Dennis T. Ko

A population-based study of the drug interaction between proton pump inhibitors and clopidogrel

Background: Most proton pump inhibitors inhibit the bioactivation of clopidogrel to its active metabolite. The clinical significance of this drug interaction is unknown. Methods: We conducted a population-based nested case–control study among patients aged 66 years or older who commenced clopidogrel between Apr. 1, 2002, and Dec. 31, 2007, following hospital discharge after treatment of acute myocardial infarction. The cases in our study were those readmitted with acute myocardial infarction within 90 days after discharge. We performed a secondary analysis considering events within 1 year. Event-free controls (at a ratio of 3:1) were matched to cases on age, percutaneous coronary intervention and a validated risk score. We categorized exposure to proton pump inhibitors before the index date as current (within 30 days), previous (31–90 days) or remote (91–180 days). Results: Among 13 636 patients prescribed clopidogrel following acute myocardial infarction, we identified 734 cases readmitted with myocardial infarction and 2057 controls. After extensive multivariable adjustment, current use of proton pump inhibitors was associated with an increased risk of reinfarction (adjusted odds ratio [OR] 1.27, 95% confidence interval [CI] 1.03–1.57). We found no association with more distant exposure to proton pump inhibitors or in multiple sensitivity analyses. In a stratified analysis, pantoprazole, which does not inhibit cytochrome P450 2C19, had no association with readmission for myocardial infarction (adjusted OR 1.02, 95% CI 0.70–1.47). Interpretation: Among patients receiving clopidogrel following acute myocardial infarction, concomitant therapy with proton pump inhibitors other than pantoprazole was associated with a loss of the beneficial effects of clopidogrel and an increased risk of reinfarction.

Risks Associated With Statin Therapy A Systematic Overview of Randomized Clinical Trials

Background— Although statins reduce the risk of cardiovascular events, concerns about adverse effects may deter physicians from prescribing these agents. We performed a systematic overview of randomized statin trials to quantify the risks of musculoskeletal, renal, and hepatic complications associated with therapy. Methods and Results— Major statin trials were identified by electronic search of the MEDLINE database from 1966 to December 2005. We included English language reports of adults with documented hyperlipidemia; double-blind, random allocation of ≥100 patients to statin monotherapy versus placebo; and reports of myalgia, creatine kinase elevations, rhabdomyolysis, transaminase elevations, and discontinuation due to adverse events. Among 74 102 subjects enrolled in 35 trials (follow-up range, 1 to 65 months), statin therapy (excluding cerivastatin) did not result in significant absolute increases in risks of myalgias (risk difference/1000 patients [RD], 2.7; 95% CI, −3.2 to 8.7), creatine kinase elevations (RD, 0.2; 95% CI, −0.6 to 0.9), rhabdomyolysis (RD, 0.4; 95% CI, −0.1 to 0.9), or discontinuation due to any adverse event (RD, −0.5; 95% CI, −4.3 to 3.3). The absolute risk of transaminase elevations was significantly higher with statin therapy (RD, 4.2; 95% CI, 1.5 to 6.9). Conclusions— On the basis of data available from published clinical trials, statin therapy is associated with a small excess risk of transaminase elevations, but not of myalgias, creatine kinase elevations, rhabdomyolysis, or withdrawal of therapy compared with placebo. Further study is necessary to determine whether the results from these published clinical trials are similar to what occurs in routine practice, particularly among patients who are older, have more severe comorbid conditions, or receive higher statin doses than most patients in these clinical trials.

