Michalina Kołodziejczak

Optimal duration of dual antiplatelet therapy after percutaneous coronary intervention with drug eluting stents: meta-analysis of randomised controlled trials

Objective To assess the benefits and risks of short term (<12 months) or extended (>12 months) dual antiplatelet therapy (DAPT) versus standard 12 month therapy, following percutaneous coronary intervention with drug eluting stents. Design Meta-analysis of randomised controlled trials. Data sources PubMed, Embase, Cumulative Index to Nursing and Allied Health Literature, Scopus, Web of Science, Cochrane Library, and major congress proceedings, searched from 1 January 2002 to 16 February 2015. Review methods Trials comparing short term (<12 months) or extended (>12 months) DAPT regimens with standard 12 month duration of therapy. Primary outcomes were cardiovascular mortality, myocardial infarction, stent thrombosis, major bleeding, and all cause mortality. Results 10 randomised controlled trials (n=32 287) were included. Compared to 12 month DAPT, a short term course of therapy was associated with a significant reduction in major bleeding (odds ratio 0.58 (95% confidence interval 0.36 to 0.92); P=0.02) with no significant differences in ischaemic or thrombotic outcomes. Extended versus 12 month DAPT yielded a significant reduction in the odds of myocardial infarction (0.53 (0.42 to 0.66); P<0.001) and stent thrombosis (0.33 (0.21 to 0.51); P<0.001), but more major bleeding (1.62 (1.26 to 2.09); P<0.001). All cause but not cardiovascular death was also significantly increased (1.30 (1.02 to 1.66); P=0.03). Conclusions Compared with a standard 12 month duration, short term DAPT (<12 months) after drug eluting stent implementation yields reduced bleeding with no apparent increase in ischaemic complications, and could be considered for most patients. In selected patients with low bleeding risk and very high ischaemic risk, extended DAPT (>12 months) could be considered. The increase in all cause but not cardiovascular death with extended DAPT requires further investigation.

Off-pump coronary artery bypass grafting improves short-term outcomes in high-risk patients compared with on-pump coronary artery bypass grafting: Meta-analysis

OBJECTIVES To assess the benefits and risks of off-pump coronary artery bypass (OPCAB) versus coronary artery bypass grafting (CABG) through a meta-analysis of randomized controlled trials (RCTs), and to investigate the relationship between outcomes and patient risk profile. METHODS PubMed, Embase, the Cumulative Index of Nursing and Allied Health Literature, Scopus, Web of Science, Cochrane Library, and major conference proceedings databases were searched for RCTs comparing OPCAB and CABG and reporting short-term (≤ 30 days) outcomes. Endpoints assessed were all-cause mortality, myocardial infarction (MI), and cerebral stroke. RESULTS The meta-analysis included 100 studies, with a total of 19,192 subjects. There was no difference between the 2 techniques with respect to all-cause mortality and MI (odds ratio [OR], 0.88; 95% confidence interval [CI], 0.71-1.09; P = .25; I(2) = 0% and OR, 0.90; 95% CI, 0.77-1.05; P = .19; I(2) = 0%, respectively). OPCAB was associated with a significant 28% reduction in the odds of cerebral stroke (OR, 0.72; 95% CI, 0.56-0.92; P = .009; I(2) = 0%). A significant relationship between patient risk profile and benefits from OPCAB was found in terms of all-cause mortality (P < .01), MI (P < .01), and cerebral stroke (P < .01). CONCLUSIONS OPCAB is associated with a significant reduction in the odds of cerebral stroke compared with conventional CABG. In addition, benefits of OPCAB in terms of death, MI, and cerebral stroke are significantly related to patient risk profile, suggesting that OPCAB should be strongly considered in high-risk patients.

Comprehensive Meta-Analysis of Safety and Efficacy of Bivalirudin Versus Heparin With or Without Routine Glycoprotein IIb/IIIa Inhibitors in Patients With Acute Coronary Syndrome

