Pharmacotherapy in pulmonary arterial hypertension: a systematic review and meta-analysis

Background

Previous meta-analyses of treatments for pulmonary arterial hypertension (PAH) have not shown mortality benefit from any individual class of medication.

Methods

MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials were searched from inception through November 2009 for randomized trials that evaluated any pharmacotherapy in the treatment of PAH. Reference lists from included articles and recent review articles were also searched. Analysis included randomized placebo controlled trials of at least eight weeks duration and studies comparing intravenous medication to an unblinded control group.

Results

1541 unique studies were identified and twenty-four articles with 3758 patients were included in the meta-analysis. Studies were reviewed and data extracted regarding study characteristics and outcomes. Data was pooled for three classes of medication: prostanoids, endothelin-receptor antagonists (ERAs), and phosphodiesterase type 5 (PDE5) inhibitors. Pooled relative risks (RRs) and 95% confidence intervals (CIs) were calculated for mortality, 6-minute walk distance, dyspnea scores, hemodynamic parameters, and adverse effects. Mortality in the control arms was a combined 4.2% over the mean study length of 14.9 weeks. There was significant mortality benefit with prostanoid treatment (RR 0.49, CI 0.29 to 0.82), particularly comparing intravenous agents to control (RR 0.30, CI 0.14 to 0.63). Mortality benefit was not observed for ERAs (RR 0.58, CI 0.21 to 1.60) or PDE5 inhibitors (RR 0.30, CI 0.08 to 1.08). All three classes of medication improved other clinical and hemodynamic endpoints. Adverse effects that were increased in treatment arms include jaw pain, diarrhea, peripheral edema, headache, and nausea in prostanoids; and visual disturbance, dyspepsia, flushing, headache, and limb pain in PDE5 inhibitors. No adverse events were significantly associated with ERA treatment.

Conclusions

Treatment of PAH with prostanoids reduces mortality and improves multiple other clinical and hemodynamic outcomes. ERAs and PDE5 inhibitors improve clinical and hemodynamic outcomes, but have no proven effect on mortality. The long-term effects of all PAH treatment requires further study.     

Preeclampsia and ABO blood groups: a systematic review and meta-analysis

Preeclampsia (PE) is a multifactorial pregnancy-specific syndrome which represents one of the leading causes of maternal mortality worldwide. Inherited thrombophilia have been investigated as risk factor for the development of PE and it is currently known that ABO blood group may impact haemostatic balance, having the non-O blood groups (A, B or AB) subjects increased risk for thrombus formation, as compared to those of group O. We performed a systematic review of the literature for published studies investigating whether ABO blood groups could influence PE developing. A sensitive search of four databases identified 45 unique titles. The retrieved papers were assessed independently by authors and a rigorous process of selection and data extract was conduct. Methodological quality of the included studies was also evaluated. Two studies met eligibility criteria. As a main finding of our systematic review, an association between the AB blood group and the occurrence of PE was detected based on two original studies. Considering the role of ABO blood groups on the hemostatic process and thrombus formation, special attention should be given to pregnant patients carrying the AB blood group in order to prevent the syndrome and improve prognosis.     

Effect of tomato,lycopene and related products on blood pressure: A systematic review and network meta-analysis

