Beryl M. Jackson

Poor prognosis of patients presenting with symptomatic myocardial infarction but without chest pain

OBJECTIVE To describe the clinical features, prognosis, and treatment of patients presenting with atypical forms of acute myocardial infarction. DESIGN Consecutive cases of possible acute myocardial infarction were sought from coronary care registers, biochemistry records, and hospital management systems. Case notes were reviewed and predefined epidemiological and clinical variables were abstracted. SETTING 20 adjacent hospitals in the former Yorkshire region. PATIENTS 3684 consecutive cases of possible acute myocardial infarction admitted in a three month period were identified, of whom 2096 had a first episode of confirmed acute myocardial infarction. RESULTS 20.2% of all patients admitted with an eventual diagnosis of acute myocardial infarction presented with symptoms other than chest pain. Compared with the group presenting with chest pain, these patients were older (76.6v 69.1 years, p < 0.001), were more often women (54.6% v 35.3%, p < 0.001), and were more likely to have a history of heart failure (18.6%v 6.9%, p < 0.001). They had a higher 30 and 365 day mortality (49.2% and 61.0%, respectively) compared with patients presenting with chest pain (17.9% and 26.2%). In a Cox regression analysis the hazard ratio for presentation without chest pain was 1.60 (95% confidence interval 1.30 to 1.97) (p < 0.001) adjusted for age, heart rate, blood pressure, left ventricular impairment, and infarction with ST segment elevation as covariates. Importantly, they were also less likely to receive treatments with a proven ability to improve prognosis. CONCLUSIONS Atypical presentation of myocardial infarction without chest pain is common and associated with increased mortality. This may result in part from a failure to use beneficial treatment strategies.

Hepatic metabolism and transporter gene variants enhance response to rosuvastatin in patients with acute myocardial infarction: the GEOSTAT-1 Study.

Background—Pharmacogenetics aims to maximize benefits and minimize risks of drug treatment. Our objectives were to examine the influence of common variants of hepatic metabolism and transporter genes on the lipid-lowering response to statin therapy. Methods and Results—The Genetic Effects On STATins (GEOSTAT-1) Study was a genetic substudy of Secondary Prevention of Acute Coronary Events—Reduction of Cholesterol to Key European Targets (SPACE ROCKET) (a randomized, controlled trial comparing 40 mg of simvastatin and 10 mg of rosuvastatin) that recruited 601 patients after myocardial infarction. We genotyped the following functional single nucleotide polymorphisms in the genes coding for the cytochrome P450 (CYP) metabolic enzymes, CYP2C9*2 (430C>T), CYP2C9*3 (1075A>C), CYP2C19*2 (681G>A), CYP3A5*1 (6986A>G), and hepatic influx and efflux transporters SLCO1B1 (521T>C) and breast cancer resistance protein (BCRP; 421C>A). We assessed 3-month LDL cholesterol levels and the proportion of patients reaching the current LDL cholesterol target of <70 mg/dL (<1.81 mmol/L). An enhanced response to rosuvastatin was seen for patients with variant genotypes of either CYP3A5 (P=0.006) or BCRP (P=0.010). Furthermore, multivariate logistic-regression analysis revealed that patients with at least 1 variant CYP3A5 and/or BCRP allele (n=186) were more likely to achieve the LDL cholesterol target (odds ratio: 2.289; 95% CI: 1.157, 4.527; P=0.017; rosuvastatin 54.0% to target vs simvastatin 33.7%). There were no differences for patients with variants of CYP2C9, CYP2C19, or SLCO1B1 in comparison with their respective wild types, nor were differential effects on statin response seen for patients with the most common genotypes for CYP3A5 and BCRP (n=415; odds ratio: 1.207; 95% CI: 0.768, 1.899; P=0.415). Conclusion—The LDL cholesterol target was achieved more frequently for the 1 in 3 patients with CYP3A5 and/or BCRP variant genotypes when prescribed rosuvastatin 10 mg, compared with simvastatin 40 mg. Clinical Trial Registration—URL: http://isrctn.org. Unique identifier: ISRCTN 89508434.

A simple benchmark for evaluating quality of care of patients following acute myocardial infarction

OBJECTIVE To develop a simple risk model as a basis for evaluating care of patients admitted with acute myocardial infarction. METHODS From coronary care registers, biochemistry records and hospital management systems, 2153 consecutive patients with confirmed acute myocardial infarction were identified. With 30 day all cause mortality as the end point, a multivariable logistic regression model of risk was constructed and validated in independent patient cohorts. The areas under receiver operating characteristic curves were calculated as an assessment of sensitivity and specificity. The model was reapplied to a number of commonly studied subgroups for further assessment of robustness. RESULTS A three variable model was developed based on age, heart rate, and systolic blood pressure on admission. This produced an individual probability of death by 30 days (P30) where P30 = 1/(1 + exp(−L30)) and L30 = −5.624 + (0.085 × age) + (0.014 × heart rate) − (0.022 × systolic blood pressure). The areas under the receiver operating characteristic curves for the reference and test cohorts were 0.79 (95% CI 0.76 to 0.82) and 0.76 (95% CI 0.72 to 0.79), respectively. To aid application of the model to routine clinical audit, a normogram relating observed mortality and sample size to the likelihood of a significant deviation from the expected 30 day mortality rate was constructed. CONCLUSIONS This risk model is simple, reproducible, and permits quality of care of acute myocardial infarction patients to be reliably evaluated both within and between centres.

