Convalescent plasma and COVID-19: Time for a second-second look?

In this short narrative, we highlight some of our experiences leading the US Convalescent Plasma Program at the beginning of the pandemic in the spring and summer of 2020. This includes a brief summary of how the program emerged and high-level lessons we learned. We also share our impressions about why convalescent plasma was used at scale in the United States, early in the pandemic and share ideas that might inform the use of convalescent plasma in future outbreaks of novel infectious diseases.

Research Involving Participants With Impaired Consent Capacity: An Examination of Methods to Determine Capacity to Consent.

OBJECTIVE: To examine methods of assessing consent capacity in research protocols involving participants with impaired consent capacity, and examine instruments used to evaluate research consent capacity. METHODS: A retrospective review of 330 active research protocols involving participants lacking capacity to consent over a 10-year period (January 1, 2009, through March 1, 2019) was conducted to collect protocol characteristics (medical specialty, level of risk and type of study, consent and assent procedures, and type of vulnerable or protected population). Methods to assess consent capacity are described, and instruments to assess consent capacity are summarized. RESULTS: The specialties most frequently involving participants with impaired consent capacity in research were Neurology (27.3%), Critical Care (16.7%), and Surgery (10%). Type of studies are observational (43.9%), clinical trials (33%), chart review (11.5%), biobank (6.1%), and biomarker (5.5%). Minimal risk (53.3%) outnumbered greater than minimal risk (46.7%) studies. Most obtained written informed consent (77%) and assent (40.9%). The most common method to assess consent capacity was direct assessment by investigators (32.7%). Only 86 (26%) studies used instruments to assess consent capacity. Of the 13 instruments used, the most common was the Evaluation of Decision-Making Capacity for Consent to Act as a Research Subject, and is the only instrument that assesses all four components of decisional capacity: understanding, appreciation, reasoning, and choice. CONCLUSION: Generally, there was lack of uniformity in determining capacity to consent to research participation. Very few studies used instruments to assess consent capacity. Institutional review boards can provide greater guidance for research consent capacity determination.

Use of convalescent plasma in COVID-19 patients with immunosuppression.

In the absence of effective countermeasures, human convalescent plasma has been widely used to treat severe acute respiratory syndrome coronavirus 2, the causative agent of novel coronavirus disease 19 (COVID-19), including among patients with innate or acquired immunosuppression. However, the association between COVID-19-associated mortality in patients with immunosuppression and therapeutic use of convalescent plasma is unknown. We review 75 reports, including one large matched-control registry study of 143 COVID-19 patients with hematological malignancies, and 51 case reports and 23 case series representing 238 COVID-19 patients with immunosuppression. We review clinical features and treatment protocols of COVID-19 patients with immunosuppression after treatment with human convalescent plasma. We also discuss the time course and clinical features of recovery. The available data from case reports and case series provide evidence suggesting a mortality benefit and rapid clinical improvement in patients with several forms of immunosuppression following COVID-19 convalescent plasma transfusion. The utility of convalescent plasma or other forms of antibody therapy in immune-deficient and immune-suppressed patients with COVID-19 warrants further investigation.

Pooled Patient-Level Analysis of Inclisiran Trials in Patients With Familial Hypercholesterolemia or Atherosclerosis.

