Toxicity testing in the 21st century: a vision and a strategy

Advances in molecular biology, biotechnology, and other fields are paving the way for major improvements in how scientists evaluate the health risks posed by potentially toxic chemicals found at low levels in the environment. These advances would make toxicity testing quicker, less expensive, and more directly relevant to human exposures. This National Research Council report creates a far-reaching vision for the future of toxicity testing.     

Pramipexole in restless legs syndrome: an evidence-based review of its effectiveness on clinical outcomes

INTRODUCTION: Restless legs syndrome (RLS) affects 5-15% of adults, but is often unrecognized and consequently misdiagnosed. The International Restless Legs Scale (IRLS) has been developed and validated to assess the severity of RLS. Currently, the most common treatment for RLS is levodopa, but this may lead to augmentation of symptoms. Pramipexole has been developed as an alternative treatment for patients diagnosed with RLS. AIMS: The objective of this article is to review the evidence of the effectiveness of pramipexole for the clinical management of patients with RLS. EVIDENCE REVIEW: There is clear evidence that pramipexole reduces the leg movements associated with RLS, as measured by improvements in both the IRLS and the Clinical Global Impression (CGI) score. There is also moderate evidence that the drug improves sleep quality. Pramipexole clearly improves the anxiety and depression often associated with RLS. Augmentation may be associated with pramipexole treatment, but the evidence is contradictory and augmentation may be more associated with patients pretreated with levodopa or with patients with primary RLS rather than those with secondary RLS. Pramipexole therapy appears to be well tolerated, with only mild-to-moderate adverse events reported. OUTCOMES SUMMARY: Pramipexole reduces leg movements in RLS, and is well tolerated. Further investigation is required to confirm the preliminary evidence that pramipexole restores normal sleep architecture and restores a normal quality of life in patients with RLS. Health economic studies would be valuable in demonstrating the true impact of pramipexole on the social burden of RLS.     

Hospital-acquired pneumonia in the 21st century: a review of existing treatment options and their impact on patient care

Hospital-acquired pneumonia is a common nosocomial infection, with significant morbidity and mortality, and represents a major therapeutic challenge to clinicians. The therapeutic approach must be patient-oriented and institution-specific. The specific risk factors of each patient, such as previous antibiotic exposure, underlying diseases, length of hospital stay and the local patterns of antimicrobial resistance, should guide physicians in their decision of the initial optimal empirical therapy. Delays in the initiation or inappropriate/inadequate initial therapy are related to increased mortality and worse outcomes. In responding patients, as soon as culture data are available, efforts should be made to change the initial broad spectrum antibiotic regimen to a more targeted one (de-escalation). The optimal duration of treatment is a matter of debate, but courses longer than 1 week are rarely justified.     

Hospital-acquired pneumonia in the 21st century: a review of existing treatment options and their impact on patient care

Hospital-acquired pneumonia is a common nosocomial infection, with significant morbidity and mortality, and represents a major therapeutic challenge to clinicians. The therapeutic approach must be patient-oriented and institution-specific. The specific risk factors of each patient, such as previous antibiotic exposure, underlying diseases, length of hospital stay and the local patterns of antimicrobial resistance, should guide physicians in their decision of the initial optimal empirical therapy. Delays in the initiation or inappropriate/inadequate initial therapy are related to increased mortality and worse outcomes. In responding patients, as soon as culture data are available, efforts should be made to change the initial broad spectrum antibiotic regimen to a more targeted one (de-escalation). The optimal duration of treatment is a matter of debate, but courses longer than 1 week are rarely justified.     

Antimicrobial selection for community-acquired lower respiratory tract infections in the 21st century: a review of gemifloxacin

