International Journal of Cardiology 192 (2015) 49–55
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Ischemic heart disease, prescription of optimal medical therapy and geriatric syndromes in community-dwelling older men: A population-based study Danijela Gnjidic a,b,c,⁎,1, Alexander Bennett b,e,h,i,1, David G. Le Couteur b,c,d, Fiona M. Blyth b,c, Robert G. Cumming c,f, Louise Waite c, David Handelsman b,d, Vasi Naganathan b,c, Slade Matthews b,g, Sarah N. Hilmer b,e,h,i a
Faculty of Pharmacy, University of Sydney, Sydney, NSW, Australia Sydney Medical School, University of Sydney, Sydney, NSW, Australia c Ageing and Alzheimers Institute, Concord RG Hospital, Sydney, NSW, Australia d ANZAC Research Institute, Concord Hospital, Sydney, NSW, Australia e Kolling Institute of Medical Research, Royal North Shore Hospital, Sydney, New South Wales, Australia f Sydney School of Public Health, University of Sydney, Sydney, NSW, Australia g Discipline of Pharmacology, University of Sydney, Sydney, NSW, Australia h Department of Clinical Pharmacology, Royal North Shore Hospital, Sydney, New South Wales, Australia i Department of Aged Care, Royal North Shore Hospital, Sydney, New South Wales, Australia b
a r t i c l e
i n f o
Article history: Received 3 October 2014 Received in revised form 24 March 2015 Accepted 7 May 2015 Available online 9 May 2015 Keywords: Ischemic heart disease Older people Medication guidelines Geriatric syndromes All-cause mortality
a b s t r a c t Background: Guideline recommended management of ischemic heart disease (IHD) suggests the concomitant use of antiplatelet, beta-blocker, renin angiotensin system blocker and statin therapy. In older people exposure to multiple medications has been associated with adverse events and geriatric syndromes. The study aimed to investigate the use of medications for IHD in older men with and without geriatric syndromes, and whether adherence to medication guidelines impacts on adverse outcomes. Methods: Community-dwelling men, aged ≥70 years and enrolled in the Concord Health and Ageing in Men Project were studied. Data on self-reported IHD, number of guideline recommended medications (use of four guideline medications considered optimal medical therapy) and geriatric syndromes (frailty, falls, cognitive impairment and urinary incontinence) were obtained. Cox regression was used to assess the relationship between optimal medical therapy and adverse outcomes (mortality and institutionalization), stratifying by geriatric syndromes. Results: At baseline, 462 (27%) men self-reported a history of IHD and of these, 226 (49%) had at least one geriatric syndrome. Among men with IHD, no significant difference was observed in patterns of prescribing between those with and without geriatric syndromes. Compared to zero medications, optimal medical therapy among men with IHD was associated with lower mortality [hazard ratio, HR = 0.40 (95% CI: 0.21–0.95)] and institutionalization risk (HR = 0.31; 95% CI: 0.09–0.81). The presence of geriatric syndromes did not modify the association of increasing use of guideline recommended medications and clinical outcomes. Conclusion: In older men with IHD, greater adherence to medication guidelines appears to be positively associated with better clinical outcomes, independent of geriatric syndromes. © 2015 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Ischemic heart disease (IHD) has a major negative impact on the health of older people. The prevalence of IHD in Australia is estimated
⁎ Corresponding author at: Faculty of Pharmacy, Bank Building A15, Science Rd, University of Sydney, The University of Sydney, NSW 2006, Australia. E-mail address: [email protected] (D. Gnjidic). 1 These authors contributed equally to the work.
http://dx.doi.org/10.1016/j.ijcard.2015.05.045 0167-5273/© 2015 Elsevier Ireland Ltd. All rights reserved.
to be 17% among those aged ≥75 [1]. Moreover, IHD is more common in older men than older women with 37% and 26% of men and women ≥65 years being affected by IHD, and is associated with greater morbidity in older men [1]. Previous studies have shown that geriatric syndromes such as frailty, falls, cognitive impairment and urinary incontinence are common among older people with IHD [2–5]. People with geriatric syndromes take, on average, a greater number of medicines [6] and are consequently at an increased risk of polypharmacy and adverse drug reactions, two common markers of poor clinical outcomes in the older population [7].
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Medications used in the treatment of patients with IHD aim to prevent disease progression from stable angina to acute coronary syndrome (ACS), or repeat cardiac events after an ACS. Like those in other countries [8,9], Australian guidelines recommend the concomitant use of statin, antiplatelet, angiotensin-converting enzyme inhibitor (ACEI) and beta-blocker therapy for people with IHD [10]. This is supported by a plethora of randomized controlled trials (RCTs) conducted in younger robust individuals showing these medications reduce the risk of vascular events and mortality when used as secondary prevention in IHD [11–15]. It is well documented that older people, especially those with geriatric syndromes, are often excluded from RCTs, in particular cardiology trials, due to their substantial health problems [16,17]. As well as this, it has been reported that older people with IHD who follow clinical practice guidelines may in fact be at a greater risk of harm [4]. None of the currently available clinical guidelines however make specific recommendations for older individuals. In order to assess the effectiveness of medications taken for IHD in real-world settings, observational studies are needed [18], yet few have been undertaken addressing this question in older people with geriatric syndromes [19]. With this in mind we analyzed data from a cohort of community-dwelling older men with the following specific study objectives: (1) To assess the prevalence of medication guideline adherence in those with and without geriatric syndromes (frailty, falls, urinary incontinence and cognitive impairment) in older men with IHD; (2) To determine associations between adherence to IHD medication management guidelines and adverse outcomes (institutionalization, mortality) in older men with and without geriatric syndromes; (3) To determine if any combinations of specific evidence-based medications were associated with institutionalization and mortality in this population of older men with IHD.