A randomized, controlled trial of simvastatin versus rosuvastatin in patients with acute myocardial infarction: the Secondary Prevention of Acute Coronary Events – Reduction of Cholesterol to Key European Targets Trial

Aims We sought to evaluate reports that rosuvastatin 10 mg is a more efficacious treatment of hyperlipidaemia than is simvastatin 40 mg, hoping to assess this issue in the previously unstudied context of acute myocardial infarction. Methods and results The Secondary Prevention of Acute Coronary Events - Reduction of Cholesterol to Key European Targets (SPACE ROCKET) Trial was an investigator-led, open-label, blinded-endpoint, multicentre, randomized, controlled trial assessing the proportion of patients, at 3 months, achieving European Society of Cardiology 2003 (ESC-03) lipid targets of total cholesterol (TC) less than 4.5 mmol/l (174 mg/dl) or low-density lipoprotein cholesterol (LDLc) less than 2.5 mmol/l (97 mg/dl). Of 1263 patients randomized, 77.6% simvastatin versus 79.9% rosuvastatin achieved ESC-03 targets [odds ratio (OR): 1.16; 95% confidence interval (CI): 0.88–1.53; P = 0.29]. There were statistically significant differences for simvastatin versus rosuvastatin, respectively, for mean LDLc 2.03 mmol/l (78 mg/dl) versus 1.94 mmol/l (75 mg/dl; P =0.009) and also mean TC 3.88 mmol/l (150 mg/dl) versus 3.75 mmol/l (145 mg/dl; P =0.005). A post-hoc analysis showed higher achievement of the new ESC, American Heart Association and American College of Cardiology optimal lipid target of LDLc less than 1.81 mmol/l (70 mg/dl) with rosuvastatin (45.0%) compared with simvastatin (37.8%; OR: 1.37; 95% CI: 1.09–1.72; P = 0.007). The proportion of patients achieving the Fourth Joint Task Force European Guidelines (2007) of TC less than 4.0 mmol/l (155 mg/dl) and LDLc less than 2.0 mmol/l (77 mg/dl) was 38.7% for simvastatin 40 mg and 47.7% for rosuvastatin 10 mg (OR: 1.48; 95% CI: 1.18–1.86; P = 0.001). Conclusion We observed no superiority of either treatment for the ESC-03 lipid targets. Rosuvastatin 10 mg lowered mean cholesterol more effectively than simvastatin and achieved better results for the latest, more stringent, ESC target.

Change in serum lipids after acute coronary syndromes: secondary analysis of SPACE ROCKET study data and a comparative literature review.

BACKGROUND It has long been an accepted belief that serum cholesterol significantly falls after myocardial infarction and that a return to pre-event levels takes approximately 3 months. The magnitude and clinical significance of this fall has recently been challenged. METHODS In the Secondary Prevention of Acute Coronary Events-Reduction Of Cholesterol to Key European Targets (SPACE ROCKET) trial, we measured serum lipids of individuals on day 1 and between days 2 and 4 after acute myocardial infarction (AMI). Second, we performed a thorough literature review and compared all studies reporting data on absolute changes in lipids immediately after AMI, using weighted means. RESULTS Of 1263 SPACE ROCKET participants, 128 had paired lipid measurements where both samples had been measured using identical methods at baseline and on days 2-4 after AMI. The mean lowering in total cholesterol between day 1 and day 2-4 was 0.71 mmol/L (95% CI 0.58-0.84; P < 0.0001) and in triglycerides was 0.10 mmol/L (-0.14-0.33; P = 0.405). A total of 25 papers showing absolute lipid changes post-AMI were identified. The combined data demonstrated a mean fall in total cholesterol of 9% to 11% from baseline over days 3-14 post-AMI, whereas for triglycerides, there was a rise of 18% from baseline to between day 9 and 12 weeks. CONCLUSIONS After a secondary analysis of SPACE ROCKET data and a comparison of previously published data, we report a 10% fall in total cholesterol after AMI-a difference that is of high clinical significance. Consequently, measurement of serum lipids in patients with AMI should be performed within the first hours after presentation.