Community-acquired lower respiratory tract infections (LRTIs) are more prevalent in the elderly than in children and younger adults and form a significant proportion of all consultations and hospital admissions in this older age group. Furthermore, in a world of increasing life expectancy the trend seems unlikely to be reversed. Antimicrobial treatment of community-acquired pneumonia (CAP) must cover Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis, and in many circumstances should also cover the intracellular (atypical) pathogens. In contrast, acute exacerbations of chronic bronchitis (AECB) are mainly associated with H. influenzae and S. pneumoniae and not with atypical bacteria: in severe cases, other Gram-negative bacteria may be involved. Frequently in LRTIs, the aetiology of the infection cannot be identified from the laboratory specimens and treatment has to be empirical. In such situations it is important to not only to use an antibiotic that covers all likely organisms, but also one that has good activity against these organisms given the local resistance patterns. Gemifloxacin is a new quinolone antibiotic that targets pneumococcal DNA gyrase and topoisomerase IV and is highly active against S. pneumoniae including penicillin-, macrolide- and many ciprofloxacin-resistant strains, as well as H. influenzae and the atypical pathogens. In clinical trials in CAP and AECB, gemifloxacin has been shown to be as effective a range of comparators and demonstrated an adverse event profile that was in line with the comparator agents. In one long-term study in AECB significantly more patients receiving gemifloxacin than clarithromycin remained free of recurrence after 26 weeks. The improved potency, broad spectrum of activity and proven clinical and bacteriological efficacy and safety profile should make it a useful agent in the 21st century battle against community-acquired LRTIs.     

The use of patient-reported outcomes in advanced breast cancer clinical trials: a review of the published literature

Objective: As a means to measure quantifiable signs, symptoms, and impacts of a disease or its treatment, patient-reported outcome (PRO) instruments can be applied to numerous settings, including use in drug development to support labeling claims. This research summarizes the use of PROs in trials for 16 commonly used regulatory approved treatments for advanced or metastatic breast cancer.

Methods: For each treatment (n?=?16), a literature search was conducted in MEDLINE, Embase, and PsycINFO. The primary criterion for selection was the report of studies that used PROs to evaluate treatment benefit and/or toxicity in advanced or metastatic breast cancer. From this, a sub-set of articles for each treatment were selected for full-text review where PRO-related information was extracted and summarized.

Results: The searches yielded 1727 publications. Following abstract review, 1702 were excluded because they failed to meet criteria, or were duplicates or less relevant for PRO information reported. Thus, 25 articles were reviewed in detail for this evaluation. Eleven PRO instruments were identified from these publications. The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire – Core (EORTC QLQ-C30) was utilized the most frequently (n?=?13, 52.0%). Most publications reported PROs positioned as secondary endpoints (n?=?20, 80.0%); described some of the statistical analyses applied to PRO data (n?=?21, 84.0%); and specified PRO results (n?=?23, 92.0%).

Conclusions: While several of the publications provided some information on how PROs were utilized, many did not describe details for PRO administration, scoring, analyses, and results interpretation. While it is encouraging that PROs are often used in clinical trials for patients with metastatic breast cancer, they are not commonly used to support endpoints that establish the basis for label claims. Because they yield direct insight into the patient experience of a condition, PROs may be used to provide a more comprehensive perspective of the benefits and risks from treatment.     

A further consideration on long-acting injectable versus oral antipsychotics in the treatment of schizophrenia: a narrative review and critical appraisal

ABSTRACT

Introduction: Many patients with schizophrenia exhibit difficulties in maintaining adherence to oral antipsychotics, calling for more reliable drug delivery systems.

Areas covered: While non-randomized studies have indicated consistent effectiveness of long-acting injectable antipsychotics (LAIs) over oral counterparts to prevent negative consequences such as relapse, hospitalization and all-cause discontinuation, efficacy results from randomized controlled comparative trials have not been that impressive. The results rely heavily on the study design and the population studied. Further, LAIs are frequently used as an adjunctive to ongoing other antipsychotics or psychotropics, but not solely, in the real world.

Expert opinion: To put LAI–oral comparisons into clinical context, the following information is urgently necessary: (1) How LAIs compare with each other in head-to-head comparisons? (2) How effective is it to switch among different LAIs? (3) How early in the treatment stage should LAIs be utilized? (4) How long the interval of LAI administration can be extended? (5) How LAIs compare with clozapine in head-to-head comparisons? (6) How effective are LAIs when clozapine is ineffective? (7) How effective is clozapine when LAIs are ineffective? (8) How effective is it to combine clozapine and LAIs when neither is effective alone? This paper narratively discusses these critical perspectives.     

Medicines in the 21st century Or pills,politics, potions,and profits: Where is public policy?

