Use of aspirin and statins for the primary prevention of myocardial infarction and stroke in patients with human immunodeficiency virus infection

Abstract

This retrospective, cross-sectional study evaluated whether HIV-infected patients received aspirin and statins for the primary prevention of myocardial infarction and stroke. Among the 258 patients included, 50.4% (n = 130/258) of the patients had a high risk of myocardial infarction and 14% (n = 36/258) of stroke. Overall, 43.1% (n = 56/130) and 50% (n = 18/36) of the patients were prescribed aspirin for the primary prevention of myocardial infarction and stroke, respectively. Among the patients who required statin therapy, 42.5% (n = 34/80) and 37.1% (n = 13/35) of patients received it for the primary prevention of myocardial infarction and stroke, respectively. The patients who had hypertension (odds ratio 3.8, 95% confidence interval 1.5–10.9) and diabetes mellitus (odds ratio 5.6, 95% confidence interval 2.6–12.4) were more likely to receive aspirin. Interventions are needed to improve provider awareness of the use of aspirin and statins in the primary prevention of myocardial infarction and stroke in HIV-infected patients.

Keywords

Human immunodeficiency virus HIV AIDS cardiovascular disease prevention aspirin statins myocardial infarction stroke

Aging human immunodeficiency virus (HIV)-infected patients face increased risk of coronary heart disease (CHD) and cerebrovascular events.^1–3 This is not only because they tend to be more prone to risk factors such as hypertension (HTN), dyslipidemia, diabetes mellitus (DM) and smoking, but also because of the physiologic changes that occur from antiretroviral therapy and HIV infection itself, particularly CD4 cell count < 350 cells/mm³.^4–9 Protease inhibitors, except atazanavir and darunavir, and nucleoside reverse transcriptase inhibitors have shown association with myocardial infarction (MI) but conflicting association with stroke.^10–19

Due to the lack of guidelines for HIV-infected patients on the primary prevention of MI and stroke, the same guidelines for the general public are used in clinical practice. Although aspirin (ASA) is the main drug used for the primary prevention of MI and stroke, underutilisation of ASA is prevalent among HIV-infected patients according to previous studies.^20–24 Statins have shown effective reduction in MI and stroke events in combination with ASA.^25,26 However, the prevalence of prescribing both ASA and statins in HIV-infected patients has not been evaluated. The primary objective of this study was to evaluate the prevalence of ASA and statin use for the primary prevention of MI and stroke in HIV-infected patients. The secondary objective was to determine the factors associated with ASA prescription.

Methods

Study design

This was a single-center, cross-sectional, and retrospective study conducted at an outpatient HIV clinic at a teaching hospital. The study included HIV-infected men aged between 45 and 79 and women aged between 55 and 79, who did not miss more than two consecutive appointments between 1 January 2012 and 31 December 2012. Exclusion criteria were being transgender; a history of MI and/or stroke; a history of gastrointestinal bleeding and/or ulcers; a history of non-steroidal anti-inflammatory drug (NSAID), ASA, and/or statin allergy or intolerance; the use of antiplatelet drug or NSAID other than ASA; the use of an anticoagulant; a history of rhabdomyolysis without a statin therapy; and active liver disease with elevated transaminases (>3 times the upper normal limit).

Outcome measurements

A ten-year CHD Framingham Risk Score (FRS) (https://www.framinghamheartstudy.org/risk-functions/cardiovascular-disease/10-year-risk.php#) and a five-year CHD Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) risk score (http://hivpv.org/Home/Tools/tabid/91/ctl/ExamView/mid/500/eid/0/lid/0/Default.aspx) were calculated to assess the risk of MI. Patients who had a ten-year CHD FRS ≥10% and/or a five-year CHD D:A:D risk score ≥5% were qualified to receive ASA. A ten-year stroke FRS (https://www.framinghamheartstudy.org/risk-functions/stroke/stroke.php) was calculated to assess the risk of stroke, and patients who had ≥10% were qualified to receive ASA.

Statin use was evaluated based on 2013 American College of Cardiology (ACC)/American Heart Association (AHA) guidelines for patients who were qualified to receive ASA as defined above. Patients who had low-density lipoprotein (LDL) ≥190 mg/dL, a diagnosis of DM defined as a diagnosis documented in medical records or the presence of anti-diabetic agents on the active medication list, or atherosclerotic cardiovascular disease (ASCVD) risk ≥7.5% (http://tools.cardiosource.org/ASCVD-Risk-Estimator/) were qualified to receive a statin therapy.²⁷

Statistical analysis

Continuous variables were reported as median whereas categorical variables were reported as percentages. Use of ASA for the primary prevention of MI and stroke was described as prevalence with 95% confidence interval (CI). In order to compare different groups of patients categorised by FRS and D:A:D for the evaluation on the primary prevention of MI, p value was calculated by using Fisher’s exact test with the significance defined as p value < 0.05. A multivariable logistic regression analysis was used to evaluate the factors associated with ASA prescription.

