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 Table of Contents  
REVIEW ARTICLE
Year : 2019  |  Volume : 3  |  Issue : 4  |  Page : 111-118

The risks and the benefits of early invasive strategy compared to conservative strategy in elderly patients with non-ST-elevated myocardial infarction or unstable angina: a systematic review and meta-analysis


Department of Biomedical Sciences, Meena Research Group, School of Clinical and Applied Sciences, Leeds Beckett University, Leeds, England, UK, England

Date of Submission07-Oct-2019
Date of Acceptance07-Dec-2019
Date of Web Publication26-Dec-2019

Correspondence Address:
Dr. Osama A Tashani
School of Clinical and Applied Sciences, Leeds Beckett University, Leeds
England
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/LJMS.LJMS_55_19

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  Abstract 


Background and Aim: Compared with their younger counterparts, the elderly with unstable angina (UA) or non-ST-elevation myocardial infarction (NSTMI) has been proven to have worse outcomes. People with UA/NSTEMI are managed with a combination of medical therapy, invasive angiography, and revascularization. A systematic review and meta-analysis was conducted to compare the effects and the benefits associated with the routine invasive approach versus a conservative or “selective invasive” approach for the management of UA/NSTEMI in the elderly. Methods: Data from randomized controlled trials (RCTs) were identified through search strategy filters. Five search engines and databases were searched systematically, namely PubMed, CINAHL, ScienceDirect, Web of Science, and Cochrane Library. The primary outcome of the analysis was the composite of all-cause death and myocardial infarction (MI). Results: Four RCTs with total of 3016 patients were eligible. We calculated the log risk ratio with 95% confidence intervals (CIs) for the primary endpoints of all-cause death and MI. The study analysis did not show appreciable risk reductions in all-cause mortality (log risk ratio: 0.142 and 95% CI = 0.363–0.78, 4 studies, 3016 participants, and low-quality evidence). However, it shows that there was a significant risk reduction in the incidence of MI (log risk ratio 0.519, 95% CI = 0.707–0.331, 4 studies, 3016 participants, and low quality of evidence). Conclusion: A routine invasive approach in the elderly with UA/NSTMI was not associated with any significance in terms of mortality compared with conservative approach. However, research suggests that the invasive strategy may have particular benefit in the elderly who are at high risk for recurrent events and that patients at low risk for a recurrent event may even suffer harm from such strategy approach.

Keywords: Conservative, invasive strategy, myocardial infarction, unstable angina


How to cite this article:
Idris Elghazali IM, Garoushi S, Tashani OA. The risks and the benefits of early invasive strategy compared to conservative strategy in elderly patients with non-ST-elevated myocardial infarction or unstable angina: a systematic review and meta-analysis. Libyan J Med Sci 2019;3:111-8

How to cite this URL:
Idris Elghazali IM, Garoushi S, Tashani OA. The risks and the benefits of early invasive strategy compared to conservative strategy in elderly patients with non-ST-elevated myocardial infarction or unstable angina: a systematic review and meta-analysis. Libyan J Med Sci [serial online] 2019 [cited 2020 Jan 22];3:111-8. Available from: http://www.ljmsonline.com/text.asp?2019/3/4/111/274103




  Introduction Top


Coronary heart disease (CHD) is a leading cause of death in Europe, North America, and the world.[1] In 2004, more than a third of people who were above 65 years old died from acute coronary syndrome (ACS).[2] Furthermore, among people who died of CHD, nearly 85% were more than 65 years old.[3] Morbidity and mortality rates due to CHD has increased significantly in a group of people who were above 75 years old, a group that represents only 6% of the US population but 60% of myocardial infarction (MI)-related deaths.[4]

According to the data from the World Health Organization, it is expected that the mortality rates from CHD will rise by 137% for men and 120% for women over the next 20 years.[5] This is mainly due to the growth in elderly population. In the USA, for example, it is estimated that over the next decade, the proportion of people ≥65 years of age will increase from 12.4% to 19.6%.[6] It is also expected that during this time, the absolute number of octogenarians (80–89 years of age) will experience a twofold increase from 9.3 to 19.5 million.[7]