2. Methods 2.1. Study population Participants were community-dwelling men enrolled in the Concord Health and Ageing in Men Project (CHAMP), Sydney, Australia. Eligible participants were those aged ≥70 years and living in the study region recruited between January 2005 and June 2007 [20]. Participants living in residential aged care facilities were excluded. The electoral roll was used to identify men eligible for the study (n = 2815), who were then contacted by phone or mail resulting in a 54% participation (n = 1511). An additional 194 men living in the study area heard about the study from friends or the local media and were recruited before receiving an invitation letter, giving a final sample of 1705 participants. For the current study, analysis was restricted to 1694 participants due to missing data on geriatric syndromes and/or medications (n = 11). Participants underwent baseline assessments, which comprised a selfcompleted study questionnaire and a clinical assessment that consisted of physical performance measures, neuropsychological testing, and medication inventory [21]. Participants also agreed to be contacted every 2 years for follow-up assessment. The study was approved by the Sydney Local Health District Human Research Ethics Committee Concord Repatriation General Hospital, Sydney, Australia. 2.2. IHD assessment and other comorbidities IHD and comorbidity were assessed using participant self-report. IHD was considered present if a person reported having angina or a history of myocardial infarct/ACS/heart attack. Data on the time of the IHD diagnosis or the disease severity was not available. Reporting a history of myocardial infarct/ACS/heart attack was also analyzed as an ACS
subgroup of men with IHD. Diseases that were also assessed by selfreport included diabetes, hypertension, heart failure, thyroid dysfunction, osteoporosis, Paget's disease, stroke, Parkinson's disease, epilepsy, intermittent claudication, chronic obstructive lung disease, asthma, liver disease, chronic kidney disease or renal failure, cancer (excluding non-melanoma skin cancers) and arthritis [20]. Height and weight were measured and body mass index (BMI) was calculated as kilogram per square meter. The World Health Organization (WHO) criteria were used for hemoglobin levels (b13 g/dL) to define anemia among older men. 2.3. Medication assessment A medication inventory was performed for each participant by trained study personnel during the clinic assessment. This was performed using the brown bag medication collection method, a method based on selfreport in which participants are instructed to bring their prescription and over-the-counter medications into the clinic. During the clinic visit, participants were asked whether they had taken any medication in the past month. Medications were then coded using the Iowa Drug Information Service (IDIS) codes. Clinical guidelines for IHD recommend statin, antiplatelet, beta-blocker and an ACEI/angiotensin receptor blocker [18, 22]. The men were categorized into five medication guideline groups based on the number of four classes of recommended medications they were taking (0, 1, 2, 3 or 4), with a score of four indicating optimal medical therapy. 2.4. Geriatric syndrome assessment Data were obtained for four geriatric syndromes including frailty, falls, urinary incontinence and cognitive impairment, using methods previously described and validated [6,23–25]. For frailty, similar criteria were used as in the Cardiovascular Health Study (CHS). This involved objectively assessing participants for weight loss/shrinking, weakness, exhaustion, slowness and low physical activity [26]. Participants were considered frail if they obtained three or more of the five components. For weakness (defined as the lowest sample quintile for grip strength) and slowness (defined as the lowest sample quintile for walking speed), the same criterion used in the CHS was employed. However, weight loss (defined as current weight lower by ≥15% than the highest self-reported life-time weight), exhaustion (assessed using the 12-item Short Form Health Survey [27]) and low activity (defined as being in the lowest quartile of activity using the Physical Activity Scale for the Elderly [28]) were assessed using an adapted criteria. This was due to the unavailability of some measurements in this study that were used in the CHS methodology [6]. Participants were screened for cognitive impairment using the Mini Mental State Examination (MMSE) [17] and the Informant Questionnaire on Cognitive Decline (IQCODE) [18] during the baseline clinic assessment. Participants with a MMSE less than or equal to 26 and/or IQCODE greater than 3.6 were invited to have detailed clinical assessments by a study geriatrician. At a weekly consensus meeting two geriatricians, a neurologist and a neuropsychologist reviewed all medical, cognitive, informant and functional data and reached a final diagnosis of cognitive status for each participant. At the end of the screening and clinical assessments, participants were categorized as having dementia, mild cognitive impairment (MCI) or cognitively intact. Those participants with a diagnosis of dementia or MCI were classified as cognitively impaired [29]. The International Consultation of Incontinence Questionnaire (ICIQ) self-administered questionnaire was used to assess the presence of urinary incontinence. Men were classified as incontinent if they reported leaking urine at least twice a week in the past four weeks [30]. Participants who had two self-reported falls in the previous 12-months at the baseline interview were considered fallers [31]. Lastly, a participant was classified as part of the ‘combined geriatric syndrome’ subgroup if they had at least one of the previously mentioned
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four geriatric syndromes. Participants (n = 11) with missing data for more than two of the geriatric syndromes were excluded.
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Table 1 Baseline characteristics of participants in the total population and those with ischemic heart disease (IHD).
2.5. Study outcomes
Characteristic
Total population (n = 1694)
Participants with IHD (n = 462)
The adverse outcomes assessed in this study were institutionalization and death. Data on adverse outcomes were obtained by 4-monthly telephone calls with subjects or informants. Persons not contactable by telephone were instead sent letters by mail. The New South Wales Registry of Births, Deaths and Marriages was used to ascertain deaths which included those men who withdrew from the study but agreed to passive follow up. For mortality, follow up time was defined as time between baseline assessment to date of death or end of study period. Time at which contact was made with the death registry was the date considered the study end date for withdrawn participants who were still alive. Institutionalization was defined as entry into nursing home facility or hostel at any time during the follow up period of up to 6.8 years (average 4 years) [21]. Australian admission to residential aged care can be either to a hostel (low-level care) or nursing home (high-level care).
Age Currently married Years of education (≥7) Country of birth Australia ESB immigrant Non-ESB immigrant Self-rated health (≥good) Mean number of medicines Body mass index, kg/m2 Anemiaa, b13.0 g/L Number of comorbidities Chronic disease Diabetes Hypertension Heart failure Renal disease Geriatric syndromes Frailty Falls Cognitive impairment Incontinence Presence of GS (≥1) Guideline medications Statin Beta-blocker Antiplatelet ACEI ARB Adverse outcomes Institutionalization Mortality
77 ± 5.5 1269 (74) 1427 (84)
78 ± 5.8 334 (72) 404 (87)
849 (50) 105 (6) 740 (43) 1176 (69) 4.0 ± 2.9 27.8 ± 4.0 241 (14) 2.6 ± 1.8
242 (53) 33 (7) 187 (41) 274 (59) 5.9 ± 2.9 27.8 ± 3.7 86 (5) 4.0 ± 1.7
308 (18) 780 (46) 85 (5) 58 (3)
117 (25) 244 (53) 54 (12) 24 (1)
158 (9) 322 (19) 214 (13) 232 (14) 669 (39)
66 (14) 118 (26) 59 (13) 79 (17) 226 (49)
742 (44) 375 (22) 725 (43) 382 (23) 369 (22)
337 (73) 191 (41) 309 (67) 145 (31) 107 (23)
165 (10) 458 (27)
47 (10) 168 (36)
2.6. Statistical analysis The study was powered to detect a hazard reduction decrease as large as 35% for the primary outcome (mortality). It was calculated that 26 participants per guideline medication group would be required to detect a significant effect at the 80% power level and p-values less than 0.05. Descriptive statistics were summarized as mean ± standard deviation or counts (proportions), as appropriate. Two-tailed p-values of b0.05 were considered significant. Chi squared analysis was used to assess guideline recommended medication use in men with IHD after stratifying by presence of combined geriatric syndrome (geriatric syndromes assessed included frailty, falls, cognitive impairment and urinary incontinence). Unadjusted Cox regression was used to assess associations between IHD and mortality and institutionalization and the associations between numbers of guideline recommended medications and adverse outcomes, with and without geriatric syndromes. Adjusted Cox regression was also used to assess combinations of different guideline recommended medications. Covariates adjusted for included age, education, marital status, comorbidities and medication number (excluding participants' guideline recommended medications). Adjusted survival curves were stratified by presence of at least one geriatric syndrome. The proportional hazards assumption for the cox models was assessed for a range of variables (age, living status, presence of geriatric syndromes, guideline recommended medications and polypharmacy) by graphically assessing whether the stratified variable lines were parallel in the cox regression log minus log plot output. Finally, to assess the robustness of our analyses, we performed sensitivity analyses in a subgroup of those men that previously had an ACS. Results are presented as hazard ratios (HRs) with 95% confidence intervals (CIs). Analyses were performed using IBM SPSS (Version 21.0.1 SPSS Inc., Chicago, IL, USA).
