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Resistant Hypertension Epidemiology and Medical Therapy Saudi Perspective

Abdulaziz Aldammas, MD. Cardiology Consultant PSHC, King Fahad Medical City

The systematic approach to diagnosis begins with the definition… • Blood pressure (BP) that remains above goal, in spite of…

• compliance with maximum doses… • of ≥3 antihypertensive medications… • from different classes, ideally including a diuretic

BP Goal

• Reversible causes identified and addressed

1. Calhoun DA, et al. Circulation. 2008;117:e510-e526. 2. Mancia G, et al. Eur Heart J. 2007;28:1462-1536.

The systematic approach to diagnosis begins with the definition… • Use of diuretic recommended but not required • Doses should be optimal but not necessarily maximal • Controlled resistant hypertension: high blood pressure controlled but with use of 4 or more agents should be considered resistant

Not all patients with uncontrolled hypertension are treatment resistant Uncontrolled Hypertension Includes patients who lack BP control for any reason: •Inadequate treatment regimens •Poor adherence •Undetected secondary hypertension •True treatment resistance

Treatment-Resistant Hypertension • BP that remains above goal with maximum tolerated doses of ≥3 antihypertensive medications of different classes; ideally, 1 of the 3 agents should be a diuretic

A common and increasing problem… • 100 million people worldwide has uncontrolled hypertension • 15% -20% are estimated to have treatment-resistant hypertension • increased by 62% in the last 20 years

1. Persell, S. Hypertension. 2011;57:1076-1080.. 2. Lloyd-Jones D, et al. Circulation. 2010;121:e46-e215. 3. Egan BM, et al. Circulation. 2011;124:1046-1058.

Prevalence of Resistant Hypertension • •

In ALLHAT after nearly 5 years of treatment, 27% of 33,000 subjects had resistant hypertension Based on the five-year observation in ALLHAT, the authors estimate that the incidence of refractory hypertension was approximately 15%

In the controlled Onset Verapamil Investigation of Cardiovascular End points (CONVINCE) trial in individuals older than 55 years, 18% had resistant hypertension

In the Valsartan Anti hypertension long-term us Evaluation (Value) trial, at least 15% of subjects had resistant hypertension after 30 months of therapy with three or more drugs Peralta CA et al. Hypertension 2005 Cushman WC et al. Clin Hypertens

Awareness, Treatment & Control

*Controlled to < 140/90

Wolf-Maier et al., 2004. Hypertension Treatment and Control in Five European Countries, Canada, and the United States. Hypertension, 43:10-17.

HTN â&#x20AC;&#x201C; Prevalence - Arabs 23.1%

40.6% 28.5%

30.6% 32.3%






36.6% 26.3%



27% 18.2%

Data collected from different references.



HTN â&#x20AC;&#x201C; Prevalence

Data collected from different references.

75% in Saudi Do Not Reach BP Goal

Patients (%)

England Sweden





1- Wolf-Maier et al. Hypertension 2004;43:10â&#x20AC;&#x201C;17 2- Al-Rukban et al, Saudi Med J. 2007 Jan;28(1):85-90

Hypertension Prevalence in Saudi Arabia

Hypertension Prevalence in Saudi Arabia

Resistant hypertension is associated with a substantially increased risk of CV events CV Event Rate (5-year follow-up) Controlled Hypertension Treatment Resistant

5% 19%

Differences between groups were apparent from very early in the follow-up period, indicating the urgent need for BP control in patients with treatmentresistant hypertension Am J Hypertens. 2005;18:1422-1428

Cardiovascular Mortality Risk Doubles with Each 20/10 mmHg Increment in Systolic/Diastolic Blood Pressure* CV mortality risk 8

8X risk

6 4

4X risk

2 0

1X risk

2X risk





Systolic BP/Diastolic BP (mmHg) *Individuals aged 40â&#x20AC;&#x201C;69 years

Lewington et al. Lancet 2002;360:1903-1913.

Who is at risk? Patient Characteristics Associated With TreatmentResistant Hypertension* Olderage age Older

Obesity Obesity

Femalesex sex Female

Excessivedietary dietary Excessive saltingestion ingestion salt

Diabetes Diabetes Highbaseline baseline High bloodpressure pressure blood

Leftventricular ventricular Left hypertrophy hypertrophy *Based on analyses of data from the Framingham Study and The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Calhoun DA, et al. Circulation. 2008;117:e510-e526.