The association of left ventricular ejection fraction, mortality, and cause of death in stable outpatients with heart failure ☆

OBJECTIVES The aim of this study was to assess the prognostic importance of left ventricular ejection fraction (LVEF) in stable outpatients with heart failure (HF). BACKGROUND Although LVEF is an accepted prognostic indicator of prognosis in HF patients, the relationship of LVEF and mortality across the full spectrum of LVEF is incompletely understood. METHODS We examined the association of LVEF and outcomes among 7,788 stable HF patients enrolled in the Digitalis Investigation Group trial. RESULTS During mean follow-up of 37 months, mortality was substantial in all LVEF groups (range, LVEF <or= 15%, 51.7%, LVEF > 55%, 23.5%). Among patients with LVEF <or= 45%, mortality decreased in a near linear fashion across successively higher LVEF groups (LVEF < 15%, 51.7%; LVEF 36% to 45%, 25.6%; p < 0.0001). This association was present after multivariable adjustment, although the magnitude of this associated risk was reduced (LVEF <or= 15%: hazard ratio [HR] 1.77, 95% confidence interval [CI] 1.48 to 2.11; LVEF 16% to 25%: HR 1.44, 95% CI 1.28 to 1.61; LVEF 26% to 35%: HR 1.10, 95% CI 0.98 to 1.28; LVEF 36% to 45%: referent). In contrast, mortality rates were comparable among patients with LVEF > 45% both before (LVEF 46% to 55%: 23.3%; LVEF > 55%: 23.5%; p = 0.25), and after multivariable adjustment (LVEF 46% to 55%: HR 0.92, 95% CI 0.77 to 1.10; LVEF > 55%: HR 0.88, 95% CI 0.71 to 1.09; LVEF 36% to 45%: referent). Patients with lower LVEF were at increased absolute risk of death due to arrhythmia and worsening HF, but these were leading causes of death in all LVEF groups. CONCLUSIONS Among HF patients in sinus rhythm, higher LVEFs were associated with a linear decrease in mortality up to an LVEF of 45%. However, increases above 45% were not associated with further reductions in mortality.

Effectiveness of Public Report Cards for Improving the Quality of Cardiac Care The EFFECT Study: A Randomized Trial

CONTEXT Publicly released report cards on hospital performance are increasingly common, but whether they are an effective method for improving quality of care remains uncertain. OBJECTIVE To evaluate whether the public release of data on cardiac quality indicators effectively stimulates hospitals to undertake quality improvement activities that improve health care processes and patient outcomes. DESIGN, SETTING, AND PATIENTS Population-based cluster randomized trial (Enhanced Feedback for Effective Cardiac Treatment [EFFECT]) of 86 hospital corporations in Ontario, Canada, with patients admitted for acute myocardial infarction (AMI) or congestive heart failure (CHF). INTERVENTION Participating hospital corporations were randomized to early (January 2004) or delayed (September 2005) feedback of a public report card on their baseline performance (between April 1999 and March 2001) on a set of 12 process-of-care indicators for AMI and 6 for CHF. Follow-up performance data (between April 2004 and March 2005) also were collected. MAIN OUTCOME MEASURES The coprimary outcomes were composite AMI and CHF indicators based on 12 AMI and 6 CHF process-of-care indicators. Secondary outcomes were the individual process-of-care indicators, a hospital report card impact survey, and all-cause AMI and CHF mortality. RESULTS The publication of the early feedback hospital report card did not result in a significant systemwide improvement in the early feedback group in either the composite AMI process-of-care indicator (absolute change, 1.5%; 95% confidence interval [CI], -2.2% to 5.1%; P = .43) or the composite CHF process-of-care indicator (absolute change, 0.6%; 95% CI, -4.5% to 5.7%; P = .81). During the follow-up period, the mean 30-day AMI mortality rates were 2.5% lower (95% CI, 0.1% to 4.9%; P = .045) in the early feedback group compared with the delayed feedback group. The hospital mortality rates for CHF were not significantly different. CONCLUSION Public release of hospital-specific quality indicators did not significantly improve composite process-of-care indicators for AMI or CHF. TRIAL REGISTRATION http://clinicaltrials.gov Identifier: NCT00187460.