Abbreviations: ESB — English Speaking Background, ADL — activities of daily living, IADL — Instrumental Activities of Daily Living, GS — geriatric syndrome, GRMs — Guideline Recommended Medications, ACEI — angiotensin-converting enzyme inhibitor, ARB — angiotensin receptor blocker, RACF — Residential Aged Care Facility. Data presented as mean ± SD or number of total participants or with IHD (percentage of total participants or subgroup with IHD). a World Health Organization criteria for anemia: hemoglobin b13.0 g/dL for men.
an antiplatelet drug, 65 out of 153 (42%) were being prescribed warfarin and 43 out of 153 (28%) were taking a proton pump inhibitor. In the total population, compared to participants without IHD, participants with IHD had a significantly greater risk of mortality (HR = 1.71; 95% CI: 1.42–2.06) but not institutionalization (HR = 1.26; 95% CI: 0.90–1.77). Data from the Cox regression analyses among men with IHD are presented in Table 3. In the IHD subgroup, optimal medical therapy was significantly associated with a lower rate of mortality in the adjusted model (HR = 0.40; 95% CI: 0.21–0.95). The use of three of the four guideline recommended medications was also significantly associated with reduced mortality among participants with IHD. In relation to institutionalization, adjusted models showed that use of two, three and four medications was associated with the reduced institutionalization
3. Results Baseline characteristics of study participants are shown in Table 1. Of the 1694 participants, 462 (27%) had self-reported IHD. Mean number of medications was 5.9 ± 2.9 for men with IHD. Of the four medications recommended by guidelines, statin use was most common followed by use of antiplatelet medications. Baseline characteristics of men with IHD according to geriatric syndrome status are presented in supplementary table (see Table S1). No significant differences were observed in the use of the guideline recommended medications between men with at least one geriatric syndrome compared to those without a geriatric syndrome (Table 2). Among participants with IHD that were not prescribed a betablocker, 61 out of 271 (23%) had self-reported asthma or chronic obstructive pulmonary disease. Of those with IHD that were not prescribed
Table 2 Prevalence of guideline recommended medications in men with IHD (n = 462), stratified by the presence and absence of geriatric syndromes. Number of guideline medications 0 medication 1 medication 2 medications 3 medications 4 medications
Participants with IHD n (%)
Without GS n (%)
With GS n (%)
P-value
36 (8%) 70 (15%) 133 (29%) 148 (32%) 75 (16%)
19 (8%) 36 (15%) 59 (25%) 80 (34%) 42 (18%)
17 (8%) 34 (15%) 74 (33%) 68 (30%) 33 (15%)
0.8 0.9 0.07 0.4 0.1
Abbreviations: GS — Geriatric Syndrome; IHD — ischemic heart disease. Data presented as: number of participants (percentage of medication use within geriatric syndrome population). Chi-squared analysis. * represents significance of P b 0.05.
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Table 3 Associations between use of guideline recommended medications and institutionalization and death in men with IHD (n = 462). Guideline medication number
0 (n = 36) 1 (n = 70) 2 (n = 133) 3 (n = 32) 4 (n = 75)
Unadjusted HR (95% CI)
Adjusted HR (95% CI)
Institutionalization
Death
Institutionalization
Death
1.00 0.52 (0.19–1.42) 0.31 (0.13–0.91)* 0.29 (0.12–0.74)* 0.29 (0.05–0.77)*
1.00 0.58 (0.34–1.12) 0.62 (0.38–1.03) 0.42 (0.24–0.73)* 0.31 (0.22–0.63)*
1.00 0.49 (0.24–1.21) 0.34 (0.10–0.83)* 0.30 (0.05–0.73)* 0.32 (0.09–0.81)*
1.00 0.70 (0.38–1.21) 0.73 (0.42–1.24) 0.54 (0.32–0.84)* 0.40 (0.21–0.95)*
Abbreviations: HR — hazard-risk, CI — confidence interval. Cox regression adjusted for potential confounders; age, comorbidity, number of non-guideline medications, education, marital status. n represents the number of persons taking guideline medications (percentage of medication use in participants with IHD) * represents significance of P b 0.05.
among participants with IHD. The results of the sensitivity analyses in participants with ACS showed similar HR estimates (results available on request from the authors). Fig. 1 shows the adjusted survival curves for mortality and institutionalization in the IHD participants by geriatric syndrome. For mortality, cumulative survival was greatest among men with IHD and receiving optimal medical therapy, followed by three recommended medications, while the use of no guideline recommended medications predicted the poorest survival. No significant differences were observed between
B
cumulative survival
A
those taking one or two guideline recommended medications. The association between medication guideline adherence and adverse outcomes was the same in those with and without a geriatric syndrome. A comparison of the specific types of guideline recommended medications that comprise medication guideline adherence for IHD and their association with mortality and institutionalization are displayed in Fig. 2. Participants taking any one or more of the guideline recommended medication classes had a HR of 0.82 (95% CI: 0.70–0.96). Participants not receiving a statin and an antiplatelet medication had a HR for
D
cumulative survival
C
Fig. 1. Cox regression adjusted survival curves for time until death and institutionalization by reported medication guideline adherence stratified by the presence of geriatric syndrome. This figure shows risk of mortality in those (A) without (n = 236) and (B) with (n = 226) geriatric syndrome in men with ischemic heart disease (IHD); risk of institutionalization (C) without (n = 236) and (D) with (n = 226) geriatric syndrome in men with IHD. Adjusted for potential confounders; age, comorbidity, number of non-guideline medications, education, and marital status. Accompanying overall hazard risk ratios are presented in Table 3.
