Effect of Antecedent Hypertension on Mortality after Acute Coronary Syndromes in Coronary Intervention Era: A Meta-analysis

doi:10.21203/rs.3.rs-2838721/v1

Background

Effect of antecedent hypertension on mortality after acute coronary syndromes (ACS) in the percutaneous coronary intervention (PCI) era is less clear. The aim of this meta-analysis was to assess effect of antecedent hypertension on short and long-term mortality after ACS in the coronary intervention era.

Methods

PubMed, Medline, EMBASE and the Cochrane library were systematically searched up to April 2023. Ten studies with total of 64, 989 of patients met the inclusion criteria. The outcomes of interest were (i) all-cause in-hospital mortality; (ii) long-term all- cause mortality.

Results

No significant difference was observed in in-hospital mortality between antecedent hypertension group and non-antecedent hypertension with pooled odds ratio (OR): 1.07, 95% confidence interval (CI): 0.79–1.45; I2 = 82%, the same as ST elevation myocardial infarction (STEMI) group (pooled OR: 1.01, 95% CI: 0.73– 1.39; I2 = 66%). However, result was statistically significant for non-ST elevation myocardial infarction (NSTE-ACS) patients, with pooled OR: 0.67, 95% CI: 0.55–0.82; p = 0.0001, I2 = 0%. Antecedent hypertension was related to increased long-term mortality of patients with ACS (pooled OR 1.28, 95% CI 1.16–1.40, p = 0.0001; I2 = 0%), the same as STEMI subgroups.

Conclusion

In PCI era antecedent hypertension was associated with higher long-term mortality in ACS patients, but no significant difference was observed in in-hospital mortality between hypertension and non- hypertension. However, for NSTE-ACS patients’ antecedent hypertension may be a protective factor related to in- hospital mortality.

antecedent hypertension

acute coronary syndrome

percutaneous coronary intervention

mortality

Arterial hypertension is an established risk factor for development of atherosclerosis[1].In 2009, Guanmin Chen had analyzed adverse cardiovascular outcomes associated with antecedent hypertension after myocardial infarction[2]. In the meta-analysis, preexisting hypertension was associated with adverse events for survivors of myocardial infarctions. Importantly, the strength of association of antecedent hypertension with all-cause mortality outcomes decreased over time.[2] Currently, revascularization for acute coronary syndromes (ACS) patients is mainly percutaneous coronary intervention (PCI). However, effect of antecedent hypertension on outcomes after ACS in the PCI era is less clear. Some studies revealed that antecedent hypertension contributes to an adverse prognosis. [3–5] However, Paul Erne and his colleagues had demonstrated that outcome of ACS patients with preexisting hypertension was associated with an improved in-hospital and this effect disappeared within 1 year after discharge. [6] Other studies also found antecedent hypertension was not an independent significant predictor of adverse long-term outcome in ACS patients. [7–9]

Given these inconsistent results, we performed a meta-analysis of studies to examine effect of antecedent hypertension on short and long-term mortality after ACS in the coronary intervention era.

The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline was followed for this meta-analysis.[10] Additionally, the ethical approval was not necessary because our meta-analysis was based on data from previously published studies.

Search strategy

PubMed, Medline, EMBASE and the Cochrane library were systematically searched up to April 2023 (see Fig. 1 for detailed search strategy). The Boolean operator “and” was used for following major search themes. The first, “hypertension,” combined exploded versions of the Medical Subject Headings “hypertensive" and “high blood pressure”. The second, “acute coronary syndrome,” combined exploded versions of the terms “acute myocardial infarction,” “ST segment elevation myocardial infarction,” “non-ST segment elevation myocardial infarction," and "unstable angina." The third, “percutaneous coronary intervention,” combined exploded versions of the terms "reperfused,” and “angioplasty.” Additionally, only English language publications were considered relevant to this search strategy. The search was performed by 2 independent researchers (Shanshan Qi and Youqin Zhan).

