Hypertension in the Elderly: Some Practical Considerations

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REVIEW KASHIF N. CHAUDHRY, MD PATRICIA CHAVEZ, MD JERZY GASOWSKI, MD a Mount Sinai School of Medicine, St. Luke’s-Roosevelt Hospital Center, Department of Internal Medicine and Englewood Hospital Program, Columbia University College of Physi- Gerontology, Jagiellonian University, Englewood, NJ cians and Surgeons, New York, NY Krakow, Poland

TOMASZ GRODZICKI, MD b FRANZ H. MESSERLI, MD, FACC, FACP c Department of Internal Medicine and St. Luke’s-Roosevelt Hospital Center, Columbia Gerontology, Jagiellonian University, University College of Physicians and Surgeons, Krakow, Poland New York, NY Hypertension in the elderly: Some practical considerations

■■ ABSTRACT he management of hypertension has ad- Tvanced significantly in the last few decades. Data from randomized controlled trials suggest that But the race for more effective means to control treating hypertension in the elderly, including octogenar- this epidemic and its associated complications ians, may substantially reduce the risk of cardiovascular is far from won. A high percentage of patients disease and death. However, treatment remains challeng- in the United States have hypertension that ing because of comorbidities and aging-related changes. is uncontrolled. Most of these belong to the most rapidly growing demographic group in the We present common case scenarios encountered while United States, ie, the elderly. managing elderly patients with hypertension, including It is estimated that more than 70% of med- secondary hypertension, adverse effects of drugs, labile ical practice will be directed to geriatric needs hypertension, orthostatic hypotension, and dementia. in the coming years. It is therefore very im- ■■ portant for clinicians to be comfortable with KEY POINTS managing hypertension in the elderly. Therapy should be considered in all aging hypertensive patients, even the very elderly (> 80 years old). ■■ A GROWING PROBLEM IN AN AGING POPULATION Most antihypertensive drugs can be used as first-line Between 1980 and 2009, the US population treatment in the absence of a compelling indication for a age 65 and older increased from 25.6 million to specific class, with the possible exception of alpha-block- 39.6 million, of which 42% are men and 58% ers and beta-blockers. women.1 This number is expected to reach 75 million by the year 2040. People over 85 years An initial goal of less than 140/90 mm Hg is reasonable of age are the fastest growing subset of the US in elderly patients, and an achieved systolic blood pres- population.2 As many as 50% of people who sure of 140 to 145 mm Hg is acceptable in octogenarians. were born recently in countries such as the United States, the United Kingdom, France, Denmark, and Japan will live to celebrate Start with low doses; titrate upward slowly; and monitor their 100th birthday.3 closely for adverse effects. According to the Framingham Heart Study, by age 60 approximately 60% of the popula- Thiazide diuretics should be used with caution in the tion develops hypertension, and by 70 years elderly because of the risk of hyponatremia. about 65% of men and about 75% of women have the disease. In the same study, 90% of a Dr. Gasowski has disclosed teaching and speaking for the Servier and Zentiva companies. those who were normotensive at age 55 went b Dr. Grodzicki has disclosed teaching and speaking for the Servier and Novartis companies. on to develop hypertension. The elderly also c Dr. Messerli has disclosed consulting for Novartis, Daiichi Sankyo, Pfizer, Takeda, Abbott, PharmApprove, Gilead, Servier, Bayer, and Medtronic and receiving grant support from Forest and are more likely to suffer from the complica- Boehringer Ingelheim. tions of hypertension and are more likely to doi:10.3949/ccjm.79a.12017 have uncontrolled disease.

