110 1 week

I) Risk Stratification (JNC-VI)

1) Risk Group A

• No risk factors, target organ disease, or known cardiovascular disease

• Lifestyle modification for high normal or stage 1 HTN up to 12 mos.

• Initial drug therapy for Stages 2 and 3.

2) Risk Group B

• At least one risk factor not including diabetes, no target organ disease or known cardiovascular disease.

• As above though lifestyle modification for only 6 mos.

3) Risk Group C

• Diabetes, target organ disease, or known cardiovascular disease.

• Drug therapy for all patients.

• If heart failure, renal insufficiency, or diabetes:

• Initiate therapy for high normal readings of 130/85.

• Treatment goal of 130/85.

J) Ambulatory Blood Pressure Monitoring

1) Potential Indications

• Suspected "white coat HTN." This may account for up to 20% of presumed hypertensive patients

(JAMA 1988;259:225-8).

• Apparently severe HTN with no evidence of end organ disease.

• Report of normal bp reads in other settings.

• Hypotensive symptoms on reeds despite normal office readings.

• Evaluation of treatment resistant HTN.

2) Results of Ambulatory bp Monitoring.

• Average measurements of 10 mm systolic and 5 mm diastolic lower by either home self measurement or 24 hr ambulatory bp when compared with office readings (Ann Int Med 1993;118:867-882).

• Acceptable normal values for home readings therefore lower at < 135/85 (JNC-VI).

3) Natural History of White Coat HTN

• In one study, 60 of 81 patients (75%) with white coat HTN progressed to true hypertension over an average follow-up of 6 years (J Hypertens 2006; 14:327-32).

• Therefore patients with white coat HTN should not be considered the same as normotensive patients.

• More frequent follow up of these patients is recommended.

4) Short-Term Follow-Up

• 419 patients in randomized trial of antihypertensive treatment based on either conventional office readings or automated ambulatory measurement (JAMA 2006;278:1065-72):

•Stepped therapy of lisinopril, then HCTZ, then amlodipine as required by bp readings.

•Patients randomized to ambulatory monitoring more frequently required no meds (26% vs. 7%) and less often required multi-drug regimens (27% vs. 43%) over 6 mos. follow up.

•Left ventricular mass as a proxy for end organ effects was similar in both groups at the end of 6-month study.

•Costs were the same in both groups. The decreased cost of meds was offset by the cost of ambulatory monitoring.

•1187 hypertensive and 205 normotensive patients were further stratified by ambulatory 24 hr bp monitoring (Hypertension 1994;24:793).

• Average follow up 3.2 years.

•Treatment of patients was variable and uncontrolled. Follow-up bps not reported.

•Relative risk of major cardiovascular events when compared with normotensive patients

(a) 1.04 for white coat hypertensives

(b) 3.80 for ambulatory hypertensives with expected night time bp drop

(c) 10.6 for ambulatory hypertensives with no night time bp drop.

•126 white coat hypertensives and 353 treated hypertensives followed prospectively for 10 years (Circulation 2006;98:1892)

•Incidence of cerebrovascular events

(a) 3.7% for hypertensives

(b) 0.8% for white coat hypertensives

• Incidence of coronary events

(a) 15.3% for hypertensives

(b) 7.9% for white coat hypertensives

• No normotensive control population in this study

5) Long-Term Benefit

• Major studies showing beneficial effect of Rx of HTN have been based on office measurements.

• No long-term prospective studies show benefit of Rx based on home bp monitoring.

6) Recommendation

• ACP position paper (Ann Int Med 1993;118:891-892) suggests use as adjunct but not as sole measure of successful Rx.

• Recommend for suspected white coat hypertension before initiating therapy.

N) Treatment Goals

1) Target bp values:

• Diastolic bp 90.

• Diastolic bp 85 in presence of diabetes, renal insufficiency, or heart failure (JNC-VI).

• Debate as to additional benefit of lower goals.

• Some have raised concern about the "J-Curve" hypothesis especially in the elderly and patients with CAD.

• HOT trial of patients Rx with felodipine and randomized to dbp of either 90,85, or 80 (Lancet 2006;351:2755-62).

• No J shaped curve seen with dbp as low as 70 mm Hg

• Maximum cardiovascular risk reduction seen with dbp 82.6 mm Hg.

O) Lifestyle Modification

1) All patients as initial therapy (Med Clin NAmer 2006 Nov;81:1289-1303)

2) In the Treatment of Mild Hypertension Study, a mean drop in both dbp and sbp of 9 mm was achieved with lifestyle modification alone (JAMA 1993;270:713-724).

3) Weight reduction if BMI >27

• Ten pounds may lead to response.

4) Exercise

• Minimum of 30 minutes brisk walking 3 times per week, at a level of perceived exertion with no distress

• Goal 30-45 minutes most days of the week.

5) Moderation of alcohol

• No more than 24 oz beer, 8 oz wine, or 2 oz liquor per day.

6) Sodium restriction

• Approximately 50% of hypertensive patients are salt sensitive

• Particularly in blacks and the elderly

7) Adequate dietary potassium in form of fresh fruits and vegetables.

8) Smoking cessation.

9) Relaxation and biofeedback

• Data show no clear benefit for either prevention or treatment.

Q) Initial Drug Selection

1) Commonly used first-line agents are equally effective in lowering blood pressure.

• In the Treatment of Mild Hypertension study of 902 patients, the following drugs were administered as monotherapy over an average of 4.4 years (JAMA 1993;270:713-724).