D. Gnjidic et al. / International Journal of Cardiology 192 (2015) 49–55
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Adjusted HRs (95%CI)
A
0.40 (0.21-0.95)* 0.65 (0.54-0.80)* 0.64 (0.54-0.78)*
0.69 (0.56-0.81)* 0.76 (0.63-0.94)* 0.61 (0.50-0.79)* 0.65 (0.51-0.83)* 0.69 (0.54-0.88)* 0.80 (0.62-0.99)* 0.86 (0.67-1.10) 0.94 (0.74-1.20)
B
Adjusted HRs (95% CI) 0.32 (0.09-0.81)* 0.77 (0.56-1.10) 0.80 (0.56-1.10) 0.79 (0.58-1.07) 0.66 (0.48-0.92)* 0.85 (0.57-1.27) 0.79 (0.53-1.20) 0.75 (0.50-1.12) 0.66 (0.43-1.01) 0.63 (0.42-0.96)* 0.61 (0.41-0.93)*
Fig. 2. Hazard ratio for optimal medical therapy and the effects of specific combinations of guideline recommended medications on mortality (A) and institutionalization (B). Abbreviations: w/o — without, GRMs — Guideline Recommended Medications, ACEI — angiotensin-converting enzyme inhibitor, ARB — angiotensin receptor blocker, and HR — hazard risk. Adjusted for potential confounders; age, comorbidity, number of non-guideline medications, education, and marital status. * represents significance (P b 0.05).
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mortality of 0.94 (95% CI: 0.74–1.20) and participants not receiving a beta-blocker or an ACEI/ARB had a HR of 0.61 (95% CI: 0.50–0.79). In relation to institutionalization, when removal of two medication classes occurred, those not taking a statin and an antiplatelet (and consequently taking a beta-blocker and/or an ACEI/ARB) had the lowest reduction in institutionalization (HR = 0.61; 95% CI: 0.41–0.93).
4. Discussion To our knowledge, this is the first study to investigate the impact of geriatric syndromes on medication guideline adherence and on adverse outcomes in older men with IHD. There were no differences in IHD prescribing between older men with and without geriatric syndromes. Optimal medical therapy was associated with better survival in men with IHD, while exposure to two or more of the four guideline recommended medications was associated with lowest risk of institutionalization in men with IHD, independent of presence of geriatric syndromes. Of the four guideline recommended medications, antiplatelet medications followed by statins appeared to confer the greatest benefit to participant survival. Complete medication guideline adherence was low in participants with IHD (16%). This is consistent with a number of studies that have shown there is an underuse of evidence-based IHD medicines [32–34]. Previous studies have investigated the association between age and the use of guideline recommended medications in IHD [33,35,36]. However, to our knowledge no studies have investigated the impact of geriatric syndromes on IHD prescribing. In the IHD subgroup, no significant differences were observed in number of guideline recommended medications in those with and without geriatric syndromes. This may indicate that prescribers may not feel it is necessary to tailor therapy for this disease or, that dose adjustment may be a more appropriate method of adjusting utilization for people with geriatric syndromes. Among participants with IHD, compared to no medications, optimal medical therapy reduced mortality risk by 60% (HR = 0.40; 95% CI: 0.21–0.95). Similar results were found in those with a history of ACS, consistent with previous studies in high cardiovascular risk populations [18,22,33]. With regards to institutionalization, use of two or more guideline recommended medications was associated with reduced risk of admission by 69% in men with IHD. When assessing the association between number of guideline recommended medications and adverse outcomes, no differences were observed in those with geriatric syndromes compared to those without geriatric syndromes. This is unexpected given recent studies that suggest less is better when prescribing for older adults with concurrent geriatric syndromes [4,6]. However it may be that for this particular disease, which carries a high risk of sudden death, or for this community-dwelling population of older men, the main risk for adverse outcomes is the disease rather than the interaction between guideline recommended medications and geriatric syndromes. On the other hand, for older patients with other diseases that do not carry the risk of sudden death, the use of optimal medical therapies should be regularly reviewed to minimize the risk of serious adverse effects or other harms. More importantly, these findings call for other studies, ideally clinical trials to provide evidence-based recommendations for the treatment of older patients with IHD and other diseases, including older patients with polypharmacy and multimorbidity. In this study, use of antiplatelet mediations followed by statins were the guideline recommended medications most strongly associated with reducing mortality risk, consistent with existing evidence [12,14,37]. Interestingly, inconsistent with previous studies [13,15], beta-blocker and ACEI/ARB use were less strongly associated with reducing mortality risk. Underutilization compared to the other medications may have reduced any associations in this population. Suboptimal adherence occurring in observational studies has also been hypothesized as an explanation for different findings to those in RCTs, given that adherence is often closely monitored in RCTs [38].
5. Study strengths and limitations This study has several important strengths. Validated tools were used to assess geriatric syndromes, and potential confounding was reduced by adjusting for a range of variables. A careful and systematic medication inventory was performed by checking all medications, thereby minimizing exposure misclassification. Our study also had some limitations, the most salient of which was the study design. Although observational studies have significant constraints compared to RCTs, it is unlikely an RCT will include older participants with multimorbidity and geriatric syndromes. As well, RCTs performed in younger robust individuals often do not apply to older participants as a result of differences in physiology and environment [39]. Generalizability to other settings may be reduced given that the sample comprised men from a defined study area, however our results appear comparable with those previously reported [18,22]. Moreover, the findings of this study apply only to community-dwelling older men with secondary prevention of IHD. Participation in the study was voluntary, and clinical characteristics of participants may have differed from those of non-participants, which may have biased the sample. However, the response rate in the CHAMP study is similar to other comparable cohort studies of this type. Another limitation is reliance on self-reported IHD. The reliability of self-report data may vary according to the type of chronic disease, however, self-report of IHD has shown good reliability compared with the validated evidence of disease [40]. Some of those participants taking no guideline recommended medications may have had their indicated IHD medications withdrawn because they were approaching the end of life and receiving palliative care. Moreover, it is unknown whether guideline recommended medications were stopped, started or the dose was changed during the follow-up. The impact of incompletely accounting for competing co-morbidities on death and institutionalization may have contributed to residual confounding as well as confounding by indication and disease severity. 6. Conclusion In this cohort of community dwelling older men, the presence of geriatric syndromes appeared to have little impact on IHD prescribing. Greater adherence to medication guidelines was associated with improved survival in men, with and without geriatric syndromes. Risk of institutionalization was significantly lower when receiving two or more of the four guideline recommended medications compared with zero medications. Antiplatelet, followed by statin use, appeared to reduce risk of mortality by the greatest amount. Additional studies investigating geriatric syndromes, management of other chronic diseases and adverse outcomes are required to further elucidate the complex interplay that is occurring in the aging population. Until there are studies to provide recommendations for older frail people specifically, the use of optimal medical therapy should be assessed with the context of other comorbidities, polypharmacy, risk of adverse drug reactions and geriatric syndromes to optimize therapeutic decisions in this population. Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.ijcard.2015.05.045. Conflict of interest statement The authors report no relationships that could be construed as a conflict of interest. Acknowledgments The CHAMP study was funded by the Australian National Health and Medical Research Council (project grant number 301916) and the Ageing and Alzheimers Research Institute of the Concord Hospital. The
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authors thank all of the staff working on CHAMP and the participants in the project. Danijela Gnjidic is supported by a National Health and Medical Research Council Early Career Fellowship.