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Compared with younger patients with simi- rived from randomized controlled trials for lar blood pressure, elderly hypertensive patients any population, let alone the elderly. The have lower cardiac output, higher peripheral generally recommended blood pressure goal resistance, wider pulse pressure, lower intra- of 140/90 mm Hg for elderly hypertensive pa- vascular volume, and lower renal blood flow.4 tients is based on expert opinion. These age-related pathophysiologic differences Moreover, it is unclear if the same target must be considered when treating antihyper- should apply to octogenarians. According to a tension in the elderly. 2011 American College of Cardiology/Ameri- can Heart Association (ACC/AHA) expert ■■ IS TREATING THE ELDERLY BENEFICIAL? consensus report,8 an achieved systolic blood pressure of 140 to 145 mm Hg, if tolerated, Most elderly hypertensive patients have mul- can be acceptable in this age group. tiple comorbidities, which tremendously affect An orthostatic decline in blood pressure the management of their hypertension. They accompanies advanced age and is an inevi- are also more likely than younger patients to table adverse effect of some antihypertensive have resistant hypertension and to need mul- drugs. Accordingly, systolic blood pressure tiple drugs to control their blood pressure. In lower than 130 and diastolic blood pressure the process, these frail patients are exposed to lower than 70 mm Hg are best avoided in oc- a host of drug-related adverse effects. Thus, it togenarians.8 Therefore, when hypertension is relevant to question the net benefit of treat- is complicated by coexisting conditions that ment in this age group. require a specific blood pressure goal, it would Many studies have indeed shown that seem reasonable to not pursue the lower target treating hypertension reduces the risk of stroke as aggressively in octogenarians as in elderly and other adverse cardiovascular events. A patients under age 80. decade ago, Staessen et al,5 in a meta-analysis Having stated the limitations in the qual- of more than 15,000 patients between ages ity of data at hand—largely observational—it 62 and 76, showed that treating isolated sys- is relevant to mention the Systolic Blood Pres- tolic hypertension substantially reduced mor- sure Intervention trial (SPRINT).9 This ongo- About 60% of bidity and mortality rates. Moreover, a 2011 ing randomized, multicenter trial, launched by the population meta-analysis of randomized controlled trials the National Institutes of Health, is assessing in hypertensive patients age 75 and over also whether maintaining blood pressure levels develops concluded that treatment reduced cardiovas- lower than current recommendations further hypertension cular morbidity and mortality rates and the in- reduces the risk of cardiovascular and kidney cidence of heart failure, even though the total diseases or, in the SPRINT-MIND substudy, of by age 60 mortality rate was not affected.6 age-related cognitive decline, regardless of the Opinion on treating the very elderly (≥ type of antihypertensive drug taken. Initially 80 years of age) was divided until the results planning to enroll close to 10,000 participants of the Hypertension in the Very Elderly trial over the age of 55 without specifying any age- (HYVET)7 came out in 2008. This study doc- group ranges, the investigators later decided umented major benefits of treatment in the to conduct a substudy called SPRINT Senior very elderly age group as well. that will enroll about 1,750 participants over The consensus, therefore, is that it is ap- the age of 75 to determine whether a lower propriate, even imperative, to treat elderly hy- blood pressure range will have the same ben- pertensive patients (with some cautions—see eficial effects in older adults. the sections that follow). Given the limitations in the quality and applicability of published data (coming from ■■ GOAL OF TREATMENT IN THE ELDERLY small, nonrandomized studies with no long- term follow-up), SPRINT is expected to pro- Targets for blood pressure management have vide the evidence needed to support standard been based primarily on observational data in vs aggressive hypertension control among the middle-aged patients. There is no such thing elderly. The trial is projected to run until late as an ideal blood pressure that has been de- 2018.

