|Year : 2017 | Volume
| Issue : 3 | Page : 90-98
Underutilization of aspirin in people living with human immunodeficiency virus at increased risk for acute myocardial infarction: Systematic review and meta-analysis
Stella Pak1, Tian Chen2, Mohammed Ruzieh1, Jonathan Clark3, Douglas Federman1
1 Department of Medicine, University of Toledo Medical Center, Toledo, OH, USA
2 Department of Mathematics and Statistics, University of Toledo, Toledo, OH, USA
3 Department of Education and Quality, Diplomat Specialty Pharmacy Incorporation, Flint, MI, USA
|Date of Web Publication||4-Jul-2017|
Department of Medicine, Ruppert Health Center, Room 0012, 3000 Arlington Avenue, Toledo, OH 43614
Source of Support: None, Conflict of Interest: None
Context: With the increased availability of potent combination antiretroviral therapies, the life expectancy of people living with human immunodeficiency virus (PLHIV) has greatly increased. This rapid improvement in lifespan has served as a catalyst for a paradigm shift in human immunodeficiency virus (HIV) care. The focus of HIV care models has transitioned from the sole treatment of acute opportunistic infections to comprehensive management of chronic diseases, such as cardiovascular disease (CVD). Multiple studies have demonstrated that PLHIV are 50% more likely to develop acute myocardial infarction (AMI), compared to the general population. Cardiovascular risk prevention is becoming an essential component of the overarching HIV treatment plan. Aims: This meta-analysis aims to compare the rate of aspirin use for AMI prevention in indicated patients between PLHIV and general population. Methods: PubMed, EMBASE, Web of Science, Cochrane Library, CINAHL, and MEDLINE databases were used to identify observational cohort trials. Studies were assessed by two reviewers for inclusion criteria. Two separate random-effects meta-analyses' models were performed using the DerSimonian and Laird method. Heterogeneity was assessed using the I2 value. Meta-regression with study level variables was used to explore potential sources of heterogeneity. The funnel-plot-based trim-and-fill method was applied to detect and adjust for potential publication bias. Statistical tests were two-sided and P< 0.05 was considered statistically significant. Results: A total of 13 studies were included for analysis. In these trials, 30.4% of PLHIV with increased risk for coronary heart disease (CHD) used aspirin for AMI prevention, compared to 36.9% of patients at risk of CHD in the general population. Conclusions: The results of this meta-analysis provide evidence that aspirin is underutilized in both PLHIV and the general population across broad geographical zones. Aspirin use was found to be markedly lower in PLHIV compared to the general population. This is the first study to pool results from regional studies to assess disparities in aspirin use for AMI prevention between PLHIV and the general population across broad geographical zones.
Keywords: Acute myocardial infarction, aspirin, cardiovascular disease, coronary heart disease, people living with human immunodeficiency virus
|How to cite this article:|
Pak S, Chen T, Ruzieh M, Clark J, Federman D. Underutilization of aspirin in people living with human immunodeficiency virus at increased risk for acute myocardial infarction: Systematic review and meta-analysis. J Clin Prev Cardiol 2017;6:90-8
|How to cite this URL:|
Pak S, Chen T, Ruzieh M, Clark J, Federman D. Underutilization of aspirin in people living with human immunodeficiency virus at increased risk for acute myocardial infarction: Systematic review and meta-analysis. J Clin Prev Cardiol [serial online] 2017 [cited 2017 Aug 23];6:90-8. Available from: http://www.jcpconline.org/text.asp?2017/6/3/90/209378
| Introduction|| |
Owing to the widespread availability and efficacy of combination antiretroviral therapy (cART), the lifespan of the people living with human immunodeficiency virus (PLHIV) has significantly improved in recent years. The subsequent increase of aging-associated disease states in the PLHIV population has revealed that human immunodeficiency virus (HIV) infection is associated with increases in the risk of coronary heart disease (CHD), including acute myocardial infarction (AMI). Multiple studies have demonstrated that PLHIV are approximately 50% more likely to develop AMI compared to the general population, after adjustment for traditional cardiovascular risk factors.
Protease inhibitors (PIs) are a common component of cART regimens and are known to disturb the regulatory mechanisms for lipid and glucose metabolism. The use of PIs is associated with increased prevalence of CHD in the HIV-infected population. HIV infection also causes chronic inflammation, immune dysfunction, altered coagulation profiles, and other physiological changes that additively contribute to the potential for the development of cardiovascular disease (CVD) in PLHIV. Additional factors, such as higher prevalence of smoking and socioeconomic deprivation in PLHIV, may also play a role in the development of cardiovascular dysfunction.,
Higher 1-year mortality rates after the first episode of AMI have been reported in PLHIV, compared to the general population. For patients infected with HIV, AMI tends to occur at a younger age and leads to a higher rate of post-AMI complications, such as congestive heart failure. These correlations emphasize the importance of preventive care for AMI risk reduction in PLHIV.