BACKGROUND: Inclisiran is a double-stranded small interfering RNA that suppresses proprotein convertase subtilisin-kexin type 9 (PCSK9) translation in the liver, leading to sustained reductions in low-density lipoprotein cholesterol (LDL-C) and other atherogenic lipoproteins with twice-yearly dosing. OBJECTIVES: The purpose of this study was to conduct a patient-level pooled analysis from 3 phase 3 studies of inclisiran. METHODS: Participants with heterozygous familial hypercholesterolemia (ORION-9 [Trial to Evaluate the Effect of Inclisiran Treatment on Low Density Lipoprotein Cholesterol (LDL-C) in Subjects With Heterozygous Familial Hypercholesterolemia (HeFH)]), atherosclerotic cardiovascular disease (ASCVD) (ORION-10 [Inclisiran for Participants With Atherosclerotic Cardiovascular Disease and Elevated Low-density Lipoprotein Cholesterol]), or ASCVD and ASCVD risk equivalents (ORION-11 [Inclisiran for Subjects With ASCVD or ASCVD-Risk Equivalents and Elevated Low-density Lipoprotein Cholesterol]) taking maximally tolerated statin therapy, with or without other LDL-C-lowering agents, were randomly assigned in a 1:1 ratio to receive either inclisiran or placebo, administered by subcutaneous injection on day 1, day 90, and every 6 months thereafter for 540 days. The coprimary endpoints were the placebo-corrected percentage change in LDL-C level from baseline to day 510 and the time-adjusted percentage change in LDL-C level from baseline after day 90 to day 540. Levels of other atherogenic lipoproteins and treatment-emergent adverse events were also assessed. RESULTS: A total of 3,660 participants (n = 482, n = 1,561, and n = 1,617 from ORION-9, -10, and -11, respectively) underwent randomization. The placebo-corrected change in LDL-C with inclisiran at day 510 was -50.7% (95% confidence interval: -52.9% to -48.4%; p < 0.0001). The corresponding time-adjusted change in LDL-C was -50.5% (95% confidence interval: -52.1% to -48.9%; p < 0.0001). Safety was similar in both groups. Treatment-emergent adverse events at the injection site were more frequent with inclisiran than placebo (5.0% vs. 0.7%), but were predominantly mild, and none were severe or persistent. Liver and kidney function tests, creatine kinase values, and platelet counts did not differ between groups. CONCLUSIONS: These pooled safety and efficacy data show that inclisiran, given twice yearly in addition to maximally tolerated statin therapy with or without other LDL-C lowering agents, is an effective, safe, and well-tolerated treatment to lower LDL-C in adults with heterozygous familial hypercholesterolemia, ASCVD, or ASCVD risk equivalents.

Effect of inclisiran, the small-interfering RNA against proprotein convertase subtilisin/kexin type 9, on platelets, immune cells, and immunological biomarkers: a pre-specified analysis from ORION-1.

AIMS: Small-interfering RNA (siRNA)-based targeting of proprotein convertase subtilisin/kexin type 9 (PCSK9) represents a novel therapeutic approach that may provide a convenient, infrequent, and safe dosing schedule to robustly lower low-density lipoprotein cholesterol (LDL-C). Given the long duration of action, however, establishing safety in particular with respect to immunogenicity is of paramount importance. In earlier clinical studies of other RNA-targeted treatment approaches (antisense oligonucleotide therapy) immunological and haematological adverse effects, in particular thrombocytopenia and pro-inflammatory effects, have been reported. Here, we present the pre-specified safety analysis from ORION-1 evaluating platelets, immune cells, immunological markers, antidrug antibodies, and clinical immunogenicity adverse events (AEs) under PCSK9 siRNA treatment with inclisiran. METHODS AND RESULTS: The pre-specified safety analysis from ORION-1 was performed in six different inclisiran dosing regimens in patients at high risk of cardiovascular disease with elevated LDL-C levels. Patients received either a single dose (SD: 200 mg, n = 60; 300 mg, n = 62 or 500 mg, n = 66) or double-dose starting regimen (DD: 100 mg, n = 62; 200 mg, n = 63; or 300 mg, n = 61 on days 1 and 90) of inclisiran or placebo (SD: n = 65; DD: n = 62). The effects of inclisiran on haematological parameters including platelet counts, lymphocytes, and monocytes as well as on the immune markers interleukin 6 (IL-6) and tumour necrosis factor-α (TNF-α) were examined after 180 days. Immunogenicity was further evaluated by analysis of anti-drug-antibodies (ADAs) towards inclisiran in 6068 study samples and by careful analysis of immunogenicity AEs as part of the pharmacovigilance strategy. At day 180, no significant alterations of platelet counts were observed in any of the dosing groups (change from baseline, SD: 200 mg: 0.8%; 300 mg: -0.5%; 500 mg: -1.8%; DD: 100 mg: 1.3%; 200 mg: -0.5%; 300 mg: 1.0%; no significant difference for any group as compared with placebo). No significant effects on other immune cells, including leucocytes, monocytes, or neutrophils were detected. Notably, no significant increase of inflammatory biomarkers (IL-6 or TNF-α) with either the SD or DD regimen became evident. There was no evidence for immunogenicity based on ADA level analysis and careful review of clinical immunogenicity AEs in none of the treatment regimens. CONCLUSION: In this pre-specified safety analysis of ORION-1 for the siRNA therapeutic inclisiran, no adverse effects on measures of inflammation or immune activation nor adverse effects on platelets or clinical immunogenicity AEs were observed over at least 6-month treatment. These safety findings in the largest analysis of an RNAi study in humans to date provide strong reassurance about the safety of inclisiran and the potential of cardiovascular RNA-targeted therapies.

