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Effective Strategies to Treat Difficult-to-Control Hypertension: 

Effective Strategies to Treat Difficult-to-Control Hypertension Joel Handler MD Hypertension Lead Care Management Institute Kaiser Permanente

Slide2: 

Resistant hypertension is defined by a blood pressure of at least 140/90 or at least 130/80 in patients with diabetes or renal disease despite adherence to treatment with full doses of at least three antihypertensive medications, including a diuretic. JNC 7

Resistant hypertension is primarily a systolic and age related problem: 

Resistant hypertension is primarily a systolic and age related problem Diastolic BP goal achieved ≥ 90% in the major trials Systolic BP goal achieved 60-65% in the major trials True resistance occurs in about 15%

Evaluation of Resistant Hypertension: 

Evaluation of Resistant Hypertension Measurement artifacts Medication adherence Lifestyle issues Interfering or exogenous substances Obstructive sleep apnea Drug-related causes: med changes Secondary hypertension

Measurement Artifacts: 

Measurement Artifacts Upper arm measurements on bared arm Proper cuff size 5 minutes of rest for first measurement; wait at least one minute for second measurement Arm supported on furniture with cuff at heart level Back supported, legs uncrossed, feet on floor No talking Bladder emptied if necessary

Requirements for White Coat Effect Determination: 

Requirements for White Coat Effect Determination Multiple (4) nurse BPs will obviate most white coat effect AAMI, BHS, EHS approved home BP apparatus with memory chip Yearly validation of home BP machine Protocoled home BPs emphasizing morning determinations Mean home BP < 135/85 mm Hg

Evaluation of Resistant Hypertension: 

Evaluation of Resistant Hypertension Measurement artifacts Medication adherence Lifestyle issues Interfering or exogenous substances Obstructive sleep apnea Drug-related causes: med changes Secondary hypertension

Medical Adherence: 

Medical Adherence Adherence ≥80% with prescribed medication is minimum level required for pharmacologic benefit 85% of patients admitting to less than complete adherence are taking less than 75% prescribed medication 39% patients reporting perfect adherence take less than 75% of their medication Physician messaging makes a difference

Beta Blocker Therapy and Symptoms of Depression, Fatigue, and Sexual Dysfunction: Meta Analysis: 

Beta Blocker Therapy and Symptoms of Depression, Fatigue, and Sexual Dysfunction: Meta Analysis Depression: 7 trials; 10,622 patients Fatigue: 10 trials; 17,682 patients Sexual Dysfunction: 6 trials, 14,897 patients Fatigue: 4 withdrawals/1000 patients/year Mostly with propanolol Sexual Dysfunction: 2 withdrawals/1000; nocebo effect described in previous ED study Depression: No significant difference Ko et al. JAMA 2002; 288: 351-357

Managing Medication Myths and Side Effects to Encourage Adherence : 

Managing Medication Myths and Side Effects to Encourage Adherence Thiazide, thiazide-like Beta blockers Calcium channel blockers

Thiazide Related Gout: 

Thiazide Related Gout Thiazide related hyperuricemia is dose related HDFP Trial: 15 episodes of gout over 5 years in 3693 patients treated with chlorthalidone 25-100mg (equivalent to 50-200 mg HCTZ) Low dose thiazide (HCTZ 12.5-25 mg) is not contraindicated in gout

Thiazide Myths Exposed: 

Thiazide Myths Exposed Significant cross reactivity with sulfa antibiotics has not been demonstrated; sulfa allergic patients have the same mildly increased reactivity to penicillin and thiazide (NEJM 2003;349:1628-35); thiazide can be administered to patients with sulfa allergy Thiazide is first line treatment for calcium kidney stones due to idiopathic hypercalciuria and also treats idiopathic calcium lithiasis; avoid thiazide with hyperparathyroidism (raises serum Ca)

Criteria for Panic Attacks and Panic Disorder: a cause of medication intolerance: 