OBJECTIVES The aim of this meta-analysis was to compare the 30-day safety and efficacy of bivalirudin with those of heparin with or without routine administration of a glycoprotein IIb/IIIa inhibitor (GPI) in patients with acute coronary syndrome (ACS). BACKGROUND Bivalirudin has been a mainstay of anticoagulation in patients with ACS compared with heparin. The extent to which trial results have been affected by the coadministration of heparin with a GPI, however, remains unclear. METHODS A total of 13 randomized, controlled trials involving 24,605 patients were included. RESULTS There was no significant difference in 30-day mortality or myocardial infarction rate with bivalirudin compared with heparin with or without routine GPI administration. A reduction of 30-day major bleeding was observed with bivalirudin compared with heparin that was significant when GPI was routinely administered (odds ratio [OR]: 0.52, 95% confidence interval [CI]: 0.45 to 0.60), p < 0.001) but not with provisionally administered GPI (OR: 0.66, 95% CI: 0.33 to 1.32; p = 0.24). The occurrence of stent thrombosis (ST) at 30 days was significantly increased with bivalirudin compared with heparin plus routinely administered GPI (OR: 1.67, 95% CI: 1.13 to 2.45, p = 0.02), but not compared with heparin plus provisionally administered GPI (OR: 2.08, 95% CI: 0.35 to 12.32, p = 0.42). The rate of acute ST (≤ 24 h), however, was almost 4.5-fold higher with bivalirudin compared with heparin with or without GPI, whereas the rate of subacute ST (24 h to 30 days) did not differ significantly. CONCLUSIONS Overall, bivalirudin in ACS patients is associated with a significant reduction of major bleeding compared with heparin plus routinely administered GPI, but with a marked increase in ST rates compared with heparin with or without GPI.

Meta-analysis of time-related benefits of statin therapy in patients with acute coronary syndrome undergoing percutaneous coronary intervention

Patients with acute coronary syndromes (ACSs) still experience high rates of recurrent coronary events, particularly, early in their presentation. Statins yield substantial cardiovascular benefits, but the optimal timing of their administration, before or after percutaneous coronary intervention (PCI), remains unclear. We aimed to perform a meta-analysis of randomized controlled trials of statin administration before or after PCI versus no statin or low-dose statin in patients with ACS. Primary end points were 30-day all-cause mortality and 30-day myocardial infarction (MI) stratified by pre- and post-PCI statin administration. Secondary end points were major adverse cardiac events (MACEs) or major adverse cardiac and cerebrovascular events (MACCEs). Long-term analysis beyond 30 days was also performed. Twenty randomized controlled trials enrolling 8,750 patients were included. At 30 days, the rate of MI was significantly lower in the statin group (odds ratio [OR] 0.67, 95% confidence interval [CI] 0.53 to 0.84, p = 0.0007) with a trend toward reduced mortality (p = 0.06) and significant reductions in MACE and MACCE compared with no or low-dose statin. The 30-day incidence of MI was markedly lower when statins were administered before PCI (OR 0.38, 95% CI 0.24 to 0.59, p <0.0001) rather than after PCI (p = 0.28). The direction and magnitude of the estimates for before and after PCI versus no statin or low-dose statin were sustained at long term, not reaching statistical significance for MI (OR 0.81, 95% CI 0.65 to 1.01, p = 0.06) but with significant reductions in MACE (p = 0.0002). By meta-regression, earlier statin administration correlated significantly with lower risk of MI, MACE, and MACCE at 30 days. In conclusion, the present meta-analysis indicates a time-related impact of statin therapy on clinical outcomes of patients with ACS undergoing PCI: the earlier the administration before PCI, the greater the benefits.

Complete revascularisation in ST-elevation myocardial infarction and multivessel disease: meta-analysis of randomised controlled trials

Background Current guidelines recommend culprit-only revascularisation (COR) in haemodynamically stable patients with ST-segment elevation myocardial infarction (STEMI) and multivessel (MV) disease. Contrarily, growing body of evidence available from recent randomised controlled trials (RCTs) demonstrates improved outcomes with complete MV-percutaneous coronary intervention (PCI). Methods and results We performed a meta-analysis of RCTs comparing complete MV-PCI with non-complete MV-PCI in STEMI and MV disease. Complete MV-PCI was defined as revascularisation to non-infarct-related artery lesions during index procedure, non-complete MV-PCI-encompassed COR and staged approaches. Multiple databases and congress proceedings from major cardiovascular societies’ meetings were screened for relevant studies. Primary endpoint was the composite of major adverse cardiac events (MACE) typically defined as death, recurrent myocardial infarction (MI) and repeat revascularisation. Secondary endpoints were cardiovascular mortality, recurrent MI and repeat revascularisation. Outcomes were analysed at longest available follow-up with differences accounted for with adjusted models by person-years. Seven RCTs (N=1303) were included. The median follow-up was 12 months. Complete MV-PCI reduced the odds of MACE compared with non-complete MV-PCI (OR (95% CIs) 0.59 (0.36 to 0.97), p=0.04) driven by reduction in recurrent MI (0.48 (0.27 to 0.85), p=0.01) and repeat revascularisation (0.51 (0.31 to 0.84), p=0.008). Complete MV-PCI was associated with a non-significant trend towards reduced cardiovascular mortality (0.54 (0.26 to 1.10), p=0.09) as well. In a sensitivity analysis, none of the baseline clinical variables significantly influenced overall estimates. Conclusions In STEMI and MV disease, complete MV-PCI as compared with non-complete strategy reduces MACE by 41%, driven by a 52% reduction in recurrent MI and 49% reduction in repeat revascularisation.

