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Abstract

  1. Top of page
  2. Abstract
  3. Hypertension Pathophysiology
  4. Literature Review
  5. Conclusions and Future Directions
  6. References

J Clin Hypertens (Greenwich). 2012;14:711–717. ©2012 Wiley Periodicals, Inc.

One quarter of Americans will be older than 80 by 2030, and hypertension in this group will be ubiquitous. Most studies of hypertension exclude octogenarians and are not able to be generalized because of differences in physiologic and social phenomena. This review evaluates the existing literature in an effort to identify unresolved issues and guide future areas of investigation. Hypertension has been well characterized in adults and the young elderly, and the focus is on optimizing treatment regimens. However, research specifically involving this rapidly growing minority is sparse. Most studies are still trying to characterize blood pressure goals, and only one major series has begun to evaluate treatment options. Based on available evidence, it appears that an appropriate blood pressure goal may be somewhat higher in octogenarians and that thiazide diuretics may be the initial treatment of choice.

By 2030, one quarter of Americans will be older than 80 years.1 Such increased longevity is partially due to improvements in the treatment of chronic diseases, namely hypertension. A continuous, linear, age-related increase in systolic blood pressure (SBP) has been documented in both sexes and in most racial and ethnic groups.2,3

Treatment of hypertension in octogenarians, however, is challenging. End-organ damage complicates management, and response is not as predictable as for younger adults because of differences in physiology. Cognitive and social needs, such as reliance on caregivers, further complicate circumstances.

Most of the existing studies on hypertension have upper age limits of 70 to 75 years. Even when octogenarians are included, it is only as a small subgroup, making these studies nongeneralizable. Therefore, the authors of this article decided to review the literature on treatment of hypertension in the elderly with the intention of better characterizing the issues surrounding and the specific needs of the octogenarian subgroup.

Hypertension Pathophysiology

  1. Top of page
  2. Abstract
  3. Hypertension Pathophysiology
  4. Literature Review
  5. Conclusions and Future Directions
  6. References

Pathophysiologic changes of aging are markedly present in octogenarians. Recognition of these changes allows for better understanding and management of age-related hypertension.

Cumulative exposures to oxidative stress contribute to endothelial dysfunction and hypertrophy of vascular cells. In turn, the relaxation factor nitric oxide is compromised, and vessels become less distensible.4,5 This results in increased pulse wave velocity and SBP, restricting forward flow and limiting organ perfusion. Autonomic and baroreceptor dysfunction, cardiac arrhythmias and impaired cerebral adjustments lead to fluctuance in blood pressure (BP) and disruption of vascular homeostasis, further compromising perfusion. Resultant hypoperfusion leads to falls and cerebrovascular accidents, left ventricular hypertrophy, and acute coronary syndromes.6

In addition to intrinsic vascular changes, kidney function deteriorates over time. The glomerular filtration rate (GFR) declines by 8 mL/minute/1.73 m2 per decade after the age of 40, influenced by 10% less renal blood flow during this timeframe. GFR decreases and basement membranes undergo progressive folding and thickening, leading to tuft collapse and glomerular sclerosis. By age 40, sclerotic glomeruli account for 5% of all glomeruli, increasing to 30% in octogenarians.4 Sodium-potassium excretion is impaired, causing volume overload and further increasing BP.

Literature Review

  1. Top of page
  2. Abstract
  3. Hypertension Pathophysiology
  4. Literature Review
  5. Conclusions and Future Directions
  6. References

Unlike the former notion that high BP was necessary for perfusion of vital organs, there is mounting evidence that control of BP continues to be of importance beyond middle age. Hundreds of papers attempt to define hypertension and describe optimal management; however, results are conflicting and many questions remain.

Systolic hypertension was an early concern, followed by diastolic hypertension. Mixed hypertension, in which both types are present, has been implicated in poor outcomes, as have elevated mean pressures and high pulse pressure, which is the difference between systolic (SBP) and diastolic blood pressures (DBP)s.7 Additionally, the type of graphical relationship BP has with mortality is unclear. U-shaped, J-shaped, positive, and negative relationships have all been reported.8 While it is commonly believed that high BP is dangerous, in early literature and again recently, mortality has been associated with low BP.7–10

Coronary and noncoronary cardiovascular events, particularly myocardial infarction and stroke, are end points that are most commonly discussed. The current paradigm is that adverse events increase across all elevated measures of BP and across all age groups when hypertension is defined as a BP >140/90 mm Hg.6,11,12 A meta-analysis published in 2002 reported greater than 2-fold differences in stroke and cardiovascular death for each difference in 20 mm Hg SBP and 10 mm Hg DBP for the 40- to 69-year age group, with an annual absolute difference in risk that was greater with older age. This study lends support to the concept that even small improvements in BP may significantly decrease risk, especially for older age groups.8,13,14Figure 1, Figure 2, and Figure 3 display outcomes from this study.14