BackgroundA number of randomized controlled trials (RCTs) have been conducted to evaluate the hypotensive effects of tomato, lycopene, and related products. However, the findings were conflicting, partly due to differences in the types of products investigated. Therefore, this study aimed to assess and compare the hypotensive effects of different tomato-related preparations through a network meta-analysis based on randomized controlled trials.Study designA systematic review and network meta-analysis.MethodsA network meta-analysis based on a systematic review of RCTs comparing the effect of various tomato, lycopene and related products versus placebo on blood pressure in adults was performed. PubMed, EMBASE, SCOPUS, and Clinicaltrial.gov databases were searched up to October 2020 without language restrictions. The primary outcomes were systolic and diastolic blood pressure. Mean differences (MDs) along with 95% confidence intervals (CIs) were estimated and pooled using a random-effects model. Heterogeneity was assessed using the global inconsistency test.ResultsA total of 11 studies including six forms of tomato, lycopene and related products met the inclusion criteria. Among these trials, eight (N = 617) and seven trials (N = 501) were included in the analysis of systolic (SBP) and diastolic blood pressure (DBP) outcomes, respectively. The standardized tomato extract (STE) significantly decreased SBP compared to placebo, with a pooled MD (95% CI) of –5.89 (–9.13 to –2.64) mmHg. The effect on DBP was not significant, with a pooled MD (95% CI) of –3.51 (–7.39 to 0.38) mmHg. Subgroup analysis in hypertensive patients showed that STE significantly reduced both SBP and DBP with pooled MDs (95% CIs) of –8.09 (–11.52 to –4.67) and –4.25 (–6.97 to –1.53) mmHg, respectively, compared to placebo. Other forms of tomato, including other dose ranges of standardized tomato extract, tomato-containing diet, lycopene-free preparation, and synthetic lycopene, did not show consistent and significant effects on either SBP or DBP in all analyses.ConclusionStandardized tomato extract (STE) significantly decreased SBP compared to placebo in a mixed population of healthy volunteers and hypertensive patients. The BP-lowering effect was more pronounced among hypertensive patients. No significant BP effects were seen with other forms of tomato, lycopene and related products in the overall population or any subgroup of the population.     

Effects of intensive blood pressure lowering on the progression of chronic kidney disease: a systematic review and meta-analysis

Background:

Recent guidelines suggest lowering the target blood pressure for patients with chronic kidney disease, although the strength of evidence for this suggestion has been uncertain. We sought to assess the renal and cardiovascular effects of intensive blood pressure lowering in people with chronic kidney disease.

Methods:

We performed a systematic review and meta-analysis of all relevant reports published between 1950 and July 2011 identified in a search of MEDLINE, Embase and the Cochrane Library. We included randomized trials that assigned patients with chronic kidney disease to different target blood pressure levels and reported kidney failure or cardiovascular events. Two reviewers independently identified relevant articles and extracted data.

Results:

We identified 11 trials providing information on 9287 patients with chronic kidney disease and 1264 kidney failure events (defined as either a composite of doubling of serum creatinine level and 50% decline in glomerular filtration rate, or end-stage kidney disease). Compared with standard regimens, a more intensive blood pressure–lowering strategy reduced the risk of the composite outcome (hazard ratio [HR] 0.82, 95% confidence interval [CI] 0.68–0.98) and end-stage kidney disease (HR 0.79, 95% CI 0.67–0.93). Subgroup analysis showed effect modification by baseline proteinuria (p = 0.006) and markers of trial quality. Intensive blood pressure lowering reduced the risk of kidney failure (HR 0.73, 95% CI 0.62–0.86), but not in patients without proteinuria at baseline (HR 1.12, 95% CI 0.67–1.87). There was no clear effect on the risk of cardiovascular events or death.

Interpretation:

Intensive blood pressure lowering appears to provide protection against kidney failure events in patients with chronic kidney disease, particularly among those with proteinuria. More data are required to determine the effects of such a strategy among patients without proteinuria.Chronic kidney disease is a major public health problem worldwide, affecting 10%–15% of the adult population.¹ Blood pressure–lowering agents are the mainstay of management strategies aiming to slow the progression of chronic kidney disease, as well as a core aspect of strategies aiming to reduce cardiovascular risk.^2–4 Observational studies have shown a log-linear increase in the risk of kidney failure with high blood pressure levels across the observed range,^5–7 suggesting that further lowering blood pressure could reduce the risk of kidney failure at most blood pressure levels. Current guidelines recommend a blood pressure target below 130/80 mm Hg for patients with chronic kidney disease,^8–10 but this recommendation is mostly based on observational studies and a single randomized trial (the Modification of Diet in Renal Disease [MDRD] study) that focused on kidney protection.¹¹ Subsequent trials of different targets in people with chronic kidney disease have yielded inconsistent results,^12,13,14 leading to criticism by the recent Canadian Hypertension Education Program guideline (which suggested a less aggressive target) of other guidelines, with suggestions that their blood pressure recommendations went beyond the available evidence. This criticism has been supported by a recent systematic review (no meta-analysis was performed) that focused on 3 trials and reported inconclusive results overall but raised the possibility that proteinuria was an effect modifier.¹⁵ The final result has been clinician uncertainty about optimal blood pressure levels in patients with chronic kidney disease.We sought to synthesize the results of all available trials that evaluated the effects of different blood pressure targets in people with chronic kidney disease and to better define the balance of risks and benefits associated with different intensities of blood pressure lowering in this population.     

