Treatment of combined hypertension and orthostatic hypotension in older adults: more questions than answers still remain

The clinical combination of hypertension, especially isolated systolic hypertension, and orthostatic hypotension (OH) is an increasingly well-recognized phenomenon affecting older patients [1–4]. The essential clinical dilemma that this patient group poses for clinicians is how to provide a degree of protection against future adverse vascular events, particularly stroke, while not predisposing to syncope and falls (and therefore fractures) due to OH. The problem has, at its root, the conundrum that both hypertension per se, and many antihypertensive medications, can exacerbate age-related impairments of the physiological processes that regulate blood flow after orthostasis [4].

In the 4-year interval since we last highlighted this topic in Expert Review of Cardiovascular Therapy, the management of this clinical problem remains largely unguided by direct evidence from clinical trials and is dependent on assessing each older patient on their individual characteristics [3]. In the absence of evidence, physicians are often faced with decision-making based on data from studies that included only small numbers of older adults. In addition, clinicians frequently have to bear in mind clinical factors that may, in combination with OH and related to medication usage, add to a patient’s future risk of a fall.

The evidence that our unit uses in clinical decision-making for this complex patient group will be detailed in this article. We include some newer data, based on large-scale epidemiological data, that may help clinicians quantify individual older patients’ future fracture risks [5]. In combination with quantification of individuals future adverse vascular event risk, from established sources such as the European Joint Societies Guidelines, clinicians can estimate which adverse event is the greater risk for an individual patient: a major vascular event (such as a stroke) or a major fracture (such as a hip fracture) occurring after a fall [6].

Hypertension & orthostatic hypotension is common in older adults

Highlighting this common clinical problem appears worthy of consideration when the number of older people taking antihypertensive medication is borne in mind. This number is increasing as the population ages and as guidelines recommend tighter blood pressure control [7]. Even in the absence of OH-predisposing medication, the combination of hypertension with OH appears to be common, with studies such as The Cardiovascular Health Study reporting that as many as 23% of those over the age of 65 years with untreated isolated systolic hypertension, have evidence of OH [1]. Outside of clinical trial settings, it is more common to encounter older hypertensive patients with OH who are currently taking antihypertensive medication.

Cardiovascular drugs are the most commonly identified drug precipitants of OH, but other drug classes such as tricyclic antidepressants and α₁-adrenergic receptor antagonists, used in the treatment of prostatic symptoms, are also commonly encountered in older patient groups [8]. In many cases, OH may not become apparent in an older hypertensive patient for a significant time period after a hypertension diagnosis is made, or for a significant time period after antihypertensive medication is introduced. Therefore, clinicians must remain alert to the possibility that antihypertensive medication, which initially appeared to be well tolerated, could now have become a contributory factor to a recent fall or syncopal event.

Making a diagnosis of orthostatic hypotension in an older hypertensive adult

In clinical practice, the diagnosis of drug-induced OH, or OH related to hypertension, is often made on the balance of probability when suggestive symptoms or unexplained falls occur, rather than with absolute certainty. When potential culprit drugs are withdrawn and symptoms improve, clinicians are often reluctant to rechallenge patients with the withdrawn drug for fear of syncope or falls recurring. Standard definitions of OH, traditionally based and poorly reflective of the variance in physiological responsiveness between individual patients, are in many cases unhelpful [4]. For example, a 20-mmHg systolic blood pressure decrease after orthostasis occurring in two older hypertensive adults may not indicate an equivalent future syncopal or fall risk if both do not have symptom reproduction accompanying their change. Likewise, additional factors, such as the duration of hypotension, may also influence the significance of OH in an individual patient. Therefore, the availability of a detailed hemodynamic assessment of blood pressure changes in OH is central to clinical decision-making in this patient group.

Newer diagnostic tools, particularly tilt-table testing with beat-to-beat (phasic) blood pressure monitoring, allow more precise quantification of OH. Use of such techniques can aid decision-making when medication withdrawal is being considered. A recent study by Van der Valde et al. explored this area [8]. They performed tilt-table testing on a group of patients attending a geriatric medicine outpatient clinic before and 6 months after withdrawal of fall risk-increasing drugs. All potential fall risk-increasing drugs were identified at initial assessment, and any agents thus identified were stopped or withdrawn over a month. When such patients were reassessed after drug withdrawal, they had improvement of their blood pressure responses to orthostasis. This suggests that tilt-table testing may be useful in providing definitive hemodynamic evidence of OH, thereby corroborating the clinician’s decision to terminate antihypertensive medication.

Prescribing considerations

Individual drug classes should not be considered equivalent in terms of their potential to cause or contribute to OH in older adults. In most studies, nitrates and α₁-adrenergic receptor antagonists are the most commonly implicated drug classes [8,10]. Some antihypertensive medication combinations, especially the use of diuretic medication with calcium channel blockers, also appear to be implicated commonly in this area [8].

Clinicians should also not assume that all members of any individual drug class are equally likely to predispose older hypertensive adults to OH. For example, hypotensive effects are not equivalent among individual angiotensin-converting enzyme inhibitors because of differences in their respective pharmacokinetics. Perindopril appears to be associated less with OH than other angiotensin-converting enzyme inhibitors such as enalapril or Captopril, for example [11]. For many drug classes, precise information regarding the relative tolerability of individual drugs in older adults may not be available. It appears prudent, therefore, to use antihypertensive medications that have a slower onset of action in older adults, to commence their use at low doses and to remain alert to the possibility of drug-related hypotension in older hypertensives even if patients had previously appeared to tolerate that agent well.