Selection criteria

We included clinical trials to evaluate effect of antecedent hypertension on ACS patients mainly treated with PCI. Eligible studies included ACS patients mainly treated with optimal PCI. Meanwhile, effect of antecedent hypertension on mortality should be reported in the included studies. If the reperfusion strategies were mainly coronary artery bypass grafting or fibrinolytic therapy (more than 50% included population), these studies were excluded. Meta-analyses, case studies and letter to editors were also excluded. All the studies identified by the search strategy were reviewed by the title and abstract by 2 investigators (Shanshan Qi and Youqin Zhan). If the abstracts of the studies reported the effect of antecedent hypertension on ACS patients, all the identified abstracts were considered eligible for full- text review. In the second stage, full-text reports were reviewed if they reported the reperfusion strategies. References of suitable articles were also manually checked for relevant studies.

Data Extraction and Review

Data extraction was independently performed by 2 investigators (Shanshan Qi and Youqin Zhan) mainly following the recommendations of the Quality of Reporting of Meta-Analyses statement.[11] Details of the publication (i.e., authors, year of publication), inclusion/exclusion criteria, information and data related to the total number of patients involved in the hypertension and non-hypertension groups respectively, the types of study involved, data concerning the baseline features of the patients included, percent of PCI strategies, the reported cardiovascular outcomes and follow-up periods were systematically extracted. If the eligible studies have assessed the adjusted confounding factors, the adjusted hazard ratio should be given priority to be extracted. Divergences on the aforementioned information were resolved by all the authors' consensus.

The outcomes of interest were (i) all-cause in-hospital mortality; (ii) long-term all-cause mortality.

Statistical Analysis

All potentially references in the systemic review and meta-analysis were managed by EndNote software. Meta-analysis was performed using Review Manager (RevMan version 5.3; Cochrane Collaboration, Oxford, UK). We used Odd Ratios (OR) as the common measure of association across studies, with the hazard ratios directly considered as ORs. Own to the adjusted hazard ratio or OR given priority to be extracted for meta-analysis, so generic inverse variance methods were performed to evaluate the pooled effects of OR. Heterogeneity across the subgroups was assessed using Cochrane Q-statistic test. A low value of I2 represented a low heterogeneity, whereas an increasing I2 value represented an increasing heterogeneity among the subgroups assessed. The studies were pooled using fixed effects models with low heterogeneity (I2<50%). Otherwise, if I2 was greater than 50%, a random effect model was used appropriately. ORs with 95% Confidence Intervals (CIs) were also calculated for the subgroup analysis of the interesting events. Publication bias was visually estimated by assessing funnel plots. Sensitivity analysis was performed to determine by subgroup analysis. The statistical test was 2-tailed with P less than 0.05 chosen at the level of significance.

Two thousand and thirty-one articles were retrieved during the search process. Most papers were excluded based on titles and/or abstract because they were either not related to the title of this research, or they were duplicates. Then thirty-nine full-text articles were assessed for eligibility. A further 29 articles were eliminated because 25 articles were not mentioned the PCI were the mainly reperfusion management or not reported mortality and 4 articles were review article. Finally, according to the inclusion and exclusion criteria, only 10 articles enrolling 64,989 patients were eventually selected and included in this meta-analysis. The flow diagram showing studies' selection has been represented in Figure 1.

Of the ten included studies, nine studies evaluated the effects of antecedent hypertension on long- term mortality after ACS [3-9, 12, 13] Meanwhile six studies measured the effect of antecedent hypertension on1 in-hospital mortality after ACS [6-9, 12, 14]. Importantly, in some studies they divided all the included patients into STEMI and NSTE-ACS respectively, and then subgroup analysis also performed according to the pattern.

Description of included studies and quality assessment

The baselines of included studies' characteristics are summarized in table 1. A total number of 64,989 patients were involved in this analysis (35, 918 patients were hypertension). Average age across the studies ranged from 61 years to 72 years. The percentage of PCI strategy in most of studies was over 70%. Of 6 studies [3, 4, 8, 12-14], they only included ACS patients treated with PCI. Follow-up period ranged from 1 year to 8 years. The potential confounding adjusted factors differed across included studies and the main adjusted factors were age, sex, and diabetes. Reported outcomes, follow-up periods and adjusted risk factors were also presented in table 1. Among included studies, study quality criteria of blinding to ascertain outcome and recruiting consecutive patients were not explicitly specified. ORs were determined for all studies, either reported or calculated from the number of events reported. Only 3 studies hadn't reported the adjusted risk factor[8, 13, 14].