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TABLE 1 to lower blood pressure more in older adults than in younger adults. In the DASH trial,12 Compelling indications for specific classes systolic blood pressure decreased by 8.1 mm of antihypertensive drugs as initial drug therapy Hg with sodium restriction in hypertensive patients age 55 to 76 years, compared with 4.8 Heart failure mm Hg for adults aged 23 to 41 years. In the Chlorthalidone (Hygroton), indapamide (Lozol), beta-blockers, angioten- Trial of Nonpharmacologic Interventions in sin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers 13 (ARBs), calcium channel blockers, aldosterone receptor antagonists the Elderly (TONE), in people ages 60 to 80 who were randomized to reduce their salt in- After myocardial infarction take, urinary sodium excretion was 40 mmol/ Beta-blockers, ACE inhibitors, ARBs, aldosterone receptor antagonists, day lower and blood pressure was 4.3/2.0 mm nondihydropyridine calcium channel blockers Hg lower than in a group that received usual Coronary artery disease or high cardiovascular risk care. Accordingly, reducing salt intake is par- Thiazides, ACE inhibitors, calcium channel blockers, beta-blockers ticularly valuable for blood pressure manage- 14 Angina pectoris ment in the salt-sensitive elderly. Beta-blockers, calcium channel blockers Drug therapy Aortopathy, aortic aneurysm The hypertension pandemic has driven exten- Beta-blockers, ARBs, ACE inhibitors, calcium channel blockers sive pharmaceutical research, and new drugs Diabetes mellitus continue to be introduced. The major classes ACE inhibitors, ARBs, calcium channel blockers, nebivolol (Bystolic), of drugs commonly used for treating hyperten- carvedilol (Coreg) sion are diuretics, calcium channel blockers, Chronic kidney disease and renin-angiotensin system blockers. Each ACE inhibitors, ARBs class has specific benefits and adverse-effect profiles. Recurrent stroke prevention It is appropriate to start antihypertensive Thiazides, ACE inhibitors, ARBs, calcium channel blockers drug therapy with the lowest dose and to mon-

ADAPTED FROM National High Blood Pressure Education Program. The Seventh Report of itor for adverse effects, including orthostatic the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Bethesda, MD: National Heart, Lung, and Blood Institute; 2004 Aug. hypotension. The choice of drug should be http://www.ncbi.nlm.nih.gov/books/NBK9630. guided by the patient’s comorbid conditions (TABLE 1) and the other drugs the patient is taking.15 If the blood pressure response is in- ■■ MANAGEMENT APPROACH adequate, a second drug from a different class IN THE ELDERLY should be added. In the same manner, a third drug from a different class should be added if Blood pressure should be recorded in both the blood pressure remains outside the opti- arms before a diagnosis is made. In a number mal range on two drugs. of patients, particularly the elderly, there are The average elderly American is on significant differences in blood pressure read- more than six medications.16 Some of these ings between the two arms. The higher read- are for high blood pressure, but others in- ing should be relied on and the corresponding teract with antihypertensive drugs (TABLE 2), arm used for subsequent measurements. and some, including nonsteroidal anti-inflammatory drugs (NSAIDs) and steroids, Lifestyle interventions directly affect blood pressure. Therefore, Similar to the approach in younger patients the drug regimen of an elderly hyperten- with hypertension, lifestyle interventions are sive patient should be reviewed carefully at the first step to managing high blood pressure every visit. The Screening Tool of Older in the elderly. The diet and exercise inter- Person’s Prescriptions (STOPP), a list of ventions in the Dietary Approaches to Stop 65 rules relating to the most common and Hypertension (DASH) trial have both been most potentially dangerous instances of in- shown to lower blood pressure.10,11 appropriate prescribing and overprescrib- Restricting sodium intake has been shown ing in the elderly,17 has been found to be