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Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Ischemic heart disease, prescription of optimal medical therapy and geriatric syndromes in community-dwelling older men: A population-based study Danijela Gnjidic a,b,c,⁎,1, Alexander Bennett b,e,h,i,1, David G. Le Couteur b,c,d, Fiona M. Blyth b,c, Robert G. Cumming c,f, Louise Waite c, David Handelsman b,d, Vasi Naganathan b,c, Slade Matthews b,g, Sarah N. Hilmer b,e,h,i a
Faculty of Pharmacy, University of Sydney, Sydney, NSW, Australia Sydney Medical School, University of Sydney, Sydney, NSW, Australia c Ageing and Alzheimers Institute, Concord RG Hospital, Sydney, NSW, Australia d ANZAC Research Institute, Concord Hospital, Sydney, NSW, Australia e Kolling Institute of Medical Research, Royal North Shore Hospital, Sydney, New South Wales, Australia f Sydney School of Public Health, University of Sydney, Sydney, NSW, Australia g Discipline of Pharmacology, University of Sydney, Sydney, NSW, Australia h Department of Clinical Pharmacology, Royal North Shore Hospital, Sydney, New South Wales, Australia i Department of Aged Care, Royal North Shore Hospital, Sydney, New South Wales, Australia b
a r t i c l e
i n f o
Article history: Received 3 October 2014 Received in revised form 24 March 2015 Accepted 7 May 2015 Available online 9 May 2015 Keywords: Ischemic heart disease Older people Medication guidelines Geriatric syndromes All-cause mortality
a b s t r a c t Background: Guideline recommended management of ischemic heart disease (IHD) suggests the concomitant use of antiplatelet, beta-blocker, renin angiotensin system blocker and statin therapy. In older people exposure to multiple medications has been associated with adverse events and geriatric syndromes. The study aimed to investigate the use of medications for IHD in older men with and without geriatric syndromes, and whether adherence to medication guidelines impacts on adverse outcomes. Methods: Community-dwelling men, aged ≥70 years and enrolled in the Concord Health and Ageing in Men Project were studied. Data on self-reported IHD, number of guideline recommended medications (use of four guideline medications considered optimal medical therapy) and geriatric syndromes (frailty, falls, cognitive impairment and urinary incontinence) were obtained. Cox regression was used to assess the relationship between optimal medical therapy and adverse outcomes (mortality and institutionalization), stratifying by geriatric syndromes. Results: At baseline, 462 (27%) men self-reported a history of IHD and of these, 226 (49%) had at least one geriatric syndrome. Among men with IHD, no significant difference was observed in patterns of prescribing between those with and without geriatric syndromes. Compared to zero medications, optimal medical therapy among men with IHD was associated with lower mortality [hazard ratio, HR = 0.40 (95% CI: 0.21–0.95)] and institutionalization risk (HR = 0.31; 95% CI: 0.09–0.81). The presence of geriatric syndromes did not modify the association of increasing use of guideline recommended medications and clinical outcomes. Conclusion: In older men with IHD, greater adherence to medication guidelines appears to be positively associated with better clinical outcomes, independent of geriatric syndromes. © 2015 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Ischemic heart disease (IHD) has a major negative impact on the health of older people. The prevalence of IHD in Australia is estimated
⁎ Corresponding author at: Faculty of Pharmacy, Bank Building A15, Science Rd, University of Sydney, The University of Sydney, NSW 2006, Australia. E-mail address: [email protected] (D. Gnjidic). 1 These authors contributed equally to the work.
http://dx.doi.org/10.1016/j.ijcard.2015.05.045 0167-5273/© 2015 Elsevier Ireland Ltd. All rights reserved.
to be 17% among those aged ≥75 [1]. Moreover, IHD is more common in older men than older women with 37% and 26% of men and women ≥65 years being affected by IHD, and is associated with greater morbidity in older men [1]. Previous studies have shown that geriatric syndromes such as frailty, falls, cognitive impairment and urinary incontinence are common among older people with IHD [2–5]. People with geriatric syndromes take, on average, a greater number of medicines [6] and are consequently at an increased risk of polypharmacy and adverse drug reactions, two common markers of poor clinical outcomes in the older population [7].
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Medications used in the treatment of patients with IHD aim to prevent disease progression from stable angina to acute coronary syndrome (ACS), or repeat cardiac events after an ACS. Like those in other countries [8,9], Australian guidelines recommend the concomitant use of statin, antiplatelet, angiotensin-converting enzyme inhibitor (ACEI) and beta-blocker therapy for people with IHD [10]. This is supported by a plethora of randomized controlled trials (RCTs) conducted in younger robust individuals showing these medications reduce the risk of vascular events and mortality when used as secondary prevention in IHD [11–15]. It is well documented that older people, especially those with geriatric syndromes, are often excluded from RCTs, in particular cardiology trials, due to their substantial health problems [16,17]. As well as this, it has been reported that older people with IHD who follow clinical practice guidelines may in fact be at a greater risk of harm [4]. None of the currently available clinical guidelines however make specific recommendations for older individuals. In order to assess the effectiveness of medications taken for IHD in real-world settings, observational studies are needed [18], yet few have been undertaken addressing this question in older people with geriatric syndromes [19]. With this in mind we analyzed data from a cohort of community-dwelling older men with the following specific study objectives: (1) To assess the prevalence of medication guideline adherence in those with and without geriatric syndromes (frailty, falls, urinary incontinence and cognitive impairment) in older men with IHD; (2) To determine associations between adherence to IHD medication management guidelines and adverse outcomes (institutionalization, mortality) in older men with and without geriatric syndromes; (3) To determine if any combinations of specific evidence-based medications were associated with institutionalization and mortality in this population of older men with IHD.
