Peter L. Thompson

Effect of adrenaline on survival in out-of-hospital cardiac arrest: A randomised double-blind placebo-controlled trial

BACKGROUND There is little evidence from clinical trials that the use of adrenaline (epinephrine) in treating cardiac arrest improves survival, despite adrenaline being considered standard of care for many decades. The aim of our study was to determine the effect of adrenaline on patient survival to hospital discharge in out of hospital cardiac arrest. METHODS We conducted a double blind randomised placebo-controlled trial of adrenaline in out-of-hospital cardiac arrest. Identical study vials containing either adrenaline 1:1000 or placebo (sodium chloride 0.9%) were prepared. Patients were randomly allocated to receive 1 ml aliquots of the trial drug according to current advanced life support guidelines. Outcomes assessed included survival to hospital discharge (primary outcome), pre-hospital return of spontaneous circulation (ROSC) and neurological outcome (Cerebral Performance Category Score - CPC). RESULTS A total of 4103 cardiac arrests were screened during the study period of which 601 underwent randomisation. Documentation was available for a total of 534 patients: 262 in the placebo group and 272 in the adrenaline group. Groups were well matched for baseline characteristics including age, gender and receiving bystander CPR. ROSC occurred in 22 (8.4%) of patients receiving placebo and 64 (23.5%) who received adrenaline (OR=3.4; 95% CI 2.0-5.6). Survival to hospital discharge occurred in 5 (1.9%) and 11 (4.0%) patients receiving placebo or adrenaline respectively (OR=2.2; 95% CI 0.7-6.3). All but two patients (both in the adrenaline group) had a CPC score of 1-2. CONCLUSION Patients receiving adrenaline during cardiac arrest had no statistically significant improvement in the primary outcome of survival to hospital discharge although there was a significantly improved likelihood of achieving ROSC.

Hyperhomocysteinemia but Not the C677T Mutation of Methylenetetrahydrofolate Reductase Is an Independent Risk Determinant of Carotid Wall Thickening The Perth Carotid Ultrasound Disease Assessment Study (CUDAS)

BACKGROUND Hyperhomocysteinemia has been identified as a potential risk factor for atherosclerosis. This study examined whether a modest elevation of plasma total homocysteine (tHcy) was an independent risk factor for increased carotid artery intimal-medial wall thickness (IMT) and focal plaque formation in a large, randomly selected community population. We also examined whether vitamin cofactors and the C677T genetic mutation of the methylenetetrahydrofolate reductase (MTHFR) enzyme were major contributors to elevated plasma tHcy and carotid vascular disease. METHODS AND RESULTS In 1111 subjects (558 men, 553 women) 52+/-13 years old (mean+/-SD; range, 27 to 77 years) recruited from a random electoral roll survey, we measured fasting tHcy and performed bilateral carotid B-mode ultrasound. For the total population, mean tHcy was 12.1+/-4.0 micromol/L. Plasma tHcy levels were correlated with IMT (Spearman rank rs=0.31, P=0.0001). After adjustment for age, sex, and other conventional risk factors, subjects in the highest versus the lowest quartile of tHcy had an odds ratio of 2.60 (95% CI, 1.51 to 4.45) for increased IMT and 1.76 (95% CI, 1.10 to 2.82) for plaque. Serum and dietary folate levels and the C677T mutation in MTHFR were independent determinants of tHcy (all P=0.0001). The mutant homozygotes (10% of the population) had higher mean tHcy than heterozygotes or those without the mutation (14.2 versus 12.3 versus 11.6 micromol/L, respectively, P=0.0001). The inverse association of folate levels with tHcy was steeper in the mutant homozygotes. Despite this, the C677T MTHFR mutation was not independently predictive of increased carotid IMT or plaque formation. CONCLUSIONS Mild hyperhomocysteinemia is an independent risk factor for increased carotid artery wall thickness and plaque formation in a general population. Lower levels of dietary folate intake and the C677T mutation in MTHFR are important causes of mild hyperhomocysteinemia and may therefore contribute to vascular disease in the community.

