Acute coronary syndromes in human immunodeficiency virus patients: a meta-analysis investigating adverse event rates and the role of antiretroviral therapy.
ABSTRACT Highly active antiretroviral therapy (HAART) dramatically reduces human immunodeficiency virus (HIV)-associated morbidity and mortality, but adverse effects of HAART are becoming an increasing challenge, especially in the setting of acute coronary syndromes (ACS). We thus performed a comprehensive review of studies focusing on ACS in HIV patients.
MEDLINE/PubMed was systematically screened for studies reporting on ACS in HIV patients. Baseline, treatment, and outcome data were appraised and pooled with random-effect methods computing summary estimates [95% confidence intervals (CIs)]. A total of 11 studies including 2442 patients were identified, with a notably low prevalence of diabetes [10.86 (4.11, 17.60); 95% CI]. Rates of in-hospital death were 8.00% (2.8, 12.5; 95% CI), ascribable to cardiovascular events for 7.90% (2.43, 13.37; 95% CI), with 2.31% (0.60, 4.01; 95% CI) developing cardiogenic shock. At a median follow-up of 25.50 months (11.25, 42; 95% CI), no deaths were recorded, with an incidence of 9.42% of acute myocardial infarction (2.68, 16.17; 95% CI) and of 20.18% (9.84, 30.51; 95% CI) of percutaneous coronary revascularization. Moreover, pooled analysis of the studies reporting incidence of acute myocardial infarction in patients exposed to protease inhibitors showed an overall significant risk of 2.68 (odds ratio 1.89, 3.89; 95% CI).
Human immunodeficiency virus patients admitted for ACS face a substantial short-term risk of death and a significant long-term risk of coronary revascularization and myocardial infarction, especially if receiving protease inhibitors.
- Thrombosis and Haemostasis 08/1998; 80(1):208-9. · 6.09 Impact Factor
- [show abstract] [hide abstract]
ABSTRACT: We report the long-term outcome of percutaneous coronary interventions (PCI) in 12 HIV-infected patients. Two patients died from a HIV-related infection and seven patients suffered from severe clinical and/or angiographic restenosis requiring additional interventions or causing severe angina pectoris. Only three patients remained symptom free. We conclude that HIV-infected patients should be considered as high risk group and treated routinely with drug-eluting stents.Catheterization and Cardiovascular Interventions 01/2007; 68(6):879-81. · 2.51 Impact Factor
- [show abstract] [hide abstract]
ABSTRACT: We have previously demonstrated an association between combination antiretroviral therapy and the risk of myocardial infarction. It is not clear whether this association differs according to the class of antiretroviral drugs. We conducted a study to investigate the association of cumulative exposure to protease inhibitors and nonnucleoside reverse-transcriptase inhibitors with the risk of myocardial infarction. We analyzed data collected through February 2005 from our prospective observational study of 23,437 patients infected with the human immunodeficiency virus. The incidence rates of myocardial infarction during the follow-up period were calculated, and the associations between myocardial infarction and exposure to protease inhibitors or nonnucleoside reverse-transcriptase inhibitors were determined. Three hundred forty-five patients had a myocardial infarction during 94,469 person-years of observation. The incidence of myocardial infarction increased from 1.53 per 1000 person-years in those not exposed to protease inhibitors to 6.01 per 1000 person-years in those exposed to protease inhibitors for more than 6 years. After adjustment for exposure to the other drug class and established cardiovascular risk factors (excluding lipid levels), the relative rate of myocardial infarction per year of protease-inhibitor exposure was 1.16 (95% confidence interval [CI], 1.10 to 1.23), whereas the relative rate per year of exposure to nonnucleoside reverse-transcriptase inhibitors was 1.05 (95% CI, 0.98 to 1.13). Adjustment for serum lipid levels further reduced the effect of exposure to each drug class to 1.10 (95% CI, 1.04 to 1.18) and 1.00 (95% CI, 0.93 to 1.09), respectively. Increased exposure to protease inhibitors is associated with an increased risk of myocardial infarction, which is partly explained by dyslipidemia. We found no evidence of such an association for nonnucleoside reverse-transcriptase inhibitors; however, the number of person-years of observation for exposure to this class of drug was less than that for exposure to protease inhibitors.New England Journal of Medicine 05/2007; 356(17):1723-35. · 51.66 Impact Factor
outcome data were appraised and pooled with random-effect methods computing summary estimates [95% confi-
dence intervals (CIs)]. A total of 11 studies including 2442 patients were identified, with a notably low prevalence
of diabetes [10.86 (4.11, 17.60); 95% CI]. Rates of in-hospital death were 8.00% (2.8, 12.5; 95% CI), ascribable to
cardiovascular events for 7.90% (2.43, 13.37; 95% CI), with 2.31% (0.60, 4.01; 95% CI) developing cardiogenic
shock. At a median follow-up of 25.50 months (11.25, 42; 95% CI), no deaths were recorded, with an incidence
of 9.42% of acute myocardial infarction (2.68, 16.17; 95% CI) and of 20.18% (9.84, 30.51; 95% CI) of percutaneous
coronary revascularization. Moreover, pooled analysis of the studies reporting incidence of acute myocardial infarction in
patients exposed to protease inhibitors showed an overall significant risk of 2.68 (odds ratio 1.89, 3.89; 95% CI).