Characteristics and Long-Term Outcomes of Patients With Prior Coronary Artery Bypass Grafting Undergoing Primary Percutaneous Coronary Intervention for ST-Segment Elevation Myocardial Infarction.

Limited data are available on characteristics and long-term outcomes of patients with coronary artery bypass grafts (CABG) undergoing primary percutaneous coronary intervention for ST-elevation myocardial infarction (STEMI). Between January 2000 to December 2014, we identified STEMI patients with prior CABG undergoing primary percutaneous coronary intervention from 3 sites. Kaplan-Meier methods to estimate survival and major adverse cardiac events (MACE) were employed and compared to a propensity matched cohort of non-CABG STEMI patients. Independent predictors of outcomes were analyzed with Cox modeling. Of the 3,212 STEMI patients identified, there were 296 (9.2%) CABG STEMI patients, having nearly similar frequencies of culprit graft (47.6%) versus culprit native (52.4%) as the infarct-related artery (IRA). At 10 years, the adjusted survival was 44% in CABG STEMI versus 55% in non-CABG STEMI (HR 1.26; 95%CI 0.86 to 1.87; p = 0.72). Survival free of MACE was lower for CABG STEMI (graft IRA, 37%; native IRA, 46%) as compared to non-CABG STEMI controls (63%) (p = 0.02). Neither CABG history nor IRA (native vs graft) was independently associated with death or MACE in multivariable analysis. Temporal trends showed no significant change in death or MACE rates of CABG STEMI patients over time. In conclusion, long term survival of CABG STEMI patients is not significantly different than matched STEMI patients without prior CABG; however, CABG STEMI patients were at significantly higher risk for MACE events.

Inclisiran for the Treatment of Heterozygous Familial Hypercholesterolemia.

BACKGROUND: Familial hypercholesterolemia is characterized by an elevated level of low-density lipoprotein (LDL) cholesterol and an increased risk of premature atherosclerotic cardiovascular disease. Monoclonal antibodies directed against proprotein convertase subtilisin-kexin type 9 (PCSK9) have been shown to reduce LDL cholesterol levels by more than 50% but require administration every 2 to 4 weeks. In a phase 2 trial, a twice-yearly injection of inclisiran, a small interfering RNA, was shown to inhibit hepatic synthesis of PCSK9 in adults with heterozygous familial hypercholesterolemia. METHODS: In this phase 3, double-blind trial, we randomly assigned, in a 1:1 ratio, 482 adults who had heterozygous familial hypercholesterolemia to receive subcutaneous injections of inclisiran sodium (at a dose of 300 mg) or matching placebo on days 1, 90, 270, and 450. The two primary end points were the percent change from baseline in the LDL cholesterol level on day 510 and the time-adjusted percent change from baseline in the LDL cholesterol level between day 90 and day 540. RESULTS: The median age of the patients was 56 years, and 47% were men; the mean baseline level of LDL cholesterol was 153 mg per deciliter. At day 510, the percent change in the LDL cholesterol level was a reduction of 39.7% (95% confidence interval [CI], -43.7 to -35.7) in the inclisiran group and an increase of 8.2% (95% CI, 4.3 to 12.2) in the placebo group, for a between-group difference of -47.9 percentage points (95% CI, -53.5 to -42.3; P<0.001). The time-averaged percent change in the LDL cholesterol level between day 90 and day 540 was a reduction of 38.1% (95% CI, -41.1 to -35.1) in the inclisiran group and an increase of 6.2% (95% CI, 3.3 to 9.2) in the placebo group, for a between-group difference of -44.3 percentage points (95% CI, -48.5 to -40.1; P<0.001). There were robust reductions in LDL cholesterol levels in all genotypes of familial hypercholesterolemia. Adverse events and serious adverse events were similar in the two groups. CONCLUSIONS: Among adults with heterozygous familial hypercholesterolemia, those who received inclisiran had significantly lower levels of LDL cholesterol than those who received placebo, with an infrequent dosing regimen and an acceptable safety profile. (Funded by the Medicines Company; ORION-9 ClinicalTrials.gov number, NCT03397121.).