The delivery of health care over the past century, including drugs for the past 60 years, has brought significant gains to the overall health of the world population. The recent advances in genomics carry the promise, as yet not fulfilled, of far greater benefits perhaps, as far as molecular medicines are concerned of actually delivering Paul Ehrlich's “magic bullet.” However, the delivery of currently available health benefits to the world has been remarkably non‐uniform and the major fraction of the world's population still remains inadequately served by basic public health services, including clean water and sanitation. Additionally, this same population is devastated by diseases including malaria, tuberculosis, and AIDS. This discrepancy in health care parallels the economic disparities that exist between nations and that are in fact increasing rather than decreasing. The absence of health care is a driving force for the generation and maintenance of poverty. The issue is less science than it is public policy and the will of the rich world to generate the infrastructural environments under which the rewards of science can be shared equitably. The delivery of biomedical science in the future is discussed both in terms of the science that will drive advances and the public policy issues that must be implemented to ensure delivery of scientific benefits. Drug Dev. Res. 59:269–291, 2003. © 2003 Wiley‐Liss, Inc.     

Effects of tolterodine ER on patient-reported outcomes in sexually active women with overactive bladder and urgency urinary incontinence

ABSTRACT

Objective: To assess the effects of tolterodine extended release (ER) on patient-reported outcomes (PROs) in sexually active women with overactive bladder (OAB) and urgency urinary incontinence (UUI).

Research design and methods: This multicenter, double-blind, placebo controlled trial included 411 women aged?≥18 years reporting OAB symptoms for ≥3 months; ≥8 micturitions per 24 hours (including ≥0.6 UUI episodes and ≥3 OAB micturitions) in 5-day bladder diaries at baseline, and being in a sexually active relationship for ≥6 months. Subjects randomized to placebo or tolterodine ER completed validated OAB- or incontinence-specific questionnaires, including the Patient Perception of Bladder Condition (PPBC), Overactive Bladder Questionnaire (OAB-q), Urgency Perception Scale (UPS), and the Incontinence Impact Questionnaire (IIQ) at baseline and week 12, as well as the Perception of Treatment Benefit and Treatment Satisfaction questions at week 12. This study is registered with ClinicalTrials.gov (identifier: NCT00143481)

Results: The mean age of enrolled women was approximately 48 years. Compared with placebo, the tolterodine ER group reported significant baseline to week 12 improvements in PPBC responses (p?=?0.0048); OAB-q Symptom Bother, total Health-Related Quality of Life (HRQL), and HRQL domain scores (all p?<?0.05); IIQ Emotional Health domain scores (p?<?0.05); proportions of subjects reporting treatment benefit (79 vs. 54%; p?<?0.0001) and satisfaction (78 vs. 59%; p?<?0.0001). Improvements on the UPS were not significantly different.

Conclusions: Tolterodine ER treatment was associated with improvements in multiple OAB- and incontinence-specific PROs in a sexually active, relatively young, and racially diverse population of women. The findings provide clinicians with new insights into the impact of OAB and its treatment on HRQL in this population, which has been underrepresented in previous OAB studies. Study limitations include a potential underestimation of the impact of OAB symptoms resulting from the exclusion of women who may not be sexually active because of their urinary symptoms.

Trial registration: ClinicalTrials.gov identifier: NCT00143481.     

Extended-release niacin with laropiprant: a review on efficacy,clinical effectiveness and safety

Mixed hyperlipidaemia is an important risk factor for the development of cardiovascular disease. The global management of mixed hyperlipidaemia is often more difficult than the treatment of pure hypercholesterolaemia in terms of goal attainments. Despite the significant clinical benefits provided by statins, many patients with mixed hyperlipidaemia do not achieve their recommended low-density and non-high-density lipoprotein cholesterol target goals with statin monotherapy. The combination of ezetimibe plus fenofibrate is a new alternative to improve the overall atherogenic lipid profile of patients with mixed hyperlipidaemia. However, the absence of comparative data with statin monotherapy and of long-term clinical studies suggests reservation of the combination of ezetimibe plus fenofibrate as a second-line therapy. Nevertheless, this combination therapy of ezetimibe plus fenofibrate seems particularly useful for patients with a poor response or intolerance to statin monotherapy.     