Proprotein Convertase Subtilisin/Kexin Type 9 Monoclonal Antibodies for Acute Coronary Syndrome: A Narrative Review

Key Summary Points Proprotein convertase subtilisin/kexin type 9 (PCSK9) increases coronary plaque vulnerability. It exerts effects on plaques through several pathways, including proinflammatory low-density lipoprotein oxidation and direct modification of plaque composition. Levels of PCSK9 increase during acute coronary syndrome (ACS) as a consequence of cardiac ischemia. Levels of PCSK9 peak during ACS, which relates to the time to maximal effect of PCSK9 antibodies. Treatment with PCSK9 antibodies could benefit patients with ACS through reduction of low-density lipoprotein cholesterol levels and through early plaque stabilization via anti-inflammatory and antithrombotic mechanisms. Trials of PCSK9 antibodies that evaluate clinical outcomes in patients with ACS are warranted. Acute coronary syndrome (ACS) remains associated with a high rate of adverse events despite advances in interventional and pharmacologic strategies (1, 2). Along with antiplatelet and anticoagulation therapies and early revascularization, intensive statin therapy is used to reduce deaths and ischemic cardiovascular events in patients with ACS (36). However, these patients still have high rates of adverse clinical outcomes that are attributable to the culprit plaque responsible for the index event and to residual ischemic risk from nonculprit coronary plaques that are more vulnerable and prone to rupture during ACS (1). Monoclonal antibodies that target proprotein convertase subtilisin/kexin type 9 (PCSK9) are a new lipid-lowering therapy. They bind PCSK9 and prevent degradation of low-density lipoprotein (LDL) receptors, which increases LDL cholesterol clearance from the circulation (7, 8). Preliminary evidence also supports other potential mechanisms that are mediated by PCSK9 antibodies in reducing cardiovascular events. In this review, we discuss the relationship among PCSK9 levels, myocardial ischemia, and plaque instability; the pharmacokinetic profile of PCSK9 antibodies that may make them appropriate for ACS treatment; and the potential influence of these agents on proinflammatory and prothrombotic pathways. We posit that these findings provide a rationale for use of PCSK9 antibodies in patients with ACS and highlight the need for further investigation in this area. Methods We searched MEDLINE, Cochrane Central Register of Controlled Trials, Google Scholar, EMBASE, proceedings of major cardiovascular societies (European Society of Cardiology, American College of Cardiology, and American Heart Association), and the PCSK9 Education and Research Forum (www.pcsk9forum.org) from inception through 6 January 2015 for English-language studies (in animals or humans) that evaluated the following: PCSK9-mediated pathways, the enzymes relationship with myocardial ischemia or plaque vulnerability, and pharmacokinetics and effects of PCSK9 inhibition. Two authors (E.P.N. and M.K.) independently read each study and selected or highlighted those that were relevant for review. Mechanisms of Recurrent Ischemia in ACS and the Role of PCSK9 The ischemic burden in ACS reflects the contributions of both the culprit coronary plaque and several nonculprit, unstable plaques. Plaque vulnerability predisposes to rupture and erosion, which are substrates for coronary thrombosis (9). A prospective, natural-history study of coronary atherosclerosis that enrolled 697 patients with ACS showed that subsequent major adverse cardiovascular events could be almost equally attributed to culprit and nonculprit lesions (12.9% and 11.6%, respectively) (1). These results support the concept that a generalized risk beyond a single culprit lesion exists owing to several unstable plaques in the coronary tree in ACS. An increased PCSK9 level is associated with more severe atherosclerosis and higher rates of cardiovascular events that were potentially triggered by destabilization of coronary plaque (10, 11). Two retrospective, angiographic studies (the Ottawa Heart Genomics Study and the Emory Cardiovascular Biobank) reported an increase in PCSK9 levels in patients with acute myocardial infarction versus stable coronary artery disease. Multivariable logistic-regression analysis showed that plasma PCSK9 levels were an independent predictor of coronary artery disease (10). In the ATHEROREMO-IVUS (European Collaborative Project on Inflammation and Vascular Wall Remodeling in AtherosclerosisIntravascular Ultrasound) Study, PCSK9 levels assessed before coronary angiography were related to the composite end point of death and ACS at 1-year follow-up (event rate with PCSK9 above median vs. below median, 6.6% vs. 3.1%; P=0.049). In a multivariable analysis, higher levels were associated with an increased incidence of the composite end point of death and ACS (hazard ratio per 100-g/L increase in the PCSK9 level, 1.42 [95% CI, 1.02 to 1.99]; P=0.040) that was independent of serum LDL cholesterol levels or statin use. Events