2. Methods 2.1. Study population Participants were community-dwelling men enrolled in the Concord Health and Ageing in Men Project (CHAMP), Sydney, Australia. Eligible participants were those aged ≥70 years and living in the study region recruited between January 2005 and June 2007 [20]. Participants living in residential aged care facilities were excluded. The electoral roll was used to identify men eligible for the study (n = 2815), who were then contacted by phone or mail resulting in a 54% participation (n = 1511). An additional 194 men living in the study area heard about the study from friends or the local media and were recruited before receiving an invitation letter, giving a final sample of 1705 participants. For the current study, analysis was restricted to 1694 participants due to missing data on geriatric syndromes and/or medications (n = 11). Participants underwent baseline assessments, which comprised a selfcompleted study questionnaire and a clinical assessment that consisted of physical performance measures, neuropsychological testing, and medication inventory [21]. Participants also agreed to be contacted every 2 years for follow-up assessment. The study was approved by the Sydney Local Health District Human Research Ethics Committee Concord Repatriation General Hospital, Sydney, Australia. 2.2. IHD assessment and other comorbidities IHD and comorbidity were assessed using participant self-report. IHD was considered present if a person reported having angina or a history of myocardial infarct/ACS/heart attack. Data on the time of the IHD diagnosis or the disease severity was not available. Reporting a history of myocardial infarct/ACS/heart attack was also analyzed as an ACS
subgroup of men with IHD. Diseases that were also assessed by selfreport included diabetes, hypertension, heart failure, thyroid dysfunction, osteoporosis, Paget's disease, stroke, Parkinson's disease, epilepsy, intermittent claudication, chronic obstructive lung disease, asthma, liver disease, chronic kidney disease or renal failure, cancer (excluding non-melanoma skin cancers) and arthritis [20]. Height and weight were measured and body mass index (BMI) was calculated as kilogram per square meter. The World Health Organization (WHO) criteria were used for hemoglobin levels (b13 g/dL) to define anemia among older men. 2.3. Medication assessment A medication inventory was performed for each participant by trained study personnel during the clinic assessment. This was performed using the brown bag medication collection method, a method based on selfreport in which participants are instructed to bring their prescription and over-the-counter medications into the clinic. During the clinic visit, participants were asked whether they had taken any medication in the past month. Medications were then coded using the Iowa Drug Information Service (IDIS) codes. Clinical guidelines for IHD recommend statin, antiplatelet, beta-blocker and an ACEI/angiotensin receptor blocker [18, 22]. The men were categorized into five medication guideline groups based on the number of four classes of recommended medications they were taking (0, 1, 2, 3 or 4), with a score of four indicating optimal medical therapy. 2.4. Geriatric syndrome assessment Data were obtained for four geriatric syndromes including frailty, falls, urinary incontinence and cognitive impairment, using methods previously described and validated [6,23–25]. For frailty, similar criteria were used as in the Cardiovascular Health Study (CHS). This involved objectively assessing participants for weight loss/shrinking, weakness, exhaustion, slowness and low physical activity [26]. Participants were considered frail if they obtained three or more of the five components. For weakness (defined as the lowest sample quintile for grip strength) and slowness (defined as the lowest sample quintile for walking speed), the same criterion used in the CHS was employed. However, weight loss (defined as current weight lower by ≥15% than the highest self-reported life-time weight), exhaustion (assessed using the 12-item Short Form Health Survey [27]) and low activity (defined as being in the lowest quartile of activity using the Physical Activity Scale for the Elderly [28]) were assessed using an adapted criteria. This was due to the unavailability of some measurements in this study that were used in the CHS methodology [6]. Participants were screened for cognitive impairment using the Mini Mental State Examination (MMSE) [17] and the Informant Questionnaire on Cognitive Decline (IQCODE) [18] during the baseline clinic assessment. Participants with a MMSE less than or equal to 26 and/or IQCODE greater than 3.6 were invited to have detailed clinical assessments by a study geriatrician. At a weekly consensus meeting two geriatricians, a neurologist and a neuropsychologist reviewed all medical, cognitive, informant and functional data and reached a final diagnosis of cognitive status for each participant. At the end of the screening and clinical assessments, participants were categorized as having dementia, mild cognitive impairment (MCI) or cognitively intact. Those participants with a diagnosis of dementia or MCI were classified as cognitively impaired [29]. The International Consultation of Incontinence Questionnaire (ICIQ) self-administered questionnaire was used to assess the presence of urinary incontinence. Men were classified as incontinent if they reported leaking urine at least twice a week in the past four weeks [30]. Participants who had two self-reported falls in the previous 12-months at the baseline interview were considered fallers [31]. Lastly, a participant was classified as part of the ‘combined geriatric syndrome’ subgroup if they had at least one of the previously mentioned
D. Gnjidic et al. / International Journal of Cardiology 192 (2015) 49–55
four geriatric syndromes. Participants (n = 11) with missing data for more than two of the geriatric syndromes were excluded.
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Table 1 Baseline characteristics of participants in the total population and those with ischemic heart disease (IHD).
2.5. Study outcomes
Characteristic
Total population (n = 1694)
Participants with IHD (n = 462)
The adverse outcomes assessed in this study were institutionalization and death. Data on adverse outcomes were obtained by 4-monthly telephone calls with subjects or informants. Persons not contactable by telephone were instead sent letters by mail. The New South Wales Registry of Births, Deaths and Marriages was used to ascertain deaths which included those men who withdrew from the study but agreed to passive follow up. For mortality, follow up time was defined as time between baseline assessment to date of death or end of study period. Time at which contact was made with the death registry was the date considered the study end date for withdrawn participants who were still alive. Institutionalization was defined as entry into nursing home facility or hostel at any time during the follow up period of up to 6.8 years (average 4 years) [21]. Australian admission to residential aged care can be either to a hostel (low-level care) or nursing home (high-level care).
Age Currently married Years of education (≥7) Country of birth Australia ESB immigrant Non-ESB immigrant Self-rated health (≥good) Mean number of medicines Body mass index, kg/m2 Anemiaa, b13.0 g/L Number of comorbidities Chronic disease Diabetes Hypertension Heart failure Renal disease Geriatric syndromes Frailty Falls Cognitive impairment Incontinence Presence of GS (≥1) Guideline medications Statin Beta-blocker Antiplatelet ACEI ARB Adverse outcomes Institutionalization Mortality
77 ± 5.5 1269 (74) 1427 (84)
78 ± 5.8 334 (72) 404 (87)
849 (50) 105 (6) 740 (43) 1176 (69) 4.0 ± 2.9 27.8 ± 4.0 241 (14) 2.6 ± 1.8
242 (53) 33 (7) 187 (41) 274 (59) 5.9 ± 2.9 27.8 ± 3.7 86 (5) 4.0 ± 1.7
308 (18) 780 (46) 85 (5) 58 (3)
117 (25) 244 (53) 54 (12) 24 (1)
158 (9) 322 (19) 214 (13) 232 (14) 669 (39)
66 (14) 118 (26) 59 (13) 79 (17) 226 (49)
742 (44) 375 (22) 725 (43) 382 (23) 369 (22)
337 (73) 191 (41) 309 (67) 145 (31) 107 (23)
165 (10) 458 (27)
47 (10) 168 (36)
2.6. Statistical analysis The study was powered to detect a hazard reduction decrease as large as 35% for the primary outcome (mortality). It was calculated that 26 participants per guideline medication group would be required to detect a significant effect at the 80% power level and p-values less than 0.05. Descriptive statistics were summarized as mean ± standard deviation or counts (proportions), as appropriate. Two-tailed p-values of b0.05 were considered significant. Chi squared analysis was used to assess guideline recommended medication use in men with IHD after stratifying by presence of combined geriatric syndrome (geriatric syndromes assessed included frailty, falls, cognitive impairment and urinary incontinence). Unadjusted Cox regression was used to assess associations between IHD and mortality and institutionalization and the associations between numbers of guideline recommended medications and adverse outcomes, with and without geriatric syndromes. Adjusted Cox regression was also used to assess combinations of different guideline recommended medications. Covariates adjusted for included age, education, marital status, comorbidities and medication number (excluding participants' guideline recommended medications). Adjusted survival curves were stratified by presence of at least one geriatric syndrome. The proportional hazards assumption for the cox models was assessed for a range of variables (age, living status, presence of geriatric syndromes, guideline recommended medications and polypharmacy) by graphically assessing whether the stratified variable lines were parallel in the cox regression log minus log plot output. Finally, to assess the robustness of our analyses, we performed sensitivity analyses in a subgroup of those men that previously had an ACS. Results are presented as hazard ratios (HRs) with 95% confidence intervals (CIs). Analyses were performed using IBM SPSS (Version 21.0.1 SPSS Inc., Chicago, IL, USA).