Table 1. Study characteristics and reported outcomes with respective follow up periods.

Studies	Type of study	Total of patients (n)	Age (year)	antecedent hypertension	STEMI	Management of PCI	Reported outcomes	Follow-up periods	Adjusted factors
Sebastian 2016^[3]	Cohort	795	62 [51–71]	540	100%	100%	Mortality	12 months	age, gender, smoking status, diabetes, heart rate, Killip-class, vessel disease
Paul 2015[^6]	Prospective	41, 771	65.4(12.2)	24 916	56.1%	75%	mortality	In-hospital; 12 months	age, sex, Killip class greater than 2, CCI greater than 1 and presence of a STEMI
Giuseppe 2014^[4]	Retrospective	6,298	61.4 ±11.6	2764	100%	100%	Death	1201 ±440 days	age, gender, diabetes, hypercholesterolemia, previous MI, previous revascularization, time-to-treatment, smoking, anterior MI, preprocedural TIMI 3 flow, infarct-related artery, multivessel disease, type of DES, postprocedural TIMI 3 flow
Emanuele 2013^[9]	Cohort	1,695	72 (64–76)	873	60.8%	100% for STEMI 83.3% for NSTEMI	mortality	In-hospital 40.2 months	age, admission LVEF, admission creatinine and diabetes for NSTEMI, previous MI, peak TnI level and coronary disease extension were added for STEMI
Lazzeri 2012^[8]	Cohort	560	66.2±12.2	300	100%	100%	Mortality	In-hospital 32.5 months	none
Dong 2009^[7]	Prospective	7,784	64.4±12.9	3,775	59.1%	70%	Mortality	In-hosptial One-year	Old age, female sex, post procedural TIMI flow grade ≤2, systolic blood pressure <90 mmHg on admission, LVEF <45%, Killip class ≥III, multi-vessel disease, antecedent hypertension, diabetes mellitus, and administration of reperfusion therapy
Markus 2009^[5]	Prospective	2,329	67±10	974	36%	50%	Mortality	eight years	diabetes, age, Killip class, systolic blood pressure and heart rate on hospital admission and presence of renal dysfunction and LVEF
Magdalena 2010^[14]	Cohort	366	60.3±11.9	234	100%	100%	Mortality	In-hosptial	None
lee 2012^[12]	Cohort	2,438	65.6±12.8	1218	49.7%	100%	Mortality	In-hospital, 12 months	gender, age, STEMI, previous history of cerebrovascular accident, smoking, Killip class, LVEF, eGFR, multivessel CAD, implantation of bare-metal stent, postprocedural TIMI flow grade, use of beta blocker, and use of statin.
Guido 2006^[13]	Cohort	953	63±12	324	100%	100%	Mortality	5-year	None

STEMI, ST segment elevated myocardial infarction; PCI, percutaneous coronary intervention; NSTEMI, non-ST segment elevated myocardial infarction; CCI, Charlson Comorbidity Index; MI, myocardial infarction; TIMI, thrombolysis myocardial infarction; LVEF, left ventricular ejection fraction; CAD, coronary artery disease; eGFR, estimated glomerular filtration rate.

