A systematic review and meta-analysis on the effectiveness of an invasive strategy compared to a conservative approach in elderly patients with non-ST elevation acute coronary syndrome

4 Joan Dymphna P. Reaño, MD1, Maria Grethel C. Dimalala, MD2, Louie Alfred B. Shiu, MD3, 5 Karen V. Miralles, MD3, Noemi S. Pestaño, MD3, Felix Eduardo R. Punzalan, MD3, Bernadette 6 Tumanan-Mendoza, MD3, Michael Joseph T. Reyes, MD3,4, Rafael R. Castillo, MD3,5,6 7 8 1 Fellow in Adult Cardiology, Manila Doctors Hospital, Manila, Philippines 9 2Fellow in Interventional Cardiology, Manila Doctors Hospital, Manila, Philippines 10 3 Consultant in Adult Cardiology, Manila Doctors Hospital, Manila, Philippines 11 4 Consultant in Interventional Cardiology, Manila Doctors Hospital, Manila, Philippines 12 5Professor in Cardiovascular Medicine, Adventist University of the Philippines, Silang, Philippines 13 6Dean Emeritus, FAME Leaders Academy, Makati, Philippines 14 15 Correspondence to: 16 Dr. Joan Dymphna P Reaño, Manila Doctors Hospital, 667 United Nations Avenue, Ermita, Manila, 17 Philippines 18 Email address: jdp.reano@gmail.com; medicalfiles.inquirer@gmail.com 19 Mobile tel. no.: +63 917 5089 757 20 21 Short/running title: Management strategies in elderly with NSTEMI 22 23 24 25 26 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. not certified by peer review) (which was The copyright holder for this preprint this version posted August 29, 2019. ; https://doi.org/10.1101/19004044 doi: medRxiv preprint


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Based on the World Health Organization's Global Burden of Disease report, ischemic heart 63 disease (IHD) is the overall leading cause of death worldwide. 1 Although the annual number of 64 hospital discharges for acute coronary syndromes (ACS) in developed countries has declined 65 slowly over the past two decades, the number has increased in developing countries. 2 In the 66 Philippines, cardiovascular disease (CVD) remains the leading cause of mortality. 3 The Philippine

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Heart Association ACS registry reported that ACS is prevalent in the age range 51-70, with mean of care leading to improved survival in ACS, but this was mainly observed in relatively younger 73 individuals (<65 years of age) and in men. These guidelines emphasize intensive and early medical 74 and interventional therapy, particularly for those at high risk. 4,5,6 75 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. not certified by peer review) (which was The copyright holder for this preprint this version posted August 29, 2019. ;https://doi.org/10.1101/19004044 doi: medRxiv preprint 4 The 2014 AHA/ACC NSTEACS Guidelines generally recommend that older patients with 76 NSTEACS should be treated with goal-directed medical therapy, together with an early invasive 77 strategy, and revascularization as appropriate. 5   CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. not certified by peer review) (which was The copyright holder for this preprint this version posted August 29, 2019. ;https://doi.org/10.1101/19004044 doi: medRxiv preprint 5 Specific:

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Among elderly patients with NSTEACS, to determine the effectiveness of invasive strategy 102 compared to conservative treatment, in 6 months (short-term) to 3 years (long-term), in reducing:

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. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. not certified by peer review)   Cochrane databases. MESH and free text of the following main key terms were used: "randomized 137 controlled trials", "elderly", "non-ST elevation acute coronary syndrome", "invasive strategy", 138 "conservative management", "invasive strategy versus conservative strategy", "major adverse 139 cardiovascular events", "all-cause mortality", "cardiovascular mortality", "myocardial infarction", 140 "stroke", "recurrent angina", "need for revascularization". The last search was done on 10 August 141 2017.

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Eligibility assessment was performed independently in an unblinded standard manner by CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. not certified by peer review) (which was The copyright holder for this preprint this version posted August 29, 2019. ; https://doi.org/10.1101/19004044 doi: medRxiv preprint 7 eligible but did not report the event rates per treatment group. To access needed data in this 150 particular study, correspondence with the author via email was done, but with no reply from the . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. not certified by peer review) (which was The copyright holder for this preprint this version posted August 29, 2019. ; https://doi.org/10.1101/19004044 doi: medRxiv preprint 8 assessment, and intention-to-treat analysis was done using the quality scale for meta-analytic 163 review, the Cochrane Collaboration Tool for Risk of Bias.

Data analysis
166 Review Manager 5.3 was used to analyze the data. Analysis of dichotomous data was done 167 using risk ratio, 95% confidence interval, and Mantel-Haenszel method with fixed effects model.

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Heterogeneity between trials was tested using a standard Chi-square test and I 2 statistics. The p-169 value of <0.10 was considered to be statistically significant and I 2 of ³50% is considered to have 170 high heterogeneity.