Treatment effect of alirocumab according to age group, smoking status, and hypertension: Pooled analysis from 10 randomized ODYSSEY studies.

BACKGROUND: Age, smoking, hypercholesterolemia, and hypertension are major risk factors for atherosclerotic cardiovascular disease. OBJECTIVE: We examined whether the effects of alirocumab on low-density lipoprotein cholesterol (LDL-C) differed according to age, hypertension, or smoking status. METHODS: Data were pooled from 10 Phase 3 ODYSSEY randomized trials (24-104 weeks' duration) in 4983 people with heterozygous familial hypercholesterolemia (FH) or non-familial hypercholesterolemia (3188 on alirocumab, 1795 on control [620 on ezetimibe and 1175 on placebo]). Most participants received concomitant maximum tolerated statin therapy. In 8 trials, the alirocumab dose was increased from 75 mg every 2 weeks (Q2W) to 150 mg Q2W at Week 12 if predefined risk-based LDL-C goals were not achieved at Week 8 (≥70 mg/dL in very high cardiovascular risk; ≥100 mg/dL in moderate or high cardiovascular risk). Two trials compared alirocumab 150 mg Q2W vs placebo. The efficacy and safety of alirocumab were assessed post hoc in subgroups stratified by age (<65, ≥65 to <75, ≥75 years) and baseline hypertension or smoking status. RESULTS: Alirocumab reduced LDL-C by 23.7% (75/150 mg vs ezetimibe + statin) to 65.4% (150 mg vs placebo + statin) from baseline to Week 24 vs control. Subgroup analyses confirmed no significant interactions in response to alirocumab between age group, hypertension, or smoking status. Overall rates of treatment-emergent adverse events were similar between alirocumab and control groups. CONCLUSIONS: In this pooled analysis from 10 trials, alirocumab led to substantial LDL-C reductions vs control in every age group and regardless of hypertension or smoking status. Alirocumab was well tolerated in all subgroups.

Side Effects of CV Medications Following Hospitalization for ACS Are Associated With More Frequent Health-Care Contacts.

BACKGROUND: Patients hospitalized for first acute coronary syndrome (ACS) are frequently discharged on multiple new medications. The short-term tolerability of these medications is unknown. METHODS: This single-center cohort study assessed 30-day health-care utilization and how it may be impacted by medication prescribing trends. We included Olmsted County patients presenting with ACS and previously undiagnosed coronary artery disease in 2008 to 2009. All health-care contacts were reviewed 30 days after index hospital discharge for potential adverse medication effects including documented hypotension or bradycardia, or symptoms likely attributed to the medications. RESULTS: The study included 86 patients; their mean age was 63 (standard deviation: 15.5 years). Antianginal or antihypertensive cardiovascular (CV) medications were prescribed to 98% of patients at discharge; 76% were prescribed 2 or more. There were 233 health-care contacts in 30 days; 90 (39%) of these contacts were unscheduled. More CV medications tended to be prescribed to patients with unscheduled contacts, both pre-ACS ( P = .045) and upon hospital discharge ( P = .051). Hypotension and/or bradycardia at follow-up occurred in 52 patients (60%). Surprisingly, there was no association between hypotension and/or bradycardia at follow-up and increased health-care utilization ( P = .12). Potential adverse drug effects were reported in 34 (40%) patients. These patients had significantly more total health-care contacts ( P < .001) and unscheduled health-care contacts (median 0 vs 1.5; P < .001). CONCLUSIONS: Symptoms of adverse drug effects were associated with more frequent health-care utilization after ACS. Clinicians need to consider this while striving to increase patient compliance with post-ACS medications and optimize care transitions.

Cancer History Portends Worse Acute and Long-term Noncardiac (but Not Cardiac) Mortality After Primary Percutaneous Coronary Intervention for Acute ST-Segment Elevation Myocardial Infarction.