The United Kingdom has experienced a significant growth in the number of elderly population who were admitted with ACS.[8] Compared with their younger counterparts, the elderly with unstable angina (UA) or NSTMI have been proven to have a worse outcome.[9] However, recent data have demonstrated the prognostic benefit of early angiography and coronary revascularization in NSTMI or UA.[10],[11] Older people are underrepresented in these trials, and therefore, the benefits of early invasive strategy in the elderly are controversial.[8] Actually, there is no agreement on how elderly population with ACSs can be managed. What are the risks and benefits of percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG)? What are the outcomes of the invasive approach and how do they compare to the conservative approach? Can we expect those patients at higher risk from invasive approach? When should conservative approach be selected in the elderly? The aim of this review is to answer these questions in order to provide new data so that the use of early invasive approach in older patients with NSTMI or UA becomes clearer. There was an overview in this age group conducted more than 9 years ago in 2003,[8] which was based on retrospective observational cohort studies, but the conclusion from this review cannot be generalized in the elderly. Other old studies examined the effect of sex and age and other factors on cardiovascular outcomes, but there were also not conclusive.[9],[10],[11] However, dedicated randomized clinical trials for the risks and the benefits of early intervention approach in the elderly were conducted in this age group recently.[12],[13] In addition, there are also another four RCTs that compare both strategies in which data for an elderly patient can be extracted.[14],[15],[16],[17] Therefore, we are going to conduct this systematic review to fill the gap in literature.


  Methods Top


Criteria for considering studies for this review

Type of studies

Randomized controlled trials (RCTs) that compared invasive with conservative strategies in elderly people with non-ST-elevation myocardial infarction or UA (NSTMI/UA) will be included. Studies which were only undertaken in the stent era will be considered for inclusion. If studies in nonstent era would have been included, the analysis could undervalue the positive outcomes of a routine invasive strategy which is used nowadays and different from old invasive strategies in terms of medication and stents. The strategies of revascularization in the included studies are PCI or CABG, when needed. In addition, the majority of studies that will be included should use stents regularly in the procedures of revascularization (PCI). In recent years, few studies have concentrated on the ideal timing of an invasive approach. Although these studies share several criteria for inclusion, there was no randomization, and they did not compare between both invasive and conservative strategies. Therefore, these studies will be excluded from this review.

Types of participants

Both males and females who are at least 65 years old of age and had an episode of angina pain at rest or chest pain which is not relieved by medications will be included. The index period of pain should be within 72 h of randomization. Moreover, patients should have at least one of the following criteria: (1) raised levels of cardiac enzymes, for example, creatine kinase-myocardial band or troponins; (2) new ST depression on electrocardiograph (ECG); (3) ischemic T-wave inversion; (4) transient ST elevation (<20 min) or inversion of T-wave in two leads at least; and (5) already diagnosed coronary artery disease (CAD), as concluded by a history of revascularization or catheterization. In general, patients were ineligible in most of the included studies if they had any of the following: (1) secondary causes of raise cardiac enzymes or changed kinetics (e.g., renal insufficiency); (2) persistent ST elevation (i.e., more than 20 min); (3) cardiogenic shock or severe congestive cardiac failure; (4) acute myocardial ischemia due to secondary causes (e.g., tachyarrhythmia, anemia, thyrotoxicosis, uncontrolled hypertension, and fever); (5) major comorbidities or serious systemic disease that would prevent an invasive approach; (6) intolerance of antiplatelet therapy and anticoagulation; (7) refractory symptoms; (8) a procedure of coronary revascularization within the previous 30 days; and (9) arrhythmias that required immediate catheterization.