Quantitative data synthesis

Antecedent hypertension and in-hospital mortality

Six included studies evaluated effects of antecedent hypertension on in-hospital mortality after ACS [6-9, 12, 14]. No significant difference was observed in in-hospital mortality between hypertension group and non-hypertension with pooled OR:1.07,95% CI:0.79-1.45; p=0.68,12= 82%. Since our data included STEMI patients and NSTE-ACS patients, further subgroup analyses were conducted separating these two categories of patients. Moreover, for the STEMI patients there also wasn't significant difference in in-hospital mortality between hypertension group and non- hypertension group (pooled OR: 1.01, 95% CI:0.73-1.39; p=0.97,12=66%). However, the result was statistically significant for NSTE-ACS patients, with pooled OR:0.67,95% CI:0.55-0.82; p= 0.0001, I2 = 0%. In other words, antecedent hypertension has been observed as a protective factor for NSTE-ACS patients treated PCI. The forest plot was presented in Figure 2.

Antecedent hypertension and long-term mortality

Nine included studies evaluated the effect of antecedent hypertension on long-term mortality for ACS patients treated with PCI [3-9, 12, 13]. The follow-up duration ranged from 12 months to 8 years. The pooled results showed that antecedent hypertension was related to the increased long-term mortality of patients with ACS (pooled OR 1.28,95% CI 1.16-1.40, p=0.0001; I2=0%). Furthermore, the STEMI patients were analyzed separately. The meta-analysis of 5 studies [3, 4, 8, 9, 13] revealed that antecedent hypertension was also associated with significantly increased long-term mortality with pooled OR: 1.20, 95% CI: 1.03-1.40; p=0.02, I2=31%. Unfortunately, only one study evaluated the effect of antecedent hypertension on long-term mortality after NSTEMI. The result was no statistically significant with OR: 0.83, 95% CI: 0.53-1.38, p-0.12. As the disparity between STEMI and NSTEMI for antecedent hypertension and in-hospital mortality, there was also difference between STEMI and NSTEMI for antecedent hypertension and long-term mortality. The forest plot was presented in Figure 3.

Publication bias and funnel plots

Based on a visual inspection of the funnel plot obtained, no evidence of publication bias for the included studies that assessed long-term mortality (Figure 4a). However, visual inspection of funnel plots indicated an asymmetry for the included studies that evaluated the in-hospital mortality (Figure 4b). The asymmetry of funnel plot may be due to insufficient number of trials (which may lead to a small-study effect) and significant statistical heterogeneity.

Heterogeneity and sensitivity analysis

For the pooled analysis of antecedent hypertension on long-term mortality after ACs, there was no heterogeneity, the same as the subgroup analysis for STEMI patients. Heterogeneity was found when meta-analysis of antecedent hypertension on in-hospital mortally for the included six studies. The difference between STEMI and NSTE-ACS subgroup may partially explain the heterogeneity. For the aforementioned analyses evaluating antecedent hypertension on in-hospital and long-term mortality after ACS in PCI era, sensitivity analyses yielded consistent results through subgroup analysis.

To our knowledge, this is the most comprehensive meta-analysis to evaluate effect of antecedent hypertension on mortality after acute coronary syndromes in the coronary intervention era. Main findings of the current analysis included 10 studies in the PCI era as the following: (i) Antecedent hypertension is not associated with increased in-hospital mortality for ACS patients, the same as STEMI subgroup patients. However, antecedent hypertension is significantly related to decreased in-hospital mortality for NSTE-ACS patients. (ii) After controlling for multiple cardiovascular risk factors, antecedent hypertension was associated with higher long-term mortality in ACS patients, the same as in STEMI patients.

The results are partially consistent with a previous meta-analysis that included 8 randomized clinical trials and 9 cohort studies, with the conclusion that antecedent hypertension in patients with myocardial infarction is a risk factor for long-term mortality [2]; In contrast to the previous meta- analysis, revascularization management of ACS patients retrieved in the present analysis was almost PCI, which representing the modern management method for ACS patients. Meanwhile, both in- hospital and long-term mortality related to antecedent hypertension were included for pooled analysis. However, as mentioned in previous meta-analysis,17 included studies published before 2009, the association of antecedent hypertension with all-cause mortality outcomes decreased over time for myocardial infarction patients. Furthermore, over the last years, reperfusion strategies and pharmacological treatment were significantly optimized and consequently improved the outcome of ACS patients[15]. The improvement may have modified the relationship between hypertension and the clinical course after ACS [16]. However, in our pooled analysis antecedent hypertension was also verified as a risk factor for long-term mortality for ACS patients in the PCI era, the same as in the STEMI subgroup analysis. Importantly, our findings highlight that even in the contemporary era of PCI antecedent hypertension can be also used to identify as a risk factor ACS patient. ACS patients with hypertension might also benefit from more intensified medical treatment strategies including intensive antihypertensive treatment. On the other hand, for NSTEMI subgroup included only one study[9], antecedent hypertension was not related to long-term mortality. This should be evaluated further in the future.