Abbreviations: ESB — English Speaking Background, ADL — activities of daily living, IADL — Instrumental Activities of Daily Living, GS — geriatric syndrome, GRMs — Guideline Recommended Medications, ACEI — angiotensin-converting enzyme inhibitor, ARB — angiotensin receptor blocker, RACF — Residential Aged Care Facility. Data presented as mean ± SD or number of total participants or with IHD (percentage of total participants or subgroup with IHD). a World Health Organization criteria for anemia: hemoglobin b13.0 g/dL for men.
an antiplatelet drug, 65 out of 153 (42%) were being prescribed warfarin and 43 out of 153 (28%) were taking a proton pump inhibitor. In the total population, compared to participants without IHD, participants with IHD had a significantly greater risk of mortality (HR = 1.71; 95% CI: 1.42–2.06) but not institutionalization (HR = 1.26; 95% CI: 0.90–1.77). Data from the Cox regression analyses among men with IHD are presented in Table 3. In the IHD subgroup, optimal medical therapy was significantly associated with a lower rate of mortality in the adjusted model (HR = 0.40; 95% CI: 0.21–0.95). The use of three of the four guideline recommended medications was also significantly associated with reduced mortality among participants with IHD. In relation to institutionalization, adjusted models showed that use of two, three and four medications was associated with the reduced institutionalization
3. Results Baseline characteristics of study participants are shown in Table 1. Of the 1694 participants, 462 (27%) had self-reported IHD. Mean number of medications was 5.9 ± 2.9 for men with IHD. Of the four medications recommended by guidelines, statin use was most common followed by use of antiplatelet medications. Baseline characteristics of men with IHD according to geriatric syndrome status are presented in supplementary table (see Table S1). No significant differences were observed in the use of the guideline recommended medications between men with at least one geriatric syndrome compared to those without a geriatric syndrome (Table 2). Among participants with IHD that were not prescribed a betablocker, 61 out of 271 (23%) had self-reported asthma or chronic obstructive pulmonary disease. Of those with IHD that were not prescribed
Table 2 Prevalence of guideline recommended medications in men with IHD (n = 462), stratified by the presence and absence of geriatric syndromes. Number of guideline medications 0 medication 1 medication 2 medications 3 medications 4 medications
Participants with IHD n (%)
Without GS n (%)
With GS n (%)
P-value
36 (8%) 70 (15%) 133 (29%) 148 (32%) 75 (16%)
19 (8%) 36 (15%) 59 (25%) 80 (34%) 42 (18%)
17 (8%) 34 (15%) 74 (33%) 68 (30%) 33 (15%)
0.8 0.9 0.07 0.4 0.1
Abbreviations: GS — Geriatric Syndrome; IHD — ischemic heart disease. Data presented as: number of participants (percentage of medication use within geriatric syndrome population). Chi-squared analysis. * represents significance of P b 0.05.
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Table 3 Associations between use of guideline recommended medications and institutionalization and death in men with IHD (n = 462). Guideline medication number
0 (n = 36) 1 (n = 70) 2 (n = 133) 3 (n = 32) 4 (n = 75)
Unadjusted HR (95% CI)
Adjusted HR (95% CI)
Institutionalization
Death
Institutionalization
Death
1.00 0.52 (0.19–1.42) 0.31 (0.13–0.91)* 0.29 (0.12–0.74)* 0.29 (0.05–0.77)*
1.00 0.58 (0.34–1.12) 0.62 (0.38–1.03) 0.42 (0.24–0.73)* 0.31 (0.22–0.63)*
1.00 0.49 (0.24–1.21) 0.34 (0.10–0.83)* 0.30 (0.05–0.73)* 0.32 (0.09–0.81)*
1.00 0.70 (0.38–1.21) 0.73 (0.42–1.24) 0.54 (0.32–0.84)* 0.40 (0.21–0.95)*
Abbreviations: HR — hazard-risk, CI — confidence interval. Cox regression adjusted for potential confounders; age, comorbidity, number of non-guideline medications, education, marital status. n represents the number of persons taking guideline medications (percentage of medication use in participants with IHD) * represents significance of P b 0.05.
among participants with IHD. The results of the sensitivity analyses in participants with ACS showed similar HR estimates (results available on request from the authors). Fig. 1 shows the adjusted survival curves for mortality and institutionalization in the IHD participants by geriatric syndrome. For mortality, cumulative survival was greatest among men with IHD and receiving optimal medical therapy, followed by three recommended medications, while the use of no guideline recommended medications predicted the poorest survival. No significant differences were observed between
B
cumulative survival
A
those taking one or two guideline recommended medications. The association between medication guideline adherence and adverse outcomes was the same in those with and without a geriatric syndrome. A comparison of the specific types of guideline recommended medications that comprise medication guideline adherence for IHD and their association with mortality and institutionalization are displayed in Fig. 2. Participants taking any one or more of the guideline recommended medication classes had a HR of 0.82 (95% CI: 0.70–0.96). Participants not receiving a statin and an antiplatelet medication had a HR for
D
cumulative survival
C
Fig. 1. Cox regression adjusted survival curves for time until death and institutionalization by reported medication guideline adherence stratified by the presence of geriatric syndrome. This figure shows risk of mortality in those (A) without (n = 236) and (B) with (n = 226) geriatric syndrome in men with ischemic heart disease (IHD); risk of institutionalization (C) without (n = 236) and (D) with (n = 226) geriatric syndrome in men with IHD. Adjusted for potential confounders; age, comorbidity, number of non-guideline medications, education, and marital status. Accompanying overall hazard risk ratios are presented in Table 3.
