Resistant Hypertension

Prof. Dr. Magdy Abdel Hamid , MD , FSCAI Professor of Cardiology Cairo University Resistant Hypertension
Resistant hypertension is defined as persistent elevation of blood pressure above 140/90 mmHg in patients who are adhering to triple-drug regimen including a diuretic, and all three drugs are prescribed near maximum recommended doses for at least three months.
For older patients with isolated systolic hypertension, resistance is defined as failure of an adequate triple-drug regimen to reduce systolic blood pressure below 160 mmHg.
The diagnosis of resistant hypertension requires accurate blood pressure measurement to confirm persistently elevated blood pressure levels .
Resistant hypertension is almost always multifactorial in etiology. Successful treatment requires identification and reversal of lifestyle factors contributing to treatment resistance; diagnosis and appropriate treatment of secondary causes of hypertension; and use of effective multidrug regimens . Referral to a specialist or a hypertension centre should be considered, because resistant
hypertension is recognized to be often associated with subclinical organ damage and a high added cardiovascular risk .
Although an inadequate response to antihypertensive therapy is unfortunately common, true resistant hypertension is rare
I. Definition:
Persistent elevation of blood pressure above 140/90 mmHg in patients who are adhering to triple-drug regimen including a diuretic, and all three drugs are prescribed near maximum recommended doses for at least three months.
For older patients with isolated systolic hypertension, resistance is defined as failure of an adequate triple-drug regimen to reduce systolic blood pressure below 160 mmHg.
Patient Characteristics Associated With Resistant Hypertension
● Older age
● High baseline blood pressure
● Obesity
● Excessive dietary salt ingestion
● Chronic kidney disease
● Diabetes
● Left ventricular hypertrophy
● Black race
● Females
Patients with resistant hypertension are more likely to have target organ damage and are at greater risk of stroke, myocardial infarction, and/or heart failure compared to patients with more easily controlled hypertension.
The high cardiovascular risk is attributable in part to long-standing, poorly controlled hypertension and to the coexistence of other cardiovascular risk factors, including left ventricular hypertrophy, obesity, diabetes, hyperlipidemia, chronic kidney disease, and obstructive sleep apnea.
II. Causes Of Inadequate Responsiveness To Therapy
(1) Poor Blood Pressure Measurement Technique
e.g., using a small cuff size in an obese arm .
(2) False High Blood Pressure
Twenty to 50% of patients referred to specialized clinics for evaluation have normal blood pressure on ambulatory monitoring. Three important causes are identified:
● Office (white coat) Hypertension
15-30 % of patients diagnosed with hypertension actually have normal blood pressure at home.
● Pseudo-hypertension
Seen in elderly patients with atherosclerotic arteries, and calcified brachial artery. The cuff pressure is inappropriately high compared with intra-arterial pressure.
Features of White Coat
Hypertension
Definition:
● Abnormal office blood pressure ≥ 140/90 mmHg
● Normal daytime ABPM Prevalence of white coat hypertension
● 15-30 % of general population
● 30 % in pregnancy
Risks of white coat hypertension
● Considerably less than sustained hypertension
● Probable small risk compared to normotensives
● Possibly a pre-hypertensive state
● May not be an entirely innocent condition
Clinical implications
● Few clinical characteristics to assist diagnosis
● Must be considered in newly diagnosed hypertensives
● Should be considered before starting treatment
● Must be placed in context of over all risk profile
● Common in the elderly and pregnancy
● Less drug prescription
● Need for follow - up and remonitoring.
(3) True High Blood Pressure
● Inappropriate Drug Therapy
A suboptimal medical regimen accounts for approximately 40% of patients referred to a tertiary care clinic for resistant hypertension.
- Incorrect drug combination: e.g., using drugs from the same pharmacologic group.
- Inadequate dosing: e.g., small dose, short acting preparation given once daily.
● Poor compliance with treatment
Poor adherence to the prescribed medical regimen is possibly the most common etiology of resistant hypertension. One-half of all patients discontinue antihypertensive medications within one year.
- Drugs: interruption, discontinuation, or irregular treatment..
Causes of poor compliance with treatment
- Side effects of medication
- Cost of medication
- Lack of consistent and continuous primary care
- Inconvenient and chaotic dosing schedules
- Instructions not understood
- Inadequate education of patients
- Dementia (e.g., memory deficit)
● Lifestyle: high salt intake, alcohol excess, uncontrolled obesity, continuous stressful exposures
Ingestion of substances that can elevate blood pressure:
● NSAIDs (nonsteroidal anti inflammatory drugs).
● Oral contraceptives.
● Glucocorticoids.
● Mineralocorticoids.
● Sympathomimetics (e.g., nasal decongestants, appetite suppressants).
● Licorice.
