RESISTANT HYPERTENSION What is it and How to Treat? Robert J Herman, MD FRCPC University of Calgary

Disclosures None

Learning Objectives Know the definition of resistant hypertension Have an approach to the work up and effective treatment of a patient with resistant hypertension Consider second line approaches Understand the benefits and limitations to new alternatives such as renal denervation

Definition: Blood pressure that remains above goal in spite of the concurrent use of 3 antihypertensive agents of different classes. Ideally, 1 should be a diuretic and all agents should be prescribed at optimal doses. AHA Scientific Statement Hypertension 2008;51:1403-1419

Resistant hypertension Inadequate medication 45-60% Improper use of diuretics Secondary hypertension 5-20% Chronic Kidney Disease Renal artery stenosis Hyperaldosteronism Thyroid disease Hyperadrenalism Pheochromocytoma Non-compliance/non-adherence 16-60% Whitecoat Hypertension 20-25% Sleep apnea 83% Adapted from Resistant Hypertension. Larochelle, presented at the CHC 2011

Resistant Hypertension Pseudo-Resistant HTN Error in BP Measurement Improper cuff size Improper measurement technique Whitecoat Hypertension Non Adherence Patient factors Physician factors Interference by medications or other exogenous agents True Resistant HTN

Primary Aldosteronism Primary Aldo is common in Resistant hypertension 20% Obesity and metabolic syndrome are very common in IHA, but not APA –3 Hydroxysteroid dehydrogenase is over-expressed in zona glomerulosa cells of adrenals from IHA pts and may have a role in aldosterone synthesis

Nishizaka MK, et al. Am J Hypertens 2003; 16:925-30.

Pimenta E, et al. Curr Hypertens Rep 2007; 9:353-9

Other evidence supporting a role of mineralocorticoids in resistant hypertension: Vasan RS. Framingham Offspring Study NEJM 2004;351: 33-41

Sympathetic Activation Metabolic Syndrome Sympathetic Activation PA Salt Overload

Sympathetic Activation DM Metabolic Syndrome Sympathetic Activation PA Salt Overload OSA CKD

Hirotaka Shibata, Hiroshi Itoh. Am J Hypertens 2012; 25:514-23.

Aldosterone-Associated Hypertension Definition: Hypertension with an elevated ARR, an elevated plasma aldosterone level, but suppress normally with salt or Captopril testing (i.e., not Primary Aldosteronism) Clinical: BP control is achieved in many of these patients after treatment with an aldosterone antagonist

Aldosterone Escape or Aldosterone Breakthrough Definition: Increased concentrations of aldosterone and resistance to BP-lowering treatment following a period of use of an ACI-I or or an ARB. Originally described in CHF and chronic kidney disease where it occurs in 10-53% of these patients. Clinical: An aldosterone antagonist should be added for most indications in patients on an ACE-I or an ARB

How to Treat:

Sodium recommended: 2300 mg or less/day Salt country….. Sodium recommended: 2300 mg or less/day Food Sodium Commercial Broth 900 mg/cup Canned Soup 550-1000 mg/cup Canned Tomato Sauce 1000 mg/cup Frozen Meals Up to 1500 mg/portion Delicatessen 500-1000 mg/2-3 cuts Pasta with seasoning 500-1000 mg/cup Les aliments commercialement préparés, comme les soupes, les bouillons, les sauces, les aliments assaisonnés, sont des mines importantes de sel, sans compter les croustilles, les frites, les noix salées qu’on mange souvent. C Blais IRCM 19