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Figure 1.  Stroke mortality rate in each decade of age vs usual blood pressure at the start of that decade.14

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Figure 2.  Ischemic heart disease (IHD) mortality rate in each decade of age vs usual blood pressure at the start of that decade.14

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Figure 3.  Other vascular (not stroke or ischemic heart disease) mortality rate in each decade of age vs usual blood pressure at the start of that decade.14

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Finally, with more than 5 classes of drugs available and new options offered daily, drug companies and physicians alike are working to define an optimal treatment protocol for hypertension. Despite this, evidence published prior to the current decade is composed of reviews and clinical trials that have either completely excluded octogenarians or lumped them into “elderly.”9,15–18 Thus, there remains considerable uncertainty regarding target BP for the octogenarian population, with concern for overtreatment as a cause of adverse events.

What follows is an examination of treatment studies with mixed age groups, a discussion of literature involving octogenarians, and finally a review of the current hypertension guidelines.

Studies With Mixed Age Groups

Studies defining “elderly” as older than 65 have solidly demonstrated the benefits of hypertension treatment for the young elderly population,8 but the delineation is unclear for older patients. Randomized controlled studies are few and results are conflicting.8,9,19 Variations in populations and protocols prevent direct comparison across studies. Described here are the trials that have most strongly influenced current treatment protocols for hypertension in the elderly.

The VA Cooperative Studies from the 1970s refer to the first study of hypertension treatment, which in 1966 examined the incidence of stroke in men vs women on treatment vs placebo.20 This gave rise to a trial that reported an approximately 20-mm Hg decrease in DBP and lower rates of stroke, coronary events, congestive heart failure, and death among men (average age 50 and DBP 90–114 mm Hg) taking hydrochlorothiazide (HCTZ) plus reserpine plus hydralazine vs the equivalent placebos.21 A follow-up paper reported that only 11% of people with hypertension were aware of their disease and were being treated, emphasizing the need for further study and education.20

Three series investigating the benefits of treatment, the Systolic Hypertension in the Elderly Program (SHEP), the Swedish Trial in Old Patients With Hypertension (STOP-Hypertension), and the Medical Research Council (MRC) trial evaluated diuretic plus β-blocker regimens.

The SHEP trial randomized patients (average age 72 years, SBP >160 mm Hg) to treatment with chlorthalidone vs placebo. Dosages were increased and additional drugs (hydralazine, reserpine, metoprolol, or placebo) were added if goal SBP was not reached. This study reported a 60% vs 33% success rate of significant SBP and DBP reduction, proving that these medications are effective in the treatment of systolic hypertension.17 A follow-up study using a chlorthalidone plus atenolol regimen reported a significant 36% reduction in total stroke as well as reductions in fatal and nonfatal myocardial infarction, major cardiovascular events, and death from all causes.18,19

The STOP-Hypertension trial randomized patients (70–84 years, SBP 180–230 mm Hg, DBP >90 mm Hg or 105–120 mm Hg regardless of SBP) to either placebo or a commonly used regimen (HCTZ plus amiloride, atenolol, metoprolol, or pindolol). Active treatment with these drugs significantly reduced BP and revealed decreases in cardiovascular death, stroke morbidity, and total mortality.15,19

Superiority was first described in the MRC trial, which randomized patients (ages 65–74, SBP 160–209, DBP <115 mm Hg) to placebo, atenolol, or HCTZ plus amiloride. Patients showed significant reductions in the rate of stroke (25%) and all cardiovascular events (17%). In subgroup analysis, the diuretic group was found to have superior outcomes for all 3 events while the β-blocker group did not, concluding that diuretic therapy was more effective.16

Trials of new drug classes quickly made their way into the literature. The Systolic Hypertension in Europe (SYST-EUR) and Study on Cognition and Prognosis in the Elderly (SCOPE) trials are two such examples.

