Antihypertensive treatmentin elderly and risk of falls : a systematic review

Degree project, 30 ECTS [2019-06-07]

Antihypertensive treatment

in elderly and risk of falls

a systematic review

Author: Emil Skanebo Bachelor in medicine Örebro Universitet Örebro, Sweden Supervisor: Peter Engfeldt Associate Professor, MD, PhD Primary Care Department in Kumla Region Örebro County Örebro, Sweden

Word count

Abstract: [222] Manuscript: [2542]

Abstract

Introduction

The consequences of falling can be fatal to elderly. The mortality, morbidity and the risk of anxiety and depression increases following a fall. Drug prescription is a preventable fall risk, making the association between antihypertensive medications and risk of falling an important area of investigation.

Aim

Compile the results from studies which have examined the effect of initiating or changing the antihypertensive medication on fall risk in people aged 60 years or older.

Methods

Data sources: MEDLINE and Cochrane databases. Study selection: Original articles of cohort-, case control-, case crossover-, cross-sectional- and randomized controlled trial type, published between January 2000 and May 2019 and written in English were included. Data assessment: 6 studies met the criteria and were included. Study quality was assessed for each study.

Results

Three studies found significant short-term increase in fall risk, regardless of drug type. One study discovered an 18% increase in fall risk for every 5-day gap in treatment. Two studies evaluated antihypertensive drug types separately and found contradictive results of thiazide diuretics on short-term fall risk. Calcium channel blockers showed a protective effect and beta blockers an increased risk during the first 3 weeks after initiating treatment.

Conclusions

No consistent consensus was seen regarding the short-term fall risk in separate

antihypertensive drug types, though most studies agree in a short-term risk increase after general antihypertensive treatment initiation or change.

Abbreviations

ACEi Angiotensin Converting Enzyme inhibitor AHT Antihypertensive

ARB Angiotensin Receptor Blocker

BB Beta-blocker

CCB Calcium Channel Blocker CI Confidence Interval

HR Hazard Ratio

IR Incidence Rate

IRR Incidence Rate Ratio Loop Loop diuretics

MeSH Medical Subject Headings

OR Odds Ratio

RR Risk Ratio

SBU Statens Beredning för Medicinsk och Social Utvärdering (Swedish Agency for Health Technology Assessment and Assessment of Social Services)

SD Standard Deviation Thiazide Thiazide diuretics

Introduction

The consequences of falling can be immense in an elderly individual; it is one of the major causes of injury, reduced functionality and death [1]. In addition to the increased mortality and morbidity associated with falling, severe physical injuries occur in about 10% of falls [2,3]. Apart from this is the adjacent risk of psychological damage from a fall, including fear-induced immobility, increased need of aid in the home and daily living as well as anxiety and depression [4]. Though studies have shown the protective effect of antihypertensives on cardiovascular disease [5–7], some studies point towards an increased risk of falls and serious fall injuries in elderly from the use of antihypertensives [8–11]. These effects are possibly explained by age-related intensification of side-effects including orthostatic hypotension, balance and walking disturbances, pharmacologically induced dizziness and electrolyte disturbances [12,13]. Drug prescription is one of the few fall risks which can be affected. Since antihypertensives is the largest group of drugs prescribed to elderly [14–16], the association between these drugs and risk of falling is an important area to investigate. In earlier studies no clear consensus between antihypertensives and risk of falling has been found. Some studies reported no impact on the fall risk [17–20], some point towards a

protective effect [21,22] and other studies reported that the risk was increased with the use of these drugs [9,23–25]. Most of these studies looked at antihypertensives as a group, which makes it hard to estimate the risk profile of individual drugs. Studies in later years have found significant associations between falls and the initiation, adjustment or dose increase of

antihypertensives [10,26–32].

Aim

The aim of this study was to compile the results from studies which have examined the effect of initiating or changing the antihypertensive (AHT) medication on fall risk in people aged 60 years or older.

Methods

Data sources

MEDLINE and Cochrane databases were systematically searched, targeting articles written in English. The selected databases were considered large enough to contain a sufficient number of articles for the systematic review. Original articles published between January 2000 and May 2019 qualified for inclusion. The search was based on the two MeSH search terms “Antihypertensive Agents” and “Accidental falls”, along with exploded text searches originating in the MeSH terms. Reference lists of selected articles were scanned for additional articles suitable for inclusion. No grey literature was searched.