Common plant toxicology: a comparison of national and southwest Ohio data trends on plant poisonings in the 21st century

Data from the American Association of Poison Control Centers (AAPCC) and the Cincinnati-based Drug and Poison Information Center (DPIC) were analyzed to determine the incidence and trends of human plant poisonings since the year 2000. Approximately 3.4% of the approximately 4.3 million annual calls to the AAPCC centers involved plants, with a higher fraction (4.5%) for pediatric exposures. Nearly 70% of plant exposures occurred in children under six. Only 8% of cases required treatment in a health-care facility, and only 0.1% (in 2008) were considered severe outcomes. The most prominent groups of plants involved in exposures are those containing oxalates, and the most common symptom is gastroenteritis. The top 12 identified plants (in descending order) nationally were Spathiphyllum species (peace lilly), Philodendron species (philodendron), Euphorbia pulcherrima (poinssettia), Ilex species (holly), Phytolacca americana (pokeweed), Toxicodendron radicans (poison ivy), Capsicum (pepper), Ficus (rubber tree, weeping fig), Crassula argentea (jade plant), Diffenbachia (dumb cane), Epipremnum areum (pothos) and Schlumbergera bridesii (Christmas cactus). Broad overlaps between the DPIC and the AAPCC incidence data were noted, with essentially the same plant species in each dataset. The nature of the various toxins, the symptomatology and potential treatments are discussed for the highest ranking plant species.     

Impact of pharmacist care in the management of autoimmune disorders: A systematic review of randomized control trials and non-randomized studies

IntroductionAutoimmune disorders are chronic, self-mediated, misdirected immune responses against their own immune system. It required intensive, complex and costly drug treatment regimen increased the risk of pharmacotherapy error and adversely affects patients. Hence, pharmacist care will have vital roles in autoimmune disorders to achieve health related outcomes.ObjectivesThis review aimed to gather evidence on the impact of pharmacist care on clinical, humanistic and economic outcomes, adherence to medications, and drug related problems in the management of autoimmune disorders among the usual care group.MethodologyA comprehensive review conducted in compliance with the PRISMA statement and systematic search was performed across five databases included PubMed Central, Web of Sciences, Scopus, Cochrane Library and google scholar from inception until August 2020. This research included full-text articles of randomized and non-randomized studies that evaluated impact of pharmacist care in autoimmune disorders.ResultsA total of nine studies were included (seven RCTs and two non-RCTs), including 829 patients with autoimmune disorders. A total of four studies (80%) show an enhancement in at least one clinical parameter due to pharmacist care. A substantial improvement in at least one humanistic parameter observed in all five studies (100%). While four out of five studies (80%) clearly displayed a remarkable improvement in medication adherence in the pharmacist care group from baseline to the completion of follow-ups. One study quantified a 99.08% resolution of DRPs in the pharmacist care group. Another study estimated the cost of medical resources uses per patient and found no difference in cost-effectiveness over six months between groups.ConclusionThis review reinforces the vital contribution of pharmacists to achieve clinical outcomes, humanistic outcomes, adherence to medications and DRPs in the efficient management of autoimmune disorders. However, no notable changes in economic outcomes were observed in this review.     

The efficacy and safety of novel oral anticoagulants for the preventive treatment in atrial fibrillation patients: a systematic review and meta-analysis

Abstract

Background: Novel oral anticoagulants, including direct factor Xa inhibitors and direct factor IIa inhibitors, have been used to prevent stroke in patients with atrial fibrillation (AF) for a decade. In this study, the efficacy and safety of the novel oral anticoagulants were assessed in AF patients.

Methods: No language restrictions were applied. Study selection and data extraction were carried out by searching PubMed, EMBASE, OVID, the BIOSIS, the Web of Science, Clinical Trials Registers, Cochrane Central Register of Controlled Trials and the China Academic Library and Information System. Each database was searched from its inception date to June 2013. Using odds ratio (OR) as an indicator, we systematically evaluated the primary efficacy endpoints and safety endpoints, as well as 10 secondary endpoints.

Result: Compared to the control drugs, the novel oral anticoagulants showed an OR decreased by 26% (OR: 0.74, 95% confidence interval (CI): 0.62–0.88) for stroke or systemic embolism, decreased by 24% (OR: 0.76, 95% CI: 0.64–0.90) for major bleeding, decreased by 10% (OR: 0.90, 95% CI: 0.84–0.95) for death from any cause, decreased by 27% for disabling or fatal stroke (OR: 0.73, 95% CI: 0.54–0.97), decreased by 31% (OR: 0.69, 95% CI: 0.60–0.8) for fatal bleeding, and decreased by 8% (OR: 0.92, 95% CI: 0.88–0.95) for serious adverse events. However, there was no significant difference in acute myocardial infarction, systemic embolism, major bleeding or clinically relevant non-major, all bleeding events, all adverse events and liver function disorder, between the novel oral anticoagulants and control drugs (p?>?0.05).