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a reliable tool in this regard, with a kap- TABLE 2 pa-coefficient of 0.75. Together with the Screening Tool to Alert Doctors to Right Interactions of some common antihypertensive [ie, Appropriate, Indicated] Treatment drugs 17 (START), which lists 22 evidence-based ANTIHYPERTENSIVE DRUGS MAJOR DRUG INTERACTIONS prescribing indicators for common condi- Angiotensin-converting Aliskiren (Tekturna) tions in the elderly, these criteria provide enzyme (ACE) inhibitors Allopurinol (Zyloprim) clinicians with an easy screening tool to Fleet enema combat polypharmacy. Leflunomide (Arava) Given the multitude of factors that go into Potassium-sparing diuretics deciding on a specific management strategy in Potassium supplements the elderly, it is not possible to discuss individ- ualized care in all patients in the scope of one Amlodipine (Norvasc) Ezetimibe/simvastatin (Vytorin) paper. Below, we present several case scenarios Itraconazole (Sporanox) that internists commonly encounter, and sug- Diltiazem (Cardizem) Amiodarone (Cordarone) gest ways to approach each. Beta-blockers Colchicine (Colcrys) ■■ Case 1: Secondary hypertension Erythromycin Ezetimibe/simvastatin A 69-year-old obese man who has hyperten- Fentanyl (Actiq) sion of recent onset, long-standing gastro- Lovastatin (Mevacor) esophageal reflux disease, and benign prostatic Itraconazole Ranolazine (Ranexa) hypertrophy comes to your office, accompa- nied by his wife. He has never had hyperten- Metoprolol Aminophylline sion before. His body mass index is 34 kg/m2. (Lopressor) Diltiazem On physical examination, his blood pressure is Verapamil (Calan) 180/112 mm Hg. Thiazides Amiodarone Dofetilide (Tikosyn) We start with this case to emphasize the im- Fleet enema portance of considering causes of secondary Lithium hypertension in all patients with the disease 18 (TABLE 3). Further workup should be pursued Furosemide (Lasix) Aminoglycosides in those who appear to have “inappropriate” Amiodarone hypertension. This could present as refractory Dofetilide Fleet enema hypertension, abrupt-onset hypertension, hy- Lithium pertension that is first diagnosed before age 20 or after age 60, or loss of control over previ- Spironolactone (Aldactone) ACE inhibitors ously well-controlled blood pressure. Second- Angiotensin receptor blockers ary hypertension must always be considered Lithium when the history or physical examination sug- Other potassium-sparing diuretics gests a possible cause. Potassium supplements Renal artery stenosis increases in incidence with age. Its prevalence is reported to be as high as 50% in elderly patients with oth- aged people.20 Numerous studies have found er signs of atherosclerosis such as widespread that the severity of obstructive sleep apnea peripheral artery disease.19 corresponds with the likelihood of systemic Obstructive sleep apnea also commonly hypertension.21–23 Randomized trials and me- coexists with hypertension and its prevalence ta-analyses have also concluded that effective also increases with age. In addition, elderly treatment with continuous positive airway patients with obstructive sleep apnea have a pressure reduces systemic blood pressure,24–27 higher incidence of cardiovascular complica- although by less than antihypertensive medi- tions, including hypertension, than middle- cations do.

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TABLE 3 Signs and symptoms that suggest specific causes of secondary hypertension in the elderly, and common drugs implicated

SIGNS AND SYMPTOMS POSSIBLE CAUSE OF SECONDARY HYPERTENSION DIAGNOSTIC TESTS

Increase in serum creatinine concentration Renal artery stenosis Computed tomographic (≥ 0.5 to 1 mg/dL [44.2 to 88.4 μmol/L]) after angiography starting angiotensin-converting enzyme Doppler ultrasonography inhibitor or angiotensin receptor blocker of renal arteries Renal bruit Magnetic resonance imaging with gadolinium contrast media

Bradycardia or tachycardia Thyroid disorders Thyroid-stimulating hormone Cold or heat intolerance level Constipation or diarrhea Irregular, heavy, or absent menstrual cycle

Hypokalemia Aldosteronism (rare in elderly) Renin and aldosterone levels to calculate aldosterone/renin ratio

Apneic events during sleep Obstructive sleep apnea Polysomnography (sleep study) Daytime sleepiness Sleep apnea clinical score with Snoring nighttime pulse oximetry

Drugs Immunosuppressants Steroids Nonsteroidal anti-inflammatory drugs Decongestants Buspirone (BuSpar) Carbamazepine (Tegretol) Clozapine (Clozaril) Fluoxetine (Prozac) Lithium Tricyclic antidepressants

Adapted from Viera AJ, Neutze DM. Diagnosis of secondary hypertension: an age-based approach. Am Fam Physician 2010; 82:1471–1478.