SYST-EUR randomized patients older than 60 years with isolated systolic hypertension to treatment with nitrendipine plus enalapril and/or HCTZ. Significant reductions were seen for rates of total stroke (42%), nonfatal stroke (44%), fatal and nonfatal cardiac end points including sudden death (26%), isolated nonfatal cardiac end points (33%), and fatal and nonfatal cardiovascular end points (31%). This study concluded that the calcium channel blocker reduces the rate of cardiovascular complications of isolated systolic hypertension.19,22

The Study on Cognition and Prognosis in the Elderly randomized patients (70–89 years, SBP 160–179, DBP 90–99 mm Hg) to candesartan plus or minus HCTZ, concluding that a slightly lower BP while taking this angiotensin receptor blocker was associated with significant reduction in nonfatal stroke.23,24

These studies represent the majority of rigorous drug therapy trials for the treatment of hypertension in the elderly. None of them focus specifically on octogenarians, and discrepancies in treatment regimens prevent a direct comparison of these results.15–18,22–24

Studies Specific to Octogenarians

For younger patients, the dangers of hypertension are well understood, and the focus is on treatment. However, the literature on octogenarians is still evaluating BP goals and mortality benefits. The papers discussed in this section are a representation of the few studies that specifically address the needs of this important subgroup.

In a 1988 observational study, an inverse relationship between BP and mortality was observed. This raised questions of whether hypertension ceases to be a risk factor in the very old and whether treatment of high BP in this age group is harmful.10

Subset data from a meta-analysis published in 1999 reported that controlling BP in octogenarians resulted in significantly decreased rates of fatal and nonfatal stroke, major cardiovascular events, and heart failure (34%, 22% and 39%). However, it was unable to delineate an age threshold beyond which treatment of hypertension should be withheld. Interestingly, the point is made that the addition of just one large hypothetical trial without significant results would invalidate some of their findings, demonstrating the fragility of these relationships.13

A population-based longitudinal study by Satish and colleagues compared a young elderly (65–84 years) with an old elderly (above 85 years) group. Men in the older group experienced a significantly lower mortality rate with SBP >180 mm Hg than with SBP <130 mm Hg and a negative hazard of death associated with each 10-mm Hg increase in SBP, describing a U-shaped relationship. A negative relationship was seen between mortality and DBP for both groups. This study suggests that optimal BP is higher for the very old.8

Similar results were seen in a study by Rastas and associates of patients older than 85. Questionnaires regarding health, medication, cognition, and functional status were utilized to avoid potentially confounding effects of comorbidities. SBP <140 mm Hg and DBP <80 mm Hg were significantly associated with an increased risk of death. SBP <140 mm Hg remained significant in multivariate analysis, with risk of death being highest in this group.7

Oates and coworkers reported another U-shaped relationship for survival in a retrospective cohort study wherein patients with SBP up to 139 mm Hg and DBP up to 89 mm Hg were less likely to die than patients with lower BP, suggesting that overly aggressive control might be harmful, but only to the upper limit of control (139/89 mm Hg). Mortality at lower BP may be due to medication-related adverse effects, and survival at a BP within the higher range of control may to be due to better organ perfusion. In contrast to other studies, no significant relationship was demonstrated in those with BP >140/80 mm Hg.25

Finally, the Hypertension in the Very Elderly Trial (HYVET) series is the first to use a randomized controlled design to study the impact of specific treatment agents on the mortality of hypertensive octogenarians. Patients with SBP >160 mm Hg were randomized to the diuretic indapamide or placebo. The angiotensin-converting enzyme inhibitor perindopril was added if BP goal was not reached, and patients were removed from the study if BP was persistently elevated. A significant reduction in stroke death, heart failure, all death, and all cardiovascular events was reported, along with nonsignificant reductions in stroke events and cardiovascular death. Figure 4 displays Kaplan-Meier curves for study end points. The finding of a significant reduction of death from any cause made this one of the few studies showing a clear benefit of hypertension treatment in the very old. This study suggests a treatment goal of 150/80 mm Hg, which is the first time a goal has been suggested other than 140/80 mm Hg.26

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Figure 4.  Kaplan-Meier estimates of the rate of end points according to study group. For the active-treatment group compared with the placebo group, the unadjusted hazard ratios (95% confidence intervals) were as follows: for fatal or nonfatal stroke, 0.70 (0.49–1.01) (A); for death from any cause, 0.79 (0.65–0.95) (B); for death from cardiovascular causes,0.77 (0.60–1.01) (C); for death from stroke, 0.61 (0.38–0.99) (D); and for heart failure, 0.36 (0.22–0.58) (E).26

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Although the results of these studies specifically involving octogenarians are by no means conclusive, they suggest that a BP somewhat higher than current goals may be better for this group of individuals.

Guidelines

The most recent hypertension guidelines are from the American College of Cardiology Foundation (ACCF) and the American Heart Association (AHA) in 2011. Prior to that, the European Society of Hypertension (ESH) and the European Society of Cardiology (ESC) published a collaboration piece, and statements were also offered by the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure (JNC 7) and a World Health Organization (WHO) collaboration with the International Society of Hypertension (ISH).