Low-Dose Colchicine for Secondary Prevention of Cardiovascular Disease

OBJECTIVES The objective of this study was to determine whether colchicine 0.5 mg/day can reduce the risk of cardiovascular events in patients with clinically stable coronary disease. BACKGROUND The presence of activated neutrophils in culprit atherosclerotic plaques of patients with unstable coronary disease raises the possibility that inhibition of neutrophil function with colchicine may reduce the risk of plaque instability and thereby improve clinical outcomes in patients with stable coronary disease. METHODS In a clinical trial with a prospective, randomized, observer-blinded endpoint design, 532 patients with stable coronary disease receiving aspirin and/or clopidogrel (93%) and statins (95%) were randomly assigned colchicine 0.5 mg/day or no colchicine and followed for a median of 3 years. The primary outcome was the composite incidence of acute coronary syndrome, out-of-hospital cardiac arrest, or noncardioembolic ischemic stroke. The primary analysis was by intention-to-treat. RESULTS The primary outcome occurred in 15 of 282 patients (5.3%) who received colchicine and 40 of 250 patients (16.0%) assigned no colchicine (hazard ratio: 0.33; 95% confidence interval [CI] 0.18 to 0.59; p < 0.001; number needed to treat: 11). In a pre-specified secondary on-treatment analysis that excluded 32 patients (11%) assigned to colchicine who withdrew within 30 days due to intestinal intolerance and a further 7 patients (2%) who did not start treatment, the primary outcome occurred in 4.5% versus 16.0% (hazard ratio: 0.29; 95% CI: 0.15 to 0.56; p < 0.001). CONCLUSIONS Colchicine 0.5 mg/day administered in addition to statins and other standard secondary prevention therapies appeared effective for the prevention of cardiovascular events in patients with stable coronary disease.

Effects of Intensive Versus Moderate Lipid-Lowering Therapy on Myocardial Ischemia in Older Patients With Coronary Heart Disease Results of the Study Assessing Goals in the Elderly (SAGE)

Background— Clinical trials have demonstrated that, compared with placebo, intensive statin therapy reduces ischemia in patients with acute coronary syndromes and in patients with stable coronary artery disease. However, no studies to date have assessed intensive versus moderate statin therapy in older patients with stable coronary syndromes. Methods and Results— A total of 893 ambulatory coronary artery disease patients (30% women) 65 to 85 years of age with ≥1 episode of myocardial ischemia that lasted ≥3 minutes during 48-hour ambulatory ECG at screening were randomized to atorvastatin 80 mg/d or pravastatin 40 mg/d and followed up for 12 months. The primary efficacy parameter (absolute change from baseline in total duration of ischemia at month 12) was significantly reduced in both groups at month 3 and month 12 (both P<0.001 for each treatment group) with no significant difference between the treatment groups. Atorvastatin-treated patients experienced greater low-density lipoprotein cholesterol reductions than did pravastatin-treated patients, a trend toward fewer major acute cardiovascular events (hazard ratio, 0.71; 95% confidence interval, 0.46, 1.09; P=0.114), and a significantly greater reduction in all-cause death (hazard ratio, 0.33; 95% confidence interval, 0.13, 0.83; P=0.014). Conclusions— Compared with moderate pravastatin therapy, intensive atorvastatin therapy was associated with reductions in cholesterol, major acute cardiovascular events, and death in addition to the reductions in ischemia observed with both therapies. The contrast between the therapies’ differing efficacy for major acute cardiovascular events and death and their nonsignificant difference in efficacy for reduction of ischemia suggests that low-density lipoprotein cholesterol–lowering thresholds for ischemia and major acute cardiovascular events may differ. The Study Assessing Goals in the Elderly (SAGE) demonstrates that older men and women with coronary artery disease benefit from intensive statin therapy.

Elevated Interleukin-18 Levels Are Associated With the Metabolic Syndrome Independent of Obesity and Insulin Resistance

Objective—Activated innate immunity is thought to be involved in the pathogenesis of metabolic syndrome and type 2 diabetes. Interleukin-18 (IL-18) is a pleiotropic proinflammatory cytokine with important regulatory functions in the innate immune response. We sought to determine whether an elevated IL-18 concentration was a risk predictor for metabolic syndrome in a community population independent of obesity and hyperinsulinemia. Methods and Results—A representative general population, aged 27 to 77 years, without clinical diabetes was studied for clinical and biochemical risk factors for metabolic syndrome. Serum IL-18 concentration measured in 955 subjects correlated with metabolic syndrome traits including body mass index (BMI), waist circumference, triglyceride, high-density lipoprotein (inversely), and fasting glucose and insulin levels (all P<0.001). Mean IL-18 levels rose progressively with the increasing number of metabolic risk factors (ANOVA P<0.001). After adjusting for age, gender, BMI, and insulin levels, increasing IL-18 tertiles were associated with an odds ratio for metabolic syndrome of 1.0, 1.42, and 2.28, respectively (P trend=0.007). The graded risk relation was even stronger in nonobese subjects and not attenuated when adjusted for C-reactive protein and IL-6 levels. Conclusion—Our findings support the hypothesis that activation of IL-18 is involved in the pathogenesis of the metabolic syndrome.