Use of uterine artery Doppler ultrasonography to predict pre-eclampsia and intrauterine growth restriction: a systematic review and bivariable meta-analysis

Background

Alterations in waveforms in the uterine artery are associated with the development of pre-eclampsia and intrauterine growth restriction. We investigated the predictive accuracy of all uterine artery Doppler indices for both conditions in the first and second trimesters.

Methods

We identified relevant studies through searches of MEDLINE, EMBASE, the Cochrane Library and Medion databases (all records to April 2006) and by checking bibliographies of identified studies and consulting with experts. Four of us independently selected studies, extracted data and assessed study validity. We performed a bivariable meta-analysis of sensitivity and specificity and calculated likelihood ratios.

Results

We identified 74 studies of pre-eclampsia (total 79 547 patients) and 61 studies of intrauterine growth restriction (total 41 131 patients). Uterine artery Doppler ultrasonography provided a more accurate prediction when performed in the second trimester than in the first-trimester. Most Doppler indices had poor predictive characteristics, but this varied with patient risk and outcome severity. An increased pulsatility index with notching was the best predictor of pre-eclampsia (positive likelihood ratio 21.0 among high-risk patients and 7.5 among low-risk patients). It was also the best predictor of overall (positive likelihood ratio 9.1) and severe (positive likelihood ratio 14.6) intrauterine growth restriction among low-risk patients.

Interpretation

Abnormal uterine artery waveforms are a better predictor of pre-eclampsia than of intrauterine growth restriction. A pulsatility index, alone or combined with notching, is the most predictive Doppler index. These indices should be used in clinical practice. Future research should also concentrate on combining uterine artery Doppler ultrasonography with other tests.Pre-eclampsia and intrauterine growth restriction remain important causes of maternal and perinatal morbidity and mortality.^1–3 Maternal complications of pre-eclampsia include coagulopathy, renal and liver failure, and stroke.¹ Adults who were affected by intrauterine growth restriction in utero are at increased risk for cardiovascular disease, hypertension and type 2 diabetes.^4,5Pre-eclampsia and intrauterine growth restriction are characterized by abnormal placenta formation,⁶ which results in inadequate uteroplacental blood flow. This has led to the idea of using Doppler ultrasonography to assess the velocity of uterine artery blood flow as part of routine ultrasound screening.⁷ Low end-diastolic velocities and an early diastolic notch characterize the waveforms of uterine artery blood flow in women who are not pregnant or are in their first trimester. Persistence of a diastolic notch (beyond 24 weeks'' gestation) or abnormal flow velocity ratios have been associated with inadequate trophoblast invasion.⁸Accurate prediction of pre-eclampsia and intrauterine growth restriction is crucial to allow judicious allocation of resources for monitoring and preventive treatment to improve maternal and perinatal outcomes.^9,10 However, studies investigating the predictive accuracy of uterine artery Doppler indices (Box 1) have revealed considerably varied results. Thus, it is questionable whether uterine artery Doppler ultrasonography should be used as a predictive test. We undertook this review to investigate the accuracy of all uterine artery Doppler indices in predicting pre-eclampsia and intrauterine growth restriction.Open in a separate windowBox 1     

Toxocariasis and epilepsy: systematic review and meta-analysis

Objective

Human toxocariasis is a zoonotic infection caused by the larval stages of Toxocara canis (T. canis) and less frequently Toxocara cati (T. cati). A relationship between toxocariasis and epilepsy has been hypothesized. We conducted a systematic review and a meta-analysis of available data to evaluate the strength of association between epilepsy and Toxocara spp. seropositivity and to propose some guidelines for future surveys.