Study selection, inclusion and exclusion criteria

Only original studies of cohort-, case control-, case crossover-, cross-sectional- and randomized controlled trial type were included if the study investigated the relationship between the short-term risk of falling and initiation, dose adjustment or change in AHT medication in a population aged 60 years or older. Case studies, comments, responses, letters, review articles and animal studies were all excluded when going through titles and abstracts. AHT medication was defined as medical drugs with the primary indication of lowering the blood pressure. Studies evaluating beta-blocker eye drops or alfa1-antagonists used for benign prostatic hyperplasia were for that reason excluded. Both direct definitions of a fall [33,34] and indirect outcomes connected to a fall, such as typically fall-related fractures, were used. Studies observing stroke patients were excluded because the blood pressure in these patients is unpredictable and strongly affected by their medical condition. Study

populations with dementia or substance abuse were excluded because of the associated risk of low compliance to the treatment plan, unless the person was presumed capable of handling his/her medicines or if the person had a caregiver. Figure 1 demonstrates the selection process.

Data extraction

The screening of titles, abstracts and later full texts was performed by the author E.S. and the supervisor P.E. separately. Any article without total consensus for exclusion was included for full text analysis. The following data was then extracted from each article: year, country, study design, population characteristics (age, proportion males/females, setting, population size), follow up period, results in odds ratio (OR), risk ratio (RR) or incidence risk (IR), and

method used for data collection regarding AHT drug intake and falls. See table 1 in the appendix for a summary of the data extracted from each study.

Assessment of study quality

The assessment template provided by SBU [35] was used for the study quality assessment, summarized in table 2. The methods for collecting data about medication and fall

ascertainment were taken into consideration when determining study quality, both specified in table 2.

Results

Out of 192 search results in the database search, 6 articles remained after the exclusion steps [22,36–40]. The included studies were analyzed, and data was extracted. See table 1 in the appendix for a summary of the data extracted from each study. The assessment template provided by SBU [35] was then used for the study quality assessment, summarized in table 2. The possible grades of study quality were Poor, Fair or Good (with increasing study quality). Table 2. Study quality assessment with help from the SBU assessment template* and the

methods for collecting data about medications and falls.

Author, year Study

quality

Method for AHT

treatment ascertainment

Method for fall ascertainment Banu et al. 2018 [39] Fair Medical records Medical records Butt et al. 2013 [36] Good Prescription records Diagnose codes Dillon et al. 2019 [40] Fair Prescription records Self-reported Gribbin et al. 2011 [22] Fair Prescription records Diagnose codes Shimbo et al. 2016 [38] Good Prescription records Diagnose codes Solomon et al. 2011 [37] Fair Prescription records Diagnose codes

* The SBU assessment template [35] AHT = Antihypertensive

Five cohort studies [22,36–38,40] and one case-control study [39] were included. Diagnose codes were used in 4 studies to evaluate falls [22,36–38]. The codes used could either be directly linked to falling [22,36] or codes linked to events such as fractures [37,38], where falling can be an assumed mechanism of origin. One study used self-reporting of falls [40]. The last study used medical records both for ascertainment of falls and medications [39], which made it the only study not using prescription records to determine the AHT treatment. The follow up time differed between studies, see table 1 in the appendix, partly explained by the different study designs. Most studies adjusted for age and sex.

Figure 1. The selection process with exposed reasons for exclusion.

Banu et al [39] found an increased fall risk recently after a change in AHT treatment (OR = 3.66; 95% CI 1.19-11.23; p = 0.01), where added AHT drug, dose increase and change of AHT type were included in their definition of a change in AHT treatment. They did not evaluate the different AHT types separately, and no clear definition was specified for the risk time evaluated.

Butt et al [36] looked at the fall risk during the first 14 days after initiation of a single-drug AHT treatment. Regardless of drug examined, the risk was significantly increased (IRR = 1.94; 95% CI 1.75-2.16) during the first 14 days.