related to definite culprit lesions occurred in 19% of patients, and events related to nonculprit lesions occurred in 4.7% (11). In a cross-sectional study of patients with atherosclerosis, those with the most severe coronary stenoses based on their Gensini score (a metric to evaluate coronary atherosclerosis severity) also had the highest plasma PCSK9 levels (12). Taken together, these preliminary studies suggest a potential benefit of PCSK9 inhibition for both culprit and nonculprit plaques through stabilization of the atherosclerotic plaque. PCSK9 and Instability of Coronary Plaque Mounting evidence suggests that PCSK9 has adverse effects on coronary plaques through several pathways, including proinflammatory LDL oxidation and direct modification of plaque composition (1316) (Figure 1). The enzyme is associated with an inflammatory response that is largely based on nuclear factor-Bmediated expression of proinflammatory genes, including cytokines, chemokines, and adhesion molecules (Table) (14, 1733). A recent study done in 581 patients found a positive linear association between the fraction and amount of necrotic core tissue of the coronary plaque and increased PCSK9 levels (11). In the coronary plaque, PCSK9 inhibition decreases macrophages and necrotic core content and promotes apoptosis (15, 34). The PCSK9 antibodies modify the internal milieu of the coronary plaque by increasing inflammatory monocyte recruitment, a known cellular plaque component that triggers destabilization (35). The PCSK9-induced nuclear factor-B pathway can enhance the thrombotic substrate in atherosclerotic plaques through upregulation of tissue factor (36). These observations provide a rationale for considering PCSK9 antibodies in the early phase of ACS. Figure 1. Several adverse mechanisms on coronary plaque by PCSK9. ACS = acute coronary syndrome; LDL = low-density lipoprotein; MMP = matrix metalloproteinase; NF-B = nuclear factor-B; PCSK9 = proprotein convertase subtilisin/kexin type 9. Table. NF-B Pathways Exerted by PCSK9 Dynamics of PCSK9 and Optimal Timing of PCSK9 Inhibition in the Early Phase of ACS Cardiovascular risk is high during the first hours of the index ACS event. Cardiac ischemia triggers upregulation of PCSK9 synthesis and causes dynamic changes in enzyme levels (10, 37). In a recent animal study, plasma PCSK9 concentration was increased at 12 to 96 hours after myocardial infarction, with a peak at 48 hours. In concert with these increased levels, expression of hepatic PCSK9 messenger RNA was upregulated 2.2-fold at 12 hours and 4.1-fold at 24 hours (37). The pharmacokinetics and pharmacodynamics of PCSK9 antibodies seem appropriate for management of acute ACS. Drug administration results in a rapid decrease in PCKS9 levels, which is followed by a reduction in LDL cholesterol levels (38, 39). The peak in PCSK9 levels during ACS relates to the time to maximal effect of PCSK9 antibodies (Figure 2). Although this peak occurs at 48 hours during the acute period of ACS, the highest concentration and PCSK9-lowering effect are reached within 3 days after administration of a 75-mg subcutaneous dose of alirocumab (38). The pharmacologic profile of PCSK9 antibodies exhibits both an early effect during the peak of PCSK9 levels in ACS with consequent potential for early stabilization of culprit and nonculprit plaque and a medium- to long-term action driven by sustainable reduction in LDL cholesterol levels. Figure 2. Time pattern of change of PCSK9 levels from experimental studies. AMI = acute myocardial infarction; GAPDH = glyceraldehyde-3-phosphate dehydrogenase; PCSK9 = proprotein convertase subtilisin/kexin type 9. * Evidence from animal studies. Randomized, controlled trials and a meta-analysis showed that statin therapy initiated before percutaneous coronary intervention (PCI) reduced periprocedural adverse events, which supports statin therapy before intervention in ACS (40). Although PCI provides greater clinical benefits than medical therapy in ACS (41), it is also associated with periprocedural events related to prothrombotic activation, distal embolization of atherothrombotic debris, reperfusion injury, and microvascular dysfunction (42, 43). Thus, there may be a role for early adjunctive therapy in the context of PCI for ACS. The mechanism of potential benefit after treatment with PCSK9 antibodies in patients with ACS may be 2-fold, involving both LDL cholesterol reduction and plaque stabilization. This potential to reduce inflammation and oxidative stress and inhibit prothrombotic pathways may translate into greater plaque stabilization and increased coronary blood flow at the time of culprit-lesion PCI. These effects could contribute to improved clinical outcomes similar to those seen with early statin administration among patients with ACS (40). In aggregate, these data suggest that the administration of PCSK9 antibodies to patients with ACS could be associated with clinical benefit that is at least similar to that seen in low- and medium-risk stable patients w