Human immunodeficiency virus patients admitted for ACS face a substantial short-term risk of death and a significant
long-term risk of coronary revascularization and myocardial infarction, especially if receiving protease inhibitors.
- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -
Acute coronary syndromes † HIV † Mortality † Antiretroviral therapy; Meta-analysis † Observational registries
Coronary artery disease
Acute coronary syndromes in human
immunodeficiency virus patients: a meta-analysis
investigating adverse event rates and the role
of antiretroviral therapy
Fabrizio D’Ascenzo1*, Enrico Cerrato1, Giuseppe Biondi-Zoccai2, Claudio Moretti1,
Pierluigi Omede `1, Filippo Sciuto1, Mario Bollati1, Maria Grazia Modena2,
Fiorenzo Gaita1, and Imad Sheiban1
1Division of Cardiology, University of Turin, S. Giovanni Battista ‘Molinette’ Hospital, Corso Bramante 88-90, Turin 10126, Italy; and2Division of Cardiology, University of Modena
and Reggio Emilia, Modena, Italy
Received 7 September 2011; revised 8 November 2011; accepted 17 November 2011; online publish-ahead-of-print 20 December 2011
See page 813 for the editorial comment on this article (doi:10.1093/eurheartj/ehr413)
Highlyactive antiretroviraltherapy(HAART)dramaticallyreduceshumanimmunodeficiencyvirus(HIV)-associated mor-
bidityand mortality, but adverse effects ofHAARTare becoming an increasing challenge, especiallyin thesetting ofacute
coronary syndromes (ACS). We thus performed a comprehensive review of studies focusing on ACS in HIV patients.
MEDLINE/PubMed was systematically screened for studies reporting on ACS in HIV patients. Baseline, treatment, and
Antiretroviral therapies dramatically reduced human immunodefi-
ciency virus (HIV)-associated morbidity and mortality.1Conse-
quently, detrimental effects of both disease progression and
antiretroviral therapy are becoming an increasing challenge for
physicians managing this high-risk subset of patients.2
In the USA, cardiovascular disease represents the third cause of
death or hospitalization for these patients.3Coronary artery
disease is an emerging complication, related both to traditional
risk factors and to specific features of these patients. Actually
smoking and hypertriglyceridaemia are more common than
among non-HIV patients, while both the heightened proinflamma-
torystate and antiretroviraldrugs4–8offera substrate for the devel-
opment of premature atherosclerosis and atherothrombosis.9–11
Many studies have provided features and outcomes with acute
coronary artery disease in HIV patients, and the influence of anti-
retroviral therapy in them, providing notable results, often limited
*Corresponding author. Tel: +393333992707; Fax: +39 0116336769, Email: email@example.com
Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2011. For permissions please email: firstname.lastname@example.org
European Heart Journal (2012) 33, 875–880
by the small number of patients. Especially, some reports demon-
strated a higher incidence of acute coronary syndromes (ACS) in
patients under treatment with antiretroviral drugs, in particular
Thus, a meta-analysis was performed to critically appraise risk
factors and outcomes of these patients, and their relationship
with antiretroviral drugs.