OBJECTIVE: To define the effect of a history of cancer on in-hospital and long-term mortality after primary percutaneous coronary intervention (PCI) for ST-segment elevation myocardial infarction (STEMI). PATIENTS AND METHODS: In this retrospective cohort study of 2346 patients with STEMI enrolled in the Mayo Clinic PCI registry from November 1, 2000, through October 31, 2010, we identified 261 patients (11.1%) with a history of cancer. The in-hospital and long-term outcomes (median follow-up, 6.2 years; interquartile range=4.3-8.5 years), including cardiac and noncardiac death and heart failure hospitalization, of these patients were compared with those of 1313 cancer-negative patients matched on age, sex, family history of coronary artery disease, and date of STEMI. RESULTS: Patients with cancer had higher in-hospital noncardiac (1.9% vs 0.4%; P=.03) but similar cardiac (5.8% vs 4.6%; P=.37) mortality as matched controls. The group at highest acute mortality risk were those diagnosed as having cancer within 6 months before STEMI (hazard ratio [HR]=7.0; 95% CI, 1.4-34.4; P=.02). At 5 years, patients with cancer had similar cardiac mortality (4.2% vs 5.8%; HR=1.27; 95% CI, 0.77-2.10; P=.35) despite more heart failure hospitalizations (15% vs 10%; HR=1.72; 95% CI, 1.18-2.50; P=.01) but faced higher noncardiac mortality (30.0% vs 11.0%; HR=3.01; 95% CI, 2.33-3.88; P<.001) than controls, attributable solely to cancer-related deaths. CONCLUSION: One in 10 patients in this contemporary registry of patients undergoing primary PCI for STEMI has a history of cancer. These patients have more than a 3 times higher acute in-hospital and long-term noncardiac mortality risk but no increased acute or long-term cardiac mortality risk with guideline-recommended cardiac care.

Incidence and 1-Year Outcomes of Perioperative Atrial Arrhythmia in Elderly Adults After Hip Fracture Surgery.

OBJECTIVES: To determine the incidence and 1-year outcomes of an elderly population with perioperative atrial arrhythmia (PAA) within 7 days of hip fracture surgery. DESIGN: Retrospective cohort study. SETTING: The Rochester Epidemiology Project (REP). PARTICIPANTS: Elderly adults consecutive undergoing hip fracture repair from 1988 to 2002 in Olmsted County, Minnesota (N = 1,088, mean age 84.0 ± 7.4, 80.2% female). MEASUREMENTS: Baseline clinical variables were analyzed in relation to survival using Cox proportional hazards methods for comparison. RESULTS: Sixty-one participants (5.6%) developed PAA within the first 7 days. During 1 year of follow-up, 239 (22%) participants died. PAA was associated with greater mortality (45% vs 21%; hazard ratio (HR) = 2.8, 95% confidence interval (CI) = 1.9-4.2). Other mortality risk factors were male sex (HR = 2.0, 95% CI = 1.5-2.6), congestive heart failure (HR = 2.1, 95% CI = 1.7-2.8), chronic renal insufficiency (HR = 2.0, 95% CI = 1.5-2.8), dementia (HR = 2.9, 95% CI = 2.2-3.7), and American Society of Anesthesiologists risk Class III, IV, or V (HR = 3.3, 95% CI = 1.9-5.9). CONCLUSION: Elderly adults undergoing hip fracture surgery who develop PAA within 7 days have significantly higher 1-year mortality than those who do not. Further studies are indicated to determine whether prevention of PAA will reduce mortality in this population.

Questions and answers on proper peri-operative management of antiplatelet therapy after coronary stent implantation to prevent stent thrombosis.

Stent thrombosis (ST) is a rare but life-threatening complication of coronary artery stenting. Although dual-antiplatelet therapy is an effective management strategy in reducing the risk for ST, some patients may need to interrupt their regimens because of unforeseen circumstances, such as the requirement for surgery. In conclusion, this case presentation highlights some pertinent issues related to ST, including its risk factors, the perioperative management of antiplatelet agents, and treatment for ST.

Clinical presentation and outcome of perioperative myocardial infarction in the very elderly following hip fracture surgery.