Statins and risk of new-onset diabetes mellitus: is there a rationale for individualized statin therapy?

Statins (hydroxymethylglutaryl-coenzyme-A reductase inhibitors) are first-line agents for the management of hyperlipidemia in patients at high risk of cardiovascular (CV) events, and are the most commonly prescribed CV drugs worldwide. Although safe and generally well tolerated, there is growing evidence to suggest that statins are associated with an elevated occurrence of new-onset diabetes mellitus (DM). Recent experimental and clinical data have prompted the US Food and Drug Administration to add information to statin labels regarding the increased risk of development of type 2 DM. The main purpose of this review is to critically discuss the clinical evidence regarding the association of statin use with new-onset DM, the CV benefit/risk ratio with statins, and the rationale for individualized statin therapy.

Survival Benefits of Invasive Versus Conservative Strategies in Heart Failure in Patients With Reduced Ejection Fraction and Coronary Artery Disease: A Meta-Analysis.

Background— Heart failure with reduced ejection fraction caused by ischemic heart disease is associated with increased morbidity and mortality. It remains unclear whether revascularization by either coronary artery bypass grafting (CABG) or percutaneous coronary intervention (PCI) carries benefits or risks in this group of stable patients compared with medical treatment. Methods and Results— We performed a meta-analysis of available studies comparing different methods of revascularization (PCI or CABG) against each other or medical treatment in patients with coronary artery disease and left ventricular ejection fraction ⩽40%. The primary outcome was all-cause mortality; myocardial infarction, revascularization, and stroke were also analyzed. Twenty-one studies involving a total of 16 191 patients were included. Compared with medical treatment, there was a significant mortality reduction with CABG (hazard ratio, 0.66; 95% confidence interval, 0.61–0.72; P<0.001) and PCI (hazard ratio, 0.73; 95% confidence interval, 0.62–0.85; P<0.001). When compared with PCI, CABG still showed a survival benefit (hazard ratio, 0.82; 95% confidence interval, 0.75–0.90; P<0.001). Conclusions— The present meta-analysis indicates that revascularization strategies are superior to medical treatment in improving survival in patients with ischemic heart disease and reduced ejection fraction. Between the 2 revascularization strategies, CABG seems more favorable compared with PCI in this particular clinical setting.

Implantable Cardioverter-Defibrillators for Primary Prevention in Patients With Ischemic or Nonischemic Cardiomyopathy: A Systematic Review and Meta-analysis