Dillon et al [40] was the only study with self-reported falls and also had a slightly different measuring method for drug intake ascertainment. They looked at the prescription data of

Database search N = 192

Abstracts N = 47

Full text articles N = 17 Excluded by title N = 143 Excluded abstracts N = 32 9 letters 7 reviews 6 wrong aim/question 6 published before 2000 2 inaccessible

2 not written in English

Excluded full text articles N = 11 8 wrong aim/question 2 wrong medications 1 stroke patients Included articles N = 6 Included from reference lists

N = 2

Duplicates excluded N = 2

antihypertensives and estimated the number of 5-day gaps between drug intake as a way to measure the adherence to the drug prescription. They found an 18% risk increase for every 5-day gap in the AHT treatment (RR = 1.18; 95% CI 1.02-1.37; p = 0.024).

Gribbin et al [22] looked at new prescriptions of different types of antihypertensives

separately, and found a significantly increased fall risk during the first 3 weeks after initiating a new treatment with thiazide diuretics (IRR = 2.80; 95% CI 1.7-4.57). During the same period, calcium channel blockers seemed to have a protective effect on fall risk (IRR = 0.75; 95% CI 0.60-0.92). From day 22, beta blockers showed increased fall risk (IRR = 1.23; 95% CI 1.02-1.48).

Shimbo et al [38] found an increased risk of serious fall injuries during the first 15 days after initiating (OR = 1.36; 95% CI 1.19-1.55), adding (OR = 1.16; 95% CI 1.10-1.23) or titrating (OR = 1.13; 95% CI 1.08-1.18) AHT treatment. The risk decreased after day 15 in all included groups of antihypertensives.

Solomon et al [37] chose to describe the risk of typical osteoporotic fractures in each AHT drug type with the fall risk of calcium channel blockers as a reference point and found significant risk reductions among users of both angiotensin receptor blockers (HR = 0.76; 95% CI 0.68-0.86) and thiazide diuretics (HR = 0.85; 95% CI 0.76-0.97). Other types of AHT drugs showed no significant change of fall risk. Compared to the fracture rate per 1000 person-years in the entire study population (IR = 35.2; 95% CI 34.4-36.1), thiazide diuretics were associated with the lowest fracture rate (IR = 28.5; 95% CI 25.4-31.9) and loop

diuretics with the highest rate (IR = 49.0; 95% CI 46.1-52.1) without adjustment for confounders.

Discussion

Most of the studies agreed that the short-term risk of falling is increased after a change in the AHT treatment, though the study designs differ and some exceptions to that agreement were found. An increased short-term risk for all included AHT types was found in 3 studies [36,38,39]. Two of them investigated the AHT drugs as a whole [38,39] and the third evaluated each drug type separately [36], but they all found significant short-term risk increase in all included drug types. Dillon et al [40] discovered an 18% increase in fall risk for every 5-day gap in treatment, further strengthening the earlier suggested findings, though implying it from a different perspective. The two remaining studies [22,37] evaluated the risk profile of each included drug type separately. The drugs included were the same in both studies except the inclusion of loop diuretics in the study by Solomon et al [37]. It should be pointed out that the two studies used different methods for ascertainment of falls. Gribbin et al [22] used fall-related terms in diagnose coding whereas Solomon et al [37] used “classical” osteoporotic fractures in diagnose coding as a surrogate measure for falling. The widely separated findings regarding thiazide diuretics between the two studies is noteworthy though. Solomon et al [37] found that thiazide diuretics not only display absence of a risk increase, they found a protective effect against fractures compared to calcium channel blockers. In the study by Gribbin et al [22], calcium channel blockers had a significantly protective effect against fall risk the first 3 weeks after premier prescription, whereas thiazide diuretics significantly increased the risk of falls during the same time period.