Optimize The Diuretic Treatment with Chlorthalidone ASH 2007: 22nd Annual Scientific Session of the American Society of Hypertension Which Diuretic? – Researchers weigh in on benefits of chlorthalidone MedWire - ASH 2007 (Chicago, IL, USA) - May 20, 2007: The diuretic chlorthalidone is scoring high marks for its “once-a-day” dosing and its ability to lower blood pressure evenly throughout 24 hours, according to researchers at the American Society of Hypertension’s 22nd Annual Scientific Meeting held in Chicago. According to Michael Ernst, PharmD (University of Iowa, Iowa City, IA, USA), “chlorthalidone has an optimal pharmacokinetic and pharmacodynamic profile suited for once-daily dosing.” He added: “Evidence from ambulatory blood pressure monitoring indicates [that] it lowers blood pressure more effectively throughout 24 hours than HCTZ [hydrochlorothiazide], particularly observed in nighttime BP.” At doses of 12.5 to 25 mg/day, potassium wasting of chlorthalidoneis similar to that of HCTZ. Chlorthalidone has been the diuretic of choice in several major landmark hypertension trials, he said. “We will not likely see a prospective direct comparison between HCTZ and chlorthalidone on hard cardiovascular endpoints, but chlorthalidone should be the preferred thiazide-type diuretic in practice,” he said. The latest “road map” for treating hypertension comes from the NHLBI Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure (JNC 7), which advises lifestyle modification as a first step. The committee stated that thiazide diureticsshould be used as first-line treatment for most patientswith uncomplicated hypertension, either alone or combined with agents from other classes if necessary. Drug-therapy is indicated if optimal blood pressures (<140/90 mmHg, or <130/80 mmHg for those with diabetes or chronic kidney disease) are not reached through lifestyle changes. Thiazide-type diuretics are indicated for most patients, but other agents may be considered. A combination of antihypertensive agents - angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARB), beta blockers, orcalcium channel blockers (CCB) - may be considered for stage 1 hypertension (systolic blood pressure [SBP] 140-159 mmHg or diastolic blood pressure [DBP] 90-99 mmHg). For stage 2 hypertension (SBP >160 or DBP >100 mmHg), a two-drug combination is recommended for most patients - usually a thiazide-type diuretic with ACE, ARB, BB, or CCB - and other antihypertensive drugs as needed. While diuretics are hardily endorsed by the JNC 7, the question still remains: which diuretic should doctors choose for patients? During this debate, researches and leading experts alike agreed that chlorthalidone has a number of advantages over the other thiazide-type agents. Professor Ernst reported a study in which he compared HCTZ andChlorthalidone treatment on ambulatory and office blood pressures. [1] Sixteen patients received HCTZ (25 mg) and 14 patients received chlorthalidone (12.5 mg initially, then titrated to 50 mg and 25 mg respectively at 4 weeks). The study design was an 8-week crossover, with 4-week washout between drug assignments; primary outcome was change in 24-hour ambulatory mean SBP and DBP from baseline to 8 weeks. The secondary outcomes were changes in office SBP; changes in office DBP; and ambulatory daytime and nighttime SBP and DBP. The mean office SBP values were reported as follows: Week 2: Mean office SBP reduction 4.5±2.1 (HCTZ) versus 15.7±2.2 (chlorothalidone) (p=0.001) Week 4: Mean office SBP reduction 7.6±2.8 (HCTZ) versus 17.4±2.9 (chlorothalidone) (p=0.069) Week 6: Mean office SBP reduction 9.3±3.2 (HCTZ) versus 19.6±3.4 (chlorothalidone) (p=0.109) Week 8: Mean office SBP reduction 10.8±3.5 (HCTZ) versus 17.1±3.7 (chlorothalidone) (p=0.842) Mean 24-hour-daytime and drops were similar; however, the nighttime SBP change from baseline for chlorthalidone was almost twice as high as that for HCTZ, at 13.4 ± 1.9 versus 6.4±1.9, respectively. In a second presentation, Professor William Elliott, (Rush Medical College, Chicago, IL, USA) discussed results from a study comparing 24-hour ambulatory blood pressure (BP) assessed at baseline and at eight weeks, along with standard office blood pressure readings every two weeks of chlorthalidone versus HCTZ. Thirty patients were treated with either chlorthalidone (12.5 mg/day)or HCTZ (25mg/day) for four weeks, and the doses were doubled at four weeks. Chlorthalidone was found to be more effective in lowering SBP than HCTZ, Elliott stated. At eight weeks, there was a greater drop in blood pressure from baseline in SBP with chlorthalidone (25 mg/day) compared with HCTZ (50 mg/day) (24-hour mean:-12.4±1.8 mmHg vs. -7.4±1.7 mm Hg; p=0.054; nighttime mean: -13.5±1.9 mmHg vs. -6.4±1.8 mmHg; p=0.009). Office SBP reduction was lower at week 2 for chlorthalidone (12.5 mg/day) versus HCTZ, (25 mg/day) (-15.7±2.2 mm Hg vs. -4.5±2.1 mm Hg; p=0.001). However, by eight weeks, reductions were about the same (-17.1±3.7 vs. -10.8±3.5; p=0.84). Professor Elliot went on to summarize data from several outcome trials: “Chlorthalidone beat HCTZ in MRFIT [multiple risk factor intervention trial], in the HDFP [hypertension follow-up program), and in the Antihypertensive andLipid-Lowering treatment to prevent Heart Attack Trial [ALLHAT].” He stated: “If you do a rank ordering of ALLHAT, which found chlorthalidone better than ACE-1 lisoinopril, and ANBP-2 [and] ACE-2 better than HCTZ, the conclusion is that chlorthalidone is better than HCTZ. “Diuretics are especially good for hypertensives with chronic liver disease, diabetes, high risk of heart attack,” Elliott said, adding that chlorthalidone (12.5mg/d) has better efficacy, better outcomes, and a longer duration of action.” He therefore proposed “adding ‘HCTZ’ to the ‘DO NOT USE’ abbreviations list in our medical center, and making sure everyone learns how to spell “C-H-L-O-R-T-H-A-L-I-D-O-N-E.” References: 1. Ernst ME, Carter BL, Goerdt CJ, et al. Comparative antihypertentive effects of hydrochlorothiazide and chlorthalidone on ambulatory and office blood pressure. Hypertension 2006; 47: 352-8. Optimize The Diuretic Treatment with Chlorthalidone Chlorthalidone PK properties: longer t1/2, 3-fold greater potency/duration of action Clinical trials: HDFP,ALLHAT,SHEP with chlorthalidone; multiple trials with HCTZ in a combination product Comparison chlorthalidone vs HCTZ: greater 24 hour BP lowering effect at night Ernst ME et al. Hypertension 2006;47:352-8 20