Sudden death accounts for approximately half the deaths in patients with left ventricular systolic dysfunction. Life-threatening ventricular arrhythmias are the cause of most sudden deaths. Randomized clinical trials have shown that the implantable cardioverter-defibrillator (ICD) is the most effective current therapy to prevent sudden death by terminating ventricular arrhythmias. Moreover, ICD versus no ICD placement has been shown to improve survival among patients with heart failure and reduced ejection fraction (HeFrEF), with or without nonsustained ventricular tachycardia or symptoms (1). As a result, contemporary European and American guidelines assign a class I recommendation for prophylactic ICD therapy in patients with HeFrEF (24). The benefits of ICD therapy are most pronounced in the secondary prevention of life-threatening arrhythmias among high-risk patients with ischemic heart disease and ventricular dysfunction, although implantation is not recommended soon after acute myocardial infarction or in patients with an expected survival of less than 1 year (5). For primary prevention, the main indications for an ICD are related to the prevention of fatal outcomes in patients at increased risk for life-threatening ventricular tachycardia or ventricular fibrillation. In this setting, controversy recently was sparked by the findings of a clinical study questioning the benefits of ICDs and emphasizing the medical improvements in heart failure management (6). In light of this uncertainty, we aimed to systematically address, through a meta-analysis of randomized trials, the effect of ICD therapy versus conventional care for primary prevention of death of various causes in patients with ischemic or nonischemic cardiomyopathy. Methods The present meta-analysis was performed according to established methods recommended by the Cochrane guidelines and in compliance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) statement (7, 8). The protocol, although not registered, was developed on 20 September 2016, with final amendments on 31 March 2017. Originally, we aimed to assess both primary and secondary prevention settings; the current article, however, focuses only on primary prevention. Data Sources and Searches MEDLINE, Cochrane Central Register of Controlled Trials, Google Scholar, and EMBASE databases, as well as the Web sites www.tctmd.com, www.europcr.com, www.clinicaltrials.gov, www.clinicaltrialresults.org, and www.acc.org, were searched, without language restriction, from 1 April 1976 to 31 March 2017. Key words were nonischemic cardiomyopathy, ischemic cardiomyopathy, implantable cardioverter-defibrillator, implantable defibrillator, randomized controlled trials, clinical trials, mortality, death, sudden death, survival, and prevention. (For search strategies, see Supplement Table 1.) Search sources also included previous systematic reviews and abstracts as well as presentations from major cardiovascular medicine meetings. Supplement. Supplement Tables, Figures, and References to Excluded Studies Two authors (M. Koodziejczak and M. Kowalewski) independently assessed titles and abstracts identified by searches, as well as citations mentioned in any relevant systematic reviews or meta-analyses identified in the searches. Citations determined to be potentially eligible by either reviewer were selected for full-text review; both reviewers then independently assessed the full text for eligibility. Study Selection Inclusion criteria were any randomized controlled trial in humans comparing ICD therapy with conventional care (defined as control, contemporary medical therapy, antiarrhythmic medical therapy, or placebo in addition to medical care) and reporting mortality outcomes in the primary prevention setting. No restrictions based on language, follow-up, or study size were applied. Nonrandomized and single-group studies were excluded, as were studies that had a randomized design but compared ICDs with other devices or electrophysiologic procedures. Data Extraction and Quality Assessment Data were abstracted on prespecified forms by 2 independent investigators not involved in any of the retrieved studies. Hazard ratios (HRs) with 95% CIs were abstracted for all available mortality outcomes. When only other summary statistics were available, HRs were calculated according to the method of Parmar and colleagues (7). In SCD-HeFT (Sudden Cardiac Death in Heart Failure Trial), patients with ischemic or nonischemic disease were randomly assigned to receive an ICD, amiodarone, or placebo in a 1:1:1 fashion; trial data on all-cause mortality were presented (and extracted) by disease mechanism. Two investigators not involved in any trial (M. Koodziejczak and E.P.N.) independently assessed the risk of bias for each study according to the Cochrane Collaboration guidelines (treatment sequence generation; concealment of treatment allocation; blinding of participants, personnel, and outcome assessors; adequate assessment of incomplete outcome data; selective outcome reporting; other potential sources of bias) (7). Disagreements regarding extraction or risk-of-bias assessments were resolved by discussion with a third investigator (F.A.). Data Synthesis and Analyses We stratified our synthesis and analyses on the basis of the underlying cause of cardiomyopathy, nonischemic or ischemic, and pooled data for mortality outcomes. For the 3-group SCD-HeFT, we considered amiodarone