This systematic review article is an attempt to gather the current research about the impact of changing AHT medication on fall risk in elderly. The findings are clearly heterogenous, with a variety of study designs which obstructs the extraction of solid conclusions. This may partly be due to the search method. The text searches included might not have covered all

definitions of an AHT medication nor a fall. Half of the included articles were written during the last 3 years, and since MeSH terms are manually connected to new articles gradually some articles may not have been connected to their proper search terms yet, which makes them a bit harder to find. Some studies investigate the effect of different AHT drugs separately, and since not all included studies followed a similar study design the results are doubtlessly affected. Both the effect of individual drugs and the prescription bias must be taken under consideration. The fact that certain drug classes tend to be prescribed to a certain category of patients, for example frail patients at high age, could influence the study

damages from their falls [42] complicates evaluation, apart from the fact that medical adjustments and temporary pharmacological treatments often are provided during

hospitalization. Many falls in elderly require hospital care, but most falls does not. Studies including only inpatient records of falls are not looking at the bulge of falls that occur and are handled outside the hospital setting. Including inpatients only could for these reasons pose a risk of distortion of the results. The included studies had populations deriving from varying contexts, and future meta-analyses of this research area need to considerate narrowing the inclusion criteria to evade possible confounders originating in heterogeneity in study populations. Apart from population characteristics, the studies varied in their definition of a change in AHT treatment. This systematic review did not differ between groups already on AHT treatment who altered their medication and the group with their premier attempt of AHT treatment, nor was the fact that AHT medication can be given a patient on other indications than hypertension adjusted for. These are other aspects of importance in future research.

Diagnose codes were used in most studies, which poses risks of bias as not all visits and events in care settings are coded properly, if at all. Although, the alternative consisting of questionnaires require careful preparation and composing of the data collecting material in order to extract reliable results from the data. The one study using questionnaires for ascertainment of falls interviewed patients about their falls during the past 12 months [40], making the results highly dependent of the cognitive function of the population. Beside the quality in possessed memories, other aspects must be lifted regarding elderly and

self-reported falls. One of the most important factors might be the feeling of shame. Maybe future research should differ between the group of elderly self-reporting falls and the one requiring medical care for it, fractures as an example. An important aspect when considering using fractures as a surrogate measure is that the risk of a fracture could be affected by more than falling. Studies have shown that some AHT types affect the bone metabolism, contributing to a fracture risk change [43,44]. There are many factors to take under consideration when composing this type of research.

Dillon et al [40] looked at 5-day gaps in AHT treatment as a risk factor for falls. In order to evade the possible confounder of non-specific adherence problems as a risk enhancer, they set up a similar test using an antithrombotic drug not related to increased fall risk and evaluated whether gaps in the treatment plan of this medication contributed to a greater fall

risk. It turned out that non-specific adherence problems were not associated to an increased fall risk.

The benefits of AHT treatment shown in earlier studies [5–7] is clearly exceeding the risks of the treatment, but in most studies regarding this issue the population consists of relatively young, healthy individuals. Old people with large burdens of disease are often excluded from these studies. This is understandable, the group is highly heterogenous and seldom easy to handle in a group seeking maximized similarity between its members. However, this is a scientific gap in need of exploration. We are yet to discover the beneficial effect of lowering the blood pressure in relation to the risks in elderly with multiple diseases in order to set targets and limits adjusted for them.

The greatest benefit of antihypertensive drug use in hypertensive patients is the lowered risk of cardiovascular disease. The disadvantages of antihypertensives are not as often mentioned, but some studies point towards an increased risk of falls and serious fall injuries on the elderly from the use of antihypertensives [8–11]. The risk of falling must always be taken under consideration when determining blood pressure target levels.

Conclusions

The conclusions drawn from this systematic review has to be kept indistinct. The results indicate an increased short-term fall risk after a change in the AHT medication, but since the included studies investigated the issue from various perspectives, no findings were uniformly agreed. More research is necessary in this field in order to extract solid conclusions, the collected knowledge is in present day limited.

Ethical considerations

No ethical approvement is needed when doing a systematic review, since the study does not handle persons or pose a risk of any individual or group related harm.

Acknowledgment

A grand portion of gratitude is directed towards Peter Engfeldt, supervisor. This work would not have been as enjoyable without your support. Your supervising through the project has been impeccable and I could never wish for anything better in a team mate.

Jan Källman must also be mentioned and properly thanked, your guidance and overwhelming commitment in solving a real-life crisis helped me perform better than ever before.

Lastly, to my family. I will never have the words to express my gratitude for your support through every single day of this struggle. You are the sole reason for my existence, and you will forever be my greatest heroes.