Conclusions: Compared to the control drugs, the novel oral anticoagulants showed higher efficiency and safety in patients with AF, as evidenced by their superior performance not only in reducing the risk of stroke or systemic embolism with a lower risk of major bleeding but also in decreasing the incidence of death from any cause, disabling or fatal stroke, serious adverse events and fatal bleeding.     

Effectiveness and cost effectiveness of pharmacist input at the ward level: a systematic review and meta-analysis

BackgroundPharmacists play important role in ensuring timely care delivery at the ward level. The optimal level of pharmacist input, however, is not clearly defined.ObjectiveTo systematically review the evidence that assessed the outcomes of ward pharmacist input for people admitted with acute or emergent illness.MethodsThe protocol and search strategies were developed with input from clinicians. Medline, EMBASE, Centre for Reviews and Dissemination, The Cochrane Library, NHS Economic Evaluations, Health Technology Assessment and Health Economic Evaluations databases were searched.Inclusion criteria specified the population as adults and young people (age >16 years) who are admitted to hospital with suspected or confirmed acute or emergent illness. Only randomised controlled trials (RCTs) published in English were eligible for inclusion in the effectiveness review. Economic studies were limited to full economic evaluations and comparative cost analysis. Included studies were quality-assessed. Data were extracted, summarised. and meta-analysed, where appropriate.ResultsEighteen RCTs and 7 economic studies were included. The RCTs were from USA (n = 3), Sweden (n = 2), Belgium (n = 2), China (n = 2), Australia (n = 2), Denmark (n = 2), Northern Ireland, Norway, Canada, UK and Netherlands. The economic studies were from UK (n = 2), Sweden (n = 2), Belgium and Netherlands. The results showed that regular pharmacist input was most cost effective. It reduced length-of-stay (mean = −1.74 days [95% CI: 2.76, −0.72], and increased patient and/or carer satisfaction (Relative Risk (RR) = 1.49 [1.09, 2.03] at discharge). At £20,000 per quality-adjusted life-year (QALY)-gained cost-effectiveness threshold, it was either cost-saving or cost-effective (Incremental Cost Effectiveness Ratio (ICER) = £632/QALY-gained). No evidence was found for 7-day pharmacist presence.ConclusionsPharmacist inclusion in the ward multidisciplinary team improves patient safety and satisfaction and is cost-effective when regularly provided throughout the ward stay. Research is needed to determine whether the provision of 7-day service is cost-effective.     

Donepezil in Alzheimer's disease: an evidence-based review of its impact on clinical and economic outcomes

INTRODUCTION: Donepezil is indicated for the symptomatic treatment of mild to moderate Alzheimer's disease. It is a specific and reversible inhibitor of acetylcholinesterase (AChE); by increasing levels of available acetylcholine, donepezil may compensate for the loss of functioning cholinergic brain cells. AIMS: This review evaluates the clinical impact of donepezil by assessing randomized controlled and open-label naturalistic trials, as well as observational studies. A broad perspective is gained of its effectiveness on various outcomes. EVIDENCE REVIEW: There is strong evidence that donepezil has efficacy against the three major domains of Alzheimer's disease symptoms, namely functional ability, behavior, and cognition. The strongest evidence is for improvement or less deterioration in global outcomes and cognition in the short to medium term. There is limited evidence that improved global outcomes are maintained in the long term and clear evidence to support long-term maintenance of cognitive benefits. Also, donepezil appears to maintain function in the long term and there is some level 1 and 2 evidence of improved or limited deterioration in behavior or mood in the short to medium term. Despite donepezil's effects on major symptoms of Alzheimer's disease, its impact on patients' quality of life has not been consistently demonstrated, perhaps reflecting the difficulty of assessing this aspect in this patient population. Donepezil may also lessen caregiver burden. Donepezil has some effect on markers of brain function, but more data are needed to confirm a neuroprotective effect. There is limited and conflicting evidence that long-term donepezil treatment delays time to institutionalization. There is some evidence that donepezil may be cost effective, especially when unpaid caregiver costs are considered. Donepezil is generally safe and well tolerated. CLINICAL VALUE: AChE inhibitors are the only agents recommended for the treatment of cognitive decline in patients with mild to moderate Alzheimer's disease. Donepezil is more effective than placebo and is well tolerated in improving the major symptoms of this disease. Improvements are usually modest, although stabilization of cognitive and functional symptoms with donepezil can also be considered an important clinical outcome. Donepezil may lessen caregiver burden. Donepezil may also be cost effective, especially when unpaid caregiver costs are considered. More data are required from randomized controlled trials with long-term follow-up to confirm its cost effectiveness and impact on quality of life, disease progression, and time to institutionalization.     