A nondipping nocturnal blood pressure pattern on 24-h ambulatory blood pressure monitoring (ABPM) [17,18], predicts a significantly higher cardiovascular mortality, especially in older patients. With this in mind, there may be a role for a less orthodox timing of medication administration of antihypertensives in this group. Although there is no specific evidence to support this strategy, it does have two potential benefits. First, any drug-induced hypotension that occurs during the night will occur when the patient is less likely to be upright and active and, therefore, may help to reduce the risk of a fall occurring. Second, lowering nocturnal blood pressure in this older patient group will help to lower blood pressure load, which is likely to have a beneficial effect on future adverse vascular event risk. This strategy would require careful selection of a relatively short-acting antihypertensive taken after retiring to bed, which would have minimal effect at the time of first orthostatic challenge the following morning. Evidence for such an approach remains limited to anecdotal reports at present.

Clinical assessment of older adults with hypertension & orthostatic hypotension

The evaluation of the older adult patient group in our unit focuses on obtaining reliable sources of hemodynamic information and, thereafter, conducting a number of risk assessments. Tilt-table testing with phasic blood pressure monitoring (by means of digital artery photoplethysmography) is used to determine the extent of the patient’s hypotensive tendency. The blood pressure load present is quantified using 24-h ambulatory monitoring. A careful medication and falls history is taken. A detailed cardiovascular and neurological examination are prioritized at the patient’s initial assessment.

After the initial baseline data are obtained, as described earlier, the principal clinical decision to be addressed is which potential adverse event is the greater risk to an individual older adult: a major vascular event, such as a stroke, or a major injury, such as a fracture, occurring as a result of a syncope-related fall. Use of major-event predictive tools is common in clinical practice and guides introduction of secondary preventative medications by allowing risk stratification of individual patients. We believe that combining the use of two such tools, the Fracture Risk Assessment (FRAX^®) tool, which estimates the 10-year absolute risk of sustaining a major fracture, such as a hip fracture, and the European Joint Societies Cardiovascular Risk tables, which estimate the 10-year risk of a patient sustaining a major vascular event (e.g., a stroke or myocardial infarction), can help clinicians decide whether treatment of an older adult’s hypertension or OH takes priority over the other disorder. However, as stated earlier, this approach remains unproven and there remains a lack of specific evidence, derived from well-designed clinical trials, to answer this clinical question.

Nonpharmacological management strategies

Management of older patients with this combination of hemodynamic conditions requires consideration of nonpharmacological interventions, as well as reflection on the prescribing principles for this group outlined previously. Several nonpharmacologic strategies have been postulated in the past to improve symptoms of OH. These include water drinking, increasing salt intake, physical counter-maneuvers, lower limb-compression hosiery, and sleeping with the head of the bed elevated. The underlying mechanisms of action are to increase circulating plasma volume through increasing fluid resorption in the kidney and attenuation of physiological diuresis, or improving venous return in the case of the physical counter maneuvers and lower limb-compression hosiery. In principle, the aim of successful treatment of the combined disorder of isolated systolic hypertension and OH is not to aggravate resting blood pressure but to minimize blood pressure drops that occur with orthostasis. Therefore, increasing circulating plasma volume with increased salt intake, for example, may attenuate the blood pressure drops associated with posture change, but it may also have the effect of increasing baseline blood pressure.

Sleeping with the head of the bed elevated has been included in several guidelines on treatment of OH [12]. However, a certain amount of scepticism exists regarding its effectiveness and tolerability. Initial evidence supporting this intervention was predominantly in the form of case reports. Follow-up studies have been favorable, but their interpretation is hindered by small sample sizes and studies examining a number of interventions at once [13,14]. Examining an intervention such as head-of-bed elevation in a randomized, controlled trial format in this particular group of patients will always present challenges. Confirming compliance at home is difficult. It may be reasonable to extrapolate data with regard to the physiological evidence from studies in a younger cohort. Fan et al. studied a group of young healthy volunteers before and after a 1-week period of sleeping with the head of the bed elevated. They found that head-of-bed elevation had a nocturnal antidiuretic effect with both intra- and extra-vascular accumulation of fluid and was associated with a reduced postural drop in systolic blood pressure and improved orthostatic tolerance [15].

In addition, use of lower limb-compression hosiery provides a means through which blood pressure decreases after orthostasis can be minimized without elevating resting blood pressure or increasing blood pressure load [16]. In practice, however, poor compliance tends to limit the potential usefulness of lower limb-compression hosiery in this patient group.

Conclusion

In conclusion, direct evidence from specifically designed randomized clinical trials is still lacking in the management of combined hypertension and OH. For clinicians, there remains a constant dilemma of how to minimize the cardiovascular and cerebrovascular complications of chronic hypertension without increasing the risk of complications from OH-related syncope and falls. Avoidance of fall risk-increasing drugs, selection of an antihypertensive with favorable pharmacokinetic properties and concurrent use of nonpharmacological interventions remains the standard. There may be a role for nocturnal administration of antihypertensive medications in this group. In older patients who appear to be at significant risk of both adverse vascular events and also of future syncope-linked falls and fractures, the use of predictive tools, employed in combination, may help guide decision-making with regard to initiation, continuation or withdrawal of antihypertensive medication.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.