A causal relationship between obstructive enoma, though possible, are less prevalent sleep apnea and hypertension has not been es- in the elderly. tablished with certainty. It is recommended, however, that patients with resistant hyper- Case continued tension be screened for obstructive sleep ap- Physical examination in the above patient nea as a possible cause of their disease. revealed an epigastric systolic-diastolic bruit, Other causes of secondary hyperten- a sign that, although not sensitive, is highly sion to keep in mind when evaluating pa- specific for renal artery stenosis, raising the tients who have inappropriate hypertension suspicion of this condition. Duplex ultra- include thyroid disorders, alcohol and to- sonography of the renal arteries confirmed bacco use, and chronic steroid or NSAID this suspicion. The patient underwent angi- use. Pheochromocytoma and adrenal ad- ography and revascularization, resulting in a

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distinct fall in, but not normalization of, his treatment groups over a 29-month follow-up blood pressure. period. Hence, although we advise that causes of Detecting and treating renal artery stenosis secondary hypertension be considered in cas- Though we do not intend to detail the di- es of inappropriate hypertension, aggressive agnostic approaches and treatments for the management must be pursued on a case-by- various causes of secondary hypertension, we case basis. need to briefly mention those for renal artery stenosis. ■■ CASE 2: DRUG ADVERSE EFFECTS According to the 2006 ACC/AHA guidelines on peripheral artery disease,28 testing for A 75-year-old Hispanic woman with a his- renal artery stenosis is indicated only if a sub- tory of treated breast cancer was recently diag- sequent corrective procedure is a viable op- nosed with hypertension. Her blood pressure tion. is controlled on amlodipine (Norvasc) 10 mg Renal arteriography remains the gold daily, and her blood pressure today is 128/80 standard for diagnosing renal artery stenosis. mm Hg. Her only complaint during this office However, noninvasive imaging has largely re- visit is some swelling of her ankles. placed it. Duplex Doppler ultrasonography, com- Edema and dihydropyridine pared with angiography, has a sensitivity of calcium channel blockers 84% to 98% depending on operator experi- Like all drugs, antihypertensive medications ence, and a specificity of 62% to 99% for come with their own set of adverse effects. detecting renal artery stenosis.29 Some of its These are more common as people age— limiting factors are the time needed to do the hence the importance of identifying and ef- study, its steep learning curve and operator- fectively managing them in the elderly popu- dependence, and interference with the results lation. by body fat and intestinal gas. Calcium channel blockers, especially the Computed tomographic angiography has dihydropyridines—ie, nifedipine (Adalat), am- The average a sensitivity of over 90% for detecting renal lodipine, felodipine (Plendil), and isradipine elderly artery stenosis, and its specificity has been (DynaCirc)—are known to cause peripheral shown to be as high as 99% in certain stud- vasodilation. Peripheral edema is a common American ies.29 Use of contrast can be a limiting factor dose-related effect in people on these drugs. In is on more in some clinical settings. one study, median leg weight increased by 80 than six Magnetic resonance angiography also of- g after amlodipine 5 mg was given for 4 weeks, fers a sensitivity of 90% to 100% and specifici- and by another 68 g on a 10-mg dose.33 medications ties of 76% to 94% for detecting renal artery ste- Ankle swelling, encountered more in nosis.29 On the other hand, it is costly, and the women, can be very bothersome. The swell- gadolinium contrast solution used is nephro- ing is related to hyperfiltration of fluid into toxic, though not as toxic as the contrast used the interstitial space secondary to intracapil- in computed tomographic angiography. lary hypertension. Calcium channel blockers As previously stated, these imaging stud- predominantly cause arteriolar dilation by ies should be used only if corrective measures paralyzing the precapillary sphincter, thereby will be undertaken if clinically significant elevating intracapillary pressure. renal artery stenosis is found. Even in such Traditionally, physicians have lowered the cases, revascularization may not be curative in dose of the calcium channel blocker, switched all cases. Its effectiveness has been compared to another drug, or added a diuretic to allevi- with that of medical management alone in a ate the swelling. However, giving a diuretic for number of studies.30,31 A meta-analysis32 of six edema induced by a calcium channel blocker key trials involving more than 1,200 patients may not relieve the edema.34 showed no difference in systolic and diastolic Peripheral edema is much less encountered blood pressures and other clinical outcomes, when a calcium channel blocker is given with including all-cause mortality, between the two an inhibitor of the renin-angiotensin system.35