Contrary to the relationship between antecedent hypertension and long-term mortality, antecedent hypertension at the time of the acute event was not related with in-hospital mortality for ACS patients in our analysis, the same as in STEMI subgroup. However, antecedent hypertension is a protective factor for NSTE-ACS patients treated with PCI. Given its role as a risk factor for ACS, history of hypertension is more common in ACS patients [17]. The predictive value of antecedent hypertension in the acute phase of ACS is intricate.

Several potential mechanisms may partially explain the complexity. Firstly, more frequent history of angina in hypertensive patients has clinical relevance, as diffuse coronary atherosclerosis stimulates collateral vessel neoformation, protecting from transmural necrosis in the NSTE-ACS phenotype [18]. Another study has also verified positive troponin and ST-segment deviations were less frequent among hypertensive patients for NSTE-ACS patients [19].Furthermore, Maurizio G.et al had revealed that the higher prevalence of cardiogenic shock in non-hypertensive subjects as compared with hypertensive individuals for acute myocardial infarction patients [20].More frequent pre-admission use of protective medications, such as aspirin, beta-blockers and statins, also partly favors the NSTEMI over the STEMI patients [21, 22]. Secondly, all the aforementioned potentially protective profiles may alleviate the determinants of antecedent hypertension for all the spectrum of ACS patients. Thirdly, for this meta-analysis ACS patients were mainly treated PCI, so the mechanical treatment on the culprit vessel may have significantly improved prognosis of these patients, possibly ameliorating the effect of hypertension on in-hospital outcome.

Some limitations of this meta-analysis have to be mentioned. Firstly, we had no access to individual patients' data. However, we mainly pooled studies with multivariate-adjusted data, which may mitigate the possibility of influencing the association between hypertension and mortality. Secondly, the lower number of studies available separately reports the effect of antecedent hypertension and mortality in NSTE-ACS patients. These subgroup analyses are difficult to interpret, especially for long-term mortality analysis. Thirdly, although reperfusion strategy of 6 studies was complete PCI, yet strategy in some other retrieved studies was not totally PCI, which might influence the pooled results on the behalf of PCI era.

This meta-analysis suggested that in the PCI era antecedent hypertension was associated with higher long-term mortality in ACS patients, but no significant difference was observed in in-hospital mortality between HTN group and non-HTN. However, for NSTE-ACS patients’ antecedent hypertension may be a protective factor related to in-hospital mortality. Due to limited data, further studies with larger population size, especially aimed to evaluate this relationship in the PCI era, are recommended to completely solve this matter.

Ethics approval and consent to participate

This is a meta-analysis study, all the included studies had been approved by their own ethics communities, so the ethics approval and consent to participate is not applicable.

Consent for publication

Not applicable.

Availability of data and materials

Due to the meta-analysis, all the data and material included in the manuscript approved the results.

Competing interests

The authors declare that they have no competing interests.

Funding

No funding.

Authors' contributions

SSQ and YQZ performed the survey and wrote the draft of manuscript. YQC and TX designed the study, helped interpret the analysis results, and assisted in modifying the manuscript. All authors read and approved the final manuscript.

Acknowledgements

We sincerely thank Xiaocong Zhang for the assistance of data management.

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No competing interests reported.

Effect of Antecedent Hypertension on Mortality after Acute Coronary Syndromes in Coronary Intervention Era: A Meta-analysis

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Abstract

Figures

Introduction

Material and methods

Results

Discussion

Conclusion

Declarations

References

Additional Declarations

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