Data Sources

Electronic databases, the database from the Institute of Neuroepidemiology and Tropical Neurology of the University of Limoges (http://www-ient.unilim.fr/) and the reference lists of all relevant papers and books were screened up to October 2011.

Methods

We performed a systematic review of literature on toxocariasis (the exposure) and epilepsy (the outcome). Two authors independently assessed eligibility and study quality and extracted data. A common odds ratio (OR) was estimated using a random-effects meta-analysis model of aggregated published data.

Results

Seven case-control studies met the inclusion criteria, for a total of 1867 participants (850 cases and 1017 controls). The percentage of seropositivity (presence of anti-Toxocara spp. antibodies) was higher among people with epilepsy (PWE) in all the included studies even if the association between epilepsy and Toxocara spp. seropositivity was statistically significant in only 4 studies, with crude ORs ranging 2.04–2.85. Another study bordered statistical significance, while in 2 of the included studies no significant association was found. A significant (p<0.001) common OR of 1.92 [95% confidence interval (CI) 1.50–2.44] was estimated. Similar results were found when meta-analysis was restricted to the studies considering an exclusively juvenile population and to surveys using Western Blot as confirmatory or diagnostic serological assay.

Conclusion

Our results support the existence of a positive association between Toxocara spp. seropositivity and epilepsy. Further studies, possibly including incident cases, should be performed to better investigate the relationship between toxocariasis and epilepsy.     

Accuracy of mucocutaneous leishmaniasis diagnosis using polymerase chain reaction: systematic literature review and meta-analysis

The diagnosis of mucocutaneous leishmaniasis (MCL) is hampered by the absence of a gold standard. An accurate diagnosis is essential because of the high toxicity of the medications for the disease. This study aimed to assess the ability of polymerase chain reaction (PCR) to identify MCL and to compare these results with clinical research recently published by the authors. A systematic literature review based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses: the PRISMA Statement was performed using comprehensive search criteria and communication with the authors. A meta-analysis considering the estimates of the univariate and bivariate models was performed. Specificity near 100% was common among the papers. The primary reason for accuracy differences was sensitivity. The meta-analysis, which was only possible for PCR samples of lesion fragments, revealed a sensitivity of 71% [95% confidence interval (CI) = 0.59; 0.81] and a specificity of 93% (95% CI = 0.83; 0.98) in the bivariate model. The search for measures that could increase the sensitivity of PCR should be encouraged. The quality of the collected material and the optimisation of the amplification of genetic material should be prioritised.     

Post-stroke infection: A systematic review and meta-analysis

Background  

stroke is the main cause of disability in high-income countries, and ranks second as a cause of death worldwide. Patients with acute stroke are at risk for infections, but reported post-stroke infection rates vary considerably. We performed a systematic review and meta-analysis to estimate the pooled post-stroke infection rate and its effect on outcome.     

Influences of exogenous insulin on arterial blood pressure measurements of the rat