Rescue Angioplasty or Repeat Fibrinolysis After Failed Fibrinolytic Therapy for ST-Segment Myocardial Infarction A Meta-Analysis of Randomized Trials

OBJECTIVES We sought to best estimate the benefits and risks associated with rescue percutaneous coronary intervention (PCI) and repeat fibrinolytic therapy as compared with conservative management in patients with failed fibrinolytic therapy for ST-segment myocardial infarction (STEMI). BACKGROUND Fibrinolytic therapy is the most common treatment for STEMI; however, the best therapy in patients who fail to achieve reperfusion after fibrinolytic therapy remains uncertain. METHODS We performed a meta-analysis of randomized trials using a fixed-effects model. We included 8 trials enrolling 1,177 patients with follow-up duration ranging from hospital discharge to 6 months. RESULTS Rescue PCI was associated with no significant reduction in all-cause mortality (relative risk [RR] 0.69; 95% confidence interval [CI] 0.46 to 1.05), but was associated with significant risk reductions in heart failure (RR 0.73; 95% CI 0.54 to 1.00) and reinfarction (RR 0.58; 95% CI 0.35 to 0.97) when compared with conservative treatment. Rescue PCI was associated with an increased risk of stroke (RR 4.98; 95% CI 1.10 to 22.5) and minor bleeding (RR 4.58; 95% CI 2.46 to 8.55). Repeat fibrinolytic therapy was not associated with significant improvements in all-cause mortality (RR 0.68; 95% CI 0.41 to 1.14) or reinfarction (RR 1.79; 95% CI 0.92 to 3.48), but was associated with an increased risk for minor bleeding (RR 1.84; 95% CI 1.06 to 3.18). CONCLUSIONS Rescue PCI is associated with improved clinical outcomes for STEMI patients after failed fibrinolytic therapy, but these benefits must be interpreted in the context of potential risks. On the other hand, repeat fibrinolytic therapy is not associated with significant clinical improvement and may be associated with increased harm.

Rates and risk factors for prolonged opioid use after major surgery: population based cohort study

Objective To describe rates and risk factors for prolonged postoperative use of opioids in patients who had not previously used opioids and undergoing major elective surgery. Design Population based retrospective cohort study. Setting Acute care hospitals in Ontario, Canada, between 1 April 2003 and 31 March 2010. Participants 39 140 opioid naïve patients aged 66 years or older who had major elective surgery, including cardiac, intrathoracic, intra-abdominal, and pelvic procedures. Main outcome measure Prolonged opioid use after discharge, as defined by ongoing outpatient prescriptions for opioids for more than 90 days after surgery. Results Of the 39 140 patients in the entire cohort, 49.2% (n=19 256) were discharged from hospital with an opioid prescription, and 3.1% (n=1229) continued to receive opioids for more than 90 days after surgery. Following risk adjustment with multivariable logistic regression modelling, patient related factors associated with significantly higher risks of prolonged opioid use included younger age, lower household income, specific comorbidities (diabetes, heart failure, pulmonary disease), and use of specific drugs preoperatively (benzodiazepines, selective serotonin reuptake inhibitors, angiotensin converting enzyme inhibitors). The type of surgical procedure was also highly associated with prolonged opioid use. Compared with open radical prostatectomies, both open and minimally invasive thoracic procedures were associated with significantly higher risks (odds ratio 2.58, 95% confidence interval 2.03 to 3.28 and 1.95 1.36 to 2.78, respectively). Conversely, open and minimally invasive major gynaecological procedures were associated with significantly lower risks (0.73, 0.55 to 0.98 and 0.45, 0.33 to 0.62, respectively). Conclusions Approximately 3% of previously opioid naïve patients continued to use opioids for more than 90 days after major elective surgery. Specific patient and surgical characteristics were associated with the development of prolonged postoperative use of opioids. Our findings can help better inform understanding about the long term risks of opioid treatment for acute postoperative pain and define patient subgroups that warrant interventions to prevent progression to prolonged postoperative opioid use.