BACKGROUND: Patterns of clinical symptoms and outcomes of perioperative myocardial infarction (PMI) in elderly patients after hip fracture repair surgery are not well defined. METHODS: A retrospective 1:2 case-control study in a cohort of 1212 elderly patients undergoing hip fracture surgery from 1988 to 2002 in Olmsted County, Minnesota. RESULTS: The mean age was 85.3 ± 7.4 years; 76% female. PMI occurred in 167 (13.8%) patients within 7 days, of which 153 (92%) occurred in first 48 hours; 75% of patients were asymptomatic. Among patients with PMI, in-hospital mortality was 14.4%, 30-day mortality was 29 (17.4%), and 1-year mortality was 66 (39.5%). PMI was associated with a higher inpatient mortality rate (odds ratio [OR], 15.1; confidence interval [CI], 4.6-48.8), 30-day mortality (hazard ratio [HR], 4.3; CI, 2.1-8.9), and 1-year mortality (HR, 1.9; CI, 1.4-2.7). CONCLUSION: Elderly patients, after hip fracture surgery, have a higher incidence of PMI and mortality than what guidelines indicate. The majority of elderly patients with PMI did not experience ischemic symptoms and required cardiac biomarkers for diagnosis. The results of our study support the measurement of troponin in postoperative elderly patients for the diagnosis of PMI, in order to implement in-hospital preventive strategies to reduce PMI-associated mortality.

Does metabolic syndrome influence bioprosthetic mitral valve degeneration and reoperation rate?

BACKGROUND: Evidence suggests that metabolic syndrome (MbS) is associated with early senescence of bioprosthetic aortic valve prostheses. The purpose of this study was to determine whether MbS is also associated with accelerated failure of bioprosthetic valves prostheses in the mitral position. METHODS: Records of all patients undergoing bioprosthetic mitral valve replacement (MVR) from 1993 to 2000 were reviewed. RESULTS: Of 114 patients undergoing bioprosthetic MVR, 48 (42%) had MbS. Mean age was 73 years (vs. 74 years for no MbS). Patients underwent MVR for regurgitation (n = 97; 85%), stenosis (n = 12; 11%), or mixed lesions (n = 4; 4%). Etiology was degenerative (n = 35; 32%), rheumatic (n = 26; 24%), ischemic (n = 30; 28%), calcific (n = 9; 8%), and endocarditis (n = 8; 8%). Mean follow-up was 4.5 years. Overall survival at 5 and 10 years was 56% and 26%, respectively. Survival was similar between groups (p = 0.15). Five patients (2 MbS; 4% vs. 3 no MbS; 5%) required mitral reoperation at a mean of 3.8 years after initial MVR. The risk of prosthetic valve failure was not different between groups (p = 0.66). Despite no initial difference in transmitral gradients, gradients beyond five-year follow-up were greater for those with MbS (6.8 mmHg MbS vs. 4.7 mmHg no MbS, p = 0.007). Independent predictors of gradient progression beyond two years were MbS (p = 0.027) and female gender (p = 0.012). There were no significant differences in valve area, regurgitation, or ejection fraction. CONCLUSIONS: Although overall survival following bioprosthetic MVR is challenging, MbS did not predict diminished survival or excess reoperative risk compared to non-MbS patients. The trend toward more rapid progression of transprosthetic gradients in MbS patients warrants further investigation.

Influence of preoperative lipid-lowering therapy on postoperative outcome in patients undergoing coronary artery bypass grafting.

Statin therapy has recently been shown to decrease adverse perioperative events in patients undergoing vascular surgery. The potential beneficial effect of lipid-lowering therapy in patients undergoing coronary artery bypass grafting (CABG) is not well known. This was an observational analysis of 4,739 patients who underwent first-time isolated CABG at a single institution from 1995 to 2001. Patients were categorized into 2 groups based on treatment with a lipid-lowering agent within 30 days before surgery. Univariate and multivariate analyses were used to determine the association between lipid-lowering therapy and survival to hospital discharge. Patients in the lipid-lowering group (n = 2,334) tended to be younger (mean age 66 +/- 10 vs 68 +/- 10 years), were more likely to be diabetic (31% vs 28%), and on beta blockers (77% vs 70%) than patients in the nonlipid-lowering group (n = 2,405). In-hospital mortality was significantly lower in the lipid-lowering group than in the nonlipid-lowering therapy group (1.4% vs 2.2%, odds ratio 0.62, 95% confidence interval 0.40 to 0.96, p = 0.03). A multivariable model demonstrated a loss of statistical significance for the effect of lipid-lowering therapy on in-hospital mortality (adjusted odds ratio 0.83, 95% confidence interval 0.5 to 1.37, p = 0.46). In conclusion, preoperative use of lipid-lowering therapy in patients undergoing CABG appears safe and is associated with improved survival to hospital discharge compared with patients not receiving lipid-lowering therapy. However, patient risk factors and other cardioprotective medication use associated with the use of preoperative lipid-lowering therapy appear to explain the association with improved survival.

