Individualised therapy of angiotensin converting enzyme (ACE) inhibitors in stable coronary artery disease: overview of the primary results of the PERindopril GENEtic association (PERGENE) study

In patients with stable coronary artery disease (CAD) without overt heart failure, ACE inhibitors are among the most commonly used drugs as these agents have been proven effective in reducing the risk of cardiovascular events. Considerable individual variations in the blood pressure response to ACE inhibitors are observed and as such heterogeneity in clinical treatment effect would be likely as well. Assessing the consistency of treatment benefit is essential for the rational and cost-effective prescription of ACE inhibitors. Information on heterogeneities in treatment effect between subgroups of patients could be used to develop an evidence-based guidance for the installation of ACE-inhibitor therapy. Obviously, therapy should only be applied in those patients who most likely will benefit. Attempts to develop such treatment guidance by using clinical characteristics have been unsuccessful. No heterogeneity in risk reduction by ACE inhibitors has been observed in relation to relevant clinical characteristics. A new approach to such ‘guided-therapy’ could be to integrate more patient-specific characteristics such as the patients’ genetic information. If proven feasible, pharmacogenetic profiling could optimise patients’ benefit of treatment and reduce unnecessary treatment of patients. Cardiovascular pharmacogenetic research of ACE inhibitors in coronary artery disease patients is in a formative stage and studies are limited. The PERGENE study is a large pharmacogenetic substudy of the EUROPA trial, aimed to assess the achievability of pharmacogenetic profiling. We provide an overview of the main results of the PERGENE study in terms of the genetic determinants of treatment benefit and blood pressure response. The main results of the PERGENE study show a pharmacogenetic profile related to the treatment benefit of perindopril identifying responders and non-responders to treatment

Intensive lowering of LDL cholesterol with 80 mg versus 20 mg simvastatin daily in 12,064 survivors of myocardial infarction: a double-blind randomised trial

Background: lowering of LDL cholesterol reduces major vascular events, but whether more intensive therapy safely produces extra benefits is uncertain. We aimed to establish efficacy and safety of more intensive statin treatment in patients at high cardiovascular risk.Methods: we undertook a double-blind randomised trial in 12 064 men and women aged 18–80 years with a history of myocardial infarction. Participants were either currently on or had clear indication for statin therapy, and had a total cholesterol concentration of at least 3·5 mmol/L if already on a statin or 4·5 mmol/L if not. Randomisation to either 80 mg or 20 mg simvastatin daily was done centrally using a minimisation algorithm. Participants were assessed at 2, 4, 8, and 12 months after randomisation and then every 6 months until final follow-up. The primary endpoint was major vascular events, defined as coronary death, myocardial infarction, stroke, or arterial revascularisation. Analysis was by intention to treat. This study is registered, number ISRCTN74348595.Findings: 6031 participants were allocated 80 mg simvastatin daily, and 6033 allocated 20 mg simvastatin daily. During a mean follow-up of 6·7 (SD 1·5) years, allocation to 80 mg simvastatin produced an average 0·35 (SE 0·01) mmol/L greater reduction in LDL cholesterol compared with allocation to 20 mg. Major vascular events occurred in 1477 (24·5%) participants allocated 80 mg simvastatin versus 1553 (25·7%) of those allocated 20 mg, corresponding to a 6% proportional reduction (risk ratio 0·94, 95% CI 0·88–1·01; p=0·10). There were no apparent differences in numbers of haemorrhagic strokes (24 [0·4%] vs 25 [0·4%]) or deaths attributed to vascular (565 [9·4%] vs 572 [9·5%]) or non-vascular (399 [6·6%] vs 398 [6·6%]) causes. Compared with two (0·03%) cases of myopathy in patients taking 20 mg simvastatin daily, there were 53 (0·9%) cases in the 80 mg group.Interpretation: the 6% (SE 3·5%) reduction in major vascular events with a further 0·35 mmol/L reduction in LDL cholesterol in our trial is consistent with previous trials. Myopathy was increased with 80 mg simvastatin daily, but intensive lowering of LDL cholesterol can be achieved safely with other regimens.Funding: Merck; The Clinical Trial Service Unit also receives funding from the UK Medical Research Council and the British Heart Foundation

Use of high-intensity statin therapy with simvastatin 80 mg and atorvastatin 80 mg in primary care

Original article can be found at: http://onlinelibrary.wiley.com Copyright Wiley-Blackwell [Full text of this article is not available in the UHRA]Aims:  Cardiovascular disease (CVD) is the most common cause of death worldwide. Pharmaceutical risk reduction with high-intensity statin therapy is advisable for high-risk patients. Clinicians face a conflict between prescribing for cost (simvastatin 80 mg) or for efficacy (atorvastatin 80 mg). The aim of this audit was to examine the use, efficacy and tolerability of high intensity statin treatment (simvastatin 80 mg; atorvastatin 80 mg) in primary care. Methodology:  Electronic medical records were examined from two general practitioners’ surgeries. Analyses involved Mann–Whitney U and χ2 tests. Results:  A total of 116 patients had taken simvastatin 80 mg or atorvastatin 80 mg. Patients were similar between treatment groups: mostly men (62.9%), over 60 years old (68.1%), non-smokers (81.0%) taking statins for secondary prevention (56.9%). More patients on simvastatin withdrew from treatment as a result of inefficacy (49.3% vs. 23.2%, p = 0.025) compared with the atorvastatin group. Furthermore, patients on simvastatin were more likely to be failing conventional targets of lipid control, compared with patients on atorvastatin 80 mg (43.5% vs. 21.3%, p = 0.006). Tolerability was similar between the two groups. Discussion:  UK guidelines recommend simvastatin 80 mg as an economic choice, despite scant evidence at this dose and recent safety concerns. Conversely, robust evidence exists for atorvastatin 80 mg. Head-to-head clinical trials or clinical studies comparing these agents are lacking. The present study suggests that atorvastatin 80 mg compares favourably to simvastatin in terms of efficacy and has a similar tolerability profile. Conclusion:  This retrospective observational study suggests that despite national guidelines, atorvastatin 80 mg is used in clinical practice and is more effective and at least as well tolerated as simvastatin 80 mg.Peer reviewe