Hepatic Metabolism and Transporter Gene Variants Enhance Response to Rosuvastatin in Patients With Acute Myocardial InfarctionClinical Perspective

Background—Pharmacogenetics aims to maximize benefits and minimize risks of drug treatment. Our objectives were to examine the influence of common variants of hepatic metabolism and transporter genes on the lipid-lowering response to statin therapy. Methods and Results—The Genetic Effects On STATins (GEOSTAT-1) Study was a genetic substudy of Secondary Prevention of Acute Coronary Events—Reduction of Cholesterol to Key European Targets (SPACE ROCKET) (a randomized, controlled trial comparing 40 mg of simvastatin and 10 mg of rosuvastatin) that recruited 601 patients after myocardial infarction. We genotyped the following functional single nucleotide polymorphisms in the genes coding for the cytochrome P450 (CYP) metabolic enzymes, CYP2C9*2 (430C>T), CYP2C9*3 (1075A>C), CYP2C19*2 (681G>A), CYP3A5*1 (6986A>G), and hepatic influx and efflux transporters SLCO1B1 (521T>C) and breast cancer resistance protein (BCRP; 421C>A). We assessed 3-month LDL cholesterol levels and the proportion of patients reaching the current LDL cholesterol target of <70 mg/dL (<1.81 mmol/L). An enhanced response to rosuvastatin was seen for patients with variant genotypes of either CYP3A5 (P=0.006) or BCRP (P=0.010). Furthermore, multivariate logistic-regression analysis revealed that patients with at least 1 variant CYP3A5 and/or BCRP allele (n=186) were more likely to achieve the LDL cholesterol target (odds ratio: 2.289; 95% CI: 1.157, 4.527; P=0.017; rosuvastatin 54.0% to target vs simvastatin 33.7%). There were no differences for patients with variants of CYP2C9, CYP2C19, or SLCO1B1 in comparison with their respective wild types, nor were differential effects on statin response seen for patients with the most common genotypes for CYP3A5 and BCRP (n=415; odds ratio: 1.207; 95% CI: 0.768, 1.899; P=0.415). Conclusion—The LDL cholesterol target was achieved more frequently for the 1 in 3 patients with CYP3A5 and/or BCRP variant genotypes when prescribed rosuvastatin 10 mg, compared with simvastatin 40 mg. Clinical Trial Registration—URL: http://isrctn.org. Unique identifier: ISRCTN 89508434.

Hepatic Metabolism and Transporter Gene Variants Enhance Response to Rosuvastatin in Patients With Acute Myocardial InfarctionClinical Perspective: The GEOSTAT-1 Study

Background—Pharmacogenetics aims to maximize benefits and minimize risks of drug treatment. Our objectives were to examine the influence of common variants of hepatic metabolism and transporter genes on the lipid-lowering response to statin therapy. Methods and Results—The Genetic Effects On STATins (GEOSTAT-1) Study was a genetic substudy of Secondary Prevention of Acute Coronary Events—Reduction of Cholesterol to Key European Targets (SPACE ROCKET) (a randomized, controlled trial comparing 40 mg of simvastatin and 10 mg of rosuvastatin) that recruited 601 patients after myocardial infarction. We genotyped the following functional single nucleotide polymorphisms in the genes coding for the cytochrome P450 (CYP) metabolic enzymes, CYP2C9*2 (430C>T), CYP2C9*3 (1075A>C), CYP2C19*2 (681G>A), CYP3A5*1 (6986A>G), and hepatic influx and efflux transporters SLCO1B1 (521T>C) and breast cancer resistance protein (BCRP; 421C>A). We assessed 3-month LDL cholesterol levels and the proportion of patients reaching the current LDL cholesterol target of <70 mg/dL (<1.81 mmol/L). An enhanced response to rosuvastatin was seen for patients with variant genotypes of either CYP3A5 (P=0.006) or BCRP (P=0.010). Furthermore, multivariate logistic-regression analysis revealed that patients with at least 1 variant CYP3A5 and/or BCRP allele (n=186) were more likely to achieve the LDL cholesterol target (odds ratio: 2.289; 95% CI: 1.157, 4.527; P=0.017; rosuvastatin 54.0% to target vs simvastatin 33.7%). There were no differences for patients with variants of CYP2C9, CYP2C19, or SLCO1B1 in comparison with their respective wild types, nor were differential effects on statin response seen for patients with the most common genotypes for CYP3A5 and BCRP (n=415; odds ratio: 1.207; 95% CI: 0.768, 1.899; P=0.415). Conclusion—The LDL cholesterol target was achieved more frequently for the 1 in 3 patients with CYP3A5 and/or BCRP variant genotypes when prescribed rosuvastatin 10 mg, compared with simvastatin 40 mg. Clinical Trial Registration—URL: http://isrctn.org. Unique identifier: ISRCTN 89508434.