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Five randomized controlled trials involving a total of 2,495 patients met the inclusion 174 criteria. The data on population characteristics, intervention type, and measured outcomes were 175 extracted from each trial ( Table 1)   CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. not certified by peer review) . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. not certified by peer review) (which was The copyright holder for this preprint this version posted August 29, 2019. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. not certified by peer review)

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Only one study did not specify the time to intervention but only mentioned "during initial 184 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. not certified by peer review) (which was The copyright holder for this preprint this version posted August 29, 2019. ; https://doi.org/10.1101/19004044 doi: medRxiv preprint 13 admission". 11 Two out of the five trials included CABG as part of the intervention when 185 indicated. 12,13 In the control group all the trials used standard medical treatment . [10][11][12][13][14] 186 All trials assessed the outcome of all-cause mortality. All trials except one reported the 187 outcome of myocardial infarction. 11 All trials except two assessed the outcome of stroke. 11,14 The 188 outcomes of revascularization were reported by all except by two studies. 10,11 Lastly, the events of 189 cardiovascular death and recurrent angina were assessed only by one study. 13

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The Cochrane collaboration tool was used to assess the risk of bias. The random sequence 191 generation, allocation concealment, incomplete outcome data, blinding of participants and 192 personnel, blinding of outcome assessment, and intention-to-treat analysis were evaluated for each 193 trial. All included trials were assessed to have low risk for bias (

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The pooled analysis showed that invasive strategy is beneficial over conservative treatment in 215 preventing MI with an overall risk ratio of 0.62 (95% CI 0.49 to 0.79) but with significant 216 heterogeneity (p value of 0.0001, I 2 = 63%).

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Meta-analysis of data from the five trials included in this study showed that an early 253 invasive strategy appears to be beneficial in suitable elderly patients > 65 years old with NSTEACS.

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There was significantly less need for revascularization in the invasive strategy group compared to 255 the conservative treatment group. This finding implies that more patients in the conservative group

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For the outcomes of death and MI, an invasive strategy showed a statistically significant 265 benefit over conservative treatment but with significant heterogeneity. The possible sources of 266 heterogeneity for the outcomes of death and MI may be the small number of events and sample 267 sizes. In two studies, the elderly population was just a subgroup analysis of the total population. 10-

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. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. not certified by peer review) (which was The copyright holder for this preprint this version posted August 29, 2019. ; https://doi.org/10.1101/19004044 doi: medRxiv preprint 18 11 Hence, the population in the subgroup analysis may not be powered enough to detect the 269 differences in the intervention and outcomes of interest. Furthermore, there were differences in age

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In the reduction of stroke, invasive strategy showed benefit over conservative treatment 278 but this was not statistically significant. The outcomes for cardiovascular mortality and recurrent 279 angina were assessed only in one study 13 , which showed also a non-statistically significant benefit 280 of invasive strategy over conservative treatment among elderly NSTEACS patients.

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Overall, this study does not support the relatively conservative tendency when dealing with 282 elderly patients with NSTEACS in real-life clinical setting. The elderly population is considered a 283 high-risk group wherein more than half the mortality in NSTEACS occur 5 and a more aggressive 284 approach in suitable patients may be more appropriate and beneficial. Among people who die of 285 ischemic heart disease, 83% were >65 years of age. 1 This mortality rate is expected to increase in 286 the forthcoming decades due to improving life expectancy of the elderly. Age is one of the most 287 important predictors of risk in NSTEACS. Each 10-year increase in age results in a 75% increase 288 in hospital mortality in ACS patients. 15 Despite the relatively higher risk in this age group, elderly 289 ACS patients are under-represented in clinical trials such that subjects older than 75 years of age 290 account for less than 10%, and those older than 85 years account for less than 2% of all NSTEACS 291 subjects. 7 This highlights the need for more clinical trials and studies in this age group. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. not certified by peer review) (which was The copyright holder for this preprint this version posted August 29, 2019. ; https://doi.org/10. 1101/19004044 doi: medRxiv preprint 19 Cardiology/American Heart Association Guidelines) registry showed that NSTEMI patients aged 295 ≥ 65 years who experienced an in-hospital major bleed had a 33% increased risk of 30-day 296 mortality. 16 However, the advancement of equipment and technique has made PCI safer for even 297 very elderly patients (≥ 90 years of age) with high success rates and declining major bleeding risk. 17 298 299

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Results of this meta-analysis suggest some benefits with an early invasive strategy 301 compared to a conservative treatment approach in the management of elderly patients with 302 NSTEACS. There was a significantly lower rate of revascularization in the invasive strategy group 303 compared to the conservative treatment group. A statistically significant benefit favoring invasive 304 strategy was also noted in the reduction of death and myocardial infarction but with significant 305 heterogeneity. These findings do not support the bias against early routine invasive intervention in 306 the elderly group with NSTEACS.

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Although an early invasive strategy may be favorable among elderly patients presenting 308 with NSTEACS, the certainty of benefit versus risk still needs to be supported by larger clinical 309 trials and registries with uniform age cutoff for elderly, particularly > 65 years old, to provide high  Patients with Coronary Heart Disease. ASEAN Heart Journal. Vol. 24, no.1, 27 -78 (2016)       . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. not certified by peer review) . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. not certified by peer review) . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. not certified by peer review) . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. not certified by peer review) . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. not certified by peer review) . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. not certified by peer review) (which was The copyright holder for this preprint this version posted August 29, 2019. is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. not certified by peer review) . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. not certified by peer review) . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. not certified by peer review) (which was The copyright holder for this preprint this version posted August 29, 2019. ; https://doi. org/10.1101/19004044 doi: medRxiv preprint