Monocyte Count, But Not C-Reactive Protein or Interleukin-6, Is an Independent Risk Marker for Subclinical Carotid Atherosclerosis

Background and Purpose— Systemic inflammatory markers have been shown to predict future cardiovascular events, but whether they are associated with early atherosclerosis is uncertain. We investigated the relationship of inflammatory markers interleukin-6 (IL-6), high-sensitive C-reactive protein (hs-CRP), fibrinogen, monocyte count, and white cell count (WCC) with subclinical carotid atherosclerosis in a healthy community population. Methods— B-mode carotid ultrasound was performed on 1111 randomly selected male and female subjects aged 27 to 77 years. Serum IL-6, hs-CRP, plasma fibrinogen, monocyte count, and WCC were measured on all subjects, along with conventional cardiovascular risk factors. Results— Multivariate analysis showed that IL-6 (P <0.0001), fibrinogen (P =0.007), and monocyte count (P =0.001) were associated with carotid plaque formation in the whole population. Monocyte count remained associated independently with carotid plaque formation when adjusted further for conventional risk factors (odds ratio per SD increase in monocyte count 1.4; 95% CI, 1.13 to 1.73; P =0.002). IL-6 (P <0.0001), fibrinogen (P <0.0001), and monocyte count (P =0.04) were also associated with carotid intima-medial thickness (IMT) in the whole population. However, when adjusted further for conventional risk factors, none remained independently predictive of carotid IMT. Further analysis showed an age–monocyte interaction (P =0.03), with monocyte count being an independent predictor of carotid IMT in the older age group only (>53 years; P =0.003). Conclusion— In a healthy community population, monocyte count is a better independent predictor of common carotid IMT and plaque formation than IL-6, hs-CRP, fibrinogen, and WCC. Monocyte count may represent an inexpensive, easy-to-measure risk marker for subclinical carotid atherosclerosis.

Circulating adiponectin levels associate with inflammatory markers, insulin resistance and metabolic syndrome independent of obesity

Background:Adiponectin is an abundantly expressed adipocyte-specific protein, whose level is decreased in obesity, and which appears to be a key participant in developing inflammation, insulin resistance and metabolic syndrome (MetS). We examined whether the relationship between adiponectin and inflammatory markers, insulin resistance and MetS was independent of obesity.Methods and results:The study was performed in 1094 men and women, aged 27–77 years, from a representative community population. We measured serum inflammatory markers, homoeostasis model assessment of insulin resistance (HOMA-IR) and prevalent MetS using National Cholesterol Education Program ATPIII criteria. Sex- and age-adjusted plasma adiponectin concentration was inversely correlated with body mass index (BMI), waist–hip ratio, diastolic blood pressure, triglycerides, glucose and fasting insulin, and positively correlated with HDL cholesterol (all P<0.005). Log plasma adiponectin was a significant negative correlate of the levels of C-reactive protein, interleukin-6, interleukin-18, fibrinogen and white cell count independent of level of obesity. Log plasma adiponectin was also an inverse associate of log HOMA-IR (P<0.001) independent of obesity. Subjects in the top compared to bottom sex-specific plasma adiponectin quartile had a multivariate-adjusted odds ratio (OR) of 0.21 (95% CI, 0.11–0.42; P<0.001) for prevalent MetS, and the association was independent of age, sex, BMI, log insulin and log intereukin-18 levels.Conclusion:Our findings suggest that higher circulating adiponectin levels may mitigate against adipose-related inflammation, insulin resistance and MetS as much in lean as obese persons. At any rate circulating adiponectin level is a strong risk marker for MetS, which is independent of measures of adiposity, insulin resistance and inflammatory markers.