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Etisk reflektion

Studien berör ett delvis outforskat område. Antihypertensiva läkemedel har visats ge en generellt ökad fallrisk, men få studier har utforskat fallrisken kort tid efter initiering eller förändring av antihypertensiv behandling. Flera aspekter på frågan har lyfts i tidigare studier, men mångfald i metodval och populationer försvårar metaanalys. De få reviews som gjorts i området måste därför tolkas med försiktighet. Gruppen behandlade hypertoni-patienter i samhället är en enorm grupp och sträcker sig över långa åldersspann. Riskerna med vinklade resultat kan därför få stora konsekvenser om resultaten skulle översättas till klinisk praxis. Många skulle beröras av nya fynd, det är en stor grupp och ett outforskat forskningsområde. Författare har ett ansvar att inte basunera ut uppgifter på sätt som kan misstolkas, det är otroligt viktigt att förtydliga den vetenskapliga tyngden bakom resultaten och slutsatserna som redovisas.

Systematiska översikter är fenomenala forskningsmetoder, de kan konkretisera enorma mängder information till hanterbara slutsatser. Det gör översikter till ett viktigt verktyg, i vissa fall avgör de hur vi hanterar utmaningar i klinisk vardag. Det ställer också höga krav, översikter måste genomföras med strikt vetenskaplighet och öppenhet för oönskade resultat. I studien hanteras varken personliga data eller människokroppar, vilket underlättar det etiska övervägandet under själva studieförfarandet. Däremot kan en översikt som denna, över ett område som fortfarande utforskas, bidra med information till en begränsad kunskapsbank. Med en population så stor som den berörda så måste man vara tydlig med att vi fortfarande vet väldigt lite. Förhastade slutsatser är i allra högsta grad oönskade.

Cover letter

Please consider the enclosed manuscript, ”Antihypertensive treatment in elderly and the risk of falls – a systematic review”. I think the readers of the Journal of Hypertension would find the contents very interesting and thoughtful. The authors have approved the final version of the manuscript and agree that Journal of Hypertension is the first choice of publisher. The review has not been published in any other context; no other publisher has yet been granted access to the manuscript.

We have looked at the association of a change in the antihypertensive medication and the short-term risk of falling in a population aged 60 years and older.

In our review we clarify that studies regarding the short-term fall risk lack consensus and explore the underlying causes. Even though the same area is investigated, the study designs differ in critical ways, making uniform statements and clear conclusions difficult to extract. The final conclusion of our review had to be kept indistinct, but the most important part is the discussion about the continuation of this research area. We believe that our input and the revealed issues regarding standardization of study designs will contribute to a future research with better and more relevant structure and preparation, where extracted results can develop clinical guidelines and contribute to a better health care.

We hope you will consider publishing our article in your journal. Sincerely, Emil Skanebo Medical Science Dpt Örebro University Örebro, Sweden Mail: emil.skanebo@mail.se Phone: +46(0)70 123 123 12

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edicin

er?

Har du hört talas om blodtryck? Det är trycket blodet har när det färdas genom blodkärlen i kroppen, man kan tänka på det som vattentrycket i

trädgårdsslangen.

Det är viktigt att hålla b

lodtrycket på en lagom nivå, och ibl

and behöver man mediciner för att h

jälpa kroppen med det. De medicinerna

kallas antihypertensiva.

Problemet är att vissa mediciner ökar risken för att man ramlar och slår sig av olika anledningar, och antihypertensiva är

en av dem. Man vet däremot inte säkert om risken är förhöjd direkt efter att man

börjat ta antihypertensiva, så det tänkte vi ta reda på.

Det visade sig att studier som tittat på det här har använt sig av massa olika metoder för att ta reda på det, vilket gjorde det svårt att sammanfatta vad alla tyckte på en gång. De flesta var överens om att det fanns en viss riskökning, men de framförde det på väldigt olika sätt. Vissa saker tyckte forskarna helt tvärtemot varandra.

Slutsatsen av vår undersökning blev helt enkelt att det här är ett område som vi behöver undersöka ytterligare. Forskare behöver komma överens om gemensamma metoder att undersöka det här för att vi

ska kunna dra ordentliga slutsatser av vad de upptäcker i sin forskning.