| Background and Objection:Coronary heart disease (CHD) is one of the most common cardiovascular disease in people over45years in most developed and developing cpumrries.World health organization forecast that CHD will become the first cause of death all.over world by the year2020, after effective controls of severe infectious doseases Acute coronary syndrome (ACS) including ST-segment elevation myocamdial infarciton (STEMI), non-ST-segment elevation myocardial infarction (NSTEMI),unstable angina pectoris (UAP) and sudden cardiac death is the most serious clinical manifestations of CHD. After the onset of ACS, the future risk of adverse cardiovascular outcomes such as cardiovascular death, non-fatal myocardial infarction, rehospitalisation and revascularization owing to angina, heart failure, stroke obviously increase.Traditional cardiovascular risk factors and biomarkers have been used to predict the occurrence of adverse outcomes after ACS. However, there are still patients whose risk of adverse cardiovascular outcomes is underestimated. The mortality rate of cardiac troponin (cTn) negative patients in6month after ACS was5.9%and the risk rate of recurrent myocardial infarction was alomst5.9%. A lot of studies are dedicating in finding new biomarkers which could accurately predict the prognosis of patients with ACS.New markers of plaque instability have been identified in recent years, among which, pregnancy-associated plasma protein-A (PAPP-A) appears to offer an interesting profile. Data from animal and human histological study suggest that PAPP-A is markedly enriched in ruptured and eroded unstable plaques of coronary arteries. Circulating levels of PAPP-A have been shown to be elevated in patients with ACS compared with patients with chronic stable angina (SAP) or healthy subjects. A large number of studies have examined the prognostic value of PAPP-A in patients with ACS but the results were conflicting. Some studies found that PAPP-A was a valuable predictor of adverse cardiovascular outcomes in patients with ACS, while others found no prognostic value of PAPP-A. There is an increasing need to synthesise all the evidence. Herein, we present this meta-analysis to assess the association between higher PAPP-A levels and risk of long-term adverse cardiovascular outcomes after ACS occurs.Methods and materialsThis study was conducted following the meta-analysis of observational studies in epidemiology guidelines, simultaneously conforming to most of the preferred reporting items for systematic reviews and meta-analyses guidelines.We performed an electronic search of PubMed, EMBASE, OVID, Web of Knowledge and the Cochrane library from inception of each database to September,2012. We included studies if they met all the following criteria:(1) cohort studies or post hoc analyses of randomized controlled trial(RCT);(2) studies with a follow-up duration of at least1month;(3) subjects were patients with angiographically vaidated actue coronary syndrome and patients with acute chest pain in a heterogeneous emergency room;(4) outcomes were death, cardiovascular death, rehospitalisation and revascularization owing to angina and non-fatal myocardial infarction;(5) risk estimates with95%confidence intervals(CIs) were reported or could be calculated.(6) blood samples for PAPP-A assays were obtained within72h from the onset of symptoms or on admission to hospital. The quality of included studies were assessed based on the Newcastle-Ottawa Scale for quality of observational studies in meta-analyses. Random effects meta-analysis and relative risk (RR) were used to estimate the association between PAPP-A levels and adverse cardiovascular outcomes after ACS. Heterogeneity was assessed using the Higgins I-squared statistic (I2). Sensitivity analyses were carried out to characterize possible sources of statistical heterogeneity, by excluding studies one-by-one.Subgroup analyses based on study design, study location, duration of follow-up, mean age, heparin use, measurement of association chosen and confounder factors adjustments were conducted to identify the risk-subgroup interactions that could explain the inter-study differences.Publication bias was assessed using funnel spot and the Egger regression asymmetry test. Software Review Manager (RevMan5.1, Copenhagen) and Stata (Statal0.0, Texas) were used for the statistical analyses. All the P values were two tailed, and P values<0.05were considered statistically significant.Results:Fourteen studies were included in our meta-analysis involving9413patients. The overall meta-analysis showed that patients with higher PAPP-A values had1.97times the risk of death, cardiovascular death, rehospitalisation and revascularization owing to angina and non-fatal myocardial infarction for patients with lower PAPP-A levels (RR1.97,95%CI:1.49-2.60, P<0.00001). Higher PAPP-A values were associated with increased adverse cardiovascular outcomes, suggesting that PAPP-A could be a valuable predictor of adverse cardiovascular outcomes in patients with ACS.1. Subgroup analysis based on study designThere are3post hoc analyses of RCT involving5962patients and11cohort studies involving3451patients. In post hoc analyses of RCT, patients with higher PAPP-A values had1.30times the risk of adverse cardiovascular outcomes for patients with lower PAPP-A levels (RR1.30,95%CI:1.08-1.57, P=0.006). In cohort studies, patients with higher PAPP-A values had2.32times the risk of adverse cardiovascular outcomes for patients with lower PAPP-A levels (RR2.32,95%CI:1.66-3.26, P<0.00001). The association between higher PAPP-A values and increased adverse cardiovascular outcomes in post hoc analyses of RCT was statistically bigger than that in cohort studies (RR2.32vs1.30, P=0.003).2. Subgroup analysis based on study locationEight studies were from Europe countries involving3562patients and6studies were from non-Europe countries involving5851patients. In studies from Europe countries, patients with higher PAPP-A values had1.79times the risk of adverse cardiovascular outcomes for patients with lower PAPP-A levels (RR1.79,95%CI:1.18-2.71, P=0.006). In