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A meta-analysis concluded that the incidence ics, on the other hand, have their main effect of peripheral edema was lowered by 38% with at the thick ascending limb, reducing the os- such a combination. The same study found molality at the medullary interstitium and not angiotensin-converting enzyme (ACE) in- affecting proximal water reabsorption. Addi- hibitors significantly more efficacious for this tionally, loop diuretics have a shorter half-life effect than angiotensin receptor blockers than thiazides, which makes hyponatremia (ARBs).35 more likely to happen with thiazides. ACE inhibitors and ARBs are known to In patients who develop hyponatremia sec- cause venodilation, thereby lowering intra- ondary to diuretic use, appropriate treatment capillary pressure. It is probable that this ef- includes stopping the medication, restricting fect helps remove the extra fluid sequestered water intake, and repleting electrolyte stores.38 in the capillary bed by the arteriolar dilation As with any cause of chronic hyponatremia, from the calcium channel blocker. correction must be cautiously monitored and Pedal edema associated with use of a cal- not hastily done. cium channel blocker occurs much more com- Therefore, we advise adding a thiazide diu- monly in the elderly than in the young. It is ric with caution in the elderly, and we advise clearly dose-dependent, and the incidence avoiding thiazides in patients with high water peaks after 6 months of therapy. In the patient or alcohol intake. described above, adding a low dose of an ACE inhibitor or an ARB (if the patient is ACE in- ■■ Case 3: Dementia and hypertension hibitor-intolerant) should relieve the swelling. A 74-year-old man with long-standing hyper- Hyponatremia and diuretics tension, gout, and chronic obstructive pul- Electrolyte imbalances are another common monary disease was recently diagnosed with problem encountered in the elderly. Even Alzheimer dementia. He takes enalapril (Va- though for years attention has been directed sotec) 10 mg daily for his blood pressure. His to the potassium level, hyponatremia has been blood pressure is 130/78 mm Hg. The generally equally associated with adverse effects in the recommended elderly, such as an increased risk of fractures as Dementia is one of the most important and shown in the Rotterdam study.36 common neurologic disorders in the elderly. blood pressure In 180 hypertensive inpatients, mean age With the rise in average life expectancy, its goal of 76.4, Sharabi et al37 found the incidence of hy- magnitude has grown to cause a substantial 140/90 mm Hg ponatremia to be three times higher in women emotional and economic burden on society than in men (odds ratio 3.10, 95% confidence and health care. for elderly interval 2.07 to 4.67). Patients were 10 times Midlife hypertension has been demonstrat- patients more likely to be affected after age 65 and 14 ed to be an important modifiable risk factor times more likely after age 75. Most of the pa- for late-life cognitive decline,39 mild cognitive is based on tients affected (74.5%) used a thiazide-type impairment,40 and dementia of all causes.41 It expert opinion, diuretic. Even though in many of the patients has been suggested that hypertension might diuretics were used for more than 1 year be- be part of the pathogenesis of dementia, and not randomized fore hyponatremia developed, susceptible pa- targeting high blood pressure might prevent controlled trials tients—such as the frail elderly—can develop its onset. severe hyponatremia within days of starting to Moreover, a significant reduction in both Al- use a thiazide.38 zheimer and vascular dementia was demonstrat- Severe hyponatremia is potentially life- ed (risk reduction 55%) with the use of a long- threatening. Most cases are caused by thiazide acting dihydropyridine calcium channel blocker rather than loop diuretics.38 Thiazides inhibit (nitrendipine) in the Syst-Eur study.42 However, electrolyte transport at the cortical diluting data from studies such as Systolic Hypertension sites. As they decrease the glomerular filtra- in the Elderly Program (SHEP) and the HYVET tion rate acutely, they increase proximal water substudy of cognitive function assessement43 reabsorption (making the plasma hypotonic), showed no difference in dementia between pla- reducing water delivery distally. Loop diuret- cebo and active therapy with chlorthalidone