Criteria for Panic Attacks and Panic Disorder: a cause of medication intolerance Panic attack is a discrete period of intense fear or discomfort involving ≥4 of the following symptoms: Shortness of breath (dyspnea) or smothering sensation Dizziness, unsteady feelings, or faintness Palpitations or accelerated heart rate (tachycardia) Trembling or shaking Sweating Choking Nausea or abdominal distress Hot flushes or chills Chest pain or discomfort

Case Study: 

Case Study 65 year old male with long standing anxiety disorder on paroxetine (Paxil) intolerant to HCTZ due to mouth dryness, also intolerant to atenolol with tremors, and both lisinopril and nifedipine with fatigue was referred to Hypertension Clinic because of refractory hypertension due to medication intolerance.

Case Study: 

Case Study His psychiatrist attributed these symptoms to his underlying anxiety disorder. Paroxetine and bupropion (wellbutrin) were nonefficacious, but clonazepam (klonopin) led to a reduction in somatic complaints. HCTZ was successfully reinitiated, and in combination with lisinopril and atenolol led to control of his hypertension.

Evaluation of Resistant Hypertension: 

Evaluation of Resistant Hypertension Measurement artifacts Medication adherence Lifestyle issues Interfering or exogenous substances Obstructive sleep apnea Drug-related causes: med changes Secondary hypertension

Slide20: 

Lifestyle Modifications

Slide21: 

Modan M, et.al. Hypertens 1991;17:565-573

Slide22: 

SOS study. Sjostrom et al. NEJM 20047;351;2683-2691

Evaluation of Resistant Hypertension: 

Evaluation of Resistant Hypertension Measurement artifacts Medication adherence Lifestyle issues Interfering or exogenous substances Obstructive sleep apnea Drug-related causes: med changes Secondary hypertension

Interfering or Exogenous Substances: 

Interfering or Exogenous Substances NSAIDs Sympathomimetic drugs: phenylephrine, cocaine, amphetamines Alcohol >1 drink/day for women, >2 drinks/day for men Dietary salt > 5 grams daily Cyclosporine, tacrolimus, steroids Buspirone (Bu Spar) Venlafaxine (Effexor XR)

Slide25: 

Continued- Metoclopramide (Reglan) Oral contraceptives Black licorice (50 gms daily x 2 weeks) Tricyclic antidepressants Erythropoiten Herbs: ginseng, ginger, yohimbine Topical testosterone Cancer chemotherapy: angiogenesis inhibitors Clonidine + beta blocker (due to combo pressor effect and clonidine drug holiday on BB, but also avoid combined rate slowers)

Evaluation of Resistant Hypertension: 

Evaluation of Resistant Hypertension Measurement artifacts Medication adherence Lifestyle issues Interfering or exogenous substances Obstructive sleep apnea Drug-related causes: med changes Secondary hypertension

Obstructive Sleep Apnea: 

Obstructive Sleep Apnea Associated with resistant hypertension Prototype: obese middle age male with large neck Pathophysiologic role of sympathetic nervous system and RAAS (renin angiotensin aldosterone system) Underpowered studies show BP reduction with CPAP Get sleep study in resistant hypertension, treat sleep apnea with CPAP, probably will not reduce BP

Slide28: 

n.s. n.s. p=0.022 p=0.024 p=0.037 p<0.001 Reduction of blood pressure (BP) and heart rate (HR) after 6 months of bi-level or continuous positive airway pressure treatment in patients taking and not taking BP-lowering drugs (BPLD). SBP = systolic: DBP = diastolic BP. Borgel et al. AJH 2004;17:1081-1087

Evaluation of Resistant Hypertension: 

Evaluation of Resistant Hypertension Measurement artifacts Medication adherence Lifestyle issues Interfering or exogenous substances Obstructive sleep apnea Drug-related causes: med changes Secondary hypertension

Slide30: 

Cause of Resistance Cause of resistance found in 133/141 – 94% (83/91 – 91%) cases Primary cause of resistant hypertension Garg JP, et al. Am J Hypertens 2003;16:925-930