Systematic review of the literature on triclosan and health outcomes in humans

The ability of epidemiologic evidence to inform regulatory decisions is largely dependent on the coherence and quality of the published literature. This systematic review examines the quality and consistency of studies assessing health outcomes associated with exposure to triclosan (TCS), an antimicrobial chemical with a short physiologic half-life. We used elements of the Biomonitoring, Environmental Epidemiology, and Short-Lived Chemicals instrument to evaluate aspects of study quality. Each methodological domain – overall design, exposure assessment, and data analysis – was categorized according to three tiers where Tier 1 indicated the highest quality. We also examined consistency of methods, results and reporting as considerations for weight of evidence (WOE) assessment. Studies were considered sufficiently comparable if they addressed the same or similar research questions. Forty-two studies met the criteria for inclusion. Only one randomized cross-over clinical trial of TCS was assigned to Tier 1 for all three domains. Most other studies were assigned to Tier 3 for at least one domain. Although the available literature examined more than 100 different health endpoints and reported hundreds of different measures of association, few studies were considered comparable. For reported measures of association, most were not significantly different from the null; the few statistically significant results represented isolated findings without a discernable across- or within-study pattern. We conclude that the current body of epidemiologic literature does not allow a meaningful WOE assessment due to methodological limitations of individual studies and lack of inter-study consistency. On the other hand, methodologically stronger studies may be used to inform future research.     

An update on the clinical consequences of polypharmacy in older adults: a narrative review

ABSTRACT

Introduction: Polypharmacy, the use of multiple medications by one individual, is increasingly common among older adults. Caring for the growing number of older people with complex drug regimens and multimorbidity presents an important challenge in the coming years.

Areas covered: This article reviews the international trends in the prevalence of polypharmacy, summarizes the results from previous reviews on polypharmacy and negative health outcomes, and updates a previous review on the clinical consequences of polypharmacy by focusing on studies published after 2013. This narrative review, which is based on a literature search in MEDLINE and EMBASE from January 1990 to June 2018, was undertaken to identify relevant articles. Search terms included variations of polypharmacy and multiple medications.

Expert opinion: The prevalence of polypharmacy is increasing worldwide. More than half of the older population is exposed to polypharmacy in some settings. Polypharmacy is associated with a broad range of clinical consequences. However, methods to assess the dangers of polypharmacy should be refined. In our opinion, the issue of ‘confounding by multimorbidity’ has been underestimated and should be better accounted for in future studies. Moreover, researchers should develop more clinically relevant definitions of polypharmacy, including measures of inappropriate or problematic polypharmacy.     

Nicorandil improves clinical outcomes in patients with stable angina pectoris requiring PCI: a systematic review and meta-analysis of 14 randomized trials

Introduction: Clinical trials concerning the effects of nicorandil in stable coronary artery disease (CAD) remain controversial. This study sought to evaluate the clinical outcomes of nicorandil following elective percutaneous coronary intervention (PCI).

Areas covered: A meta-analysis including eligible randomized controlled trials (RCTs) with data on the nicorandil in stable CAD from Pubmed, EMBase, and Cochrane library (up to March 2018) was conducted. The primary end points were postprocedural incidence of myocardial infarction (MI) and contrast-induced nephropathy (CIN). The second end point was major adverse cerebrovascular and cardiovascular events (MACCE). Fourteen RCTs with a total of 1947 elective CAD patients were selected. Nicorandil significantly reduced the incidence of MI [n = 8; relative risk (RR) = 0.58; P = 0.001; I² = 33.7%], and CIN (n = 5; RR = 0.36; P < 0.00001; I² = 15.4%). However, There was no lowered risk of MACCE in nicorandil-treated patients [n = 10; odds RR = 0.75; P = 0.19; I² = 0.0%]. Subsequent trial sequential analyses confirmed the effect of nicorandil on MI and CIN in PCI.

Expert commentary: The present systematic review and meta-analysis suggests that nicorandil could improve clinical outcomes in terms of perioperative MI and CIN. However, the effect of nicorandil on the MACCE risk is not obvious. Future high-quality, large-scale clinical trials should majorly concern about the long-term clinical effect of nicorandil.