The present research was elaborated according to the current guide-
lines, including the recent Preferred Reporting Items for Systematic
reviews and Meta-Analyses (PRISMA) amendment to the Quality of
Reporting of Meta-analyses (QUOROM) statement, and recommenda-
tions from The Cochrane Collaboration and Meta-analysis Of Obser-
vational Studies in Epidemiology (MOOSE).14–17
restriction was applied.
Search strategy and study selection
Pertinent articles were searched in Medline, Cochrane Library, Biomed
Central, and Google Scholar in keeping with established methods15
with Mesh strategy and with terms related to HIV patients admitted
with a diagnosis of ACS: (coronary AND (stent* OR ptca OR angio-
plasty OR cabg OR (bypass AND (graft* OR surgery)) AND (hiv
OR aids OR (human AND immunodeficiency AND virus)). Studies ap-
praising only HIV patients or HIV and non-HIV patients were included.
Two independent reviewers (G.B.-Z. and F.D.) first screened
retrieved citations at the title and/or abstract level, with divergences
resolved after consensus. If potentially pertinent, they were then
appraised as complete reports according to the following explicit se-
lection criteria. Studies were included if investigating HIV patients pre-
senting with ACS, while exclusion criteria were (i) non-human setting,
(ii) duplicate reporting (in which case the manuscript reporting the
largest sample of patients with HIV was selected), or (iii) HIV patients
undergoing cardiac surgical procedure other than for ACS.
following data on pre-specified forms: authors, journal, and year of pub-
lication,location ofthe study group, baselinefeatures, death,myocardial
adverse outcomes and their relationship to antiretroviral therapies.
Rates of death, of cardiovascular death, and of cardiogenic shock
were appraised. Moreover, at follow-up, rates of myocardial infarction,
evaluated according to European Guidelines,16and of percutaneous
coronary revascularization (both repeat revascularization on the
target vessel/lesion and on de novo stenosis) were evaluated.
Internal validity and quality appraisal
Unblinded independent reviewers (G.B.-Z. and F.D.) evaluated the
quality of included studies on pre-specified forms. Modifying the
MOOSE items to take into account the specific features of included
studies,17we separately abstracted and appraised study design,
setting, data source, as well as risk of analytical, selection, adjudication,
detection, and attrition bias (expressed as low, moderate, or high risk
of bias, as well as incomplete reporting leading to inability to ascertain
the underlying risk of bias). Moreover, we awarded overall credibility of
studies included to summarized previous features. Zero points were
assigned for retrospective design and one-centre study, and one for
prospective arrangement and for a multicentre setting. Moreover,
two points were ascribed for low risk of bias, one for moderate risk,
and zero for high risk or unclear. If the sum of these scores was 10,
a very high credibility was granted, if it was between 7 and 9 high,
between 4 and 6 moderate, between 1 and 3 low, and 0 very low.
Data analysis and synthesis
Continuous variables are reported as mean (standard deviation) or
median (range). Categorical variables are expressed as n/N (%). Statis-
tical pooling was performed according to a random-effect model with
generic inverse-variance weighting, computing risk estimates with 95%
confidence intervals (CIs), using RevMan 5 (The Cochrane Collabor-
ation, The Nordic Cochrane Centre, and Copenhagen, Denmark). A
small study bias was appraised by graphical inspection of funnel
plots. Standard hypothesis testing was set at the two-tailed 0.05 level.
A total of 236 citations were first screened and appraised at the
abstract level; 19 articles were selected, among which 4 were
excluded because of investigating also non-coronary cardiac
surgery,18–21three because of including HIV patients undergoing
percutaneous coronary intervention also in stable clinical settings,
1,22,23and 2 because of investigating baseline features of HIV
Finally, 11 studies
The methodological assessment is reported in Table 1, showing
an overall good quality of the selected studies, most of them being
prospective, half of them multicentre, without a high risk of ana-
lysed bias. Moreover, for each study, definitions of adverse
events and single follow-up were evaluated (see Supplementary
material online, Appendix Table SA).
A total of 2442 patients were included, showing at pooled ana-
lysis an overall average incidence of traditional cardiovascular risk
factors, except for diabetes [10.86 (4.11, 17.60); 95% CI] (Table 2).