Results

The outpatient HIV clinic had a total of 1464 established patients. Based on age, 845 patients were excluded, and 264 patients were further excluded due to having a history of more than two consecutively missed appointments. Out of 355 patients, 97 patients were further excluded based on other exclusion criteria. As a result, there was a total number of 258 patients included for the study (Figure 1).

Figure 1.

Patient selection.

Primary prevention of MI

Out of 258 patients, 50.4% (n = 130/258) were at a high risk of having an MI based on the ten-year CHD FRS and/or five-year CHD D:A:D risk score. Overall, the median age was 59 years and the majority of the patients were men. The median length of HIV infection was 14 years, the majority of patients had an undetectable viral load, and HTN was the most common cardiovascular disease (CVD) (Table 1). The overall prevalence of ASA use for the primary prevention of MI was 0.43 (n = 56/130; 95% CI 0.35–0.52). There was no significant difference in ASA use even if the risk of MI was determined by either FRS or D:A:D risk score (Table 2). Although 61.5% (n = 80/130) of the patients required a statin therapy, only 42.5% (n = 34/80) of them received it (Figure 2).

Table 1.

Demographic data of HIV-infected patients at increased risk of MI and stroke.

Variables	CHD				Stroke
Variables	FRS ≥10% (n = 49)	D:A:D risk score ≥5% (n = 14)	FRS ≥10% and D:A:D risk score ≥5% (n = 67)	Overall increased risk of CHD (n = 130)	FRS ≥10% (n = 36)
Age, median (range)	57 (45–73)	59.5 (50–75)	61 (45–78)	59 (45–78)	65 (55–78)
Gender, n (%)
Female	21 (42.9)	4 (28.6)	18 (26.9)	43 (33.1)	12 (33.3)
Male	28 (57.1)	10 (71.4)	49 (73.1)	87 (66.9)	24 (66.7)
Obesity (BMI ≥30 kg/m²), n (%)	14 (28.6)	4 (28.6)	18 (26.9)	36 (27.7)	8 (22.2)
Length of HIV infection, years, median (range)	13 (0.83–26)	19.5 (7–30)	14 (0.25–30)	14 (0.25–30)	14 (1–28)
CD4 count (cells/mm³), median (range)	510 (12–1276)	554.5 (42–1374)	620 (27–2593)	569 (12–2593)	553 (12–1164)
Plasma HIV-1 RNA <48 copies/mL, n (%)	34 (69.4)	9 (64.3)	51 (76.1)	94 (72.3)	24 (66.7)
On antiretroviral therapy, n (%)	49 (100)	14 (100)	66 (98.5)	129 (99.2)	36 (100)
Hypertension, n (%)^a	33 (67.3)	10 (71.4)	58 (86.6)	101 (77.7)	36 (100)
Diabetes mellitus, n (%)^b	11 (22.4)	4 (28.6)	35 (52.2)	50 (38.5)	16 (44.4)
Current smoking, n (%)	11 (22.4)	7 (50)	32 (47.8)	50 (38.5)	12 (33.3)
Current alcohol use, n (%)	9 (18.4)	3 (21.4)	15 (22.4)	27 (20.8)	7 (19.4)
Current drug abuse, n (%)	4 (8.2)	1 (7.1)	9 (13.4)	14 (10.8)	4 (11.1)
History of depression, n (%)	8 (16.3)	3 (21.4)	9 (13.4)	20 (15.4)	6 (16.7)
HCV co-infection, n (%)	12 (24.5)	4 (28.6)	16 (23.9)	32 (24.6)	12 (33.3)

BMI: body mass index; HCV: hepatitis C virus.

Hypertension: a documented diagnosis in medical records, presence of anti-hypertensive medication on the active medication list, or systolic blood pressure ≥140 mmHg and/or diastolic blood pressure ≥90 mmHg.

Diabetes mellitus: a documented diagnosis in medical records or presence of anti-diabetic agent on the active medication list.

Table 2.

Prevalence of ASA use in HIV-infected patients at increased risk of MI.

	FRS ≥10% (n = 49)	D:A:D risk score ≥5% (n = 14)	FRS ≥10% and D:A:D risk score ≥5% (n = 67)	Overall increased risk of CHD (n = 130)	p Value
Use of ASA, n (%)	17 (34.7)	6 (42.9)	33 (49.3)	56 (43.1)
Prevalence (95% CI)	0.35 (0.23–0.49)	0.43 (0.21–0.67)	0.49 (0.38–0.61)	0.43 (0.35–0.52)	0.303

Figure 2.

Prevalence of statin use in HIV-infected patients at increased risk of MI and stroke.

Primary prevention of stroke

Out of 258 patients, 14% (n = 36/258) were at a high risk of having a stroke based on the ten-year stroke FRS. Overall, the median age was 65 years and the majority of the patients were men. The status of HIV infection was similar to that of the patients evaluated for the primary prevention of MI, and HTN was the most common CVD (Table 1). The prevalence of ASA use was 0.5 (n = 18/36; 95% CI 0.34–0.66). Although 97.2% (n = 35/36) of the patients required a statin therapy, only 37.1% (n = 13/35) of those received it (Figure 2).