D. Gnjidic et al. / International Journal of Cardiology 192 (2015) 49–55
53
Adjusted HRs (95%CI)
A
0.40 (0.21-0.95)* 0.65 (0.54-0.80)* 0.64 (0.54-0.78)*
0.69 (0.56-0.81)* 0.76 (0.63-0.94)* 0.61 (0.50-0.79)* 0.65 (0.51-0.83)* 0.69 (0.54-0.88)* 0.80 (0.62-0.99)* 0.86 (0.67-1.10) 0.94 (0.74-1.20)
B
Adjusted HRs (95% CI) 0.32 (0.09-0.81)* 0.77 (0.56-1.10) 0.80 (0.56-1.10) 0.79 (0.58-1.07) 0.66 (0.48-0.92)* 0.85 (0.57-1.27) 0.79 (0.53-1.20) 0.75 (0.50-1.12) 0.66 (0.43-1.01) 0.63 (0.42-0.96)* 0.61 (0.41-0.93)*
Fig. 2. Hazard ratio for optimal medical therapy and the effects of specific combinations of guideline recommended medications on mortality (A) and institutionalization (B). Abbreviations: w/o — without, GRMs — Guideline Recommended Medications, ACEI — angiotensin-converting enzyme inhibitor, ARB — angiotensin receptor blocker, and HR — hazard risk. Adjusted for potential confounders; age, comorbidity, number of non-guideline medications, education, and marital status. * represents significance (P b 0.05).
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mortality of 0.94 (95% CI: 0.74–1.20) and participants not receiving a beta-blocker or an ACEI/ARB had a HR of 0.61 (95% CI: 0.50–0.79). In relation to institutionalization, when removal of two medication classes occurred, those not taking a statin and an antiplatelet (and consequently taking a beta-blocker and/or an ACEI/ARB) had the lowest reduction in institutionalization (HR = 0.61; 95% CI: 0.41–0.93).
4. Discussion To our knowledge, this is the first study to investigate the impact of geriatric syndromes on medication guideline adherence and on adverse outcomes in older men with IHD. There were no differences in IHD prescribing between older men with and without geriatric syndromes. Optimal medical therapy was associated with better survival in men with IHD, while exposure to two or more of the four guideline recommended medications was associated with lowest risk of institutionalization in men with IHD, independent of presence of geriatric syndromes. Of the four guideline recommended medications, antiplatelet medications followed by statins appeared to confer the greatest benefit to participant survival. Complete medication guideline adherence was low in participants with IHD (16%). This is consistent with a number of studies that have shown there is an underuse of evidence-based IHD medicines [32–34]. Previous studies have investigated the association between age and the use of guideline recommended medications in IHD [33,35,36]. However, to our knowledge no studies have investigated the impact of geriatric syndromes on IHD prescribing. In the IHD subgroup, no significant differences were observed in number of guideline recommended medications in those with and without geriatric syndromes. This may indicate that prescribers may not feel it is necessary to tailor therapy for this disease or, that dose adjustment may be a more appropriate method of adjusting utilization for people with geriatric syndromes. Among participants with IHD, compared to no medications, optimal medical therapy reduced mortality risk by 60% (HR = 0.40; 95% CI: 0.21–0.95). Similar results were found in those with a history of ACS, consistent with previous studies in high cardiovascular risk populations [18,22,33]. With regards to institutionalization, use of two or more guideline recommended medications was associated with reduced risk of admission by 69% in men with IHD. When assessing the association between number of guideline recommended medications and adverse outcomes, no differences were observed in those with geriatric syndromes compared to those without geriatric syndromes. This is unexpected given recent studies that suggest less is better when prescribing for older adults with concurrent geriatric syndromes [4,6]. However it may be that for this particular disease, which carries a high risk of sudden death, or for this community-dwelling population of older men, the main risk for adverse outcomes is the disease rather than the interaction between guideline recommended medications and geriatric syndromes. On the other hand, for older patients with other diseases that do not carry the risk of sudden death, the use of optimal medical therapies should be regularly reviewed to minimize the risk of serious adverse effects or other harms. More importantly, these findings call for other studies, ideally clinical trials to provide evidence-based recommendations for the treatment of older patients with IHD and other diseases, including older patients with polypharmacy and multimorbidity. In this study, use of antiplatelet mediations followed by statins were the guideline recommended medications most strongly associated with reducing mortality risk, consistent with existing evidence [12,14,37]. Interestingly, inconsistent with previous studies [13,15], beta-blocker and ACEI/ARB use were less strongly associated with reducing mortality risk. Underutilization compared to the other medications may have reduced any associations in this population. Suboptimal adherence occurring in observational studies has also been hypothesized as an explanation for different findings to those in RCTs, given that adherence is often closely monitored in RCTs [38].
5. Study strengths and limitations This study has several important strengths. Validated tools were used to assess geriatric syndromes, and potential confounding was reduced by adjusting for a range of variables. A careful and systematic medication inventory was performed by checking all medications, thereby minimizing exposure misclassification. Our study also had some limitations, the most salient of which was the study design. Although observational studies have significant constraints compared to RCTs, it is unlikely an RCT will include older participants with multimorbidity and geriatric syndromes. As well, RCTs performed in younger robust individuals often do not apply to older participants as a result of differences in physiology and environment [39]. Generalizability to other settings may be reduced given that the sample comprised men from a defined study area, however our results appear comparable with those previously reported [18,22]. Moreover, the findings of this study apply only to community-dwelling older men with secondary prevention of IHD. Participation in the study was voluntary, and clinical characteristics of participants may have differed from those of non-participants, which may have biased the sample. However, the response rate in the CHAMP study is similar to other comparable cohort studies of this type. Another limitation is reliance on self-reported IHD. The reliability of self-report data may vary according to the type of chronic disease, however, self-report of IHD has shown good reliability compared with the validated evidence of disease [40]. Some of those participants taking no guideline recommended medications may have had their indicated IHD medications withdrawn because they were approaching the end of life and receiving palliative care. Moreover, it is unknown whether guideline recommended medications were stopped, started or the dose was changed during the follow-up. The impact of incompletely accounting for competing co-morbidities on death and institutionalization may have contributed to residual confounding as well as confounding by indication and disease severity. 6. Conclusion In this cohort of community dwelling older men, the presence of geriatric syndromes appeared to have little impact on IHD prescribing. Greater adherence to medication guidelines was associated with improved survival in men, with and without geriatric syndromes. Risk of institutionalization was significantly lower when receiving two or more of the four guideline recommended medications compared with zero medications. Antiplatelet, followed by statin use, appeared to reduce risk of mortality by the greatest amount. Additional studies investigating geriatric syndromes, management of other chronic diseases and adverse outcomes are required to further elucidate the complex interplay that is occurring in the aging population. Until there are studies to provide recommendations for older frail people specifically, the use of optimal medical therapy should be assessed with the context of other comorbidities, polypharmacy, risk of adverse drug reactions and geriatric syndromes to optimize therapeutic decisions in this population. Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.ijcard.2015.05.045. Conflict of interest statement The authors report no relationships that could be construed as a conflict of interest. Acknowledgments The CHAMP study was funded by the Australian National Health and Medical Research Council (project grant number 301916) and the Ageing and Alzheimers Research Institute of the Concord Hospital. The
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authors thank all of the staff working on CHAMP and the participants in the project. Danijela Gnjidic is supported by a National Health and Medical Research Council Early Career Fellowship.
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