The JNC 7 guidelines recommend treatment goals of <140/90 mm Hg for the general population and <130/80 mm Hg in people with diabetes or chronic kidney disease. Treatment should typically begin with a thiazide diuretic. JNC 7 states that two thirds of individuals older than 65 have hypertension, often with the worst control, but it does not delineate specific guidelines for the elderly. Instead, it recommends using the same BP goals as for the general population, but to start at lower drug doses and monitor for side effects.11

The WHO/ISH report from 2003 demonstrates similar targets of <140/90 and <130/80 mm Hg, respectively, with a low-dose diuretic as the initial drug of choice for patients younger than 80 years. At older ages, this committee suggests that judgment should be made on an individual basis due to the lack of data for this group and that therapy should not be withdrawn solely due to age.12

The ESH/ESC 2007 guidelines present the same treatment goals, with similar recommendations for initial therapy. No specific agent is recommended, but like the WHO/ISH report, this paper recognizes the lack of conclusive data in octogenarians and again recommends against stopping treatment solely based on age.27

The previous three reports are helpful in establishing best-practice BP treatment goals for the younger population, but they do not offer much regarding patients of advanced age.

In contrast, the ACCF/AHA consensus statement offers informal guidelines. Recommendations are to aim for an SBP goal of 140 mm Hg to 145 mm Hg, avoiding pressures lower than 130/65 mm Hg, since it is not known at what point perfusion of vital organs is affected. Low-dose thiazide diuretics, calcium antagonists, and renin-angiotensin-aldosterone blockers are recommended as preferred agents, and vigilance for adverse effects is warranted.6

These four papers guide the majority of decisions regarding hypertension treatment across the United States. However, only one is able to provide any recommendation specific to octogenarians. This is a reflection of just how little consistent evidence exists regarding this population, and it is a strong call for further investigation.

Conclusions and Future Directions

  1. Top of page
  2. Abstract
  3. Hypertension Pathophysiology
  4. Literature Review
  5. Conclusions and Future Directions
  6. References

Decisions regarding hypertension treatment in octogenarians are extrapolated from data collected from patients who are much younger.25 This has resulted in a vague and conflicting body of evidence from which it is difficult to draw reliable conclusions, and no official guidelines have been presented. Unresolved questions persist regarding whom to treat, when to initiate and stop treatment, and the relative effectiveness of different drug classes.8 There is a great need to know whether, at some age, hypertension ceases to be a risk factor for adverse outcomes and whether aggressive treatment continues to be beneficial.7

Although hypertension is typically treated with medication, this may not be the best option for octogenarians who are intolerant to current agents. Lifestyle modifications such as smoking cessation, exercise, and low-sodium intake may play a strong role in lowering BP in this group.

Additionally, interventional approaches to BP control are on the rise. One experimental treatment is an implantable subcutaneous pulse generator that stimulates the carotid baroreceptors, leading to a decrease in BP through parasympathetic nervous system activation.28 Another recent intervention is selective renal sympathetic denervation, revisiting the pre-drug era technique of surgical sympathectomy, but using a specially designed catheter to target sympathetic nerve fibers running along the renal arteries. By ablating these fibers, significant long-term reductions in BP have been observed.29 However, neither of these techniques has been specifically evaluated in octogenarians and both remain experimental, so there is a need for further study before they can be integrated into mainstream use.

It is the hope of these authors that this review has identified the key literature surrounding this important discussion regarding one of the fastest-growing age groups contributing to our society and that it may be used as a basis for further research in this arena.

Disclosures:  The authors report no specific funding in relation to this research and no conflicts of interest to disclose.