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(Hygroton) (in SHEP) or indapamide (Lozol) Morris et al51 calculated the percentile scores (in the HYVET substudy). of four cognitive tests according to the level Disorders of calcium homeostasis are as- of blood pressure. Patients with systolic blood sociated with the brain’s aging process. Prob- pressures of 100 mm Hg, 120 mm Hg, and ably, the neuroprotective effect of nitrendip- 180 mm Hg scored lower on the Mini Men- ine seen in Syst-Eur was due to its ability to tal State Examination than those in the 140 affect this process, independent of its blood to 160 mm Hg range. Patients with diastolic pressure-lowering effect. blood pressures between 80 and 90 mm Hg In another prospective study, people over appeared to have the best cognitive function. 60 years of age who complained of subjective This further emphasizes that blood pressure memory loss showed a significant and positive control must be pursued in the very elderly, association between memory scores and the albeit less aggressively. The MIND substudy of use of calcium channel blockers (+0.14 ± 0.09 the SPRINT trial9 is likely to shed more light in users vs −0.12 ± 0.06 in nonusers; P = .016) on this relationship. independently of age, sex, white matter hy- When needed for optimal blood pressure perintensities, and carotid wall cross-sectional control in a hypertensive patient at risk of de- area, all of which were associated with worse mentia, a calcium channel blocker of the di- memory scores.44 hydropyridine type or a centrally active ACE Drugs that block the renin-angiotensin inhibitor, or both, is preferable. system have also been proposed to delay the onset and slow the progression of dementia.45 ■■ CASE 4: LABILE HYPERTENSION A small randomized, controlled trial suggested that centrally active ACE inhibitors—those A 74-year-old man with hypertension and di- that cross the blood-brain barrier, such as cap- abetes mellitus comes to see you in the office. topril (Capoten), lisinopril (Prinivil), ramipril On physical examination, his blood pressure is (Altace), and fosinopril (Monopril)—slow 175/110 mm Hg. His blood pressure during his cognitive decline in Alzheimer dementia last visit 3 months ago was 120/75. He brings more than non-centrally active ACE inhibi- a log with him that shows random fluctua- High blood tors or calcium channel blockers.46 tions in his blood pressure readings. He takes pressure Sink et al47 examined data from participants hydrochlorothiazide 25 mg daily for his blood in the Cognition Substudy of the Cardiovascu- pressure. must be lar Health Study48 on the effect of ACE inhibi- controlled tors on cognitive decline. ACE inhibitors, as Hypertension in some patients continuously in the very a class, showed no benefit in reducing the risk fluctuates between low and high levels. A of dementia compared with other antihyper- study in Canada found that up to 15% of all elderly, tensive drug classes. However, centrally active adult hypertensive patients might have labile albeit less ACE inhibitors, compared with other medica- hypertension.52 In the presence of a normal tions, were associated with a 65% reduction average blood pressure, visit-to-visit blood aggressively in cognitive decline per year of drug exposure pressure variability is usually considered a triv- (P = .01). Non-centrally active ACE inhibitors ial matter. However, some but not all studies worsened cognitive decline. have shown that such visit-to-visit variability It appears that the brain’s renin-angioten- in blood pressure is an independent predictor sin system plays a role in the pathogenesis of of future cardiovascular events in hyperten- dementia. Indeed, ACE has been shown to sive patients, independent of the mean sys- degrade amyloid-beta protein, and its level tolic blood pressure.52–54 was increased in brain tissue of Alzheimer pa- Blood pressure fluctuates from heartbeat to tients postmortem.49 heartbeat, from morning to night, from winter The relationship between blood pressure to summer, and from sitting to standing, and it and cognitive function appears to be curvilin- is prone to increase with exertion, stress, and ear, so that low blood pressure in late life is other factors. But excessive fluctuations in the also associated with dementia and Alzheimer elderly are most likely the result of excessive dementia.50 In 5,816 patients age 65 and older, stiffness of the arterial tree and a decrease in