Pooled analysis of HIV disease characteristics are reported in
Table 3, showing a time from HIV diagnosis to ACS of 7.45 years
(2.38, 12.51; 95% CI), with most of the patients exposed to nucleo-
side reverse-transcriptase inhibitors [84.23% (74.15, 94.3; 95% CI)]
and protease inhibitors [66.21% (59.77, 72.65; 95% CI)].
At admission, most patients presented with ST-segment eleva-
tion myocardial infarction (STEMI) [57.19% (47.64, 66.75; 95%
CI)], with one-vessel disease as the most angiographic presentation
[52.83% (34.83, 70.83; 95% CI)], and percutaneous transluminal
coronary angioplasty as the most exploited revascularization strat-
egy [54.23% (38.97, 69.49; 95% CI)] (Table 4).
Figure 1 Review profile.
F. D’Ascenzo et al.
Rates of in-hospital death (Figure 2) were 8.00% (2.8, 12.5; 95%
CI), ascribable to cardiovascular events for 7.90% (2.43, 13.37; 95%
CI), with 2.31% (0.60, 4.01; 95% CI) developing cardiogenic shock.
At a median follow-up of 25.50 months (11.25, 42; 95% CI), no
deaths were recorded, with an incidence of 9.42% of acute myo-
cardial infarction (2.68, 16.17; 95% CI) and of 20.18% (9.84,
30.51; 95% CI) of percutaneous coronary revascularization.
Patients with hypertriglyceridaemia
Diabetic mellitus type 2 patients
Patients actual or previous smoker
Pooled analysis (95% CI)a
61 (58, 64)
80.45 (77.22, 83.69)
22.29 (14.23, 30.34)
42.50 (33.35, 51.64)
45.03 (23.68, 66.38)
10.86 (4.11, 17.60)
60.30 (56.62, 63.99)
aAll data reported as mean or percentages.
Time from diagnosis of HIV infection (years) 7.45 (2.38, 12.51)
Median CD4+ cell count per mm3
Human immunodeficiency virus disease
66.21 (59.77, 72.65)Patients exposed to protease inhibitors
(previous and current)
Duration of therapy (years)
Patients exposed to non-nucleoside
reverse-transcriptase inhibitors (previous
Patients exposed to nucleoside
4.01 (0.95, 7.07)
29.81 (8.36, 51.26)
84.23 (74.15, 94.31)
aAll data reported as mean or percentages.
Region of origin
appraisal of selected studies
Methodological evaluation and quality
11 studies (%)
1 Africa (10%)
4 Europe (36%)
5 North America (45%)
1 worldwide (10%)
Location of the study
Organization of the study
Source of data
Risk of analytical bias
Risk of selection bias
Risk of attrition bias
Risk of adjudication bias
Patients admitted with unstable angina/
non-segment elevation myocardial
Patients admitted with segment elevation
Percutaneous transluminal coronary
Coronary artery bypass graft
angiographic findings, and revascularization strategies
Acute coronary syndrome presentation,
46.08 (38.13, 54.02)
57.19 (47.64, 66.75)
52.83 (34.83, 70.83)
46.27 (36.30, 56.24)
54.23 (38.97, 69.49)
11.80 (4.32, 19.28)
aAll data reported as mean or percentages.
Figure 2 In-hospital and long-term outcomes. *Up to 30 days.
**Follow-up of 25.50 (11.25, 42 months, 95% CI).
HIV and ACS
Moreover, pooled analysis of two25,28studies reporting the inci-
dence of acute myocardial infarction in patients exposed to prote-
ase inhibitors showed an overall significant risk of 2.68 (odds ratio
1.89, 3.89; 95% CI).
Nowadays, HIV-infected patients live longer owing to more effect-
ive antiretroviral therapy. At the same time, while this population
becomes older, the cardiovascular risk of morbidity and death
increases, and also the prevalence of chronic conditions related
to this disease. With our systematic review and meta-analysis,
we intended to summarize available data about risk factors, angio-
graphic and clinical presentation at admission, and safety of anti-
retroviral therapy, reporting the current knowledge about the
physiopathology of HIV infection.