Coronary Artery Bypass Graft Surgery vs Percutaneous Interventions in Coronary Revascularization: A Systematic Review

IMPORTANCE Ischemic heart disease is the leading cause of death globally. Coronary artery bypass graft (CABG) surgery and percutaneous coronary intervention (PCI) are the revascularization options for ischemic heart disease. However, the choice of the most appropriate revascularization modality is controversial in some patient subgroups. OBJECTIVE To summarize the current evidence comparing the effectiveness of CABG surgery and PCI in patients with unprotected left main disease (ULMD, in which there is >50% left main coronary stenosis without protective bypass grafts), multivessel coronary artery disease (CAD), diabetes, or left ventricular dysfunction (LVD). EVIDENCE REVIEW A search of OvidSP MEDLINE, EMBASE, and Cochrane databases between January 2007 and June 2013, limited to randomized clinical trials (RCTs) and meta-analysis of trials and/or observational studies comparing CABG surgery with PCI was performed. Bibliographies of relevant studies were also searched. Mortality and major adverse cardiac and cerebrovascular events (MACCE, defined as all-cause mortality, myocardial infarction, stroke, and repeat revascularization) were reported wherever possible. FINDINGS Thirteen RCTs and 5 meta-analyses were included. CABG surgery should be recommended in patients with ULMD, multivessel CAD, or LVD, if the severity of coronary disease is deemed to be complex (SYNTAX >22) due to lower cardiac events associated with CABG surgery. In cases in which coronary disease is less complex (SYNTAX ≤22) and/or the patient is a higher surgical risk, PCI should be considered. For patients with diabetes and multivessel CAD, CABG surgery should be recommended as standard therapy irrespective of the severity of coronary anatomy, given improved long-term survival and lower cardiac events (5-year MACCE, 18.7% for CABG surgery vs 26.6% for PCI; P = .005). Overall, the incidence of repeat revascularization is higher after PCI, whereas stroke is higher after CABG surgery. Current literature emphasizes the importance of a heart-team approach that should consider coronary anatomy, patient characteristics, and local expertise in revascularization options. Literature pertaining to revascularization options in LVD is scarce predominantly due to LVD being an exclusion factor in most studies. CONCLUSIONS AND RELEVANCE Both CABG surgery and PCI are reasonable options for patients with advanced CAD. Patients with diabetes generally have better outcomes with CABG surgery than PCI. In cases of ULMD, multivessel CAD, or LVD, CABG surgery should be favored in patients with complex coronary lesions and anatomy and PCI in less complicated coronary disease or deemed a high surgical risk. A heart-team approach should evaluate coronary disease complexity, patient comorbidities, patient preferences, and local expertise.

Meta-analysis: effects of percutaneous coronary intervention versus medical therapy on angina relief.

BACKGROUND Several meta-analyses have evaluated the efficacy of percutaneous coronary intervention (PCI) compared with medical therapy, but none has focused on angina relief. PURPOSE To summarize the evidence on the degree of angina relief from PCI compared with medical therapy in patients with stable coronary artery disease. DATA SOURCES The Cochrane Library (1993 to June 2009), EMBASE (1980 to June 2009), and MEDLINE (1950 to June 2009), with no language restrictions. STUDY SELECTION Two independent reviewers screened citations to identify randomized, controlled trials of PCI versus medical therapy in patients with stable coronary artery disease. DATA EXTRACTION Two independent reviewers abstracted data on patient characteristics, study conduct, and outcomes. A random-effects model was used to combine data on freedom from angina and to perform stratified analyses based on duration of follow-up, inclusion of patients with recent myocardial infarction, coronary stent utilization, recruitment period, and utilization of evidence-based medications. DATA SYNTHESIS A total of 14 trials, enrolling 7818 patients, met the inclusion criteria. Although PCI was associated with an overall benefit on angina relief (odds ratio, 1.69 [95% CI, 1.24 to 2.30]), important heterogeneity across trials was observed. The incremental benefit of PCI observed in older trials (odds ratio, 3.38 [CI, 1.89 to 6.04]) was substantially less and possibly absent in recent trials (odds ratio, 1.13 [CI, 0.76 to 1.68]). An inverse relationship between use of evidence-based therapies and the incremental benefit of PCI was observed. LIMITATIONS Information about the long-term use of medication was incomplete in most trials. Few trials used drug-eluting stents. Meta-regression analyses used aggregated study-level data from few trials. CONCLUSION Percutaneous coronary intervention was associated with greater freedom from angina compared with medical therapy, but this benefit was largely attenuated in contemporary studies. This observation may be related to greater use of evidence-based medications in contemporary trials. PRIMARY FUNDING SOURCE Canadian Institutes of Health Research.