With increased aging and a corresponding rise in potential for AMI in PLHIV, prophylactic cardiovascular care will need to become a key aspect of HIV management. Despite the increased prevalence of CHD in PLHIV, there has been a scarcity of literature involving the evaluation and optimization of preventive cardiovascular care in this population.
Aspirin is an antiplatelet medication widely utilized for primary and secondary prevention of cardiovascular events. The United States Preventive Services Task Force (USPSTF) recommends aspirin use for primary prevention in patients aged 50–59 years who have a 10% or greater 10-year CVD risk. The USPSTF also supports aspirin use for secondary prevention in individuals with history of CVD. The efficacy of aspirin in primary prevention of myocardial infarction (MI) is supported by a pooled analysis of ten trials performed by USPSTF, which found a 22% reduction of nonfatal MIs in the recommended population. A meta-analysis from the Antithrombotic Trialists' Collaborative found that the use of aspirin for secondary prevention lowered the rate of nonfatal MIs by 33%. In addition, aspirin can be safely coadministered with most antiretroviral therapies used for HIV treatment. Coadministration of antiviral therapies with other cardiovascular medications (e.g., statins, calcium channel blockers) may cause unwanted drug interactions that can impact treatment safety and efficacy.
Recent epidemiological studies assessing aspirin use in PLHIV have been limited to small-scale analyses. The purpose of this study was to: (1) pool results from small-scale studies to determine the aspirin utilization rate for AMI prevention in increased-risk individuals with HIV and (2) compare the aspirin utilization rate in PLHIV with the general population.
| Methods|| |
Following search terms were used to find articles with aspirin usage for AMI prevention in general population with increased risk: (“primary prevention” [Majr] or “risk assessment” [Mesh]) and “aspirin/therapeutic use” (Majr) and “CVDs/prevention and control” (Majr) not “atrial fibrillation” (all field) not “clopidogrel” (tiab) not “stroke” (TI) not “warfarin” (TI) not “men” (TI) not “women” (TI) not “trial” (TI) not (“risks” [TI] or “risk” [TI]) not (“benefits” [TI] or “benefit” [TI]) and (“Research Support, N.I.H., Extramural” [PT] or “Research Support, Non-USA Government” [PT] or “cross-sectional studies” [MH]) not “review” (TI) in PubMed, “acetylsalicylic acid”/de and “MI”/de and “cross-sectional study”/de and “prevention”/de in Embase, “aspirin”: Ti, ab, kw and “prevention”: Ab and “CHD” in Cochrane Library, TI = (aspirin not resistance not resistant not gastrointestinal [GI] not GI not hemorrhagic not men not women not cancer not economic not clopidogrel not case study not efficacy) and TS = (MI and CVD and prevention not resistance not resistant not infection not radiology not kidney not GI not bleeding) and SU = (cardiovascular system cardiology) and CU = (USA) in Web of Science, AB (aspirin and MI and prevention and risk factors) and MJ CVDs in CINAHL, MJ aspirin and TI aspirin and TI use and TI survey (with the limiter for full-text availability) in MEDLINE.
Following are search terms used for to find articles with aspirin utilization data on PLHIV at increased risk for AMI: “HIV” (TI/AB) or “HIV” (TI/AB) and “aspirin” (TI/AB) and “HIV” (TI) or “HIV” (TI) and “diabetes” (TW) and “aspirin” (TW) in PubMed, “acetylsalicylic acid”/de and “HIV infection”/de and “cross-sectional study”/de in Embase, HIV: Ti, ab, kw and “aspirin” in Cochrane Library, TS = (aspirin and HIV and prevention) in Web of Science, and AB (aspirin and HIV) in CINAHL.
The preferred reporting items for systematic reviews and meta-analyses statement was used as a basis for title and abstract screening, full-text critical appraisal, and relevant data extraction. Two reviewers independently screened all titles and abstracts, then rated each included study using the systematic review tool Covidence (Covidence, Victoria, Australia) to appraise internal validity and extract data from included studies. Disagreements were resolved with discussion between the two reviewers, or with a third reviewer included. The process of the systematic review is schematically shown in [Figure 1] and [Figure 2].
|Figure 1: Systematic review process for the people living with human immunodeficiency virus|
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To minimize the risk of relevant study omission, trial searches were performed using five and six databases for the general population and PLHIV, respectively. Database queries were performed from December 29, 2016, to January 14, 2017. Search specifications for each database are listed in [Table 1]. Cited references of articles included in the full-text appraisal were searched.