The risk of coronary heart disease in HIV patients is influenced
both from traditional risk factors and from specific features of this
disease. Our meta-analysis shows an overall average incidence of
traditional cardiovascular risk factors, except for diabetes, as can
be expected in a young population. In contrast, in some studies,
cigarette smoking was more prevalent in HIV patients.32Moreover,
lack of data makes it not possible to analyse the burden of illicit
drug users, which was reported more frequently among
HIV-infected patients and which i’s known to confer a higher
thrombotic risk.33Nonetheless, as confirmed in the present
work, in various large cohorts, HIV-infected patients showed
high percentages of hypertriglyceridaemia, also related to their
young age.34,35Many authors36–38suggest virus involvement in
the atherosclerosis process through direct effects on cholesterol
processing and transport, attraction and activation of monocytes
at the intimal wall, inducing inflammatory response and endothelial
In our meta-analysis, high rates of in-hospital death were
recorded, probably because of STEMI being the most common
ST-segment elevation myocardial infarction rates were higher
than in contemporary ACS registries of non-HIV patients,39,40
and similar differences were found for multivessel involvement.
These two factors combined together could easily explain high
rates of in-hospital events in HIV patients.41The peculiar type of
coronary disease in HIV patients derived both from cardiovascular
risk factors and enhanced from viral pathological process and side
effects of antiretroviral drugs could explain such findings.
Furthermore, our report confirms an important risk of non-fatal
reinfarction after ACS. This finding could be in part explained con-
sidering the young age of the population. Also the prothrombotic
state may be involved in the higher incidence of thrombo-embolic
events and in-stent thrombosis as reported in some studies.19The
whole mechanisms underlying the disease are probably not com-
pletely clear, but again the HIV infection by itself and the antiretro-
viral therapy associated with chronic inflammation could play a role
in the risk of plaque rupture and atherothrombosis.42,43As
reported previously,44,45HIV infection has a direct toxic effect
upon the endothelium and increases interleukin-6 production
that is implicated in the pathogenesis of ACS. Moreover, the
prothrombotic tendency increases proportionally to the viral
load and the CD4 cell count.
No deaths were recorded in the follow-up. This could be due to
many reasons. First, HIV patients may benefit from the use of more
recent therapies and/or aggressive risk factor modification. More-
over, the present meta-analysis included studies obtained from
centres with great experience and expertise in managing patients
with HIV and coronary artery disease.
Finally, we observe that most of the patients presenting with
coronary artery disease are exposed to protease inhibitors or nu-
cleoside reverse-transcriptase inhibitors. In the pooled analysis, we
are able to include only the protease inhibitors therapy, whereas
incomplete data about other therapies are available in the selected
articles. The metabolic syndrome consisting of lipid abnormalities
and insulin resistance induced by the protease inhibitors certainly
plays a role as a cofactor promoting the progression of underlying
coronary lesions eliciting plaque inflammation and rupture.
Anyway, as reported from many authors,46,47a clear dose–effect
relationship has not been found. The better way to manage
these patients is addressing the modifiable risk factor, keeping
close attention to drug interactions in the presence of a high car-
diovascular risk profile.
Our work shares several important limitations. First, data about
the odds ratio for myocardial infarction after proton-pump inhibi-
tors use derived neither from randomized clinical trial nor from
multivariate adjustment, thus being generating hypothesis only,
without the aim of inference. Moreover, we appraised infrequent
events, with all the limits about reporting uncommon outcomes.47
Secondly, no data were pooled about the influence of nucleoside
and non-reverse-transcriptase inhibitors on outcomes, because
of the absence in the included original researches, Thirdly, data
about illicit drugs used, especially cocaine, were present in only
one study,2and thus, it was not possible to address their influence
on outcomes. Furthermore, in the selected articles, data about
therapy were not reported probably because of its recent approval
by the Food and Drug Administration.45These classes of drugs
could provide new insights because of the critical role of chemo-
kines and their receptors in the pathology of atherosclerosis.
Moreover, no data on cardiac rupture and reperfusion success
were obtained, thus limiting the exploration of mechanisms of
Supplementary material is available at European Heart Journal
Conflict of interest: none declared.
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