2010 Cochrane Review: five crossover RCTs AB BACKGROUND: Spironolactone is an aldosterone antagonist, considered fourth line therapy for hypertension in patients already treated with multiple medications. OBJECTIVES: Primary: to determine the effect of spironolactone on patient mortality, morbidity, and to quantify the magnitude of blood pressure lowering effect of spironolactone monotherapy.Secondary: to determine the prevalence of adverse reactions observed with spironolactone monotherapy and to determine if there is a blood-pressure lowering dose response with spironolactone. SEARCH STRATEGY: We searched the following databases: Cochrane Central Register of Controlled Trials (3rd Quarter 2009), MEDLINE (2005 - Sept. 2009), and EMBASE (2007 - Sept. 2009). References from retrieved studies were reviewed to identify any studies missed in the initial search. No language restrictions were applied. SELECTION CRITERIA: We selected RCTs studying patients with primary hypertension. We excluded studies of patients with secondary or gestational hypertension, and studies where patients were receiving multiple antihypertensives. DATA COLLECTION AND ANALYSIS: Two reviewers independently reviewed the search results for studies meeting our criteria. Three reviewers extracted data and assessed trial quality using a standardized data extraction form. Data synthesis and analysis was performed using RevMan 5. MAIN RESULTS: Meta-analysis of the 5 cross-over studies found a reduction in SBP of 20.09 mmHg (95%CI:16.58-23.06,p<0.00001) and a 6.75 mmHg (95%CI:4.8-8.69,p<0.00001) reduction in DBP. These results were statistically significant and there was no evidence of heterogeneity between the studies. There may be a dose response effect with spironolactone up to 50 mg/day, but the confidence intervals around the mean end-of-study blood pressure for doses ranging 25-500 mg/day all overlapped. In other words, it appears that doses >50mg/day do not produce further reductions in either SBP or DBP. One cross-over study found that spironolactone 25 mg/day did not statistically significantly change SBP or DBP compared to placebo, SBP: -9.9 (95%CI:-21.15,1.35); DBP -2.34 (95%CI:-7.92,3.06). AUTHORS' CONCLUSIONS: From the limited available evidence, spironolactone appears to lower blood pressure compared to placebo to a similar degree in patients with primary (essential) hypertension when doses of 100-500 mg/day are given. A dose of 25 mg/day did not statistically significantly reduce systolic or diastolic blood pressure, compared to placebo. Given the lack of a dose-response, coupled with a possible increased risk in adverse events with higher doses, doses of 25 to 100 mg/day are reasonable. There is no evidence of the effect of spironolactone on clinical outcomes in hypertensive patients. [References: 50] Chapman N et al. Hypertension 2007; 49: 839-845 2010 Cochrane Review: five crossover RCTs mean BP decreases of 20/7 mmHg no DRAE at Spironolactone doses below 100 mg/day no data on clinical outcomes 21

RHTN Rx: Lower on the list of combinations CEB Clonidine Beta-blockers Often may be used for other indications eg, CAD, HF These are renin blockers Labetalol has added 1-blockade Aliskirin Alpha blockade: Doxazosin: Caveat - withdrawn from ALLHAT Adapted from Resistant Hypertension, presented by Zarnky Rocky Mountain/ACP Internal Medicine Meeting 2011

Results of ALTITUDE

Renal denervation

Steps in the Investigation and Treatment of RHTN Confirm the BP measurement Evaluate non-adherence Identify interfering medications, other agents Screen for secondary causes of HTN Identify abnormal lifestyle issues Optimize antihypertensive therapy Add or switch to chlorthalidone 25 mg/d Add an aldosterone antagonist (12.5-50 mg/d spionolactone) Follow, follow and follow up, again … Adapted from Resistant Hypertension. Larochelle, presented at the CHC 2011