Chronickidney kidney Chronic disease disease

Blackrace race Black

Is it Truly a Resistant Hypertension • • • • • •

Measure BP accurately Is patient compliant? Confirm appropriate treatment Consider “White Coat Hypertension” Consider “pseudoresistantce” Consider secondary causes

Treatment-resistant hypertension: a systematic approach to evaluation and management Confirm Accuracy of BP Measurement •Utilize correct BP measurement technique •Rule out white-coat effect

Address Lifestyle Barriers to BP Control •Interfering substances •Dietary salt intake •Alcohol consumption •Obesity

Optimize Pharmacotherapy and Adherence • Regimen of 3 drugs of different classes, including a diuretic •Assess and improve adherence to the treatment regimen •Intensify pharmacologic therapy

Consider Referral to a Specialist •Treatment for secondary causes of hypertension •Hypertension specialist for intensive management of true treatment-resistant hypertension

Difficult-to-control hypertension may be due to underlying conditions •

Patients should be screened for these disorders if suggestive findings are identified upon history taking, physical exam, or basic laboratory testing

Secondary Cause Renal artery disease Aldosteronism Renal parenchymal disease

Patients with treatment-resistant hypertension and a secondary cause will rarely achieve BP control until the underlying cause is treated

Calhoun DA, et al. Circulation. 2008;117:e510-e526. Moser M, Setaro JF. N Engl J Med. 2006;355:385-392..

Hyperthyroidism or hypothyroidism

Est Prevalence (%) 3.0-4.0 1.5-15.0 (higher in recent series) 1.0-8.0 (depends on Cr level) 1.0-3.0

Coarctation of the aorta


Cushing’s syndrome




Secondary Causes of Resistant Hypertension Common • • • •

Obstructive sleep apnea Renal disease Primary aldosteronism Renal artery stenosis

Uncommon • • • •

Pheochromocytoma Cushing’s disease Hyperparathyroidism Aortic coarctation

Sleep Apnea syndrome • Up to 60% of patients with Obstructive Sleep Apnea (OSA) may have hypertension • OSA is an independent risk factor for hypertension • Hypertension in OSA patients is often resistant • CPAP therapy has been shown to significantly reduce systolic blood pressure J Hypertens 2001, 19:2271-77

Primary Aldosteronism • A much more common cause of hypertension than had been demonstrated historically • Prevalence is 13% among patients with severe hypertension 180/110 mm Hg • Prevalence in patients with resistant hypertension is approximately 20%-30% • Serum potassium levels were rarely low in patients confirmed to have primary aldosteronism, suggesting that hypokalemia is a late manifestation

CT Angiography in a Patient with Secondary HT


Bilateral Atherosclerotic RAS with Functioning Lt. Kidney

Pseudo-resistant Hypertension â&#x20AC;˘ The cuff pressure is inappropriately high compared with intra-arterial pressure because of extensive atheromatous and/or medial hyperplasia in the arterial tree â&#x20AC;˘ The condition increases with age and diagnosis requires a high index of suspicion

Clinical clues suggestive of pseudo-hypertension • Marked hypertension in the absence of target organ damage • Antihypertensive therapy produces symptoms consistent with hypotension in the absence of successful reduction of BP • Radiological evidence of pipe stem calcification in the brachial arteries • Brachial artery pressure higher than lower extremity pressure • Severe and isolated systolic hypertension • Inflating the BP cuff above the systolic BP: the maneuver is considered positive if a hard cord-like radial artery can still be palpated (Positive Osler’s maneuver)

Poor adherence is a common cause of pseudoresistance

Van Wijk BLG, et al. J Hypertens. 2005;23:2101-2107.

Tips for assessing and improving medication adherence • Signs of nonadherence – Missed office visits – Lack of physiological evidence of therapy, such as • No change in BP • Absence of anticipated common side effects • Check for suspected nonadherence by – Discussing medication use with spouse or caregiver – Verifying prescription refills with the pharmacy – Reviewing factors causing nonadherence and counseling patients on importance of therapy

What to expect: lifestyle modification effects on BP Modifications* Reduce weight

Recommendation Maintain normal body weight (BMI of 18.5-24.9 kg/m2)

Approximate SBP Reduction 3-20 mm Hg

Adopt DASH diet

Rich in fruit, vegetables, and low-fat dairy; reduced saturated and total fat content

8-14 mm Hg

Reduce dietary sodium

<100 mmol (2.4 g)/day

2-8 mm Hg

Increase physical activity

Aerobic activity >30 min/day, most days of the week

4-9 mm Hg

*Combining â&#x2030;Ľ2 of these modifications may or may not have an additive effect on blood pressure reduction. SBP = systolic blood pressure; BMI = body mass index; DASH = Dietary Approaches to Stop Hypertension.