|Table 1: Summary proportions with and without publication bias for people living with human immunodeficiency virus and general population, respectively|
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The inclusion criteria for both populations included (a) rate of aspirin utilization measurement available; (b) goal of aspirin therapy was primary or secondary AMI prevention (b) individuals with an increased risk status for AMI. In our study, increased risk status was defined as one or more of the followings: Framingham risk score ≥6%; previous history of CHD or ischemic stroke; individuals with ≥2 of the following conditions: hypertension, dyslipidemia, diabetes, or smoking; PLHIV with diabetes who are over 40-year-old or currently on highly active antiretroviral therapy; (c) adult individuals aged at least 18 years; (d) study population within the United States. PLHIV-specific inclusion criteria included HIV-seropositive status. General population-specific inclusion criteria included a representative subset of the total population in the United States.
The exclusion criteria applied to both populations included (a) poorly defined population characteristics; (b) incompatible study population; (c) studies including subjects used in other, more inclusive studies; (d) study population outside of the United States; and (e) case studies.
Two separate random-effects meta-analyses were performed to investigate the proportion of aspirin use for PLHIV and the general population. The DerSimonian and Laird method was applied to derive the summary estimate. Proportions were calculated using logit transformation (log-odds). Heterogeneity was assessed using the I2 value. Meta-regression with study level variables was used to explore potential sources of heterogeneity. HIV specialization of clinics in PLHIV studies, length of the study (years), starting and ending year, location (single state or multistate), data collection (primary or secondary), mean age, and male percentage were considered as explanatory variables in the meta-regression. Due to the relatively small number of studies assessed, univariate meta-regression was performed. The funnel-plot-based “trim-and-fill” method was applied to detect and adjust for potential publication bias. All statistical tests were two-sided and P< 0.05 was considered statistically significant. All statistical analyses were performed using the R program (R Foundation; Vienna, Austria).
| Results|| |
People living with human immunodeficiency virus
Seven studies were selected from 64 articles through the review process described.,,,,,,
A total of 62 articles from the initial search were screened and 48 articles were excluded before full-text appraisal based on exclusion criteria. Two additional studies were also assessed., Appendix 1 shows the summary of the seven studies included for PLHIV population.[14–20] A total of 2,814 patients were included for PLHIV analysis.
Seven studies were selected out of 146 articles through the review process illustrated.,,,,,,
A total of 143 articles were identified from the six databases. Of these, 115 trials were excluded through screening. Three additional studies were also assessed based on a search of cited references.,, Following critical appraisal, seven studies were eligible for analysis.,,,,,, Appendix 2 shows a summary of studies included for the general population. A total of 25,211 patients were included for general population analysis.
People living with human immunodeficiency virus
A total of seven trials were included in the meta-analysis for PLHIV. The overall estimate of aspirin use in this population was 30.4% (95% confidence interval [CI]: 21.3%–41.3%; I2 = 93.57%). The associated forest plot is presented in [Figure 3]. The trim-and-fill funnel plot [Figure 4] indicated that one data point might be missing on the right side and the estimated proportion of aspirin use in PLHIV after adjustment for publication bias was 33.8% (95% CI: 24.0%–45.3%; I2 = 93.57%) [Table 1]. Publication bias minimally influenced overall findings for PLHIV. The study length was found to be the most likely contributing factor in the wide variation in the probability of aspirin use in the univariate meta-regression (P = 0.012) and represented 60.2% (R2) of the between-studies variance. Starting and end year also had considerable effect on the probability of aspirin use (P = 0.0060, R2 = 59.20%and P= 0.0174, R2 = 11.84%, respectively).
|Figure 3: Forest plot for people living with human immunodeficiency virus|
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|Figure 4: Trim-and-filled funnel plot of proportion estimates of aspirin usage for people living with human immunodeficiency virus – one data point added (shown as empty circle)|
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A total of seven studies were included in the meta-analysis for the general population. The overall estimate of aspirin use in this population was 36.9% (95% CI: 29.0%–45.6%; I2 = 99.31%) [Table 1]. The associated forest plot is presented in [Figure 5]. The trim-and-fill funnel plot [Figure 6] revealed no detectable publication bias. Age was the single factor that significantly contributed to the probability of aspirin utilization in univariate meta-regression (P = 0.004) and represented 84.7% (R2) of the between-studies variations. P value calculated from Wald-test comparison of PLHIV and general population was 0.34.
|Figure 6: Trim-and-filled funnel plot of proportion estimates of aspirin usage for general population – no data point added|
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| Conclusions|| |
The rate of aspirin use was found to be lower in patients with increased risk of AMI in PLHIV (30.4%, 95% CI: 21.3%–41.3%), compared to patients with risk factors in the general population (36.9%; 95% CI: 29.0%–45.6%). Due to a low number of included studies, these results did not reach the level of statistical significance (P = 0.34) [Figure 7]. A statistically insignificant P value indicates that this result is more than 5% likely to have occurred by chance. However, it does not disprove the clinical importance and relevance of the present outcome.
| Discussion|| |
Aspirin has become a cornerstone of care for secondary prevention of AMI and is recommended for primary prevention in high-risk populations. This meta-analysis revealed a widespread and persistent underutilization of aspirin for AMI prevention in PLHIV. Aspirin underutilization was also found to be prevalent in the general population, although at a rate of over 6% higher than in PLHIV (30.4% vs. 36.9%).