Sodium bicarbonate-based hydration prevents contrast-induced nephropathy: a meta-analysis

BackgroundContrast-induced nephropathy is the leading cause of in-hospital acute renal failure. This side effect of contrast agents leads to increased morbidity, mortality, and health costs. Ensuring adequate hydration prior to contrast exposure is highly effective at preventing this complication, although the optimal hydration strategy to prevent contrast-induced nephropathy still remains an unresolved issue. Former meta-analyses and several recent studies have shown conflicting results regarding the protective effect of sodium bicarbonate. The objective of this study was to assess the effectiveness of normal saline versus sodium bicarbonate for prevention of contrast-induced nephropathy.MethodsThe study searched MEDLINE, EMBASE, Cochrane databases, International Pharmaceutical Abstracts database, ISI Web of Science (until 15 December 2008), and conference proceedings for randomized controlled trials that compared normal saline with sodium bicarbonate-based hydration regimen regarding contrast-induced nephropathy. Random-effects models were used to calculate summary odds ratios.ResultsA total of 17 trials including 2,633 subjects were pooled. Pre-procedural hydration with sodium bicarbonate was associated with a significant decrease in the rate of contrast-induced nephropathy (odds ratios 0.52; 95% confidence interval 0.34–0.80, P = 0.003). Number needed to treat to prevent one case of contrast-induced nephropathy was 16 (95% confidence interval 10–34). No significant differences in the rates of post-procedure hemodialysis (P = 0.20) or death (P = 0.53) was observed.ConclusionSodium bicarbonate-based hydration was found to be superior to normal saline in prevention of contrast-induced nephropathy in this updated meta-analysis.

Clinical ResearchInterventional CardiologyRescue Angioplasty or Repeat Fibrinolysis After Failed Fibrinolytic Therapy for ST-Segment Myocardial Infarction: A Meta-Analysis of Randomized Trials

OBJECTIVES We sought to best estimate the benefits and risks associated with rescue percutaneous coronary intervention (PCI) and repeat fibrinolytic therapy as compared with conservative management in patients with failed fibrinolytic therapy for ST-segment myocardial infarction (STEMI). BACKGROUND Fibrinolytic therapy is the most common treatment for STEMI; however, the best therapy in patients who fail to achieve reperfusion after fibrinolytic therapy remains uncertain. METHODS We performed a meta-analysis of randomized trials using a fixed-effects model. We included 8 trials enrolling 1,177 patients with follow-up duration ranging from hospital discharge to 6 months. RESULTS Rescue PCI was associated with no significant reduction in all-cause mortality (relative risk [RR] 0.69; 95% confidence interval [CI] 0.46 to 1.05), but was associated with significant risk reductions in heart failure (RR 0.73; 95% CI 0.54 to 1.00) and reinfarction (RR 0.58; 95% CI 0.35 to 0.97) when compared with conservative treatment. Rescue PCI was associated with an increased risk of stroke (RR 4.98; 95% CI 1.10 to 22.5) and minor bleeding (RR 4.58; 95% CI 2.46 to 8.55). Repeat fibrinolytic therapy was not associated with significant improvements in all-cause mortality (RR 0.68; 95% CI 0.41 to 1.14) or reinfarction (RR 1.79; 95% CI 0.92 to 3.48), but was associated with an increased risk for minor bleeding (RR 1.84; 95% CI 1.06 to 3.18). CONCLUSIONS Rescue PCI is associated with improved clinical outcomes for STEMI patients after failed fibrinolytic therapy, but these benefits must be interpreted in the context of potential risks. On the other hand, repeat fibrinolytic therapy is not associated with significant clinical improvement and may be associated with increased harm.