● Phenothiazines.
● Antidepressants.
● Cyclosporine.
● MAO inhibitors and tyramine rich foods.
● Erythropoietin.
● Cocaine.
(4) True Resistant Hypertension
● Extracellular Volume Expansion
- Inadequate diuretic therapy
- Renal insufficiency.
- Direct vasodilators.
- Excessive sodium intake
● Secondary Hypertension
III. MANAGEMENT (SEE ALGORITHM )
The first step in managing resistant hypertension lies in a careful history taking , a meticulous examination of the patient and goodinvestigational back-up, primarily to exclude secondary causes of hypertension .
Blood pressure should be measured accurately according to guidelines. False-high blood pressure readings should be excluded. Vasopressor medications, and drug therapy needs to be reviewed for appropriateness of drug dose and combination.
Out-of-office BP monitoring
Apparently resistant patients should be evaluated by out-of office blood pressure measurements, either by self measurement of blood pressure at home or by ambulatory monitoring. Both home and ambulatory blood pressure measurements help to identify white coat hypertension. Ambulatory measurements are a better predictor than office blood pressure measurements of cardiovascular morbidity (ie, end-organ damage) and mortality in patients with resistant hypertension
It will be necessary to test whether compliance is good or not, and careful history taking may provide the key to the cause: being drinking of alcohol, for example, may explain why blood pressure of an individual is difficult to control.
Ultimately, many patients will need administration of more than three drugs. At present, the optimal choice of the 3rd, 4th and 5th line antihypertensive agents has not been addressed by proper randomized trials.
Recent observational studies suggest that the aldosterone antagonist , spironolactone in a low dose usually 25 mg daily provides significant additional blood pressure reduction when added to multidrug treatment regimens of patients with resistant hypertension . Particular caution is advised in people with a reduced GFR and serum potassium should be lower than 5.0 mmol/l as they are at increased risk of hyperkaelemia .Risk of hyperkalemia is increased in older patients, patients with diabetes and/or CKD, or when added to ongoing treatment with ACE inhibitors, ARBs, and/or NSAIDs. Serum potassium and creatinine values should be checked approximately 2 weeks after treatment initiation and periodically thereafter.
Diuretics — Persistent volume expansion (typically not sufficient to produce edema) contributes to resistant hypertension, even among patients who have been on conventional doses of thiazide diuretics.
Effective diuretic use is almost always necessary to achieve blood pressure control in patients with resistant hypertension . Diuretics should be titrated until the blood pressure goal or the maximum recommended dose has been reached or the patient has signs suggestive of overdiuresis such as fatigue, orthostatic hypotension, or decreased tissue perfusion as evidenced by an otherwise unexplained elevation in the serum creatinine concentration. If overdiuresis is suspected, diuretic therapy needs to be reduced.
In those with little renal impairment, chlorthalidone is preferred to hydrochlorothiazide for the treatment of resistant hypertension .Chlorthalidone has a more potent antihypertensive effect than hydrochlorothiazide due, in part, to its much longer half-life. Monitoring of serum electrolytes is necessary .Among patients with an estimated glomerular filtration rate of less than 30 mL/min per m2, thiazide diuretics are less effective and loop diuretics, such as furosemide , torsemide or bumetanide, may be necessary for effective volume control. Furosemide is relatively short acting and usually requires at least twice daily dosing. A loop diuretic with a longer duration of action and more consistent absorption, such as torsemide , may be more effective .
When use of spironolactone is not possible or not tolerated, then higher dose thiazide-like diuretic, alpha blockers or beta blockers are suitable alternatives for step 4 treatment, with careful monitoring of electrolytes and renal function .
Consider referral of resistant hypertensive patients to a hypertension specialist.
Catheter-based radiofrequency ablation of renal sympathetic nerves — Renal denervation by catheter-based radiofrequency ablation of the renal sympathetic nerves may lower the blood pressure in patients with resistant hypertension . The afferent and efferent renal nerves are interrupted by applying radiofrequency energy to the renal artery wall via an endovascular approach. The randomized Simplicity-2 Trial has shown, that this procedure is safe and effective in reducing blood pressure . However , Long-term data regarding efficacy and safety of radiofrequency ablation remain limited.
Suggested Readings :
1-Hypertension: clinical management of hypertension in adults .Nice guidelines , 2011 .www.nice.org.uk/guidance/CG34
2-Reappraisal of European guidelines on hypertension management: a European Society of Hypertension Task Force document . Journal of Hypertension 2009, 27:2121–2158
3- Resistant Hypertension: Diagnosis, Evaluation, and Treatment . Hypertension. 2008 ;51:1403-1419.
4- Management of hypertension in Egypt and developing countries : Guidelines Egyptian Hypertension Society , 2004.