Studies were undertaken with adult male rats to test the hypothesis that euglycemic hyperinsulinemia would alter mean arterial blood pressure (MAP) and heart rate (HR) relationships by activation of the sympathetic nervous system. Conscious rats were infused either with insulin or control vehicle (0, 0.47, 1.5, 4.7, 15.0 mU.kg-1.min-1) for 75 min before injection of hexamethonium. Compared with the control period, insulin infusion significantly increased MAP by 7.1 +/- 0.1, 12.7 +/- 2.0, and 19.7 +/- 0.3 (SE) mmHg and HR by 44 +/- 8.4, 66 +/- 10.3, and 95 +/- 6.3 beats/min, respectively, during the three highest rates of infusion. The dose-dependent increases in MAP and HR were due to increases in the activity of hexamethonium-sensitive pathways. In chemically sympathectomized rats, insulin infusion did not produce a significant increase in either MAP or HR. The influence of exogenous norepinephrine on MAP and HR was also studied after insulin infusion. Compared with the insulin-vehicle infusion, insulin infusion significantly depressed (P less than 0.05) the norepinephrine dose-response increase in MAP. In addition, isolated smooth muscle strips were studied to determine the influence of insulin on their in vitro responses to increasing doses of norepinephrine. Although insulin did not alter contractility, it significantly (P less than 0.05) decreased the sensitivity of the vascular strips to norepinephrine. Collectively, the data from these euglycemic experiments indicated that infusions of insulin caused increases in HR and MAP because of activation of the sympathetic nervous system, even though the responsiveness of the vascular smooth muscle was depressed.     

Metformin in polycystic ovary syndrome: systematic review and meta-analysis

Objective To assess the effectiveness of metformin in improving clinical and biochemical features of polycystic ovary syndrome.Design Systematic review and meta-analysis.Data sources Randomised controlled trials that investigated the effect of metformin compared with either placebo or no treatment, or compared with an ovulation induction agent.Selection of studies 13 trials were included for analysis, including 543 women with polycystic ovary syndrome that was defined by using biochemical or ultrasound evidence.Main outcome measure Pregnancy and ovulation rates. Secondary outcomes of clinical and biochemical features of polycystic ovary syndrome.Results Meta-analysis showed that metformin is effective in achieving ovulation in women with polycystic ovary syndrome, with odds ratios of 3.88 (95% confidence interval 2.25 to 6.69) for metformin compared with placebo and 4.41 (2.37 to 8.22) for metformin and clomifene compared with clomifene alone. An analysis of pregnancy rates shows a significant treatment effect for metformin and clomifene (odds ratio 4.40, 1.96 to 9.85). Metformin has an effect in reducing fasting insulin concentrations, blood pressure, and low density lipoprotein cholesterol. We found no evidence of any effect on body mass index or waist:hip ratio. Metformin was associated with a higher incidence of nausea, vomiting, and other gastrointestinal disturbance.Conclusions Metformin is an effective treatment for anovulation in women with polycystic ovary syndrome. Its choice as a first line agent seems justified, and there is some evidence of benefit on variables of the metabolic syndrome. No data are available regarding the safety of metformin in long term use in young women and only limited data on its safety in early pregnancy. It should be used as an adjuvant to general lifestyle improvements and not as a replacement for increased exercise and improved diet.     

Nitrite infusion increases cerebral blood flow and decreases mean arterial blood pressure in rats: A role for red cell NO

It has been proposed that the reduction of nitrite by red cells producing NO plays a role in the regulation of vascular tone. This hypothesis was investigated in rats by measuring the effect of nitrite infusion on mean arterial blood pressure (MAP), cerebral blood flow (CBF) and cerebrovascular resistance (CVR) in conjunction with the accumulation of red cell NO. The relative magnitude of the effects on MAP and CBF as well as the time dependent changes during nitrite infusion are used to distinguish between the effects on the peripheral circulation and the effects on the cerebral circulation undergoing cerebral autoregulation. The nitrite infusion was found to reverse the 96% increase in MAP and the 13% decrease in CBF produced by L-NAME inhibition of e-NOS. At the same time there was a 20-fold increase in oxygen stable red cell NO. Correlations of the red cell NO for individual rats support a role for red cell nitrite reduction in regulating vascular tone in both the peripheral and the cerebral circulation. Furthermore, data obtained prior to treatment is consistent with a contribution of red cell reduced nitrite in regulating vascular tone even under normal conditions.     