• Enalapril may be less effective as monotherapy (not significantly different from placebo in this study)

Drug Change in Systolic BP Change in Diastolic BP
Acebutolol - 13.9 - 11.5
Amlodipine - 14.1 - 12.2
Chlorthalidone - 14.6 - 11.1
Doxazocin - 13.4 - 11.2
Enalapril - 11.3 -9.7
Placebo -8.6 -8.6

2) However, only diuretics and beta-blockers have been shown to reduce mortality and morbidity in prospective trials.

• Therefore, diuretics and beta-blockers are recommended as drugs of choice for monotherapy in the absence of compelling clinical indication for other agents (JNC-VI).

• JNC-VI guidelines are more flexible in identifying clinical situations where other drugs might be used as monotherapy.

• African-Americans

• More salt and volume sensitive.

• Diuretics are drugs of first choice unless contraindication.

• Calcium channel blockers and alpha-blockers also effective.

• ACE inhibitors and beta-blockers less effective than in whites.

• Multi-drug regimens more often required.

• Elderly Patients

• Diuretics are preferred agents.

• Beta blockers or long acting calcium channel blockers (especially isolated systolic HTN) are alternatives.

• Avoid drugs known to cause orthostatic hypotension such as alpha-blockers.

5) Drug Selection with Coexisting Disease

• For special clinical circumstances, preferred drugs may provide benefit to another coexisting disease.

• This benefit must be weighed against the potential downside of withholding beta-blockers or diuretics, which are the agents proven to be associated with decreased long term mortality.

• For the following four situations, the benefit is sufficiently compelling that they should be used unless contraindicated (JNC-VI):

• ACEI for diabetes with proteinuria.

• ACEI for systolic heart failure.

• Diuretics (preferred) or long-acting dihydropyridine calcium blockers for isolated systolic hypertension in the elderly (based on Syst-Eur trial Lancet 2006; 35:757-764).

• Beta-blockers and ACEI (with systolic dysfunction) post myocardial infarction.

• The UKPDS study, published after JNC-VI, challenges the view that ACEI uniquely reduce the risk of overt albuminuria and of other diabetic complications (BMJ 2006;317:713-720).

• Study of atenolol, captopril, and less tight bp control in 1148 hypertensive patients with type II diabetes

• Randomized to study drug as monotherapy.

• If bp targets not achieved, sequentially added furosemide, nifedipine, methyldopa, and prazosin.

• Nine years average follow up

• No difference in following clinical endpoints between captopril and atenolol treated groups:

5) Potential mechanisms

• Negative inotropic effect

• Proarrhythmia

• Coronary steal

• Reflex tachycardia and sympathetic activation (esp. nifedipine)

6) Studies showing beneficial effect of long-acting calcium channel blockers

• Reduced mortality in two studies of systolic HTN in the elderly (Syst-Eur trial, STONE trial)

• Reduced mortality post non Q wave MI.

• Case control study of 189 patients with first cardiovascular event (Lancet 2006;349:594-8)

• Adjusted odds ratios for cardiovascular event for users of:

(a) Short-acting calcium blockers » 3.88

(b) Long-acting calcium blockers » 0.76

• Framingham cohort (Arch Intern Med 2006;158:1882)

• No difference in mortality among patients with HTN treated with calcium channel blockers when compared to pts treated with other agents. Most patients using long-acting agents.

7) Financial conflict of interest in reports of safety of calcium blockers

• Review of 70 articles of calcium channel blockers classified the authors position as supportive, neutral, or critical of their safety (NEJM 2006;338:101-6

• Authors who were supportive of calcium blockers were nearly 3 times as likely to have a financial relationship with a manufacturer of calcium channel blockers than critical authors (96% versus 37%).

8) Future Directions

• Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) (Am J Hypertension 2006;9:342-60)

• > 40,000 patients are being randomized to amlodipine, lisinopril, doxazosin, or chlorthalidone.

• End points will include non-fatal and fatal coronary artery disease.

• May help to resolve safety issues of calcium channel blockers.

9) Recommendation

• Avoid use of short-acting nifedipine (FDA recommendation Feb. 2006).

• Reasonable to avoid all short-acting calcium channel blockers pending results from prospective long-term trials.

• Long-acting calcium channel blockers may be considered:

• Systolic HTN in the elderly

• Coronary artery disease

• Atrial arrhythmias and HTN

• Migraine and HTN

• Long-acting calcium channel blockers still not recommended routinely as monotherapy in JNC-VI.

S) Diuretics in Treatment of Hypertension

1) May be underutilized despite proven track record and endorsement of JNC-VI guidelines as a recommended initial therapy. Concerns have been raised about excess cardiac mortality:

• In a study of men with abnormal EKG, antihypertensive therapy was associated with an increased risk of coronary mortality, 32 deaths/thousand vs. 18 deaths/thousand (Am J Cardiol 1985;55:1).

• Cumulative outcomes in control and treated groups in the MRC and MRFIT trials of 25,000 patients with mild hypertension showed no reduction in coronary deaths with treatment.

T) Resistant Hypertension

1) Defined as persistent bp >140/90 despite near maximal doses of 3 drugs including a diuretic.

2) Non compliance with therapy

• Cost

• Side effects

• Inadequate patient education

• Inadequate patient instructions in use

3) White coat hypertension

4) Medication doses too low

5) Inadequate use of diuretics.

6) Other meds, ie, NSAIDs, oral contraceptives, decongestants, alcohol.

7) Secondary causes of HTN.

8) Severe essential HTN.