Erectile dysfunction as a predictor for subsequent atherosclerotic cardiovascular events: Findings from a linked-data study

INTRODUCTION In spite of the mounting interest in the nexus between erectile dysfunction (ED) and cardiovascular (CV) diseases, there is little published information on the role of ED as a predictor for subsequent CV events. AIM This study aimed to investigate the role of ED as a predictor for atherosclerotic CV events subsequent to the manifestation of ED. Method. The investigation involved the retrospective study of data on a cohort of men with ED linked to hospital morbidity data and death registrations. By using the linked data, the incidence rates of atherosclerotic CV events subsequent to the manifestation of ED were estimated in men with ED and no atherosclerotic CV disease reported prior to the manifestation of ED. The risk of subsequent atherosclerotic CV events in men with ED was assessed by comparing these incidence rates with those in the general male population. MAIN OUTCOME MEASURE Standardized incidence rate ratio (SIRR), comparing the incidence of atherosclerotic CV events subsequent to the manifestation of ED in a cohort of 1,660 men with ED to the incidence in the general male population. RESULTS On the basis of hospital admissions and death registrations, men with ED had a statistically significantly higher incidence of atherosclerotic CV events (SIRR 2.2; 95% confidence interval 1.9, 2.4). There were significantly increased incidence rate ratios in all age groups younger than 70 years, with a statistically highly significant downward trend with increase of age (P < 0.0001) across these age groups. Younger age at first manifestation of ED, cigarette smoking, presence of comorbidities and socioeconomic disadvantage were all associated with higher hazard ratios for subsequent atherosclerotic CV events. CONCLUSIONS The findings show that ED is not only significantly associated with but is also strongly predictive of subsequent atherosclerotic CV events. This is even more striking when ED presents at a younger age.

Stroke after acute myocardial infarction: relation to infarct size.

In a consecutive series of 783 patients with acute myocardial infarction, 13 (1.7%) suffered a stroke. In all but one case the strokes occurred among the 255 patients whose peak creatine kinase (CK) concentrations fell in the upper third of the range of values (over 1160 IU/l, about eight times the upper limit of normal); the exception was a patient with a pre-existing ventricular aneurysm. The incidence of stroke in the patients with CK over 1160 IU/l was 4.7%, 24 times the incidence when peak CK was below this value (0.2%). Higher peak serum enzyme concentrations were associated with an even higher incidence of stroke. Comparison of peak enzyme concentrations with cumulated CK showed a close correlation (r = 0.90 with peak CK; r = 0.85 with peak aspartate transaminase), suggesting that the peak enzyme values reflected infarct size. Thus the risk of stroke after infarction was a function of the size of the myocardial infarct; two-thirds of the patients had negligible risk of stroke and did not need anticoagulant prophylaxis.

Long-term risk stratification for survivors of acute coronary syndromes ☆: Results from the long-term intervention with pravastatin in ischemic disease (LIPID) study

OBJECTIVES We developed a prognostic strategy for quantifying the long-term risk of coronary heart disease (CHD) events in survivors of acute coronary syndromes (ACS). BACKGROUND Strategies for quantifying long-term risk of CHD events have generally been confined to primary prevention settings. The Long-term Intervention with Pravastatin in Ischemic Disease (LIPID) study, which demonstrated that pravastatin reduces CHD events in ACS survivors with a broad range of cholesterol levels, enabled assessment of long-term prognosis in a secondary prevention setting. METHODS Based on outcomes in 8,557 patients in the LIPID study, a multivariate risk factor model was developed for prediction of CHD death or nonfatal myocardial infarction. Prognostic indexes were developed based on the model, and low-, medium-, high- and very high-risk groups were defined by categorizing the prognostic indexes. RESULTS In addition to pravastatin treatment, the independently significant risk factors included: total and high density lipoprotein cholesterol, age, gender, smoking status, qualifying ACS, prior coronary revascularization, diabetes mellitus, hypertension and prior stroke. Pravastatin reduced coronary event rates in each risk level, and the relative risk reduction did not vary significantly between risk levels. The predicted five-year coronary event rates ranged from 5% to 19% for those assigned pravastatin and from 6.4% to 23.6% fur those assigned placebo. CONCLUSIONS Long-term prognosis of ACS survivors varied substantially according to conventional risk factor profile. Pravastatin reduced coronary risk within all risk levels; however, absolute risk remained high in treated patients with unfavorable profiles. Our risk stratification strategy enables identification of ACS survivors who remain at very high risk despite statin therapy. CT Am Coil Cardiol 2001;38:56-63) (C) 2001 by the American College of Cardiology.