and placebo as conventional care in the main analyses; we also performed a separate all-cause mortality analysis comparing ICD therapy with amiodarone (antiarrhythmic medical therapy). We used time-to-event outcomes reported for the randomly assigned groups (intention-to-treat principle). We used HRs to summarize time-to-event outcomes, because they account for time as well as the number of events (7). Heterogeneity was assessed by using the Cochran Q test (9). Statistical heterogeneity was summarized by the I 2 statistic, which quantifies the percentage of variation in study results caused by heterogeneity rather than chance (9). Pooled HRs were calculated by using the KnappHartung small-sample estimator method (10). Potential publication bias was examined by constructing a funnel plot in which the SE of the log HR was plotted against the HR of the selected outcomes. Prespecified sensitivity analyses were performed for all-cause mortality in subgroups based on age (<65 years and 65 years), sex, ventricular function (ejection fraction <25% and 25%), heart failure (New York Heart Association [NYHA] class I to II and class III to IV), diabetes mellitus, time after myocardial infarction (<18 months and 18 months), and baseline QRS length (<120 ms and 120 ms). Because event rates for subgroup analyses were provided in only 1 study (DANISH [Danish Study to Assess the Efficacy of ICDs in Patients with Non-ischemic Systolic Heart Failure on Mortality]), exact summary event rates were not calculated; individual study-subgroup data were summarized by using HRs and their respective 95% CIs whenever applicable, by using the random-effects model. Further sensitivity analyses including and excluding studies with early ICD placement after myocardial infarction or coronary bypass surgery were conducted. R, version 3.2.3 (R Foundation), and Comprehensive Meta-analysis software, version 2 (Biostat), were used for statistical computations and graphics. Role of the Funding Source This review received no funding or other support (such as supply of data). No external organizations or patients were involved in defining questions, developing the protocol, carrying out the review, interpreting the data, or deciding to submit the review for publication. Results Study Selection and Patient Population The PRISMA flow chart showing the publication screening process, the search strategies, and a list of excluded studies with reasons for exclusion are provided in Supplement Figure 1 and Supplement Tables 1 and 2. Of 2340 potentially relevant articles, 639 were excluded on the basis of title content and 1656 were excluded after abstract or full-text review. Of the remaining 45 trials, 11 studies, involving 8716 patients, met eligibility criteria (6, 1120). Four trials enrolled 1781 patients with nonischemic cardiomyopathy (6, 1113), 6 trials enrolled 4414 patients with ischemic cardiomyopathy (1520), and 1 trial included 2521 patients with both types of cardiomyopathy (14). Characteristics of the trials and participants are detailed in the Appendix Table and Supplement Table 3. Most of the included studies compared ICD therapy with conventional care; however, 1 study compared ICD therapy specifically with amiodarone (13), and 1 had a 3-group design comparing ICDs, amiodarone, and placebo (14). Mean follow-up was 3.2 years (range, 1.7 to 5.6 years). The earliest trial was published in 1996, but most of the studies were done in the first decade of the 21st century; only 1 study was published in 2016. All trials were funded, at least in part, by industry. Appendix Table. Characteristics of Included Trials: Design, Follow-up, and Timing of Intervention After Diagnosis or Surgery Mean ventricular ejection fraction of trial participants was 26.20%. Most patients had moderately symptomatic heart failure (NYHA class II or III). Only 2 studies included patients with class IV heart failure, who made up 1.0% and 4.6% of the total patient population, respectively (6, 17). Almost half the study population had a history of hypertension, and one third had diabetes mellitus. The lowest burden of comorbid conditions was in DANISH (31.2% and 18.9% had hypertension and diabetes, respectively). Patients included in the studies received several pharmacotherapies: 67.35% received -blockers, 80.12% angiotensin-converting enzyme inhibitors, 62.65% digoxin, and 68.40% diuretics (Supplement Table 4). Pharmacotherapy, however, varied across trials, with -blockers administered

From proprotein convertase subtilisin/kexin type 9 to its inhibition: state-of-the-art and clinical implications

Statins are recommended as first-line therapy for patients with hypercholesterolaemia. A sizable proportion of patients, however, does not reach therapeutic goals, is statin intolerant, or, despite optimal statin therapy, is at high risk of ischaemic events. Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a major role in lipid metabolism and several comorbidities. Monoclonal antibodies targeting PCSK9 are a new lipid-lowering approach with the potential to improve clinical outcomes in patients with dyslipidaemia. In this review, we discuss current experimental and clinical evidence of the role of PCSK9 and its inhibition on lipid metabolism and several pathologic conditions with a focus on clinical outcomes. A state-of-the-art analysis of current clinical evidence and future directions on PCSK9 and its inhibition is provided.