Types of interventions

Initially, all elderly patients with instable angina or non-ST-elevated MI UA/NSTEMI were managed with some of the medical treatments. The medical therapy can be further classified into two categories: anti-ischemic and antiplatelet. Anti-ischemic includes bed rest, beta-blockers, and nitroglycerine or calcium channel blockers if beta-blockers are contraindicated.[18] Antiplatelet therapy includes aspirin, clopidogrel or prasugrel, heparin, and glycoprotein IIb/IIIa receptor antagonists. After initial medical treatment, patients were assigned randomly to invasive treatment or conservative treatment. Both treatment approaches are different with respect to the use of angiography and subsequent revascularization percentages.[18] The two treatment approaches under comparison are as follows: (A) routine invasive approach: where angiography with or without revascularization should be used in all participants; (B) conservative or “selective invasive” approach: medical therapy and angiography with or without subsequent revascularization indicated only in case of cardiac ischemia, for example, recurrent ischemia, a positive stress test, or dynamic ECG changes. It is also important to note that in the conservative strategy, urgent angiography should be done in case of ischemia, and therefore it is called “selective invasive.” Depending on the findings of the angiography, revascularization modalities (PCI or CABG) will be decided. CABG is the best method of the revascularization approach for any of the following ischemic conditions: ischemia of three vessels with an ejection fraction (EF) of no more than 0.50, left main CAD, and two-vessel disease with EF of <0.50 and proximal left anterior descending involvement or ischemia.[19]

Outcomes

Primary outcomes

The two primary outcomes are death from all causes and MI. In case of patients who were admitted with UA, the outcome which will be measured is the rate of incidence of new MI, but if patients were admitted with non-ST-elevation myocardial infarction, the measured outcome will be re-infarction rate. In general, either re-infarction or new MI, it was referred as MI by all studies and it included a combination of common ischemic features such as ECG changes, chest pain, and raised cardiac enzymes. A common definition of periprocedural MI has been agreed as a rise in the cardiac enzymes to three times the upper limit.[20]

Secondary outcomes

The secondary outcomes were rehospitalization for ACS and complications of angiography or revascularization (e.g., bleeding, procedure-related MI, and stroke).

Search methods for identification of studies

A thorough literature search is one of the essential stages in conducting a systematic review in order to reduce the chances of selection bias and to include the majority of the related studies.[21] The search strategy in this review was directed and stated in accordance with PRISMA guidelines and Cochrane Collaboration whenever possible.[22] Five search engines and databases were searched systematically, namely PubMed, CINAHL, ScienceDirect, Web of Science, and Cochrane Library. The academic support provided by the university including guidance from librarians and research support sessions has hugely provided the essential skills needed for developing the search strategy. As there were significant advances in the procedures and the treatment of the UA and NSTMI, and to reach an efficient opinion about the review topic in the contemporary era, only related studies conducted in the period from 1996 and onward were considered due to the low rates of stent use before that year.[23] Medical Subject Headings and free-text search were used when searching the literature. All the way through the searching process, titles of relevant studies were checked, and their abstracts were reviewed for their importance to the topic under the review. Full articles of relevant studies were accessed according to the eligibility criteria. Finally, hand-searching of these full articles for their bibliographic references were performed, though there is a risk of reference bias, because authors might select only references which confirm their hypothesis.[24] However, this process was suitable to find other possibly related studies.

Quality assessment of the studies

In 2005, The Cochrane Collaborations developed a new approach for addressing the quality of randomized trials.[25] A 3 days' conference of epidemiologists, statisticians, and review authors in Cambridge, UK, was enough to agree and to write the protocol of the tool. The judgment of the risk of bias is challenging, and therefore, the Cochrane Collaboration developed certain tools to help reviewers during making these judgments. The tool involves the measurements of the risk of bias arising from several domains (random sequence generation, allocation concealment, blinding, incomplete outcome data, and selective outcome reporting and other biases).