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the windkessel (cushioning) function of the with standing. aorta. As a consequence, even small-volume Systolic orthostatic hypotension has been changes in the intravascular system can trig- shown to be a significant and independent pre- ger large blood pressure fluctuations. dictor of cardiovascular morbidity and death.56 There is some evidence that antihyperten- Moreover, syncope and subsequent falls are sive drug classes may differ in their effects on an important cause of injury and death in the visit-to-visit blood pressure variability. In a elderly.57 The clinical combination of hyper- 2010 study comparing the effects of different tension and orthostatic hypotension is, there- antihypertensive drugs on blood pressure vari- fore, especially challenging. A compromise ation, calcium channel blockers and non-loop between accepting a higher cardiovascular risk diuretics were associated with less variation in at either end of the spectrum with an added systolic blood pressure, and calcium channel higher risk for fall at the lower end has to be blockers reduced it the most.55 made. In the patient described above, switching To prevent orthostatic hypotension in the to a low-dose calcium channel blocker with a elderly, it is important to avoid prescribing thorough follow-up is a reasonable plan. high-risk drugs. When starting antihypertensive therapy, a low dose should be used, and ■■ CASE 5: ORTHOSTATIC HYPOTENSION the dose should be titrated upward very slowly and cautiously. If orthostatic hypotension is A 73-year-old woman with long-standing hyper- suggested by the history or by the orthostatic tension complains of some dizziness, especially test, which is warranted in all elderly hyper- when getting out of bed in the morning. On phys- tensive patients before starting or signifi- ical examination, her blood pressure is 134/100 cantly altering therapy, the potential culprit mm Hg sitting and 115/90 standing. She takes drug should be withdrawn and the patient amlodipine 10 mg daily, enalapril 10 mg daily, reassessed. Improved hydration, elevating the and chlorthalidone 25 mg daily. Chlorthalidone head of the bed, and taking the antihyperten- had been added on her last visit 1 month before. sive drug at night are ways to improve symp- Testing for toms, but these remain largely unproven. renal artery As a result of the increase in the number of In this patient, the newly added chlortha- elderly patients with hypertension and guide- lidone was stopped, and her symptoms im- stenosis is lines recommending better control in this age proved. indicated only group, the number of elderly patients on anti- if a subsequent hypertensive drugs has risen significantly. At ■■ PSEUDOHYPERTENSION the same time, the elderly have increasingly corrective presented with adverse effects of treatment. Since hypertension is defined by a numerical procedure is Orthostatic hypotension is a drop in systolic value, it is prudent that this value be accurate. pressure of 20 mm Hg or more or a drop in dia- Treating a falsely high reading or leaving a a viable option stolic pressure of 10 mm Hg or more on stand- falsely low reading untreated will predispose ing, with or without symptoms. These are caused the elderly patient to increased risk either by cerebral hypoperfusion and include dizziness, way. One rare condition in the elderly that lightheadedness, generalized weakness, visual can give a falsely high blood pressure reading blurring, and, in severe cases, syncope. is pseudohypertension. Alpha-blockers and nitrates have been Pseudohypertension is a condition in most commonly implicated in causing ortho- which indirect blood pressure measured by the static hypotension, due to venous pooling. cuff method overestimates the true intra-arte- Clearly, not all antihypertensive drugs are rial blood pressure due to marked underlying equal with regard to their venodilatory effects. arteriosclerosis. The Osler maneuver can be Thiazide diuretics, by causing fluid volume used to differentiate true hypertension from depletion, and beta-blockers, by interfering pseudohypertension.58 This is performed by with compensatory cardioacceleration with palpating the pulseless radial or brachial artery upright posture, are also commonly involved distal to the inflated cuff. If the artery is palpa- in causing an excessive blood pressure drop ble despite being pulseless, the patient is said

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to be “Osler-positive” and likely has pseudo- ing. Also, elevated blood pressure without ap- hypertension.58 propriate target organ disease should raise the Pseudohypertension should be suspected suspicion of pseudohypertension. Apart from if the patient has orthostatic hypotension de- the Osler maneuver, measuring the intraarte- spite normal blood pressure sitting and stand- rial pressure can confirm this diagnosis. ■

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