studies from non-Europe countries, patients with higher PAPP-A values had2.26times the risk of adverse cardiovascular outcomes for patients with lower PAPP-A levels (RR2.26,95%CI:1.48-3.44, P=0.0001). The associations between higher PAPP-A values and increased adverse cardiovascular outcomes in European studies was not significantly different from that in non-European studies (RR1.79vs2.26, P=0.44), suggesting that PAPP-A had similar prognostic values in both European and non-European studies.3. Subgroup analysis based on duration of follow-upThere are5studies with a duration of follow-up less than1year involving1367patients and9studies with a duration of follow-up more than1year involving8046patients. The future risk of adverse cardiovascular outcomes within1year in patients with higher PAPP-A values is3.33times as compared with patients with lower PAPP-A levels (RR3.33,95%CI:2.51-4.42, P<0.00001). The future risk of adverse cardiovascular outcomes more than1year in patients with higher PAPP-A values is1.42times as compared with patients with lower PAPP-A levels (RR1.42,95%CI:1.13-1.79, P=0.003). The association between higher PAPP-A values and increased short-term(<1year) outcomes was statistically bigger than the association between higher PAPP-A values and increased long-term(≥1year) outcomes (RR3.33vs1.42, P<0.00001).4. Subgroup analysis based on mean age There were9studies in which mean age of patients involved were younger than65years and3studies in which mean age of patients involved were older than65years. In subgroup analysis of4738patients younger than65years, those with higher PAPP-A values had1.89times the risk of adverse cardiovascular outcomes for those with lower PAPP-A levels (RR1.89,95%CI:1.26-2.84, P=0.002). In subgroup analysis of818patients older than65years, those with higher PAPP-A values had2.26times the risk of adverse cardiovascular outcomes for those with lower PAPP-A levels (RR2.26,95%CI:1.42-3.61, P=0.0006). The associations between higher PAPP-A values and increased adverse cardiovascular outcomes in patients older than65years was not significantly different from that in patients younger than65years(RR2.26vs1.89, P=0.57), suggesting that PAPP-A had similar prognostic values in both subgroups.5. Subgroup analysis based on heparin useThere were8studies involving7023patients in which boold samples of PAPP-A were obtained after heparin use and6studies involving2390patients in which boold samples of PAPP-A were obtained without heparin use. In studies in which blood levels of PAPP-A were affected by heparin use, patients with higher PAPP-A values had2.18times the risk of adverse cardiovascular outcomes for patients with lower PAPP-A levels (RR2.18,95%CI:1.50-3.16, P<0.0001). In studies in which blood levels of PAPP-A were not affected by heparin use, patients with higher PAPP-A values had1.71times the risk of adverse cardiovascular outcomes for those with lower PAPP-A levels (RR1.71,95%CI:1.06-2.75,P=0.03). No significant differences were found in the risk estimates between the two subgroups with and without heparin us (RR2.18vs1.71, P=0.43).6. Subgroup analysis based on measurement of association chosenThere were respectively6studies used HR and RR as the measurement of rsik estimates and the other2studies chose OR as the measurement of rsik estimates. In studies involving1181patients in which OR was estimated, subgroup analysis suggested that PAPP-A could not predict adverse cardiovascular outcomes(RR1.88, 95%CI:0.69-5.16, P=0.22). PAPP-A had lower prognostic value in subgroup analysis of studies in which HR was estimated as compared with that in subgroup analysis of studies in which RR was used(RR1.37vs3.15, P=0.0002). In studies in which HR was estimated, patients with higher PAPP-A levels were associated with1.37-fold higher risks of adverse cardiovascular outcomes as compared with those with lower PAPP-A levels(RR1.37,95%CI:1.06-1.77, P=0.02). In studies in which RR was estimated, patients with higher PAPP-A levels were associated with3.15-fold higher risks of adverse cardiovascular outcomes as compared with those with lower PAPP-A levels(RR3.15,95%CI:2.33-4.26, P<0.00001).7. Subgroup analysis based on confounder factors adjustmentSeven studies reported both unadjusted and adjusted risk estimates involving7442patients. The pooled RR and its95%CI of unadjusted risk estimates was1.86(RR1.86,95%CI:1.43-2.43, P<0.00001). The pooled RR and its95%CI of adjusted risk estimates was1.66(RR1.66,95%CI:1.14-2.41, P=0.008). The prognostic value of PAPP-A was not significantly reduced after adjustment for confounder factors such as age, sex, smoke, hypertension, hyperlipidemia and diabetes mellitus (RR1.86vs1.66, P=0.61). The prognostic role of PAPP-A was independent of traditional risk factors and other markers.Conclusion1. This meta-analysis of14studies support an association between higher PAPP-A levels and increased risk of adverse cardiovascular outcomes in9413patients with ACS. In the follow-up duration that ranged from1to47months after ACS occurred, patients with higher PAPP-A values had1.97times in the risk of death, cardiovascular death, rehospitalisation and revascularization owing to angina and non-fatal myocardial infarction of patients with lower PAPP-A levels (RR1.97,95%CI:1.49-2.60, P<0.00001). PAPP-A could be a valuable predictor of adverse cardiovascular outcomes in patients with ACS.2. Higher PAPP-A values were statistically associated with increased adverse cardiovascular outcomes in all subgroup studies except the one using OR as the measurement of association chosen.3. The prognostic value of PAPP-A were similar in European and non-European countries as well as in patients older and younger than65years, and its prognostic value was not affected by heparin use and confounder factors. However, its predicting value decreased as time went by. Significant subgroup differences were observed in subgroups stratified by follow-up duration, study design and the measurement of association chosen, suggesting that those are the main sources of heterogeneities. |
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