The evaluation of bias domains is critical in this study since empirical evidence has confirmed that a lack of proper randomization, concealment of allocation, blinding, and loss to follow-up between intervention groups may influence the results of these interventions.[26]


  Results Top


The selection process

The literature search conducted for this review yielded 1482 hits; of these, 885 remained after excluding duplicate papers [Figure 1]. A further exclusion on the basis of the title and the abstract yields 25 studies which deemed to be relevant and were about the treatment of UA and NSTMI. Three studies were excluded (RITA, ICTUS, and VINO)[17],[27],[28] because the subgroup analysis for age group under review cannot be obtained, and the authors of these studies were contacted by e-mails, but they did not reply, and the OASIS-5[29] trial was excluded because it was designed to examine the effects on women only. Among the rest of the studies, 17 studies were excluded for different reasons. In addition, seven of the main RCTs were excluded from the update because they had compared an early to a delayed invasive strategy. These studies mostly focused on the best timing of an invasive strategy (e.g., ISAR-COOL,[30] ABOARD,[31] OPTIMA,[32] LIPSIANSTMI,[33] ELISA,[34] Zhang 2010,[35] and TIMACS[36]).
Figure 1: PRISMA flow diagram of studies' selection process

Click here to view


As mentioned earlier, studies from the prestent era are irrelevant to current practice and lead to underestimation of the value of the invasive strategy. Therefore, another three trials were excluded because they were undertaken in the prestent era or did not encourage the routine use of stents in the invasive strategy (MATE 1998,[37] TIMI-3b,[38] and VANQWISH 1998[39]). Moreover, five nonrandomized studies (MITI 2000,[40] Teixeira 2009,[41] GUSTO2b 2003,[42] Bauer,[43] and Global Registry[44]) were excluded as only high-quality RCTs are included in this review. Finally, four studies were found appropriate for inclusion and fulfill the criteria for this review. The studies were After Eighty study,[12] Italian Elderly,[13] FRISC,[10] and TACTICS-TIMI 18.[45]

Characteristics of patients in the selected studies

The patients' characteristics in the selected studies were heterogeneous [Table 1]. The inclusion criteria contained different mixtures of the following core criteria: ECG changes, chest pain, raised level(s) of cardiac enzyme(s), or known case of ischemic heart disease (CAD). The age groups involved in all studies were above 65 years old with a mean age of 82 for both Italian Elderly[13] and After Eighty[12] and 65 and 66 years for FRISC[10] and TACTICS-TIMI 18,[45] respectively.
Table 1: Characteristics of the selected studies

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Interventions

In the routine invasive approach, angiography was to be performed in all patients regardless of symptom status. In comparison, in the conservative approach, angiography only indicated in patients with investigational or clinical evidence of ischemia. Hence, angiography is an essential part of both treatment approaches, and it did not represent a crossover in the conservative arm, providing that it was preceded by evidence of myocardial ischemia.

Outcomes

The most common described outcomes are death and MI. Death was reported as all-cause mortality. The definition of MI was different between the included studies but included a combination of common ischemic features such as ECG changes, chest pain, and raised cardiac enzymes. The authors in the After Eighty studies defined MI as new symptoms of ischemia combined with an increase in cardiac troponin enzyme exceeding the 99th percentile of a normal population. FRISC study the definition of MI was based on chest pain and elevated cardiac enzymes more than the upper limit of the normal value, whereas Italian elderly people defined MI as chest pain at rest with ECG changes. The follow-up period was 6 months in TACTICS-TIMI 18, 1 year for both the Italian Elderly ACS and After Eighty, and 5 years in FRISC.

Risk of bias assessment

The four included studies were assessed using the Cochrane tool for assessing the risk of bias in RCTs,[25] and the results are illustrated in [Figure 2]. Overall, all the studies were not able to avoid the performance and detection bias because neither subjects nor personnel were blinded. However, the risk of selection bias in all studies was relatively low.
Figure 2: Risk of bias assessment of included studies

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Allocation

Most of the included studies judged to be of low risk of bias for randomized sequence generation and allocation concealment as they used block size 5 stratified randomization, random number tables, and sealed envelopes (FRISC,[10] Italian Elderly ACS,[13] and After Eighty[12]). Only one trial is of unclear risk of bias for random sequence generation TACTICS-TIMI 18[45] as no details were provided on the method of randomization.