Effects of early treatment with statins on short-term clinical outcomes in acute coronary syndromes: a meta-analysis of randomized controlled trials.

CONTEXT: The short-term effects of early treatment with statins in patients after the onset of acute coronary syndromes (ACS) for the outcomes of death, myocardial infarction (MI), and stroke are unclear. OBJECTIVE: To evaluate relevant outcomes of patients from randomized controlled trials comparing early statin therapy with placebo or usual care at 1 and 4 months following ACS. DATA SOURCES AND STUDY SELECTION: Systematic search of electronic databases (MEDLINE, EMBASE, PASCAL, Cochrane Central Register) from their inception to August 2005, which was supplemented by contact with experts in the field. Two reviewers independently determined the eligibility of randomized controlled trials that compared treatment with statins with a control, were initiated within 14 days after onset of ACS, and had a minimal follow-up of 30 days. Trials with cerivastatin were only included in a sensitivity analysis. DATA EXTRACTION: Information on baseline characteristics of included trials and patients, reported methodological quality, lipid levels, and clinical outcome was independently extracted by 2 investigators. Investigators from each included trial contributed additional data if necessary. DATA SYNTHESIS: Twelve trials involving 13 024 patients with ACS were included in the meta-analysis. The risk ratios for the combined end point of death, MI, and stroke for patients treated with early statin therapy compared with control therapy were 0.93 (95% confidence interval [CI], 0.80-1.09; P = .39) at 1 month and 0.93 (95% CI, 0.81-1.07; P = .30) at 4 months following ACS. There were no statistically significant risk reductions from statins for total death, total MI, total stroke, cardiovascular death, fatal or nonfatal MI, or revascularization procedures (percutaneous coronary intervention or coronary artery bypass graft surgery). Sensitivity analyses with restriction to trials of high quality or with additional data from a large trial using cerivastatin indicated summary risk ratios even closer to 1. CONCLUSION: Based on available evidence, initiation of statin therapy within 14 days following onset of ACS does not reduce death, MI, or stroke up to 4 months.

Reduced risks of death and CHF are associated with statin therapy administered acutely within the first 24 h of AMI.

BACKGROUND: Reports have demonstrated an association between statin therapy during the first day of hospitalization for acute myocardial infarction (AMI) and reduced mortality. There are little data about whether early statin therapy reduces risk of CHF and alters timing of death. METHODS: We identified 3226 consecutive patients with AMI from 1993 through 2000 and divided them into early statin therapy (statins were administered within the initial 24 h of hospitalization, n=220) and non-statin therapy groups (n=3006). We compared mortality risks, rates of CHF development and measures of peak CK and CK-MB values between the groups. RESULTS: In-hospital mortality was lower in the early statin therapy group (2.7%) compared to the non-statin therapy group (9.2%), p=0.001. We observed no differences in the median time to death (statin group 132 h vs. non-statin group 72 h), p=0.3. Patients with very early statin treatment had lower peak CK (624 ng/ml) and CK-MB (46 ng/ml) values compared to non-statin patients (848 ng/ml and 84 ng/ml), p<0.01. Patients in the early statin group had lower risks of developing CHF during hospitalization (10.2 %) compared to the non-statin group (25.7%), p<0.001. CONCLUSION: Very early administration of statin therapy during the first day of hospitalization for AMI was associated with lower in-hospital mortality, lower rates of developing CHF and reduced peak biomarker release. These data support a benefit from early statin therapy in AMI and support the need for prospective studies which test whether very early statin therapy might also reduce infarct size.