Factors associated with ASA prescription

Patients with HTN (odds ratio [OR] 3.8, 95% CI 1.5--10.9) and DM (OR 5.6, 95% CI 2.6–12.4) were a more likely to be on ASA; whereas patients with a viral load ≥ 48 copies/mL (OR 0.4, 95% CI 0.17–0.9) and currently smoking (OR 0.26, 95% CI 0.11–0.55) were less likely to be on ASA (Table 3).

Table 3.

Factors associated with ASA prescription (n = 130).

Variables	p Values	OR (95% CI)
Age	0.064
Gender	0.927
CD4 count between 50–200 cells/mm³	0.157
Plasma HIV-1 RNA ≥48 copies/mL	0.024	0.4 (0.17–0.9)
Hypertension	0.008	3.8 (1.5–10.9)
Diabetes mellitus	<0.001	5.6 (2.6–12.4)
Current smoking	<0.001	0.26 (0.11–0.55)
HCV co-infection	0.761

Discussion

The United States Preventive Services Task Force (USPSTF) 2009 guidelines recommend the use of ASA for the primary prevention of MI in men aged between 45 and 79 and stroke in women aged between 55 and 79.²⁰ However, AHA recommends ASA for patients at a high risk of CHD in the absence of contraindications and at a high risk of stroke if the benefits outweigh the risks, regardless of gender.^27,28 Based on the disparity between the guidelines and the lack of recommendations specifically for HIV-infected patients to date, our study included both genders based on the age recommended by USPSTF.

Underutilisation of ASA by HIV-infected patients has been reported from previous studies. The rates of ASA use reported by Reinsch et al.²² were 2.4% and 31.9% in patients with ten-year CHD FRS of 10–20% and >20%, respectively. Tornero et al.²³ reported a rate of 5.4%. Burkholder et al.²⁴ analysed the use of ASA for the primary prevention of MI and stroke in HIV-infected patients, which reported a rate of 17%. Our study also found underutilisation of ASA; however, the prevalence of ASA prescription was higher than that of the previous studies. Our study demonstrated underutilisation of statins as well; however, previous studies are unavailable to make a direct comparison. Unlike the results from Burkholder et al.,²⁴ which found that current smoking was associated with ASA prescription, our study found that it was less likely. Smokers tend to be less adherent to recommended preventive care and medication use compared to non-smokers, which includes the use of low-dose ASA for the prevention of cardiovascular events.^29,30

Use of FRS in HIV-infected patients is controversial since they were not considered for the development of FRS. It has been reported that FRS may underestimate the presence of sub-clinical atherosclerosis in HIV-infected patients.³¹ Based on the need for a CHD risk prediction method that is more specific for HIV-infected patients, the D:A:D risk score was developed. According to Serrano-Villar et al.,³² the D:A:D risk score predicted the presence of sub-clinical atherosclerosis better than FRS in HIV-infected patients, although both underestimated the risk of CHD in 15–20% of patients. Our study showed that there were 49 patients at a high risk of CHD based on the FRS and 14 based on the D:A:D risk score. Thus, using either the FRS or D:A:D risk score alone may inadvertently exclude HIV-infected patients who are at risk of an MI.

ASA is available over the counter, which may allow patients to purchase the drug without notifying the providers; however, it is unlikely that our study excluded a significant number of patients due to this reason. Most of the patients in the clinic had their medical costs including prescription and non-prescription drugs covered by Medicaid, the AIDS Drug Assistance Program (ADAP), or other public healthcare programmes due to their low socio-economic status. Thus, the providers wrote prescriptions even for over-the-counter drugs, including ASA, so that the patients did not have to pay out of their own pocket. Moreover, pharmacists providing services in the clinic often did medication reconciliation for the patients, which further decreased the risk of having an incomplete record.

The strengths of our study are the use of both the FRS and D:A:D risk score and an analysis of the primary prevention of MI and stroke separately in HIV-infected patients. Assessment of both ASA and statin use was another strength because there is a lack of previous data evaluating the use of both medications in HIV-infected patients for the primary prevention of MI and stroke. However, our study has some limitations. It was a single-center, cross-sectional, and retrospective study. Since some of the variables such as blood pressure and lipid panel used to calculate the risk scores were from the most recent appointments, possible variability of risk scores over time was not taken into account. There was a lack of complete documentation on family CVD history and past antiretroviral use for some patients. If family CVD history or the use of certain antiretrovirals was not documented in medical records, then patients were considered not to have such history.

In conclusion, interventions are needed to improve provider awareness in the use of ASA and statins for the primary prevention of MI and stroke as HIV-infected patients are at an increased risk of CVD compared to non-HIV-infected patients.

Footnotes

Acknowledgements

The following manuscript has been presented as a poster at 53rd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC); 10–13 Sept 2013; Denver, CO. This manuscript has also been presented as a poster and received New York State Council of Health-System Pharmacists Research and Education Foundation (NYSCHP-REF) award at 52nd New York State Council of Health-system Pharmacists (NYSCHP) Annual Assembly; 1–5 May 2013; Verona, NY.

Declaration of Conflicting Interest

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

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