Blinding

All included studies were judged to be of high risk of performance and detection bias. This is because of the nature of interventions used and the outcome under attention as no attempt to blind participants, health-care providers, and outcome assessors. The blinding of outcome assessors was performed in one trial by an independent event committee Italian Elderly ACS,[13] and thus, it is judged to be of low-risk detection bias.

Incomplete outcome data

All trials were judged to be of low risk of attrition bias.

Other potential sources of bias

Two of the studies, i.e. FRISC[10] and Italian Elderly ACS,[13] were judged to be at low risk of other biases, whereas TACTICS-TIMI 18[45] was found to be at unclear risk of bias.

Meta-analysis

Heterogeneity

Heterogeneity measurement indicated that there are no substantial discrepancies between the studies as I2 was down to be approaching 0% in both death and MI outcomes.

Log risk ratio effect sizes

For the two primary outcomes, the forest plots of log risk ratios are presented in [Figure 3] and [Figure 4]. In the death (all causes), the overall log risk ratio was −0.142 and the effect size (Z value) was − 1.266 and it was not significant (P = 0.205). Indeed, only one study effect size was significant (P = 0.05) and that was the FRISC trial.[10] Therefore, there are no significant differences overall between invasive and conservative treatments for this primary outcome. As far as the MI is concerned, it can be concluded from the forest plot that invasive treatment is more effective than the conservative one in reducing MI events as the overall effect size was significant at P< 0.001 (Z = −5.415). In this comparison, the invasive intervention is clearly more effective than the conservative treatments. Only one study result was not significant at P = 0.276 (Italian Elderly Trail).
Figure 3: Forest plot of the log risk ratio of the invasive group versus that of the conservative group showing that the overall effect size is not significant suggesting that there are no differences between the interventions with regard to death (all causes)

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Figure 4: Forest plot of the log risk ratio of the invasive group versus that of the conservative group, showing that the overall effect size is significant suggesting that the invasive procedure is more effective with regard to myocardial infarction

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Publication bias

The funnel plots of the two primary outcomes suggested that there is no publication bias as the values scattered symmetrically on the plot.


  Discussion Top


This systematic review included four RCTs of total of 3016 patients with UA or NSTMI, comparing between routine invasive approach and conservative approach. There were no statistically significant differences between invasive and conservative treatments in all-cause mortality (log risk ratio: 0.142 and 95% confidence interval (CI): 0.363–0.78, P = 0.205, 4 studies, 3016 participants, and low-quality evidence.

All the four trails reported the outcomes after a different period of follow-up. FRISC study has the longest period of follow-up with about 5 years compared to about 1 year of follow-up for both Italian Elderly study[13] and After Eighty study[12] and only a 6-month period for TACTICS-TIMI18.[45] However, although there was a difference in the duration of the follow-up, the rate of death due to all causes after each different period was not significant in favor of invasive approach.

One of the main findings of this review is that it shows that there was a significant risk reduction in the incidence of MI log risk ratio. Elderly population are at high risk to have more complicated ischemic lesions, and thus, early diagnostic angiography in the invasive approach can predict those and prevent the incidence of MI. In comparison, the conservative approach, angiography is indicated only in case of recurrent ischemia which makes it difficult to detect patients at high risk to prevent MI. However, this has no effect on the overall survival. This is because the invasive treatment approach is double-edged sword sever complicated ischemic lesion so prevent the occurrence of acute MI, but on the other hand, it could lead to serious fatal complications such as bleeding, particularly in vulnerable group like elderly.

Some of the limitations encountered are as follows: some of the selected articles are prone to recall bias and selection bias, the duration of follow-up varied significantly between included studies, and there were only four RCTs which recruited the elderly who were above 65 years.


  Conclusion Top


To sum up, a routine invasive approach in the elderly with UA/NSTMI was not associated with any significance in terms of mortality compared with conservative approach. However, the incidence of MI was much lower with the routine invasive approach. Elderly population are at high risk to have more complicated ischemic lesions, and thus, early diagnostic angiography in the invasive approach can predict those and prevent the incidence of MI. Moreover, the benefits of a routine invasive strategy may be more meaningful in high-risk patients, with high-level troponin.



Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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