Slide31: 

Achievement of goal blood pressure (BP), by cause of resistance Garg JP, et al. Am J Hypertens 2005;18:619-626

Diuretic Maximization: 

Diuretic Maximization Chlorthalidone 25 mg Roughly twice as potent as HCTZ and longer acting: 25mg chlorthalidone = 50mg HCTZ More hypokalemia Thiazide-like, can be used with mild HCTZ rash or dizziness Combination pill: tenoretic 25/50mg, 25/100mg Furosemide BID (cr cl < 30 cc/min; thiazide related hyponatremia)

Slide34: 

Figure 2. Effects of HCTZ and chlorthalidone on SBP as a function of daily dose (mg) Carter BL. Hypertens 2004; 43:4-9

Slide35: 

What additional agents to add? What combinations work?

Spironolactone: 

Spironolactone Used for resistant hypertension with normal aldosterone levels, 12.5-50mg/daily Additional benefits: antiproteinuric, improves heart failure survival (RALES) 10% gynecomastia Not when creatinine > 2.5, K > 5.0 Consider using with chlorthalidone

Slide37: 

Spironolactone-induced reduction in systolic blood pressure BP and diastolic BP at 6 weeks, 3 months and 6 months follow-up in subjects with resistant hypertension (n=76). BP reduction was significant at all timepoints compared to baseline. Nishizaka MK, et al. Am J Hypertens 2003;16;925-930

Slide38: 

SBP DBP Chapman N. ASCOT. Hypertens 2007; 49:839-845

Slide39: 

Life-threatening Hyperkalemia during a Combined Therapy with the Angiotensin Receptor Blocker Candesartan and Spironolactone HIDEKI FUJII *, HAJIME NAKAHAMA *, FUMIKI YOSHIHARA *, SATOKO NAKAMURA * TAKASHI INENAGA *, and YUHEI KAWANO * Kobe J Med Sci 2005; 51:1-6

Drug Combinations: 

Drug Combinations Chlorthalidone 25mg + spironolactone 12.5-50 mg Excellent diuretic maximization, also vs hypokalemia Dihydropyridine/nondihydropyridine CCBs 12/20 (60%) in Garg et al. brought to goal BP Option in elderly with thiazide intolerance Edema problem ACEI plus ARB Mostly 4-8 week studies Risk of ARF in animal studies ACEI/ARB were not maxed out Additional reduction mild: 4/3 mm Hg Best application in proteinuric patients

Direct Vasodilators: 

Direct Vasodilators Hydralazine sequence is 25 BID to 50 BID to 100mg BID Minoxidil sequence is 2.5mg, to 5mg, to 5mg BID, to 10 mg BID, to 20 mg BID Need a BB and a diuretic on board Watch for headache and fluid retention

Minoxidil: 

Minoxidil Excellent drug for resistant hypertension Direct vasodilator causing reflex tachycardia and fluid retention Need BB on board to prevent myocardial ischemia Dosage range 2.5mg to 20 mg BID Temporarily discontinue drug with marked edema, than restart with more diuretic 90% ST-T change within 2 weeks, later resolve

A1-Adrenergic Receptor Blockers: 

A1-Adrenergic Receptor Blockers Not to be used for monotherapy: ALLHAT (class effect) May be used as an add-on for resistant hypertension May cause urinary incontinence, especially in females, due to bladder outlet relaxation

Additional Agents/ Devices: 

Additional Agents/ Devices Combined alpha- and beta-blockers (labetalol, carvedilol) Reserpine 0.05-0.1 mg Isosorbide vs augmentation pressure Device-guided slow breathing exercises (Resperate) Device-mediated electrical carotid sinus baroreceptor stimulation Thoracic bioimpedance measurements

Evaluation of Resistant Hypertension: 

Evaluation of Resistant Hypertension Measurement artifacts Medication adherence Lifestyle issues Interfering or exogenous substances Obstructive sleep apnea Drug-related causes: med changes Secondary hypertension