Substances that Can Interfere with Blood Pressure Control • Alcohol • Oral contraceptives • Cyclosporine • Erythropoietin • Natural licorice • Herbal compounds

Substances that Can Interfere with Blood Pressure Control •

Non-Narcotic Analgesics - Non-steroidal anti-inflammatory agents including aspirin - Selective COX-2 inhibitors

Sympathomimetic agents - decongestants - diet pills - cocaine

Stimulants -methylphenidate -dexmethylphenidate, -dextroamphetamine - amphetamine, methamphetamine -modafinil

A simple step-wise algorithm to expedite BP control Step 1

Patient≥55 ≥55years yearsold old Patient OR OR Anyage ageblack blackperson personofof Any African or Caribbean origin African or Caribbean origin


InitiateACEI ACEIororARB ARB Initiate

Yes InitiateCCB CCB Initiate

BP still above goal?

Step 2

BP still above goal?


BP still above goal?

Step 3

CCB++ACEI ACEIororARB ARB++thiazide-like thiazide-likediuretic diuretic CCB

BP still above goal?

Step 4

•• •• ••

Evaluatefor fortreatment-resistant treatment-resistanthypertension hypertension Evaluate Consideradding addingfurther furtherdiuretic diureticororαα-ororβ-blocker β-blocker Consider Consider referral to a hypertension specialist Consider referral to a hypertension specialist

National Institute for Health and Clinical Excellence. 2011. Hypertension: Clinical management of primary hypertension in adults. CG127. London, National Institute for Health and Clinical Excellence.

Spironolactone Spironolactone can be effective in many patients with treatment-resistant hypertension • Design: Uncontrolled extension of the ASCOT trial • Patients who did not achieve BP control on their assigned 3-drug regimen had additional agents added at investigator’s discretion • Population: 1411 patients prescribed spironolactone for HTN in addition to their trial-assigned regimen • Treatment: spironolactone 25 mg once daily (median dose) • Results: With the addition of spironolactone, mean BP fell by 21.9/9.5 mm Hg (P<0.001). • Adverse events*: Experienced by 13% of patients. Gynecomastia (6%) and biochemical abnormalities (2%), mainly hyperkalemia, were most frequent

Hypertension. 2011;57:1076-1080.

Renal denervation as a therapeutic approach â&#x20AC;˘ Renal denervation is a minimally invasive, catheter-based procedure that modulates the output of nerves lying within the renal artery wall, leading into and out of the kidneys* â&#x20AC;˘ Renal sympathetic denervation involves selectively disabling renal nerves within the SNS, thus impacting the mechanical and hormonal activities of the kidneys, as well as the electrical activation of the rest of the SNS â&#x20AC;˘ Prince Salman Heart Center Experience *Hypertension. 2009;54:1195-1201.

Baroreflex activation therapy as a therapeutic approach • Baroreceptor stimulation is an investigational* therapeutic approach that treats hypertension by modulating sympathetic nerve activity1 • Using a system similar to a pacemaker that is surgically and permanently implanted, the therapy is administered via electrical stimulation of the carotid baroreceptors • Therapy attempts to normalize sympathovagal imbalance by reducing the activity of the SNS2 while increasing parasympathetic activity3 1. Bisognano JD, et al. J Am Coll Cardiol. 2011;58:765-773. 2. Heusser K, et al. Hypertension. 2010;55:619-626. 3. Wustmann K, et al. Hypertension. 2009;54:530-536

Refer to Specialist â&#x20AC;˘ Refer to appropriate specialist for known or suspected secondary cause(s) of hypertension â&#x20AC;˘ Refer to hypertension specialist if blood pressure remains uncontrolled after 6 months of treatment

Referral to hypertension specialists â&#x20AC;˘ A retrospective study found that patients with treatment-resistant hypertension achieved an 18/9 mm Hg drop in BP, and control rates increased from 18% to 52% at 1-year follow-up1 â&#x20AC;˘ In another retrospective study, 53% of patients with treatment-resistant hypertension were controlled to BP target (<140/90 mm Hg)2 1. Bansal N, et al. Am J Hypertens. 2003;16:878-880. 2. Garg JP, et al. Am J Hypertens. 2005;18:619-626.

Take Home Messages • Resistant hypertension affects approximately 10-20% of the hypertensive patient population • Non-compliance to anti-hypertensive therapy remains the most common cause of resistant hypertension • Primary hyperaldosteronism is not as uncommon as previously thought, • Low-renin resistant hypertension responds to aldosterone blockade when other drugs are apparently inadequately effective

Take Home Messages â&#x20AC;˘ Referral to a hypertension specialist may prove beneficial â&#x20AC;˘ Investigational treatments based on a new appreciation for the role of the SNS are being developed

What do we need in Saudi Arabia? • Resistant Hypertension prevalence is unknown but expected to be high • More research is needed • Establishment of Specialized Hypertension clinic • Hypertension awareness campaign