References

  1. Top of page
  2. Abstract
  3. Hypertension Pathophysiology
  4. Literature Review
  5. Conclusions and Future Directions
  6. References
  • 1
    US Bureau of the Census. Current Populations Report: 2003. Washington, DC: US Bureau of the Census; 2003.
  • 2
    Burt VL, Whelton P, Roccella EJ, et al. Prevalence of hypertension in the US adult population: results from the Third National Health and Nutrition Examination survey, 1988–1991. Hypertension. 1995;25:305313.
  • 3
    Lawes CM, Vander Hoorn S, Law MR, et al. Blood pressure and the global burden of disease 2000. Part 1: estimates of blood pressure levels. J Hypertens. 2006;24:413422.
  • 4
    Wilcox CS. Pathogenesis of Hypertension. In: Greenberg A, ed. Primer on Kidney Disease, 5th ed. Philadelphia, PA: Saunders Elsevier; 2009:544549.
  • 5
    Timiras PS. Physiological Basis of Aging and Geriatrics, 2nd ed. Boca Raton, FL: CRC Press; 1994:199215.
  • 6
    Aronow WS, Fleg JL, Pepine CJ, et al. Expert consensus document: ACCF/AHA 2011 expert consensus document on hypertension in the elderly: a report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents. Circulation. 2011;123:24342506.
  • 7
    Rastas S, Pirttila T, Viramo P, et al. Association between blood pressure and survival over 9 years in a general population aged 85 and older. J Am Geriatr Soc. 2006;54:912918.
  • 8
    Satish S, Freeman DH, Ray L, Goodwin JS. The relationship between blood pressure and mortality in the oldest old. J Am Geriatr Soc. 2001;49:367374.
  • 9
    Bulpitt CJ, Beckett NS, Cooke J, et al. Hypertension in the Very Elderly Trial working. Results of the pilot study for the hypertension in the very elderly trial. J Hypertens. 2003;21:24092417.
  • 10
    Mattila K, Haavisto M, Rajala S, Heikinheimo R. Blood pressure and five year survival in the very old. BMJ. 1988;296:887889.
  • 11
    Chobanian AV, Bakris GL, Black HR, et al. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure: the JNC 7 report. Hypertension. 2003;42:12061252.
  • 12
    World Health Organization, International Society of Hypertension Writing Group. 2003 World Health Organization (WHO)/International Society of Hypertension (ISH) statement on management of hypertension. J Hypertens. 2003;21:19831992.
  • 13
    Gueyffier F, Bulpitt C, Boissel J, et al. INDANA Group. Antihypertensive drugs in very old people: a subgroup meta-analysis of randomized controlled trials. Lancet. 1999;353:793796.
  • 14
    Prospective Studies Collaboration. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet. 2002;360:19031913.
  • 15
    Dahlof B, Lindholm LH, Hansson L, et al. Morbidity and mortality in the Swedish trial in old patients with hypertension (STOP-Hypertension). Lancet. 1991;338:12811285.
  • 16
    MRC Working Party. Medical Research Council trial of treatment of hypertension in older adults: principal results. BMJ. 1992;304:405412.
  • 17
    Perry HM, Smith WM, McDonald RH, et al. Morbidity and mortality in the Systolic Hypertension in the Elderly Program (SHEP) pilot study. Stroke. 1989;20:413.
  • 18
    SHEP Cooperative Research Group. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. Final results of the Systolic Hypertension in the Elderly Program (SHEP). JAMA. 1991;265:32553264.
  • 19
    Kithas PA, Supiano MA. Practical recommendations for treatment of hypertension in older patients. Vasc Health Risk Manag. 2010;6:561569.
  • 20
    Freis ED. The Veterans Administration Cooperative study on antihypertensive agents: implications for stroke prevention. Stroke. 1974;5:7677.
  • 21
    Veterans Administration Cooperative Study Group on Antihypertensive Agents. Effects of treatment on morbidity in hypertension: results in patients with diastolic blood pressure averaging 90 through 114mmHg. JAMA. 1970;213:11431152.
  • 22
    Staessen JA, Fagard R, Thijs L, et al. The Systolic Hypertension in Europe (Syst-Eur) Trial Investigators. Randomised double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension. Lancet. 1997;350:757764.
  • 23
    Hansson L, Lithell H, Skoog I, et al. Study on cognition and prognosis in the elderly (SCOPE). Blood Press. 1999;8:177183.
  • 24
    Lithell H, Hansson L, Skoog I, et al. The study on cognition and prognosis in the elderly (SCOPE): principal results of a randomized double-blind intervention trial. J Hypertens. 2003;21:875886.
  • 25
    Oates DJ, Berlowitz DR, Glickman ME, et al. Blood pressure and survival in the oldest old. J Am Geriatr Soc. 2007;55:383388.
  • 26
    Beckett NS, Peters R, Fletcher AE, et al. HYVET Study Group. Treatment of hypertension in patients 80 years of age or older. N Engl J Med. 2008;358:18871898.
  • 27
    Mancia G, De Backer G, Dominiczak A, et al. ESH-ESC Task Force on the Management of Arterial Hypertension. 2007 ESH-ESC practice guidelines for the management of arterial hypertension. J Hypertens. 2007;25:17511762.
  • 28
    Ng MM, Sica DA, Frishman WH. Rheos: an implantable carotid sinus stimulation device for the nonpharmacologic treatment of resistant hypertension. Cardiol Rev. 2011;19:5257.
  • 29
    Papademetriou V, Doumas M, Tsioufis K. Renal sympathetic denervation for the treatment of difficult-to-control or resistant hypertension. Int J Hypertens. 2011;201:196518. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3095896. Accessed May 28, 2012.