Workup Scenarios Where Secondary Hypertension Syndromes May be Considered: 

Workup Scenarios Where Secondary Hypertension Syndromes May be Considered Under age 30 resistant to two or more drugs with no other obvious etiology, i.e., morbid obesity Hypertension refractory to maximal doses of four or five drugs Hospitalization for hypertensive crisis (though crisis is mostly due to medication noncompliance) New diastolic BPs > 100 mm Hg over age 60

Slide47: 

Hypertension with severe target organ damage (i.e. blindness, acute renal insufficiency, or encephalopathy) Hypertension with recurrent pulmonary edema- rule out renovascular Resistant hypertension with hypokalemia: rule out hyperaldosteronism, renal vascular etiology, pheochromocytoma, Cushing’s syndrome Resistant hypertension with 3 to 4+ proteinuria- an indicator of primary rather than secondary renal disease (causes of nephrotic syndrome)

Suggested Screening Tests for Secondary Hypertension Syndromes (Rarely Necessary): 

Suggested Screening Tests for Secondary Hypertension Syndromes (Rarely Necessary) Captopril renogram (only if kidney function is normal) or renal artery magnetic resonance angiography (MRA) Hyperaldosteronism: morning aldosterone/plasma renin activity ratio ≥20 when absolute aldosterone level ≥15 ng/dl with potassium ≥ 3.5 meq/l performed on all drugs except spironolactone (must be off spironolactone >6 weeks). Pheochromocytoma (extremely rare): 24 hour urine for total metanephrines and catecholamines

Slide49: 

Thyroid-stimulating hormone (TSH): hypothyroidism as well as hyperthyroidism cause hypertension Calcium:hyperparathyroidism may cause hypertension, but HTN usually persists post parathyroidectomy for primary hyperpara If patient is under age 35 and systolic pressure in right leg or left arm is more than 10 mmHg lower than the systolic pressure of the right arm, order echocardiogram to rule out aortic coarctation

Slide50: 

Cushing’s syndrome: dexamethasone suppression test (DST) giving 1mg dexamethasone between 11 p.m. and midnight, 8 a.m. plasma cortisol should be < 2.5 mcg/dl (approximately 15% false positives); alternative is to order 24-hour urine free cortisol independently, or as follow-up to a positive DST

Clinical Clues for the Diagnosis of Renovascular Hypertension: 

Clinical Clues for the Diagnosis of Renovascular Hypertension Historical and clinical findings: Abrupt onset hypertension after age 55 Increasing blood pressure in previously controlled hypertension Malignant hypertension Recurrent “flash” pulmonary edema Worsening renal function with angiotension-converting enzyme inhibitor or angiotensin receptor blocker therapy Epigastric atherosclerosis elsewhere Tobacco use

Clinical Characteristics of 131 Patients with Proved Renovascular Hypertension: note overlap: 

Clinical Characteristics of 131 Patients with Proved Renovascular Hypertension: note overlap

Cardiovascular Outcomes in Renal Atherosclerotic Lesions (CORAL): 

Cardiovascular Outcomes in Renal Atherosclerotic Lesions (CORAL) 2005-2010; 1080 patients Renal stenting vs medical therapy Primary end point: event-free survival Inclusion criteria: Systolic BP ≥ 155 mmHg 2 or more antihypertensives ≥ 1 renal arteries stenosed ≥60% <80% with ≥20 mmHg gradient, or ≥80% < 100% stenosis by angiography

Summary of Med Changes: 

Summary of Med Changes Use chlorthalidone 25mg Add spironolactone 12.5 – 50 mg Consider adding hydralazine or minoxidil Consider alpha1-blocking agents,and combination alpha-beta blockers Consider CCB combination therapy especially with diuretic intolerance

Evaluation of Resistant Hypertension: 

Evaluation of Resistant Hypertension Measurement artifacts Medication adherence Lifestyle issues Interfering or exogenous substances Obstructive sleep apnea Drug-related causes: med changes Secondary hypertension

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