The broad array of aging-related conditions in the setting of HIV infection is a newly emerging challenge for many primary care providers and HIV specialists. Furthermore, the lack of research regarding cardiovascular care for PLHIV may contribute to the lack of preventive care guidelines in this population. Response to the growing needs of the aging PLHIV population is imperative and requires interdisciplinary efforts to create standards of care. More research is needed to develop innovative solutions that improve the quality and efficacy of cardiovascular preventive care for this vulnerable population.
The efficacy of aspirin for AMI prevention in the presence of nonclassical risk factors (e.g., chronic inflammation, coagulation abnormality, immune system deficiency, and other physiological changes from viral infection) has not been elucidated. Measurement of the relative efficacy of aspirin in nonstudy PLHIV compared to the general population would provide more specific data regarding cardiovascular risk prevention for this growing patient population. This meta-analysis revealed significant variation in the rate of aspirin utilization among currently published studies. This is likely due to the absence of national recognition and research focus on cardiovascular risk reduction for PLHIV. Variations in the clinical practices of HIV specialists may also be a contributing factor. In addition, approximately 59% of PLHIV receive both HIV management and primary care services from HIV specialist providers. These specialists tend to focus on the treatment of HIV and HIV-related conditions, such as opportunistic infections and HIV-related lymphoma, rather than the management of other chronic diseases. Published results of Cheng, et al. and Fultz, et al. support that the majority of HIV providers have a lower comfort level when treating non-HIV-related conditions, compared to the management of HIV and its associated conditions. This unmet need for holistic primary care services in PLHIV must be addressed with interdisciplinary efforts in the medical community. Many PLHIV have low socioeconomic status and struggle with transportation barriers to health care access. Delivering primary and HIV care at a one-stop clinic might help link and retain more PLHIV in primary care. Collaboration between HIV specialists, primary care providers, and other health-care practitioners is paramount to develop evidence-based strategies for the establishment of long-term, comprehensive care in this population.
This is the first meta-analysis to pool results from studies including aspirin utilization rates in patients at increased risk for AMI in PLHIV compared to the general population with risk factors. The goal of this research is to prompt further studies that improve the guidance of medical care for non-HIV-related diseases in PLHIV.
Our study has some limitations that should be considered. The included studies are observational studies with confounding variables, such as family history of CVD, which may have influenced study outcomes. Another limitation is the heterogeneity present in analysis methods with variation in data collection techniques. Given the scarcity of studies on PLHIV and the geographical variations, caution should be taken in drawing conclusions from this analysis.
Three out of seven studies included for general population were based on self-reported medical histories. The agreement rate between the medical record and self-reported data for medication use is reported to be 85%. Self-reported data tend to have higher specificity of 93% (compared to 86% with the medical record). Alternatively, medical records tend to have higher sensitivity (82%) compared to 68% in self-reported surveys. Thus, medical records are less likely to miss pertinent information. The use of patient-reported data may have influence the study outcomes. The structure of the questionnaires used in the surveys also may have influenced the accuracy of recall on medication use.
The majority of PLHIV data used in this analysis came from medical centers not specialized for HIV care, whereas 59% of PLHIV receive health care from HIV-specialized clinics. This fundamental difference could have affected our final outcome, due to differences in practice environments and standards of care.
The most significant source of heterogeneity in PLHIV was the length of the studies. However, length of the studies did not significantly affect the heterogeneity seen in general population. The additional variation in length of the studies reflects the prevalence of small-scaled dataset involving aspirin use in PLHIV.
In addition, this study is limited by the scarce amount of data available for analysis. This paucity of evidence prevents firm conclusions about the rate of aspirin utilization in PLHIV compared to the general population. Additional research is needed to clarify our understanding in this area.
Future research directions
A relevant study objective for future research would involve assessment of health-care provider awareness of HIV infection as an independent risk factor for AMI. Another potential area of interest would be the assessment of health-care providers' awareness of the informational needs for their HIV-seropositive patients involving increased risk of AMI. The study year and length in these future trials may reflect the change in standards of care regarding length of aspirin use for cardio-preventive care in this population.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7]