The height premium: A systematic review and meta-analysis

The taller people are, the more money they tend to earn. This phenomenon is widely known as the height premium. However, it is not yet known whether the height premium is universal, or whether it varies by context. To that end, a systematic review of the literature was performed. Five databases were searched until August 2020. Ultimately, a list of 42 studies were included in a narrative synthesis, and 17 studies were included in a meta-analysis. Based on the meta-analysis, we found evidence that the height premium varied by context: the height premium was smaller in the U.S. and Australia, and larger in Latin America and Asia. Within geographies, there appeared to be a larger height premium for men than for women. Cultural factors, labor market structures and biology may play a role in determining the strength of the height premium.     

Alcohol intake and blood pressure: a systematic review implementing a Mendelian randomization approach

Background

Alcohol has been reported to be a common and modifiable risk factor for hypertension. However, observational studies are subject to confounding by other behavioural and sociodemographic factors, while clinical trials are difficult to implement and have limited follow-up time. Mendelian randomization can provide robust evidence on the nature of this association by use of a common polymorphism in aldehyde dehydrogenase 2 (ALDH2) as a surrogate for measuring alcohol consumption. ALDH2 encodes a major enzyme involved in alcohol metabolism. Individuals homozygous for the null variant (*2*2) experience adverse symptoms when drinking alcohol and consequently drink considerably less alcohol than wild-type homozygotes (*1*1) or heterozygotes. We hypothesise that this polymorphism may influence the risk of hypertension by affecting alcohol drinking behaviour.

Methods and Findings

We carried out fixed effect meta-analyses of the ALDH2 genotype with blood pressure (five studies, n = 7,658) and hypertension (three studies, n = 4,219) using studies identified via systematic review. In males, we obtained an overall odds ratio of 2.42 (95% confidence interval [CI] 1.66–3.55, p = 4.8 × 10⁻⁶) for hypertension comparing *1*1 with *2*2 homozygotes and an odds ratio of 1.72 (95% CI 1.17–2.52, p = 0.006) comparing heterozygotes (surrogate for moderate drinkers) with *2*2 homozygotes. Systolic blood pressure was 7.44 mmHg (95% CI 5.39–9.49, p = 1.1 × 10⁻¹²) greater among *1*1 than among *2*2 homozygotes, and 4.24 mmHg (95% CI 2.18–6.31, p = 0.00005) greater among heterozygotes than among *2*2 homozygotes.

Conclusions

These findings support the hypothesis that alcohol intake has a marked effect on blood pressure and the risk of hypertension.     

Selenium levels and skin diseases: systematic review and meta-analysis

BackgroundSeveral studies have investigated the association between selenium levels and skin diseases, but reached inconsistent results.ObjectiveThis systematic review and meta-analysis was conducted to evaluate the association between selenium levels and skin diseases.MethodsA systematic search was conducted in public databases to identify all relevant studies, and study-specific standard mean differences (SMD) and 95% confidence intervals (CI) were pooled to compare the selenium levels between different groups.ResultsTwenty-seven studies were identified with a total of 1315 patient and 7181 healthy controls. Compared with controls, no significant difference in selenium was found in patients with vitiligo (SMD = 0.53, 95% CI: –0.40 to 1.45), alopecia areata (SMD = 0.47, 95% CI: –2.72 and 3.65), or eczema (SMD = 0.12, 95% CI: –0.24 to 0.48). A lower selenium level was found in patients with psoriasis (SMD = –0.62, 95% CI: –1.15 to –0.10), acne vulgaris (SMD = –1.02, 95% CI: –1.45 to –0.60), chloric acne (SMD = –2.35, 95% CI: –3.15 to –1.55), and atopic dermatitis (SMD = –2.62, 95% CI: –3.00 to –2.24). As for disease severity, severe patients had a higher selenium level than mild patients in psoriasis (SMD = 0.72, 95% CI: 0.07–1.38), but no difference was found in vitiligo (SMD = –0.26, 95% CI: –2.38 to 1.85) and alopecia areata (SMD = 0.46, 95% CI: –0.34 to 1.26).ConclusionSelenium levels were associated with several skin diseases and the disease severity, and high selenium levels tended to be a protective factor in certain skin diseases.